2021 California Medical Licensure Program~Ifnyj0h2ycolotkvwikvf40n10-30-2020 11-18-47 AM.Pdf

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CME FOR PHYSICIANS AND OTHER HEALTH CARE PROVIDERS 2021 CALIFORNIA MEDICAL LICENSURE PROGRAM TARGETED SERIES OF CME FOR LICENSE RENEWAL PROGRAM INCLUDES:

12CREDITS PAIN MANAGEMENT AND APPROPRIATE TREATMENT OF TERMINALLY ILL*

*CALIFORNIA PHYSICIANS MANDATORY CME REQUIREMENT: Must complete one-time requirement within the minimum established time period.

CME FOR: AMA PRA CATEGORY 1 CREDITS™ MIPS MOC STATE LICENSURE CA.CME.EDU InforMed is Accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. FAX 1.800.647.1356 your professional information, payment information, professional your questions method and answers to the evaluation MAIL PROGRAM PRICE Jacksonville, FL 32233 1015 Atlantic Blvd #301 Blvd Atlantic 1015 $135.00 C OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN FOR GUIDELINES C OPIOID PRESCRIBING D LEARNER RECORDS: ANSWER SHEET & PAYMENT INFO PAYMENT SHEET & ANSWER LEARNER RECORDS: RECEIVE CREDIT REQUIRED TO EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, PRESCRIBING, ON RESPONSIBLE GUIDANCE EVIDENCE-BASED AND HARM REDUCTION MANAGEMENT, EFFECTIVE ONE | 4 CREDITS* COURSE C TWOCOURSE | 4 CREDITS* THE END OF LIFE CARE AT COMPASSIONATE THREE | 2 CREDITS* COURSE MANAGING PAIN ACUTE FOUR | 2 CREDITS* COURSE 71 90 112 01 34 2021 CALIFORNIA 2021 ONLINE CA.CME.EDU and dying patients. *Completion of entire of *Completion treatment of terminally ill terminally treatment of program satisfies the twelve program satisfies the twelve (12) credit CME requirement in pain management and the vvvvvW INFORMED TRACKS WHAT YOU NEED, WHEN YOU NEED IT

California Professional License Requirements

PHYSICIANS MANDATORY CONTINUING MEDICAL EDUCATION REQUIREMENT FOR LICENSE RENEWAL

PAIN MANAGEMENT/TERMINALLY ILL PATIENTS The Medical Board of California requires all physicians (excluding pathologists and radiologists) to earn twelve (12) credits of continuing education in pain management and the treatment of terminally ill and dying patients (business and professions code §2190.5). Physicians must complete this one-time requirement by the second renewal of their medical license or four (4) years from the date of their initial license, whichever occurs first. When earned, these credits count toward the total hours required during that biennium.

OTHER PHYSICIAN CME REQUIREMENTS The Medical Board of California requires 50 AMA PRA Category 1 CreditsTM of continuing medical education credits each biennium as a prerequisite for physicians to renew their medical license.

Also, under California’s law, the Medical Board requires that all general internal medicine and family practice physicians, that have a patient population of which 25 percent are age 65 years or older, complete at least 20 percent of their 50 credits each biennium in the field of geriatric medicine.

What This Means For You: You must earn the mandatory twelve (12) credits in pain management and the appropriate treatment of terminally ill and dying patients between the date you were granted an initial license and the earlier of your second license renewal or four (4) years.

LICENSE RENEWAL INFORMATION

Medical Board of California 50 AMA PRA Category 1 Credit(s) TM including 2005 Evergreen Street, Suite 1200 Sacramento, CA 95815 12 CREDITS in Pain Management / Terminally Ill* Email: [email protected] *One-time mandatory CME requirement P : 1-800-633-2322

Disclaimer: The above information is provided by InforMed and is intended to summarize state CE/CME license requirements for informational purposes only. This is not intended as a comprehensive statement of the law on this topic, nor to be relied upon as authoritative. All information should be verified independently.

i MOC/MIPS CREDIT INFORMATION

In addition to awarding AMA PRA Category 1 CreditsTM, the successful completion of enclosed activities may award the following MOC points and credit types. To be awarded MOC points, you must obtain a passing score and complete the corresponding Activity Evaluation. Table 1. MOC Recognition Statements Successful completion of certain enclosed CME activities, which includes participation in the evaluation component, enables the participant to earn up to the amounts and credit types shown in Table 2 below. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit. Board Programs ABA American Board of Anesthesiology’s redesigned Maintenance of Certification in AnesthesiologyTM (MOCA®) program, known as MOCA 2.0® ABIM American Board of Internal Medicine’s Maintenance of Certification (MOC) program

ABO American Board of Ophthalmology’s Maintenance of Certification (MOC) program

ABOHNS American Board of Otolaryngology – Head and Neck Surgery’s Continuing Certification program (formerly known as MOC)

ABPath American Board of Pathology’s Continuing Certification Program

ABP American Board of Pediatrics’ Maintenance of Certification (MOC) program.

Table 2. Credits and Type Awarded Activity Title AMA PRA Category 1 ABA ABIM ABO ABOHNS ABPath ABP CreditsTM Compassionate Care at 2 AMA PRA Category 1 2 Credits 2 Credits 2 Credits 2 Credits 2 Credits 2 Credits the End of Life CreditsTM LL MK LL & SA SA LL & SAM LL + SA Managing Acute Pain 2 AMA PRA Category 1 2 Credits 2 Credits 2 Credits 2 Credits 2 Credits 2 Credits CreditsTM LL MK LL & SA SA LL & SAM LL + SA Legend: LL = Lifelong Learning, MK = Medical Knowledge, SA = Self-Assessment, SAM = Self-Assessment Module, LL+SA = Lifelong Learning & Self-Assessment, PS = Patient Safety

Table 3. CME for MIPS Statement Completion of each accredited CME activity meets the expectations of an Accredited Safety or Quality Improvement Program (IA PSPA_28) for the Merit-based Incentive Payment Program (MIPS). Participation in this Clinical Practice Improvement Activity (CPIA) is optional for eligible providers. v DATA REPORTING: Federal, State, and Regulatory Agencies require disclosure of data reporting to all course participants. InforMed abides by each entity’s requirements for data reporting to attest compliance on your behalf. Reported data is governed by each entity’s confidentiality policy. To report compliance on your behalf, it’s mandatory that you must achieve a passing score and accurately fill out the learner information, activity and program evaluation, and the 90-day follow up survey. Failure to accurately provide this information may result in your data being non-reportable and subject to actions by these entities.

ii For more than 51 years InforMed has been providing high-level education activities to physicians and other health care professionals. Through our level of engagement with a wide variety of stakeholders, including our physician association, we have become the foremost public health policy continuing medical education organization in the United States. We are recognized as the leading provider of mandatory CME activities to physicians as a means of updating knowledge, improving competencies and fulfilling requirements for federal, state, regulatory and license renewal.

Dear California Medical Professionals,

InforMed is pleased to offer this collection of CME activities for physicians that are licensed by the state of California. The uniquely tailored curriculum is customized to the educational needs of California medical professionals. Participants earn AMA PRA Category 1 Credit™ through these self-directed, on-demand courses.

The CME series is designed to streamline the education requirements of the Medical Board of California. You are required to earn 12 credit hours in approved CME courses for pain management and terminally ill patients. This must be completed by your second license renewal date or within four years of your initial license date, whichever occurs first. Licensees who complete all the courses in this program satisfy this mandatory CME requirement. All activities are independently sponsored by InforMed Continuing Medical Education without commercial support.

Thank you for choosing InforMed as your CME provider. Please do not hesitate to contact us with any questions, concerns or suggestions.

-InforMed CME Team

Visit CA.CME.EDU, select NETPASS to begin. CA.CME.EDU

1015 Atlantic Blvd #301 Jacksonville, FL 32233

Inquiries related to any part of the program or associated materials including, but not limited to, interpretation of any ACCME, AMA, ABMS Specialty Boards, FDA, federal, state, and/or regulatory agency standards and statues may be submitted in writing to: Legal Compliance and Rulings, 1015 Atlantic Boulevard #301, Jacksonville, FL 32233

i EVIDENCE-BASED GUIDANCE ON RESPONSIBLE

Release Date: 10/2018 PRESCRIBING, EFFECTIVE MANAGEMENT, 4 AMA PRA Enduring Material Review Date: 10/2020 Category 1 Credits™ (Self Study) AND HARM REDUCTION Exp. Date: 02/2022

TARGET AUDIENCE

This course is designed for all physicians and health care providers involved in the treatment and monitoring of patients prescribed controlled substances. Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required. COURSE OBJECTIVE Return your customer information/ The purpose of this course is to educate health care providers about answer sheet, evaluation, and the requirements of the Controlled Substances Act and safe prescribing payment to InforMed by mail, phone, fax practices for both opioid and non-opioid controlled substances. In addition, or complete online at course some of the medical conditions for which controlled substances are most website under NETPASS. commonly prescribed will be reviewed, along with recommendations for responsible management of these conditions with specific controlled substances.

LEARNING OBJECTIVES

Completion of this course will better enable the course participant to: 1. Explain the purpose and role of the Controlled Substances Act (CSA) as it relates to clinical practice. 2. Explain the similarities and differences between the 5 DEA schedules for controlled substances. 3. Know what pieces of information must be included on all prescriptions for controlled substances. 4. Describe at least 4 signs that a controlled substance may be inappropriately prescribed. 5. Describe the key steps recommended for the responsible prescribing of controlled substances. 6. Describe pharmacological treatment options for treating pain, anxiety disorder, insomnia, narcolepsy, obesity, and attention-deficit hyperactivity disorder. 7. Describe at least 4 practices clinicians can use to minimize diversion of controlled substances. 8. Know the 6 approved pharmacotherapies for treating alcohol and opioid use disorders.

ACCREDITATION STATEMENT InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

DESIGNATION STATEMENT InforMed designates this enduring material for a maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. 1 FACULTY Melissa B. Weimer, DO, MCR, FASAM Chief of Behavioral Health and Addiction Medicine Saint Peter’s Health Partners Clinical Assistant Professor of Medicine Oregon Health and Science University 4 Stephen Braun Pain Management Medical Writer and Terminally Braun Medical Media Ill Patients

Beth Dove Medical Writer Dove Medical Communications SPECIAL DESIGNATION

This course satisfies four (4) CME credit ACTIVITY PLANNER hours on Pain Management and the Appropriate Treatment of the Terminally Ill. Joseph J. McGurrin

DISCLOSURE OF INTEREST The Medical Board of California requires most physicians and surgeons to complete In accordance with the ACCME Standards for Commercial Support of a one-time mandatory 12 hours of CME in CME, InforMed implemented mechanisms, prior to the planning and the subjects of pain management and the treatment of terminally ill & dying patients. implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE

The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity: • Melissa B. Weimer, DO, MCR, FASAM • Stephen Braun • Beth Dove • Joseph J. McGurrin

STAFF AND CONTENT REVIEWERS InforMed staff, input committee and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

3 The Controlled Substances Act the drug or other substance. This will determine into Schedule IV Substances which schedule (if any) the drug or other substance Substances in this schedule are thought to have The federal government’s first attempt at will be placed. a low potential for abuse relative to substances in regulating medications was through the Harrison Act schedule III and have currently accepted medical uses 10 Schedules of Controlled Substances passed in 1914. The Harrison Act criminalized what, in the United States. Examples include alprazolam, Controlled substances under the CSA are at that time, was considered to be the “recreational” clonazepam, diazepam, lorazepam, phenobarbital, classified into one or more of five schedules. use of opium, morphine, and cocaine. While these temazepam, and triazolam. drugs could still be legally obtained, physicians, Schedule I Substances dentists and veterinary surgeons were now required Schedule V Substances Substances in this schedule are deemed to have to register, document, and pay taxes on any packages Substances in this schedule have a low potential a high potential for abuse, have been determined to containing these drugs. Over the next few years, for abuse relative to substances listed in schedule IV. have no currently-accepted medical use in the United thousands of prescribers who did not comply with the These are generally used for antitussive, antidiarrheal, States, and evidence for their safe use under medical law were arrested, convicted, and jailed. and analgesic purposes. Examples include cough supervision has not been accepted. Some examples In 1970, the United States government passed the preparations containing not more than 200 mg of of substances listed in schedule I are: heroin, Federal Comprehensive Drug Abuse Prevention and codeine per 100 milliliters or per 100 grams. lysergic acid diethylamide (LSD, i.e. “acid”), peyote, Control Act. Now known as the Controlled Substances and 3,4-methylenedioxymethamphetamine (MDMA, Classes of Controlled Substances Act (CSA), the law consists of three parts, including i.e.“ecstasy”). (Note: government-approved scientific The CSA regulates five classes of drugs: rehabilitation services for people with substance use and clinical research is currently underway with • Opioids disorder, the regulation and distribution of controlled some Schedule I drugs, such as LSD, exploring their • Sedative-Hypnotics substances, and regulation of the importation utility to treat a variety of mental health disorders, • Stimulants and export of controlled substances.11 The Drug including addiction, the results of which may alter • Hallucinogens Enforcement Administration (DEA) administers all • Anabolic steroids their classification in the future.15) parts of the CSA. The CSA is continually updated to With the exception of anabolic steroids, controlled add, remove, or transfer over 160 substances across Schedule II Substances substances are abused to alter mood, thought, and schedules. This monograph reflects the most recent Substances in this schedule are considered feeling through their actions on the central nervous issue of Title 21 Code of Federal Regulations (CFR) to have a high potential for abuse which may lead system (brain and spinal cord). Some of these drugs Part 1300. It is limited to describing the controlled to psychological or physical dependence, and alleviate pain, anxiety, or depression. Some induce substances most frequently encountered by health yet the drug or substance also has one or more sleep and others energize. Though most controlled 12 care providers and is not a comprehensive list. currently accepted medical use in the United States. substances can be therapeutically useful, the “feel Since many controlled drugs are important tools Examples include many opioid pain medications, and good” effects of these drugs may contribute to their in the clinician’s pharmaceutical armamentarium, the stimulants such as amphetamine, methamphetamine, potential for abuse. CSA attempts to balance two competing needs: to methylphenidate, and cocaine. The extent to which a substance can reliably maintain an adequate and uninterrupted supply of produce intensely pleasurable feelings (euphoria) Schedule III Substances these controlled substances for legitimate purposes increases the likelihood of that substance being Substances in this schedule have less potential for while simultaneously reducing their diversion and abused.14 13 abuse than substances in schedules I or II and abuse abuse. Table 1 lists some of the controlled substances may lead to moderate or low physical dependence or The CSA places all substances which were in some that are commonly encountered and/or prescribed manner regulated under existing federal law into one high psychological dependence. These substances in clinical settings. Note that some substances, of five schedules (with the exceptions of alcohol and also have currently accepted medical uses in the such as many common products that emit fumes tobacco). This placement is based on the substance’s United States. Examples include buprenorphine that can be inhaled to alter consciousness, are not perceived medical use, potential for abuse, safety, and products containing not more than 90 mg of scheduled because doing so would impede legitimate 14 and dependence liability. The law also provides a codeine per dosage unit (i.e. Tylenol with codeine®). commerce. New substances are continually being mechanism for new substances to be added to or Examples of schedule III non-opioid drugs include either discovered or invented which have abuse transferred between schedules or for substances to benzphetamine, ketamine, and anabolic steroids such potential and, thus, the list of controlled substances be removed from control. as oxandrolone. continues to grow. In determining into which schedule a drug or other Opioids substance should be placed, or whether a substance Did You Know? Opioids are used to treat moderate to severe should be decontrolled or rescheduled, certain Some drugs or substances appear in two pain that does not respond to non-opioids alone. 14 factors are required to be considered, including: or more schedules, depending on the They are often combined with non-opioids because 1. The drug’s actual or relative potential for abuse specifics of their formulation. For example, this permits use of lower doses of the opioid (i.e., 2. Scientific evidence of the drug’s pharmacological raw cannabis is listed as Schedule I, dose-sparing effect). Nearly all types of pain respond effect, if known although products containing one or more to opioids; however, nociceptive pain is generally 3. Its history and current pattern of abuse of the active ingredients in cannabis (i.e., more responsive to opioids than neuropathic pain, 4. The scope, duration, and significance of abuse 17 5. What, if any, risk there is to public health tetrahydrocannabinol, or THC) are listed as which may require higher doses of opioids. Opioids 6. The drug’s psychic or physiological dependence Schedule III. Likewise, gamma-hydroxybutyric play a major role in the treatment of acute pain (e.g., liability acid (GHB) as a street drug is Schedule I, trauma, postoperative pain), breakthrough pain, 7. Whether the substance is an immediate although when formulated in a product for cancer pain, and some types of chronic non-cancer precursor of a substance already controlled clinical use it is listed as Schedule III. pain. Opioids may also help relieve certain types of After considering the above listed factors, the DEA neuropathic pain, such as the acute pain of herpes administrator may make specific findings concerning zoster.

4 Table 1. Commonly-prescribed Controlled Substances16 addiction risk (aside from those specifically made to reduce abuse risk), so selection of agent should be Schedule Substance Common Name based on the patient’s pain complaint, lifestyle, and II Hydrocodone Vicodin, Norco (with acetaminophen) preferences.19 Generally, if opioids are used at all, it II Oxycodone Oxycontin, others is better to offer short-acting opioids PRN (Table 2). II Morphine Duramorph, Infumorph, Arymo ER, others Extended-release (ER) or long-acting (LA)) opioids (with duration of action typically between 4 and 72 II Hydromorphone Exalgo, others hours) may be helpful for patients who have difficulty II Amphetamine Dexedrine, Adderall managing an “as needed” regimen, or who are II Lisdexamfetamine Vyvanse physically dependent on opioid analgesics and require II Methylphenidate Concerta, Ritalin, Methylin continued use to maintain their functioning. Scheduled long-acting opioids have the advantage II Phenobarbital Nembutal of producing a steady state, without the cycling effect III Buprenophine Suboxone, Buprenex, Butrans, others of pain relief and withdrawal associated with short- III Codeine acting opioids, which could, theoretically, lead to 20 III Anabolic steroids Anabolic steroids problematic behavior patterns. With ER/LA agents, however, patients may end up using more drug than III Chlorphentermine Pre-Sate, Lucofen, Apsedon, Desopimon is actually needed, and physiological adaptations to III Dronabinol Marinol the steady state may ultimately decrease efficacy.21 IV Tramadol Ultram, ConZip Clinicians should warn patients that oral ER/LA IV Alprazolam Xanax opioids should not be broken, chewed, or crushed, and patches should not be cut or torn prior to use, IV Barbital Veronal, Plexonal, Barbitone since this may lead to rapid release of the opioid and IV Carisoprodol Soma could cause overdose or death. IV Chlordiazepoxide Librium, Libritabs, Limbitrol, SK-Lygen Prescribers considering ER/LA opioid IV Clonazepam Klonopin, Clonopin products should consider carefully the general characteristics, toxicities, and drug interactions for IV Diazepam Valium, Diastat these agents. [For detailed information on current IV Lorazepam Ativan ER/LA opioid analgesics, see the FDA Blueprint for IV Midazolam Versed Prescriber Education, available at: https://www. IV Modafinil Provigil accessdata.fda.gov/drugsatfda_docs/rems/Opioid_ IV Phentermine Ionamin, Fastin, Adipex-P, Zantryl analgesic_2018_09_18_FDA_Blueprint.pdf]. Knowledge of particular opioid-drug interactions, and IV Phenobarbital Phenobarbital the underlying pharmacokinetic and pharmacodynamic IV Temazepam Restoril mechanisms, allows for safer administration of opioid IV Zaleplon Sonata analgesics. Methadone can be an effective opioid, for IV Zolpidem Ambien, Ivadal, Stilnoct, StilNox example, but it must be prescribed carefully and with full knowledge of its highly variable pharmacokinetics IV Zopiclone Lunesta and pharmacodynamics. V Pregabalin Lyrica Abuse-deterrent formulations Opioids as a class include many specific agents The term “pharmacovigilance” refers to the range Concern about opioid misuse and abuse has available in a wide range of formulations and routes of procedures and processes used to achieve this spurred efforts to create abuse-deterrent opioid of administration, including: goal. These procedures need not be burdensome and formulations. Two agents commonly available, which • Oral (e.g., tablets, capsules, solutions, lollipops) are akin to similar risk/benefit calculations required are co-formulated with an opioid antagonist are • Transdermal in the prescription of a great many other therapeutic 18 Targiniq ER (oxycodone and naloxone) and Embeda • Transmucosal agents. What makes opioids of particular concern ER (morphine and naltrexone). The abuse-deterrent • Rectal is the fact that they are highly sought-after by people forms of long-acting oxycodone also contain a • Intrathecal who use drugs and criminal elements in society. In polymer that makes the pill difficult to crush, snort, Combination products join an opioid with a non- addition, opioids have a wide range of potential or melt for injection. Transdermal opioid formulations opioid analgesic, usually for use in patients with adverse effects that can expose a patient to serious were thought to be less vulnerable to misuse, but moderate pain. Using a combination product when morbidity and even mortality. such formulations can be abused.22 Abuse-deterrent dose escalation is required risks increasing adverse Risk is increased among: older adults; those with opioid formulations do not prevent users from simply effects from the non-opioid co-analgesic, even if an impaired renal or hepatic function; individuals with consuming too much of a medication or using it increase of the opioid dose is appropriate. In such obesity, cardiopulmonary disorders, sleep apnea, or without a prescription. cases, using a pure opioid is preferable. Care, in mental illness; and in patients who combine opioids In 2016, the most commonly misused subtype of particular, must be given to not exceed maximal daily with other respiratory depressants such as alcohol, prescription pain relievers consisted of hydrocodone doses of acetaminophen. sedative-hypnotics, benzodiazepines, or barbiturates. products (6.9 million abusers), which include In their daily practice, clinicians who treat patients Extended-release/long-acting opioids Vicodin®, Lortab®, Norco®, Zohydro® ER, and with opioid pain medications must balance pain relief Little evidence exists that specific analgesic generic hydrocodone.23 with the risks associated with opioid analgesics. formulations or dosing schedules affect efficacy or 5 Side Effects Sedative-Hypnotics Quick Sedative-Hypnotics Facts Binding of opioids to receptors in various body Sedative-hypnotics, lower arousal levels and regions (e.g., CNS, GI tract) results in both therapeutic reduce nervous system excitability via a range of Physical signs of depressant overdose: effects and side effects. Potential side effects of pharmacological mechanisms, the most prominent • Shallow respiration opioids as a class include respiratory depression, of which are facilitation of gamma-aminobutyric acid • Clammy skin sedation, mental clouding or confusion, nausea, (GABA) receptors, opioid receptors, or inhibition • Dilated pupils • Weak and rapid pulse vomiting, constipation, itching, and urinary retention. of glutamatergic or catecholaminergic activity.24 • Slurred speech With the exception of constipation, these side effects Although widely-prescribed for their anxiety-relieving, • Loss of motor coordination tend to subside with time. Constipation is so common, muscle-relaxing, and sleep-inducing properties, • Blurred vision in fact, that when patients use opioids and do not sedative-hypnotics are also widely abused for these • Nausea have constipation, clinicians should consider possible properties as well as their abilities to induce euphoria. • Vomiting reasons ranging from rapid bowel transit time to drug Because ethanol acts on many of the same neuronal • Low blood pressure diversion. Constipation requires proactive treatment, receptor targets as many of the sedative-hypnotics, Drugs causing similar effects: with stimulating laxatives prescribed at the time of lethal synergistic effects may occur. • Alcohol (ethanol) initiating opioids, and frequent re-evaluation. With Barbiturates were the first class of synthetic • Antihistamines the exception of constipation, uncomfortable or sedative-hypnotics to be introduced and many specific • Certain antipsychotics unpleasant side effects may potentially be reduced by types with varying durations of action are FDA- Available forms: switching to another opioid or route of administration approved for indications such as the relief of anxiety, • Tablets (such side effects may also be alleviated with the promotion of sleep, or the treatment of epilepsy. • Capsules adjunctive medications). Benzodiazepines were discovered in the 1950s • Syrups Use caution when prescribing opioids to patients and have largely eclipsed barbiturates for a range • Injectable liquids with conditions that may be complicated by adverse of indications including anxiety, insomnia, muscle GABA receptor sites and produce similar sedative effects from opioids, including chronic obstructive spasms, alcohol withdrawal, and as premedication effects.27 Common non-benzodiazepines include pulmonary disease (COPD), congestive heart failure, 25 for certain medical or dental procedures. Although zolpidem (Ambien®), Zaleplon (Sonata®) and sleep apnea, current or past alcohol or substance use initially thought to be less prone to induce tolerance Eszopiclone (Lunesta®). disorder, mental illness, advanced age, or patients and dependence than barbiturates, benzodiazepines with a history of renal or hepatic dysfunction. Gamma-hydroxybutyric acid (GHB) and its are now recognized to be just as liable to diversion chemical analogs are widely used, both as a All newly pregnant women should have a urine and abuse.26 Benzodiazepines are categorized as drug test administered by the appropriate women’s prescription medicine (Xyrem®), and as industrial either short-, intermediate- or long-acting. Short- solvents or components in many commercial products. health provider. In addition, providers should discuss and intermediate-acting benzodiazepines are a birth control plan to prevent unintended pregnancy Sold as a liquid or as a powder that is dissolved in preferred for the treatment of insomnia; longer- another liquid and swallowed, GHB induces euphoric with every woman of child-bearing age who has acting benzodiazepines are used for the treatment of reproductive capacity when opioids are initiated due and calming effects as well as amnesia. anxiety, though they are not effective for long term Carisoprodol is a centrally-acting skeletal to the high likelihood of neonatal abstinence syndrome 24 treatment of anxiety. muscle relaxant whose primary active metabolite in children whose mothers use opioids throughout Flunitrazepam (Rohypnol®) is a benzodiazepine their pregnancies. Finally, it is not recommended that is meprobamate, a substance with well established that has never been approved by the FDA in the United 28 chronic pain be treated with controlled substances abuse potential similar to that of benzodiazepines. States, but which is available by prescription in other A number of reports show that carisoprodol has through telemedicine. 14 countries and also as illegal preparations. Because it been abused for its sedative and relaxant effects, to All chronic opioid therapy should be handled by can impair judgment and induce amnesia, particularly a single provider or practice and all prescriptions augment or alter the effects of other drugs, and by when combined with ethanol, flunitrazepam has been the intentional combination of carisoprodol and other should be filled in a single pharmacy, unless the 14 associated with sexual assault. non-controlled medications because of the relative provider is informed and agrees that the patient can Non-benzodiazepines are molecularly distinct go to another pharmacy for a specific reason. ease (as compared to controlled substances) of from benzodiazepines, although they act on the same obtaining prescriptions.

Table 2: Long Acting vs. Immediate Release Opioids Long acting opioids Immediate release opioids Buprenorphine patch (Butrans) Codeine (generics) Fentanyl patch (Duragesic) Fentanyl – transmucosal (Abstral, Actiq, Fentora, Lazanda, Onsolis, Subsys) Hydrocodone (Zohydro ER) Hydrocodone+acetaminophen (generics, Norco, Vicodin, Xodol) Hydromorphone ER (generics, Exalgo) Hydromorphone (generics, Dilaudid) Methadone (generics, Dolophine, Methadose) Levorphanol (generics) Morphine ER (generics, Avinza, Kadian, MS Contin) Meperidine (generics, Demerol, Meperitab) Oxycodone (Oxycontin) Morphine (generics) Oxymorphone ER (generics, Opana ER) Oxycodone (generics, Roxicodone) Tapentadol (Nucynta ER) Oxymorphone (generics, Opana) Tramadol ER (generics, ConZip, Ultram ER) Tapentadol (Nucynta) Tramadol (generics, Ultram)

6 The diversion and abuse of carisoprodol and its for depression, especially treatment-resistant 24 Tolerance v. Addiction adverse health effects appear to have dramatically depression. Cocaine has limited medical uses as a Tolerance is an unavoidable neurophysical increased in recent years.29 Clinicians have begun to topical local anesthetic and for reducing bleeding of adaptation of the brain to the presence of a see a withdrawal syndrome consisting of insomnia, mucous membranes in the mouth, throat, and nasal drug. As a result, patients can be expected vomiting, tremors, muscle twitching, anxiety, and ataxia cavities. Other stimulants such as crack cocaine have to need higher doses of medication to obtain the same effect. Tolerance also implies that a in patients who abruptly cease intake of large doses no approved medical uses. person will experience withdrawal symptoms if a of carisoprodol. Hallucinations and delusions may The clandestine production of amphetamines drug is suddenly stopped. also occur. The withdrawal symptoms are very similar in the past decade has increased dramatically, to those described for meprobamate withdrawal, particularly the production of methamphetamine, Addiction is the compulsive seeking and use of suggesting that what may actually be occurring is which is a potent central nervous system stimulant a drug despite continuing harm and dysfunction. 14 Continued use of a substance by someone who withdrawal from meprobamate accumulated as a and highly addictive. (Note that a single brand of is addicted decreases their functioning; use of result of intake of excessive amounts of carisoprodol. methamphetamine, Desoxyn,® is approved by the a substance by a non-addict typically improves However carisoprodol itself is capable of modulating FDA for the treatment of attention deficit disorders.) functioning. GABA function, and this may contribute both to the So-called “bath salts” are synthetic stimulants, drug’s abuse potential and to the occurrence of a also known as synthetic cathinones, which is the active or whose professional license has been temporarily withdrawal syndrome with abrupt cessation of intake. chemical found naturally in the khat plant.14 “Bath suspended cannot hold a DEA license or legally salts” are sold as powders, tablets, or capsules under prescribe controlled substances. Similarly, prescribers Stimulants various brand names. They are usually ingested by must have a DEA license in the state where they are Stimulants induce a range of effects on the body sniffing/snorting, though they can also be taken orally, professionally licensed. and mind by enhancing activity of the central and smoked, or put into a solution for injection. Providers must be aware of regulatory peripheral nervous systems. Common effects, which Tolerance to higher doses of stimulants can developments and legislation associated with the vary depending on the stimulant in question, may 32 develop quickly, as can psychological dependence. prescribing requirements for controlled substances. include: enhanced alertness, wakefulness, endurance, Abrupt cessation of stimulants is typically followed This section will review the appropriate documentation productivity, and motivation; increased sexual arousal, by a “crash” of depression, anxiety, extreme fatigue, for writing prescriptions, DEA prescriber registration, locomotion, heart rate, and blood pressure; and and drug craving. Accidental death may be caused renewal, and revocation of registration. diminished appetite. Many stimulants temporarily by cardiovascular collapse, dehydration, or high fever improve mood or induce feelings of euphoria. Rules for Documentation (physical exertion increases the hazards of stimulant Stimulants exert their effects through a number All prescriptions for controlled substances must use because of the effects of stimulants on the body’s of different pharmacological mechanisms, the most be either typed or written in ink or indelible pencil, hypothalamic temperature-regulation mechanisms). prominent of which are facilitation of norepinephrine though some states (e.g., New York) mandate that Gabapentinoids such as pregabalin (Lyrica®) as and/or dopamine activity, adenosine receptor all prescriptions for controlled substances be sent via well as the original agent gabapentin (Neurontin®) 33 antagonism, and nicotinic acetylcholine receptor electronic prescription (i.e., e-prescribed). Although are approved to treat a variety of conditions, agonism.24 Not all stimulants are listed as controlled a designated individual may write the prescription, it including post-herpetic neuralgia, fibromyalgia, and substances. Caffeine, theophylline, and nicotine are must be manually signed by the responsible provider. neuropathic pain associated with diabetes, and some widely used and legally available. Amphetamines All prescriptions must contain the following literature suggests that clinicians may be prescribing and methylphenidate are controlled substances but elements: these drugs off-label as alternatives to opioids.30 are also widely-prescribed to treat attention-deficit • Prescriber’s name, address, and DEA Currently in Schedule V, in 2016, gabapentin was the disorders, sleep disorders such as narcolepsy and registration number 10th most commonly-prescribed medication in the shift-work disorders, and as adjuvant medications • Manual signature of prescriber United States: 64 million gabapentin prescriptions • Patient’s name and address 30 were dispensed, up from 39 million in 2012. • Date of issue Quick Stimulant Facts Although data are limited, they suggest that • Drug name gabapentinoid abuse and misuse may be growing, Physical signs of stimulant overdose: • Drug strength both when taken alone and in combination with • Tremors • Dosage • Headache opioids, benzodiazepines, or other central nervous • Quantity prescribed • Flushed skin system depressants. Drug users say gabapentin pills, • Number of refills (may be 0) • Chest pain with palpitations known as “johnnies” or “gabbies,” which often sell for • Directions for use • Excessive sweating less than a dollar each, enhance the euphoric effects Schedule II controlled substance prescriptions • Vomiting of heroin and when taken alone in high doses can must be written and signed by the prescriber. 30 • Abdominal cramps produce a marijuana-like high. Under certain very strict circumstances, they can Drugs causing similar effects: DEA Requirements for Prescribing Controlled Substances be e-prescribed, but the electronic medical record • Although often classified as a is required to have specific authentication steps. hallucinogen, MDMA (ecstasy) is a To be eligible for DEA registration and legally Schedule II medications cannot be refilled; they stimulant and can induce responses prescribe controlled substances, a health care require a new prescription each time they are filled. similar to classic stimulants provider must meet certain requirements. He or she In case of emergency, the prescriber may telephone Available forms: “must be a physician, dentist, veterinarian, hospital, the prescription for a schedule II controlled substance • Tablets or other person licensed, registered, or otherwise into the pharmacy, but the prescriber must follow up • Capsules permitted by the United States or the State in which with a written prescription within seven days. Schedule • Powder he or she practices to dispense controlled substances III and IV controlled substance prescriptions may • “Rocks” in the course of professional practice.”31 As a result, be written, called in or faxed to the pharmacy, and • Injectable liquids a prescriber who does not have a professional license they have a maximum of five refills in six months. 7 Prescriptions for schedule V controlled substances do Appropriate and Inappropriate Prescribing This law became effective April 13, 2009. As of not have a limit on refills. Practices that date, it is illegal under federal law to deliver, The legal standard that a controlled substance Registration, Renewal, and Termination of DEA distribute, or dispense a controlled substance by may only be prescribed, administered, or dispensed License means of the Internet unless the online pharmacy for a legitimate medical purpose by a provider acting To prescribe controlled substances, practitioners holds a modification of DEA registration authorizing in the usual course of professional practice has been must be registered with the DEA. There are three ways it to operate as an online pharmacy. construed to mean that the prescription must be to obtain DEA Form 224 and apply for registration:4 Security Requirements Related to Controlled “in accordance with a standard of medical practice • DEA Diversion Web Site: Substances generally recognized and accepted in the United DEAdiversion.usdoj.gov The CFR requires all registrants to provide States.”4 • DEA field office effective controls and procedures to guard against Federal courts have long recognized that it is • Registration Call Center: 1-800-882-9539 theft and diversion of the controlled substances not possible to define the phrase “legitimate medical Once obtained, the Certificate of Registration they store or handle. Factors used to determine the purpose in the usual course of professional practice” (DEA Form 223) must be kept at the registered adequacy of these security controls include:4 precisely enough to cover all of the varied situations location and be easily retrieved for official inspection. 1. The location of the premises and the relationship providers may encounter in clinical practice.4 There DEA registration should be renewed every three years such location bears on security needs are, however, recurring patterns that suggest using DEA Form 224a. The DEA will mail the renewal 2. The type of building and office construction inappropriate prescribing of controlled substances by 3. The type and quantity of controlled substances form to the address listed on the current registration a clinician:4 stored on the premises 45 days before the expiration date. The renewal can • An inordinately large quantity of controlled 4. The type of storage medium (safe, vault, or be completed online at DEAdiversion.usdoj.gov, or the steel cabinet) substances prescribed or large numbers 5. The control of public access to the facility printed renewal form can be mailed to: of prescriptions issued compared to other Drug Enforcement Administration 6. The adequacy of registrant’s monitoring system providers in an area (alarms and detection systems) Registration Unit • No physical examination given 7. The availability of local police protection Central Station • Advising a patient to fill prescriptions at different Registered health care providers are required to P.O. Box 28083 pharmacies store Schedule II through V controlled substances in Washington, D.C. 20038-8083 • Issuing prescriptions knowing that the patient a securely locked, substantially constructed cabinet. Prescribers are required to update the DEA if was delivering the drugs to others In order to maximize security related to controlled they change their business address or discontinue • Issuing prescriptions in exchange for sex or substances, DEA recommends that health care their business. money • Prescribing controlled drugs at intervals providers not employ any of the following persons Revoking a DEA License inconsistent with legitimate medical treatment if they will have potential access to controlled The DEA can deny, suspend, or revoke registration • The use of street slang rather than medical substances: if the prescriber has committed any of the following:4 terminology for the drugs prescribed 1. Any person who has been convicted of a felony 1. Falsified the DEA application • No logical relationship between the drugs offense related to controlled substances 2. Been convicted of a felony associated with a prescribed and treatment of the condition 2. Any person who has been denied a DEA controlled substance allegedly existing registration 3. Lacks a state practitioner license or registration 3. Any person who has had a DEA registration 4. Cannot participate in Medicaid or Medicare Each case must be evaluated on its own merits revoked 5. Acted in a way that is inconsistent with public in view of the totality of circumstances particular to 4. Any person who has surrendered a DEA interest, including sustaining state licensing the provider and patient. Regulatory agencies, for registration for cause or professional disciplinary society sanctions example, are typically aware that what constitutes “an Lastly, practitioners should notify the DEA field or being convicted of a federal or state crime inordinately large quantity of controlled substances,” office in their area of the theft or significant loss of associated with controlled substances can vary greatly from patient to patient. A particular any controlled substances upon discovery.4 Locum Tenens quantity of a powerful Schedule II opioid might Health care providers who are working in a be blatantly excessive for the treatment of mild Disposal of Controlled Substances locum tenens capacity must understand the laws temporary pain, and yet be insufficient to treat the A practitioner may dispose of out-of-date, surrounding their DEA registration. Physicians who unremitting pain of a cancer patient.4 damaged, or otherwise unusable or unwanted function in a locum tenens capacity temporarily controlled substances, including samples, by substitute for a permanently employed physician while Regulations Pertaining to Internet Access to transferring them to a registrant who is authorized 4 he or she is on leave. Some locum tenens physicians Controlled Substances to receive such materials. These registrants are may also provide temporary care in a short-staffed In 2008, an amendment to the CSA was passed referred to as “Reverse Distributors.” The practitioner hospital or clinic. If these practitioners work within to add new regulatory requirements and criminal should contact their local DEA field office for a list of provisions designed to combat the proliferation of so- authorized Reverse Distributors. Schedule I and II a single state, they must be licensed and registered 14 within that state.34 If they register at one location in the called “rogue Internet sites.” The Ryan Haight Act controlled substances should be transferred via the state but practice at a different location, they are not made it illegal to dispense controlled substances in DEA Form 222, while Schedule III–V compounds may required to re-register with the DEA. However, if they all schedules via the Internet. An online pharmacy is be transferred via invoice. The practitioner should work throughout the U.S. and administer, dispense, defined as a person, entity, or Internet site, whether maintain copies of the records documenting the or prescribe controlled substances in several states, in the United States or abroad, that knowingly or transfer and disposal of controlled substances for a 4 they must obtain a separate DEA registration in intentionally delivers, distributes, dispenses, or period of two years. each state where they work, use the hospital’s DEA offers to deliver, distribute, or dispense, a controlled license if the hospital agrees, or transfer their DEA substance by means of the Internet. registration from one state to another.

8 Guidelines for Prescribing Controlled Substances Health care providers who prescribe controlled Harm Reduction and Risk Mitigation substance to patients must understand all of the Providers should consider and implement risk Patients have long turned to health care providers associated risks. For example, in one study examining mitigation strategies prior to prescribing controlled to relieve suffering or improve their health or general the interaction between prescribing physicians and substances. Clinical decision making should remain functioning. However, health care providers face older patients on chronic anxiolytics, the prescribing patient-centered including focusing on patient safety. challenges when they prescribe controlled substances physicians continued prescribing anxiolytic Risk mitigation strategies alone or in combination to their patients to help achieve these ends. Providers medications to their patients because they believed improve patient safety. The strategies and their find themselves balancing issues of safety, a complex that elderly patients were at low risk of addiction.35 frequency should be commensurate with risk factors array of therapeutic options, compliance with This practice is problematic, however, because even and include: governmental regulation and a mandate to alleviate though the patients were at low risk of addiction they • An informed consent conversation covering the patient suffering. were also at increased risk of falls, motor vehicle risks and benefits of treatment with a controlled Since the Controlled Substances Act was passed collisions, and functional decline associated with the substance as well as alternative therapies in 1970, more than 160 medications have been substances being prescribed. • Ongoing, random urine drug testing (including added, transferred, or removed from the lists of Before a provider prescribes a controlled appropriate confirmatory testing), although 16 controlled substances. As part of their obligation substance, he or she must understand all alternative providers should be aware that such testing to be responsible health care providers, prescribers treatments and be able to justify why the patient can be expensive and is not always covered by a must be aware of new legislation and regulatory requires a controlled substance. Once a physician patient’s insurance 32 requirements associated with practicing medicine. accurately diagnoses a disease, he or she cannot • Checking state prescription drug monitoring However, prescribers are not always aware of the simply prescribe a controlled substance, but must programs latest additions, changes, and deletions made in remain updated on all of the latest management • Monitoring for overdose potential and suicidality the schedules of non-opioid controlled substances. options including lifestyle changes, medical • Providing overdose education Nevertheless, the Drug Enforcement Agency can management, or surgical interventions. Moreover, • Prescribing naloxone rescue medication if punish prescribers who fail to comply with the latest health care providers are obligated to thoroughly indicated updates by revoking their prescribing license, closing document the patient history, physical examination Evaluation and Risk Assessment their businesses, implementing fines, or inflicting and alternative treatments before prescribing a A Universal Precautions approach to prescribing prison time. These negative outcomes may be controlled substance.31 prevented if prescribers educate themselves about controlled substances assumes that all patients which medications are on the controlled substances PLEASE SPEND THE ALLOTTED TIME ON are capable of prescription drug misuse and that list and how to safely prescribe them to patients. EXERCISE 1. procedures should be implemented to mitigate Case Study Exercise 1 Instructions: Spend 5-10 minutes reviewing the case study below and considering the questions and commentary that follow. Jenny Cook is a 42 year old woman who has recently relocated and become your patient. On her first visit to your clinic, she reports that her personal health has been quite good, except for an extra 100 pounds that she has been struggling to lose since she gained weight in college 20 years ago. She is sedentary and works at an office job, but she says she walks at the high school track for at least 30 minutes, 3 times a week. She reports, however, that she has been feeling a strange “fluttering” in her chest during those walks for the past 6 months. She doesn’t think it is anything serious, but decided to mention it anyway.

Question 1: What follow-up questions do you have about the patient’s chief complaint?

Commentary on Question 1: The patient’s chief complaint is the “fluttering” she has in her chest while exercising. Although she alludes to weight gain, it is important for you to investigate her possible arrhythmia first. As always, you must ask about the nature, timing, exacerbating and relieving factors associated with her “fluttering.” You should also ask her about any co-morbid conditions, past medical history, past surgical history, family history of heart disease or thyroid disease, and if she is taking any medications. When she tells you her medications, you must evaluate the side-effect profile of each medication. Except for the extra weight, the patient denies any past medical or past surgical history. She does not have any allergies to medications, and she regularly takes a birth control pill, multivitamin, and phentermine. She requests re-fills on all of her medications. When you ask her how long she has been taking phentermine, she responds that she has been taking it on and off since it was initially prescribed for her by the health care provider at University Health Services. She had been taking the combination fenfluramine/phentermine (fen-phen), but stopped when that drug was taken off the market. However, a friend of hers, who is a nurse practitioner, began prescribing phentermine to Jenny again 5 years ago. Now that Jenny has moved to a different state, her friend told her that she could no longer prescribe phentermine because it is a controlled substance. Question 2: Describe any concerns you have about the patient’s health history?

Commentary on Question 2: Although the patient denies any past medical problems, she has been taking phentermine for many years. Phentermine is a non-opioid stimulant controlled substance used for weight loss. It was previously approved as a combination medication with the drug fenfluramine to create fen-phen. Fen-phen was taken off the market when several studies showed that its side-effect profile included significant cardiac complications, with valvular regurgitation impacting over 20% of patients.36 Although the combination drug was taken off the market, patients who used to take the medication are still at risk for adverse events. You should be concerned that this patient did not undergo a cardiac evaluation after discontinuing fen-phen. In addition, phentermine is not meant to be used long-term, and patients who are currently taking this drug should be carefully monitored. This patient has been taking the drug chronically, and she was not monitored appropriately by a health care provider. (Case study continues later in this monograph.) 9 this risk. These procedures include making a clear medical management with a non-controlled substance, Provider/Patient Agreements diagnosis of the disorder being treated, assessing or surgical intervention. The provider should also ask Once the patient has been selected for risk of drug misuse, obtaining informed consent if the patient’s symptoms improved or deteriorated in management with any controlled substance, a robust regarding the abuse liability of controlled substances, response to prior interventions. treatment agreement should be used to build trust and continually re-evaluating treatment effectiveness In order to safely manage the patient, the health in the patient-physician relationship and to clarify and patient adherence.37 care provider should find out if the patient is suffering expectations. Treatment agreements consist of Health care providers must perform and document from any co-morbid diseases or conditions, including informed consent language, descriptions of the a complete history and physical in accordance with a history of substance use disorders or harm related treatment and what to expect, responsibilities of both the usual course of professional practice before to substance use. parties, reasonable alternatives, benefits, and risks. legally prescribing any controlled substances. The To safely treat patients with controlled While data supporting the effectiveness of treatment documented history should include a description of substances, providers should be aware of risk factors agreements are lacking, they are considered a the patient’s chief complaint, attempted treatments, for overdose and addiction. Addiction risk factors standard practice. Possible side effects, including and co-morbid conditions. The physical examination include a personal or family history of any substance addiction and overdose, need to be fully and clearly should be used to identify co-morbid conditions and use disorder (including current tobacco use), and explained, both in writing and verbally. should include a neurological assessment. Essential psychiatric comorbidity.38 Chronic respiratory illness, Continual assessment of adherence and questions about symptoms include: acute psychiatric instability, uncontrolled suicidality, effectiveness of the treatment with a controlled • What are the symptoms? active substance use disorder, concomitant use of substance is crucial. A functional assessment of • When did the symptoms start? benzodiazepines or other known CNS depressants changes in daily activities, quality of life, and medication • Was there an inciting event? (including alcohol) and known diversion in the past side effects is helpful in weighing the effectiveness of • How do symptoms impact daily life? • What did the patient do in response to the are other relative contraindications to controlled the prescribed medication. Medication adherence and 39 symptoms? substance prescribing. other drug use can be assessed using regular urine • Has the patient been treated for this problem Providers should also perform a directed physical drug screenings PMP queries, and pill counts. in the past? exam and review any additional diagnostic studies • If so, were they prescribed a controlled or labs the patients may have required in the past. PLEASE SPEND THE ALLOTTED TIME ON substance? Patients may need to undergo additional imaging or EXERCISE 3 (PAGE 12). • Who prescribed the controlled substance and at diagnostic testing. As above, a urine drug screen may what doses? be needed at baseline when there is a high suspicion Patient Education About Controlled Substances Questions to consider when taking a history include: of an active substance use disorder (alternatively, Responsible prescribing of controlled substances • Does the patient have any other medical requires clinicians to fully educate patients about the disorders? and less subjectively, all patients may be required to many issues related to safe use, storage, and disposal º Specifically for sedatives, any respiratory submit a baseline urine drug screen). On physical disorders, frequent falls, or cognitive examination, the health care provider should be of such substances. Not only will educating patients issues? vigilant for signs of intoxication or withdrawal, track possibly improve their adherence to any medication º Specifically for stimulants, any marks from injection drug use, bruising from needles, regimen, it may prevent accidental overdose or cardiovascular issues? and physical exam findings that do not fit with the inadvertent diversion to non-authorized users. • Does the patient have a history of substance presenting complaint (for example, the patient is at an Controlled substances of all kinds require a higher use disorders, including tobacco use? 40 level of care and responsibility on the part of patients º Is there evidence in the chart of a appropriate weight but seeking weight reduction). due to their potential for misuse or abuse. Hence, history of a substance use disorder that Once a rigorous clinical assessment has the patient may not be disclosing? Do established a clear indication for the prescription, the education about safe use, storage, and disposal they have a collateral contact, such as clinician and patient must balance the potential benefit should be part of every provider-patient interaction a spouse, to verify this? Is a urine drug of the medication in treating the diagnosis with the involving these substances. This education may screening needed to confirm? risks inherent to the medication including addiction and include verbal instructions delivered by a prescriber, • Has the patient ever had an opioid (or other overdose. Although most risk-management screening nurse or other trained clinic staff person, written substance) overdose? handouts, guidance through other media (such as • Does the patient have a history of psychiatric tools are designed for prescribing opioids, they can DVDs or the Internet), or referral to other resources disorders? If so, is the disorder currently also be modified and applied to screen patients for active? Is there any potential for suicide? risk of misuse of non-opioid controlled substances. (such as a local clinic webpage or national resources). • Is the patient prescribed other central nervous The most common of these are the Opioid Risk Tool All patient-directed materials should be written at a th th system (CNS) depressants? (ORT), the DIRE Score, and the Screener and Opioid 6 -7 grade reading level, or lower depending on • Is there evidence of drug diversion in the past? Assessment for Patients with Pain (SOAPP). It should patient literacy. • Is there a family history of substance use be noted that these tools assess risk and should not Patients should be instructed about the proper disorders? use and administration of any prescribed controlled • Are there children in the household? be used to determine whether or not opioids should substances, including special directions about timing • Can medications be secured? be prescribed. • Is there a history of trauma or abuse? Several mental health assessment tools are of doses, whether to administer the medication with If the patient is currently taking a controlled available and may be prudent to use if there is food or without, and any foods or other medications substance, the provider should ask for the name and suspicion of an underlying psychiatric disorder, which to avoid while administering. Here are some other key location of the previously treating physician and, if may enhance risk of misuse of controlled substances, ideas to convey to patients about proper use: available, check a prescription monitoring program if left untreated. • Read the prescription container label each time to check dosage (PMP) to corroborate that information. The health PLEASE SPEND THE ALLOTTED TIME ON • Never use medicines after the expiration date care provider must learn if the patient has attempted EXERCISE 2 (PAGE 11). • Never share medicines with others other treatment modalities, including dietary • Do not take a medicine with alcohol or other modification, physical therapy, behavioral therapies, sedatives 10 Case Study Exercise 2

Instructions: Spend 15-20 minutes reading the case study below, reviewing the mental health assessment tools, and considering the questions that follow. Harold, a well-dressed 62-year-old African American man, uses a walker to slowly make his way down your clinic hallway. In the exam room, he says he has always been physically active, playing golf and enjoying long walks. He was diagnosed with metastatic prostate cancer 17 years ago, but the cancer has been held in check by a novel chemotherapeutic agent. Now, however, he has severe (8 out of 10) axial lumbar pain due to disc herniation at the L4 – L5 region. For the past four months he says he’s been unable to play golf or do any of his former activities, in addition to being tired from disrupted sleep. He describes breakthrough pain occurring despite the Tylenol #3 he was prescribed. “I just can’t go on like this,” he says. “You’ve got to help me out.”

Mental Health Assessment Tools 1. Patient Health Questionnaire –2 (PHQ-2). This is a simple two-item screening tool. If it is positive on either item, the clinician should offer another more detailed questionnaire to better assess the presence or absence of a depressive disorder. One link to this screening tool: cqaimh.org/pdf/tool_phq2.pdf 2. Patient Health Questionnaire–9 (PHQ-9). This nine-item tool screens for a depressive disorder, and often is used as a follow-up to the PHQ-2 if it is positive. It’s easy to score and use and available at: integration.samhsa.gov/images/res/PHQ%20-%20Questions.pdf 3. Zung Self-Rating Depression Scale (Zung). This is a 20-item written questionnaire available at: mentalhealthministries.net/resources/flyers/zung_scale/zung_ scale.pdf 4. Hamilton Depression Rating Scale (Ham-D). This is 21-item screening questionnaire. Scores <7 are normal. http://img.medscape.com/pi/emed/ckb/ psychiatry/79926-1889862-1859039-2124408.pdf 5. Generalized Anxiety Disorder 7-item Scale (GAD) available at: integration.samhsa.gov/clinical-practice/GAD708.19.08Cartwright.pdf 6. Primary Care PTSD (PC-PTSD). This is a four-item screening test for post-traumatic stress disorder available at: integration.samhsa.gov/clinical-practice/PC-PTSD.

Question 1: Which of these tools might be appropriate to use with Harold?

Question 2: How might Harold’s mental health issues interact with the management of his pain?

Question 3: What other tools or techniques might be used to better characterize Harold’s overall mental and physical functioning? (E.g., taking a psychosocial history; using the DSM-5 to diagnose his mental status; or asking questions aimed at assessing his level of physical and social functioning.)

• Do not take a medicine to promote sleep (unless Educating patients about proper disposal of misuse has occurred and does not diagnose the it has been specifically prescribed for that use) unused controlled substances is also important. presence of a substance use disorder, and, thus, • Never break, chew, or crush medicines The U.S. Food and Drug Administration recommends should be used only as one tool to assess adherence • Transdermal products may be affected by a variety of disposal methods, depending on the or for the presence of a substance use disorder. external heat, fever, and exertion, which can specific drug being disposed.41 Some states, however, In the context of family practice settings, increase absorption of a medication, leading to may have different or more stringent guidelines. unobserved urine collection is usually an acceptable a potentially fatal overdose California, for example, instructs consumers not to procedure for drug testing. Prescribers, however, • Transdermal products with metal foil backings are not safe for use in MRI scanners flush any medicines down the toilet or drain. If flushing should be aware of the many ways in which urine Patients should be continually reminded that medicines is not allowed in your state, instruct patients specimens can be adulterated. Specimens should sharing, selling, or giving away controlled substances to follow the instructions of a pharmacist for disposal be shaken to determine if soap products have been is against the law and poses significant hazards not or to mix the medicines with an undesirable substance, added, for example. The urine color should be noted just to the recipient of the medications, but to society such as used coffee grounds, put the mixture into a on any documentation that accompanies the specimen at large. disposable container with a lid or a sealable bag, and for evaluation, since unusually colored urine could Health care providers must also educate patients place it in the trash. (Note: in 2014, the DEA loosened indicate adulteration. If possible, urine temperature about the importance of proper storage of controlled regulations to allow pharmacies, hospitals, clinics, and and pH should be measured immediately after 42 substances. Even children or close relatives can other authorized collectors to serve as drop-off sites collection. be tempted to use medications they have not been for unused prescription drugs). One way to reduce the risk of urine test prescribed, and these are often the way controlled The DEA sponsors the National Take Back Initiative false positives or false negatives is to develop a substances become available to non-authorized uses. which coordinates periodic take-back programs relationship with a single laboratory, become familiar It is best if all controlled substances are stored in a at thousands of state and local law enforcement with its testing tools and threshold values, and use locked cabinet or other secure storage unit. Storage agencies across the country. More information about the same screening and confirmatory tests regularly areas should be cool, dry, and out of direct sunlight. these programs can be found at: deadiversion.usdoj. to build familiarity with the range of normal results. Remind patients not to store medications in their car, gov/drug_disposal/takeback/. Providers should only order the minimum necessary testing on a regular basis, however, as lab costs due to keep medications in the original containers, and to Urine drug screening to unnecessary testing can become quite expensive. avoid storing medications in the refrigerator or freezer Urine drug screening is noninvasive and widely For low risk patients, the number of tests needed per unless specifically directed to do so by a healthcare available. Urine drug testing should be used to screen year may be as few as 2, or every 6 months. It is also provider or pharmacist. Patients, family members, or for the presence of prescribed and non-prescribed generally not necessary to obtain quantitative results care-givers should also monitor pill containers so they medications and illicit drugs. Urine drug testing does to confirm medication adherence. will know if any pills are missing. not definitively confirm whether prescription drug

11 Case Study Exercise 3 Instructions: Spend 10-15 minutes reviewing the sample controlled substance patient agreement below, then answer the questions that follow related to the “Janet” scenario above: Janet is an 82-year-old Caucasian woman. Her husband died of an ischemic stroke five years ago, and now her son Tim, who lives nearby, looks after her. Janet has had chronic left hip pain ever since a hip fracture repair two years ago developed a serious infection. She comes in to see you with Tim because she is having worsening pain. Although she has always been quick-witted and articulate, in recent years Janet has had memory problems, often pausing in mid-sentence as she searches for a name or word that’s “right on the tip of her tongue.” She views these memory lapses as completely normal, although Tim finds them worrisome. According to Janet, the pain medication she was prescribed (short-acting hydrocodone/acetaminophen) is not enough to quell the pain in her hip (she says both are now hurting). According to Tim, however, Janet often forgets how much medicine she has taken. Tim feels Janet is relying too heavily on the analgesics—he believes strongly that much of Western medicine is misguided, overly invasive, and overly reliant on “pills for everything.” Janet dismisses Tim’s concerns and presses for a long-acting opioid she saw advertised on television.

SAMPLE PATIENT AGREEMENT: Controlled Substance Treatment

PATIENT NAME: PRIMARY CARE PHYSICIAN/SITE:

I understand that this agreement between myself; and (insert name of medical office/group) is intended to clarify the manner in which chronic (long-term) controlled substances will be used to manage my chronic pain. Chronic controlled opioid therapy for patients who do not suffer from cancer pain is a controversial issue. I understand that there are side effects to this therapy; these include, but are not limited to, allergic reactions, depression, sedation, decreased mental ability, itching, difficulty in urinating, nausea and vomiting, loss of energy, decreased balance and falling, constipation, decreased sexual desire and function, potential for overdose and death. Care should be taken when operating machinery or driving a car while taking these medications, particularly if you feel impaired. When controlled substances are used long-term, some particular concerns include the development of physical dependence and addiction can occur. I understand these risks and have had my questions answered by my health care provider. I understand that my (insert name of medical group) health care provider will prescribe controlled substances only if the following rules are adhered to: • All controlled substance prescriptions must be obtained from your (insert name of medical group) primary care provider. If a new condition develops, such as trauma or surgery, then the health care provider caring for that problem may prescribe opioids for the increase in pain that may be expected. I will notify my primary care provider within 48-hours of my receiving an opioid or any other controlled substance from any other licensed medical provider. For females only: If I become pregnant while taking this medicine, I will immediately inform my obstetrician and obtain counseling on risks to the baby. • I will submit urine and/or blood on request for testing at any time without prior notification to detect the use of non-prescribed drugs and medications and confirm the use of prescribed ones. I will submit to pill counts without notice as per health care providers’ request. I will pay any portion of the costs associated with urine and blood testing that is not covered by my insurance. • All requests for refills must be made by contacting my (insert name of medical group) primary care provider during business hours at least 3-workdays in advance of the anticipated need for the refill. All prescriptions must be filled at the same pharmacy, which is authorized to release a record of my medications to this office upon request. A copy of this agreement will be sent to my pharmacy. • Pharmacy name/address/telephone: • The daily dose may not be changed without my (insert name of medical group) primary care provider’s consent. This includes either increasing or decreasing the daily dose. • Prescription refills will not be given prior to the planned refill date determined by the dose and quantity prescribed. I will accept generic medications. • Accidental destruction, loss of medications or prescriptions will not be a reason to refill medications or rewrite prescriptions early. I will safeguard my controlled substance medications from use by family members, children or other unauthorized persons. • You may be referred to an appropriate specialist to evaluate your physical condition. • You may be asked to have an evaluation by either a psychiatrist or psychologist to help manage your medication needs. • If your provider determines that you are not a good candidate to continue with the medication, you may be referred to a detoxification program or evaluation by a pain management center. • These medications may be discontinued or adjusted at your provider’s discretion. I understand that it is my provider’s policy that all appointments must be kept or canceled at least 2-working days in advance. I understand that the original bottle of each prescribed controlled substance medication must be brought to every visit. I understand that I am responsible for meeting the terms of this agreement and that failure to do so will/may result in my discharge as a patient of (insert name of medical group). Grounds for dismissal from (insert name of medical group) include, but are not limited to: evidence of recreational drug use; drug diversion; altering scripts; obtaining controlled substance prescriptions from other providers without notifying this office; abusive language toward staff; development of progressive tolerance; use of alcohol or intoxicants; and engagement in criminal activities. Patient’s Signature: Date:

Question 1: Would this agreement be appropriate for use with Janet?

Question 2: Would this agreement need to be modified in any way because of the specifics of Janet’s case?

Question 3: Would it be prudent to include a family member in the discussion about treatment and to serve as a witness to the agreement?

12 Prescribers should be familiar with the metabolites representatives, and law enforcement and drug Collecting data associated with each opioid that may be detected in court personnel.2 Most PDMPs permit providers to Pharmacies must submit required data to their urine, since the appearance of a metabolite can be delegate access to a mid-level practitioner, such as a state’s PDMP for each prescription they dispense for misleading. A patient prescribed codeine, for example, registered nurse or a pharmacy technician.2 In more specified controlled substances. Pharmacies in the may test positive for morphine because morphine is than half of states, prescribers and pharmacists are U.S. Department of Veterans Affairs and in the Indian a metabolite of codeine. Similar misunderstandings required to register with their respective PDMP; in Health Service are also authorized to submit data to may occur for patients prescribed hydrocodone who some of these states, registrants are also required PDMPs, and such pharmacies in many states do so.7 appear positive for hydromorphone or oxycodone to access the PDMP for a patient’s prescription Depending on a state’s legislative requirements, the and oxymorphone. If questions arise, it is important history before prescribing or dispensing controlled following entities/ individuals may also be required to to reach out to the lab toxicologist for consultation. substances.2 submit prescription data when dispensing controlled Additionally, it is not recommended that providers substances: emergency departments, wholesale PDMPs Today make decisions about patient care solely based on distributors, licensed hospital pharmacies, physicians, PDMP databases in most states are housed within the result of one urine drug test. It is important to veterinarians, dentists, and medical and behavioral a licensing or public health agency; in a few states, interpret the results with other clinical information. health service providers. they are located within a law enforcement agency. Most Information collected typically includes date Table 3: Metabolites of Common Opioid states track prescriptions for Schedule II–V controlled dispensed, patient, prescriber, pharmacy, medication, Pain Medications medications, and some also track unscheduled and quantity. This information is submitted to medications with misuse potential (e.g., ephedrine, Drug Metabolites databases in electronic form. The intervals at which which can be used to make methamphetamine). Morphine Morphine pharmacies are required to submit data vary by state. Most PDMPs update their data on a daily or weekly Hydromorphone Typically, prescriptions for intravenous basis, enabling prescribers and dispensers to assess Codeine medications and those filled by hospice palliative a patient’s recent patterns of use or misuse. Systems care are not submitted to PDMPs. In addition, federal Codeine Codeine are evolving toward even more frequent updating; in confidentiality rules exempt medications dispensed Morphine 2012, Oklahoma became the first state to institute at opioid treatment programs (OTPs)—that is, Hydrocodone real-time reporting, with prescription data available when a medication for the treatment of a substance Hydrocodone Hydrocodone within 5 minutes after medication is dispensed.44 use disorder (e.g., methadone, buprenorphine) is Hydromorphone Real-time reporting can offer some advantages; in dispensed at an OTP, patient-identifying information is 6-Hydrocodol particular, emergency department care providers can not submitted to the PDMP. There are some exceptions find near real-time prescription histories for patients Oxycodone Oxycodone specified in the federal regulations. presenting for acute care. Oxymorphone OTP-based prescribers may access PDMP Some state PDMPs provide batch reporting; Hydrocodone information to help manage the care of their patients, this is a utility that enables prescribers to obtain and the Substance Abuse and Mental Health Services Source: Webster LR, and Dove B. Avoiding Opioid summary histories for a group of patients, such as Administration (SAMHSA) encourages them to do so.1 Abuse While Managing Pain. Lifesource. 2007. those scheduled for upcoming appointments. The It is especially important that OTP-based physicians practitioner can review the summaries to determine Prescription Drug Monitoring Programs (PDMPs) and physicians who are qualified to prescribe whether a full report should be ordered for any PDMPs are state-operated databases that collect buprenorphine for opioid use disorder (i.e., physicians particular patient. information on dispensed medications. The first PDMP who have received a waiver under the Drug Addiction Most state PDMPs are authorized to send was established in 1939 in California, and by 1990 Treatment Act of 2000) access the PDMP, because unsolicited reports to providers, licensing boards, another eight state programs had been established.43 these physicians are the only practitioners who have or law enforcement agencies when a prescriber’s or PDMPs periodically send reports to law enforcement, full knowledge of their patients’ controlled medication prescription recipient’s activity exceeds thresholds regulatory, or licensing agencies as part of efforts histories. established by the PDMP.45 Unsolicited reports can to control diversion of medication by prescribers, alert healthcare providers to intervene with patients Privacy and security pharmacies, and organized criminals. Such diversion whose prescription-related behavior may suggest States work hard to ensure the privacy and can occur through medication or prescription theft or substance misuse, whereas unsolicited reports security of health information to prevent identity illicit selling, prescription forgery or counterfeiting, to investigative agencies or licensure boards can theft and medical fraud. One such safeguard is that nonmedical prescribing, and other means, including support investigations into potential drug diversion or many PDMPs are prohibited from providing identifying diversion schemes associated with sleep clinics problematic prescribing. information about individual patients or practitioners (sedative-hypnotics and barbiturates), weight clinics More than half of the states are building systems in reports to law enforcement agencies, except in (stimulants), and pain clinics (opioid medications).43 to allow for data sharing across systems, agencies, and specified situations such as in response to a subpoena The first PDMPs, which were paper-based, did not 7 states. Benefits of this system integration include the or for an active case investigation. Such prohibitions provide reports to healthcare providers for use during following: providers can obtain patient prescription are also intended to protect confidentiality and avoid individual patient care; however, today’s electronic history within the electronic health record system potential targeting of providers engaged in legitimate databases have a variety of features that make them instead of logging into two separate systems; state prescribing and dispensing activities. practical for such care. Depending on the particular Medicaid agencies can share information with federal state law, the types of professionals who may register health service providers (e.g., U.S. Department of Using PDMP data to access PDMP records include prescribers (e.g., Veterans Affairs, Indian Health Service); and adjacent PDMP reports can be used by a healthcare primary care doctors, nurse practitioners, physician states are able to share information to address practitioner with other support tools (e.g., assistants), dispensers (e.g., pharmacists), medical illicit cross-border prescription filling or to provide documentation templates, patient data reports and examiners, practitioner licensure board members, for better coordination of the care that a patient is summaries, computerized alerts and reminders) third-party payers, public health and safety agency receiving in different states. when screening a new patient or monitoring a current 13 patient. The practitioner can review the patient’s shopping (obtaining overlapping prescriptions from patterns that may indicate aberrant, illicit, or unsafe prescription record from the PDMP to confirm or different doctors for intended nonmedical use) or prescribing by medical professionals. augment information provided by the patient’s own pharmacy shopping (visiting multiple pharmacies to Evidence for Effectiveness reports and the medical exam. Providers can promote fill prescriptions); these are called “multiple provider Provider surveys, case studies, state evaluations, patients’ acceptance of this tool by proactively episodes.” and other reports offer growing evidence that informing them that PDMP data are routinely checked PDMP data are best used in conjunction with individual state databases are reducing diversion for all patients to enhance care and that confidentiality other sources of information, including clinical while also improving individual clinical decision and privacy are protected by law and regulation. assessment, before making any determinations making and prescribing practices and lowering rates For example, when treating for chronic pain, a about aberrant behavior, because no validated and of admissions for substance use treatment.8 practitioner can check the state PDMP for data on standardized criteria for the threshold of questionable For example, after New York and Tennessee the patient’s history of prescriptions for controlled activity have been established. A patient who has required prescribers to consult their state’s database substances. This information can be used to obtained prescriptions from multiple providers is not before prescribing pain medications, the percentage determine whether the patient is already receiving necessarily a “doctor shopper”; the patient could of patients with multiple provider episodes (receiving opioid medications or other medications that, when have legitimately received prescriptions from different prescriptions from five or more prescribers or filling combined with an opioid prescription, might put him specialists for diverse conditions (e.g., a terminal prescriptions at five or more pharmacies in a 3-month or her at risk for overdose. The Centers for Disease disease or disorder, chronic pain, postsurgical pain). period) dropped 75% and 36%, respectively.47 Control and Prevention (CDC) advises: “Clinicians There are also plausible reasons why a patient might Evidence from states with mandates also suggests should review PDMP data when starting opioid therapy fill prescriptions at multiple pharmacies (e.g., because that PDMP use supports appropriate prescribing and for chronic pain and periodically during opioid therapy different pharmacies may be closer to work or home, dispensing. In the 1-year period beginning 2 months for chronic pain, ranging from every prescription to because a particular pharmacy offered a coupon). after Kentucky’s mandate on enrollment and use every 3 months.”46 For these reasons, a proposed operational definition of its PDMP went into effect (in July 2012), overall Whether updated in real time or at some other of shopping behavior for medications at high risk dispensing of controlled substances in the state regular interval, a PDMP provides longitudinal for misuse or diversion is having “overlapping declined 8.5 percent. In approximately the same information from which a healthcare practitioner prescriptions written by different prescribers and filled period, prescriptions for buprenorphine (a medication can identify patterns of inappropriate prescription at three or more pharmacies.”7 used in treatment of opioid use disorder) increased medication use or risky substance use behavior. When PDMP data, combined with other nearly 90 percent.47 According to the PDMP Center PDMP data may suggest that a patient has an information, indicate that a patient may be engaging for Excellence, these two data points indicate that the uneventful prescription history, giving confidence to in aberrant behavior, the practitioner can use this PDMP mandate suppresses inappropriate prescribing the practitioner that the patient has a legitimate need information in the medical setting with the patient as but does not impinge on legitimate prescribing.47 for any scheduled prescription medications under a basis for an immediate conversation or intervention. PDMP use may also be a factor in reducing consideration. To ensure that the patient does not misuse prescribed mortality associated with opioid use. A 2016 study The data can also reveal whether the patient has medication, the practitioner can monitor PDMP data of 34 states (32 with PDMPs) found that the rate of been prescribed medication that may create a risk in conjunction with urine drug testing and use of a opioid-related deaths declined in states in the year for interaction with a medication the practitioner is treatment agreement (a contract between patient and after PDMP implementation. States whose PDMPs had considering prescribing. For example, the data can practitioner on what each of them will do). more robust features (e.g., more frequently updated suggest the total level of morphine equivalent to Before prescribing an opioid for pain, the data) experienced greater reductions in deaths which a patient already has access and whether the practitioner can assess PDMP data to ensure that a compared with states whose PDMPs did not have patient has access to other medication(s) that may, patient is not obtaining, through other prescribers, those features.48 in combination, put the patient at risk for overdose. medication with sedative effects (e.g., other opioids, Ohio’s experience indicates that PDMPs can be Another potential use of the data is to determine benzodiazepines), which could heighten risk of a significant tool in a broader program to encourage whether a patient has failed to fill a prescription for overdose when used simultaneously with the opioid. and enforce safe prescribing practices. In 2011, the medication previously prescribed by that practitioner; PDMPs provide another valuable function in that state adopted rules that mandate prescriber and in such situations, the practitioner can initiate a providers can use them to periodically review dispenser use of the PDMP under certain conditions. conversation about why the patient is not taking the their own prescribing record, to confirm that their At the same time, the state instituted other measures medication as indicated. Drug Enforcement Administration (DEA)-controlled designed to curb misuse of prescription drugs, A practitioner can also use PDMP data to monitor substance number has not been used illegally by including crackdowns on pill mills (physicians, clinics, patients with suspected or known substance use another person. or pharmacies that prescribe or dispense controlled disorders by checking patient records for medically Not only prescribers but also pharmacists are medications inappropriately or for nonmedical unwarranted concurrent use of prescription enhancing patient care through their use of PDMPs. reasons), licensing restrictions on pain management medication (e.g., high doses of several prescriptions, For example, pharmacists can identify interaction risks clinics to prevent over prescription of opioid pain including long- and short-acting opioids as well as from multiple prescriptions. Pharmacists can also medications, and the institution of a drug take-back benzodiazepines) and use of multiple prescribers initiate conversations with patients whose prescription program. In the first quarter of 2014 alone, the or pharmacies. Other indicators of potentially use patterns indicate possible substance misuse, PDMP received requests for 2 million reports.48 problematic prescription use that a practitioner can and they can refer such patients for screening and A concern that has been raised about PDMPs look for when reviewing PDMP data include early counseling and link them with informational resources is that they could suppress the availability of opioid refills and dose escalation. on substance use disorders and substance use medication for legitimate cases of pain. A 2016 Behavior that suggests substance misuse, a disorder treatment. Alternatively, they can contact study found that across 24 states implementing substance use disorder, or diversion is known as the patient’s prescriber, who may be best positioned PDMPs, a sustained 30 percent reduction in the aberrant drug-related behavior. PDMP data can alert to provide resources or referrals. Pharmacists can rate of prescribing Schedule II opioids occurred; a practitioner to aberrant behavior such as doctor also use PDMP data to flag suspicious prescribing

14 however, there was no significant impact on the opioid medications occurred after heroin use rates Providers should also understand the side-effects overall prescribing of pain medication (the study did had begun trending upward.52 The authors point to of each medication and how to monitor controlled not evaluate whether patients’ pain was effectively heroin’s increased accessibility, reduced price, and substances for signs of misuse, addiction or abuse. managed).49 high purity as factors that may have contributed to Anxiety One small study (N=179) of patients presenting increases in the drug’s use. In addition, the review The CSA lists numerous anxiolytics as with nonacute pain conditions in an emergency highlighted studies of Florida and Staten Island, controlled substances. Scheduled drugs include department found that in 41 percent of the cases, NY, that found that policy-induced reductions in the the benzodiazepines, barbiturates, and so- clinicians altered their prescribing plan after consulting rates of opioid prescribing were associated with called “z-drugs” such as zolpidem, zaleplon and the state’s PDMP; changes went in both directions, reductions in overall opioid-related deaths (that is, eszopiclone. Benzodiazepines such as alprazolam, with the planned opioid prescribing reduced in 61 deaths related to either heroin or opioid medication clonazepam, diazepam and lorazepam have largely percent of the cases and increased in 39 percent.50 use). Based on the overall findings of the review, the replaced barbiturates for the short-term treatment Other initial studies indicate that PDMPs do not authors recommended enhanced use of PDMPs as of anxiety.53 Because many anxiolytics have sedating have a suppressive effect, although they may affect part of a comprehensive strategy. properties, these medications are also commonly the types of opioids that are prescribed.7 A 2009 Accessing PDMPs used as sleep-inducing (hypnotic) agents. study found that, between 1997 and 2003, compared A healthcare provider must enroll in a PDMP to Anxiety disorders share features of excessive with states without PDMPs, states with PDMPs had become an authorized user before obtaining access fear and anticipation of future threat. Fear leads to a smaller number of shipments per capita (from to its data. Typically, the enrollment procedure involves autonomic arousal, a feeling of imminent danger, and suppliers to distributors such as pharmacies) for certifying credentials, authenticating providers an impulse to escape. Physical symptoms associated oxycodone (a medication highly associated with drug through proper identification, and establishing secure with anxiety include chest tightness, dyspnea, diversion) and reduced admissions for the treatment system access through passwords and/or biomarkers. tachycardia, flushing, dry mouth, tremor, dizziness, of prescription opioid misuse. At the same time, These procedures are intended to restrict entry to blurry vision, nausea or vomiting, abdominal pain, overall opioid shipments increased, indicating no users with legitimate purposes for accessing the diarrhea, and urinary urgency.54 chilling effect on the prescribing of opioids overall. data. Several states have developed streamlined Fear and anxiety can be non-pathologic, transient According to a study on Project Lazarus—a program registration systems that make enrollment easier, emotions. In contrast, pathologic anxiety disorders in Wilkes County, NC, that combines PDMP surveillance while still maintaining confidentiality and security. persist for longer than six months, exist when certain data with public health education, prevention, and PDMP use complements other measures that behaviors are no longer developmentally appropriate, treatment efforts—overdose deaths in the county providers can take to prevent misuse and diversion of or are out of proportion to the threatening event or declined 69 percent from 2009 to 2011, even though prescription medications and to help ensure the safety object. They must also cause distress, significantly the number of opioid prescriptions remained nearly of patients using them. PDMPs are an increasingly alter the patient’s routine, and diminish his or her level and was higher than the state average. valuable and easy-to-use resource for healthcare functioning in everyday life. Examples of anxiety In a pilot study of the Indiana PDMP in 2012, providers who prescribe and dispense controlled disorders include separation anxiety disorder, specific physicians reported that the clinical care they medication. Regulation and oversight of these phobias, social anxiety disorder, panic disorder, provided was enhanced by use of PDMPs; depending databases ensure that the benefits for clinical care do agoraphobia, substance/medication-induced anxiety on their patients’ clinical needs, physicians both not jeopardize patient privacy and security. Providers disorder, and generalized anxiety disorder (GAD). reduced (by 58%) and increased (by 7%) the number are encouraged to register to use their state’s PDMP Obsessive compulsive disorders and trauma-related of prescriptions written or number of pills dispensed. and to routinely query the database in regard to their disorders are also common causes of anxiety Another concern is the perception that increased patients’ prescription histories. This practice can help symptoms, though DSM 5 has separated them from prescription monitoring through PDMPs may be curtail prescription medication misuse and diversion, other anxiety disorders. a factor that causes people who are dependent reduce risk of substance use disorders, and prevent Although anxiety disorders are very common, on prescription opioids to switch to heroin use, opioid overdoses and deaths little progress has been made in developing new contributing to heroin-related overdose deaths anxiolytics over the past 50 years.55 Anxiolytics form a (the rate of heroin-related deaths almost tripled Condition-specific recommendations heterogeneous group of agents with a wide range of from 2010 through 2013). However, according to General considerations efficacy and some of these medications are controlled an analysis of 2002–2011 data from the National Drugs with the highest risk for addiction typically substances with a high potential for morbidity and Survey on Drug Use and Health, of people who initiate elicit rapid dopamine release in the midbrain. mortality. Barbiturates and benzodiazepines are nonmedical use of pain relievers, only 3.6% transition Therefore, potent high-dose immediate-onset commonly prescribed for patients suffering from to heroin use within 5 years of initiation. According to medications have greater abuse liability than do anxiety. However, selective-serotonin uptake inhibitors the report Trends in Heroin Use in the United States: their less-potent lower-dose extended-release (SSRIs) and behavioral interventions may be more 2002 to 2013, “The concern that efforts to prevent counterparts. effective, may have better long-term responses, and the illegal use of prescription opioids are causing It should be remembered that controlled have a much smaller abuse potential.56 people to turn to heroin is not supported by the trend substances are often the last therapeutic option data. . . . Although research indicates that people who that should be considered to manage a disease or Barbiturates previously misused prescription pain relievers were condition, with behavioral, non-pharmacologic, and Barbiturates were commonly used in the past more likely to initiate heroin use than people who non-controlled medications tried prior to a trial of as sedatives and hypnotics. However, they have had not misused prescription pain relievers, most any controlled substances. Health care providers serious safety problems and have been replaced people who misuse prescription pain relievers do not should be aware of all the available treatment options by benzodiazepines outside the operating room. 51 progress to heroin use.” for each disease and be able to justify why they Barbiturates pose a risk of coma in high doses, induce Furthermore, according to a 2016 review believe a controlled substance is the best therapeutic tolerance, possess drug-interfering metabolites, article, implementation of most policy decisions intervention. create physical dependency, and incite severe aimed at reducing rates of nonmedical use of withdrawal symptoms. Side-effects of these agents

15 include drowsiness, decreased concentration, nausea, records only provided limited information that was comorbidities. The provider should ask the patient and dizziness. CNS, cardiovascular, and respiratory insufficient to safely prescribe benzodiazepines.60 about prescribed medications, caffeine intake, alcohol depression may cause overdose death. Approximately one-third of patients who have intake, and herbal supplements. Withdrawal from barbiturates can cause long term use of benzodiazepines will experience Initial treatment for chronic insomnia should seizures, delirium, anxiety, weakness, restlessness, withdrawal symptoms within two to 10 days of involve cognitive behavioral therapy for insomnia tremors, nausea, vomiting, cardiac arrest, and stopping use. Some patients will experience withdrawal (CBT-I), which is multimodal treatment involving death. Barbiturates are still being used for surgical symptoms on tapering benzodiazepines to a lower education, stimulus control instructions, time-in-bed anesthesia and phenobarbital is used cautiously as dose. Withdrawal symptoms include hyperarousal restriction, and relaxation training. 66 Some patients an anticonvulsant. Carisoprodol is still prescribed symptoms, such as insomnia, anxiety, photophobia, take over-the-counter antihistamines, opioids, or as a muscle relaxant. It lacks effectiveness as a heightened sensitivity to sound, unsteadiness, drink alcohol in an effort to treat insomnia. Providers long term agent and should be used only for short and seizures.61 Patients in a nationwide study in should discourage patients from using opioids or periods, avoided in the elderly, and avoided in patients Switzerland who abused benzodiazepines described alcohol as sleep agents. Antihistamines reduce sleep with substance use disorders. It is metabolized to self-medication for anxiety and insomnia as the primary quality and produce residual daytime drowsiness, meprobamate, which, though it was marketed as safer motivation for misusing this controlled substance.62 making them a poor choice for treating insomnia. than barbiturates, has most of the pharmacological Most patients began taking benzodiazepines after Although benzodiazepines are commonly prescribed effects and dangers of barbiturates. their provider prescribed the medication, and the for their hypnotic properties, patients should not prescribing provider usually detected the misuse.62 rely on benzodiazepines to treat chronic insomnia, Benzodiazepines Benzodiazepines should be prescribed for and providers should preferentially prescribe non- Benzodiazepines have largely replaced short-term use only and very cautiously in older benzodiazepine sleep agents, and then only for barbiturates for short-term treatment of anxiety adults. Chronic daily use of benzodiazepines can acute insomnia and for intermittent use for no more although they have a significant risk of morbidity lead to a profound physical dependence that is than 3-4 weeks.65 Although the margin of safety for and mortality, including addiction, injuries due to difficult to address. Adverse events associated with both benzodiazepines and benzodiazepine receptor side-effects, potentially lethal interactions with other benzodiazepine use in older adults include motor agonists (so-called Z-drugs) is relatively wide, adverse substances, and a risk of death from overdose. In vehicle collisions, falls, cognitive difficulties, delirium, effects may include anterograde amnesia, complex 2010, 29% of overdose deaths in the United States sleep disturbances, drug-drug interactions, and sleep-related behaviors, falls, cognitive impairment, involved benzodiazepines, though 77% of those impaired function.35 Studies of older patients who respiratory depression, and rebound insomnia.23 deaths also involved opioid analgesics. When not used are taking benzodiazepines show that they come Pharmaceutical intervention for treating in combination with other drugs, benzodiazepines are to rely on them for any anxiety symptoms, deny the insomnia should be used when non-pharmaceutical implicated in only 3.7% of drug overdoses.57 presence of side-effects and are reluctant to taper treatments are ineffective, when insomnia significantly In 2010, 2.2% of Americans misused or discontinue use even when they understand interferes with function, or when the underlying tranquilizers, of which benzodiazepines were the the risks of continued use.63 Health care providers cause is addressed but insomnia persists.67 Health major constituent. Nearly 10% of these individuals prescribe these medications because they view them care providers should prescribe the lowest effective met criteria for a benzodiazepine use disorder.5 as effective, rapidly acting, and eliciting strong patient dose and for a short duration. The provider should In a case-control study, risk factors for death from satisfaction.64 Providers may minimize risks of these avoid prescribing hypnotics for patients who have prescribed drug overdose included one or more medications and may not view them as problematic an underlying history of respiratory depression, sedative/hypnotic medication prescriptions, male sex, in older patients because of the relatively low risk of myasthenia gravis, substance use disorder, or acute older age, increased number of prescriptions, higher addiction. As a result, they may not monitor these cerebrovascular accident. dose of opioid analgesics, and a prescription for patients stringently or try to wean them off of long- buprenorphine, fentanyl, hydromorphone, methadone, Temazepam term use of these drugs. These beliefs contradict or oxycodone.58 Benzodiazepines produce behavioral Temazepam is a benzodiazepine used to treat practice guidelines and do not meet standard of care. disinhibition and amnesia and can enhance opioid- patients with insomnia who wake up frequently during induced euphoria. Thus patients misusing both Insomnia the night.68 Its peak sedative effect occurs 2-3 hours benzodiazepines and opioids may lose track of how Insomnia is the most common sleep disorder and after it is taken, so patients must take this medication much they have taken and be inclined to take more. chronic insomnia is described as insomnia lasting several hours before bedtime. It is a schedule IV Side-effects of long-term benzodiazepine use include longer than three months that is not better explained controlled substance. tachycardia, hypertension, rebound anxiety, agitation, by use of substances, medications, or by another Z-Drugs disorientation, hallucinations, and seizures.59 disorder.65 The routine evaluation of insomnia Like benzodiazepines, the Z-drugs (Zolpidem, Before prescribing benzodiazepines, providers involves obtaining a thorough history and performing Zaleplon, and Eszopiclone) enhance the effect should obtain a current list of medications, and a physical examination. In obtaining a history, the of gamma-aminobutyric acid (GABA), the major discuss and document the patient’s drug and alcohol health care provider should ask questions about inhibitory neurotransmitter. Because they modulate history. Concomitant use of benzodiazepines and medical and psychiatric co-morbidities including sleep a more specific GABA receptor subtype, the Z-drugs alcohol can increase the risk of overdose death and apnea (the STOP-Bang questionnaire [stopbang.ca] were thought to be less addictive and have less the provider may be held liable for unsafe prescribing is a good sleep apnea screening tool for primary abuse potential than benzodiazepines. Evidence practices if he or she has failed to document and care), substance use disorders, and stress. The shows, however, that they elicit a similar behavioral address these risk factors.60 Benzodiazepines should provider may want to discuss the patient’s sleep profile including reinforcing effects, abuse potential, only be prescribed with extreme caution to patients habits with the patient’s partner or caregiver in case tolerance, physical dependence, and subjective with past or current alcohol use disorder. In one pilot he or she has noticed any sleep abnormalities such effects.69 While Z-drug addiction is uncommon, the study, an audit of medical clinic records showed that as snoring, sleep apnea, sleepwalking, or unusual risk increases at higher doses and in patients with 57% of the records did not contain any information limb movements. Physical examination should a history of substance use disorders.69 They can all about the patients’ alcohol use and the remaining include a neurological exam and an assessment for cause withdrawal symptoms if abruptly discontinued

16 after prolonged use. Side-effects are similar in all three While they are awake, many patients describe arrhythmias, hypertension, angina, and circulatory and can include nightmares, agitation, hallucinations, persistent mental cloudiness, loss of concentration, collapse. Amphetamines should not be prescribed or dizziness, daytime drowsiness, headache and fatigue, and extreme exhaustion. Therefore, health administered to patients with cardiovascular disease gastrointestinal problems. care providers prescribe treatments such as or who are taking MAO-inhibitors. Lastly, patients Other agents modafinil/armodafinil, amphetamines, SSRI’s, and taking amphetamines may experience anorexia, Doxepin is appropriate for sleep maintenance TCA’s to improve wakefulness during the day. At night, nausea/vomiting, abdominal pain or diarrhea. insomnia and may be useful for patients with patients with narcolepsy experience disrupted sleep, Chlorpromazine, an alpha-blocker, is the antidote for contraindications to benzodiazepines or Z-drugs.70 with hallucinations, paralysis, insomnia, and other amphetamine overdose. Other agents that may be effective for chronic sleep difficulties. Consequently, other treatments, Though the percentage of past month users of insomnia include suvorexant, remelteon, and low including behavioral interventions, attempt to improve prescription stimulants has remained stable, the Drug doses of the sedating antidepressants trazodone and duration and quality of sleep. Sodium oxybate is the Abuse Warning Network data show that the number only medication approved in the United States to treat of emergency room visits related to nonmedical use mirtazapine.22 cataplexy. of prescription stimulants has increased 189% since Narcolepsy First-line agents for patients with excessive 2004.78 The misuse of stimulants is most common in Narcolepsy is characterized by neural daytime sleepiness are modafinil/armodafinil alone adolescents and is often associated with the desire for dysregulation of the sleep-wake cycle. As a result, or in combination with sodium oxybate.74 Alternative cognitive enhancement and euphoria.14 Use patterns individuals suddenly fall asleep in the middle of the treatments include amphetamines (including tend to coincide with examination periods and as a day in “sleep attacks” and experience episodes of methylphenidate), SSRI’s, and TCA’s. means to counter the effects of binge drinking and extreme daytime sleepiness.71 Males and females are marijuana use.79 As with opioids, immediate-release Modafinil/armodafinil equally affected, and narcolepsy is a life-long chronic formulations have more abuse liability, and long- Modafinil and armodafinil (r-enantiomer) have condition that often begins between the ages of 7 and acting and tamper-resistant formulations have been replaced amphetamines to become the first-line 25 years. Associated symptoms include vivid dreams, developed to discourage misuse. Stimulants should stimulants for patients with narcolepsy.75 These hallucinations, and total paralysis immediately before be prescribed with caution and closely monitored in medications reduce excessive daytime drowsiness falling asleep or after waking. Some people with patients with a history of substance use disorder. and improve alertness with a better side-effect narcolepsy also have cataplexy, a loss of voluntary profile than amphetamines. They share a mechanism muscle tone that makes the sufferer limp and unable Attention-Deficit/Hyperactivity of action with amphetamines, namely blocking to move. These patients suffer from poor sleep in Disorder (ADHD) dopamine reuptake, though the observed effects are general and often enter REM sleep several minutes Attention-Deficit/Hyperactivity Disorder is one of much milder.76 Modafinil is a schedule IV controlled after falling asleep, in contrast to people with normal the most commonly-diagnosed disorders of childhood. substance. It has been shown to have similar mood sleep cycles who enter REM sleep 80-100 minutes According to the CDC, 11% of children between the elevating properties, though to a lower degree.76 after falling asleep. ages of 4 and 17 (6.4 million children) have been Withdrawal symptoms include anhedonia, lethargy, 80 To diagnose narcolepsy, health care providers diagnosed with ADHD in the United States. Boys are anxiety and insomnia. must take a careful sleep history to determine if twice as likely as girls to receive a diagnosis and the shift-work, circadian rhythm abnormalities, or pre- Sodium oxybate average age of diagnosis is 7 years old. Furthermore, existing sleep deprivation are present. The provider Sodium oxybate (gamma hydroxybutyrate, GHB, the rate of diagnosis has been increasing 5% per should note any symptoms consistent with cataplexy. Xyrem) is a sedative approved to decrease daytime year since 2003. 75 ADHD treatment involves both medical and Excessive daytime sleepiness and cataplexy are sleepiness and cataplexy in the United States. It behavioral interventions, with about half of pathognomonic for this disease. Approximately half restores sleep continuity, decreases hallucinations, preschoolers with ADHD taking a medication for this of patients have all four symptoms of hallucinations, and reduces sleep paralysis. Sodium oxybate must be disease in 2011.80 Health care providers frequently sleep paralysis, cataplexy, and excessive daytime administered twice per night because of its short half- prescribe amphetamines and methylphenidate, 72 life, and dose titration can be challenging. Side-effects sleepiness. Preschool-age children may have schedule II controlled substances, for the management different symptoms, including inattentiveness, include nocturnal confusion, sleepwalking, dizziness, 73 of ADHD. emotional lability, and hyperactivity. nausea and enuresis. Patients who are taking this Neurobiological findings in children with ADHD Patients may be sent home with a sleep journal medication should avoid alcohol and other sedating include delayed brain maturation, inhibitory control and asked to keep track of their sleep patterns for medications because overdose of sodium oxybate defects, noradrenergic dysfunction, and dopaminergic 71 several weeks. A thorough physical examination can lead to fatal respiratory depression. These safety dysfunction.81 However, the diagnosis of ADHD must be performed to exclude any other underlying concerns mean that the medication is tightly restricted remains a clinical diagnosis. The American Academy disease state that may cause similar symptoms, and classified as a schedule III controlled substance, of Pediatrics recommends that primary care providers although cataplexy is rarely found outside of although in a recent analysis, rates of addiction are consider evaluating pediatric patients between the 77 narcolepsy. relatively low, <1%. ages of 4 and 18 who present with academic or Treating narcolepsy is difficult because this behavioral problems and symptoms of inattention, 71 Methylphenidate and amphetamine disease is due to permanently low hypocretin levels. 82 Amphetamines block dopamine reuptake or hyperactivity, and impulsivity. Providers should use Although bench scientists are working on stem-cell the criteria for a diagnosis of ADHD as described in the therapies to replace hypocretin-producing cells, increase dopamine synaptic release, which can DSM 5. These criteria for diagnosing ADHD require a currently-approved treatments focus on alleviating improve alertness, decrease appetite, and reduce persistent pattern of inattention and/or hyperactivity- symptoms. Patients with narcolepsy find this disease daytime drowsiness. Side-effects include neurological, highly disruptive to their everyday function. They may cardiovascular, and gastrointestinal symptoms. impulsivity. For a diagnosis of inattention, at least fall asleep during work or school, in the middle of a Neurological symptoms range from insomnia, six out of nine symptoms must have been present conversation, or during a meal. More dangerously, irritability, tremor, and dizziness to confusion, for the past six months in children younger than 17 they may fall asleep while driving or operating heavy delirium, panic, and suicidal ideation. Cardiovascular years. These symptoms must be developmentally machinery. side-effects can be serious, including cardiac inappropriate and disrupt school/work and social life. 17 ADHD can have predominantly inattentive effects include anorexia, sleep difficulties, abdominal effects include gastrointestinal distress, somnolence, presentation, predominantly hyperactive/impulsive pain, and headaches. Some children have diminished and anorexia. Rare side-effects include increase presentation, or combined presentation. Providers height with long-term use.82 Psychiatric symptoms in suicidal ideation and drug-induced hepatitis. should document the severity of ADHD, ranging from in younger children may include mood lability and Atomoxitine may be more appropriate than stimulants mild to severe depending on the number of symptoms dysphoria. Although rare, hallucinations and psychotic for patients with a personal or family history of and impairment of social or occupational functioning. symptoms have been reported as a side-effect of substance use disorders, or if there is concern for They should also make sure to assess the child and stimulant use. Health care providers and parents are misuse or diversion due to its longer-acting effects. rule out other causes of symptoms or co-morbid most concerned about reported cases of sudden ER Guanfacine conditions, such as deafness or cognitive delay. cardiac death in previously healthy children who had Extended release guanfacine is a non-stimulant Guidelines suggest that health care providers been prescribed stimulants to treat ADHD. Providers adrenergic agonist.82 It is used to treat hypertension, should take an interdisciplinary approach to must make sure to ask the child and parents about any anxiety, and ADHD. Side-effects include somnolence treating ADHD. Educational interventions, behavioral specific cardiac symptoms or history of cardiovascular and dry mouth. approaches, and medication all may have roles in disease in the child. Furthermore, providers must managing this disorder. For children ages 4-5 years, obtain a thorough family history and ask about any ER Clonidine the health care provider should prescribe behavior cases of sudden death in the family, hypertrophic Like guanfacine, clonidine is an alpha-agonist that can therapy to be administered by the parent and/or cardiomyopathy, Wolf-Parkinson-White syndrome, be used to treat mild to moderate hypertension, as teacher as first-line intervention. If the child continues or long QT syndrome. Health care providers should well as ADHD.68 Side-effects include mild sedation and to have moderate or severe functional disturbance avoid prescribing stimulants if they are concerned dry mouth, but the patient may experience rebound or there is no improvement in behavior, the provider about increased risk of side-effects or potential for hypertension if clonidine is abruptly withdrawn. Alpha- 86 may prescribe methylphenidate. For older children, substance misuse or diversion. 2-adrenergic agonists usually are used when children ages 6-11 years, the health care provider should When prescribing stimulants, it is not only respond poorly to a trial of stimulants or atomoxetine, prescribe teacher and/or parent administered important to establish an accurate diagnosis of have unacceptable side effects, or have significant behavioral intervention, FDA approved medication, ADHD, but also to monitor symptoms and for evidence coexisting conditions or both. Evidence is strongest for prescribing of misuse.83 Stimulant diversion and misuse can stimulants, followed by, in descending order of efficacy be minimized, to some extent, by prescribing long- Obesity for adolescents, atomoxetine, extended release acting stimulants with less potential for abuse, and by Obesity is a complex chronic disease that is guanfacine, and extended release clonidine. The keeping track of prescription dates.87,88 Having open becoming increasingly common internationally and values and preferences of the patient and family are discussions with parents and patients about the risk of in the United States. The World Health Organization critical factors in deciding whether or not to initiate misuse and diversion is helpful, such that patients can (WHO) reports that more than 1.9 billion people medication.83 be prepared if they are asked to sell their medications worldwide are obese or overweight, and the worldwide Behavioral interventions are preferred to and so that parents are aware of the risks.87 prevalence of obesity doubled between 1980 and medication as the initial intervention for preschool The nonmedical use of prescription stimulants 2014.90 In the United States, approximately 34.9% of children with ADHD and are adjuncts to medication for represents the second most-common form of illicit adults, or 78.6 million people, have obesity.91 People school-aged children and adolescents.83 drug use in college, second only to marijuana use.89 who suffer from obesity have significant increases in The choice of the initial medication depends upon a A 2008 study showed that lifetime rates of diversion morbidity and mortality.90 number of factors, including:83,84 ranged from 16% to 29% of students with stimulant Weight loss can significantly improve obesity- • The duration of desired coverage (completion prescriptions who were asked to give, sell, or trade associated morbidity and mortality. Patients with of homework or driving may require coverage their medications.88 Risk factors for diversion in obesity or overweight are at risk for type 2 diabetes, into the evening) this study included white race, being a members of weight loss of 2.5-5 kg over at least two years can • The ability of the child to swallow pills or a fraternity or sorority, individuals with lower grade decrease the risk of obesity-associated type 2 capsules 92 point averages, use of immediate-release compared diabetes by 30-60%. Similarly, in overweight or • The time of day when the target symptoms occur to extended-release preparations. Reported reasons obese adults with or without cardiovascular risk • The desire to avoid administration at school factors, lipid levels improve in a dose-response • Coexisting tic disorder for use, misuse, and diversion of stimulants include • Coexisting emotional or behavioral condition to concentrate, improve alertness, “get high,” or to manner with weight loss. • Potential adverse effects experiment.88 In order to effectively treat obesity, health • History of substance use disorders in patient Evaluation for substance use disorders and binge care providers should understand the appropriate or household member: avoid stimulants or use drinking should also be undertaken when prescribing behavioral and dietary changes patients must make stimulants with less potential for abuse (slow- stimulants for ADHD. Although there is a higher risk in order to lose weight and maintain weight loss. release, long acting) of misuse and diversion of stimulants in those with a They should also understand when it is appropriate • Preference of the child/adolescent and his/her history of substance use disorders, it should be noted to recommend medical management or surgical parent/guardian that a critical risk factor for having ongoing substance intervention, and the risks and benefits of those • Expense (in general, short acting stimulants are use disorders in adulthood is the persistence of interventions. least expensive) ADHD symptoms and adequate treatment of ADHD in Obesity can be very challenging to treat, in part Methylphenidate and amphetamine childhood is associated with a lower risk of subsequent because of physiological mechanisms that cause the In one study evaluating the role of drug and alcohol use disorders.88 human body to resist weight loss. Providers must learn the necessary skills for how to motivate patients psychostimulants (such as methylphenidate, Atomoxetine while also respecting their autonomy. Effective dexamphetamine, and modafinil) in managing co- Atomoxitine is generally less effective than management often involves interdisciplinary teamwork morbid ADHD and non-ADHD disorders, these stimulants for ADHD symptoms.82 It is a non-stimulant with nutritionists and other trained consultants. medications improved concentration, mood, and norepinephrine reuptake inhibitor that can be used 85 cognitive function while decreasing fatigue. Side- as second-line medical management of ADHD. Side- 18 Treatment for obesity includes dietary restriction, trials show clinically meaningful weight loss ranging Phentermine/topiramate was approved by the Food comprehensive lifestyle intervention, medical from 37–47% for lorcaserin, 35–73% for orlistat, and Drug Administration (FDA) in 2012. It is well- management, and surgical intervention. Here we and 67–70% for maximally dosed phentermine/ tolerated with dose-dependent adverse events. focus just on medical management with controlled topiramate-ER.93 Phentermine, an anorexic agent Safety concerns include tachycardia, teratogenicity, substances. used to treat obesity, is classified as a schedule III metabolic acidosis, psychiatric disorders, and In 2011, 2.74 million patients were having controlled substance. cognitive adverse events.3 It should not be used in their morbid obesity treated pharmacologically.93 patients with cardiovascular disease (hypertension Phentermine Pharmaceutical interventions for weight reduction or coronary heart disease) or in pregnant women Phentermine is an anorexic agent. It reduces food may suppress appetite, reduce absorption, or because of an increased risk of orofacial clefts in intake by causing early satiety. It is an amphetamine- increase energy expenditure.94 Medications currently infants exposed to the combination drug during the like drug that interferes with norepinephrine release. approved for pharmacological weight management first trimester of pregnancy. A similar drug, sibutramine was withdrawn from include short-term use of phentermine, orlistat, the market in 2010 because of its association with PLEASE SPEND THE ALLOTTED TIME ON phentermine/topiramate, lorcaserin, naltrexone/ increased risk of cardiovascular events and stroke. EXERCISE 4. bupropion, and liraglutide.95 Placebo-controlled Case Study Exercise 4 Instructions: Spend 10-15 minutes reviewing the continuation case study below and considering the questions and commentary that follow. Jenny returns for a follow-up visit after completing a cardiovascular evaluation, which you ordered because of her heart-flutter symptoms and previous use of fen-phen. Even though her evaluation was negative for abnormalities, she has thought about the risks of phentermine and decided that she would like to consider alternative interventions for managing her obesity. In particular, she is concerned that her history of fen-phen use and a family history of heart disease might lead to cardiac problems in the future. You agree to not refill her prescription for phentermine. Question 1: Describe alternative options Jenny may have for weight loss. (Options may include pharmaceutical and non-pharmaceutical alternatives.)

Commentary on Question 1: The patient’s non-pharmaceutical weight loss options include dietary changes, exercise, behavioral therapy, and surgical interventions. Dietary interventions for morbidly obese women may entail caloric reduction producing at least a 500 kcal/day deficit, resulting in a goal of 1,200-1,500 kcal consumed per day. Exercise goals include at least 150 minutes of aerobic activity per week, and behavioral therapy is meant to encourage adherence to dietary changes and physical activity.89 The patient should discuss whether or not she is a good candidate for surgical intervention with her bariatric surgeon in order to decide if any surgical interventions may help her with weight loss. You refer Jenny to a comprehensive lifestyle intervention program at a local academic center. There, the patient begins taking orlistat, goes on an American Heart Association-approved diet, and starts walking and jogging for 30 minutes 6 times a week. She is carefully monitored by the medical team at her comprehensive lifestyle intervention program. Two months later, Jenny returns to your clinic. She has lost 10 lbs, and she is determined to continue on her program. However, she has been having difficulty sleeping for the past month, and was wondering if you could prescribe a medication she saw advertised on television to help her sleep. Question 2: You note that the sleep agent the patient would like you to prescribe is a schedule IV controlled substance. How would you proceed with your insomnia evaluation?

Commentary on Question 2: First, obtain a thorough history, including a sleep history, and review the patient’s medical and psychiatric co-morbid conditions. The provider should ask the patient about prescribed medications, caffeine intake, alcohol intake, and herbal supplements. If anyone else knows about the patient’s sleep habits, ask that person if he or she has noticed any unusual patient sleep patterns, including snoring, sleep apnea, sleepwalking, or unusual limb movements. Next, perform a physical examination including a neurological assessment to identify any co-morbidities. Consider administering an Epworth Sleepiness Scale or the STOP-Bang test to assess for sleep apnea during the clinic visit. Finally, request that the patient keep a sleep log for 2 weeks to identify patterns of sleep disruption. She should follow up in 3 weeks with the results. In the meantime, review and encourage behavioral interventions to improve sleep, include exercise, relaxation therapy, and good sleep habits.65 Jenny returns to see you for a follow-up visit. She is excited to be losing weight and feeling healthier than she has ever felt in her adult life. However, she has recently been considering bariatric surgery and would like to discuss her options with you. After reviewing the risks and benefits of surgical intervention with her, you both agree to wait to see if she makes significant weight-loss progress through her current program. If she changes her mind, you plan to refer her to a bariatric surgeon affiliated with the local academic center. The patient also brings the results of her sleep journal and reports that her insomnia is getting worse, despite her adherence to sleep inducing behaviors and diligent use of melatonin. She is frustrated and exhausted. Question 3: You decide to prescribe a schedule IV controlled substance for a short time to treat the patient’s insomnia. What 6 additional steps must you take to ensure you are following best practices for prescribing a controlled substance?

Commentary on Question 3: Here are the recommended steps for ensuring best practices for prescribing a controlled substance: 1. Document a thorough history and complete physical examination. 2. Discuss the side-effects and addictive potential of the controlled substance with the patient. 3. Check the prescription drug monitoring database to corroborate the patient’s controlled substance history. 4. Document that you have discussed any history of substance use, concerns from the patient’s family members, and details about the patient’s treatment plan in the chart. Advise the patient to not use concomitant alcohol. 5. Establish guidelines and describe the duration of treatment. 6. Carefully monitor the patient for any evidence of misuse during treatment.

19 Pain Control Because the focus of this monograph is on controlled Caution is also required because a significant Pain remains the most common reason people substances, the rest of this section will review issues portion of patients can be expected not to use an seek health care.96 In fact, the incidence of chronic related specifically to the use of opioids for analgesia. opioid medication as prescribed. Fleming et al., pain in the U.S. is estimated to be greater than that conducted in-depth interviews with 801 patients Prescribe with caution of diabetes, heart disease, and cancer combined.97,98 prescribed long-term opioid therapy from a primary The utility of opioid analgesics for treating chronic 105 Inadequately treating pain can lead to a wide range care provider and found the following: non-cancer pain is being increasingly questioned and • 39% of patients increased their dose without of adverse consequences (in addition to causing a broad consensus is developing that these agents direction from a health care provider needless suffering) including diminished quality of are not, in fact, suited for many patients with this • 26% engaged in purposeful over-sedation life, and a higher risk for anxiety or depression.99 type of pain. Clinical guidelines for the use of opioids • 20% drank alcohol concurrent with opioid use Pain is also a major cause of work absenteeism, in chronic non-cancer pain have shifted in recent • 18% used opioids for purposes other than pain underemployment, and unemployment.96 years to focus on non-medication treatments. They relief Pain must be treated, but many types of pain • 12% hoarded their pain medications have stressed the risks of opioids and strengthened treatments exist. Opioid analgesics may—or may • 8% obtained extra opioids from other doctors procedures that prescribers should use to reduce the not—be the right choice, particularly for those The risk of overdose with opioid analgesics is risk of addiction and misuse.100,18,101 suffering from chronic non-cancer pain. Opioids significant and, as with risk of abuse/dependence, Little evidence supports the assertion that long- 110 do not address all of the physical and psychosocial rises with both dose and duration. term use of opioids provides clinically significant pain dimensions of chronic pain, and they pose a In addition to the risks for misuse, addiction, relief or improves quality of life or functioning for most wide range of potential adverse effects, including and overdose, opioids can exert a wide range chronic non-cancer related pain.102 The Agency for challenging side effects and the risk of abuse, of uncomfortable or harmful adverse effects, Healthcare Research and Quality (AHRQ), for example, the most common of which are neurologic addiction, and death. recently found no studies that compare opioid therapy (somnolence, dizziness), endocrine (hypogonadism), Many pharmacologic and non-pharmacologic with either a placebo or a non-opioid treatment gastrointestinal (nausea, vomiting, and constipation), approaches to treating painful conditions are available for long-term (>1 year) pain management.103 A sexual (erectile dysfunction), and cutaneous to primary care physicians. These options should be Cochrane review of opioids for long-term treatment of (pruritus). In randomized trials of opioids, 50%-80% employed by using the following general principles: non-cancer pain found that many patients discontinue of patients report an adverse side effect, and about • Identify and treat the source of the pain, if 25% withdraw due to an adverse event.102,111,112 long-term opioid therapy (especially oral opioids) due possible, although treatment can begin before Although less common, there is also a dose- to adverse events or insufficient pain relief.102 the source of the pain is determined dependent increase in risk of fractures in opioid • Select the simplest approach to pain A large—and growing—body of evidence, on users compared to non-users, with risk highest in the management. This generally means using non- the other hand, demonstrates that opioids pose many period following initiation, particularly for short-acting pharmacologic approaches as much as possible significant risks for adverse effects, abuse, addiction, opioids.113,114 and/or trying medications with the least severe and accidental overdose leading to death from An area of potential concern is the possibility potential side effects first, and at the lowest respiratory depression. that chronic opioid use may have immunosuppressive effective doses Estimating the risk that patients face of becoming effects. Evidence from cell cultures and animal models • Establish a function-based management plan if addicted to opioid analgesics is difficult because is suggestive, and this is an area requiring further treatment is expected to be long-term rigorous, long-term studies of these risks in patients investigation.70 Dublin et al., in a population-based In treating pain, clinicians can avail themselves of five without co-existing substance-use disorders have case-control study, found a significantly higher risk 5 basic modalities of pain-management: not been conducted. A few surveys conducted in of pneumonia in immunocompetent older adults who 1. Cognitive-behavioral approaches community practice settings, however, estimate were prescribed opioids.115 The risk was particularly 2. Rehabilitative approaches rates of prescription opioid abuse of between 4% to high for adults taking long-acting opioids.115 3. Complementary and alternative therapies 26%.104,105,106,107 Risk rises with higher opioid doses 4. Interventional approaches and longer durations of opioid use.108 Initiating Treatment With Opioids 5. Pharmacotherapy A 2011 study of a random sample of 705 Prior to an initial prescription of an opioid pain These options can be used alone or in patients prescribed long-term opioid therapy for medication, clinicians should be certain that (1) all combinations to maximize pain control and functional non-cancer pain found a lifetime prevalence rate of other potentially effective treatments that offer a more gains. Only one of these options involves medications, DSM-5-defined opioid use disorder of 35%.109 The optimal benefit-to-risk profile have been considered and opioids are only one of many types of medications variability in such results probably reflects differences or tried; (2) a complete evaluation has been with potential analgesic utility. Which options are used in opioid treatment duration, the short-term nature performed and fully documented; (3) the patient’s in a given patient depends on the type of pain, the of most studies, and disparate study populations level of opioid tolerance has been determined; and duration and severity of pain, patient preferences, and measures used to assess abuse or addiction. (4) informed consent and agreement to treat have 18 co-occurring disease states or illnesses, patient life Nonetheless, the levels of risk suggested by these been obtained. A patient having been prescribed expectancy, cost, and the local availability of the studies are significant enough to warrant extreme opioids by a previous provider is not, in and of treatment option. caution in the prescription of any opioid for a chronic itself, a reason to continue opioids, and no provider pain condition. is obligated to continue opioid therapy that was started by another provider. In addition, the use of

Calculating Morphine Milligram Equivalents (MMEs) Calculating a patient’s total daily dose of opioids is important to appropriately and effectively prescribe, manage, and taper opioid medications. This can be done with printed or online equianalgesic charts, which provide conversion factors and dose equivalents of all available opioid medications relative to a standard dose of morphine. Care must be taken in using such charts because dose is not the only relevant variable. Clinicians must also consider the route of administration, cross tolerance, half-life, and the bioavailability of a drug. In addition, the patient’s existing level of opioid tolerance must be taken into account. Printed equianalgesic charts are common, and online calculators are also freely available (a common one can be accessed at clincalc.com/Opioids). The CDC provides a helpful guide to opioid conversions available at: www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf 20 an opioid, if necessary, should be just one component Tapering protocols use of opioids and benzodiazepines, high risk patient of a treatment plan that includes other modalities of Clinicians prescribing opioid therapy should behaviors, and the presence of psychiatric, medical, pain management, such as physical therapy, exercise, continually reassess the risks and benefits of or substance use disorder comorbidities. the use of heat or cold, or any of a range of other treatment, and when risks are determined to outweigh Monitoring for Overdose Potential and Suicidality techniques that can facilitate improved function and a benefits or when patients voice a preference for Substance use disorders are a prevalent and decreased reliance on opioids. reducing their risk, opioid therapy should be tapered At the outset, both the clinician and the patient strong risk factor for suicide attempts and suicide. to a reduced dose or tapered to discontinuation. A should view a new opioid prescription as a short-term Individuals at acute risk for suicidal behavior who biopsychosocial assessment including evaluation trial of therapy. The goal of the trial is to provide data appear to be under the influence of alcohol or of co-occurring medical and psychiatric conditions, to guide decisions on the continued appropriateness other drugs, either based on clinical presentation opioid use disorder, as well as the patient’s social of opioid medications and on the specific dose and or objective data (e.g., breath or laboratory tests), support system, will guide the opioid tapering formulation of medication used. Such a trial might be should be maintained in a secure setting like a hospital as brief as a few days or as long as several months. process. Determination of the rate of opioid tapering or crisis unit until intoxication has resolved. Risk Opioid selection, initial dosing, and titration takes into account many factors that include initial assessment needs to be repeated once the patient must be individualized to the patient’s health dose, formulations available, and risk factors that is sober in order to determine appropriate next steps. status, previous exposure to opioids, and treatment increase potential for harm. Risk management options include, but are not limited plan. A decision to continue opioid therapy after an A gradual taper pace of reducing opioid dosage to, admitting the patient for inpatient hospital and appropriate trial should be based on careful review by 5-20% every two to four weeks with the option psychiatric care, making a referral for detoxification, of the trial outcomes. Outcomes to consider include: to pause periodically allows time for neurobiological or scheduling outpatient follow-up in the near future • Progress toward meeting therapeutic goals equilibration as well as the acquisition of new skills • Changes in functional status when suicidal risk is reduced. to manage pain and emotional distress. In some • Presence and nature of opioid-related adverse Intentional overdose is the most common method patients, a faster taper may be needed when risks effects of attempted suicide. Therefore, the possibility that an are too high to consider a gradual taper; consider • Changes in the underlying pain condition overdose event was an intentional act of self-directed tapering the dose by 5-20% per day or every week in • Changes in medical or psychiatric comorbidities violence should always be considered. Obtaining • Degree of opioid tolerance in the patient this patient population. Regardless of the initial speed additional information from family members, treatment • Identification of altered or aberrant behaviors, of taper, the pace of taper should be reevaluated providers, medical records, etc., can be invaluable in misuse, or diversion frequently and adjusted as needed to maximize safety making the determination between intentional and and patient comfort as safety allows. When there is Dose Titration unintentional overdose in equivocal cases. evidence of diversion or active severe opioid use Patients who are opioid-naïve or have modest The same factors that confer risk for suicidal disorder, opioids should be discontinued immediately previous opioid exposure should be started at the behavior in non-substance abusers generally also and patient should be referred for treatment of opioid lowest dose possible of a short-acting opioid and confer risk among individuals with substance use titrated slowly upward to decrease the risk of opioid- use disorder. disorders. For example, depression is a potent risk related adverse effects.18 If it is unclear whether Follow-up should occur within a range of one week factor in both substance abusers and non-substance a patient has recently been using opioids (either to one month after any opioid dosage change with the abusers. The presence of comorbidities (e.g., prescribed or non-prescribed), the clinician should frequency and type of follow-up adjusted as needed substance use disorder plus mood disorder) is the assume that the patient is opioid-naïve (i.e., not throughout the course of the taper. Each follow-up rule rather than the exception in high-risk clinical tolerant) and proceed as just described. interaction with the patient is an opportunity to populations. Opioid tolerance should always be established provide education about self-management strategies With effective treatment, illnesses and before prescribing an ER/LA opioid. The selection of and the risks associated with opioid therapy while a starting dose and manner of titration are clinical perpetuating factors can be alleviated, protective optimizing whole person approaches to pain care and decisions that must be made on a case-by-case factors and coping strategies can be fortified, and treatment of co-occurring medical and mental health basis because of the many variables involved. Some the patient’s suicidality can resolve to a state of conditions. The care team should take great efforts patients, such as frail older persons or those with clinical recovery, where the acute risk has resolved to ensure that the patient does not feel abandoned comorbidities, may require an even more cautious and the risk of relapse has been minimized. Ongoing during the opioid tapering process by maintaining therapy initiation. Short-acting opioids are usually care may be warranted to provide early detection of safer for initial therapy since they have a shorter frequent contact and emphasizing that the care team recurrence. half-life and may be associated with a lower risk of will continue to pursue non-opioid pain care options overdose from drug accumulation. during and after opioid tapering. Naloxone for overdose Further studies are needed to confirm more The risks and benefits of continuing opioid Naloxone (trade name Narcan) is a high-affinity consistent control of pain and improved adherence therapy should be evaluated along with the risks and opioid antagonist used to reverse the effects of to prescribed therapy with use of ER/LA opioids. benefits of tapering opioid therapy. It is important to opioids. It can be administered via intramuscular, Although low-dose, short-acting opioids may offer the maintain vigilance for symptoms of opioid use disorder intravenous, or intranasal routes, with virtually greatest safety for initiating opioid therapy, clinicians and/or exacerbation of an underlying mental health must recognize that short-acting opioids are not no side effects and no effect in the absence of condition that may manifest during an opioid taper. intrinsically safer than other formulations, and stress opioids. Counties and states that have implemented to their patients the importance of strict adherence to Clinicians should consider using an interdisciplinary, naloxone-based overdose prevention programs prescribed doses/administration. team-based approach that may include primary care, have significantly reduced the incidence of opioid mental health, pain specialty/rehabilitation, pharmacy, overdose and opioid overdose-related mortality.116,117 PLEASE SPEND THE ALLOTTED TIME ON and/or physical therapy during the opioid tapering The effects of naloxone typically last between 30 and EXERCISE 5 (PAGE 22). process, and in particular for patients with significant 90 minutes, which means the naloxone may wear off risk factors for adverse outcomes including very high before the effects of the opioid wear off, putting the prescribed opioid doses (> 90 mg MEDD), combined person at risk of overdose again.118

21 Case Study Exercise 5

Instructions: spend 15-20 minutes reading the following case study, then answer the questions that follow. Mike is a 30-year-old man who has come to your clinic seeking an opioid analgesic for back pain. You explain to Mike that your clinic has a policy of not prescribing controlled substances on the first visit, but that you would like to evaluate him. He initially seems annoyed and stands up to leave, but then he sits down and begins to answer your questions. He denies any past medical problems or surgical history. He did visit the ER once a few years ago for suicidal ideations, but says “I would never do that to my family” and he denies active suicidal ideation. He denies depressive symptoms. He has medication allergies to fentanyl and tramadol. When asked, he says they give him nausea but not anaphylaxis. He was given these medications in the hospital when he broke his arm a few years ago. He reports that his back pain began when he fell off a roof two years ago. It has always been located on the right side of his back, and it is associated with electric type pain that shoots down his right leg. His back pain feels like muscle strain and the only treatment he had tried in the past was oxycodone. He is not sure if anything else might improve the pain, but he is hesitant to try physical therapy because of the pain. He reports that he is unable to walk to the grocery store or go to his construction job when his back pain is severe. He walks to the grocery store because his driver’s license was suspended after he was arrested for driving under the influence last year. He tells you that he continues to drink, but “not nearly as much.” On physical examination, the patient is alert and oriented. He is not intoxicated or altered. His vital signs are all stable, heart rate is regular, lungs are clear to auscultation bilaterally, and his abdomen is soft and non-tender. His back is tender over the right side, but it is consistent with muscle pain. He has normal patellar reflexes and flexion. He has full range of motion and no neurological deficits. He does not have any tattoos, bruises, or track marks.

Now consider the following questions: Question 1: Do you think this patient is a candidate for opioid analgesics?

Question 2: What other questions might you ask?

Now continue reading about this case study.

Based on what Mike has told you, you are concerned that he is at increased risk for opioid misuse, opioid overdose or addiction due to his young age, past significant alcohol use, current ongoing use of alcohol, and history of mental illness. You request a urine toxicology screen from the patient. He agrees and you excuse yourself from the room. When you check your state’s electronic prescription database, you see that he has had only one previous prescription for an opioid. The PDMP shows that this prescription was related to an ER visit for “trauma due to fall,” consistent with the patient’s history. The urine drug screen you request is negative for all substances. When you return to speak to the patient, you tell him that you would like to treat his back pain like a chronic condition, starting with a non-opioid treatment plan, as this is first line treatment. For the next six weeks, you would like to start NSAIDs and a home exercise program.

Consider the following questions:

Question 3: What other non-pharmacologic treatment options might you consider for Mike?

Question 4: What kind of functional goals can you set up for Mike that will be both motivating and helpful in guiding further treatment options?

Now continue reading about this case study.

After 12 weeks, Mike has adequately trialed a home exercise program, a formal physical therapy program, and non-opioid medications. He is resistant to trying psychological interventions, acupuncture, and chiropractic manipulations, but has had a few massages. Overall, he is feeling stronger, but his pain still interferes with his ability to work 3-4 days per month. He states that his mood is great and he denies any alcohol use since his initial consultation. His wife is in attendance and agrees that he has not had any alcohol. You decide, based on the fact that he has not improved with adequate trials of non-medication and non-opioid interventions to start a low dose opioid, intermittently for his chronic back pain. You give him #30 hydrocodone-acetaminophen, to take daily as needed, not more than one per day. You sign a treatment agreement with him and ask him to return in 30 days, at which time, you will re-evaluate the need for opioids. For 3 months he is very compliant. He continues a home exercise program and he is able to work. On the fourth month though, he calls 14 days into his prescription and asks for a refill, stating that he had to take more because his back pain worsened after lifting something heavy at work.

Consider the following questions:

Question 5: Does Mike’s request for an early refill constitute a violation of his agreement?

Question 6: Does Mike’s request suggest that treatment should be terminated, or that the situation requires further evaluation?

Question 7: Would referral to a pain medicine specialist be indicated at this point?

22 The American Medical Association has endorsed • Opioids should be reserved for more severe pain accuracy rate in estimating presence or absence of the distribution of naloxone to anyone at risk for or pain that doesn’t respond to other analgesics the patient’s pain.129 having or witnessing an opioid overdose,119 and, as of • If opioids are indicated, the prescription should Opioids are critical to providing effective analgesia 2014, 25 states have amended or enacted laws that be for the lowest effective dose and for a limited at the end of life, and they are available in such a make it easier for health care providers to prescribe duration (e.g., < 1 week). range of strengths, routes of administration, and and dispense naloxone for use by patients and/or duration of action that an effective pain regimen can Cancer pain caregivers.120 be tailored to nearly each patient. No specific opioid Pain is one of the most common—and most When discussing naloxone with patients consider is superior to another as first-line therapy. Rectal and feared--symptoms of cancer. Pain is experienced by avoiding the single word “overdose,” which has transdermal routes of administration can be valuable about 30% of patients newly-diagnosed with cancer, negative connotations and may be off-putting.121 at the end of life when the oral route is precluded 30% - 50% of patients undergoing treatment, and Instead, use language such as “accidental overdose,” because of reduced or absent consciousness, difficulty 70% -90% of patients with advanced disease.98 “bad reaction,” or “opioid safety.” For example, one swallowing, or to reduce the chances of nausea and Unrelieved pain adversely impacts motivation, mood, might say, “Naloxone is an antidote for opioids that vomiting.130 When selecting an opioid, clinicians should interactions with family and friends, and overall quality can be sprayed in the nose or injected if there is a bad also consider cost, since expensive agents can place of life. Survival itself may be positively associated with reaction and a person cannot be woken up.” undue burden on patients and families. adequate pain control.125 Opioid pain medications are More information and many helpful resources Fear of inducing severe or even fatal respiratory the mainstay of cancer pain management and a trial about prescribing and using naloxone, including depression may lead to clinician under-prescribing of opioid therapy should be administered to all cancer patient education materials, are available from: and reluctance by patients to take an opioid patients with moderate or severe pain, regardless of prescribetoprevent.org. medication.28 Despite this fear, studies have revealed the known or suspected pain mechanism.126 no correlation between opioid dose, timing of Treating pain in special populations ER/LA opioid formulations may optimize analgesia opioid administration, and time of death in patients and lessen the inconvenience associated with the Opioids and pregnancy using opioids in the context of terminal illness.131 A use of short-acting opioids. Patient-controlled Current guidelines suggest that clinicians should consult with a specialist in palliative medicine in these analgesia with subcutaneous administration using avoid prescribing opioids during pregnancy unless situations may be advisable. an ambulatory infusion device may provide optimal the potential benefits outweigh risks.122 Some data patient control and effective analgesia.127 The full Older Adults suggest an association between the use of long- range of adjuvant medications covered earlier should The prevalence of pain among community- term opioid therapy during pregnancy and adverse be considered for patients with cancer pain, with dwelling older adults has been estimated between outcomes in newborns, including low birth weight and the caveat that such patients are often on already 25% and 50%.132 The prevalence of pain in nursing premature birth, though co-related maternal factors complicated pharmacological regimens, which homes is even higher. Unfortunately, managing pain in may play a role in these associations and causality is raises the risk of adverse reactions associated with older adults is challenging due to: underreporting of not certain.122 Exposure to these medications has also polypharmacy. If cancer pain occurs in the context symptoms; presence of multiple medical conditions; been associated with birth defects in some studies. of a patient nearing the end of life, other treatment polypharmacy; declines in liver and kidney function; Opioid withdrawal can be expected in up to half of and care considerations may be appropriate. In these problems with communication, mobility, and safety; newborns of opioid-dependent mothers (neonatal cases, patient integrated with a specialist in palliative and cognitive and functional decline in general. abstinence syndrome).122 If a mother is receiving long- care medicine may be advisable. Acetaminophen is considered the drug of choice term opioid therapy at or near the time of delivery, for mild-to-moderate pain in older adults because it a professional experienced in the management of Pain at the end of life lacks the gastrointestinal, bleeding, renal toxicities, neonatal withdrawal should be available if neonatal Pain management at the end of life seeks to and cognitive side-effects that have been observed abstinence syndrome occurs. improve or maintain a patient’s overall quality of life. with NSAIDs in older adults (although acetaminophen This focus is important because sometimes a patient may pose a risk of liver damage). Opioids must be Emergency room patients may have priorities that compete with, or supersede, used with particular caution, and clinicians should Pain is a frequent complaint of emergency the relief of pain. For some patients mental alertness “Start low, go slow” with initial doses and subsequent room (ER) patients, and ER providers are among sufficient to allow lucid interactions with loved ones titration. Clinicians should consult the American the highest prescribers of opioids to patients ages may be more important than physical comfort. 123 Geriatrics Society Updated Beers Criteria for Potentially 10-40. ER providers, however, face considerable Optimal pain management, in such cases, may mean Inappropriate Medication Use in Older Adults for challenges in determining a patient’s appropriateness lower doses of an analgesic and the experience, by further information on the many medications that may for opioid therapy. A medical history is often lacking, the patient, of higher levels of pain. not be recommended.31 and the provider seldom knows the patient personally. Since dying patients may be unconscious or only Time constraints, as well, can preclude the kinds of partially conscious, assessing their level of pain can be Treating Substance Use Disorders, including Opioid Use careful assessment and evaluation recommended difficult. Nonverbal signs or cues must sometimes be Disorder for responsible opioid prescribing. Because of used to determine if the patient is experiencing pain this, current guidelines from the American College and to what degree an analgesic approach is effective. “Unfortunately, far too few people who suffer of Emergency Physicians include the following In general, even ambiguous signs of discomfort from opioid use disorder are offered an adequate 124 recommendations: should usually be treated, although caution must be chance for treatment that uses safe and effective • ER/LA opioid medications should not be exercised in interpreting such signs.128 Reports by medications,” FDA Commissioner Scott Gottlieb, 133 prescribed for acute pain family members or other people close to a patient M.D. • PDMPs should be used where available to help should not be overlooked. In the Study to Understand Although primary care clinicians have not identify patients at high risk for opioid abuse or Prognosis and Preference for Outcomes and Risks historically been directly involved in treating substance diversion of Treatment (SUPPORT) , surrogates for patients abuse disorders, they play a critical role in recognizing who could not communicate verbally had a 73.5% early signs of these disorders, referring patients

23 to needed services, and supporting patients in the These professionals provide a variety of therapies. in combination with counseling and behavioral typically lengthy process of recovery from substance Some common therapies include: therapies. Medications can reduce the cravings and use or abuse. There are now many ways that they can • Cognitive-behavioral therapy (CBT), which other symptoms associated with withdrawal from assist with the treatment of opioid use disorder if they teaches individuals to recognize and stop a substance by occupying receptors in the brain obtain a physician waiver to prescribe buprenorphine. negative patterns of thinking and behavior. For associated with using that drug (agonists or partial instance, CBT might help a person be aware of Substance use disorders are chronic brain the stressors, situations, and feelings that lead agonists), block the rewarding sensation that comes diseases that impair one’s ability to control substance to substance use so that the person can avoid with using a substance (antagonists), or induce use. Repeated use of any controlled substance over them or act differently when they occur. negative feelings when a substance is taken. MAT time can lead to a use disorder, and long-term is by • Contingency management provides incentives to has been primarily used for the treatment of tobacco, far the most powerful risk factor for developing this reinforce positive behaviors, such as remaining alcohol, and opioid use disorders. (See Table 4 for disorder. All persons using controlled substances are abstinent from substance use. a summary of medications used to treat alcohol and at risk for developing a use disorder, even those who • Motivational enhancement therapy helps people opioid use disorders [no medications are approved with substance use disorders to build motivation take the substances as prescribed. An early sign of a and commit to specific plans to engage in as of this writing to treat marijuana use disorders, developing use disorder is gradually becoming more treatment and seek recovery. It is often used stimulant use disorders, or other substance use preoccupied with substance use and spending more early in the process to engage people in disorders].)135 time seeking the drug, using it, or recovering from its treatment. Focus on opioid use disorder effects. Persons with substance use disorder typically • 12-step facilitation therapy seeks to guide and Opioid use disorder (OUD) is associated with continue to use the drug even though they: support engagement in 12-step programs premature death from opioid overdose and other • Know the drug use is harmful such as Alcoholics Anonymous or Narcotics • Often use more than they intended Anonymous. medical complications such as AIDS, hepatitis C, and • Engage in risky behaviors such as driving while Some forms of counseling are tailored to specific sepsis. On average, OUD carries a 40-60% 20-year intoxicated or combining alcohol with other populations. For instance, young people often need mortality rate.136 Persons with OUD are at high-risk drugs a different set of treatment services to guide them for premature death, not only from opioid overdose, • Have multiple unsuccessful attempts to cut down towards recovery. Treatments for youth often involve but from other consequences. Thus, providing first- or control substance use a family component. Two models for youth that are line treatment is important to save lives as well as to • Have strong craving or urges to use one or often used in combination and have been supported improve quality of life. more substances in response to withdrawal by grants from the Substance Abuse and Mental Strong evidence supports the use of medication- symptoms, stress, negative emotions, or cues Health Services Administration are the Adolescent assisted therapy (MAT) (e.g., methadone, that the drug is available Community Reinforcement Approach (ACRA) and buprenorphine/naloxone, naltrexone) as first-line The treatment system for substance use disorders is Assertive Continuing Care (ACC).134 ACRA uses defined treatment for moderate-to-severe OUD.137 Patients comprised of multiple service components, which may procedures to build skills and support engagement and their treating clinicians may be concerned be available to various degrees in different regions. in positive activities. ACC provides intensive follow up that treatments proven effective in different OUD They include the following: and home based services to prevent relapse and is populations may not be effective for patients with • Individual and group counseling in an outpatient delivered by a team of professionals. chronic pain, or may not be necessary for patients setting Treatment provided through inpatient who have become addicted to prescription opioid • Inpatient rehabilitation rehabilitation happens within specialty substance use analgesics. This concern may be unfounded and was • Residential treatment disorder treatment facilities with a broader behavioral addressed by Weiss and colleagues in the Prescription • Intensive outpatient treatment health focus, or by specialized units within hospitals. Opioid Abuse Treatment Study.138 • Partial hospital programs Longer-term residential treatment has lengths of In studies with patients who meet DSM • Case or care management stay that can be as long as six to twelve months and 5 diagnostic criteria for opioid use disorder, • Medication treatment is relatively uncommon. These programs focus on buprenorphine maintenance therapy is more effective • Recovery support services helping individuals change their behaviors in a highly than a four-week taper with buprenorphine. MAT • 12-Step fellowship structured setting. Shorter term residential treatment with moderate dose buprenorphine/naloxone and • Peer supports is much more common, and typically has a focus on brief, structured counseling by the prescribing A person accessing treatment may not need to detoxification (also known as medically managed physician can be successful for about half of selected access every one of these components, but each can withdrawal) as well as providing initial intensive patients with prescription OUD, whereas withdrawal play an important role. These systems are embedded treatment, and preparation for a return to community- management alone, even with close weekly follow-up in a broader community and the support provided based and outpatient addiction treatment settings. and counseling, is successful for less than 10% of by various parts of that community also play an An alternative to inpatient or residential treatment patients. important role in supporting the recovery of people is partial hospitalization or intensive outpatient Furthermore, the presence of chronic pain does with substance use disorders. treatment. These programs have people attend very not seem to interfere with the success of MAT.138,139 Counseling can be provided at the individual or intensive and regular treatment sessions multiple Given the high mortality associated with OUD and the group level. Individual counseling often focuses on times a week early in their treatment for an initial safety and efficacy of MAT for OUD in multiple clinical reducing or stopping substance use, skill building, period. After completing partial hospitalization or trials and meta-analyses, MAT is recommended for adherence to a recovery plan, and social, family, and intensive outpatient treatment, individuals often “step those chronic pain patients who meet DSM-5 criteria professional/educational outcomes. Group counseling down” into regular outpatient treatment which meets for OUD. Those who do not respond to medication is often used in addition to individual counseling to less frequently and for fewer hours per week to help management alone through a primary care provider provide social reinforcement for pursuit of recovery. sustain their recovery. may benefit from a comprehensive assessment Counselors provide a variety of services to people Using medication to treat substance use and more intensive treatment of OUD and any co- in treatment for substance use disorders including disorders is often referred to as Medication-Assisted occurring conditions in SUD specialty care settings. assessment, treatment planning, and counseling. Treatment (MAT). In this model, medication is used 24 Table 4: Pharmacotherapies for treating alcohol and opioid use disorders135 Medication Use Dosage Form DEA Schedule* Application Buprenorphine- Opioid use disorder Sublingual film**:118 CIII Used for detoxification or maintenance of abstinence Naloxone 2mg/0.5mg, 4mg/1 mg, 8mg/2mg, and for individuals aged 16 or older. Physicians who wish 12mg/3mg to prescribe buprenorphine, must obtain a waiver from Sublingual tablet: 1.4mg/0.36mg, SAMHSA and be issued an additional registration number by 2mg/0.5mg, 2.9/0.71 mg, the U.S. Drug Enforcement Administration (DEA). 5.7mg/1.4mg, 8mg/2mg, 8.6mg/2.1 mg, 11.4mg/2.9mg Buccal film: 2.1 mg/0.3mg, 4.2mg/0.7mg, 6.3mg/1mg Buprenorphine Opioid use disorder Sublingual tablet: CIII This formulation is indicated for treatment of opioid Hydrochloride 2mg, 4mg, 8mg, and 12mg dependence and is preferred for induction. However, it is considered the preferred formulation for pregnant patients, patients with hepatic impairment, and patients with sensitivity to naloxone. It is also used for initiating treatment in patients transferring from methadone, in preference to products containing naloxone, because of the risk of precipitating withdrawal in these patients. Probuphine® implants: 80mgx4 For those already stable on low to moderate dose implants for a total of 320mg buprenorphine. The administration of the implant dosage form requires specific training and must be surgically inserted and removed. Methadone Opioid use disorder Tablet: 5mg, 10mg CII Methadone used for the treatment of opioid addiction in Tablet for suspension: 40mg detoxification or maintenance programs shall be dispensed Oral concentrate: 10mg/ml only by Opioid Treatment Programs (OTPs) certified by Oral solution: 5mg/5ml, 10mg/5ml SAMHSA and approved by the designated state authority. Injection: 10mg/ml Under federal regulations it can be used in persons under age 18 at the discretion of an OTP physician.119 Naltrexone Opioid use disorder; Tablets: 25mg, 50mg, and 100mg Not scheduled Provided by prescription; naltrexone blocks opioid alcohol use disorder Extended-release injectable under the receptors, reduces cravings, and diminishes the rewarding suspension: Controlled effects of alcohol and opioids. Extended-release injectable 380mg/vial Substances Act naltrexone is recommended to prevent relapse to opioids or alcohol. The prescriber need not be a physician, but must be licensed and authorized to prescribe by the state. Acamprosate Alcohol use disorder Delayed-release tablet: 333mg Not scheduled Provided by prescription; naltrexone blocks opioid under the receptors, reduces cravings, and diminishes the rewarding Controlled effects of alcohol and opioids. Extended-release injectable Substances Act naltrexone is recommended to prevent relapse to opioids or alcohol. The prescriber need not be a physician, but must be licensed and authorized to prescribe by the state. Disulfiram Alcohol use disorder Tablet: 250mg, 500mg Not scheduled When taken in combination with alcohol, disulfiram causes under the severe physical reactions, including nausea, flushing, and Controlled heart palpitations. The knowledge that such a reaction is Substances Act likely if alcohol is consumed acts as a deterrent to drinking. Notes: *For more information about the DEA Schedule and classification of specific drugs, see Appendix D - Important Facts about Alcohol and Drugs. **This dosage form may be used via sublingual or buccal routes of administration; sublingual means placed under the tongue, buccal means applied to the buccal area (in the cheek). Source: Adapted from Lee et al., (2015).120

25 Methadone for OUD and methadone.140 Buprenorphine’s opioid effects Buprenorphine treatment typically happens in three Methadone is a synthetic opioid agonist that has increase with each dose until, at relatively moderate phases:140 long been used to treat the symptoms of withdrawal doses, they level off and do not cause any additional 1. The Induction Phase is the medically monitored from heroin and other opioids. Much research opioid effect, even with further dose increases. This induction of buprenorphine treatment supports the use of methadone as an effective “ceiling effect” lowers the risk of misuse, dependency, performed in a qualified medical provider’s treatment for opioid use disorder.135 It is also used tolerance, and side effects. office or certified opioid treatment program in the treatment of patients with chronic, severe Approved for clinical use in October 2002 by the using approved buprenorphine products. The pain as a therapeutic alternative to morphine and FDA, buprenorphine represents the latest advance medication is administered when a person with other opioid analgesics. Any licensed physician can in MAT.140 Medications such as buprenorphine, a moderate to severe opioid use disorder has prescribe methadone for the treatment of pain, but in combination with counseling and behavioral abstained from using opioids for 8 to 24 hours methadone may only be dispensed for treatment of therapies, provide a whole-patient approach to the and is in the early stages of opioid withdrawal an opioid use disorder within licensed methadone treatment of opioid use disorder. When taken as (identified by a Clinical Opioid Withdrawal treatment programs.135 prescribed, buprenorphine is safe and effective.140 Scale > to 10 . It is important to note that Long-term methadone maintenance treatment Buprenorphine as an opioid use disorder treatment is buprenorphine can precipitate acute withdrawal for opioid use disorders has been shown to be more carefully regulated. Qualified physicians and advanced for patients who are not in the early stages of effective than short-term withdrawal management, practice providers are required to acquire and withdrawal and who have long-acting opioids and it has demonstrated improved outcomes for maintain certifications to legally dispense or prescribe like methadone in their bloodstream. individuals (including pregnant women and their buprenorphine. 2. The Stabilization Phase begins after a infants) with opioid use disorders.135 Studies have Unlike methadone treatment, which must be patient has stabilized on buprenorphine, has also indicated that methadone reduces deaths, HIV performed in a highly structured clinic, buprenorphine discontinued or greatly reduced their use of the risk behaviors, and criminal behavior associated with is the first medication to treat opioid use disorder problem drug, no longer has opioid cravings, opioid use. that is permitted to be prescribed or dispensed in and experiences few, if any, side effects. The Methadone treatment programs, also known physician offices, significantly increasing treatment buprenorphine dose may need to be adjusted as Opioid Treatment Programs (OTPs), must be access. Under the Drug Addiction Treatment Act of during this phase. Because of the long-acting certified by SAMHSA and registered by the U.S. Drug 2000 (DATA 2000), qualified U.S. physicians can nature of buprenorphine, once patients have Enforcement Administration. OTPs are predominantly offer buprenorphine for opioid use disorder in been stabilized, they can sometimes switch to outpatient programs that provide pharmacotherapy various settings, including in an office, community alternate-day dosing instead of dosing every in combination with behavioral therapies. OTPs hospital, health department, or correctional facility. day, though this is not common. In some cases incorporate principles of harm reduction and benefit Government-certified opioid treatment programs also patients may benefit from taking buprenorphine both program participants and the community by are allowed to dispense buprenorphine twice or three times a day, particularly patients reducing opioid use, mortality, crime associated As with all medications used in MAT, buprenorphine with chronic pain. with opioid use disorders, and infectious disease is prescribed as part of a comprehensive treatment 3. The Maintenance Phase occurs when a patient is transmission.135 plan that includes counseling and participation in doing well on a steady dose of buprenorphine. Individuals receiving medication for opioid use social support programs. The FDA has approved the The length of time of the maintenance phase is disorders in an OTP must initially take their doses daily following buprenorphine products:140 tailored to each patient and could be indefinite. under observation. Initiation of methadone treatment • Bunavail (buprenorphine and naloxone) buccal Outcomes are best for patients who remain on is done slowly and carefully. Federal law prohibits a film buprenorphine maintenance treatment. Once an dose greater than 40 mg for patients on their first • Suboxone (buprenorphine and naloxone) film individual is stabilized, an alternative approach day of treatment. Dose escalation is done slowly as • Zubsolv (buprenorphine and naloxone) would be to go into a medically supervised sublingual tablets patients stabilize on the medication. Therapeutic withdrawal, which makes the transition from a • Buprenorphine-containing transmucosal doses of methadone are typically 60-90 mg/day, physically dependent state smoother. People products for opioid use disorder though some patients may need doses much higher then can engage in further rehabilitation—with Buprenorphine’s side effects are similar to those of than this. After initiation, stabilization on methadone or without MAT—to prevent a possible relapse. other opioids and can include: generally takes about 2 weeks. Patients are monitored • Nausea, vomiting, and constipation As with any other substance use disorder, daily and given frequent urine drug tests throughout • Muscle aches and cramps treatment of opioid use disorder with buprenorphine their treatment. Once patients have stabilized fully • Cravings is most effective in combination with counseling on the medication, are no longer using other opioids, • Inability to sleep services, which can include different forms of • Distress and irritability and have stable living environments, they can become behavioral therapy and self-help programs. • Fever eligible for “take home” medication, meaning they Because of buprenorphine’s opioid effects, it self-administer methadone outside of the OTP. Take Preventing Diversion can be misused, particularly by people who do not home approval is highly monitored and regulated. A The prescribing of opioids and other controlled have an opioid use disorder. Naloxone is added to patient receiving methadone from an OTP can only substances brings with it the risk for diversion, buprenorphine to decrease the likelihood of diversion receive up to 28 days of take home medication and which is the act of removing the medication from its and misuse. When these products are taken as he/she must remain opioid abstinent at all times.135 intended and lawful use. To be lawful, the prescribing sublingual tablets, buprenorphine’s opioid effects of controlled substances, including opioids, must Buprenophine for OUD dominate and naloxone is inactive. If the sublingual occur for a legitimate medical purpose in the usual Buprenorphine is a partial opioid agonist. This tablets are crushed and injected intravenously, course of professional practice.141 The responsibility means that, like opioids, it can produce effects however, the naloxone effect dominates and can of the prescribing clinician includes reasonable such as euphoria and respiratory depression. With cause opioid withdrawal in people who are dependent measures to prevent abuse and diversion. Because buprenorphine, however, these effects are weaker on opioids. than those of full opioid agonists such as heroin diversion poses risks for patients, health care workers 26 and other facility employees, and the public at large, it In clinicians’ offices from storage, preparing or administering them, and is important for prescribing clinicians to remain alert Opioids are the most diverted of controlled disposing of drug waste. Theft of patients’ medication to signals and address them. substances, and most diversion of opioids occurs in is one form of health care worker diversion. Another Under no circumstances may a clinician prescribe outpatient settings.142 Other drug classes with high is tampering or replacing the patient’s intended an opioid or other controlled substance with the diversion potential include hallucinogens, stimulants, medication with another substance in order to use knowledge that the medication will be diverted. anabolic steroids, and other CNS depressants. (i.e., inject) the patients’ medication for themselves. Drug diversion is a crime with serious consequences Diversion by patients or persons posing as Tampering is particularly dangerous and includes the that may occur in a variety of settings and at any patients can take the form of visiting multiple providers risk the patient may be exposed to infections. point along the drug’s supply chain.142 Systemically, to receive prescriptions, drug theft, prescription pad The risks are grave for patient trust and treatment reducing diversion requires cooperation from multiple theft and forgery, and stealing prescription drugs. Any and for clinic employee safety. Yet physicians and other stakeholders, including government agencies, state formulation may be misused or diverted: Extended- clinicians rarely report their colleagues for suspected legislators, pharmaceutical retailers, physicians release (ER) opioids contain a higher dose per unit, diversion or even impairment they directly observe.142 and other clinicians, patients, pharmacists, and which makes them attractive to manipulate and abuse; Reasons include fear of retribution, belief that the pharmaceutical companies.143 however, immediate-release (IR) opioids are more issue is being addressed by someone else, and fear frequently prescribed and widely available and are that no action will come of the report.142 In hospital and acute care settings generally preferred by nonmedical users.143 The best way for facilities to respond is to have Opioids are frequently left over from surgeries, Clinical practices to minimize diversion include the clear policies and procedures in place to quickly trauma treatments, and other acute pain treatment following:149 identify diversion and intervene.142 Possibilities clinical scenarios.144,145 From 33–75% of opioids • Caution when prescribing to patients who include urine drug screening and agreement to prescribed after shoulder surgery remain unused, request combinations of drugs that may enhance comply with diversion prevention policies prior to and half of prescribed opioids remain unused effects, such as opioids with benzodiazepines hiring in addition to ongoing random or “for cause” after outpatient dental surgery.143 Many people • Thorough documentation when prescribing or testing. Newly hired facility workers should receive save opioids in the event they may need them in choosing not to prescribe opioids education to prevent diversion, and that education the future, frequently storing the medications in • Keeping a DEA registrant or license number should be ongoing. Mandatory reporting procedures unlocked locations in the home.143 These opioids confidential unless disclosure is required and methods of surveillance, including checks of and other controlled substances, which linger in • Protecting access to prescription pads prescribing records and video surveillance, should be medicine cabinets, can then become a significant • Ensuring that prescriptions are written clearly to minimize the potential for forgery in place. It is important to check relevant laws in the source for diversion. The National Survey on Drug • Moving to electronic prescribing so that paper state of practice as some states require that diversion Use and Health reported that 60% of adults who prescriptions are not required of controlled substances be reported to federal misused opioids did not have a prescription, and 41% • Adhering to strict refill policies and educating authorities and result in loss of license to practice obtained their most recent misused opioids for free office staff medicine. Certain signs should alert supervisors to from friends or relatives.146 • Using PDMPs to monitor new patients and on the possibility that diversion may be occurring, for The CDC has proposed certain prescribing refilling or adding new medications example:151 durations for episodes of surgical or other acute pain • Referring patients with extensive pain • Removing controlled substances without a treatment to reduce the quantity of unused opioids. management or prescription needs to specialists doctor’s order The CDC guideline states the following:147 in relevant fields • Removing controlled substances for patients • When opioids are used for acute pain, clinicians • Collaborating with pharmacy benefit managers “not assigned” to them should prescribe the lowest effective dose of and managed care plans that seek to determine • Removing controlled substances for patients IR opioids and should prescribe no greater medical necessity of prescriptions that have been discharged quantity than needed for the expected duration Generally speaking, risk mitigation measures • Removing controlled substances and not of pain severe enough to require opioids. to prevent nonmedical or other problematic opioid documenting them • Three days or less will often be sufficient; more use by the patient are also helpful in determining • Pulling excessive quantities of as-needed than 7 days will rarely be needed. whether a patient -- or a person posing as a patient medication compared to other health care Patients should be counseled never to share -- is diverting controlled substances. These measures workers assigned to the patient opioids with any other person and to store opioids include opioid treatment agreements to lay out • Exhibiting discrepancies in inventory on a in a locked area away from other family members and consequences of illegal behavior and initial, random, regular basis visitors.122 Leftover opioids, including transdermal and ongoing checks of the state PDMP and UDT as • Pulling out controlled substances in lower fentanyl patches, should not be placed in the trash appropriate. Diversion is one possible explanation if dosages in order to obtain more pills when the but should be taken to an authorized drug take- UDT results show the prescribed medications are not exact dosage is available back facility or, if one is not available, flushed down present. One should bear in mind, however, that the • Pulling out larger dosages of injectable the toilet or washed down the drain immediately.148 absence of the prescribed medication is not in itself medications to obtain more waste More information about drug disposal and national proof of diversion (or hoarding for later use) but is • Continuing patient complaints of pain, despite drug take-back events is available by calling 1-800- one possible explanation that should be considered documented administration of pain medications 882-9539 or visiting the website (https://www. in context with other clinical signs. When diversion • Falsifying records and failing to document waste deadiversion.usdoj.gov/drug_disposal/index.html) of has occurred, immediate discharge from care is 150 • Removing as-needed medications too frequently, the Drug Enforcement Administration. warranted. for example pulling every 2 hours when the By facility health care workers order is for every 4 hours Unfortunately, the diversion of opioids by health care workers from their places of employment is not uncommon. A single provider may have multiple opportunities to divert drugs when procuring them 27 Staff members other than health care workers The government frequently changes the may also divert medications. Support staff employees requirements for compliance with controlled who may be diverting controlled substances may be substances. Substances are added, removed, or spotted in areas where they are not unauthorized, transferred between schedules in the controlled may unnecessarily touch syringes, may stay late substance list. For example, the American Medical when their services are unnecessary, and may always Association, the Institute of Medicine, and the volunteer to help or to dispose of waste.151 If health American College of Physicians have petitioned the care workers or support staff are impaired, they may DEA to shift cannabis from Schedule I to Schedule appear sleepy, exhibit personality changes, commit II in light of the voluminous testimony that this multiple errors or be unable to perform routine tasks, substance does have valid medical uses and to take excessive sick leave or extended breaks, and be facilitate research on more effective therapeutic the target of multiple patients complaints.151 uses of the relevant compounds contained in raw To effectively combat diversion, cooperation is cannabis.152 (As noted above, this monograph does necessary across multiple teams and facility divisions. not cover cannabis because the legal, medical, and The Mayo Clinic has laid out the following set of cultural dimensions of this drug are in such flux.) recommended steps when diversion in the workplace is suspected or identified:142 In order to maintain compliance, responsible • Secure whatever evidence is available health care providers must be aware of changes in • Initiate drug testing legislation and regulatory requirements associated • Initiate a discussion with the employee’s with commonly prescribed substances. They must supervisor maintain current DEA licensure for the state in which • Review of any records documenting handling of they practice and ensure that the DEA has their controlled substances most current mailing address. When prescribers fill • Institute additional surveillance if necessary out a prescription for a controlled substance, they • Initiate recurring meetings of a drug diversion must ensure that all parts of the prescription are response team to review findings filled out properly, and they should take schedules • Quickly remove from patient care any employee into account when sending prescriptions to the found to have diverted controlled substances pharmacy or ordering re-fills. Lastly, health care • Quickly close the case of any employee providers should closely monitor patients who are determined not to have diverted controlled taking controlled substances for signs of addiction, substances overdose, side-effects, and drug-drug interactions. • Report findings to the Drug Enforcement Administration, the state pharmacy board, and Clearly, the rise of substance use disorder local law enforcement and prescription drug abuse, and the wider use of controlled substances, is related to social, cultural, Conclusions and economic forces that are larger and more powerful than any role that clinicians have in their 18 This monograph on best practices for day-to-day work with controlled substances. But prescribing controlled substances summarized at the same time, clinicians can take simple steps the United States federal legislation governing the to insure that controlled substances are prescribed prescription of controlled substances and offered safely and effectively. By so doing, those prescribers suggestions for how health care providers can help protect their patients, society at large and comply with those regulations. The monograph themselves should they encounter the scrutiny of provided a list of frequently encountered non- regulators. opioid controlled substances grouped by schedule. It reviewed the legal requirements for compliance in prescribing these substances, including how to perform critical components of the history and physical examination, assessing patients for substance use disorder risk, and documenting risk stratification. Before prescribing controlled substances, health care providers are obligated to document how they made the diagnosis and why a controlled substance is the best treatment for the patient. This monograph also reviewed some common conditions that may be treated with controlled substances.

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Blurred boundaries: the therapeutics 119. American Medical Association. AMA adopts new Disorders. http://www.healthquality.va.gov/guidelines/ and politics of medical marijuana. Mayo Clin Proc. policies at annual meeting: promoting prevention of mh/sud/index.asp. Accessed June 24, 2018. 2012;87(2):172-186. fatal opioid overdose. June, 2012 2012. 138. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive 120. Davis C. Legal interventions to reduce overdose counseling during brief and extended buprenorphine- mortality: naloxone access and overdose good naloxone treatment for prescription opioid samaritan laws. The Network for Public Health dependence: a 2-phase randomized controlled trial. Law;2014. Arch Gen Psychiatry. 2011;68(12):1238-1246. 121. San Francisco Department of Public Health. Naloxone 139. Dennis BB, Bawor M, Naji L, et al. Impact of Chronic for opioid safety: a provider’s guide to prescribing Pain on Treatment Prognosis for Patients with Opioid naloxone to patients who use opioids. 2015. Use Disorder: A Systematic Review and Meta-analysis. 122. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines Subst Abuse. 2015;9:59-80. for the use of chronic opioid therapy in chronic 140. Substance Abuse and Mental Health Services noncancer pain. J Pain. 2009;10(2):113-130. Administration. Buprenophine. 2018; https:// 123. Volkow ND, McLellan TA, Cotto JH, Karithanom M, Weiss www.samhsa.gov/medication-assisted-treatment/ SR. Characteristics of opioid prescriptions in 2009. treatment/buprenorphine. Accessed July 6 2018. 141. Code of Federal Regulations. Title 21 CFR §1306 Jama. 2011;305(13):1299-1301. Prescriptions §1306.04. https://www.deadiversion. 124. Cantrill SV, Brown MD, Carlisle RJ, et al. Clinical policy: usdoj.gov/21cfr/cfr/1306/1306_04.htm. Accessed critical issues in the prescribing of opioids for adult August 20 2018. patients in the emergency department. Annals of 142. Berge KH, Dillon KR, Sikkink KM, Taylor TK, Lanier emergency medicine. 2012;60(4):499-525. WL. Diversion of drugs within health care facilities, a 125. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its multiple-victim crime: patterns of diversion, scope, treatment in outpatients with metastatic cancer. N Engl consequences, detection, and prevention. Mayo Clin J Med. 1994;330(9):592-596. Proc. 2012;87(7):674-682.

31 EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTION

1. In the United States, approximately how many non-medical 7. Drugs in which schedule are deemed to have a high potential for users of pain relievers, tranquilizers, stimulants, and sedatives abuse or dependence but also have a currently accepted medical got their prescription drugs from a friend or relative for free? use in the US? A. < 10% A. I B. 25% B. II C. 35% C. III D. > 50% D. IV

2. What two competing needs must the CSA and regulators attempt 8. The duration of action of ER/LA opioids is typically to balance? ______. A. The need to contain the spiraling costs of prescription medications A. 30 – 90 min while also supporting the pharmaceutical industry’s need to B. 2- 4 hrs support expensive research and development efforts C. 4 – 24 hrs B. The need to maintain an adequate supply of controlled D. 4 – 72 hrs substances for legitimate purposes while simultaneously reducing their diversion and abuse 9. Uncomfortable or unpleasant side effects (aside from C. The need to regulate the pharmaceutical industry while also constipation) may potentially be reduced by which two supporting law enforcement agencies approaches? D. The need to punish those abusing prescription medications with A. Switching to another opioid or taking the opioid with food the need to provide adequate social support for addicts B. Switching to another opioid or changing the route of administration C. Adding a non-opioid analgesic or trying a complimentary 3. Which of the following factors might be used to determine into therapeutic technique which schedule a drug or other substance should be placed? D. Changing the route of administration or advising patients to avoid A. The history and current pattern of abuse of a drug alcohol consumption B. Scientific evidence of the drug’s pharmacological effect C. The drug’s actual or relative potential for abuse 10. What drug class has largely replaced barbiturates as treatment D. All of the above for anxiety and muscle spasms? A. Amphetamines 4. Into how many classes does the CSA assign drugs or other B. Benzodiazepines substances? C. Non-benzodiazepines A. 4 D. Serotonin-reuptake inhibitors B. 5 C. 6 11. Any person who handles or intends to handle controlled D. 10 substances must obtain what? A. A registration from their state Medical Board 5. Which attribute of some drugs with legitimate therapeutic uses B. A registration from the Drug Enforcement Administration increases their likelihood of being abused? C. A registration from the FDA A. Whether the drug is compounded with another drug D. A registration from the Department of Homeland Security B. Whether the drug produces pleasurable feelings C. Cost of the drug to patients 12. If a physician is filling in for another physician in another state D. Whether the drug, as packaged and manufactured, resembles as part of a locum tenens arrangement, the substitute physician other drugs with legitimate medical uses can legally prescribe controlled substances as long as he or she is legitimately registered with the DEA in his or her home state. A. True 6. Heroin, LSD, MDMA, and cannabis are currently listed in which B. False CSA schedule? A. I 13. In an emergency, a prescriber may phone or electronically B. II submit a prescription for a Schedule II drug to a pharmacy but C. III must follow up with a written prescription within 7 days. D. IV A. True B. False

32 14. Which of the following items does not need to be contained in 23. When opioid treatment is initiated, it should be viewed by both any prescription for a controlled substance? patient and clinician as ______. A. Proof of informed consent A. A commitment to long-term use of opioid therapy B. Patient’s name and address B. A commitment to gradual titration of the opioid to reach optimal C. Drug strength pain relief D. Number of refills (if any) C. A short-term trial of therapy D. An agreement to continue therapy until adequate pain relief is 15. Which of the following might suggest inappropriate prescribing achieved of controlled substances by a clinician? A. Prescribing a drug for which no logical relationship exists with the 24. Opioid tolerance must be demonstrated before prescribing any alleged condition of a patient strength of ______. B. Prescribing a substance without performing a physical examination A. A short-acting opioid C. Prescribing the substance at intervals inconsistent with legitimate B. An ER/LA opioid medical treatment C. A combination formulation of an opioid D. All of the above D. An abuse deterrent formulation of an opioid

16. The Ryan Haight Act made it illegal to ______. 25. What level of opioid dose is widely considered a red flag A. Dispense controlled substances in all schedules via the Internet warranting more intense monitoring and/or referral to an B. Dispense controlled substances in a state different from the one interdisciplinary treatment team? in which a practitioner is registered A. > 75 mg MEDD C. Dispense Schedule I substances to patients for any reason B. > 80 mg MEDD D. Dispense controlled substances to minors C. > 90 mg MEDD D. >110 mg MEDD 17. Which of the following is not a potential benefit of urine drug screening? 26. What relatively new development may reduce the incidence of A. May deter inappropriate use death from accidental overdose of an opioid medication? B. Provides objective evidence of abstinence from drugs of abuse A. Mandatory CPR training for patients C. May demonstrate to regulatory authorities a clinician’s dedication B. New restrictions on simultaneous prescribing of an opioid and a to monitoring central nervous system depressant D. Can differentiate between opioids that a patient may be using C. Greater availability of 911 emergency response systems D. Provision to patients of intranasal naloxone for home use 18. How frequently are the data in most prescription drug monitoring programs updated? 27. For patients at the end of life, optimal pain management may A. Hourly mean lower doses of an analgesic, and higher levels of pain, B. Hourly or daily in order to allow the patient mental alertness sufficient for C. Daily or weekly interactions with loved ones. D. Monthly A. True B. False 19. Drugs with the highest risk for subsequent addiction slowly elicit dopamine release in the midbrain. 28. Medication-Assisted Treatment is primarily used for treating: A. True A. Tobacco use disorder B. False B. Opioid use disorder C. Alcohol use disorder 20. Although initially thought to be less prone to induce tolerance D. All of the above and dependence than barbiturates, benzodiazepines are now recognized to be just as liable to diversion and abuse. 29. Which of the following is NOT a practice that clinicians can use A. True to minimize diversion of controlled substances? B. False A. Keeping DEA registrant or license number confidential B. Implement mandatory urine drug testing for all patients prescribed 21. Little evidence supports the assertion that long-term use of a controlled substance opioids provides clinically significant pain relief or improves C. Protecting access to prescription pads quality of life or functioning. D. Using PDMPs on refilling or adding new controlled substance A. True prescription B. False 30. Acamprosate is a medication that can be used in the treatment 22. Roughly what percent of patients reported that they increased of ______. their dose of an opioid without talking to the prescribing A. Marijuana use disorder physician in one study? B. Opioid use disorder A. 10% C. Cocaine use disorder B. 20% D. Alcohol use disorder C. 30% D. 40%

33 CDC OPIOID PRESCRIBING Release Date: 12/2016 4 AMA PRA Enduring Material Review Date: 10/2020 Category 1 Credits™ (Self Study) GUIDELINES FOR CHRONIC PAIN Exp. Date: 02/2022

TARGET AUDIENCE

This course is designed for all physicians (MD/DO), physician assistants, and nurse practitioners. Read the course materials

Complete the self-assessment questions at the end. A score of COURSE OBJECTIVE 70% is required.

Physicians, nurses, and other health care professionals must better Return your customer information/ understand their competing responsibilities related to the prescription of answer sheet, evaluation, and opioids and be able to effectively evaluate all patients for their level of payment to InforMed by mail, phone, fax risk for misuse or abuse of opioids. This course reviews the 2016 CDC or complete online at course guidelines for prescribing opioids to patients with chronic non-cancer website under NETPASS. pain. An expert panel formed to create guidelines for the use of opioids in the treatment of chronic, non-cancer pain concluded that adequate patient risk assessment and risk management for opioid abuse, addiction, and diversion is essential.

LEARNING OBJECTIVES

Completion of this course will better enable the course participant to: 1. Discuss the current scope of prescription opioid abuse, addiction, and overdose deaths. 2. Recognize recommended time frames for clinician evaluation of risks and benefits following initiation of an opioid prescription. 3. Describe the contrasting levels of evidence for the effectiveness of opioids for long-term treatment of chronic non- cancer pain and for the severity of the potential risks posed by such treatment. 4. Explain the value of function-based treatment goals as opposed to pain-relief goals. 5. Identify the 50 milligrams morphine equivalent/day (MMED) level that is recommended as a point to reassess benefits and risks of an opioid prescription. 6. Explain why special care must be taken with extended-release/long-acting (ER/LA) opioid formulations. 7. Discuss why methadone must be prescribed with particular caution. 8. Describe the recommendations about the prescription of opioid analgesics to pregnant women. 9. Identify the potential value of using PDMPs and the recommended frequency for consulting a PDMP for patients on long- term opioid therapy.

ACCREDITATION STATEMENT InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

34 FACULTY Stephen Braun Medical Writer Braun Medical Media

Elizabeth Thomas 4 MSN, WHNP-BC, NP-C Pain Management and Terminally Ill Patients

ACTIVITY PLANNER SPECIAL DESIGNATION Elizabeth Thomas MSN, WHNP-BC, NP-C This course satisfies four (4) CME credit hours on Pain Management and the Appropriate Treatment of the Terminally Ill.

FACULTY/PLANNING COMMITTEE DISCLOSURE

The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity: • Stephen Braun • Elizabeth Thomas, MSN, WHNP-BC, NP-C

STAFF AND CONTENT REVIEWERS InforMed staff and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

DISCLAIMER *2020. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc. is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought. 35 Summary the importance of appropriate and compassionate or home.20 This diagnosis has also been referred to patient care.4 Patients should receive appropriate as “abuse or dependence” and “addiction” in the This guideline provides recommendations pain treatment based on a careful consideration of literature, and is different from tolerance (diminished for primary care clinicians who are prescribing opioids the benefits and risks of treatment options. response to a drug with repeated use) and physical for chronic pain outside of active cancer treatment, Chronic pain has been variably defined dependence (adaptation to a drug that produces palliative care, and end-of-life care. The guideline but is defined within this guideline as pain that symptoms of withdrawal when the drug is stopped), addresses 1) when to initiate or continue opioids for typically lasts >3 months or past the time of normal both of which can exist without a diagnosed disorder. chronic pain; 2) opioid selection, dosage, duration, tissue healing.5 Chronic pain can be the result of an In 2013, on the basis of DSM-IV diagnosis criteria, followup, and discontinuation; and 3) assessing risk underlying medical disease or condition, injury, medical an estimated 1.9 million persons abused or were and addressing harms of opioid use. CDC developed treatment, inflammation, or an unknown cause.4 dependent on prescription opioid pain medication.21 the guideline using the Grading of Recommendations Estimates of the prevalence of chronic pain vary, but Having a history of a prescription for an opioid pain Assessment, Development, and Evaluation (GRADE) it is clear that the number of persons experiencing medication increases the risk for overdose and opioid framework, and recommendations are made on the chronic pain in the United States is substantial. use disorder22–24, highlighting the value of guidance basis of a systematic review of the scientific evidence The 1999–2002 National Health and Nutrition on safer prescribing practices for clinicians. For while considering benefits and harms, values and Examination Survey estimated that 14.6% of adults example, a recent study of patients aged 15–64 preferences, and resource allocation. CDC obtained have current widespread or localized pain lasting at years receiving opioids for chronic non-cancer pain input from experts, stakeholders, the public, peer least 3 months.6 Based on a survey conducted during and followed for up to 13 years revealed that one reviewers, and a federally chartered advisory 2001–20037, the overall prevalence of common, in 550 patients died from opioid-related overdose committee. It is important that patients receive predominantly musculoskeletal pain conditions (e.g., at a median of 2.6 years from their first opioid appropriate pain treatment with careful consideration arthritis, rheumatism, chronic back or neck problems, prescription, and one in 32 patients who escalated to of the benefits and risks of treatment options. This and frequent severe headaches) was estimated at opioid dosages >200 morphine milligram equivalents guideline is intended to improve communication 43% among adults in the United States, although (MME) died from opioid-related overdose.25 between clinicians and patients about the risks and minimum duration of symptoms was not specified. This guideline provides recommendations benefits of opioid therapy for chronic pain, improve Most recently, analysis of data from the 2012 National for the prescribing of opioid pain medication by the safety and effectiveness of pain treatment, and Health Interview Study showed that 11.2% of adults primary care clinicians for chronic pain (i.e., pain reduce the risks associated with long-term opioid report having daily pain.8 Clinicians should consider conditions that typically last >3 months or past the therapy, including opioid use disorder, overdose, and the full range of therapeutic options for the treatment time of normal tissue healing) in outpatient settings death. CDC has provided a checklist for prescribing of chronic pain. However, it is hard to estimate the outside of active cancer treatment, palliative care, and opioids for chronic pain (http://stacks.cdc.gov/view/ number of persons who could potentially benefit from end-of-life care. Although the guideline does not focus cdc/38025) as well as a website (https://www.cdc. opioid pain medication long term. Evidence supports broadly on pain management, appropriate use of long- gov/drugoverdose/prescribing/resources.html) with short-term efficacy of opioids for reducing pain and term opioid therapy must be considered within the additional tools to guide clinicians in implementing the improving function in non-cancer nociceptive and context of all pain management strategies (including recommendations. neuropathic pain in randomized clinical trials lasting non-opioid pain medications and nonpharmacologic primarily ≤12 weeks9-10, and patients receiving opioid treatments). CDC’s recommendations are made on Introduction therapy for chronic pain report some pain relief the basis of a systematic review of the best available when surveyed11-13. However, few studies have been evidence, along with input from experts, and further Background conducted to rigorously assess the long-term benefits review and deliberation by a federally chartered Opioids are commonly prescribed for of opioids for chronic pain (pain lasting >3 months) advisory committee. The guideline is intended to pain. An estimated 20% of patients presenting to with outcomes examined at least 1 year later.14 On ensure that clinicians and patients consider safer and physician offices with non-cancer pain symptoms or the basis of data available from health systems, more effective treatment, improve patient outcomes pain-related diagnoses (including acute and chronic researchers estimate that 9.6–11.5 million adults, or such as reduced pain and improved function, and 1 pain) receive an opioid prescription . In 2012, health approximately 3%–4% of the adult U.S. population, reduce the number of persons who develop opioid care providers wrote 259 million prescriptions for were prescribed long-term opioid therapy in 2005.15 use disorder, overdose, or experience other adverse opioid pain medication, enough for every adult in Opioid pain medication use presents events related to these drugs. Clinical decision 2 the United States to have a bottle of pills. Opioid serious risks, including overdose and opioid use making should be based on a relationship between prescriptions per capita increased 7.3% from 2007 disorder. From 1999 to 2014, more than 165,000 the clinician and patient, and an understanding of the to 2012, with opioid prescribing rates increasing persons died from overdose related to opioid pain patient’s clinical situation, functioning, and life context. more for family practice, general practice, and internal medication in the United States.16 In the past decade, The recommendations in the guideline are voluntary, 3 medicine compared with other specialties. Rates of while the death rates for the top leading causes rather than prescriptive standards. They are based on opioid prescribing vary greatly across states in ways of death such as heart disease and cancer have emerging evidence, including observational studies that cannot be explained by the underlying health decreased substantially, the death rate associated or randomized clinical trials with notable limitations. status of the population, highlighting the lack of with opioid pain medication has increased markedly.17 Clinicians should consider the circumstances and consensus among clinicians on how to use opioid pain Sales of opioid pain medication have increased unique needs of each patient when providing care. 2 medication. in parallel with opioid-related overdose deaths.18 Prevention, assessment, and treatment of The Drug Abuse Warning Network estimated that Rationale chronic pain are challenges for health providers and >420,000 emergency department visits were related Primary care clinicians report having systems. Pain might go unrecognized, and patients, to the misuse or abuse of narcotic pain relievers concerns about opioid pain medication misuse, particularly members of racial and ethnic minority in 2011, the most recent year for which data are find managing patients with chronic pain stressful, groups, women, the elderly, persons with cognitive available.19 Although clinical criteria have varied over express concern about patient addiction, and report impairment, and those with cancer and at the end time, opioid use disorder is a problematic pattern of insufficient training in prescribing opioids.26 Across 4 of life, can be at risk for inadequate pain treatment. opioid use leading to clinically significant impairment specialties, physicians believe that opioid pain Patients can experience persistent pain that is not well or distress. This disorder is manifested by specific medication can be effective in controlling pain, that controlled. There are clinical, psychological, and social criteria such as unsuccessful efforts to cut down or addiction is a common consequence of prolonged consequences associated with chronic pain including control use and use resulting in social problems and a use, and that long-term opioid therapy often is limitations in complex activities, lost work productivity, failure to fulfill major role obligations at work, school, overprescribed reduced quality of life, and stigma, emphasizing 36 for patients with chronic non-cancer pain.27 These opioid pain medication for painful conditions that can emergency physicians or dentists, but use in these attitudes and beliefs, combined with increasing trends or have become chronic. settings or by other specialists is not the focus of in opioid-related overdose, underscore the need This guideline is intended to apply to this guideline. Readers are referred to other sources for better clinician guidance on opioid prescribing. patients aged ≥18 years with chronic pain outside for prescribing recommendations within acute care Clinical practice guidelines focused on prescribing of palliative and end-of-life care. For this guideline, settings and in dental practice, such as the American can improve clinician knowledge, change prescribing palliative care is defined in a manner consistent with College of Emergency Physicians’ guideline for practices28, and ultimately benefit patient health. that of the Institute of Medicine as care that provides prescribing of opioids in the emergency department43; Professional organizations, states, and relief from pain and other symptoms, supports the American Society of Anesthesiologists’ guideline federal agencies (e.g., the American Pain Society/ quality of life, and is focused on patients with serious for acute pain management in the perioperative American Academy of Pain Medicine, 2009; the advanced illness. Palliative care can begin early in setting44; the Washington Agency Medical Directors’ Washington Agency Medical Directors Group, 2015; and the course of treatment for any serious illness that Group Interagency Guideline on Prescribing Opioids the U.S. Department of Veterans Affairs/Department requires excellent management of pain or other for Pain, Part II: Prescribing Opioids in the Acute and of Defense, 2010) have developed guidelines for distressing symptoms.35 End-of-life care is defined as Subacute Phase30; and the Pennsylvania Guidelines on opioid prescribing.29–31 Existing guidelines share care for persons with a terminal illness or at high risk the Use of Opioids in Dental Practice45. In addition, some common elements, including dosing thresholds, for dying in the near future in hospice care, hospitals, given the challenges of managing the painful cautious titration, and risk mitigation strategies such long-term care settings, or at home. Patients within complications of sickle cell disease, readers are as using risk assessment tools, treatment agreements, the scope of this guideline include cancer survivors referred to the NIH National Heart, Lung, and Blood and urine drug testing. However, there is considerable with chronic pain who have completed cancer Institute’s Evidence Based Management of Sickle Cell variability in the specific recommendations (e.g., treatment, are in clinical remission, and are under Disease Expert Panel Report for management of range of dosing thresholds of 90 MME/day to 200 cancer surveillance only. The guideline is not intended sickle cell disease.46 MME/day), audience (e.g., primary care clinicians for patients undergoing active cancer treatment, versus specialists), use of evidence (e.g., systematic palliative care, or end-of-life care because of the Guideline Development Methods review, grading of evidence and recommendations, unique therapeutic goals, ethical considerations, and role of expert opinion), and rigor of methods opportunities for medical supervision, and balance of Guideline Development Using the Grading of for addressing conflict of interest.32 Most guidelines, risks and benefits with opioid therapy in such care. Recommendations Assessment, Development, especially those that are not based on evidence from The recommendations address the use of and Evaluation Method scientific studies published in 2010 or later, also do opioid pain medication in certain special populations CDC developed this guideline using not reflect the most recent scientific evidence about (e.g., older adults and pregnant women) and in the Grading of Recommendations Assessment, risks related to opioid dosage. populations with conditions posing special risks Development, and Evaluation (GRADE) method (http:// This CDC guideline offers clarity on (e.g., a history of substance use disorder). The www.gradeworkinggroup.org). This method specifies recommendations based on the most recent scientific recommendations do not address the use of opioid the systematic review of scientific evidence and offers evidence, informed by expert opinion and stake- pain medication in children or adolescents aged <18 a transparent approach to grading quality of evidence holder and public input. Scientific research has years. The available evidence concerning the benefits and strength of recommendations. The method has identified high-risk prescribing practices that have and harms of long-term opioid therapy in children been adapted by the CDC Advisory Committee on 47 contributed to the overdose epidemic (e.g., high-dose and adolescents is limited, and few opioid medications Immunization Practices (ACIP). CDC has applied prescribing, overlapping opioid and benzodiazepine provide information on the label regarding safety the ACIP translation of the GRADE framework in this prescriptions, and extended-release/long-acting [ER/ and effectiveness in pediatric patients. However, guideline. Within the ACIP GRADE framework, the LA] opioids for acute pain).24,33,34 Using guidelines to observational research shows significant increases body of evidence is categorized in a hierarchy. This address problematic prescribing has the potential to in opioid prescriptions for pediatric populations from hierarchy reflects degree of confidence in the effect optimize care and improve patient safety based on 2001 to 201036, and a large proportion of adolescents of a clinical action on health outcomes. The categories evidence-based practice28, as well as reverse the cycle are commonly prescribed opioid pain medications include type 1 evidence (randomized clinical trials of opioid pain medication misuse that contributes to for conditions such as headache and sports injuries or overwhelming evidence from observational the opioid overdose epidemic. (e.g., in one study, 50% of adolescents presenting studies), type 2 evidence (randomized clinical trials with headache received a prescription for an opioid with important limitations, or exceptionally strong Scope and Audience pain medication).37,38 Adolescents who misuse opioid evidence from observational studies), type 3 evidence This guideline is intended for primary care pain medication often misuse medications from their (observational studies or randomized clinical trials clinicians (e.g., family physicians and internists) who own previous prescriptions39, with an estimated with notable limitations), and type 4 evidence (clinical are treating patients with chronic pain (i.e., pain lasting 20% of adolescents with currently prescribed opioid experience and observations, observational studies >3 months or past the time of normal tissue healing) medications reporting using them intentionally to with important limitations, or randomized clinical in outpatient settings. Prescriptions by primary care get high or increase the effects of alcohol or other trials with several major limitations). Type of evidence clinicians account for nearly half of all dispensed drugs.40 Use of prescribed opioid pain medication is categorized by study design as well as limitations opioid prescriptions, and the growth in prescribing before high school graduation is associated with in study design or implementation, imprecision of rates among these clinicians has been above a 33% increase in the risk of later opioid misuse.41 estimates, variability in findings, indirectness of average.3 Primary care clinicians include physicians as Misuse of opioid pain medications in adolescence evidence, publication bias, magnitude of treatment well as nurse practitioners and physician assistants. strongly predicts later onset of heroin use.42 Thus, effects, dose response gradient, and a constellation Although the focus is on primary care clinicians, risk of opioid medication use in pediatric populations of plausible biases that could change observations of because clinicians work within team based care, the is of great concern. Additional clinical trial and effects. Type 1 evidence indicates that one can be very recommendations refer to and promote integrated observational research is needed, and encouraged, confident that the true effect lies close to that of the pain management and collaborative working to inform development of future guidelines for this estimate of the effect; type 2 evidence means that the relationships with other providers (e.g., behavioral critical population. true effect is likely to be close to the estimate of the health providers, pharmacists, and pain management The recommendations are not intended effect, but there is a possibility that it is substantially specialists). Although the transition from use of opioid to provide guidance on use of opioids as part of different; type 3 evidence means that confidence in therapy for acute pain to use for chronic pain is hard medication-assisted treatment for opioid use disorder. the effect estimate is limited and the true effect might to predict and identify, the guideline is intended to Some of the recommendations might be relevant be substantially different from the estimate of the inform clinicians who are considering prescribing for acute care settings or other specialists, such as effect; and type 4 evidence indicates that one has very little confidence in the effect estimate, and the 37 true effect is likely to be substantially different from strategies and GRADE methods applied are provided clinical experience; and proven scientific excellence in the estimate of the effect.47,48 When no studies are in the Clinical Evidence Review (http://stacks.cdc.gov/ opioid prescribing, substance use disorder treatment, present, evidence is considered to be insufficient. view/cdc/38026). CDC developed GRADE evidence and pain management. CDC identified representatives The ACIP GRADE framework places recommendations tables to illustrate the quality of the evidence for each from leading primary care professional organizations in two categories, Category A and Category B. clinical question. to represent the audience for this guideline. Finally, CDC Four major factors determine the category of the As identified in the AHRQ sponsored clinical identified state agency officials and representatives recommendation: the quality of evidence, the balance evidence review, the overall evidence base for the based on their experience with state guidelines for between desirable and undesirable effects, values effectiveness and risks of long-term opioid therapy is opioid prescribing that were developed with multiple and preferences, and resource allocation (cost). low in quality per the GRADE criteria. Thus, contextual agency stakeholders and informed by scientific Category A recommendations apply to all persons evidence is needed to provide information about the literature and existing evidence-based guidelines. in a specified group and indicate that most patients benefits and harms of nonpharmacologic and non- Prior to their participation, CDC asked should receive the recommended course of action. opioid pharmacologic therapy and the epidemiology potential experts to reveal possible conflicts of Category B recommendations indicate that there of opioid pain medication overdose and inform the interest such as financial relationships with industry, should be individual decision making; different choices recommendations. Further, as elucidated by the intellectual preconceptions, or previously stated will be appropriate for different patients, so clinicians GRADE Working Group, supplemental information public positions. Experts could not serve if they had must help patients arrive at a decision consistent with on clinician and patient values and preferences conflicts that might have a direct and predictable patient values and preferences, and specific clinical and resource allocation can inform judgments of effect on the recommendations. CDC excluded experts situations.47 According to the GRADE methodology, benefits and harms and be helpful for translating the who had a financial or promotional relationship with a a particular quality of evidence does not necessarily evidence into recommendations. CDC conducted a company that makes a product that might be affected imply a particular strength of recommendation.48–50 contextual evidence review to supplement the clinical by the guideline. CDC reviewed potential nonfinancial Category A recommendations can be made based on evidence review based on systematic searches of conflicts carefully (e.g., intellectual property, travel, type 3 or type 4 evidence when the advantages of the literature. The review focused on the following public statements or positions such as congressional a clinical action greatly outweigh the disadvantages four areas: effectiveness of nonpharmacologic and testimony) to determine if the activities would have a based on a consideration of benefits and harms, non-opioid pharmacologic treatments; benefits direct and predictable effect on the recommendations. values and preferences, and costs. Category B and harms related to opioid therapy (including CDC determined the risk of these types of activities recommendations are made when the advantages and additional studies not included in the clinical evidence to be minimal for the identified experts. All experts disadvantages of a clinical action are more balanced. review such as studies that evaluated outcomes at completed a statement certifying that there was no GRADE methodology is discussed extensively any duration or used observational study designs potential or actual conflict of interest. Activities that elsewhere.47,51 The U.S. Preventive Services Task Force related to specific opioid pain medications, high-dose did not pose a conflict (e.g., participation in Food and (USPSTF) follows different methods for developing opioid therapy, co-prescription of opioids with other Drug Administration [FDA] activities or other guideline and categorizing recommendations (http://www. controlled substances, duration of opioid use, special efforts) are disclosed. uspreventiveservicestaskforce.org). USPSTF populations, risk stratification/mitigation approaches, CDC provided to each expert written recommendations focus on preventive services and effectiveness of treatments for addressing summaries of the scientific evidence (both the and are categorized as A, B, C, D, and I. Under the potential harms of opioid therapy); clinician and clinical and contextual evidence reviews conducted Affordable Care Act, all “non-grandfathered” health patient values and preferences; and resource for this guideline) and CDC’s draft recommendation plans (that is, those health plans not in existence prior allocation. CDC constructed narrative summaries of statements. Experts provided individual ratings to March 23, 2010 or those with significant changes this contextual evidence and used the information to for each draft recommendation statement based to their coverage) and expanded Medicaid plans are support the clinical recommendations. More details on the balance of benefits and harms, evidence required to cover preventive services recommended on methods for the contextual evidence review are strength, certainty of values and preferences, cost, by USPSTF with a category A or B rating with no cost provided in the Contextual Evidence Review (http:// recommendation strength, rationale, importance, sharing. The coverage requirements went into effect stacks.cdc.gov/view/cdc/38027). clarity, and ease of implementation. CDC hosted an in September 23, 2010. Similar requirements are in On the basis of a review of the clinical and person meeting of the experts that was held on June place for vaccinations recommended by ACIP, but do contextual evidence (review methods are described in 23–24, 2015, in Atlanta, Georgia, to seek their views not exist for other recommendations made by CDC, more detail in subsequent sections of this report), on the evidence and draft recommendations and to including recommendations within this guideline. CDC drafted recommendation statements focused better understand their premeeting ratings. CDC A previously published systematic review on determining when to initiate or continue opioids sought the experts’ individual opinions at the meeting. sponsored by the Agency for Healthcare Research for chronic pain; opioid selection, dosage, duration, Although there was widespread agreement on some and Quality (AHRQ) on the effectiveness and risks follow up, and discontinuation; and assessing risk and of the recommendations, there was disagreement on of long-term opioid treatment of chronic pain14,52 addressing harms of opioid use. To help assure the others. Experts did not vote on the recommendations initially served to directly inform the recommendation draft guideline’s integrity and credibility, CDC then or seek to come to a consensus. Decisions about statements. This systematic clinical evidence review began a multi-step review process to obtain input recommendations to be included in the guideline, addressed the effectiveness of long-term opioid from experts, stakeholders, and the public to help and their rationale, were made by CDC. After revising therapy for outcomes related to pain, function, and refine the recommendations. the guideline, CDC sent written copies of it to each of quality of life; the comparative effectiveness of the experts for review and asked for any additional different methods for initiating and titrating opioids; Solicitation of Expert Opinion comments; CDC reviewed these written comments and the harms and adverse events associated with opioids; CDC sought the input of experts to assist considered them when making further revisions to the and the accuracy of risk prediction instruments and in reviewing the evidence and providing perspective draft guideline. The experts have not reviewed the effectiveness of risk mitigation strategies on outcomes on how CDC used the evidence to develop the draft final version of the guideline. related to overdose, addiction, abuse, or misuse. For recommendations. These experts, referred to as the the current guideline development, CDC conducted “Core Expert Group” (CEG) included subject matter Federal Partner Engagement additional literature searches to update the evidence experts, representatives of primary care professional Given the scope of this guideline and the review to include more recently available publications societies and state agencies, and an expert in interest of agencies across the federal government and to answer an additional clinical question about guideline development methodology. CDC identified in appropriate pain management, opioid prescribing, the effect of opioid therapy for acute pain on long- subject matter experts with high scientific standing; and related outcomes, CDC invited its National term use. More details about the literature search appropriate academic and clinical training and relevant Institute of Occupational Safety and Health and CDC’s

38 federal partners to observe the expert meeting, that could have a clear and substantial impact on well as summaries of comments provided to CDC by provide written comments on the full draft guideline public and private sector decisions. Three experts stakeholders, constituents, and peer reviewers, and after the meeting, and review the guideline through an independently reviewed the guideline to determine the edits made to the draft guideline in response. During agency clearance process; CDC reviewed comments reasonableness and strength of recommendations; the an open meeting held on January 7, 2016, the BSC and incorporated changes. Interagency collaboration clarity with which scientific uncertainties were clearly recommended the formation of the OGW. The OGW will be critical for translating these recommendations identified; and the rationale, importance, clarity, and included a balance of perspectives from audiences into clinical practice. Federal partners included ease of implementation of the recommendations.* directly affected by the guideline, audiences that representatives from the Substance Abuse and CDC selected peer reviewers based on expertise, would be directly involved with implementing the Mental Health Services Administration, the National diversity of scientific viewpoints, and independence recommendations, and audiences qualified to provide Institute on Drug Abuse, FDA, the U.S. Department from the guideline development process. CDC representation. The OGW comprised clinicians, subject of Veterans Affairs, the U.S. Department of Defense, assessed and managed potential conflicts of interest matter experts, and a patient representative, with the Office of the National Coordinator for Health using a process similar to the one as described for the following perspectives represented: primary Information Technology, the Centers for Medicare and solicitation of expert opinion. No financial interests care, pain medicine, public health, behavioral health, Medicaid Services, the Health Resources and Services were identified in the disclosure and review process, substance abuse treatment, pharmacy, patients, Administration, AHRQ, and the Office of National Drug and non-financial activities were determined to be of and research.* Additional sought after attributes Control Policy. minimal risk; thus, no significant conflict of interest were appropriate academic and clinical training and concerns were identified. CDC placed the names of relevant clinical experience; high scientific standing; Stakeholder Comment peer reviewers on the CDC and the National Center and knowledge of the patient, clinician, and caregiver Given the importance of the guideline for a for Injury Prevention and Control Peer Review Agenda perspectives. In accordance with CDC policy, two BSC wide variety of stakeholders, CDC also invited review websites that are used to provide information about committee members also served as OGW members, from a Stakeholder Review Group (SRG) to provide the peer review of influential documents. CDC reviewed with one serving as the OGW Chair. The professional comment so that CDC could consider modifications peer review comments and revised the draft guideline credentials and interests of OGW members were that would improve the recommendations’ specificity, accordingly. carefully reviewed to identify possible conflicts of applicability, and ease of implementation. The interest such as financial relationships with industry, SRG included representatives from professional Public Comment intellectual preconceptions, or previously stated public organizations that represent specialties that To obtain comments from the public on the positions. Only OGW members whose interests were commonly prescribe opioids (e.g., pain medicine, full guideline, CDC published a notice in the Federal determined to be minimal were selected. When an physical medicine and rehabilitation), delivery Register (80 FR 77351) announcing the availability activity was perceived as having the potential to affect systems within which opioid prescribing occurs (e.g., of the guideline and the supporting clinical and a specific aspect of the recommendations, the activity hospitals), and representation from community contextual evidence reviews for public comment. was disclosed, and the OGW member was recused organizations with interests in pain management and The comment period closed January 13, 2016. CDC from discussions related to that specific aspect of opioid prescribing.* Representatives from each of received more than 4,350 comments from the general the recommendations (e.g., urine drug testing and the SRG organizations were provided a copy of the public, including patients with chronic pain, clinicians, abuse-deterrent formulations). Disclosures for the guideline for comment. Each of these representatives families who have lost loved ones to overdose, OGW are reported. CDC and the OGW identified ad-hoc provided written comments. Once input was received medical associations, professional organizations, consultants to supplement the workgroup expertise, from the full SRG, CDC reviewed all comments and academic institutions, state and local governments, when needed, in the areas of pediatrics, occupational carefully considered them when revising the draft and industry. CDC reviewed each of the comments medicine, obstetrics and gynecology, medical guideline. and carefully considered them when revising the draft ethics, addiction psychiatry, physical medicine and guideline. rehabilitation, guideline development methodology, Constituent Engagement and the perspective of a family member who lost a To obtain initial perspectives from Federal Advisory Committee Review and loved one to opioid use disorder or overdose. constituents on the recommendation statements, Recommendation The BSC charged the OGW with reviewing including clinicians and prospective patients, CDC The National Center for Injury Prevention the quality of the clinical and contextual evidence convened a constituent engagement webinar and and Control (NCIPC) Board of Scientific Counselors reviews and reviewing each of the recommendation circulated information about the webinar in advance (BSC) is a federal advisory committee that advises statements and accompanying rationales. For each through announcements to partners. CDC hosted the and makes recommendations to the Secretary of recommendation statement, the OGW considered webinar on September 16 and 17, 2015, provided the Department of Health and Human Services, the the quality of the evidence, the balance of benefits information about the methodology for developing the Director of CDC, and the Director of NCIPC.* The and risks, the values and preferences of clinicians guideline, and presented the key recommendations. BSC makes recommendations regarding policies, and patients, the cost feasibility, and the category A fact sheet was posted on the CDC Injury Center strategies, objectives, and priorities, and reviews designation of the recommendation (A or B). The OGW website (http://www.cdc.gov/injury) summarizing the progress toward injury and violence prevention. also reviewed supplementary documents, including guideline development process and clinical practice CDC sought the BSC’s advice on the draft guideline. input provided by the CEG, SRG, peer reviewers, and areas addressed in the guideline; instructions were BSC members are special government employees the public. OGW members discussed the guideline included on how to submit comments via email. CDC appointed as CDC advisory committee members; accordingly during virtual meetings and drafted a received comments during and for 2 days following as such, all members completed an OGE Form 450 summary report of members’ observations, including the first webinar. Over 1,200 constituent comments to disclose relevant interests. BSC members also points of agreement and disagreement, and delivered were received. Comments were reviewed and carefully reported on their disclosures during meetings. the report to the BSC. considered when revising the draft guideline. NCIPC announced an open meeting of the Disclosures for the BSC are reported in the NCIPC BSC in the Federal Register on January 11, Peer Review guideline. 2016. The BSC met on January 28, 2016, to discuss Per the final information quality bulletin To assist in guideline review, on December the OGW report and deliberate on the draft guideline for peer review (https://www.whitehouse.gov/sites/ 14, 2015, via Federal Register notice, CDC announced itself. Members of the public provided comments at this default/files/omb/memoranda/fy2005/m05-03.pdf), the intent to form an Opioid Guideline Workgroup (OGW) meeting. After discussing the OGW report, deliberating peer review requirements applied to this guideline to provide observations on the draft guideline to the on specific issues about the draft guideline identified because it provides influential scientific information BSC. CDC provided the BSC with the draft guideline as at the meeting, and hearing public comment, the

39 BSC voted unanimously: to support the observations risk for opioid overdose, addiction, abuse, or or randomized clinical trials with notable limitations), made by the OGW; that CDC adopt the guideline misuse; and the comparative effectiveness of or type 4 (clinical experience and observations, recommendations that, according to the workgroup’s treatment strategies for managing patients with observational studies with important limitations, report, had unanimous or majority support; and that addiction (KQ4). or randomized clinical trials with several major CDC further consider the guideline recommendations • The effects of prescribing opioid therapy versus limitations). When no studies were present, evidence for which the group had mixed opinions. CDC carefully not prescribing opioid therapy for acute pain on was considered to be insufficient. Per GRADE methods, considered the OGW observations, public comments, long-term use (KQ5). type of evidence was categorized by study design as and BSC recommendations, and revised the guideline The review was focused on the well as a function of limitations in study design or in response. effectiveness of long-term opioid therapy on long- implementation, imprecision of estimates, variability term (>1 year) outcomes related to pain, function, in findings, indirectness of evidence, publication Summary of the Clinical Evidence Review and quality of life to ensure that findings are relevant bias, magnitude of treatment effects, dose-response to patients with chronic pain and long-term opioid gradient, and constellation of plausible biases that Primary Clinical Questions prescribing. The effectiveness of short-term opioid could change effects. Results were synthesized CDC conducted a clinical systematic review therapy has already been established.10 However, qualitatively, highlighting new evidence identified of the scientific evidence to identify the effectiveness, opioids have unique effects such as tolerance and during the update process. Meta-analysis was not benefits, and harms of long-term opioid therapy for physical dependence that might influence assessments attempted due to the small numbers of studies, 47,48 chronic pain, consistent with the GRADE approach. of benefit over time. variability in study designs and clinical heterogeneity, Long-term opioid therapy is defined as use of opioids These effects raise questions about and methodological shortcomings of the studies. on most days for >3 months. A previously published whether findings on short-term effectiveness of More detailed information about data sources and AHRQ funded systematic review on the effectiveness opioid therapy can be extrapolated to estimate searches, study selection, data extraction and quality and risks of long-term opioid therapy for chronic pain benefits of long-term therapy for chronic pain. Thus, assessment, data synthesis, and update search yield 14,52 comprehensively addressed four clinical questions. it is important to consider studies that provide data and new evidence for the current review is provided CDC, with the assistance of a methodology expert, on long-term benefit. For certain opioid-related in the Clinical Evidence Review (http://stacks.cdc.gov/ searched the literature to identify newly published harms (overdose, fractures, falls, motor vehicle view/cdc/38026). studies on these four original questions. Because crashes), observational studies were included with long-term opioid use might be affected by use of outcomes measured at shorter intervals because Summary of Findings for Clinical Questions opioids for acute pain, CDC subsequently developed such outcomes can occur early during opioid therapy, The main findings of this updated review a fifth clinical question (last in the series below), and and such harms are not captured well in short-term are consistent with the findings of the 2014 AHRQ 14 in collaboration with a methodologist conducted a clinical trials. A detailed listing of the key questions is report. In summary, evidence on long-term opioid systematic review of the scientific evidence to address provided in the Clinical Evidence Review (http://stacks. therapy for chronic pain outside of end-of-life care it. In brief, five clinical questions were addressed: cdc.gov/view/cdc/38026). remains limited, with insufficient evidence to determine • The effectiveness of long-term opioid therapy long-term benefits versus no opioid therapy, though versus placebo, no opioid therapy, or non-opioid Clinical Evidence Systematic Review Methods evidence suggests risk for serious harms that appears therapy for long term (≥1 year) outcomes Complete methods and data for the 2014 to be dose-dependent. These findings supplement related to pain, function, and quality of life, AHRQ report, upon which this updated systematic findings from a previous review of the effectiveness and how effectiveness varies according to the review is based, have been published previously.14,52 of opioids for adults with chronic non-cancer pain. type/cause of pain, patient demographics, and Study authors developed the protocol using a In this previous review, based on randomized trials patient comorbidities (Key Question [KQ] 1). standardized process53 with input from experts and the predominantly ≤12 weeks in duration, opioids were • The risks of opioids versus placebo or no public and registered the protocol in the PROSPERO found to be moderately effective for pain relief, with opioids on abuse, addiction, overdose, and database.54 For the 2014 AHRQ report, a research small benefits for functional outcomes; although other harms, and how harms vary according to librarian searched MEDLINE, the Cochrane Central estimates vary, based on uncontrolled studies, a the type/cause of pain, patient demographics, Register of Controlled Trials, the Cochrane Database of high percentage of patients discontinued long-term patient comorbidities, and dose (KQ2). Systematic Reviews, PsycINFO, and CINAHL for English opioid use because of lack of efficacy and because of 10 • The comparative effectiveness of opioid dosing language articles published January 2008 through adverse events. strategies (different methods for initiating and August 2014, using search terms for opioid therapy, The GRADE evidence summary with type titrating opioids; immediate release versus ER/ specific opioids, chronic pain, and comparative study of evidence ratings for the five clinical questions LA opioids; different ER/LA opioids; immediate designs. Also included were relevant studies from an for the current evidence review are outlined (Table release plus ER/LA opioids versus ER/LA earlier review10 in which searches were conducted 1). This summary is based on studies included in opioids alone; scheduled, continuous versus without a date restriction, reference lists were the AHRQ 2014 review (35 studies) plus additional as-needed dosing; dose escalation versus reviewed, and ClinicalTrials.gov was searched. CDC studies identified in the updated search (seven dose maintenance; opioid rotation versus updated the AHRQ literature search using the same studies). Additional details on findings from the maintenance; different strategies for treating search strategies as in the original review including original review are provided in the full 2014 AHRQ 14,52 acute exacerbations of chronic pain; decreasing studies published before April, 2015. Seven additional report. Full details on the clinical evidence review opioid doses or tapering off versus continuation; studies met inclusion criteria and were added to the findings supporting this guideline are provided in the and different tapering protocols and strategies) review. CDC used the GRADE approach outlined in Clinical Evidence Review (http://stacks.cdc.gov/view/ (KQ3). the ACIP Handbook for Developing Evidence-Based cdc/38026). • The accuracy of instruments for predicting 47 Recommendations to rate the quality of evidence Effectiveness risk for opioid overdose, addiction, abuse, or for the full body of evidence (evidence from the misuse; the effectiveness of risk mitigation For KQ1, no study of opioid therapy 2014 AHRQ review plus the update) for each versus placebo, no opioid therapy, or non-opioid strategies (use of risk prediction instruments); clinical question. Evidence was categorized into the effectiveness of risk mitigation strategies therapy for chronic pain evaluated long-term (≥1 following types: type 1 (randomized clinical trials or year) outcomes related to pain, function, or quality including opioid management plans, patient overwhelming evidence from observational studies), education, urine drug testing, prescription drug of life. Most placebo controlled randomized clinical type 2 (randomized clinical trials with important trials were ≤6 weeks in duration. Thus, the body of monitoring program (PDMP) data, monitoring limitations, or exceptionally strong evidence from instruments, monitoring intervals, pill counts, evidence for KQ1 is rated as insufficient (0 studies observational studies), type 3 (observational studies, 14 and abuse-deterrent formulations for reducing contributing). 40 Harms with an immediate-release opioid, with risk greatest predictive accuracy of the ORT, the Screener and For KQ2, the body of evidence is rated in the first 2 weeks after initiation of treatment.77 Opioid Assessment for Patients with Pain-Revised as type 3 (12 studies contributing; 11 from the For comparative effectiveness and harms (SOAPP-R), and the Brief Risk Interview. For the ORT, original review plus one new study). One fair quality of ER/LA opioids, the 2014 AHRQ report included sensitivity was 0.58 and 0.75 and specificity 0.54 and cohort study found that long-term opioid therapy is three randomized, head-to-head trials of various 0.86; for the SOAPP-R, sensitivity was 0.53 and 0.25 associated with increased risk for an opioid abuse ER/LA opioids that found no clear differences in and specificity 0.62 and 0.73; and for the Brief Risk or dependence diagnosis (as defined by ICD-9-CM 1-year outcomes related to pain or function78–80 Interview, sensitivity was 0.73 and 0.83 and specificity codes) versus no opioid prescription.22 Rates of but had methodological shortcomings. A fair-quality 0.43 and 0.88. For the ORT, positive likelihood ratios opioid abuse or dependence diagnosis ranged from retrospective cohort study based on national ranged from non-informative (positive likelihood ratio 0.7% with lower dose (≤36 MME) chronic therapy to Veterans Health Administration system pharmacy close to 1) to moderately useful (positive likelihood 6.1% with higher dose (≥120 MME) chronic therapy, data found that methadone was associated with lower ratio >5). The SOAPP-R was associated with non- versus 0.004% with no opioids prescribed. Ten fair overall risk for all-cause mortality versus morphine81, informative likelihood ratios (estimates close to 1) in quality uncontrolled studies reported estimates of and a fair-quality retrospective cohort study based both studies. opioid abuse, addiction, and related outcomes.55–65 on Oregon Medicaid data found no statistically No study evaluated the effectiveness of In primary care settings, prevalence of opioid significant differences between methadone and risk mitigation strategies (use of risk assessment dependence (using DSMIV criteria) ranged from 3% long-acting morphine in risk for death or overdose instruments, opioid management plans, patient to 26% (55,56,59). In pain clinic settings, prevalence symptoms.82 However, a new observational study83 education, urine drug testing, use of PDMP data, use of addiction ranged from 2% to 14%.57,58,60,61,63–65 found methadone associated with increased risk of monitoring instruments, more frequent monitoring Factors associated with increased for overdose versus sustained release morphine intervals, pill counts, or use of abuse-deterrent risk for misuse included history of substance use among Tennessee Medicaid patients. The observed formulations) for improving outcomes related to disorder, younger age, major depression, and use of inconsistency in study findings suggests that risks overdose, addiction, abuse, or misuse. psychotropic medications.55,62 Two studies reported of methadone might vary in different settings as a on the association between opioid use and risk for function of different monitoring and management Effects of Opioid Therapy for Acute Pain on overdose.66,67 One large fair quality retrospective protocols, though more research is needed to Long-Term Use cohort study found that recent opioid use was understand factors associated with safer methadone For KQ5, the body of evidence is rated as associated with increased risk for any overdose events prescribing. type 3 (two new studies contributing). Two fair-quality and serious overdose events versus non use.66 It also For dose escalation, the 2014 AHRQ retrospective cohort studies found opioid therapy found higher doses associated with increased risk. report included one fair-quality randomized trial prescribed for acute pain associated with greater Relative to 1–19 MME/day, the adjusted hazard ratio that found no differences between more liberal dose likelihood of long-term use. One study evaluated (HR) for any overdose event (consisting of mostly escalation and maintenance of current doses after opioid-naïve patients who had undergone low-risk nonfatal overdose) was 1.44 for 20 to 49 MME/ 12 months in pain, function, all-cause withdrawals, surgery, such as cataract surgery and varicose vein day, 3.73 for 50–99 MME/day, and 8.87 for ≥100 or withdrawals due to opioid misuse.84 However, stripping.94 Use of opioids within 7 days of surgery MME/day. A similar pattern was observed for serious the difference in opioid dosages prescribed at the was associated with increased risk for use at 1 year. overdose. A good quality population-based, nested end of the trial was relatively small (mean 52 MME/ The other study found that among patients case-control study also found a dose-dependent day with more liberal dosing versus 40 MME/day). with a workers’ compensation claim for acute low association with risk for overdose death.67 Relative Evidence on other comparisons related to opioid back pain, compared to patients who did not receive to 1–19 MME/day, the adjusted odds ratio (OR) was dosing strategies (ER/LA versus immediate-release opioids early after injury (defined as use within 1.32 for 20–49 MME/day, 1.92 for 50–99 MME/day, opioids; immediate-release plus ER/LA opioids versus 15 days following onset of pain), patients who did 2.04 for 100–199 MME/day, and 2.88 for ≥200 ER/LA opioids alone; scheduled continuous dosing receive early opioids had an increased likelihood of MME/day. versus as-needed dosing; or opioid rotation versus receiving five or more opioid prescriptions 30–730 Findings of increased fracture risk maintenance of current therapy; long-term effects of days following onset that increased with greater early for current opioid use, versus non use, were strategies for treating acute exacerbations of chronic exposure. Versus no early opioid use, the adjusted OR mixed in two studies.68,69 Two studies found an pain) was not available or too limited to determine was 2.08 (95% CI = 1.55–2.78) for 1-140 MME/day association between opioid use and increased risk effects on long-term clinical outcomes. For example, and increased to 6.14 (95% confidence interval [CI] for cardiovascular events.70,71 Indirect evidence was evidence on the comparative effectiveness of opioid = 4.92–7.66) for ≥450 MME/day.95 found for endocrinologic harms (increased use of tapering or discontinuation versus maintenance, and medications for erectile dysfunction or testosterone of different opioid tapering strategies, was limited to Summary of the Contextual Evidence Review from one previously included study; laboratory- small, poor quality studies.85–87 defined androgen deficiency from one newly reviewed Primary Areas of Focus study).72,73 One study found that opioid dosages ≥20 Risk Assessment and Mitigation Contextual evidence is complementary MME/day were associated with increased odds of For KQ4, the body of evidence is rated information that assists in translating the clinical road trauma among drivers.74 as type 3 for the accuracy of risk assessment tools research findings into recommendations. CDC and insufficient for the effectiveness of use of conducted contextual evidence reviews on four topics Opioid Dosing Strategies risk assessment tools and mitigation strategies in to supplement the clinical evidence review findings: For KQ3, the body of evidence is rated reducing harms (six studies contributing; four from the • Effectiveness of nonpharmacologic (e.g., as type 4 (14 studies contributing; 12 from the original review plus two new studies). The 2014 AHRQ cognitive behavioral therapy [CBT], exercise original review plus two new studies). For initiation report included four studies88–91 on the accuracy of therapy, interventional treatments, and and titration of opioids, the 2014 AHRQ report found risk assessment instruments, administered prior to multimodal pain treatment) and non-opioid insufficient evidence from three fair-quality, open label opioid therapy initiation, for predicting opioid abuse pharmacologic treatments (e.g., acetaminophen, trials to determine comparative effectiveness of ER/ or misuse. Results for the Opioid Risk Tool (ORT)89–91 nonsteroidal anti-inflammatory drugs [NSAIDs], LA versus immediate-release opioids for titrating were extremely inconsistent; evidence for other antidepressants, and anticonvulsants), including patients to stable pain control.75,76 One new fair- risk assessment instruments was very sparse, and studies of any duration. quality cohort study of Veterans Affairs patients found studies had serious methodological shortcomings. • Benefits and harms of opioid therapy (including initiation of therapy with an ER/LA opioid associated One additional fair-quality92 and one poor quality93 additional studies not included in the clinical with greater risk for nonfatal overdose than initiation study identified for this update compared the evidence review, such as studies that were not restricted to patients with chronic pain, 41 evaluated outcomes at any duration, performed CDC constructed narrative summaries and tables low back pain106,110, NSAIDs and COX-2 inhibitors ecological analyses, or used observational study based on relevant articles that met inclusion criteria, do have risks, including gastrointestinal bleeding designs other than cohort and case-cohort which are provided in the Contextual Evidence Review or perforation as well as renal and cardiovascular control studies) related to specific opioids, (http://stacks.cdc.gov/view/cdc/38027). risks.111 FDA has recently strengthened existing high-dose therapy, co-prescription with other Findings from the contextual reviews label warnings that NSAIDs increase risks for heart controlled substances, duration of use, special provide indirect evidence and should be interpreted attack and stroke, including that these risks might populations, and potential usefulness of risk accordingly. CDC did not formally rate the quality of increase with longer use or at higher doses.112 stratification/mitigation approaches, in addition evidence for the studies included in the contextual Several guidelines agree that first and second-line to effectiveness of treatments associated with evidence review using the GRADE method. The drugs for neuropathic pain include anticonvulsants addressing potential harms of opioid therapy studies that addressed benefits and harms, values (gabapentin or pregabalin), tricyclic antidepressants, (opioid use disorder). and preferences, and resource allocation most often and SNRIs.113–116 Interventional approaches such as • Clinician and patient values and preferences employed observational methods, used short follow up epidural injection for certain conditions (e.g., lumbar related to opioids and medication risks, benefits, periods, and evaluated selected samples. Therefore radiculopathy) can provide short-term improvement and use. the strength of the evidence from these contextual in pain.117–119 Epidural injection has been associated • Resource allocation including costs and review areas was considered to be low, comparable with rare but serious adverse events, including loss of economic efficiency of opioid therapy and risk to type 3 or type 4 evidence. The quality of evidence vision, stroke, paralysis, and death.120 mitigation strategies. for non-opioid pharmacologic and nonpharmacologic CDC also reviewed clinical guidelines that pain treatments was generally rated as moderate, Benefits and Harms of Opioid Therapy were relevant to opioid prescribing and could inform comparable to type 2 evidence, in systematic reviews Balance between benefits and harms is or complement the CDC recommendations under and clinical guidelines (e.g., for treatment of chronic a critical factor influencing the strength of clinical development (e.g., guidelines on nonpharmacologic neuropathic pain, low back pain, osteoarthritis, recommendations. In particular, CDC considered and non-opioid pharmacologic treatments and and fibromyalgia). Similarly, the quality of evidence what is known from the epidemiology research about guidelines with recommendations related to specific on pharmacologic and psychosocial opioid use benefits and harms related to specific opioids and clinician actions such as urine drug testing or opioid disorder treatment was generally rated as moderate, formulations, high dose therapy, co-prescription with tapering protocols). comparable to type 2 evidence, in systematic reviews other controlled substances, duration of use, special and clinical guidelines. populations, and risk stratification and mitigation Contextual Evidence Review Methods approaches. Additional information on benefits and CDC conducted a contextual evidence Summary of Findings for Contextual Areas harms of long-term opioid therapy from studies review to assist in developing the recommendations Full narrative reviews and tables that meeting rigorous selection criteria is provided in the by providing an assessment of the balance of summarize key findings from the contextual evidence clinical evidence review (e.g., see KQ2). CDC also benefits and harms, values and preferences, and review are provided in the Contextual Evidence Review considered the number of persons experiencing cost, consistent with the GRADE approach. Given (http://stacks.cdc.gov/view/cdc/38027). chronic pain, numbers potentially benefiting from the public health urgency for developing opioid opioids, and numbers affected by opioid-related prescribing recommendations, a rapid review was Effectiveness of Nonpharmacologic and Non- harms. A review of these data is presented in the required for the contextual evidence review for the opioid Pharmacologic Treatments background section of this document, with detailed current guideline. Rapid reviews are used when Several nonpharmacologic and non-opioid information provided in the Contextual Evidence there is a need to stream-line the systematic review pharmacologic treatments have been shown to be Review (http://stacks.cdc.gov/view/cdc/38027). process to obtain evidence quickly.96 Methods used effective in managing chronic pain in studies ranging Finally, CDC considered the effectiveness of treatments to streamline the process include limiting searches in duration from 2 weeks to 6 months. For example, that addressed potential harms of opioid therapy by databases, years, and languages considered, and CBT that trains patients in behavioral techniques and (opioid use disorder). truncating quality assessment and data abstraction helps patients modify situational factors and cognitive Regarding specific opioids and protocols. CDC conducted “rapid reviews” of the processes that exacerbate pain has small positive formulations, as noted by FDA, there are serious risks contextual evidence on nonpharmacologic and non- effects on disability and catastrophic thinking.97 of ER/LA opioids, and the indication for this class opioid pharmacologic treatments, benefits and harms, Exercise therapy can help reduce pain and improve of medications is for management of pain severe values and preferences, and resource allocation. function in chronic low back pain98, improve function enough to require daily, around-the-clock, long-term Detailed information about contextual and reduce pain in osteoarthritis of the knee99 and opioid treatment in patients for whom other treatment evidence data sources and searches, inclusion hip100, and improve wellbeing, fibromyalgia symptoms, options (e.g., non-opioid analgesics or immediate- criteria, study selection, and data extraction and and physical function in fibromyalgia101. Multimodal release opioids) are ineffective, not tolerated, or synthesis are provided in the Contextual Evidence and multidisciplinary therapies (e.g., therapies would be otherwise inadequate to provide sufficient Review (http://stacks.cdc.gov/view/cdc/38027). In that combine exercise and related therapies with management of pain.121 Time-scheduled opioid use brief, CDC conducted systematic literature searches psychologically based approaches) can help reduce was associated with substantially higher average to identify original studies, systematic reviews, and pain and improve function more effectively than daily opioid dosage than as-needed opioid use in clinical guidelines, depending on the topic being single modalities.102,103 Non-opioid pharmacologic one study.122 Methadone has been associated with searched. CDC also solicited publication referrals from approaches used for pain include analgesics such as disproportionate numbers of overdose deaths relative subject matter experts. Given the need for a rapid acetaminophen, NSAIDs, and cyclooxygenase 2 (COX- to the frequency with which it is prescribed for pain. review process, grey literature (e.g., literature by 2) inhibitors; selected anticonvulsants; and selected Methadone has been found to account for as much academia, organizations, or government in the forms antidepressants (particularly tricyclics and serotonin as a third of opioid related overdose deaths involving of reports, documents, or proceedings not published and norepinephrine reuptake inhibitors [SNRIs]). single or multiple drugs in states that participated by commercial publishers) was not systemically Multiple guidelines recommend acetaminophen as in the Drug Abuse Warning Network, which was searched. Database sources, including MEDLINE, first-line pharmacotherapy for osteoarthritis104–109 or more than any opioid other than oxycodone, despite PsycINFO, the Cochrane Central Register of Controlled for low back pain110 but note that it should be avoided representing <2% of opioid prescriptions outside Trials, and the Cochrane Database of Systematic in liver failure and that dosage should be reduced of opioid treatment programs in the United States; Reviews, varied by topic. Multiple reviewers scanned in patients with hepatic insufficiency or a history of further, methadone was involved in twice as many study abstracts identified through the database alcohol abuse.109 Although guidelines also recommend single drug deaths as any other prescription opioid.123 searches and extracted relevant studies for review. NSAIDs as first-line treatment for osteoarthritis or

42 Regarding high-dose therapy, several the types of study designs and methods employed, Regarding risk mitigation approaches, epidemiologic studies that were excluded from the and there is no clear consensus regarding association limited evidence was found regarding benefits and clinical evidence review because patient samples with risk for developing obstructive sleep apnea harms. Although no studies were found to examine were not restricted to patients with chronic pain also syndrome.132 However, opioid therapy can decrease prescribing of naloxone with opioid pain medication in examined the association between opioid dosage and respiratory drive, a high percentage of patients on primary care settings, naloxone distribution through overdose risk.23,24,124–126 Consistent with the clinical long-term opioid therapy have been reported to have community-based programs providing prevention evidence review, the contextual review found that an abnormal apneahypopnea index133, opioid therapy services for substance users has been demonstrated opioid-related overdose risk is dose-dependent, with can worsen central sleep apnea in obstructive sleep to be associated with decreased risk for opioid higher opioid dosages associated with increased apnea patients, and it can cause further desaturation overdose death at the community level.147 overdose risk. Two of these studies23,24, as well as in obstructive sleep apnea patients not on continuous Concerns have been raised that the two studies in the clinical evidence review66,67, positive airway pressure (CPAP).31 Reduced renal prescribing changes such as dose reduction might be evaluated similar MME/day dose ranges for or hepatic function can result in greater peak effect associated with unintended negative consequences, association with overdose risk. In these four studies, and longer duration of action and reduce the dose such as patients seeking heroin or other illicitly compared with opioids prescribed at <20 MME/day, at which respiratory depression and overdose obtained opioids48 or interference with appropriate the odds of overdose among patients prescribed occurs.134 Age-related changes in patients aged ≥65 pain treatment.149 With the exception of a study opioids for chronic nonmalignant pain were between years, such as reduced renal function and medication noting an association between an abuse deterrent 1.367 and 1.924 for dosages of 20 to <50 MME/day, clearance, even in the absence of renal disease135, formulation of OxyContin and heroin use, showing between 1.967 and 4.624 for dosages of 50 to <100 result in a smaller therapeutic window between safe that some patients in qualitative interviews reported MME/day, and between 2.067 and 8.966 for dosages of dosages and dosages associated with respiratory switching to another opioid, including heroin, for many ≥100 MME/day. Compared with dosages of 1-<20 depression and overdose. Older adults might also reasons, including cost and availability as well as ease MME/day, absolute risk difference approximation for be at increased risk for falls and fractures related of use150, CDC did not identify studies evaluating these 50-<100 MME/day was 0.15% for fatal overdose24 to opioids.136–138 Opioids used in pregnancy can be potential outcomes. and 1.40% for any overdose66, and for ≥100 MME/ associated with additional risks to both mother and Finally, regarding the effectiveness of day was 0.25% for fatal overdose24 and 4.04% for fetus. Some studies have shown an association of opioid use disorder treatments, methadone and any overdose.66 A recent study of Veterans Health opioid use in pregnancy with birth defects, including buprenorphine for opioid use disorder have been Administration patients with chronic pain found that neural tube defects139,140, congenital heart defects140, found to increase retention in treatment and to patients who died of overdoses related to opioids and gastroschisis140; preterm delivery141, poor fetal decrease illicit opioid use among patients with opioid were prescribed higher opioid dosages (mean: growth141, and stillbirth.141 Importantly, in some use disorder involving heroin.151–153 Although findings 98 MME/day; median: 60 MME/day) than controls cases, opioid use during pregnancy leads to neonatal are mixed, some studies suggest that effectiveness (mean: 48 MME/day, median: 25 MME/day.127 Finally, opioid withdrawal syndrome.142 Patients with mental is enhanced when psychosocial treatments (e.g., another recent study of overdose deaths among health comorbidities and patients with histories of contingency management, community reinforcement, state residents with and without opioid prescriptions substance use disorders might be at higher risk than psychotherapeutic counseling, and family therapy) revealed that prescription opioid-related overdose other patients for opioid use disorder.62,143,144 Recent are used in conjunction with medication assisted mortality rates rose rapidly up to prescribed doses analyses found that depressed patients were at therapy; for example, by reducing opioid misuse and of 200 MME/day, after which the mortality rates higher risk for drug overdose than patients without increasing retention during maintenance therapy, and continued to increase but grew more gradually.128 A depression, particularly at higher opioid dosages, improving compliance after detoxification.154,155 listing of common opioid medications and their MME although investigators were unable to distinguish equivalents is provided (Table 2). unintentional overdose from suicide attempts.145 In Clinician and Patient Values and Preferences Regarding co-prescription of opioids with case-control and case-cohort studies, substance Clinician and patient values and benzodiazepines, epidemiologic studies suggest abuse/dependence was more prevalent among preferences can inform how benefits and harms of that concurrent use of benzodiazepines and opioids patients experiencing overdose than among patients long-term opioid therapy are weighted and estimate might put patients at greater risk for potentially fatal not experiencing overdose (12% versus 6% [66], the effort and resources required to effectively overdose. Three studies of fatal overdose deaths 40% versus 10% [24], and 26% versus 9% [23]). provide implementation support. Many physicians found evidence of concurrent benzodiazepine use Regarding risk stratification approaches, lack confidence in their ability to prescribe opioids in 31%–61% of decedents.67,128,129 In one of these limited evidence was found regarding benefits and safely156, to predict157 or detect158 prescription drug studies67, among decedents who received an opioid harms. Potential benefits of PDMPs and urine drug abuse, and to discuss abuse with their patients.158 prescription, those whose deaths were related to testing include the ability to identify patients who Although clinicians have reported favorable beliefs opioids were more likely to have obtained opioids from might be at higher risk for opioid overdose or opioid and attitudes about improvements in pain and multiple physicians and pharmacies than decedents use disorder, and help determine which patients will quality of life attributed to opioids 59, most consider whose deaths were not related to opioids. benefit from greater caution and increased monitoring prescription drug abuse to be a “moderate” or “big” Regarding duration of use, patients can or interventions when risk factors are present. For problem in their community, and large proportions experience tolerance and loss of effectiveness of example, one study found that most fatal overdoses are “very” concerned about opioid addiction (55%) opioids over time.130 Patients who do not experience could be identified retrospectively on the basis of two and death (48%).160 Clinicians do not consistently use clinically meaningful pain relief early in treatment (i.e., pieces of information, multiple prescribers and high practices intended to decrease the risk for misuse, within 1 month) are unlikely to experience pain relief total daily opioid dosage, both important risk factors such as PDMPs161,162, urine drug testing163, and opioid with longer-term use.131 for overdose124,146 that are available to prescribers in treatment agreements.164 This is likely due in part to Regarding populations potentially at the PDMP.124 However, limited evaluation of PDMPs challenges related to registering for PDMP access greater risk for harm, risk is greater for patients with at the state level has revealed mixed effects on and logging into the PDMP (which can interrupt sleep apnea or other causes of sleep disordered changes in prescribing and mortality outcomes.28 normal clinical work-flow if data are not integrated breathing, patients with renal or hepatic insufficiency, Potential harms of risk stratification include into electronic health record systems)165, competing older adults, pregnant women, patients with underestimation of risks of opioid therapy when clinical demands, perceived inadequate time to depression or other mental health conditions, and screening tools are not adequately sensitive, as well discuss the rationale for urine drug testing and to patients with alcohol or other substance use disorders. as potential overestimation of risk, which could lead to order confirmatory testing, and feeling unprepared to Interpretation of clinical data on the effects of opioids inappropriate clinical decisions. interpret and address results.166 on sleep-disordered breathing is difficult because of

43 Many patients do not have an opinion There are 12 recommendations (Box for both pain and function are anticipated about “opioids” or know what this term means.167 1). Each recommendation is followed by a rationale to outweigh risks to the patient. If opioids Most are familiar with the term “narcotics.” About for the recommendation, with considerations for are used, they should be combined with a third associated “narcotics” with addiction or implementation noted. In accordance with the ACIP nonpharmacologic therapy and non-opioid abuse, and about half feared “addiction” from long- GRADE process, CDC based the recommendations pharmacologic therapy, as appropriate term “narcotic” use.168 Most patients taking opioids on consideration of the clinical evidence, contextual (recommendation category: A, evidence experience side effects (73% of patients taking evidence (including benefits and harms, values and type: 3). hydrocodone for non-cancer pain11, 96% of patients preferences, resource allocation), and expert opinion. Patients with pain should receive taking opioids for chronic pain12), and side effects, For each recommendation statement, CDC notes the treatment that provides the greatest benefits relative rather than pain relief, have been found to explain recommendation category (A or B) and the type of to risks. The contextual evidence review found most of the variation in patients’ preferences related the evidence (1, 2, 3, or 4) supporting the statement that many nonpharmacologic therapies, including to taking opioids.12 For example, patients taking (Box 2). Expert opinion is reflected within each of physical therapy, weight loss for knee osteoarthritis, hydrocodone for non-cancer pain commonly reported the recommendation rationales. While there was psychological therapies such as CBT, and certain side effects including dizziness, headache, fatigue, not an attempt to reach consensus among experts, interventional procedures can ameliorate chronic drowsiness, nausea, vomiting, and constipation.11 experts from the Core Expert Group and from the pain. There is high quality evidence that exercise Patients with chronic pain in focus groups emphasized Opioid Guideline Workgroup (“experts”) expressed therapy (a prominent modality in physical therapy) effectiveness of goal setting for increasing motivation overall, general support for all recommendations. for hip100 or knee99 osteoarthritis reduces pain and and functioning.168 Patients taking high dosages Where differences in expert opinion emerged for improves function immediately after treatment and report reliance on opioids despite ambivalence about detailed actions within the clinical recommendations that the improvements are sustained for at least their benefits169 and regardless of pain reduction, or for implementation considerations, CDC notes the 2–6 months. Previous guidelines have strongly reported problems, concerns, side effects, or differences of opinion in the supporting rationale recommended aerobic, aquatic, and/or resistance perceived helpfulness.13 statements. exercises for patients with osteoarthritis of the Category A recommendations indicate knee or hip.176 Exercise therapy also can help Resource Allocation that most patients should receive the recommended reduce pain and improve function in low back pain Resource allocation (cost) is an important course of action; category B recommendations and can improve global wellbeing and physical consideration in understanding the feasibility indicate that different choices will be appropriate for function in fibromyalgia.98,101 Multimodal therapies of clinical recommendations. CDC searched for different patients, requiring clinicians to help patients and multidisciplinary biopsychosocial rehabilitation evidence on opioid therapy compared with other arrive at a decision consistent with patient values and combining approaches (e.g., psychological therapies treatments; costs of misuse, abuse, and overdose preferences and specific clinical situations. Consistent with exercise) can reduce long-term pain and disability from prescription opioids; and costs of specific risk with the ACIP47 and GRADE process48, category A compared with usual care and compared with physical mitigation strategies (e.g., urine drug testing). Yearly recommendations were made, even with type 3 and 4 treatments (e.g., exercise) alone. Multimodal therapies direct and indirect costs related to prescription evidence, when there was broad agreement that the are not always available or reimbursed by insurance opioids have been estimated (based on studies advantages of a clinical action greatly outweighed the and can be time consuming and costly for patients. published since 2010) to be $53.4 billion for non disadvantages based on a consideration of benefits Interventional approaches such as arthrocentesis medical use of prescription opioids170; $55.7 billion and harms, values and preferences, and resource and intra-articular glucocorticoid injection for for abuse, dependence (i.e., opioid use disorder), allocation. Category B recommendations were made pain associated with rheumatoid arthritis117 or and misuse of prescription opioids171; and $20.4 when there was broad agreement that the advantages osteoarthritis118 and subacromial corticosteroid billion for direct and indirect costs related to opioid- and disadvantages of a clinical action were more injection for rotator cuff disease119 can provide short- related overdose alone.172 In 2012, total expenses for balanced, but advantages were significant enough to term improvement in pain and function. Evidence is outpatient prescription opioids were estimated at $9.0 warrant a recommendation. All recommendations are insufficient to determine the extent to which repeated billion, an increase of 120% from 2002.173 Although category A recommendations, with the exception of glucocorticoid injection increases potential risks such there are perceptions that opioid therapy for chronic recommendation 10, which is rated as category B. as articular cartilage changes (in osteoarthritis) and pain is less expensive than more time-intensive Recommendations were associated with a range of sepsis.118 Serious adverse events are rare but have nonpharmacologic management approaches, many evidence types, from type 2 to type 4. been reported with epidural injection.120 pain treatments, including acetaminophen, NSAIDs, In summary, the categorization of Several non-opioid pharmacologic tricyclic antidepressants, and massage therapy, are recommendations was based on the following therapies (including acetaminophen, NSAIDs, and associated with lower mean and median annual costs assessment: selected antidepressants and anticonvulsants) are compared with opioid therapy.174 COX-2 inhibitors, • No evidence shows a long-term benefit of effective for chronic pain. In particular, acetaminophen SNRIs, anticonvulsants, topical analgesics, physical opioids in pain and function versus no opioids and NSAIDs can be useful for arthritis and low back therapy, and CBT are also associated with lower for chronic pain with outcomes examined at pain. Selected anticonvulsants such as pregabalin and median annual costs compared with opioid therapy.174 least 1 year later (with most placebo-controlled gabapentin can improve pain in diabetic neuropathy Limited information was found on costs of strategies randomized trials ≤6 weeks in duration). and post-herpetic neuralgia (contextual evidence to decrease risks associated with opioid therapy; • Extensive evidence shows the possible harms of review). Pregabalin, gabapentin, and carbamazepine however, urine drug testing, including screening and opioids (including opioid use disorder, overdose, are FDA approved for treatment of certain confirmatory tests, has been estimated to cost $211– and motor vehicle injury). neuropathic pain conditions, and pregabalin is FDA $363 per test.175 • Extensive evidence suggests some benefits approved for fibromyalgia management. In patients of nonpharmacologic and non-opioid with or without depression, tricyclic antidepressants Recommendations pharmacologic treatments compared with long- and SNRIs provide effective analgesia for neuropathic The recommendations are grouped into term opioid therapy, with less harm. pain conditions including diabetic neuropathy and three areas for consideration: Determining When to Initiate or Continue Opioids post-herpetic neuralgia, often at lower dosages • Determining when to initiate or continue opioids for Chronic Pain and with a shorter time to onset of effect than for for chronic pain. 1. Nonpharmacologic therapy and non-opioid treatment of depression (see contextual evidence • Opioid selection, dosage, duration, follow-up, pharmacologic therapy are preferred for review). Tricyclics and SNRIs can also relieve and discontinuation. chronic pain. Clinicians should consider fibromyalgia symptoms. The SNRI duloxetine is FDA • Assessing risk and addressing harms of opioid opioid therapy only if expected benefits approved for the treatment of diabetic neuropathy use.

44 BOX 1. CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative, and end-of-life care

Determining When to Initiate or Continue Opioids for Chronic Pain 1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. 2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. 3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation 4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long- acting (ER/LA) opioids. 5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day. 6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed. 7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids.

Assessing Risk and Addressing Harms of Opioid Use 8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present. 9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months. 10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs. 11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. 12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder.

* All recommendations are category A (apply to all patients outside of active cancer treatment, palliative care, and end-of-life care) except recommendation 10 (designated category B, with individual decision making required); see full guideline for evidence ratings. and fibromyalgia. Because patients with chronic gastrointestinal, and liver disease (see contextual long-term opioid use for chronic pain are uncertain, pain often suffer from concurrent depression144, evidence review). For example, acetaminophen can be risks associated with long-term opioid use are clearer and depression can exacerbate physical symptoms hepatotoxic at dosages of > 3-4 grams/day and at and significant. Based on the clinical evidence review, including pain177, patients with co-occurring pain lower dosages in patients with chronic alcohol use or long-term opioid use for chronic pain is associated and depression are especially likely to benefit from liver disease (109). NSAID use has been associated with serious risks including increased risk for opioid antidepressant medication (see Recommendation with gastritis, peptic ulcer disease, cardiovascular use disorder, overdose, myocardial infarction, and 8). Non-opioid pharmacologic therapies are not events111,112, and fluid retention, and most NSAIDs motor vehicle injury (KQ2). At a population level, more generally associated with substance use disorder, and (choline magnesium trilisate and selective COX- than 165,000 persons in the United States have died the numbers of fatal overdoses associated with non- 2 inhibitors are exceptions) interfere with platelet from opioid pain medication-related overdoses since opioid medications are a fraction of those associated aggregation.179 Clinicians should review FDA approved 1999 (see Contextual Evidence Review). with opioid medications (contextual evidence review). labeling including boxed warnings before initiating Integrated pain management requires For example, acetaminophen, NSAIDs, and opioid pain treatment with any pharmacologic therapy. coordination of medical, psychological, and social medication were involved in 881, 228, and 16,651 Although opioids can reduce pain during aspects of health care and includes primary pharmaceutical overdose deaths in the United States short-term use, the clinical evidence review found care, mental health care, and specialist services in 2010178. However, non-opioid pharmacologic insufficient evidence to determine whether pain relief when needed.180 Nonpharmacologic physical and therapies are associated with certain risks, particularly is sustained and whether function or quality of life psychological treatments such as exercise and in older patients, pregnant patients, and patients with improves with long-term opioid therapy (KQ1). While CBT are approaches that encourage active patient certain co-morbidities such as cardiovascular, renal, benefits for pain relief, function, and quality of life with participation in the care plan, address the effects of

45 179 BOX 2. Interpretation of recommendation anxiety-provoking activities, such as exercise , or (e.g., knee osteoarthritis) over oral NSAIDs in patients by providing education in relaxation techniques and aged ≥ 75 years to minimize systemic effects.176 categories and evidence type coping strategies. In many locations, there are free Experts agreed that opioids should not Recommendation Categories or low-cost patient support, self-help, and educational be considered first-line or routine therapy for chronic Based on evidence type, balance between community-based programs that can provide stress pain (i.e., pain continuing or expected to continue >3 desirable and undesirable effects, values and reduction and other mental health benefits. Patients months or past the time of normal tissue healing) preferences, and resource allocation (cost). with more entrenched anxiety or fear related to outside of active cancer, palliative, and end-of-life Category A recommendation: Applies to all pain, or other significant psychological distress, can care, given small to moderate short-term benefits, persons; most patients should receive the be referred for formal therapy with a mental health uncertain long-term benefits, and potential for serious recommended course of action. specialist (e.g., psychologist, psychiatrist, clinical harms; although evidence on long-term benefits of Category B recommendation: Individual social worker). Multi-modal therapies should be non-opioid therapies is also limited, these therapies decision making needed; different choices will considered for patients not responding to single- are also associated with short-term benefits, and be appropriate for different patients. Clinicians modality therapy, and combinations should be tailored risks are much lower. This does not mean that help patients arrive at a decision consistent depending on patient needs, cost, and convenience. patients should be required to sequentially “fail” with patient values and preferences and To guide patient-specific selection nonpharmacologic and non-opioid pharmacologic of therapy, clinicians should evaluate patients therapy before proceeding to opioid therapy. Rather, specific clinical situations. and establish or confirm the diagnosis. Detailed expected benefits specific to the clinical context recommendations on diagnosis are provided in other should be weighed against risks before initiating Evidence Type guidelines110,179, but evaluation should generally include therapy. In some clinical contexts (e.g., headache or Based on study design as well as a function of a focused history, including history and characteristics fibromyalgia), expected benefits of initiating opioids limitations in study design or implementation, of pain and potentially contributing factors (e.g., are unlikely to outweigh risks regardless of previous imprecision of estimates, variability in function, psychosocial stressors, sleep) and physical nonpharmacologic and non-opioid pharmacologic findings, indirectness of evidence, publication exam, with imaging or other diagnostic testing only therapies used. In other situations (e.g., serious bias, magnitude of treatment effects, dose- if indicated (e.g., if severe or progressive neurologic illness in a patient with poor prognosis for return to response gradient, and constellation of deficits are present or if serious underlying conditions previous level of function, contraindications to other plausible biases that could change effects. are suspected).110,179 For complex pain syndromes, therapies, and clinician and patient agreement that Type 1 evidence: Randomized clinical trials pain specialty consultation can be considered to assist the overriding goal is patient comfort), opioids might or overwhelming evidence from observational with diagnosis as well as management. Diagnosis can be appropriate regardless of previous therapies studies. help identify disease specific interventions to reverse used. In addition, when opioid pain medication is Type 2 evidence: Randomized clinical trials or ameliorate pain; for example, improving glucose used, it is more likely to be effective if integrated with important limitations, or exceptionally control to prevent progression of diabetic neuropathy; with nonpharmacologic therapy. Nonpharmacologic strong evidence from observational studies. immune-modulating agents for rheumatoid arthritis; approaches such as exercise and CBT should be Type 3 evidence: Observational studies physical or occupational therapy to address posture, used to reduce pain and improve function in patients or randomized clinical trials with notable muscle weakness, or repetitive occupational motions with chronic pain. Non-opioid pharmacologic therapy limitations. that contribute to musculoskeletal pain; or surgical should be used when benefits outweigh risks and 179 Type 4 evidence: Clinical experience and intervention to relieve mechanical/compressive pain. should be combined with nonpharmacologic therapy observations, observational studies with The underlying mechanism for most pain syndromes to reduce pain and improve function. If opioids are can be categorized as neuropathic (e.g., diabetic used, they should be combined with nonpharmacologic important limitations, or randomized clinical neuropathy, postherpetic neuralgia, fibromyalgia), or therapy and non-opioid pharmacologic therapy, trials with several major limitations. nociceptive (e.g., osteoarthritis, muscular back pain). as appropriate, to provide greater benefits The diagnosis and pathophysiologic mechanism of to patients in improving pain and function. pain have implications for symptomatic pain treatment pain in the patient’s life, and can result in sustained with medication. For example, evidence is limited or 2. Before starting opioid therapy for chronic improvements in pain and function without apparent insufficient for improved pain or function with long- pain, clinicians should establish treatment risks. Despite this, these therapies are not always or term use of opioids for several chronic pain conditions goals with all patients, including realistic fully covered by insurance, and access and cost can for which opioids are commonly prescribed, such as goals for pain and function, and should be barriers for patients. For many patients, aspects low back pain182, headache183, and fibromyalgia184. consider how opioid therapy will be of these approaches can be used even when there Although NSAIDs can be used for exacerbations of discontinued if benefits do not outweigh is limited access to specialty care. For example, nociceptive pain, other medications (e.g., tricyclics, risks. Clinicians should continue opioid previous guidelines have strongly recommended selected anticonvulsants, or transdermal lidocaine) therapy only if there is clinically meaningful aerobic, aquatic, and/or resistance exercises for generally are recommended for neuropathic pain. improvement in pain and function 176 patients with osteoarthritis of the knee or hip and In addition, improvement of neuropathic pain can that outweighs risks to patient safety maintenance of activity for patients with low back begin weeks or longer after symptomatic treatment (recommendation category: A, evidence 110 pain. A randomized trial found no difference in is initiated.179 Medications should be used only after type: 4). reduced chronic low back pain intensity, frequency or assessment and determination that expected benefits The clinical evidence review found disability between patients assigned to relatively low- outweigh risks given patient-specific factors. For insufficient evidence to determine long-term benefits cost group aerobics and individual physiotherapy or example, clinicians should consider falls risk when of opioid therapy for chronic pain and found an 181 muscle reconditioning sessions. Low-cost options selecting and dosing potentially sedating medications increased risk for serious harms related to long-term to integrate exercise include brisk walking in public such as tricyclics, anticonvulsants, or opioids, and opioid therapy that appears to be dose-dependent. spaces or use of public recreation facilities for group should weigh risks and benefits of use, dose, and In addition, studies on currently available risk exercise. CBT addresses psychosocial contributors to duration of NSAIDs when treating older adults as assessment instruments were sparse and showed 97 pain and improves function Primary care clinicians well as patients with hypertension, renal insufficiency, inconsistent results (KQ4). The clinical evidence can integrate elements of a cognitive behavioral or heart failure, or those with risk for peptic ulcer review for the current guideline considered studies approach into their practice by encouraging patients disease or cardiovascular disease. Some guidelines with outcomes examined at ≥1 year that compared to take an active role in the care plan, by supporting recommend topical NSAIDs for localized osteoarthritis opioid use versus non use or placebo. Studies of patients in engaging in beneficial but potentially 46 opioid therapy for chronic pain that did not have a Clinically meaningful improvement has been defined Clinicians are encouraged to have open and honest non-opioid control group have found that although as a 30% improvement in scores for both pain and discussions with patients to inform mutual decisions many patients discontinue opioid therapy for chronic function.187 Monitoring progress toward patient- about whether to start or continue opioid therapy. non-cancer pain due to adverse effects or insufficient centered functional goals (e.g., walking the dog or Important considerations include the following: pain relief, there is weak evidence that patients who walking around the block, returning to part-time work, • Be explicit and realistic about expected benefits are able to continue opioid therapy for at least 6 attending family sports or recreational activities) of opioids, explaining that while opioids can months can experience clinically significant pain relief can also contribute to the assessment of functional reduce pain during short-term use, there is and insufficient evidence that function or quality improvement. Clinicians should use these goals in no good evidence that opioids improve pain or of life improves.185 These findings suggest that it is assessing benefits of opioid therapy for individual function with long-term use, and that complete very difficult for clinicians to predict whether benefits patients and in weighing benefits against risks of relief of pain is unlikely (clinical evidence review, of opioids for chronic pain will outweigh risks of continued opioid therapy (see Recommendation KQ1). ongoing treatment for individual patients. Opioid 7, including recommended intervals for follow-up). • Emphasize improvement in function as a primary therapy should not be initiated without consideration Because depression, anxiety, and other psychological goal and that function can improve even when of an “exit strategy” to be used if the therapy is co-morbidities often coexist with and can interfere pain is still present. unsuccessful. with resolution of pain, clinicians should use validated • Advise patients about serious adverse effects Experts agreed that before opioid therapy instruments to assess for these conditions (see of opioids, including potentially fatal respiratory is initiated for chronic pain outside of active cancer, Recommendation 8) and ensure that treatment for depression and development of a potentially palliative, and end-of-life care, clinicians should these conditions is optimized. If patients receiving serious lifelong opioid use disorder that can determine how effectiveness will be evaluated and opioid therapy for chronic pain do not experience cause distress and inability to fulfill major role should establish treatment goals with patients. meaningful improvements in both pain and function obligations. Because the line between acute pain and initial compared with prior to initiation of opioid therapy, • Advise patients about common effects of chronic pain is not always clear, it might be difficult for clinicians should consider working with patients to opioids, such as constipation, dry mouth, clinicians to determine when they are initiating opioids taper and discontinue opioids (see Recommendation nausea, vomiting, drowsiness, confusion, for chronic pain rather than treating acute pain. Pain 7) and should use nonpharmacologic and non-opioid tolerance, physical dependence, and withdrawal lasting longer than 3 months or past the time of pharmacologic approaches to pain management (see symptoms when stopping opioids. To prevent normal tissue healing (which could be substantially Recommendation 1). constipation associated with opioid use, advise shorter than 3 months, depending on the condition) patients to increase hydration and fiber intake is generally no longer considered acute. However, 3. Before starting and periodically during and to maintain or increase physical activity. establishing treatment goals with a patient who has opioid therapy, clinicians should discuss Stool softeners or laxatives might be needed. already received opioid therapy for 3 months would with patients known risks and realistic • Discuss effects that opioids might have on defer this discussion well past the point of initiation benefits of opioid therapy and patient ability to safely operate a vehicle, particularly of opioid therapy for chronic pain. Clinicians often and clinician responsibilities for managing when opioids are initiated, when dosages are write prescriptions for long-term use in 30-day therapy (recommendation category: A, increased, or when other central nervous increments, and opioid prescriptions written for ≥30 evidence type: 3). system depressants, such as benzodiazepines days are likely to represent initiation or continuation The clinical evidence review did not find or alcohol, are used concurrently. of long-term opioid therapy. Before writing an opioid studies evaluating effectiveness of patient education • Discuss increased risks for opioid use disorder, prescription for ≥30 days, clinicians should establish or opioid treatment plans as risk mitigation strategies respiratory depression, and death at higher treatment goals with patients. Clinicians seeing new (KQ4). However, the contextual evidence review dosages, along with the importance of taking patients already receiving opioids should establish found that many patients lack information about only the amount of opioids prescribed, i.e., not treatment goals for continued opioid therapy. Although opioids and identified concerns that some clinicians taking more opioids or taking them more often. the clinical evidence review did not find studies miss opportunities to effectively communicate about • Review increased risks for respiratory evaluating the effectiveness of written agreements or safety. Given the substantial evidence gaps on opioids, depression when opioids are taken with treatment plans (KQ4), clinicians and patients who set uncertain benefits of long-term use, and potential benzodiazepines, other sedatives, alcohol, illicit a plan in advance will clarify expectations regarding for serious harms, patient education and discussion drugs such as heroin, or other opioids. how opioids will be prescribed and monitored, as well before starting opioid therapy are critical so that • Discuss risks to household members and as situations in which opioids will be discontinued or patient preferences and values can be understood and other individuals if opioids are intentionally or doses tapered (e.g., if treatment goals are not met, used to inform clinical decisions. Experts agreed that unintentionally shared with others for whom opioids are no longer needed, or adverse events put essential elements to communicate to patients before they are not prescribed, including the possibility the patient at risk) to improve patient safety. starting and periodically during opioid therapy include that others might experience overdose at the Experts thought that goals should include realistic expected benefits, common and serious same or at lower dosage than prescribed for the improvement in both pain relief and function (and harms, and expectations for clinician and patient patient, and that young children are susceptible therefore in quality of life). However, there are some responsibilities to mitigate risks of opioid therapy. to unintentional ingestion. Discuss storage of clinical circumstances under which reductions in pain Clinicians should involve patients in opioids in a secure, preferably locked location without improvement in physical function might be a decisions about whether to start or continue opioid and options for safe disposal of unused more realistic goal (e.g., diseases typically associated therapy. Given potentially serious risks of long-term opioids.188 with progressive functional impairment or catastrophic opioid therapy, clinicians should ensure that patients • Discuss the importance of periodic injuries such as spinal cord trauma). Experts noted are aware of potential benefits of, harms of, and reassessment to ensure that opioids are helping that function can include emotional and social as alternatives to opioids before starting or continuing to meet patient goals and to allow opportunities well as physical dimensions. In addition, experts opioid therapy. for opioid discontinuation and consideration emphasized that mood has important interactions of additional nonpharmacologic or non-opioid with pain and function. Experts agreed that clinicians pharmacologic treatment options if opioids are may use validated instruments such as the three- not effective or are harmful. item “Pain average, interference with Enjoyment of • Discuss planned use of precautions to life, and interference with General activity” (PEG) reduce risks, including use of prescription Assessment Scale186 to track patient outcomes. drug monitoring program information (see

47 Recommendation 9) and urine drug testing Abuse-deterrent technologies have with renal or hepatic dysfunction because decreased (see Recommendation 10). Consider including been employed to prevent manipulation intended to clearance of drugs among these patients can lead to discussion of naloxone use for overdose defeat extended-release properties of ER/LA opioids accumulation of drugs to toxic levels and persistence reversal (see Recommendation 8). and to prevent opioid use by unintended routes of in the body for longer durations. Although there might • Consider whether cognitive limitations might administration, such as injection of oral opioids. As be situations in which clinicians need to prescribe interfere with management of opioid therapy (for indicated in FDA guidance for industry on evaluation immediate-release and ER/LA opioids together older adults in particular) and, if so, determine and labeling of abuse-deterrent opioids190, although (e.g., transitioning patients from ER/LA opioids to whether a caregiver can responsibly co-manage abuse-deterrent technologies are expected to immediate-release opioids by temporarily using lower medication therapy. Discuss the importance of make manipulation of opioids more difficult or less dosages of both), in general, avoiding the use of reassessing safer medication use with both the rewarding, they do not prevent opioid abuse through immediate-release opioids in combination with ER/ patient and caregiver. oral intake, the most common route of opioid abuse, LA opioids is preferable, given potentially increased Given the possibility that benefits of and can still be abused by non-oral routes. The risk and diminishing returns of such an approach for opioid therapy might diminish or that risks might “abuse-deterrent” label does not indicate that there is chronic pain. become more prominent over time, it is important no risk for abuse. No studies were found in the clinical When an ER/LA opioid is prescribed, that clinicians review expected benefits and risks of evidence review assessing the effectiveness of abuse- using one with predictable pharmacokinetics continued opioid therapy with patients periodically, at deterrent technologies as a risk mitigation strategy and pharmacodynamics is preferred to minimize least every 3 months (see Recommendation 7). for deterring or preventing abuse. In addition, abuse- unintentional overdose risk. In particular, unusual deterrent technologies do not prevent unintentional characteristics of methadone and of transdermal Opioid Selection, Dosage, Duration, Follow-Up, overdose through oral intake. Experts agreed that fentanyl make safe prescribing of these medications and Discontinuation recommendations could not be offered at this time for pain especially challenging. 4. When starting opioid therapy for chronic related to use of abuse-deterrent formulations. • Methadone should not be the first choice pain, clinicians should prescribe immediate- In comparing different ER/LA formulations, for an ER/LA opioid. Only clinicians who are release opioids instead of extended- the clinical evidence review found inconsistent results familiar with methadone’s unique risk profile release/long-acting (ER/LA) opioids for overdose risk with methadone versus other and who are prepared to educate and closely (recommendation category: A, evidence ER/LA opioids used for chronic pain (KQ3). The monitor their patients, including risk assessment type: 4). contextual evidence review found that methadone for QT prolongation and consideration of ER/LA opioids include methadone, has been associated with disproportionate numbers electrocardiographic monitoring, should transdermal fentanyl, and extended-release versions of overdose deaths relative to the frequency with consider prescribing methadone for pain. A of opioids such as oxycodone, oxymorphone, which it is prescribed for chronic pain. In addition, clinical practice guideline that contains further hydrocodone, and morphine. The clinical evidence methadone is associated with cardiac arrhythmias guidance regarding methadone prescribing for review found a fair-quality study showing a higher risk along with QT prolongation on the electrocardiogram, pain has been published previously.191 for overdose among patients initiating treatment with and it has complicated pharmacokinetics and • Because dosing effects of transdermal fentanyl ER/LA opioids than among those initiating treatment pharmacodynamics, including a long and variable are often misunderstood by both clinicians with immediate-release opioids.77 The clinical half-life and peak respiratory depressant effect and patients, only clinicians who are familiar evidence review did not find evidence that continuous, occurring later and lasting longer than peak analgesic with the dosing and absorption properties time-scheduled use of ER/LA opioids is more effective effect. Experts noted that the pharmacodynamics of transdermal fentanyl and are prepared to or safer than intermittent use of immediate-release of methadone are subject to more inter-individual educate their patients about its use should opioids or that time-scheduled use of ER/LA opioids variability than other opioids. In regard to other consider prescribing it. reduces risks for opioid misuse or addiction (KQ3). ER/LA opioid formulations, experts noted that the In 2014, the FDA modified the labeling for absorption and pharmacodynamics of transdermal 5. When opioids are started, clinicians ER/LA opioid pain medications, noting serious risks fentanyl are complex, with gradually increasing serum should prescribe the lowest effective and recommending that ER/LA opioids be reserved concentration during the first part of the 72-hour dosage. Clinicians should use caution for “management of pain severe enough to require dosing interval, as well as variable absorption based when prescribing opioids at any dosage, daily, around-the-clock, long-term opioid treatment” on factors such as external heat. In addition, the should carefully reassess evidence when “alternative treatment options (e.g., non- dosing of transdermal fentanyl in mcg/hour, which of individual benefits and risks when opioid analgesics or immediate-release opioids) is not typical for a drug used by outpatients, can be considering increasing dosage to ≥50 are ineffective, not tolerated, or would be otherwise confusing. Experts thought that these complexities morphine milligram equivalents (MME)/ inadequate to provide sufficient management of pain” might increase the risk for fatal overdose when day, and should avoid increasing dosage and not used as “as needed” pain relievers.121 FDA methadone or transdermal fentanyl is prescribed to ≥90 MME/day or carefully justify a has also noted that some ER/LA opioids are only to a patient who has not used it previously or decision to titrate dosage to ≥90 MME/day appropriate for opioid-tolerant patients, defined as by clinicians who are not familiar with its effects. (recommendation category: A, evidence patients who have received certain dosages of opioids Experts agreed that for patients not type: 3). (e.g., 60 mg daily of oral morphine, 30 mg daily of already receiving opioids, clinicians should not initiate Benefits of high-dose opioids for chronic oral oxycodone, or equianalgesic dosages of other opioid treatment with ER/LA opioids and should not pain are not established. The clinical evidence review opioids) for at least 1 week.189 Time-scheduled opioid prescribe ER/LA opioids for intermittent use. ER/LA found only one study84 addressing effectiveness of use can be associated with greater total average daily opioids should be reserved for severe, continuous dose titration for outcomes related to pain control, opioid dosage compared with intermittent, as-needed pain and should be considered only for patients who function, and quality of life (KQ3). This randomized opioid use (contextual evidence review). In addition, have received immediate-release opioids daily for at trial found no difference in pain or function between experts indicated that there was not enough evidence least 1 week. When changing to an ER/LA opioid for a more liberal opioid dose escalation strategy and to determine the safety of using immediate-release a patient previously receiving a different immediate- maintenance of current dosage. (These groups opioids for breakthrough pain when ER/LA opioids release opioid, clinicians should consult product were prescribed average dosages of 52 and 40 are used for chronic pain outside of active cancer labeling and reduce total daily dosage to account for MME/day, respectively, at the end of the trial.) At the pain, palliative care, or end-of-life care, and that this incomplete opioid cross tolerance. Clinicians should same time, risks for serious harms related to opioid practice might be associated with dose escalation. use additional caution with ER/LA opioids and consider therapy increase at higher opioid dosage. The clinical a longer dosing interval when prescribing to patients evidence review found that higher opioid dosages are

48 associated with increased risks for motor vehicle injury, after increasing dosage for changes in pain, function, by an opioid taper and arrange for management of opioid use disorder, and overdose (KQ2). The clinical and risk for harm (see Recommendation 7). Before these co-morbidities. For patients agreeing to taper to and contextual evidence reviews found that opioid increasing total opioid dosage to ≥50 MME/day, lower opioid dosages as well as for those remaining on overdose risk increases in a dose-response manner, clinicians should reassess whether opioid treatment high opioid dosages, clinicians should establish goals that dosages of 50–<100 MME/day have been found is meeting the patient’s treatment goals (see with the patient for continued opioid therapy (see to increase risks for opioid overdose by factors of Recommendation 2). If a patient’s opioid dosage for Recommendation 2), maximize pain treatment with 1.9 to 4.6 compared with dosages of 1–<20 MME/ all sources of opioids combined reaches or exceeds nonpharmacologic and non-opioid pharmacologic day, and that dosages ≥100 MME/day are associated 50 MME/day, clinicians should implement additional treatments as appropriate (see Recommendation 1), with increased risks of overdose 2.0–8.9 times the precautions, including increased frequency of follow- and consider consulting a pain specialist as needed to risk at 1–<20 MME/day. In a national sample of up (see Recommendation 7) and considering offering assist with pain management. Veterans Health Administration patients with chronic naloxone and overdose prevention education to pain who were prescribed opioids, mean prescribed both patients and the patients’ household members 6. Long-term opioid use often begins with opioid dosage among patients who died from opioid (see Recommendation 8). Clinicians should avoid treatment of acute pain. When opioids overdose was 98 MME (median 60 MME) compared increasing opioid dosages to ≥90 MME/day or should are used for acute pain, clinicians should with mean prescribed opioid dosage of 48 MME carefully justify a decision to increase dosage to prescribe the lowest effective dose of (median 25 MME) among patients not experiencing ≥90 MME/day based on individualized assessment immediate-release opioids and should fatal overdose.127 of benefits and risks and weighing factors such prescribe no greater quantity than needed The contextual evidence review found that as diagnosis, incremental benefits for pain and for the expected duration of pain severe although there is not a single dosage threshold below function relative to harms as dosages approach 90 enough to require opioids. Three days or which overdose risk is eliminated, holding dosages MME/day, other treatments and effectiveness, and less will often be sufficient; more than seven <50 MME/day would likely reduce risk among a recommendations based on consultation with pain days will rarely be needed (recommendation large proportion of patients who would experience specialists. If patients do not experience improvement category: A, evidence type: 4). fatal overdose at higher prescribed dosages. Experts in pain and function at ≥90 MME/day, or if there are The clinical evidence review found that agreed that lower dosages of opioids reduce the risk escalating dosage requirements, clinicians should opioid use for acute pain (i.e., pain with abrupt onset for overdose, but that a single dosage threshold for discuss other approaches to pain management with and caused by an injury or other process that is not safe opioid use could not be identified. Experts noted the patient, consider working with patients to taper ongoing) is associated with long-term opioid use, that daily opioid dosages close to or greater than opioids to a lower dosage or to taper and discontinue and that a greater amount of early opioid exposure 100 MME/day are associated with significant risks, opioids (see Recommendation 7), and consider is associated with greater risk for long-term use that dosages <50 MME/day are safer than dosages consulting a pain specialist. Some states require (KQ5). Several guidelines on opioid prescribing for of 50–100 MME/day, and that dosages <20 MME/ clinicians to implement clinical protocols at specific acute pain from emergency departments192–194 and day are safer than dosages of 20–50 MME/day. One dosage levels. For example, before increasing long- other settings195,196 have recommended prescribing expert thought that a specific dosage at which the term opioid therapy dosage to >120 MME/day, ≤3 days of opioids in most cases, whereas others benefit/risk ratio of opioid therapy decreases could clinicians in Washington state must obtain consultation have recommended ≤7 days197 or <14 days.30 not be identified. Most experts agreed that, in general, from a pain specialist who agrees that this is indicated Because physical dependence on opioids is an increasing dosages to 50 or more MME/day increases and appropriate.30 Clinicians should be aware of expected physiologic response in patients exposed to overdose risk without necessarily adding benefits for rules related to MME thresholds and associated opioids for more than a few days (contextual evidence pain control or function and that clinicians should clinical protocols established by their states. review), limiting days of opioids prescribed also carefully reassess evidence of individual benefits and Established patients already taking high should minimize the need to taper opioids to prevent risks when considering increasing opioid dosages to dosages of opioids, as well as patients transferring distressing or unpleasant withdrawal symptoms. ≥50 MME/day. Most experts also agreed that opioid from other clinicians, might consider the possibility Experts noted that more than a few days of exposure dosages should not be increased to ≥90 MME/day of opioid dosage reduction to be anxiety-provoking, to opioids significantly increases hazards, that each without careful justification based on diagnosis and on and tapering opioids can be especially challenging day of unnecessary opioid use increases likelihood individualized assessment of benefits and risks. after years on high dosages because of physical and of physical dependence without adding benefit, and When opioids are used for chronic pain psychological dependence. However, these patients that prescriptions with fewer days’ supply will minimize outside of active cancer, palliative, and end-of-life should be offered the opportunity to re-evaluate their the number of pills available for unintentional or care, clinicians should start opioids at the lowest continued use of opioids at high dosages in light of intentional diversion. possible effective dosage (the lowest starting dosage recent evidence regarding the association of opioid Experts agreed that when opioids are on product labeling for patients not already taking dosage and overdose risk. Clinicians should explain needed for acute pain, clinicians should prescribe opioids and according to product labeling guidance in a nonjudgmental manner to patients already taking opioids at the lowest effective dose and for no longer regarding tolerance for patients already taking high opioid dosages (≥90 MME/day) that there than the expected duration of pain severe enough to opioids). Clinicians should use additional caution when is now an established body of scientific evidence require opioids to minimize unintentional initiation of initiating opioids for patients aged ≥65 years and for showing that overdose risk is increased at higher long-term opioid use. The lowest effective dose can patients with renal or hepatic insufficiency because opioid dosages. Clinicians should empathically review be determined using product labeling as a starting decreased clearance of drugs in these patients can benefits and risks of continued high-dosage opioid point with calibration as needed based on the result in accumulation of drugs to toxic levels. Clinicians therapy and should offer to work with the patient severity of pain and on other clinical factors such as should use caution when increasing opioid dosages to taper opioids to safer dosages. For patients who renal or hepatic insufficiency (see Recommendation and increase dosage by the smallest practical amount agree to taper opioids to lower dosages, clinicians 8). Experts thought, based on clinical experience because overdose risk increases with increases in should collaborate with the patient on a tapering plan regarding anticipated duration of pain severe enough opioid dosage. Although there is limited evidence to (see Recommendation 7). Experts noted that patients to require an opioid, that in most cases of acute pain recommend specific intervals for dosage titration, a tapering opioids after taking them for years might not related to surgery or trauma, a ≤3 days’ supply previous guideline recommended waiting at least five require very slow opioid tapers as well as pauses in of opioids will be sufficient. For example, in one study half-lives before increasing dosage and waiting at the taper to allow gradual accommodation to lower of the course of acute low back pain (not associated least a week before increasing dosage of methadone opioid dosages. Clinicians should remain alert to signs with malignancies, infections, spondylarthropathies, to make sure that full effects of the previous dosage of anxiety, depression, and opioid use disorder (see fractures, or neurological signs) in a primary care are evident.31 Clinicians should re-evaluate patients Recommendations 8 and 12) that might be unmasked setting, there was a large decrease in pain until the

49 fourth day after treatment with paracetamol, with 3 months of opioid therapy the risks for opioid use patient through video and audio could be conducted, smaller decreases thereafter.198 Some experts thought disorder increase, reassessment of pain and function with in person visits occurring at least once per that because some types of acute pain might require within 1 month of initiating opioids provides an year. Clinicians should re-evaluate patients who are more than 3 days of opioid treatment, it would be opportunity to minimize risks of long-term opioid use exposed to greater risk of opioid use disorder or appropriate to recommend a range of ≤3–5 days or by discontinuing opioids among patients not receiving overdose (e.g., patients with depression or other ≤3–7 days when opioids are needed. Some experts a clear benefit from these medications. Experts noted mental health conditions, a history of substance use thought that a range including 7 days was too long that risks for opioid overdose are greatest during the disorder, a history of overdose, taking ≥50 MME/day, given the expected course of severe acute pain for first 3–7 days after opioid initiation or increase in or taking other central nervous system depressants most acute pain syndromes seen in primary care. dosage, particularly when methadone or transdermal with opioids) more frequently than every 3 months. Acute pain can often be managed without fentanyl are prescribed; that follow-up within 3 days is If clinically meaningful improvements in pain and opioids. It is important to evaluate the patient for appropriate when initiating or increasing the dosage function are not sustained, if patients are taking high- reversible causes of pain, for underlying etiologies of methadone; and that follow-up within 1 week might risk regimens (e.g., dosages ≥50 MME/day or opioids with potentially serious sequelae, and to determine be appropriate when initiating or increasing the combined with benzodiazepines) without evidence appropriate treatment. When the diagnosis and dosage of other ER/LA opioids. of benefit, if patients believe benefits no longer severity of nontraumatic, nonsurgical acute pain are Clinicians should evaluate patients to outweigh risks or if they request dosage reduction or reasonably assumed to warrant the use of opioids, assess benefits and harms of opioids within 1 to discontinuation, or if patients experience overdose or clinicians should prescribe no greater quantity than 4 weeks of starting long-term opioid therapy or of other serious adverse events (e.g., an event leading needed for the expected duration of pain severe dose escalation. Clinicians should consider follow-up to hospitalization or disability) or warning signs of enough to require opioids, often 3 days or less, intervals within the lower end of this range when serious adverse events, clinicians should work with unless circumstances clearly warrant additional opioid ER/LA opioids are started or increased or when patients to reduce opioid dosage or to discontinue therapy. More than 7 days will rarely be needed. total daily opioid dosage is ≥50 MME/day. Shorter opioids when possible. Clinicians should maximize Opioid treatment for post-surgical pain is outside follow-up intervals (within 3 days) should be strongly pain treatment with nonpharmacologic and non- the scope of this guideline but has been addressed considered when starting or increasing the dosage opioid pharmacologic treatments as appropriate (see elsewhere.30 Clinicians should not prescribe additional of methadone. At follow up, clinicians should assess Recommendation 1) and consider consulting a pain opioids to patients “just in case” pain continues benefits in function, pain control, and quality of life specialist as needed to assist with pain management. longer than expected. Clinicians should re-evaluate using tools such as the three-item “Pain average, the subset of patients who experience severe acute interference with Enjoyment of life, and interference Considerations for Tapering Opioids pain that continues longer than the expected duration with General activity” (PEG) Assessment Scale186 Although the clinical evidence review did not to confirm or revise the initial diagnosis and to and/or asking patients about progress toward find high-quality studies comparing the effectiveness adjust management accordingly. Given longer half- functional goals that have meaning for them (see of different tapering protocols for use when opioid lives and longer duration of effects (e.g., respiratory Recommendation 2). Clinicians should also ask dosage is reduced or opioids are discontinued depression) with ER/LA opioids such as methadone, patients about common adverse effects such as (KQ3), tapers reducing weekly dosage by 10%–50% fentanyl patches, or extended release versions constipation and drowsiness (see Recommendation of the original dosage have been recommended by of opioids such as oxycodone, oxymorphone, or 3), as well as asking about and assessing for effects other clinical guidelines199, and a rapid taper over morphine, clinicians should not prescribe ER/LA that might be early warning signs for more serious 2–3 weeks has been recommended in the case of opioids for the treatment of acute pain. problems such as overdose (e.g., sedation or a severe adverse event such as overdose.30 Experts slurred speech) or opioid use disorder (e.g., craving, noted that tapers slower than 10% per week (e.g., 7. Clinicians should evaluate benefits and wanting to take opioids in greater quantities or more 10% per month) also might be appropriate and better harms with patients within 1 to 4 weeks frequently than prescribed, or difficulty controlling tolerated than more rapid tapers, particularly when of starting opioid therapy for chronic use). Clinicians should ask patients about their patients have been taking opioids for longer durations pain or of dose escalation. Clinicians preferences for continuing opioids, given their effects (e.g., for years). Opioid withdrawal during pregnancy should evaluate benefits and harms of on pain and function relative to any adverse effects has been associated with spontaneous abortion and continued therapy with patients every 3 experienced. premature labor. months or more frequently. If benefits do Because of potential changes in the When opioids are reduced or discontinued, not outweigh harms of continued opioid balance of benefits and risks of opioid therapy over a taper slow enough to minimize symptoms and signs therapy, clinicians should optimize other time, clinicians should regularly reassess all patients of opioid withdrawal (e.g., drug craving, anxiety, therapies and work with patients to taper receiving long-term opioid therapy, including patients insomnia, abdominal pain, vomiting, diarrhea, opioids to lower dosages or to taper and who are new to the clinician but on long-term opioid diaphoresis, mydriasis, tremor, tachycardia, or discontinue opioids (recommendation therapy, at least every 3 months. At reassessment, piloerection) should be used. A decrease of 10% of category: A, evidence type: 4). clinicians should determine whether opioids continue the original dose per week is a reasonable starting Although the clinical evidence review did to meet treatment goals, including sustained point; experts agreed that tapering plans may be not find studies evaluating the effectiveness of more improvement in pain and function, whether the patient individualized based on patient goals and concerns. frequent monitoring intervals (KQ4), it did find that has experienced common or serious adverse events Experts noted that at times, tapers might have to be continuing opioid therapy for 3 months substantially or early warning signs of serious adverse events, paused and restarted again when the patient is ready increases risk for opioid use disorder (KQ2); signs of opioid use disorder (e.g., difficulty controlling and might have to be slowed once patients reach therefore, follow-up earlier than 3 months might be use, work or family problems related to opioid use), low dosages. Tapers may be considered successful necessary to provide the greatest opportunity to whether benefits of opioids continue to outweigh risks, as long as the patient is making progress. Once prevent the development of opioid use disorder. In and whether opioid dosage can be reduced or opioids the smallest available dose is reached, the interval addition, risk for overdose associated with ER/LA can be discontinued. Ideally, these reassessments between doses can be extended. Opioids may be opioids might be particularly high during the first 2 would take place in person and be conducted by stopped when taken less frequently than once a weeks of treatment (KQ3). The contextual evidence the prescribing clinician. In practice contexts where day. More rapid tapers might be needed for patient review found that patients who do not have pain relief virtual visits are part of standard care (e.g., in remote safety under certain circumstances (e.g., for patients with opioids at 1 month are unlikely to experience pain areas where distance or other issues make follow-up who have experienced overdose on their current relief with opioids at 6 months. Although evidence is visits challenging), follow-up assessments that allow dosage). Ultrarapid detoxification under anesthesia insufficient to determine at what point within the first the clinician to communicate with and observe the is associated with substantial risks, including death,

50 and should not be used.200 Clinicians should access prescribed for patients with mild sleep-disordered pharmacologic therapies (see Recommendation 1) appropriate expertise if considering tapering opioids breathing. Clinicians should avoid prescribing opioids and opioid therapy in this population. Given reduced during pregnancy because of possible risk to the to patients with moderate or severe sleep-disordered renal function and medication clearance even in the pregnant patient and to the fetus if the patient goes breathing whenever possible to minimize risks for absence of renal disease, patients aged ≥65 years into withdrawal. Patients who are not taking opioids opioid overdose (contextual evidence review). might have increased susceptibility to accumulation (including patients who are diverting all opioids they of opioids and a smaller therapeutic window obtain) do not require tapers. Clinicians should discuss Pregnant Women between safe dosages and dosages associated with with patients undergoing tapering the increased Opioids used in pregnancy might be respiratory depression and overdose (contextual risk for overdose on abrupt return to a previously associated with additional risks to both mother and evidence review). Some older adults suffer from prescribed higher dose. Primary care clinicians fetus. Some studies have shown an association cognitive impairment, which can increase risk for should collaborate with mental health providers and of opioid use in pregnancy with stillbirth, poor medication errors and make opioid-related confusion with other specialists as needed to optimize non- fetal growth, preterm delivery, and birth defects more dangerous. In addition, older adults are more opioid pain management (see Recommendation 1), (contextual evidence review). Importantly, in some likely than younger adults to experience co-morbid as well as psychosocial support for anxiety related cases, opioid use during pregnancy leads to neonatal medical conditions and more likely to receive multiple to the taper. More detailed guidance on tapering, opioid withdrawal syndrome. Clinicians and patients medications, some of which might interact with including management of withdrawal symptoms has together should carefully weigh risks and benefits opioids (such as benzodiazepines). Clinicians should been published previously.30,201 If a patient exhibits when making decisions about whether to initiate use additional caution and increased monitoring (see signs of opioid use disorder, clinicians should offer opioid therapy for chronic pain during pregnancy. In Recommendations 4, 5, and 7) to minimize risks of or arrange for treatment of opioid use disorder (see addition, before initiating opioid therapy for chronic opioids prescribed for patients aged ≥65 years. Recommendation 12) and consider offering naloxone pain for reproductive age women, clinicians should Experts suggested that clinicians educate older for overdose prevention (see Recommendation 8). discuss family planning and how long-term opioid adults receiving opioids to avoid risky medication- use might affect any future pregnancy. For pregnant related behaviors such as obtaining controlled Assessing Risk and Addressing Harms of women already receiving opioids, clinicians should medications from multiple prescribers and saving Opioid Use access appropriate expertise if considering tapering unused medications. Clinicians should also implement 8. Before starting and periodically during opioids because of possible risk to the pregnant interventions to mitigate common risks of opioid continuation of opioid therapy, clinicians patient and to the fetus if the patient goes into therapy among older adults, such as exercise or bowel should evaluate risk factors for opioid- withdrawal (see Recommendation 7). For pregnant regimens to prevent constipation, risk assessment for related harms. Clinicians should incorporate women with opioid use disorder, medication-assisted falls, and patient monitoring for cognitive impairment. into the management plan strategies to therapy with buprenorphine or methadone has been mitigate risk, including considering offering associated with improved maternal outcomes and Patients with Mental Health Conditions naloxone when factors that increase should be offered (202) (see Recommendation 12). Because psychological distress frequently risk for opioid overdose, such as history Clinicians caring for pregnant women receiving opioids interferes with improvement of pain and function in of overdose, history of substance use for pain or receiving buprenorphine or methadone for patients with chronic pain, using validated instruments disorder, higher opioid dosages (≥50 MME/ opioid use disorder should arrange for delivery at a such as the Generalized Anxiety Disorder (GAD)-7 and day), or concurrent benzodiazepine use, facility prepared to monitor, evaluate for, and treat the Patient Health Questionnaire (PHQ)-9 or the PHQ- are present (recommendation category: A, neonatal opioid withdrawal syndrome. In instances 4 to assess for anxiety, post traumatic stress disorder, evidence type: 4). when travel to such a facility would present an undue and/or depression (205), might help clinicians The clinical evidence review found burden on the pregnant woman, it is appropriate to improve overall pain treatment outcomes. Experts insufficient evidence to determine how harms of deliver locally, monitor and evaluate the newborn for noted that clinicians should use additional caution opioids differ depending on patient demographics neonatal opioid withdrawal syndrome, and transfer and increased monitoring (see Recommendation 7) or patient comorbidities (KQ2). However, based on the newborn for additional treatment if needed. to lessen the increased risk for opioid use disorder the contextual evidence review and expert opinion, Neonatal toxicity and death have been reported in among patients with mental health conditions certain risk factors are likely to increase susceptibility breastfeeding infants whose mothers are taking (including depression, anxiety disorders, and PTSD), to opioid-associated harms and warrant incorporation codeine (contextual evidence review); previous as well as increased risk for drug overdose among of additional strategies into the management plan to guidelines have recommended that codeine be patients with depression. Previous guidelines have mitigate risk. Clinicians should assess these risk factors avoided whenever possible among mothers who are noted that opioid therapy should not be initiated periodically, with frequency varying by risk factor and breast feeding and, if used, should be limited to the during acute psychiatric instability or uncontrolled patient characteristics. For example, factors that lowest possible dose and to a 4-day supply (203). suicide risk, and that clinicians should consider vary more frequently over time, such as alcohol use, behavioral health specialist consultation for any require more frequent follow up. In addition, clinicians Patients with Renal or Hepatic Insufficiency patient with a history of suicide attempt or psychiatric 31 should consider offering naloxone, re-evaluating Clinicians should use additional caution disorder. In addition, patients with anxiety disorders patients more frequently (see Recommendation and increased monitoring (see Recommendation 7) to and other mental health conditions are more likely 7), and referring to pain and/or behavioral health minimize risks of opioids prescribed for patients with to receive benzodiazepines, which can exacerbate specialists when factors that increase risk for harm, renal or hepatic insufficiency, given their decreased opioid-induced respiratory depression and increase such as history of overdose, history of substance use ability to process and excrete drugs, susceptibility risk for overdose (see Recommendation 11). disorder, higher dosages of opioids (≥50 MME/day), to accumulation of opioids, and reduced therapeutic Clinicians should ensure that treatment for depression and concurrent use of benzodiazepines with opioids, window between safe dosages and dosages and other mental health conditions is optimized, are present. associated with respiratory depression and overdose consulting with behavioral health specialists when (contextual evidence review; see Recommendations 4, needed. Treatment for depression can improve pain Patients with Sleep-Disordered Breathing, 5, and 7). symptoms as well as depression and might decrease Including Sleep Apnea overdose risk (contextual evidence review). For Patients Aged ≥65 Years Risk factors for sleep-disordered treatment of chronic pain in patients with depression, Inadequate pain treatment among breathing include congestive heart failure, and clinicians should strongly consider using tricyclic persons aged ≥65 years has been documented obesity. Experts noted that careful monitoring and or SNRI antidepressants for analgesic as well as (204). Pain management for older patients can be cautious dose titration should be used if opioids are antidepressant effects if these medications are not challenging given increased risks of both non-opioid otherwise contraindicated (see Recommendation 1). 51 Patients with Substance Use Disorder substance use disorder specialists and pain specialists use disorder, patients taking benzodiazepines with Illicit drugs and alcohol are listed as regarding pain management for persons with active opioids (see Recommendation 11), patients at risk for contributory factors on a substantial proportion of or recent past history of substance abuse. Experts returning to a high dose to which they are no longer death certificates for opioid-related overdose deaths also noted that clinicians should communicate with tolerant (e.g., patients recently released from prison), (contextual evidence review). Previous guidelines have patients’ substance use disorder treatment providers and patients taking higher dosages of opioids (≥50 recommended screening or risk assessment tools to if opioids are prescribed. MME/day). Practices should provide education on identify patients at higher risk for misuse or abuse of overdose prevention and naloxone use to patients opioids. However, the clinical evidence review found Patients with Prior Nonfatal Overdose receiving naloxone prescriptions and to members of that currently available risk-stratification tools (e.g., Although studies were not identified that their households. Experts noted that naloxone co- Opioid Risk Tool, Screener and Opioid Assessment for directly addressed the risk for overdose among prescribing can be facilitated by clinics or practices Patients with Pain Version 1, SOAPP-R, and Brief Risk patients with prior nonfatal overdose who are with resources to provide naloxone training and by Interview) show insufficient accuracy for classification prescribed opioids, based on clinical experience, collaborative practice models with pharmacists. of patients as at low or high risk for abuse or misuse experts thought that prior nonfatal overdose would Resources for prescribing naloxone in primary care (KQ4). Clinicians should always exercise caution when substantially increase risk for future nonfatal or fatal settings can be found through Prescribe to Prevent at considering or prescribing opioids for any patient opioid overdose. If patients experience nonfatal http://prescribetoprevent.org. with chronic pain outside of active cancer, palliative, opioid overdose, clinicians should work with them and end-of-life care and should not overestimate the to reduce opioid dosage and to discontinue opioids 9. Clinicians should review the patient’s history ability of these tools to rule out risks from long-term when possible (see Recommendation 7). If clinicians of controlled substance prescriptions using opioid therapy. continue opioid therapy for chronic pain outside state prescription drug monitoring program Clinicians should ask patients about their of active cancer, palliative, and end-of-life care in (PDMP) data to determine whether the drug and alcohol use. Single screening questions can patients with prior opioid overdose, they should patient is receiving opioid dosages or be used.206 For example, the question “How many discuss increased risks for overdose with patients, dangerous combinations that put him or her times in the past year have you used an illegal drug carefully consider whether benefits of opioids at high risk for overdose. Clinicians should or used a prescription medication for nonmedical outweigh substantial risks, and incorporate strategies review PDMP data when starting opioid reasons?” (with an answer of one or more considered to mitigate risk into the management plan, such as therapy for chronic pain and periodically positive) was found in a primary care setting to be considering offering naloxone (see Offering Naloxone during opioid therapy for chronic pain, 100% sensitive and 73.5% specific for the detection to Patients When Factors That Increase Risk for ranging from every prescription to every of a drug use disorder compared with a standardized Opioid-Related Harms Are Present) and increasing 3 months (recommendation category: A, diagnostic interview.207 Validated screening tools such frequency of monitoring (see Recommendation 7) evidence type: 4). as the Drug Abuse Screening Test (DAST) (208) when opioids are prescribed. PDMPs are state-based databases that and the Alcohol Use Disorders Identification Test collect information on controlled prescription drugs (AUDIT) (209) can also be used. Clinicians should Offering Naloxone to Patients When Factors dispensed by pharmacies in most states and, in use PDMP data (see Recommendation 9) and drug That Increase Risk for Opioid-Related Harms Are select states, by dispensing physicians as well. In testing (see Recommendation 10) as appropriate Present addition, some clinicians employed by the federal to assess for concurrent substance use that might Naloxone is an opioid antagonist that government, including some clinicians in the Indian place patients at higher risk for opioid use disorder can reverse severe respiratory depression; its Health Care Delivery System, are not licensed in the and overdose. Clinicians should also provide specific administration by lay persons, such as friends and states where they practice, and do not have access to counseling on increased risks for overdose when family of persons who experience opioid overdose, PDMP data. Certain states require clinicians to review opioids are combined with other drugs or alcohol (see can save lives. Naloxone precipitates acute withdrawal PDMP data prior to writing each opioid prescription Recommendation 3) and ensure that patients receive among patients physically dependent on opioids. (see state level PDMP related policies on the National effective treatment for substance use disorders when Serious adverse effects, such as pulmonary edema, Alliance for Model State Drug Laws website at http:// needed (see Recommendation 12). cardiovascular instability, and seizures, have www.namsdl.org/prescription-monitoring-programs. The clinical evidence review found been reported but are rare at doses consistent cfm). The clinical evidence review did not find studies insufficient evidence to determine how harms of with labeled use for opioid overdose (210). The evaluating the effectiveness of PDMPs on outcomes opioids differ depending on past or current substance contextual evidence review did not find any studies related to overdose, addiction, abuse, or misuse use disorder (KQ2), although a history of substance on effectiveness of prescribing naloxone for overdose (KQ4). However, even though evidence is limited on use disorder was associated with misuse. Similarly, prevention among patients prescribed opioids the effectiveness of PDMP implementation at the based on contextual evidence, patients with drug or for chronic pain. However, there is evidence for state level on prescribing and mortality outcomes28, alcohol use disorders are likely to experience greater effectiveness of naloxone provision in preventing the contextual evidence review found that most fatal risks for opioid use disorder and overdose than opioid-related overdose death at the community overdoses were associated with patients receiving persons without these conditions. If clinicians consider level through community-based distribution (e.g., opioids from multiple prescribers and/or with patients opioid therapy for chronic pain outside of active through overdose education and naloxone distribution receiving high total daily opioid dosages; information cancer, palliative, and end-of-life care for patients with programs in community service agencies) to persons on both of these risk factors for overdose are drug or alcohol use disorders, they should discuss at risk for overdose (mostly due to illicit opiate available to prescribers in the PDMP. PDMP data also increased risks for opioid use disorder and overdose use), and it is plausible that effectiveness would be can be helpful when patient medication history is with patients, carefully consider whether benefits of observed when naloxone is provided in the clinical not otherwise available (e.g., for patients from other opioids outweigh increased risks, and incorporate setting as well. Experts agreed that it is preferable not locales) and when patients transition care to a new strategies to mitigate risk into the management plan, to initiate opioid treatment when factors that increase clinician. The contextual evidence review also found such as considering offering naloxone (see Offering risk for opioid-related harms are present. Opinions that PDMP information could be used in a way that Naloxone to Patients When Factors That Increase Risk diverged about the likelihood of naloxone being is harmful to patients. For example, it has been used for Opioid-Related Harms Are Present) and increasing useful to patients and the circumstances under which to dismiss patients from clinician practices211, which frequency of monitoring (see Recommendation it should be offered. However, most experts agreed might adversely affect patient safety. 7) when opioids are prescribed. Because pain that clinicians should consider offering naloxone management in patients with substance use disorder when prescribing opioids to patients at increased can be complex, clinicians should consider consulting risk for overdose, including patients with a history of overdose, patients with a history of substance 52 The contextual review found variation in (e.g., benzodiazepines) and consider offering urine drug tests can assist clinicians in identifying state policies that affect timeliness of PDMP data naloxone (see Recommendation 8). when patients are not taking opioids prescribed for (and therefore benefits of reviewing PDMP data) as • Clinicians should avoid prescribing opioids them, which might in some cases indicate diversion well as time and workload for clinicians in accessing and benzodiazepines concurrently whenever or other clinically important issues such as difficulties PDMP data. In states that permit delegating access to possible. Clinicians should communicate with with adverse effects. Urine drug tests do not provide other members of the health care team, workload for others managing the patient to discuss the accurate information about how much or what dose prescribers can be reduced. These differences might patient’s needs, prioritize patient goals, weigh of opioids or other drugs a patient took. The clinical result in a different balance of benefits to clinician risks of concurrent benzodiazepine and evidence review did not find studies evaluating workload in different states. Experts agreed that opioid exposure, and coordinate care (see the effectiveness of urine drug screening for risk PDMPs are useful tools that should be consulted when Recommendation 11). mitigation during opioid prescribing for pain (KQ4). starting a patient on opioid therapy and periodically • Clinicians should calculate the total MME/ The contextual evidence review found that urine drug during long-term opioid therapy. However, experts day for concurrent opioid prescriptions to testing can provide useful information about patients disagreed on how frequently clinicians should check help assess the patient’s overdose risk (see assumed not to be using unreported drugs. Urine drug the PDMP during long-term opioid therapy, given Recommendation 5). If patients are found testing results can be subject to misinterpretation PDMP access issues and the lag time in reporting to be receiving high total daily dosages of and might sometimes be associated with practices in some states. Most experts agreed that PDMP opioids, clinicians should discuss their safety that might harm patients (e.g., stigmatization, data should be reviewed every 3 months or more concerns with the patient, consider tapering inappropriate termination from care). Routine use frequently during long-term opioid therapy. A minority to a safer dosage (see Recommendations 5 of urine drug tests with standardized policies at the of experts noted that, given the current burden of and 7), and consider offering naloxone (see practice or clinic level might destigmatize their use. accessing PDMP data in some states and the lack of Recommendation 8). Although random drug testing also might destigmatize evidence surrounding the most effective interval for • Clinicians should discuss safety concerns with urine drug testing, experts thought that truly random PDMP review to improve patient outcomes, annual other clinicians who are prescribing controlled testing was not feasible in clinical practice. Some clinics review of PDMP data during long-term opioid therapy substances for their patient. Ideally clinicians obtain a urine specimen at every visit, but only send would be reasonable when factors that increase risk should first discuss concerns with their it for testing on a random schedule. Experts noted for opioid-related harms are not present. patient and inform him or her that they plan that in addition to direct costs of urine drug testing, Clinicians should review PDMP data for to coordinate care with the patient’s other which often are not covered fully by insurance and opioids and other controlled medications patients prescribers to improve the patient’s safety. can be a burden for patients, clinician time is needed might have received from additional prescribers to • Clinicians should consider the possibility of a to interpret, confirm, and communicate results. determine whether a patient is receiving high total substance use disorder and discuss concerns Experts agreed that prior to starting opioid dosages or dangerous combinations (e.g., with their patient (see Recommendation 12). opioids for chronic pain and periodically during opioid opioids combined with benzodiazepines) that put him • If clinicians suspect their patient might be therapy, clinicians should use urine drug testing or her at high risk for overdose. Ideally, PDMP data sharing or selling opioids and not taking them, to assess for prescribed opioids as well as other should be reviewed before every opioid prescription. clinicians should consider urine drug testing to controlled substances and illicit drugs that increase This is recommended in all states with well-functioning assist in determining whether opioids can be risk for overdose when combined with opioids, PDMPs and where PDMP access policies make this discontinued without causing withdrawal (see including non prescribed opioids, benzodiazepines, practicable (e.g., clinician and delegate access Recommendations 7 and 10). A negative drug and heroin. There was some difference of opinion permitted), but it is not currently possible in states test for prescribed opioids might indicate the among experts as to whether this recommendation without functional PDMPs or in those that do not patient is not taking prescribed opioids, although should apply to all patients, or whether this permit certain prescribers to access them. As clinicians should consider other possible reasons recommendation should entail individual decision vendors and practices facilitate integration of PDMP for this test result (see Recommendation 10). making with different choices for different patients information into regular clinical work-flow (e.g., Experts agreed that clinicians should not based on values, preferences, and clinical situations. data made available in electronic health records), dismiss patients from their practice on the basis of While experts agreed that clinicians should use urine clinicians’ ease of access in reviewing PDMP data is PDMP information. Doing so can adversely affect drug testing before initiating opioid therapy for chronic expected to improve. In addition, improved timeliness patient safety, could represent patient abandonment, pain, they disagreed on how frequently urine drug of PDMP data will improve their value in identifying and could result in missed opportunities to provide testing should be conducted during long-term opioid patient risks. potentially lifesaving information (e.g., about therapy. Most experts agreed that urine drug testing If patients are found to have high opioid risks of opioids and overdose prevention) and at least annually for all patients was reasonable. Some dosages, dangerous combinations of medications, or interventions (e.g., safer prescriptions, non-opioid experts noted that this interval might be too long in multiple controlled substance prescriptions written by pain treatment [see Recommendation 1], naloxone some cases and too short in others, and that the different clinicians, several actions can be taken to [see Recommendation 8], and effective treatment for follow-up interval should be left to the discretion of augment clinicians’ abilities to improve patient safety: substance use disorder [see Recommendation 12]). the clinician. Previous guidelines have recommended • Clinicians should discuss information from the more frequent urine drug testing in patients thought PDMP with their patient and confirm that the 10. When prescribing opioids for chronic pain, to be at higher risk for substance use disorder.30 patient is aware of the additional prescriptions. clinicians should use urine drug testing However, experts thought that predicting risk prior to Occasionally, PDMP information can be incorrect before starting opioid therapy and consider urine drug testing is challenging and that currently (e.g., if the wrong name or birth date has been urine drug testing at least annually to available tools do not allow clinicians to reliably entered, the patient uses a nickname or maiden assess for prescribed medications as well identify patients who are at low risk for substance use name, or another person has used the patient’s as other controlled prescription drugs and disorder. identity to obtain prescriptions). illicit drugs (recommendation category: B, In most situations, initial urine drug • Clinicians should discuss safety concerns, evidence type: 4). testing can be performed with a relatively inexpensive including increased risk for respiratory Concurrent use of opioid pain medications immunoassay panel for commonly prescribed opioids depression and overdose, with patients found with other opioid pain medications, benzodiazepines, and illicit drugs. Patients prescribed less commonly to be receiving opioids from more than one or heroin can increase patients’ risk for overdose. used opioids might require specific testing for prescriber or receiving medications that Urine drug tests can provide information about drug those agents. The use of confirmatory testing adds increase risk when combined with opioids use that is not reported by the patient. In addition, substantial costs and should be based on the need

53 to detect specific opioids that cannot be identified Recommendation 7], more frequent re-evaluation used safely and with moderate success is a reduction on standard immunoassays or on the presence of [see Recommendation 7], offering naloxone [see of the benzodiazepine dose by 25% every 1–2 unexpected urine drug test results. Clinicians should Recommendation 8], or referral for treatment for weeks.213,214 CBT increases tapering success rates and be familiar with the drugs included in urine drug testing substance use disorder [see Recommendation 12], might be particularly helpful for patients struggling panels used in their practice and should understand all as appropriate). If tests for prescribed opioids with a benzodiazepine taper.213 If benzodiazepines how to interpret results for these drugs. For example, are repeatedly negative, confirming that the patient prescribed for anxiety are tapered or discontinued, a positive “opiates” immunoassay detects morphine, is not taking the prescribed opioid, clinicians can or if patients receiving opioids require treatment which might reflect patient use of morphine, codeine, discontinue the prescription without a taper. Clinicians for anxiety, evidence-based psychotherapies (e.g., or heroin, but this immunoassay does not detect should not dismiss patients from care based on a urine CBT) and/or specific antidepressants or other synthetic opioids (e.g., fentanyl or methadone) drug test result because this could constitute patient nonbenzodiazepine medications approved for anxiety and might not detect semisynthetic opioids (e.g., abandonment and could have adverse consequences should be offered. Experts emphasized that clinicians oxycodone). However, many laboratories use an for patient safety, potentially including the patient should communicate with mental health professionals oxycodone immunoassay that detects oxycodone and obtaining opioids from alternative sources and the managing the patient to discuss the patient’s needs, oxymorphone. In some cases, positive results for clinician missing opportunities to facilitate treatment prioritize patient goals, weigh risks of concurrent specific opioids might reflect metabolites from opioids for substance use disorder. benzodiazepine and opioid exposure, and coordinate the patient is taking and might not mean the patient care. is taking the specific opioid for which the test was 11. Clinicians should avoid prescribing opioid positive. For example, hydromorphone is a metabolite pain medication and benzodiazepines 12. Clinicians should offer or arrange evidence- of hydrocodone, and oxymorphone is a metabolite concurrently whenever possible based treatment (usually medication- of oxycodone. Detailed guidance on interpretation (recommendation category: A, evidence assisted treatment with buprenorphine or of urine drug test results, including which tests to type: 3). methadone in combination with behavioral order and expected results, drug detection time in Benzodiazepines and opioids both cause therapies) for patients with opioid use urine, drug metabolism, and other considerations central nervous system depression and can decrease disorder (recommendation category: A, has been published previously.30 Clinicians should respiratory drive. Concurrent use is likely to put evidence type: 2). not test for substances for which results would not patients at greater risk for potentially fatal overdose. Opioid use disorder (previously classified affect patient management or for which implications The clinical evidence review did not address risks as opioid abuse or opioid dependence) is defined for patient management are unclear. For example, of benzodiazepine co-prescription among patients in the Diagnostic and Statistical Manual of Mental experts noted that there might be uncertainty about prescribed opioids. However, the contextual evidence Disorders, 5th edition (DSM-5) as a problematic the clinical implications of a positive urine drug review found evidence in epidemiologic series of pattern of opioid use leading to clinically significant test for tetrahyrdocannabinol (THC). In addition, concurrent benzodiazepine use in large proportions impairment or distress, manifested by at least two restricting confirmatory testing to situations and of opioid-related overdose deaths, and a case-cohort defined criteria occurring within a year.20 substances for which results can reasonably be study found concurrent benzodiazepine prescription The clinical evidence review found expected to affect patient management can reduce with opioid prescription to be associated with a near prevalence of opioid dependence (using DSM-IV costs of urine drug testing, given the substantial costs quadrupling of risk for overdose death compared diagnosis criteria) in primary care settings among associated with confirmatory testing methods. Before with opioid prescription alone.212 Experts agreed that patients with chronic pain on opioid therapy to be ordering urine drug testing, clinicians should have a although there are circumstances when it might be 3%–26% (KQ2). As found in the contextual evidence plan for responding to unexpected results. Clinicians appropriate to prescribe opioids to a patient receiving review and supported by moderate quality evidence, should explain to patients that urine drug testing benzodiazepines (e.g., severe acute pain in a patient opioid agonist or partial agonist treatment with is intended to improve their safety and should also taking long-term, stable low dose benzodiazepine methadone maintenance therapy or buprenorphine explain expected results (e.g., presence of prescribed therapy), clinicians should avoid prescribing opioids has been shown to be more effective in preventing medication and absence of drugs, including illicit and benzodiazepines concurrently whenever possible. relapse among patients with opioid use disorder.151–153 drugs, not reported by the patient). Clinicians should In addition, given that other central nervous system Some studies suggest that using behavioral ask patients about use of prescribed and other depressants (e.g., muscle relaxants, hypnotics) therapies in combination with these treatments can drugs and ask whether there might be unexpected can potentiate central nervous system depression reduce opioid misuse and increase retention during results. This will provide an opportunity for patients associated with opioids, clinicians should consider maintenance therapy and improve compliance after to provide information about changes in their use of whether benefits outweigh risks of concurrent use detoxification154,155; behavioral therapies are also prescribed opioids or other drugs. Clinicians should of these drugs. Clinicians should check the PDMP recommended by clinical practice guidelines.215 The discuss unexpected results with the local laboratory for concurrent controlled medications prescribed cited studies primarily evaluated patients with a or toxicologist and with the patient. Discussion by other clinicians (see Recommendation 9) and history of illicit opioid use, rather than prescription with patients prior to specific confirmatory testing should consider involving pharmacists and pain opioid use for chronic pain. Recent studies among can sometimes yield a candid explanation of why a specialists as part of the management team when patients with prescription opioid dependence (based particular substance is present or absent and obviate opioids are co-prescribed with other central nervous on DSM-IV criteria) have found maintenance therapy the need for expensive confirmatory testing on that system depressants. Because of greater risks with buprenorphine and buprenorphine-naloxone visit. For example, a patient might explain that the of benzodiazepine withdrawal relative to opioid effective in preventing relapse.216,217 Treatment need test is negative for prescribed opioids because she withdrawal, and because tapering opioids can be in a community is often not met by capacity to provide felt opioids were no longer helping and discontinued associated with anxiety, when patients receiving both buprenorphine or methadone maintenance therapy218, them. If unexpected results are not explained, a benzodiazepines and opioids require tapering to and patient cost can be a barrier to buprenorphine confirmatory test using a method selective enough reduce risk for fatal respiratory depression, it might treatment because insurance coverage of to differentiate specific opioids and metabolites (e.g., be safer and more practical to taper opioids first buprenorphine for opioid use disorder is often gas or liquid chromatography/mass spectrometry) (see Recommendation 7). Clinicians should taper limited.219 Oral or long acting injectable formulations might be warranted to clarify the situation. benzodiazepines gradually if discontinued because of naltrexone can also be used as medication-assisted Clinicians should use unexpected abrupt withdrawal can be associated with rebound treatment for opioid use disorder in nonpregnant results to improve patient safety (e.g., change in anxiety, hallucinations, seizures, delirium tremens, adults, particularly for highly motivated persons.220,221 pain management strategy [see Recommendation and, in rare cases, death (contextual evidence review). Experts agreed that clinicians prescribing opioids 1], tapering or discontinuation of opioids [see A commonly used tapering schedule that has been should identify treatment resources for opioid use

54 disorder in the community and should work together program certified by SAMHSA to provide supervised health records to assist clinicians’ treatment decisions to ensure sufficient treatment capacity for opioid use medication-assisted treatment for patients with at the point of care; identification of mechanisms disorder at the practice level. opioid use disorder. Clinicians should assist patients that insurers and pharmacy benefit plan managers If clinicians suspect opioid use disorder in finding qualified treatment providers and should can use to promote safer prescribing within plans; based on patient concerns or behaviors or on arrange for patients to follow up with these providers, and development of clinical quality improvement findings in prescription drug monitoring program data as well as arranging for ongoing coordination of measures and initiatives to improve prescribing and (see Recommendation 9) or from urine drug testing care. Clinicians should not dismiss patients from patient care within health systems have promise for (see Recommendation 10), they should discuss their their practice because of a substance use disorder increasing guideline adoption and improving practice. concern with their patient and provide an opportunity because this can adversely affect patient safety and In addition, policy initiatives that address barriers to for the patient to disclose related concerns or could represent patient abandonment. Identification implementation of the guidelines, such as increasing problems. Clinicians should assess for the presence of substance use disorder represents an opportunity accessibility of PDMP data within and across states, of opioid use disorder using DSM-5 criteria.20 for a clinician to initiate potentially life-saving e-prescribing, and availability of clinicians who can Alternatively, clinicians can arrange for a substance interventions, and it is important for the clinician to offer medication-assisted treatment for opioid use use disorder treatment specialist to assess for the collaborate with the patient regarding their safety disorder, are strategies to consider to enhance presence of opioid use disorder. For patients meeting to increase the likelihood of successful treatment. implementation of the recommended practices. CDC criteria for opioid use disorder, clinicians should offer In addition, although identification of an opioid use will work with federal partners and payers to evaluate or arrange for patients to receive evidence-based disorder can alter the expected benefits and risks of strategies such as payment reform and health care treatment, usually medication-assisted treatment with opioid therapy for pain, patients with co-occurring delivery models that could improve patient health buprenorphine or methadone maintenance therapy in pain and substance use disorder require ongoing pain and safety. For example, strategies might include combination with behavioral therapies. Oral or long- management that maximizes benefits relative to risks. strengthened coverage for nonpharmacologic acting injectable naltrexone, a long-acting opioid Clinicians should continue to use nonpharmacologic treatments, appropriate urine drug testing, and antagonist, can also be used in non-pregnant adults. and non-opioid pharmacologic pain treatments as medication-assisted treatment; reimbursable time for Naltrexone blocks the effects of opioids if they are appropriate (see Recommendation 1) and consider patient counseling; and payment models that improve used but requires adherence to daily oral therapy or consulting a pain specialist as needed to provide access to interdisciplinary, coordinated care. monthly injections. For pregnant women with opioid optimal pain management. As highlighted in the forthcoming report use disorder, medication-assisted therapy with Resources to help with arranging for on the National Pain Strategy, an overarching federal buprenorphine (without naloxone) or methadone has treatment include SAMHSA’s buprenorphine physician effort that outlines a comprehensive population- been associated with improved maternal outcomes locator (https://www.samhsa.gov/medication- level health strategy for addressing pain as a public and should be offered (see Recommendation 8). assisted-treatment/practitioner-program-data/ health problem, clinical guidelines complement Clinicians should also consider offering naloxone treatment-practitioner-locator); SAMHSA’s Opioid other strategies aimed at preventing illnesses and for overdose prevention to patients with opioid use Treatment Program Directory (http://dpt2.samhsa. injuries that lead to pain. A draft of the National disorder (see Recommendation 8). For patients with gov/treatment/directory.aspx); SAMHSA’s Provider Pain Strategy has been published previously.180 problematic opioid use that does not meet criteria Clinical Support System for Opioid Therapies (http:// These strategies include strengthening the evidence for opioid use disorder, experts noted that clinicians pcss-o.org), which offers extensive experience in the base for pain prevention and treatment strategies, can offer to taper and discontinue opioids (see treatment of substance use disorders and specifically reducing disparities in pain treatment, improving Recommendation 7). For patients who choose to of opioid use disorder, as well as expertise on the service delivery and reimbursement, supporting but are unable to taper, clinicians may reassess for interface of pain and opioid misuse; and SAMHSA’s professional education and training, and providing opioid use disorder and offer opioid agonist therapy if Provider’s Clinical Support System for Medication- public education. It is important that overall criteria are met. Assisted Treatment (http://pcssmat.org), which offers improvements be made in developing the workforce Physicians not already certified to provide expert physician mentors to answer questions about to address pain management in general, in addition buprenorphine in an office-based setting can undergo assessment for and treatment of substance use to opioid prescribing specifically. This guideline training to receive a waiver from the Substance Abuse disorders. also complements other federal efforts focused on and Mental Health Services Administration (SAMHSA) addressing the opioid overdose epidemic including that allows them to prescribe buprenorphine to Conclusions and Future Directions prescriber training and education, improving access treat patients with opioid use disorder. Physicians to treatment for opioid use disorder, safe storage prescribing opioids in communities without sufficient Clinical guidelines represent one strategy and disposal programs, utilization management treatment capacity for opioid use disorder should for improving prescribing practices and health mechanisms, naloxone distribution programs, law strongly consider obtaining this waiver. Information outcomes. Efforts are required to disseminate the enforcement and supply reduction efforts, prescription about qualifications and the process to obtain a guideline and achieve widespread adoption and drug monitoring program improvements, and support waiver are available from SAMHSA.222 Clinicians do implementation of the recommendations in clinical for community coalitions and state prevention not need a waiver to offer naltrexone for opioid use settings. CDC will translate this guideline into user- programs. disorder as part of their practice. friendly materials for distribution and use by health This guideline provides recommendations Additional guidance has been published systems, medical professional societies, insurers, that are based on the best available evidence that was previously215 on induction, use, and monitoring of public health departments, health information interpreted and informed by expert opinion. The clinical buprenorphine treatment (see Part 5) and naltrexone technology developers, and clinicians and engage in scientific evidence informing the recommendations is treatment (see Part 6) for opioid use disorder and dissemination efforts. CDC has provided a checklist low in quality. To inform future guideline development, on goals, components of, and types of effective for prescribing opioids for chronic pain (http://stacks. more research is necessary to fill in critical evidence psychosocial treatment that are recommended cdc.gov/view/cdc/38025), additional resources such gaps. The evidence reviews forming the basis of this in conjunction with pharmacological treatment of as fact sheets (http://www.cdc.gov/drugoverdose/ guideline clearly illustrate that there is much yet to be opioid use disorder (see Part 7). Clinicians unable prescribing/resources.html), and will provide a mobile learned about the effectiveness, safety, and economic to provide treatment themselves should arrange application to guide clinicians in implementing the efficiency of long-term opioid therapy. As highlighted for patients with opioid use disorder to receive care recommendations. CDC will also work with partners by an expert panel in a recent workshop sponsored by from a substance use disorder treatment specialist, to support clinician education on pain management the National Institutes of Health on the role of opioid such as an office-based buprenorphine or naltrexone options, opioid therapy, and risk mitigation strategies pain medications in the treatment of chronic pain, treatment provider, or from an opioid treatment (e.g., urine drug testing). Activities such as development of clinical decision support in electronic 55 “evidence is insufficient for every clinical decision that Acknowledgments National Center for Injury Prevention and Control, a provider needs to make about the use of opioids for Members of the Core Expert Group; the Core Expert Helen Kingery, MPH, Division of Unintentional Injury chronic pain”.223 The National Institutes of Health panel Group facilitator: Don Teater, MD; members of the Prevention, National Center for Injury Prevention recommended that research is needed to improve Stakeholder Review Group; peer reviewers; the Opioid and Control, Kristen Sanderson, MPH, Division of our understanding of which types of pain, specific Guideline Workgroup, consultants, and the NCIPC Unintentional Injury Prevention, National Center for diseases, and patients are most likely to be associated Board of Scientific Counselors; federal partners: Injury Prevention and Control, Kate Fox, MPP, National with benefit and harm from opioid pain medications; Richard Kronick, PhD, Deborah G. Perfetto, PharmD, Center for Injury Prevention and Control, Leslie evaluate multidisciplinary pain interventions; Agency for Healthcare Research and Quality; Jeffrey Dorigo, MA, National Center for Injury Prevention and estimate cost-benefit; develop and validate tools for A. Kelman, MD, Diane L. McNally, Centers for Medicare Control, Erin Connelly, MPA, National Center for Injury identification of patient risk and outcomes; assess the & Medicaid Services; Jonathan Woodson, MD, Dave Prevention and Control, Sara Patterson, MA, National effectiveness and harms of opioid pain medications Smith, MD, Jack Smith, MD, Christopher Spevak, Center for Injury Prevention and Control, Mark with alternative study designs; and investigate risk MD, Department of Defense; Stephen M. Ostroff, Biagioni, MPA, National Center for Injury Prevention identification and mitigation strategies and their effects on patient and public health outcomes. It MD, Christopher M. Jones, PharmD, Food and Drug and Control, and Leonard J. Paulozzi, MD, Division of is also important to obtain data to inform the cost Administration; Jim Macrae, MA, MPP, Alexander Unintentional Injury Prevention, National Center for feasibility and cost-effectiveness of recommended F. Ross, ScD, Health Resources and Services Injury Prevention and Control, CDC. actions, such as use of nonpharmacologic therapy Administration; Nora Volkow, MD, David Thomas, PhD, and urine drug testing. Research that contributes National Institute of DrugAbuse; John Howard, MD, Corresponding author: Deborah Dowell, Division of to safer and more effective pain treatment can Douglas Trout, MD, National Institute for Occupational Unintentional Injury Prevention, National Center for be implemented across public health entities and Safety and Health; Karen B. DeSalvo, MD, Jennifer Injury Prevention and Control, CDC. E-mail: gdo7@ federal agencies.4 Additional research can inform Frazier, MPH, Office of the National Coordinator, cdc.gov. the development of future guidelines for special Michael Botticelli, MEd, Cecelia McNamara Spitznas, 1Division of Unintentional Injury Prevention, National populations that could not be adequately addressed PhD, Office of National Drug Control Policy; Kana Center for Injury Prevention and Control, CDC, Atlanta, in this guideline, such as children and adolescents, Enomoto, MA, Jinhee Lee, PharmD, Substance Abuse Georgia where evidence and guidance is needed but currently and Mental Health Services Administration; Robert lacking. CDC is committed to working with partners McDonald, MBA, Jack M. Rosenberg, MD, Veterans to identify the highest priority research areas to Administration; members of the public who provided build the evidence base. Yet, given that chronic pain comment during the webinar; Douglas McDonald, is recognized as a significant public health problem, PhD, Brandy Wyant, MPH, Kenneth Carlson, Amy the risks associated with long-term opioid therapy, Berninger, MPH, Abt Associates; Thomas Frieden, MD, the availability of effective nonpharmacological and Anne Schuchat, MD, Ileana Arias, PhD, CDC Office of non-opioid pharmacologic treatment options for pain, the Director, Debra Houry, MD, National Center for and the potential for improvement in the quality of Injury Prevention and Control, Amy Peeples, MPA, health care with the implementation of recommended National Center for Injury Prevention and Control, practices, a guideline for prescribing is warranted with Arlene Greenspan, DrPH, National Center for Injury the evidence that is currently available. The balance between the benefits and the risks of long-term opioid Prevention and Control, Grant Baldwin, PhD, Division therapy for chronic pain based on both clinical and of Unintentional Injury Prevention, National Center contextual evidence is strong enough to support the for Injury Prevention and Control, Rita Noonan, issuance of category A recommendations in most PhD, Division of Unintentional Injury Prevention, cases. National Center for Injury Prevention and Control, CDC will revisit this guideline as new Julie Gilchrist, MD, Division of Unintentional Injury evidence becomes available to determine when Prevention, National Center for Injury Prevention and evidence gaps have been sufficiently closed to Control, Terry Davis, EdD, Division of Unintentional warrant an update of the guideline. Until this research Injury Prevention, National Center for Injury is conducted, clinical practice guidelines will have Prevention and Control, Wes Sargent, EdD, Division to be based on the best available evidence and of Unintentional Injury Prevention, National Center expert opinion. This guideline is intended to improve for Injury Prevention and Control, Brian Manns, communication between clinicians and patients PharmD, Division of Unintentional Injury Prevention, about the risks and benefits of opioid therapy for National Center for Injury Prevention and Control, Lisa chronic pain, improve the safety and effectiveness Garbarino, Division of Unintentional Injury Prevention, of pain treatment, and reduce the risks associated National Center for Injury Prevention and Control, with long-term opioid therapy, including opioid use Donovan Newton, MPA, Division of Analysis, Research disorder, overdose, and death. CDC is committed to and Practice Integration, National Center for Injury evaluating the guideline to identify the impact of the Prevention and Control, Joann Kang, JD, Division of recommendations on clinician and patient outcomes, Unintentional Injury Prevention, National Center for both intended and unintended, and revising the Injury Prevention and Control, Noah Aleshire, JD, recommendations in future updates when warranted. Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Jennifer VanderVeur, JD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, LeShaundra Scott, MPH, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Sarah Lewis, MPH, Division of Unintentional Injury Prevention, 56 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain

Outcome Studies Limitations Inconsistency Imprecision Type of evidence Other factors Estimates of effect/ findings Effectiveness and comparative effectiveness (KQ1) Effectiveness of long-term opioid therapy versus placebo or no opioid therapy for long-term (≥1 year) outcomes

Pain, function, None —† — — Insufficient — No evidence and quality of life Harms and adverse events (KQ2)

Risks of opioids versus placebo or no opioids on opioid abuse, addiction, and related outcomes; overdose; and other harms

Abuse or 1 cohort study Serious limitations Unknown (1 No imprecision 3 None identified One retrospective cohort addiction (n = 568,640) study) study found long-term use of prescribed opioids associated with an increased risk of abuse or dependence diagnosis versus no opioid use (adjusted OR ranged from 14.9 to 122.5, depending on dose). Abuse or 10 Very serious Very serious No imprecision 4 None identified In primary care settings, addiction uncontrolled limitations inconsistency prevalence of opioid studies (n = abuse ranged from 0.6% 3,780) to 8% and prevalence of dependence from 3% to 26%. In pain clinic settings, prevalence of misuse ranged from 8% to 16% and addiction from 2% to 14%. Prevalence of aberrant drug-related behaviors ranged from 6% to 37%.

Overdose 1 cohort study Serious limitations Unknown (1 Serious 3 None identified Current opioid use (n = 9,940) study) imprecision associated with increased risk of any overdose events (adjusted HR 5.2, 95% CI = 2.1–12) and serious overdose events (adjusted HR 8.4, 95% CI = 2.5–28) versus current nonuse.

Fractures 1 cohort study Serious limitations No inconsistency No imprecision 3 None identified Opioid use associated with (n = 2,341) increased risk of fracture and 1 case– in 1 cohort study (adjusted control study HR 1.28, 95% CI = 0.99– (n = 21,739 1.64) and 1 case-control case patients) study (adjusted OR 1.27, 95% CI = 1.21–1.33).

Myocardial 1 cohort study No limitations No inconsistency No imprecision 3 None identified Current opioid use associated infarction (n = 426,124) with increased risk of and 1 case– myocardial infarction versus control study nonuse (adjusted OR 1.28, (n = 11,693 95% CI = 1.19–1.37 and case patients) incidence rate ratio 2.66, 95% CI = 2.30–3.08).

57 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Endocrinologic 1 cross- Serious Unknown (1 No imprecision 3 None Long-term opioid use harms sectional limitations study) identified associated with increased study (n = risk for use of medications 11,327) for erectile dysfunction or testosterone replacement versus nonuse (adjusted OR 1.5, 95% CI = 1.1–1.9). Outcome Studies Limitations Inconsistency Imprecision Type of Other Estimates of effect/ evidence factors findings How do harms vary depending on the opioid dose used? Abuse or 1 cohort Serious Unknown (1 No imprecision 3 None One retrospective cohort addiction study (n = limitations study) identified study found higher doses 568,640) of long-term opioid therapy associated with increased risk of opioid abuse or dependence than lower doses. Compared to no opioid prescription, the adjusted odds ratios were 15 (95% CI = 10–21) for 1 to 36 MME/day, 29 (95 % CI = 20–41) for 36 to120 MME/day, and 122 (95 % CI = 73–205) for ≥120 MME/day. Overdose 1 cohort Serious No No imprecision 3 Magnitude of Versus 1 to <20 MME/ study (n = limitations inconsistency effect, dose day, one cohort study 9,940) and 1 response found an adjusted HR for case–control relationship an overdose event of 1.44 study (n = (95% CI = 0.57–3.62) for 593 case 20 to <50 MME/day that patients increased to 8.87 (95% CI in primary = 3.99–19.72) at ≥100 analysis) MME/day; one case-control study found an adjusted OR for an opioid-related death of 1.32 (95% CI = 0.94–1.84) for 20 to 49 MME/day that increased to 2.88 (95% CI = 1.79– 4.63) at ≥200 MME/day. Fractures 1 cohort Serious Unknown (1 Serious 3 None Risk of fracture increased study (n = limitations study) imprecision identified from an adjusted HR 2,341) of 1.20 (95% CI = 0.92–1.56) at 1 to <20 MME/day to 2.00 (95% CI = 1.24–3.24) at ≥50 MME/day; the trend was of borderline statistical significance.

58 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Myocardial 1 cohort Serious Unknown (1 No imprecision 3 None Relative to a cumulative dose infarction study (n = limitations study) identified of 0 to 1,350 MME during a 426,124) 90-day period, the incidence rate ratio for myocardial infarction for 1350 to <2700 MME was 1.21 (95% CI = 1.02–1.45), for 2,700 to <8,100 MME was 1.42 (95% CI = 1.21–1.67), for 8,100 to <18,000 MME was 1.89 (95% CI = 1.54–2.33), and for ≥8,000 MME was 1.73 (95% CI = 1.32–2.26). Motor vehicle 1 case– No Unknown (1 No imprecision 3 None No association between crash injuries control limitations study) identified opioid dose and risk of motor study (n = vehicle crash injuries even 5,300 case though opioid dosages ≥20 MME/day were associated patients) with increased odds of road trauma among drivers. Endocrinologic 1 cross- Serious Consistent No imprecision 3 None Relative to 0 to <20 MME/ harms sectional limitations identified day, the adjusted OR for study (n = ≥120 MME/day for use of 11,327) New medications for erectile dysfunction or testosterone for update: replacement was 1.6 (95% 1 additional CI = 1.0–2.4). One new cross- cross-sectional study found sectional higher-dose long-term opioid study therapy associated with (n=1,585) increased risk of androgen deficiency among men receiving immediate-release opioids (adjusted OR per 10 MME/day 1.16, 95% CI = 1.09–1.23), but the dose response was very weak among men receiving ER/LA opioids. Outcome Studies Limitations Inconsistency Imprecision Type of Other Estimates of effect/ evidence factors findings Dosing strategies (KQ3) Comparative effectiveness of different methods for initiating opioid therapy and titrating doses Pain 3 randomized Serious Serious Very serious 4 None Trials on effects of titration trials (n = limitations inconsistency imprecision identified with immediate-release 93) versus ER/LA opioids reported inconsistent results and had additional differences be-tween treatment arms in dosing protocols (titrated versus fixed dosing) and doses of opioids used.

59 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Overdose New for Serious Unknown (1 No imprecision 4 None One new cross-sectional study update: limitations study) identified found initiation of therapy with 1 cohort an ER/LA opioid associated with study (n = increased risk of overdose versus initiation with an immediate- 840,606) release opioid (adjusted HR 2.33, 95% CI = 1.26–4.32). Comparative effectiveness of different ER/LA opioids Pain and 3 randomized Serious No No imprecision 3 None No differences function trials (n= limitations inconsistency identified 1,850) Outcome Studies Limitations Inconsistency Imprecision Type of Other Estimates of effect/findings evidence factors All-cause 1 cohort Serious Serious No imprecision 4 None One cohort study found methadone mortality study (n = limitations inconsistency identified to be associated with lower 108,492) all-cause mortality risk than New for sustained-release morphine in a propensity-adjusted analysis update: 1 (adjusted HR 0.56, 95% CI = cohort study 0.51–0.62) and one cohort (n = 38,756) study among Tennessee Medicaid patients found methadone to be associated with higher risk of all-cause mortality than sustained- release morphine (adjusted HR 1.46, 95% CI = 1.17–1.73). Abuse and 1 cohort Serious Unknown (1 Serious 4 None One cohort study found some related study (n = limitations study) imprecision identified differences between ER/LA opioids outcomes 5,684) in rates of adverse outcomes related to abuse, but outcomes were nonspecific for opioid-related adverse events, precluding reliable conclusions.

ER/LA versus immediate-release opioids Endocrinologic New for Serious Unknown (1 No imprecision 4 None One cross-sectional study found harms update: limitations study) identified ER/LA opioids associated with 1 cross- increased risk of androgen sectional deficiency versus immediate- release opioids (adjusted OR 3.39, study (n = 95% CI = 2.39–4.77). 1,585)

Dose escalation versus dose maintenance or use of dose thresholds Pain, function, 1 randomized Serious Unknown (1 Very serious 3 None No difference between more or withdrawal trial (n = limitations study) imprecision identified liberal dose escalation versus due to opioid 140) maintenance of current doses in misuse pain, function, or risk of withdrawal due to opioid misuse, but there was limited separation in opioid doses between groups (52 versus 40 MME/day at the end of the trial).

60 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Outcome Studies Limitations Inconsistency Imprecision Type of Other factors Estimates of effect/findings evidence Immediate-release versus ER/LA opioids; immediate-release plus ER/LA opioids versus ER/LA opioids alone; scheduled and continuous versus as- needed dosing of opioids; or opioid rotation versus maintenance of current therapy Pain, function, None — — — Insufficient — No evidence quality of life, and outcomes related to abuse Effects of decreasing or tapering opioid doses versus continuation of opioid therapy Pain and 1 randomized Very serious Unknown (1 Very serious 4 None Abrupt cessation of morphine function trial (n = 10) limitations study) imprecision identified was associated with increased pain and decreased function compared with continuation of morphine. Comparative effectiveness of different tapering protocols and strategies Opioid 2 Very serious No Very serious 4 None No clear differences between abstinence nonrandomized limitations inconsistency imprecision identified different methods for opioid trials (n = 150) discontinuation or tapering in likelihood of opioid abstinence after 3–6 months

Risk assessment and risk mitigation strategies (KQ4)

Diagnostic accuracy of instruments for predicting risk for opioid overdose, addiction, abuse, or misuse among patients with chronic pain being considered for long-term opioid therapy Opioid risk tool 3 studies of Serious Very serious Serious 4 None Based on a cutoff score of diagnostic limitations inconsistency imprecision identified ≥4 (or unspecified), five accuracy (n = studies (two fair quality, 496) New for three poor quality) reported update:2 studies sensitivity that ranged from of diagnostic 0.20 to 0.99 and specificity accuracy (n = that ranged from 0.16 to 320) 0.88. Screener 2 studies of Very serious No Serious 3 None Based on a cutoff score of and Opioid diagnostic limitations inconsistency imprecision identified ≥8, sensitivity was 0.68 and Assessment for accuracy (n = specificity was 0.38 in one Patients with 203) study, for a positive likelihood Pain, Version 1 ratio of 1.11 and a negative likelihood ratio of 0.83. Based on a cutoff score of >6, sensitivity was 0.73 in one study. Screener New for update: Very serious No Serious 3 None Based on a cutoff score of and Opioid 2 studies of limitations inconsistency imprecision identified >3 or unspecified, sensitivity Assessment for diagnostic was 0.25 and 0.53 and Patients with accuracy (n = specificity was 0.62 and 0.73 Pain-Revised 320) in two studies, for likelihood ratios close to 1.

61 Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Brief Risk New for Very serious No Serious 3 None Based on a “high risk” Interview update: 2 limitations inconsistency imprecision identified assessment, sensitivity was 0.73 studies of and 0.83 and specificity was diagnostic 0.43 and 0.88 in two studies, for positive likelihood ratios of 1.28 accuracy (n and 7.18 and negative likelihood = 320) ratios of 0.63 and 0.19.

Outcome Studies Limitations Inconsistency Imprecision Type of Other Estimates of effect/findings evidence factors Effectiveness of risk prediction instruments on outcomes related to overdose, addiction, abuse, or misuse in patients with chronic pain Outcomes None — — — Insufficient — No evidence related to abuse Effectiveness of risk mitigation strategies, including opioid management plans, patient education, urine drug screening, use of prescription drug monitoring program data, use of monitoring instruments, more frequent monitoring intervals, pill counts, and use of abuse-deterrent formulations, on outcomes related to overdose, addiction, abuse, or misuse Outcomes None — — — Insufficient — No evidence related to abuse Effectiveness of risk prediction instruments on outcomes related to overdose, addiction, abuse, or misuse in patients with chronic pain Outcomes None – – – Insufficient – No evidence related to abuse Effectiveness of risk mitigation strategies, including opioid management plans, patient education, urine drug screening, use of prescription drug monitoring program data, use of monitoring instruments, more frequent monitoring intervals, pill counts, and use of abuse-deterrent formulations, on outcomes related to overdose, addiction, abuse, or misuse Outcomes None – – – Insufficient – No evidence related to abuse Comparative effectiveness of treatment strategies for managing patients with addiction to prescription opioids Outcomes None – – – Insufficient – No evidence related to abuse Effects of opioid therapy for acute pain on long-term use (KQ5) Long-term New for Serious No No imprecision 3 None One study found use of opioids opioid use update: limitations inconsistency identified within 7 days of low-risk surgery 2 cohort associated with increased studies likelihood of opioid use at 1 year (adjusted OR 1.44, 95% CI = (n = 1.39–1.50), and one study found 399,852) use of opioids within 15 days of onset of low back pain among workers with a compensation claim associated with increased risk of late opioid use (adjusted OR 2.08, 95% CI = 1.55–2.78 for 1 to 140 MME/day and OR 6.14, 95% CI = 4.92–7.66 for ≥450 MME/day). Abbreviations: CI = confidence interval; ER/LA = extended release/long-acting; HR = hazard ratio; MME = morphine milligram equivalents; OR = odds ratio. *Ratings were made per GRADE quality assessment criteria; “no limitations” indicates that limitations assessed through the GRADE method were not identified. †Not applicable as no evidence was available for rating.

62 Table 2. Morphine Milligram Equivalent (Mme) Doses For Commonly Prescribed Opioids Opioid Conversion factor* Codeine 0.15 Fentanyl transdermal (in mcg/hr) 2.4 Hydrocodone 1 Hydromorphone 4 Methadone 1–20 mg/day 4 21–40 mg/day 8 41–60 mg/day 10 ≥61–80 mg/day 12 Morphine 1 Oxycodone 1.5 Oxymorphone 3 Tapentadol† 0.4 Source: Adapted from Von Korff M, Saunders K, Ray GT, et al. Clin J Pain 2008;24:521–7 and Washington State Interagency Guideline on Prescribing Opioids for Pain (http://www. agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf). *Multiply the dose for each opioid by the conversion factor to determine the dose in MMEs. For example, tablets containing hydrocodone 5 mg and acetaminophen 300 mg taken four times a day would contain a total of 20 mg of hydrocodone daily, equivalent to 20 MME daily; extended-release tablets containing oxycodone 10mg and taken twice a day would contain a total of 20mg of oxycodone daily, equivalent to 30 MME daily. The following cautions should be noted: 1) All doses are in mg/day except for fentanyl, which is mcg/hr. 2) Equianal- gesic dose conversions are only estimates and cannot account for individual variability in genetics and pharmacokinetics. 3) Do not use the calculated dose in MMEs to determine the doses to use when converting opioid to another; when converting opioids the new opioid is typically dosed at substantially lower than the calculated MME dose to avoid accidental overdose due to incomplete cross-tolerance and individual variability in opioid pharmacokinetics. 4) Use particular caution with methadone dose conversions because the conversion factor increases at higher doses. 5) Use particular caution with fentanyl since it is dosed in mcg/hr instead of mg/day, and its absorption is affected by heat and other factors. †Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor. MMEs are based on degree of mu-receptor agonist activity, but it is unknown if this drug is associated with overdose in the same dose-dependent manner as observed with medications that are solely mu receptor agonists. Steering Committee and Core Expert Group Members

Steering Committee: Deborah Dowell, MD, Tamara M. Haegerich, PhD; Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC; Roger Chou, MD; on detail to CDC under contract

Core Expert Group Members: Pam Archer, MPH, Oklahoma State Department of Health; Jane Ballantyne, MD; University of Washington (retired); Amy Bohnert, PhD; University of Michigan; Bonnie Burman, ScD; Ohio Department on Aging; Roger Chou, MD; on detail to CDC under contract; Phillip Coffin, MD, San Francisco Department of Public Health; Gary Franklin, MD, MPH; Washington State Department of Labor and Industries/University of Washington; Erin Krebs, MDH; Minneapolis VA Health Care System/University of Minnesota; Mitchel Mutter, MD, Tennessee Department of Health; Lewis Nelson, MD; New York University School of Medicine; Trupti Patel, MD, Arizona Department of Health Services; Christina A. Porucznik, PhD, University of Utah; Robert “Chuck” Rich, MD, FAAFP, American Academy of Family Physicians; Joanna Starrels, MD, Albert Einstein College of Medicine of Yeshiva University; Michael Steinman, MD, Society of General Internal Medicine; Thomas Tape, MD, American College of Physicians; Judith Turner, PhD, University of Washington.

Stakeholder Review Group John Markman, MD, American Academy of Neurology; Bob Twillman, PhD, American Academy of Pain Management; Edward C. Covington, MD, American Academy of Pain Medicine; Roger F. Suchyta, MD, FAAP, American Academy of Pediatrics; Kavitha V. Neerukonda, JD, American Academy of Physical Medicine and Rehabilitation; Mark Fleury, PhD, American Cancer Society Cancer Action Network; Penney Cowan, American Chronic Pain Association; David Juurlink, BPharm, MD, PhD, American College of Medical Toxicology; Gerald “Jerry” F. Joseph, Jr, MD, American College of Obstericians and Gynecologists; Bruce Ferrell, MD, AGSF, M. Carrington Reid, MD, PhD, American Geriatrics Society; Ashley Thompson, American Hospital Association; Barry D. Dickinson, PhD, American Medical Association; Gregory Terman MD, PhD, American Pain Society; Beth Haynes, MPPA, American Society of Addiction Medicine; Asokumar Buvanendran, MD, American Society of Anesthesiologists; Robert M. Plovnick; MD, American Society of Hematology; Sanford M. Silverman, MD, American Society of Interventional Pain Physicians; Andrew Kolodny, MD, Physicians for Responsible Opioid Prescribing.

Opioid Guideline Workgroup Chair: Christina Porucznik, PhD, MSPH Workgroup Members: Anne Burns, RPh; Penney Cowan; Chinazo Cunningham, MD, MS; Katherine Galluzzi, DO; Traci Green, PhD, MSC; Mitchell Katz, MD; Erin Krebs, MD, MPH; Gregory Terman, MD, PhD; Mark Wallace, MD. Workgroup Consultants: Roger Chou, MD; Edward Covington, MD; Diana Eppolito; Michael Greene, MD; Steven Stanos, DO.

Peer Reviewers Jeanmarie Perrone, MD, University of Pennsylvania; Matthew Bair, MD, Indiana University School of Medicine;, David Tauben, MD, University of Washington NCIPC Board of Scientific Counselors Chair: Stephen Hargarten, MD, MPH; Members: John Allegrante, PhD; Joan Marie Duwve, MD, Samuel Forjuoh, MD, MPH, DrPH, FGCP; Gerard Gioia, PhD; Deborah Gorman-Smith, PhD; Traci Green, PhD; Sherry Lynne Hamby, PhD; Robert Johnson, MD; Angela Mickalide, PhD, MCHES; Sherry Molock, PhD; Christina Porucznik, PhD, MSPH; Jay Silverman, PhD; Maria Testa, PhD; Shelly Timmons, MD, PhD, FACS, FAANS; Ex Officio Members: Melissa Brodowski, PhD; Dawn Castillo, MPH; Wilson Compton, MD, MPE; Elizabeth Edgerton, MD, MPH; Thomas Feucht, PhD; Meredith Fox, PhD; Holly Hedegaard, MD, MSPH; John Howard, MD; Lyndon Joseph, PhD; Jinhee Lee, PharmD; Iris Mabry-Hernandez, MD, MPH; Valeri Maholmes, PhD; Angela Moore Parmley, PhD; Thomas Schroeder, MS.

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68 CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN Self-Assessment Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

31. What percentage of patients presenting to physician 35. How soon after starting a patient on opioid therapy offices with non-cancer pain symptoms or pain-related should a clinician evaluate the risks and benefits of the diagnoses currently receive an opioid prescription in treatment? the US? A. Within 1-4 weeks A. 5% B. Within 1-4 months B. 10% C. After 6 months C. 15% D. After a year D. 20% 36. What is one suggestion for a way to augment opioid 32. The CDC guidelines (and others) define chronic pain as treatment in order to help improve a patient’s pain and pain lasting more than ______or past the time function? of normal tissue healing. A. Use an every-other-day dosing pattern for the opioid, A. 4 weeks alternating with an NSAID analgesic B. 1 month B. Rotate the route of administration every 6 weeks C. 3 months C. Add a long-acting opioid to a prescription for an D. 6 months immediate-release opioid D. Try concurrent nonpharmacologic approaches such as 33. Although the terms “abuse,” “dependence,” and exercise or cognitive behavioral therapy “addiction,” have been used in the past to describe a problematic pattern of opioid use leading to clinically 37. Which statement accurately describes a challenge significant impairment or distress, which term is now clinicians face when considering initiating treatment generally favored? with an opioid? A. Substance use disorder A. It is difficult to predict whether an individual patient will B. Opioid use disorder experience constipation as a side effect of an opioid C. Dysfunctional opioid tolerance B. It is very difficult to predict whether benefits of opioids D. Opioid-induced dysthymia for chronic pain will outweigh risks for individual patients C. Patients are generally reluctant to sign provider/patient 34. Which statement best summarizes the CDC finding about agreements about treatment with opioids opioids for chronic pain? D. Few guidelines exist to help clinicians decide which A. Opioid analgesics should be confined to use in patients patients are appropriate for opioids with neuropathic, as opposed to nociceptive, pain syndromes 38. Which of the following is not a key point for clinicians B. Chronic non-cancer pain can be effectively treated with to discuss with patients when an opioid is prescribed? immediate-release opioid agents, but should not be A. Insurance may not cover some forms of opioids treated with long-acting or extended-release formulations B. No good evidence shows that opioids improve pain or C. No evidence shows a long-term benefit of opioids in function with long-term use pain and function versus no opioids although extensive C. Function can improve even when pain is still present evidence shows the potential harms of opioids D. Opioids pose many risks including overdose or life-long D. Evidence supports the use of opioid analgesics for long- opioid use disorder term non-cancer chronic pain except in patients with pre- existing substance use disorders

69 39. Why should ER/LA opioids be avoided when starting 45. What do the CDC guidelines suggest regarding the opioid therapy for chronic pain? prescription of opioids to pregnant women? A. They tend to be more expensive than immediate-release A. Clinicians and patients should carefully weigh risks and opioids benefits when deciding whether to start an opioid B. They are not as effective as immediate-release opioids B. Completely avoid prescribing opioids to this population C. There is a higher risk of overdose among patients C. Prescribe ER/LA opioids rather than short-acting opioids starting treatment with ER/LA opioids to avoid spike exposure to fetus D. ER/LA opioids are more difficult for patients to self- D. Prescribe opioids as needed for maternal pain, but administer monitor infant after delivery for possible neonatal abstinence syndrome 40. At which level of opioid dosing should a clinician carefully reassess the evidence of benefits and risks for 46. For the treatment of chronic pain in patients with the patient? depression, which two classes of antidepressants are A. ≥ 50 MMED recommended? B. ≥ 60 MMED A. Atypicals and dopamine-agonist antidepressants C. ≥ 80 MMED B. SSRIs and SNRIs D. ≥ 90 MMED C. MAOIs and tricyclics D. SNRIs and tricyclics 41. Most experts agree that opioid dosages should not be increased to ______without careful justification 47. The DAST and AUDIT tools are examples of which kind based on diagnosis and on an individualized assessment of assessment? of benefits and risks. A. Quantifying patients’ pain perceptions A. ≥ 50 MMED B. Assessing patient risk of opioid misuse or abuse B. ≥ 60 MMED C. Evaluating risk of physical adverse reactions to opioids C. ≥ 80 MMED D. Determining a reason for opioid pain medications D. ≥ 90 MMED 48. Which of the following is not a possible reason for 42. In general, the amount of opioids prescribed for acute prescribing naloxone to a patient who has been pain should be limited to a ____ day supply: prescribed an opioid analgesic? A. 1 A. The patient is taking a higher dose of an opioid (>50 B. 3 MMED) C. 7 B. The patient has recently been released from prison D. 10 C. The patient has history of substance use disorder D. The patient has a concurrent prescription for an SSRI 43. Long-acting (LA) and extended-release (ER) antidepressant formulations of opioids should typically not be used for treating which kind of pain? 49. How frequently should PDMP data be reviewed for A. Cancer pain patients on long-term opioid therapy? B. Acute pain A. Every 4 weeks C. End-of-life pain B. Every month D. Nociceptive pain C. Every 3 months or more frequently D. Every 6 months or more frequently 44. What is the initial suggested rate of taper for weaning patients safely off of an opioid? 50. Which of the following is not a potential benefit of urine A. Decrease of 5% of original dose/week drug testing? B. Decrease of 10% of original dose/week A. Can provide information about drug use that is not C. Decrease of 15% of original dose/week reported by the patient D. Decrease of 20% of original dose/week B. Provides objective evidence of abstinence from drugs of abuse C. Can help identify patients who are not taking opioids prescribed for them D. Can provide accurate information about how much or what dose of opioids a patient may be using 70 COMPASSIONATE CARE Release Date: 10/2020 2 AMA PRA Enduring Material AT THE END OF LIFE Exp. Date: 09/2023 Category 1 CreditsTM (Self Study)

TARGET AUDIENCE

This course is designed for all physicians (MD/DO), physician assistants, nurse practitioners and other healthcare professionals who seek to Read the course materials improve palliative/end-of-life care for their patients. Complete the self-assessment questions at the end. A score of 70% is required. Return your customer information/ answer sheet, evaluation, and COURSE OBJECTIVE payment to InforMed by mail, phone, Physicians and other healthcare professionals are constantly striving fax or complete online at course to improve care for patients in their final phase of life. This educational website under NETPASS. activity addresses the major dimensions of end-of-life care that clinicians are likely to encounter as they care for, and comfort, patients in their final phase of life.

LEARNING OBJECTIVES

Completion of this course will better enable the course participant to: 1. Explain general trends in the preferences that patients typically have for care at the end of life. 2. Discuss the appropriate role of physicians in managing patients in hospice programs. 3. Describe the advantages and the disadvantages of opioid pain medications in the context of end-of-life pain management. 4. Employ both non-pharmacologic and pharmacologic therapies to treat common symptoms associated with the end of life.

ACCREDITATION STATEMENT: InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

DESIGNATION STATEMENT: InforMed designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

71 FACULTY

Paul J. Christo, MD, MBA Associate Professor, The Johns Hopkins University School of Medicine Director, Multidisciplinary Pain Fellowship Program (2003-2011) Director, Blaustein Pain Treatment Center (2003-2008) Division of Pain Medicine 2 Pain Management Stephen Braun and Terminally Medical Writer Ill Patients Braun Medical Media

SPECIAL DESIGNATION This course satisfies two (2) CME ACTIVITY PLANNER credit hours on Pain Management and the Appropriate Treatment of the Michael Brooks Terminally Ill. Director of CME

The Medical Board of California requires most physicians and surgeons to complete a one-time mandatory twelve (12) hours of CME in the subjects of DISCLOSURE OF INTEREST: pain management and the treatment of terminally ill & dying patients. In accordance with the ACCME Standards for Commercial Support of CME, InforMed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE:

The following faculty and/or planning committee members The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to have indicated that they have relationship(s) with industry disclose relative to the content of this CME activity: to disclose: • Stephen Braun • Paul J. Christo, MD, MBA has received honoraria • Michael Brooks from GlaxoSmithKline and Daiichi Sankyo.

STAFF AND CONTENT REVIEWERS: InforMed staff, input committee and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

Although not without benefits, this process of dying effective strategies for care, and to communicate care patients have created advance directives. can result in isolation of the patient from their sensitively with patients and those close to them. • Only 12 percent of patients with an advance loved ones, as well as isolation from familiar and This CME learning activity summarizes the major directive received input from their physician in comforting surroundings. dimensions of end-of-life (EOL) care that clinicians its development. Because Americans, on average, live much are likely to encounter as they care for, and comfort, • As many as three-quarters of physicians longer now than they did in the past, a much larger patients in their final phase of life. whose patients had an advance directive were proportion of the population dies at an advanced not aware that it existed. age. More than 70 percent of those who die each Patient preferences for EOL care • Having an advance directive did not increase year are age 65 or over, and those who die in old documentation in the medical chart regarding age tend to die of different causes than those who Predicting what treatments patients will want at patient preferences. 1 die young. The dying process today tends to be the end of life is complicated by factors such as the • Advance directives helped make end-of-life more extended, in part because medical treatments patient’s age, the nature of the illness, the ability of decisions in less than half of the cases where can manage pneumonia, infections, kidney failure, medicine to sustain life, and the emotions families a directive existed. and other immediate causes of death that come in • Advance directives usually were not applicable endure when a loved one is sick or dying. When the wake of cancer or chronic disease. seriously ill patients are nearing the end of life, they until the patient became incapacitated and The field of palliative care is one response to and their families sometimes find it difficult to decide “absolutely, hopelessly ill.” st the changing profile of death in the 21 century. It whether to continue medical treatment and, if so, • Providers and patient surrogates had difficulty focuses on the prevention and relief of suffering by how much treatment and for how long. In these knowing when to stop treatment and often carefully managing symptoms and by paying close instances, patients rely on their physicians or other waited until the patient was actively dying attention to the emotional, spiritual, and practical trusted health professionals for guidance. before the advance directive was invoked. needs of patients and those close to them. Other In the best circumstances, the patient, the • Language in advance directives was usually community and professional responses include the family, and the physician have discussed treatment too vague and general to provide clear development of hospice programs, bereavement options, including the length and invasiveness of instruction. support groups, and policies and programs that treatment, chances of success, overall prognosis, • Surrogates named in the advance directive encourage communication about people’s goals and the patient’s quality of life during and after often were not present to make decisions and preferences as they approach death. the treatment. Ideally, these conversations would or were too emotionally distraught to offer Palliative care is both a general approach to continue as the patient’s condition changes. guidance. patient care (integrated with disease-modifying Frequently, however, such discussions are not • Physicians were only about 65 percent therapies) as well as a growing practice specialty. held. If the patient becomes incapacitated due to accurate in predicting patient preferences and Primary care physicians are often expected to illness, the patient’s family and physician must make tended to make errors of under-treatment, provide basic elements of palliative care (e.g., decisions based on what they think the patient even after reviewing the patient’s advance pain and symptom assessment and management, would want. directive. advance care planning), but complex cases may be While no one can predict exactly what patients • Surrogates who were family members tended best handled by palliative care specialists. will want or need when they are sick or dying, to make prediction errors of overtreatment, Decisions about the use of life-sustaining current research can help providers offer end- even if they had reviewed or discussed the treatment when a person is seriously ill or near advance directive with the patient or assisted of-life care based on preferences (both real and death have profound consequences for that hypothetical) held by the majority of patients under in its development. person, for his or her family and loved ones, and, similar circumstances.3 Research indicates that often, for health care providers. Such decisions Research also shows that care at the end of most patients have not participated in advance care life is sometimes inconsistent with the patients’ may determine the time and circumstances of planning, yet many are willing to discuss end-of-life the person’s death and may shape the person’s preferences to forgo life-sustaining treatment, and care. One way to determine patients’ preferences that patients may receive care they do not want. For experience of remaining life—where it is lived, with for end-of-life care is to discuss hypothetical whom, and with what degree of comfort or suffering. example, one study found that patient preferences situations and find out their opinions on certain to decline cardiopulmonary resuscitation (CPR) Physicians thus have a compelling responsibility to treatment patterns. These opinions can help clarify be as compassionate and competent in their care of were not translated into do-not-resuscitate and predict the preferences they would be likely to (DNR) orders.6 Another study found that patients dying patients as with patients at any other phase have it if they should become incapacitated and of their lives. received life-sustaining treatment at the same rate unable to make their own decisions. regardless of their desire to limit treatment.7 Unfortunately, the education and training of The Patient Self-Determination Act guarantees physicians and other health care professionals often Because physicians are in the best position to patients the right to accept or refuse treatment and know when to bring up the subject of end-of-life fail to provide them the attitudes, knowledge, and to complete advance medical directives.4 skills required to care well for the dying patient.2 care, they are the ones who need to initiate and guide advance care planning discussions.

73 Such discussions are usually reserved for people patient satisfaction among patients age 65 years hypothetical scenarios and probable treatments who are terminally ill or whose death is imminent, and over.10 and noting when the patient’s preferences change yet research indicates that people suffering from Patients who talked with their families or from “treat” to “do not treat,” the physician can chronic illness also need advance care planning. physicians about their preferences for end-of- begin to identify the patient’s personal preferences

Most people who die in the United States (80 to life care had less fear and anxiety, felt they had and values. 85 percent) are Medicare beneficiaries age 65 and more ability to influence and direct their medical The physician can also determine if the patient over, and most die from chronic conditions such as care, believed that their physicians had a better has an adequate understanding of the scenario, heart disease, cancer, chronic lower respiratory understanding of their wishes, and indicated a the treatment, and possible outcomes. One diseases, stroke, diabetes, Alzheimer’s disease, greater understanding and comfort level than they study indicated that elderly patients have enough and renal failure.8 had before the discussion. Compared to surrogates knowledge about advance directives, CPR, and Only about 22 percent of deaths in people age of patients who did not have an advance directive, artificial nutrition/hydration on which to base 65+ are from cancer, which generally follows an surrogates of patients with an advance directive decisions for treatment at the end of life, but they expected course, or “trajectory,” leading to death.8 who had discussed its content with the patient do not always understand their realistic chances for

Many maintain their activities of daily living until reported greater understanding, better confidence a positive outcome.11 Other research indicates that about 2 months prior to death, after which most in their ability to predict the patient’s preferences, patients significantly overestimate their probability functional disability occurs. In contrast, people with and a stronger belief in the importance of having an of survival after receiving CPR and have little or chronic diseases such as heart disease or COPD go advance directive. no understanding of mechanical ventilation.12 After through periods of slowly declining health marked Finally, patients who had advance planning patients were told their probability of survival, by sudden severe episodes of illness requiring discussions with their physicians continued to over half changed their treatment preference hospitalization, from which the patient recovers. This discuss and talk about these concerns with their from wanting CPR to refusing CPR. Patients also pattern may repeat itself, with the patient’s overall families. Such discussions enabled patients and may not know of the risks associated with the use health steadily declining, until the patient dies. For families to reconcile their differences about end- of mechanical ventilation, such as neurological these individuals there is considerable uncertainty of-life care and could help the family and physician impairment or cardiac arrest. about when death is likely to occur. Patients who come to agreement if they should need to make 2. Introduce the subject of advance care suffer from chronic conditions such as stroke, decisions for the patient. planning and offer information. Patients should dementia, or the frailty of old age go through a be encouraged to complete both an advance third trajectory of dying, marked by a steady decline Opportunities for advance planning discussions directive and durable power of attorney. The in mental and physical ability that finally results in Research indicates that physicians can conduct patient should understand that when no advance death. Patients are not often told that their chronic advance care planning discussions with many directive or durable power of attorney exists, disease is terminal, and estimating a time of death patients during routine outpatient office visits. patients essentially leave treatment decisions to for people suffering from chronic conditions is much Hospitalization for a serious and progressive their physicians and family members. Physicians more difficult than it is for those dying of cancer. illness offers another opportunity. The Patient can provide this information themselves; refer the When patients are hospitalized for health crises Self-Determination Act requires facilities such patient to other educational sources, including resulting from their chronic incurable disease, as hospitals that accept Medicare and Medicaid brochures or videos; or recommend that the medical treatment cannot cure the underlying money to provide written information to all patients patient talk with clergy or a social worker to answer illness, but it is still effective in resolving the concerning their rights to refuse or accept treatment questions or address concerns. immediate emergency and thus possibly extending and to complete advance directives. Patients often 3. Prepare and complete advance care the patient’s life. At any one of these crises the send cues to their physicians that they are ready planning documents. Advance care planning patient may be close to death, yet there often is no to discuss end-of-life care by talking about wanting documents should contain specific instructions. The clearly recognizable threshold between being very to die or asking about hospice. Certain situations, standard language contained in advance directives ill and actually dying. such as approaching death or discussions about often is not specific enough to be effective in

prognoses or treatment options that have poor directing care. Many times, instructions do not Patients value advance care planning outcomes, also lend themselves to advance care state the cutoff point of the patient’s illness that discussions planning discussions. Predicting when patients should be used to discontinue treatment and allow

According to patients who are dying and their are near death is difficult, but providers can ask the person to die. Terms such as “no advanced life families who survive them, lack of communication themselves the question: are the patients “sick support” are too vague to guide specific treatments. with physicians and other health care providers enough today that it would not be surprising to If a patient does not want to be on a ventilator, the causes confusion about medical treatments, find that they had died within the next year (or few physician should ask the patient if this is true under conditions and prognoses, and the choices that months, or 6 months)”? all circumstances or only specific circumstances. patients and their families need to make.2 One study A five-part process has been suggested to guide 4. Review the patient’s preferences on a indicated that about one-third of patients would structured discussions about end-of-life care:2 regular basis and update documentation. discuss advance care planning if the physician 1. Initiate a guided discussion. During this Patients should be reminded that advance directives brought up the subject and about one-fourth discussion, the physicians should share their can be revised at any time. Although studies show of patients had been under the impression that medical knowledge of hypothetical scenarios and that patient preferences are stable over time when advance care planning was only for people who treatments applicable to a patient’s particular considering hypothetical situations, patients often were very ill or very old.9 Only 5 percent of patients situation and find out the patient’s preferences for change their minds when confronted with an actual in this study stated that they found discussions providing or withholding treatments under certain situation or as their health status changes.13 Some about advance care planning too difficult. Other situations. The hypothetical scenarios should cover patients who stated that they would rather die than studies have shown that discussing advance care a range of possible prognoses and any disability that endure a certain condition did not choose death planning and directives with their doctor increased could result from treatment. By presenting various once that condition occurred.

74 Other research shows that patients who had allow the patient to receive a non-beneficial This means listening carefully and non-judgmentally an advance directive maintained stable treatment treatment. Physicians stated that they would also to what your patient is saying, then reflecting it preferences 86 percent of the time over a enlist the family’s help or seek a second opinion back in a slightly modified or re-framed manner.19

2-year period, while patients who did not have from another physician. This lets the clinician confirm the accuracy of their an advance directive changed their preferences Many patients do not lose their decision making understanding of the patient and gives the patient

14 both the indication that they are being heard (an all- 59 percent of the time. Both patients with and capacity at the end of life. Physicians and family without a living will were more likely to change their too-rare experience for many patients with chronic members can continue discussing treatment illness) and a chance to correct mistaken beliefs or preferences and desire increased treatment once preferences with these patients as their condition perceptions that could affect their care. they became hospitalized, suffered an accident, changes. However, physicians and families may Using a reflective listening strategy can take became depressed, or lost functional ability or encounter the difficulty of knowing when an practice. If a patient says something at odds with social activity. Another study linked changes in advance directive should become applicable for the evidence, for example, or uses threatening depression to changes in preferences for CPR.15 patients who are extremely sick and have lost their or hostile language, one’s natural reaction is to Increased depression was associated with patients’ decision making capacity but are not necessarily immediately defend oneself, rebut the charges, or changing their initial preference for CPR to refusal dying. There is no easy answer to this dilemma. deny the underlying assumptions. This can quickly of CPR, while less depression was associated with Even if patients require a decision for a situation create confrontation or a power-struggle that can be patients’ changing their preference from refusal of that was not anticipated and addressed in their difficult to reverse. In these situations it’s important to pause before speaking, and then to consciously CPR to acceptance of CPR. It is difficult for people to advance directive, physicians and surrogates still fully imagine what a prospective health state might try to simply re-state what the patient just said. For can make an educated determination based on the example, a patient may say, “Doctor, those pills you be like. Once they experience that health state, knowledge they have about the patients’ values, gave me don’t work—I told you before that I need they may find it more or less tolerable than they goals, and thresholds for treatment. something stronger.” A directly confrontational imagined. response will probably be ineffective. A better During reviews of advance directives, physicians The importance of shared decision making response would be something like “You seem to should note which preferences stay the same and Effective patient-provider communication be irritated with me because you don’t think the which change. Preferences that change indicate and shared decision making is achieved in part medications I prescribed are working for you.” that the physician needs to investigate the basis for through active listening, facilitation, and empathetic In summary, reflective listening techniques the change. comments.17 These skills lead to an engaged, provide several advantages:19 5. Apply the patient’s desires to actual dynamic relationship between patients, their • They are less likely to evoke or exacerbate circumstances. Conflicts sometimes arise during families, and health care providers. This partnership patient defensiveness • They encourage the patient to keep talking discussions about end-of-life decision-making. If should be grounded in mutuality, which includes the and reveal more about their true feelings patients desire non-beneficial treatments or refused sharing of information, creation of consensus, and • They communicate respect and caring, and beneficial treatments, most physicians state that other components of the shared decision making encourage a therapeutic alliance 18 they would negotiate with them and try to educate paradigm. • They open an opportunity for the patient to and convince them to either forgo a non-beneficial clarify exactly what he or she means treatment or to accept a beneficial treatment.16 Reflective listening If the treatment was not harmful, expensive, or An effective communication strategy in any BEFORE MOVING ONTO THE NEXT SECTION, complicated, about one-third of physicians would patient-physician relationship is reflective listening. PLEASE COMPLETE CASE STUDY 1.

Case Study 1 Spend 5 minutes reviewing the case below and considering the questions that follow. Janet is an 83-year-old woman with amyotrophic lateral sclerosis (ALS). Her speech has become very slurred, she is having difficulty chewing and swallowing, and has lost 40 pounds over the course of the past 18 months. She has never liked what she calls the “medical establishment,” takes no prescription drugs, and prefers natural and alternative methods of dealing with health issues. Her neurologist and her three grown children are all concerned about her weight loss and growing frailty and have suggested she have a percutaneous endoscopic gastrostomy (PEG) tube placed so she can get more adequate nutrition and hydration. Janet, however, is not cooperating. She has delayed making a decision and appears unwilling to discuss the matter with anybody. She is now sitting in your office, with one of her sons present, and has just replied angrily to your statement that further delays in getting a feeding tube will hasten her death. “What if I don’t see the point in continuing to live, doctor?” she says, struggling to enunciate the words. “Has it crossed your mind that I might not enjoy living under these horrible conditions?”

1. What would be a possible response to Janet’s outburst that would employ the technique of reflective listening?

2. How could you work with Janet to establish a set of care goals that would be appropriate for either course of action (i.e., having, or not having, the PEG placed)?

3. If Janet refuses the PEG, what steps could you take to make her final weeks more comfortable?

75 Preference patterns for hypothetical situations Advance planning helps physicians provide care their diagnosis, but the amount of desired details Evidence suggests that patients are more likely that patients want varies among different cultures and by education to accept treatment for conditions they consider Most people will eventually die from chronic level, age, and sex. The physician should respect better than death and to refuse treatment for conditions. These patients require the same kind the patient’s unique preferences for receiving bad conditions they consider worse than death. Patients of advance care planning as those suffering from news. also were more likely to accept treatments that were predictably terminal conditions such as cancer. Physicians may experience stress related to less invasive such as CPR than invasive treatments Understanding preferences for medical treatment providing bad news that extends beyond the actual such as mechanical ventilation (see Table 1). in patients suffering from chronic illness requires conversation. For example, physicians may be afraid Patients were more likely to accept short-term or that physicians and other health care providers simple treatments such as antibiotics than long- of eliciting an emotional reaction, being blamed for term invasive treatments such as permanent tube consider patients’ concerns about the severity of the bad news, and expressing their emotions during feeding. prospective health states, length and invasiveness the process. Physicians often withhold information It is telling that physicians, who are in a better of treatments, and prognosis. While predicting what or are overly optimistic regarding prognosis, but position than others to judge the likely value of patients might want is difficult, research offers some this can lead to confusion for patients regarding EOL services, often choose much less aggressive insights into treatment patterns and preferences their condition. There are several algorithms treatments for themselves than they offer to their under hypothetical situations that can give available to help guide the physician in the delivery patients. A study comparing 78 primary care faculty providers more insight into their patients’ desires of bad news, including the SPIKES protocol (see and residents with 831 of their patients found that under similar circumstances. By discussing advance Table 3). Skillful delivery of bad news can provide the physicians were much less likely than the patients care planning during routine outpatient visits, comfort for the patient and family. to want five of six specific treatments if they were during hospitalization for exacerbation of illness, 20 terminally ill. And 59% of the physicians chose or when the patient or physician believes death is BEFORE MOVING ONTO THE NEXT SECTION, “least aggressive” EOL treatment preferences for near, physicians can improve patient satisfaction PLEASE COMPLETE CASE STUDY 2 ON PG. 78. themselves. with care and provide care at the end of life that is Acceptance or refusal of invasive and noninvasive in accordance with the patient’s wishes. Suggested treatments under certain circumstances can predict Culturally Sensitive Communication what other choices the patient would make under components of an individualized approach to EOL Communicating effectively with both patients the same or different circumstances. Refusal of care are summarized in Table 2. and their loved ones requires an awareness of noninvasive treatments such as antibiotics strongly some of the cultural differences that can create predicted that invasive treatments such as major Communicating life-altering news unexpected barriers or misunderstandings. End- surgery would also be refused. Research also of-life discussions are particularly challenging reveals that patients were more likely to refuse “The best way to convey meaning is to tell people because of their emotional and interpersonal treatment under hypothetical conditions as their what the information means to you yourself. And intensity. Many physicians are unfamiliar with prognosis became worse. For example, more there are three words to do that: “I am worried.” common cultural variations regarding physician- adults would refuse both invasive and noninvasive They were such simple words, but it wasn’t hard to patient communication, medical decision making, treatments for a scenario of dementia with a sense how much they communicated. I had given and attitudes about formal documents such as code terminal illness than for dementia only. Adults were her the facts. But by including the fact that I was status guidelines and advance directives.25 also more likely to refuse treatment for a scenario worried, I’d not only told her about the seriousness Although cultural differences certainly exist, of a persistent vegetative state than for a coma of the situation, I’d told her that I was on her generalizations about specific cultures are not with a chance of recovery. More patients preferred side—I was pulling for her. The words also told always applicable to specific patients because treatment if there was even a slight chance for her that, although I feared something serious, there recovery from a coma or a stroke. Fewer patients there is wide variation in the ways that individuals remained uncertainties—possibilities for hope adhere or adopt the stereotypical beliefs, values, or would want complicated and invasive treatments if 22 they had a terminal illness. Finally, patients were within the parameters nature had imposed.” attitudes of a particular culture. In fact, research more likely to want treatment if they would remain --Atul Gawande, MD suggests that when compared with whites of cognitively intact rather than impaired. European descent, ethnic minorities exhibit greater Delivering bad or life-altering news to a patient is variability in their cultural beliefs and preferences.26 one of the most difficult tasks physicians encounter.23 Clinicians should be aware that different cultures Table 1. Treatment preferences among Ultimately, the determination of what is bad news lies may place different emphasis—or disagree patients age 64 and over, from most- to not with the physician, but with the person receiving completely—with principles of medical conduct that least-preferred21 the news. Although classically related to cancer or they take for granted. For example, in the United 1. Antibiotics a terminal diagnosis, bad or serious news may also States, legal documents such as advance directives 2. Blood transfusion include information related to diagnosis of a chronic and durable powers of attorney are strategies to 3. Temporary tube feeding disease (e.g., diabetes mellitus), a life-altering prolong autonomy in situations in which patients illness (e.g., multiple sclerosis), or an injury leading 4. Temporary respirator can no longer represent themselves. Other cultures, to a significant change (e.g., a season-ending knee however, de-emphasize autonomy, perceiving it as 5. Radiation injury). Most of the research into the delivery of isolating rather than empowering. These non- 6. Amputation bad news, however, has focused on patients with Western cultures believe that communities and 7. Dialysis cancer and subsequently applied to the delivery of families, not individuals alone, are affected by life- bad or serious news in non-oncologic settings. 8. Chemotherapy threatening illnesses and the accompanying medical Patients prefer to receive such news in person, decisions.27 9. Resuscitation with the physician’s full attention, and in clear, 10. Permanent respirator easy-to-understand language with adequate 11. Permanent tube feeding time for questions. Most patients prefer to know

76 Table 2. Components of individualized EOL care2 Component Rationale Frequent assessment of the patient’s Interventions and care should be based on accurately identified needs. physical, emotional, social, and spiritual well-being Management of emotional distress All clinicians should be able to identify distress and direct its initial and basic management. This is part of the definition of palliative care, a basic component of hospice, and clearly of fundamental importance.

Offer referral to expert-level palliative People with palliative needs beyond those that can be provided by non-specialist-level clinicians deserve access to care appropriate expert-level care. Offer referral to hospice if the patient People who meet the hospice eligibility criteria deserve access to services designed to meet their end-of-life needs. has a prognosis < 6 months. Management of care and direct contact Care of people with serious illness may require specialist-level palliative care physician management, and effective with patient and family for complex physician management requires direct examination, contact, and communication. situations by a specialist level palliative care physician Round-the-clock access to coordinated Patients in advanced stages of serious illness often require assistance, such as with activities of daily living, care and services medication management, wound care, physical comfort, and psychosocial needs. Round-the-clock access to a consistent point of contact that can coordinate care obviates the need to dial 911 and engage emergency medical services. Management of pain and other All clinicians should be able to identify and direct the initial and basic management of pain and other symptoms. symptoms This is part of the definition of palliative care, a basic component of hospice, and clearly of fundamental importance. Counseling of patient and family Even patients who are not emotionally distressed face problems in such areas as loss of functioning, prognosis, coping with diverse symptoms, finances, and family dynamics, and family members experience these problems as well, both directly and indirectly. Family caregiver support A focus on the family is part of the definition of palliative care; family members and caregivers both participate in the patient’s care and require assistance themselves. Attention to the patient’s social context Person-centered care requires awareness of patients’ perspectives on their social environment and of their and social needs needs for social support, including at the time of death. Companionship at the bedside at time of death may be an important part of the psychological, social, and spiritual aspects of end-of-life care for some individuals. Attention to the patient’s spiritual and The final phase of life often has a spiritual and religious component, and research shows that spiritual assistance is religious needs associated with quality of care. Regular personalized revision of the Care must be person-centered and fit current circumstances, which may mean that not all the above components care plan and access to services based will be important or desirable in all cases. on the changing needs of the patient and family

Cultures valuing non-malfeasance (doing Here are some example questions and situations When discussing medical issues with family no harm) may try to protect patients from that reflect a culturally sensitive approach to patient members, particularly through a translator, it is often the emotional and physical harm caused by interactions:25 helpful to confirm their understanding: “I want to be directly addressing death and end-of-life care. “Some people want to know everything about sure that I am explaining your mother’s treatment Many Asian and Native American cultures value their medical condition, and others do not. What is options accurately. Could you explain to me your beneficence (physicians’ obligation to promote your preference?” understanding about your mother’s condition and patient welfare) by encouraging patient hope, “Do you prefer to make medical decisions about the treatment that we are recommending?” even in the face of terminal illness. Patient or future tests or treatments for yourself, or would you “Is there anything that would be helpful for me family member preferences for nondisclosure of prefer that someone else make them for you?” to know about your family or religious views about medical information and family-centered decision To patients who request that the physician serious illness and treatment?” making may also be surprising to American-trained discuss their condition with family members: “Would “Sometimes people are uncomfortable discussing physicians. you be more comfortable if I spoke with your these issues with a doctor who is of a different race Physicians may improve their rapport with (brother, son, daughter) alone, or would you like or cultural background. Are you comfortable with ethnically diverse patients simply by showing to be present?” If the patient chooses not to be me treating you? Will you please let me know if there interest in their cultural heritage. present: “If you change your mind at any point and is anything about your background that would be would like more information, please let me know. I helpful for me to know in working with you or your will answer any questions you have (mother, father, sister, brother)?”

77 Case Study 2 Spend 5 minutes reviewing the case below and considering the questions that follow. Terry is the oldest of five siblings. He has been the primary caregiver for his father, Ralph, who is 87 and lives alone following the death of his wife four years previous. Ralph has congestive heart failure, hearing loss, and type 2 diabetes. He was recently admitted to the hospital for pneumonia. While in the hospital, he had a transient ischemic attack, which caused him to become easily confused. Then, possibly due to a micro- stroke, he lost his ability to swallow. Ralph’s attending physician advised the placement of a percutaneous endoscopic gastrostomy (PEG) tube to supply nutrition and hydration. But Ralph had made it clear in his advance directive that he did not want a feeding tube, and he reiterated that desire to Terry. “I’m not afraid to die,” he said. “It’s time to call it quits.” Terry was torn. Some of his siblings were unhappy with the prospect of refusing the tube placement—they were afraid Ralph would die before they got a chance to see him. But Terry knew his father would fight any efforts to force him to change his mind, and Terry didn’t want his last days with his father marred by conflict.

1. What would be a possible response to Ralph’s expression about not being afraid to die that would employ the technique of reflective listening?

2. How could you work with Ralph to establish a set of care goals that would be appropriate for either course of action (i.e., having, or not having, the PEG placed)?

3. If Ralph refuses the PEG, what steps could you take to make his final weeks more comfortable?

Table 3. SPIKES protocol for delivering life-altering news24 Step Key Points Example Phrases Setting Arrange for a private room or area. Have tissues available. Limit “Before we review the results, is there anyone else you would interruptions and silence electronics. Allow the patient to dress (if after like to be here?” examination). Maintain eye contact (defer charting). Include family or “Would it be okay if I sat on the edge of your bed?” friends as patient desires. Perception Use open-ended questions to determine the patient’s understanding. “When you felt the lump in your breast, what was your first Correct misinformation and misunderstandings. Identify wishful thinking, thought?” unrealistic expectations, and denial. “What is your understanding of your test results thus far?” Invitation Determine how much information and detail a patient desires. “Would it be okay if I give you those test results now?” Ask permission to give results so that the patient can control the “Are you someone who likes to know all of the details, or would conversation. If the patient declines, offer to meet him or her again in you prefer that I focus on the most important result?” the future when he or she is ready (or when family is available) Knowledge Briefly summarize events leading up to this point. Provide a warning “Before I get to the results, I’d like to summarize so that we are statement to help lessen the shock and facilitate understanding, all on the same page.” although some studies suggest that not all patients prefer to receive a “Unfortunately, the test results are worse than we initially warning. Use nonmedical terms and avoid jargon. Stop often to confirm hoped.” understanding. “I know this is a lot of information; what questions do you have so far?” Emotions Stop and address emotions as they arise. Use empathic statements to “I can see this is not the news you were expecting.” recognize the patient’s emotion. Validate responses to help the patient “Yes, I can understand why you felt that way.” realize his or her feelings are important. Ask exploratory questions to “Could you tell me more about what concerns you?” Strategy help understand when the emotions are not clear. and summary Strategy and Summarize the news to facilitate understanding. Set a plan for follow-up “I know this is all very frightening news, and I’m sure you will summary (referrals, further tests, treatment options). Offer a means of contact if think of many more questions. When you do, write them down additional questions arise. Avoid saying, “There is nothing more we can and we can review them when we meet again.” do for you.” Even if the prognosis is poor, determine and support the “Even though we cannot cure your cancer, we can provide patient’s goals (e.g., symptom control, social support). medications to control your pain and lessen your discomfort.”

78 The physician’s role in managing hospice patients be aware of some common misconceptions about physicians, although social workers, nurses, and hospice care (see Table 4). patients’ families can also make a hospice referral.) Hospice is based on the idea that the dying The majority of caregivers and families of patients patient has physical, psychological, social, BEFORE MOVING ONTO THE NEXT SECTION, who have received hospice care report that they and spiritual aspects of suffering. Hospice is PLEASE COMPLETE CASE STUDY 3 ON THE would have welcomed more information about a philosophy, not a specific place, and can be NEXT PAGE. hospice from their primary care physician at the provided in any setting, including patients’ homes, time the diagnosis was labeled terminal. nursing homes, and hospitals.28 Hospice typically Determining prognosis Most hospices expect the referring physician to involved an interdisciplinary team providing access Deciding whether a patient has a life expectancy remain in charge of the patient’s care and to be available by phone or other means for consultation, to a wide range of services to support the primary < 6 months is an unavoidably imprecise exercise, although expectations for availability vary by caregiver, who is responsible for the majority however the following scales or tools provide clinicians with some quasi-objective criteria to help hospice. In some cases, the local hospice medical of the patient care. In 2017 about 1.5 million director may be willing to cover the attending Medicare beneficiaries received hospice care, a guide decisions: • Karnofsky Performance Scale32 physician on weekends and during vacations. In 4.5% increase from the previous year and nearly general, the attending physician is expected to 29 • National Hospice Organization Medical 200,000 more people than used hospice in 2012. Guidelines for Determining Prognosis in be the primary physician of record, be available To be eligible for hospice, a patient must have Selected Non-Cancer Diseases33 by telephone or have coverage arranged, write a terminal illness and an estimated prognosis of • Palliative Performance Scale34 admission orders, and handle the routine decisions less than six months. Patients with non-cancer • Palliative Prognosis Score35 for patient care. Some hospices provide attending diagnoses (e.g., congestive heart failure, chronic physicians with standing orders that have broad obstructive pulmonary disease, stroke, dementia) Referral patterns parameters for the control of common symptoms, currently represent about 70% percent of all Continuity of care and multigenerational such as pain and dyspnea. The attending physician hospice decedents.29 The responsibility for hospice relationships allow a family physician to guide a and the hospice medical director are expected to referral in a non-cancer diagnosis often falls to the patient and family through the hospice referral provide certification to Medicare that the patient primary care physician, facilitating continuity of care process with a unique knowledge of the patient’s continues to meet hospice eligibility criteria on for the patient in his or her final days and months. In values, family issues, and communication style. a regular basis. The attending physician is also making an appropriate referral, physicians should (In general, most hospice referrals come from expected to provide medication refills when needed.

Table 4. Common misconceptions about hospice care30 Misconception Clarification Patients will be discharged from hospice if they do not There used to be a six-month regulation that penalized hospices and patients when a patient lived die within six months. too long, but it was revised and there is no longer any penalty for an incorrect prognosis if the disease runs its normal course. Patients in hospice must have a DNR order. Medicare does not require a DNR order to enroll in hospice, but it does require that patients pursue palliative, not curative, treatment; individual hospice organizations may require a DNR order before enrolling a patient. Patients in hospice must have a primary caregiver. Medicare does not require a primary caregiver, but this may be a requirement of some hospice organizations. The primary physician must transfer control of his or her Most hospice organizations encourage primary physician involvement; the primary physician patients to hospice. becomes a part of the team and contributes to the hospice plan of care. Only patients with cancer are appropriate candidates for Anyone with a life expectancy of less than six months and who chooses a palliative care approach hospice. is appropriate for hospice. Only Medicare-eligible patients may enroll in hospice. Most commercial insurance companies have benefits that mimic the Medicare Hospice Benefit; individual hospices vary in their willingness to take uninsured patients. Patients in nursing homes are not eligible for hospice. This was once true, but Medicare now covers patients in nursing homes. Patients are not eligible for hospice again if they revoke Patients who want to return to hospice care can be readmitted as long as hospice conditions of the hospice benefits. participation are met. Only physicians can refer patients to hospice. Anyone (e.g., nurse, social worker, family member, friend) can refer a patient to hospice. Hospice care precludes patients from being able to Medicare requires that hospice must cover all care related to the terminal illness; individual hospice receive chemotherapy, blood transfusions, or radiation. agencies are allowed to determine whether a specific treatment is palliative (providing symptom relief), which will guide what treatments they are willing to cover. Patients who have elected the hospice benefit can no Each insurer has rules defining eligibility for covered services; medical problems unrelated to the longer access other health insurance benefits. terminal illness continue to be covered under regular Medicare insurance. Patients in hospice cannot be admitted to the hospital. While the patient is enrolled in hospice, most insurance companies, including Medicare, will still cover hospital admissions for unrelated illnesses, as well as for the management of symptoms related to the terminal diagnosis, and respite care. Hospice care ends when a patient dies. All hospice programs must provide families with bereavement support for up to one year following the death of the patient. 79 Case Study 3 Spend 5 minutes reviewing the case below and considering the questions that follow. Note: This is an excerpt from an article by Yoojin Na, an emergency room physician at a hospital in metropolitan New York, which appeared in the New York Times. A woman held her grandfather’s hand as he lay in intensive care. The patient in question was in his 90s with progressive dementia and multiple chronic conditions. Since December, he hadn’t been able to make it more than a few weeks without a fall. The palliative-care assessment from his last admission gave him an estimated life expectancy of “weeks to months.” Everything I saw on examining him told me it was now days. Soon he wouldn’t be able to breathe on his own. I described to his granddaughter the discomfort of having a ventilator pump air into one’s lungs. I explained that such measures would only prolong his suffering. Still, she insisted that her grandfather be kept “full code” and have “everything done.” Three days later, the patient went into respiratory distress. Since he was full code, his sudden decline activated a rapid response, which meant all nearby personnel — doctors, nurses, respiratory therapists and techs — rushed to the room to resuscitate him. The inpatient doctor called the family again. This time, they agreed to make his code status D.N.R., for do not resuscitate. But the patient had turned out to have Covid-19, and the family’s DNR decision came only after many staff members were exposed reviving him. He died the next morning. The whole ordeal made me wonder why people insist on futile care even when it comes at a risk to others.

1. Why do you think the family initially insisted on having doctors use “full code” procedures for their grandfather?

2. How would you have handled the conversations with family members when communication was limited to telephones?

3. If the patient had an advance directive stating a refusal of “heroic measures” could that have been used by doctors to refuse the family’s initial insistence of “full code” procedures?

Essential drugs for quality care in dying patients Pain Management priorities that compete with, or supersede, the relief of pain. For example, the end of life can be Effective management of symptoms at the end Although pain relief is often considered— an extremely important and meaningful time.37 For of life is challenging but often can be achieved with and may sometimes be—an end unto itself, it is some patients, mental alertness sufficient to allow fewer than for six key medications. Clinicians can particularly important for clinicians to recognize maximal interactions with loved ones may be more help support patients and family by using these that, at the end of life, pain management and important than physical comfort. Optimal pain medications judiciously with the assurance that control of symptoms may be more appropriately management, in such cases, may mean lower doses it will provide a death that is as safe, dignified, viewed as means of achieving the more primary of an analgesic and the experience, by the patient, and comfortable as medically possible. Table 5 goal of improving or maintaining a patient’s overall of higher levels of pain. The point is that, at the summarizes the most common EOL medication quality of life. The meaning of “quality of life” end of life, decisions about pain relief must be more classes. Later sections of this activity will explore varies, not just from patient to patient, but even than usually balanced with a mindful consideration some of these options in greater detail. between the phases of an illness experienced of the patient’s own values and desires. by a single patient. A focus on quality of life is The types of pain syndromes arising at the end important because sometimes a patient may have of life include most of the acute and chronic pain syndromes clinicians confront in other patients, Table 5. Common medications in a “hospice comfort kit”36 and many of the same diagnostic and therapeutic Medication class Example medications Common indications strategies and skills are the same or similar. But Antipsychotics Haloperidol or risperidone Delirium, agitation pain management at the end of life does raise some Antipyretics Acetaminophen (oral or Fever unique clinical and ethical issues and, hence, these suppository) issues are appropriate for a focused consideration. In addition, the prospect of severe, unrelieved pain Benzodiazepines Lorazepam, alprazolam, Anxiety, nausea at the end of life ranks very high among patient diazepam fears. Indeed many people consider the experience Opioids Morphine, oxycodone, Dyspnea, Nociceptive pain (not generally of severe pain to be worse than death, which hydrocodone effective for neuropathic pain) underscores the importance of a thorough clinical Secretion medications Hyoscyamine, atropine Excessive oropharyngeal secretions understanding this issue.38 Managing pain and other symptoms at the end Laxatives Docusate, lactulose, senna Constipation of life is just one component of a wider effort to with docusate relieve suffering and help a patient cope with the emotional and psychological aspects of dying. 80 Nonetheless, a failure to manage pain and other oral route is precluded because of reduced or alleviated with antihistamines. Opioid rotation to a symptoms may make it impossible for the patient to absent consciousness, difficulty swallowing, or to more synthetic agent or an agent with a different attend to these important dimensions. Uncontrolled reduce the chances of nausea and vomiting.42 When route of administration, such as oxymorphone or pain can push all other priorities aside and sap selecting an opioid, clinicians should also consider transdermal fentanyl has also been reported to be a person’s energy and motivation to focus on cost, since expensive agents can place undue helpful. potentially positive goals or meaningful experiences. burden on patients and families. The potential adverse effect of respiratory A patient’s perception that his or her pain cannot Some opioids may not be appropriate in the depression may lead to clinician under-prescribing be controlled may also contribute to a broader end-of-life setting. For example, meperidine is of opioids or the reluctance by patients to take feeling that he or she has lost control over their not recommended in cancer pain management the medication.41 Despite this fear, studies have lives in general, which can precipitate a downward due to the neurotoxic effects of its metabolites.43 revealed no correlation between opioid dose, timing spiral of depression and/or hopelessness. Effective In addition, mixed agonist-antagonist opioid of opioid administration, and time of death.47,48 pain control, on the other hand, not only directly analgesics, including butorphanol, nalbuphine, and Even when a medication, such as an opioid, reduces suffering but may allow a patient the pentazocine, are not recommended in cancer pain that is intended to relieve pain and symptoms but energy and positive attitude needed to engage with management because they are more likely to cause does pose a possible risk of hastening death, it the emotional and psychological aspects of dying. psychotomimetic effects and they can precipitate is considered ethical for health care providers to the abstinence syndrome if given to a patient who prescribe and to administer the medication following Assessing Pain at the End of Life is physically dependent on a pure opioid agonist.43 the rule of “double effect.”49 This rule distinguishes The end of life is often characterized by a Opioid-related side effects must be considered between practices that are intended to relieve reduced level of consciousness or complete lack of in advance of treatment and steps must be taken pain but which may have an unintended effect of consciousness. This can make assessments of pain to minimize these effects to the extent possible, hastening death vs. practices that are actually very challenging. If a patient is not alert enough since adverse effects contribute significantly intended to hasten death. When an action has both to communicate, then nonverbal signs or cues must to analgesic nonadherence. This is particularly potentially good and bad effects, it is considered be used to determine if the patient is experiencing true for constipation and sedation. Tolerance ethically acceptable to pursue the action if four pain and to what degree an analgesic approach rarely develops to constipation and therefore it conditions are satisfied:49 is effective. In general, even ambiguous signs of must be prevented and, if unsuccessful, treated 1. The action itself (e.g., administering a pain discomfort should usually be treated, although aggressively. A prophylactic bowel regimen that medication) is not morally wrong. caution must be exercised in interpreting such includes a laxative and stool softener, such as 2. The action is undertaken with the sole intention signs.39 Patients who are actively dying may groan senna and docusate, should be used, although a of bringing about the good effect. or grunt in ways that suggest they are in pain, recent study suggested that senna alone was just 3. The action does not bring about the good effect although such sounds may, in fact, be the normal as effective.44 Bulking agents, such as psyllium, by means of the bad effect (e.g., in the case expressions attendant to the last moments or hours are ineffective and may exacerbate gastrointestinal of EOL pain medications, such medications do of life. distress unless the patient can drink significant not achieve their effect by ending life). Signs of discomfort that are accompanied by amounts of fluids. Methylnaltrexone, an opioid 4. The reason for undertaking the action is clear more rapid breathing or heart rate should be taken antagonist that works on receptors in the GI system and urgent. more seriously. Likewise, if physical stimulation of and is given subcutaneously, can be used as a the patient (i.e., during bathing) causes signs of rescue when constipation is clearly related to opioid BEFORE MOVING ONTO THE NEXT SECTION, discomfort, increased analgesia may be warranted. therapy.45 Two, more recently-approved opioid PLEASE COMPLETE CASE STUDY 4 ON THE Prolonged rapid breathing (> 20/min.) may be antagonists are naldemedine and naloxegol. NEXT PAGE. uncomfortable because of muscle fatigue and it Sedation is often attributed to opioid therapy Non-steroidal Anti-inflammatory (NSAID) may therefore be reasonable, even in the absence given at the end of life, although many other Analgesics and Acetaminophen of other evidence of discomfort, to titrate a pain drugs used at this time may be sedating, including NSAIDs or acetaminophen may be useful in medication with a target respiratory rate of 15 to benzodiazepines, antiemetics, and other agents. 39 the treatment of pain conditions mediated by 20/minute. Tolerance to opioid-induced sedation may develop inflammation, including those caused by cancer, within a few days of regular use; however, in such as bone metastases.41 NSAIDs typically cause Opioids some cases this may persist and opioid rotation less nausea than opioids, though this is most Opioid formulations are available in such variety may be warranted. A psychostimulant, such as true with low doses. NSAIDS also do not cause in the US that, typically, a pain regimen can be methylphenidate or dextroamphetamine, might be constipation, sedation, or adverse effects on mental tailored to each patient.40 Because there is great added to offset sedative effects, typically starting at functioning. NSAIDs may, therefore, be useful for the variability in how individual patients respond to a dose of 5 to 10 mg once or twice daily. One study control of moderate to severe pain, usually as an particular opioid agents, no specific agent is found that with proper timing, the administration adjunct to opioid analgesic therapy.50 The addition superior to another as first-line therapy. Although 46 of methylphenidate did not disrupt sleep. Other of NSAIDs to an opioid may allow a reduction morphine was previously considered the ‘‘gold drugs to be considered for similar indications are in the opioid dose, although such combinations standard,’’ it is now recognized that the most modafinil (Provigil) and armodafinil (Nuvigil). must be used with care. Typically, the non-opioid appropriate agent is the opioid that works for an Nausea and vomiting are relatively common co-analgesic agent, such as acetaminophen or an individual patient.41 Morphine and other opioids are in opioid-naive individuals. Around-the-clock NSAID, has a ceiling dose above which efficacy will generally available in a wide range of formulations antiemetic therapy instituted at the beginning of plateau as risk for adverse effects increases. Thus, and routes of administration, including oral, 41 opioid therapy may prevent this adverse effect. combining these products, either as separately- transmucosal, transdermal, parenteral, and rectal The antiemetic can be weaned in most cases after administered agents or in combination products, delivery. Both rectal and transdermal routes can 2 to 3 days. The itching that can occur early in the are typically used for patients who are not expected be especially valuable at the end of life when the course of opioid treatment may be at least partially to need substantial dose escalations.19 81 Case Study 4 Spend 5 minutes reviewing the case below and considering the questions that follow. Samuel is a 94-year-old man in the late stages of metastatic prostate cancer. The cancer was initially treated 16 years earlier with a radical prostatectomy and adjuvant radiation therapy, but it has recurred with infiltration to his pelvic bones. He has been under home hospice care for the past month. His pain is being treated with transdermal fentanyl which has reduced the nausea he was experiencing with oral ER/LA oxycodone. Now, however, he says he often feels “fuzzy” and “out of it” to the point that he can’t remember conversations he has had with his wife or daughter. On a visit by the hospice nurse, Sam complains about this, saying “I want to be able to say goodbye to people, and thank them, but I just feel like a zombie half the time.”

1. How might Sam’s competing desires for pain relief and mental clarity be addressed?

2. Are there any alternative pharmacological or non-pharmacological analgesic options that might be appropriate for Sam?

3. What other types of health care professionals might be called on to help Sam achieve the kinds of end-of-life communication he desires?

Using a combination product when dose Adjuvant Analgesics reduces the bioavailability of tamoxifen, potentially escalation is required risks increasing adverse Although opioid medications are a mainstay of reducing its therapeutic efficacy.59 effects from the non-opioid co-analgesic, even if pain management at the end-of-life, many other The anti-epilepsy drugs gabapentin and an increase of the opioid dose is appropriate. In classes of medications have proven effective and, pregabalin have undergone extensive testing in such cases, using a pure opioid may be preferable. in some cases, preferable to opioids (see Table 6). many non-cancer neuropathy syndromes, and a (Single-agent formulations are available for many Some exert a direct analgesic effect mediated by recent review concluded that these drugs have a types of opioids, such as morphine, oxycodone, and non-opioid receptors centrally or peripherally. Other clinically meaningful effect.57 The most common hydromorphone.) The FDA has limited to 325 mg the adjuvant “analgesics” have no direct analgesic adverse effects reported by patients are dizziness; amount of acetaminophen allowed in prescription qualities but may provide pain relief indirectly by some patients also develop fluid retention. Although opioid combination products in an attempt to limit affecting organs or body systems involved in painful the data for the efficacy of other anticonvulsants liver damage and other ill effects primarily due to sensations. are not as conclusive as those for gabapentin excessive doses of combined products.51 Some antidepressant agents appear to exert and pregabalin, existing reports suggest potential Contraindications for NSAIDs include decreased analgesic properties and may be particularly efficacy. As with most adjuvant analgesics, renal function (relatively common at the end of helpful for neuropathic pain conditions. Tricyclic antiepileptic agents are commonly used in life) and liver failure. Platelet dysfunction or other antidepressants inhibit reuptake of norepinephrine combination with opioid therapy, particularly when potential bleeding disorders, common due to cancer and serotonin, which appears to exert analgesic pain is moderate to severe. A review of cancer trials or its treatment, are also contraindications to non- effects, either directly or indirectly. These agents found that adjuvant analgesics added to opioids selective NSAIDS because of their inhibitory effects have been shown to provide clinically relevant provide additional relief, usually within 4 to 8 days, on platelet aggregation, with resultant prolonged effects in a review of analgesic studies conducted with the strongest evidence for gabapentin.60 bleeding time.52 Concurrent use of anticoagulants in neuropathic pain conditions, primarily diabetic Corticosteroids can play a valuable role in (Coumadin for example) is also a contraindication. neuropathy and other non-cancer conditions.57 treating end-of-life pain related to neuropathic pain Proton pump inhibitors or misoprostol may be Potential side effects include cardiac arrhythmias, syndromes, pain associated with stretching of the considered to prevent GI bleeding.53 conduction abnormalities, narrow-angle glaucoma, liver capsule due to metastases, for treating bone Attention has recently been focused on the and clinically significant prostatic hyperplasia. On pain (due to their anti-inflammatory effects) as well potential limited efficacy of acetaminophen in the other hand, the sleep-enhancing and mood- as for relieving malignant intestinal obstruction.61 older patients. Although it has been considered a elevating effects of these antidepressants may Dexamethasone produces the least amount of viable co-analgesic with opioids, and to be first-line benefit some patients. mineralocorticoid effect and is available in a variety therapy in elderly patients with musculoskeletal Although little evidence supports an analgesic of delivery forms, including oral, intravenous, pains or pain associated with osteoarthritis, the effect for SSRIs, some newer antidepressants, subcutaneous, and epidural.41 relative limited efficacy and significant adverse such as the serotonin-norepinephrine reuptake Local anesthetics may be useful in preventing effects of this agent, particularly hepatic and renal inhibitors have been shown to be effective in procedural pain and in relieving neuropathic toxicity, have raised concerns.54 Reduced doses of relieving neuropathic pain, including venlafaxine pain. Local anesthetics can be given topically, 2000 mg/day or the avoidance of acetaminophen and duloxetine.58 These have the added advantage intravenously, subcutaneously, or intraspinally. Both is recommended in the face of renal insufficiency of alleviating hot flashes, a common and disturbing gel and patch versions of lidocaine have been or liver failure, and particularly in individuals with a symptom, particularly in breast cancer patients shown to reduce the pain of postherpetic neuralgia history of significant alcohol use.55 undergoing hormonal therapy. Care must be taken and cancer-related neuropathic pain.62 in such situation, however, because duloxetine 82 Table 6. Adjuvant Analgesics for End-of-Life Pain Management56 Drug Class Agent Route of Potential adverse effects Indications Administration Antidepressants Nortriptyline Oral Anticholinergic effects Neuropathic pain Desipramine Oral Cardiac arrhythmia Venlafaxine Oral Nausea, dizziness Duloxetine Oral Nausea Anti-epilepsy drugs Gabapentin Oral Dizziness Neuropathic pain Pregabalin Oral Dizziness Clonazepam Oral Sedation Corticosteroids Dexamethasone Oral/IV/Sq “Steroid psychosis” Neuropathic pain, cerebral edema, spinal cord compression, bone pain, visceral pain Lidocaine Lidocaine patch Topical Erythema (rare) Neuropathic pain Lidocaine infusion IV/sq Perioral numbness, cardiac Intractable neuropathic pain changes NMDA antagonists Ketamine Oral/IV/intranasal/ Hallucinations Unrelieved neuropathic pain; need to topical reduce opioid dose Bisphosphonates Pamidronate IV Pain flare, osteonecrosis Osteolytic bone pain Clondronate IV Alendronate Zoledronic acid Cannabinoids Dronabinol (Marinol®) Oral Dizziness, nausea, tachycardia, Pain, nausea, loss of appetite, spasticity euphoria Nabilone (Cesamet® and Oral Syndros®) Intravenous or subcutaneous lidocaine at 1 to endogenously produced compounds with normal setting who are currently on long-term opioids for 5 mg/kg administered over 1 hour, followed by a regulatory, homeostatic properties.64 Unlike opioids, chronic pain could potentially be treated with either continuous infusion of 1 to 2 mg/kg/hour, has been however, there has never been a documented cannabis alone or in combination with a lower dose reported to reduce intractable neuropathic pain case of death from cannabis overdose—indeed, of opioids. From a pharmacological perspective, in patients in inpatient palliative care and home cannabis has no known lethal dose.65 cannabinoids are considerably safer than opioids hospice settings.63 The CB1 and CB2 receptors have been shown and have broad applicability in palliative care.”64 NMDA antagonists (dextromethorphan, to mediate the analgesic effects of cannabinoids.66 amantadine, and ketamine) are believed to exert This has allowed for the development of more Complementary/alternative strategies their analgesic effects by blocking receptors for selective agents that may provide analgesia while A wide range of complementary and alternative glutamate and other excitatory amino acids at minimizing cognitive or perceptual side effects. Two therapies (CAT) are commonly used in end-of-life the level of the spinal cord. Ketamine is the most oral cannabinoid preparations are FDA-approved care.69 More than half of providers that offered CAT commonly-used agent, and can be administered and available in the US (dronabinol and nabilone). offered massage, supportive group therapy, music intravenously, intramuscularly, subcutaneously, These routes of administration avoid the potential and pet therapy, guided imagery, and relaxation intranasally, sublingually, rectally, and topically. A hazards and dosing uncertainties involved with techniques.70 general recommendation is to reduce the opioid inhaled or edible forms of cannabis. A review Behaviors likely to respond to CAT interventions dose by approximately 25% to 50% when starting of the existing literature evaluating the role of include: aggression, disruption, shadowing, ketamine to avoid sedation.41 Psychotomimetic cannabinoids currently approved for human use depression, and repetitive behaviors (Table 7). reactions consisting of hallucinations, vivid imagery suggests that these agents are moderately effective Interventions should be matched to the specific delirium, confusion, and irrational behavior have for neuropathic pain with adverse effects that are needs and capabilities of the patient, and they can been reported to occur in approximately 12% of less than or comparable to existing analgesics.67 be used concurrently with any medications that individuals receiving the drug systemically.42 Adverse Cannabinoids have been shown to exert no might be employed.71,72 effects, including hallucinations and unpleasant appreciable effects on opioid plasma levels and CAT interventions are aimed at reducing pain, cognitive sensations, responded to diazepam at a may even augment the efficacy of oxycodone inducing relaxation, and enhancing a sense of dose of 1 mg intravenously.42 and morphine in patients suffering from a variety control over the pain or the underlying disease. In recent years there has been a resurgence of of chronic pain conditions, potentially allowing Breathing exercises, relaxation, imagery, hypnosis, interest in the use of cannabinoids for the relief of a reduction in the opioid doses used in such and other behavioral therapies are among the pain and the end of life. Like opioids, cannabinoids patients.68 The authors of a review of the role modalities shown to be potentially helpful to produce their pharmacological effects via actions at of cannabinoids in hospice and palliative care patients.41 specific receptors in the body that are designed for concluded: “Many patients in a palliative care

83 Table 7. Potentially helpful alternative interventions for EOL symptoms72 prevent symptoms should be used since it is generally easier to prevent symptoms than treat Intervention Applications/indications acute symptoms. Because disrupted swallowing 73,74 Environmental modifications • Support normal sleep/wake cycles function and changes in levels of consciousness can • Structure activities to reduce boredom affect patients’ ability to swallow pills, medications • Reduce unnecessary stimulation must be provided in formulations that are safe and • Create home-like environment feasible for administration. Concentrated sublingual Music therapy75 • Receptive music therapy (listening to music by a therapist who medications, dissolvable tablets, transdermal sings or selects recorded music for the recipients). patches, creams or gels, and rectal suppositories • Active music therapy (recipients engage in music-making by can be used in patients with impaired swallowing or playing small instruments, with possible encouragement to decreased responsiveness. improvise with instruments, voice, or dance.) Also music played when doing routine daily care etc. Nutrition and Hydration Bright light therapy76 • Exposure to simulated or natural lighting to promote circadian The provision of nutrition and hydration can rhythm synchronization. become a clinical challenge at the end of life and can be directly related to the use of analgesics, Aromatherapy77 • Use of plant and herb-based essential oils (indirect inhalation particularly in decisions about the preferred route via room diffuser, direct inhalation, aromatherapy massage, or of analgesic administration. As with decisions about applying essential oils to the skin) analgesia itself, the fundamental question regarding 76,78 Pet therapy • Several small studies suggest that the presence of a dog various alternatives for nutrition or hydration is reduces aggression and agitation, as well as promoting social whether the potential benefits outweigh the burdens behavior in people with dementia. from the patient’s perspective. The patient’s own expression of interest should be the primary guide. Physical modalities such as massage, use of have been developed for analgesic therapy during If a dying patient shows interest in either food heat or cold, acupuncture, acupressure, and other the removal of life-sustaining interventions, or fluids, they should never be withheld unless physical methods may be provided in consultation communication about what to expect and how things providing them clearly causes greater suffering (i.e., with physical or occupational therapy. These may proceed remain paramount to negotiating this in patients for whom oral feeding causes significant treatments can enhance patients’ sense of control care transition.84 Some patients and families may discomfort).39 In most cases, patients either do as well as greatly reduce the family caregivers’ be able to have meaningful interactions at the end not show an active interest in food or are satisfied sense of helplessness when they are engaged in of life, and thus brief interruption of sedatives and with very small amounts of specific foods (such pain relief. One study found that both massage analgesics may be reasonable. as sweet custards or ice cream) which are well- and “simple touch” induced statistically significant Rarely are dying ICU patients able to self- tolerated. The forced administration of nutrients, improvements in pain, quality of life, and physical report information about their pain.84 Thus it is either parenterally or through a nasogastric or and emotional symptom distress over time without incumbent on the critical care health professionals, gastrostomy tube, has little or no benefit to most increasing analgesic medication use.79 perhaps with the assistance of the patient’s family patients in the last days or weeks of life, and the Psychosocial interventions for end-of-life pain members, to assess pain without self-report input placement or continuation of an intravenous line or may include cancer pain education, hypnosis and from the patient. Two pain assessment instruments enteral feeding tube can be burdensome. Enteral imagery based methods, and coping skills training.80 have been validated for use in the ICU setting: the feeding tubes used during the terminal phase Educational programs are one of the most common Behavioral Pain Scale85 and the Critical-Care Pain of illness are often more useful as a means of interventions to address cancer pain barriers, Observation Tool.86 Both tools describe specific administering medications than nutrients. and current studies provide high-quality evidence observations that the patient’s ICU care providers Concerns about adequate hydration are that pain education is feasible, cost-effective, and (including family members or loved ones) can frequently misplaced. Relative dehydration can be practical in end-of-life settings.80 make that, when present, could indicate the beneficial during the terminal phase for the following Coping skills training may be beneficial for patient is experiencing pain such as grimacing, reasons:39 patients and family caregivers dealing with chronic rigidity, wincing, shutting of eyes, clenching of fists, • By decreasing urine output urinary cancer pain, although the dose and components of verbalization, and moaning.87 incontinence or difficulties of using a bedpan a coping skills training regimen remain uncertain. Reports by family members or other people or commode are reduced Other integrative and behavioral approaches found close to a patient should not be overlooked. In the • Reduced gastrointestinal secretions may to be helpful for managing end-of-life pain are Study to Understand Prognosis and Preference for reduce nausea and vomiting massage therapy and acupuncture.81 Outcomes and Risks of Treatment (SUPPORT) study, • Pain may be improved by a reduction in tumor surrogates for patients who could not communicate edema Managing Pain in Intensive Care Units verbally had a 73.5% accuracy rate in estimating • Reduction in oropharyngeal and pulmonary Several studies show that most US adults presence or absence of the patient’s pain.88 secretions may lead to reduced airway wish to die at home.82 And yet more than half of congestion and diminished pooling of deaths occur in hospitals, most with ICU care.83 Managing common EOL symptoms secretions the patient cannot clear on his or When curative approaches are not expected to her own be successful, a transition to primary comfort- Effective symptom control can allow patients at focused care and the withdrawal of ineffective or the end of their lives to pass through the dying burdensome therapies is often the compassionate process in a safe, dignified, and comfortable course. Although guidelines and detailed strategies manner. When possible, proactive regimens to 84 Nausea and vomiting Opioids should be selected and administered • Delirium (an acute state of confusion which Multiple neurotransmitter pathways in the based on patient’s comorbidities, previous opioid itself can be the result of a new-onset medical brain and gastrointestinal tract mediate nausea exposure, and ease of administration (see Table condition) and vomiting, both of which are common in 8 for initial doses). Morphine and oxycodone are • Depression EOL care. Some therapies for nausea (e.g., available in concentrated forms and sublingual • Dehydration haloperidol, risperidone, metoclopramide, and formulations, which allow rapid administration • Hypoxia (e.g., congestive heart failure, prochlorperazine) target dopaminergic pathways regardless of a patient’s level of wakefulness or pneumonia, anemia due to gastrointestinal to inhibit receptors in the brain’s chemoreceptor swallowing ability. hemorrhage) 89 trigger zone. Serotonin 5-HT3 receptor antagonists • Pain (e.g., vertebral or hip fracture, or acute such as ondansetron and palonosetron have been Delirium and agitation abdominal pain) used to treat chemotherapy and radiation therapy Delirium and agitation are commonly associated • Medication side effect related nausea, although in studies of patients with with dementia, but may also occur in patients • Emotional stress EOL-related nausea, these agents have not been without diagnosed dementia due to physiological • Reactions to changes in care, caregivers, or shown superior to older dopaminergic agents.36 or psychological changes at the end of life. caregiver behaviors Anticholinergic medications such as meclizine Manifestations can include calling out, screaming, • Boredom or transdermal scopolamine can be added if a verbal and physical aggression, agitation, vestibular component of nausea is present or apathy, hostility, sexual disinhibition, defiance, Many medications routinely used by older adults suspected. Synthetic cannabinoid agents (e.g., wandering, intrusiveness, repetitive behavior and/ can cause or worsen behavioral and psychological dronabinol) and medical marijuana (in states where or vocalizations, hoarding, nocturnal restlessness, problems. For example, anticholinergic agents it is approved for medical use) may be considered psychosis (hallucinations or delusions), emotional increase the risk of visual hallucinations, as second-line agents for nausea control, although lability, and paranoid behaviors.93,94 When a patient agitation, irritability, delirium, and aggressiveness. they should be used with caution because they can presents with delirium or agitation, the first course Psychotropics, such as benzodiazepines, can impair provoke delirium and dosing of medical marijuana of action should be to perform a comprehensive cognition, be disinhibiting, and may contribute to may be imprecise. assessment of the symptom(s): falls. Adverse drug effects are one of the most Vomiting can occur due to mechanical bowel • Antecedents: What are the triggers for the common reversible conditions in geriatric medicine. obstruction, which is common with pelvic and behavior(s)? They present an opportunity to effect a cure by gastrointestinal cancers. Management with • Behavior: Which behavior, or behaviors, are stopping the offending drug or lowering the dose. an antiemetic (e.g., haloperidol) as well as targets for intervention? This has led to the recommendation that “any new corticosteroids and analgesics is recommended.90 • Consequences: What are the consequences of symptom in an older patient should be considered a the behavior(s) for the patient and others? possible drug side effect until proven otherwise.”95 Dyspnea Family, caregivers, and nurses are often in Dyspnea is common among patients at the Non-pharmacologic management options for the best position to answer these questions. end of life and is associated with many diseases delirium and agitation Understanding these factors may reveal simple or conditions including end-stage pulmonary Evidence suggests that non-pharmacologic and effective interventions. Complex, expensive and cardiac disease, cancers, cerebrovascular approaches to delirium or agitation can produce management strategies and interventions may not disease, and dementia. A number of mechanisms equivalent outcomes, in a much shorter time and be required. can be involved in dyspnea including pneumonia, at less overall risk and cost, than pharmacologic A patient’s medical condition or a medication airway hyperreactivity, pulmonary edema, pleural therapies.96,97 A meta-analysis of community-based the patient is taking may be the primary trigger effusions, and simple deconditioning. Assessing the non-pharmacologic interventions for delirium or for delirium or agitation. Although identifying a severity of dyspnea can be challenging because agitation found significant reductions in symptoms trigger through patient history and/or physical most dyspnea scales rely on patient self-report, as well as improvements in caregiver’s reactions to examination can be challenging if the patient’s although the Respiratory Distress Observation these symptoms.97 Behaviors more likely to respond cognitive impairment is severe, clinicians should Scale (eight variables, 0-16 score) is based solely to such interventions are: agitation, aggression, persist and include family and caregivers in the on observers’ clinical assessments.91 Regardless of disruption, shadowing, depression, and repetitive process, if possible. Treatment of a reversible a patient’s measured oxygen saturation, tachypnea, behaviors. Non-pharmacologic interventions should medical problem can be much more effective and increased difficulty breathing, restlessness, and always be matched to the specific needs and safe than deploying either non-pharmacologic or grunting are clinical signs of dyspnea. capabilities of the patient, and they can be used pharmacologic interventions. Reversible causes Opioids are first-line agents for treating dyspnea concurrently with any pharmacologic therapies that of new-onset behavioral disorders in the elderly at the end of life.36 Opioids help reduce the sense of might be employed.71,72,98 include: “air hunger” and, when administered at appropriate • Acute infection (e.g., urinary tract infection, doses, do not compromise respiratory status or sepsis) hasten dying.92

Table 8. Initial opioid doses for dyspnea or pain in opioid-naïve EOL patients36 Medication Oral dose IV or subcutaneous dose Initial dosing frequency Fentanyl Transmucosal 100-200 mcg 25-100 mcg Every 2-3 hrs. Hydromorphone 2-4 mg 0.5-2 mg Every 3-4 hrs. Morphine 2.5-10 mg 2-10 mg Every 3-4 hrs. Oxycodone 2.5-10 mg NA Every 3-4 hrs. 85 Behavioral and psychological symptoms often patients sleep worse on the nights that they • Keep a light on in the room, it may be arise in response to a wide range of factors that can omit it) comforting make life uncomfortable, frightening, worrisome, • Risk of falls • Play the person’s favorite music softly irritating, or boring for people with dementia. • Paradoxical agitation • Encourage visitors to identify themselves Paying close attention to such environmental • Physical dependence with regular use102 when talking to the person factors, and eliminating or correcting them, should • Aspiration and its consequences • Keep things calm in the environment 93 • Open a window or use a fan in the room if the be the first priority for caregivers. This may person is having trouble breathing require patience, diligence, and a willingness to see Antipsychotic medications, while of potential • Continue to touch and stay close to your loved the world through the eyes and other senses of the utility in patients with severe or uncontrollable one person whose behaviors are challenging. Because delirium or agitation, should be avoided until other sensory deficits are common in older adults, and reasonable medications have been tried because of Ethical Considerations because vision and hearing deficits, in particular, their relatively high risk of side effects and adverse A potential barrier to good pain management can increase fearfulness, anxiety, and agitation, any events, including possible death. In June 2008, the at the end of life is the misconception on the part patient displaying delirium or agitation should be US Food and Drug Administration (FDA) determined of providers, family members, or both, that an assessed for these deficits, and, if any are found, that both conventional and atypical antipsychotics escalation of pain medications or other palliative they should be corrected promptly with glasses, increase the risk of death in elderly patients, and therapies will unethically hasten or cause death. improved lighting, magnifying devices, hearing aids, reiterated that antipsychotics are not indicated for 103 Although ethical and legal consensus upholds or other techniques. the treatment of dementia-related psychosis. the appropriateness of withdrawing unwanted or Other environmental factors that can increase Initiation of any medication for delirium or unhelpful therapies to avoid the prolongation of the agitation include: temperature (too hot or too cold), agitation should be at the lowest possible dose, dying process and the administration of medications noise (in or outside the room or dwelling unit), with slow titration upwards if needed to the lowest with the intent of relieving suffering, such concerns lighting (too much, too little, or quality), unfamiliarity effective dose. Patients must be monitored closely may mitigate optimal administration of therapies.105 (new people, new furniture, new surroundings), for both adverse effects and drug-drug interactions. When providers administer pain medications and disrupted routines, needing assistance but not If a medication is demonstrated to be effective, the other palliative therapies to a dying patient, the knowing how to ask, being uncomfortable from patient should be reassessed frequently, since intent should explicitly be on relief of symptoms, sitting or lying on one position for too long, or delirium or agitation symptoms are inherently and communication with the family must stress inability to communicate easily because of language unstable and subject to remission. this goal, even if the possibility exists that such difficulties. treatments could hasten death.84 Dietary and eating-related issues should be Constipation The doctrine of double effect draws a clear carefully assessed. An inability to chew properly Constipation is common at the end of life distinction between the aggressive palliation of pain or swallow easily can increase agitation, hence (because of low oral intake of food and fluids with the intent to relieve suffering and the active and a patient’s dental integrity, use of false teeth or and the adverse effects of opioids) and should purposeful hastening of death. The doctrine asserts other orthodontia, and swallowing ability should be closely managed because it can lead to pain, that the alleviation of pain is ethically justifiable as be considered. If a patient’s appetite or cycle of vomiting, restlessness, and delirium. Prevention long as the caregiver’s primary intent is alleviating hunger/satiety is not synchronized with the timing generally involves a stimulant laxative (e.g., senna) suffering.39 (The doctrine of double effect holds that of meals provided by an institution, consider with a stool softener (e.g., docusate or polyethylene an act that might have a good or bad effect is ethical options to individualize the availability of food and/ glycol). If constipation does not resolve with if the nature of the act is morally good or neutral or food choice. Difficulty preparing or eating meals, these measures, stronger laxatives, suppositories, and the intent of the act is good even if there is confusion about mealtimes, apathy, agitation, or enemas are indicated. Methylnaltrexone, potential for bad effect.)39 Health-care providers and paranoid ideation about food and fluids may naldemedine, and naloxegol can be used to treat should communicate this strategy with patient and all contribute to weight loss, which is common in opioid-related constipation that does not respond families and document the rationale for any dose patients with dementia. Avoidance of alcohol and to traditional preventive or treatment regimens. escalation used for the alleviation of pain. caffeine can promote good sleep hygiene and may 99 Contrary to fears among patient and their help stabilize mood. Caring for a Person Near Death: Tips for families, research suggests that aggressive pain Family Caregivers104 Pharmacologic management options management at the end of life does not necessarily • Continue to talk to the person and say the Although pharmacologic interventions may be shorten life. In fact, pain management may be life- things you need or want to say. Remember that necessary in some circumstances, they should prolonging by decreasing the systemic effects of the person may be able to hear, even when not only be considered if the patient is not responding uncontrolled pain that can compromise vital organ able to respond to appropriate, sustained, patient-tailored non- function.106 • Allow the person to sleep as much as he or pharmacologic interventions. Two classes of If a patient experiences intense pain, discomfort she wishes medications should be used very cautiously: or other undesirable states at the end of life despite • Reposition the person if it makes him or her benzodiazepines and antipsychotics. Although the best efforts of pain management providers, more comfortable benzodiazepines may help treat anxiousness palliative sedation (also known as terminal, • Moisten the person’s mouth with a damp cloth or agitation in the last hours or days of life, use continuous, controlled, or deep-sleep sedation) • If the person has a fever or is hot, apply a cool across longer time frames should be avoided in is an option.84 Palliative sedation is the intentional cloth to the forehead the treatment of delirium or agitation because sedation of a patient suffering uncontrollable they may cause or exacerbate a range of problems • Give medications as ordered to decrease refractory symptoms in the last days of life to the including:98,100,101 symptoms such as anxiety, restlessness, point of almost, or complete, unconsciousness • Cognitive impairment agitation or moist breathing and maintaining sedation until death—but not • Rebound insomnia (i.e., if taken as needed, intentionally causing death.107 86 Although palliative sedation may bring intolerable to ensure comfort at the end of life. The other 17. Ngo-Metzger Q, August KJ, Srinivasan M, Liao S, Meyskens suffering to an end and allow people to die symptoms that can accompany the end of life, such FL, Jr. End-of-Life care: guidelines for patient-centered communication. Am Fam Physician. 2008;77(2):167-174. peacefully, it nonetheless can be challenging to as dyspnea, agitation, delirium, and anxiety, each 18. Quill TE. Perspectives on care at the close of life. put into practice and has been criticized as “slow need to be carefully assessed and treated with Initiating end-of-life discussions with seriously ill euthanasia.”93 coordinated interventions. Fortunately, a wide array patients: addressing the “elephant in the room”. JAMA. 2000;284(19):2502-2507. Acknowledging the inherently complex and of analgesics, interventional strategies, adjuvant 19. Fishman SM. Responsible Opioid Prescribing: A Clinician’s subjective nature of decisions about palliative medications, varied routes of administration, and Guide, 2nd Ed. Washington, DC: Waterford Life Sciences; sedation, guidelines have nonetheless been complementary and alternative therapies exist that, 2012. developed to help guide responsible use of this if used cooperatively and effectively, can greatly 20. Gramelspacher GP, Zhou XH, Hanna MP, Tierney WM. Preferences of physicians and their patients for end-of- alternative. Many guidelines state that palliative improve the chances that patients and their families life care. J Gen Intern Med. 1997;12(6):346-351. sedation should only be considered when:94,108 will experience death without trauma, suffering, or 21. Cohen-Mansfield J, Droge JA, Billig N. Factors influencing • The patient is terminally ill unrelieved pain. hospital patients’ preferences in the utilization of life- sustaining treatments. Gerontologist. 1992;32(1):89-95. • Death is expected within hours or days 22. Atul Gawande. Being Mortal. New York, NY: Penquin • The patient is suffering acute symptoms References Books; 2014. 1. Field MJ, Cassel CK. Approaching Death: Improving Care 23. Berkey FJ, Wiedemer JP, Vithalani ND. Delivering Bad or unresponsive to therapy at the End of Life. Washington DC: Institute of Medicine; • Consent is obtained from the patient or his/ Life-Altering News. Am Fam Physician. 2018;98(2):99- 1997. 104. her proxy 2. Institute of Medicine. Dying in America: Improving quality 24. Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, • The withdrawal of food and water is discussed and honoring individual preferences near the end of life. Kudelka AP. SPIKES-A six-step protocol for delivering bad Washington, DC: The National Academies Press; 2015. • Families are informed that the patient will likely news: application to the patient with cancer. Oncologist. 3. Kass-Bartelmes BL, Huges R, Rutherford MK. Advance 2000;5(4):302-311. not regain consciousness and will die Care Planning: Preferences for Care at the End of Life. 25. Searight HR, Gafford J. 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Advance directives for medical care--a case for greater determining prognosis in selected non-cancer diseases. . be less important that emotional intelligence and use. N Engl J Med. 1991;324(13):889-895. Hosp J. 1996;11(2):47-63. communication skills. It may also entail a shift away 10. Smucker WD, Ditto PH, Moore KA, Druley JA, Danks JH, 34. Anderson F, Downing GM, Hill J, Casorso L, Lerch N. from previous goals of aggressive treatment with Townsend A. Elderly outpatients respond favorably to a Palliative performance scale (PPS): a new tool. J Palliat physician-initiated advance directive discussion. J Am advanced medical technology, and toward a realistic Care. 1996;12(1):5-11. Board Fam Pract. 1993;6(5):473-482. 35. Maltoni M, Nanni O, Pirovano M, et al. Successful validation assessment of what such technology can actually 11. Moore KA, Danks JH, Ditto PH, Druley JA, Townsend A, of the palliative prognostic score in terminally ill cancer provide in terms of comfort, dignity, and peace of Smucker WD. Elderly outpatients’ understanding of a patients. Italian Multicenter Study Group on Palliative Care. physician-initiated advance directive discussion. Arch Fam mind at the end of life. J Pain Symptom Manage. 1999;17(4):240-247. Med. 1994;3(12):1057-1063. 36. Albert RH. End-of-Life Care: Managing Common Ongoing pain assessment is critical in order to 12. Fischer GS, Tulsky JA, Rose MR, Siminoff LA, Arnold RM. Symptoms. Am Fam Physician. 2017;95(6):356-361. detect changes in pain such as the development Patient knowledge and physician predictions of treatment 37. Byock I. Dying Well: The Prospect for Growth at the End of preferences after discussion of advance directives. J Gen Life. New York, NY: Riverhead Books; 1997. of painful bone metastasis, resolution of treatable Intern Med. 1998;13(7):447-454. causes such as infections, or worsened neuropathic 38. Patrick DL, Pearlman RA, Starks HE, Cain KC, Cole WG, 13. Lynn J, Arkes HR, Stevens M, et al. Rethinking fundamental Uhlmann RF. Validation of preferences for life-sustaining or visceral pain due to tumor growth. Careful assumptions: SUPPORT’s implications for future reform. treatment: implications for advance care planning. Ann refinement of pain management regimens is often Study to Understand Prognoses and Preferences and Risks Intern Med. 1997;127(7):509-517. of Treatment. J Am Geriatr Soc. 2000;48(S1):S214-221. required at the end of life and may include changes 39. Forrow L, Smith HS. Pain Management in End of Life: 14. Danis M, Garrett J, Harris R, Patrick DL. Stability of Palliative Care. In: Warfield CA, Bajawa ZH, eds. Principles in the route of analgesics if patients can no longer choices about life-sustaining treatments. Ann Intern Med. & Practice of Pain Medicine, 2nd Ed. New York, NY: take oral medications, the need to rotate opioids, or 1994;120(7):567-573. McGraw-Hill; 2004. 15. Rosenfeld KE, Wenger NS, Phillips RS, et al. Factors 40. Abrahm JL. A Physician’s Guide to Pain and Symptom the addition of adjunctive or integrative therapies. associated with change in resuscitation preference Clinicians should seek expert consultation from Management in Cancer Patients. Baltimore, MD: Johns of seriously ill patients. The SUPPORT Investigators. Hopkins University Press; 2005. pain services or palliative care teams for complex Study to Understand Prognoses and Preferences for 41. Paice JA, Ferrell B. The management of cancer pain. CA cases or when pain appears to be refractory to Outcomes and Risks of Treatments. Arch Intern Med. Cancer J Clin. 2011;61(3):157-182. 1996;156(14):1558-1564. all efforts. Early referral to hospice care may 16. Fetters MD, Churchill L, Danis M. Conflict resolution at the allow time for a carefully planned pain regimen end of life. Crit Care Med. 2001;29(5):921-925.

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Crit Care Med. 2001;29(12):2258-2263. 88 Compassionate Care at the End of Life Self-Assessment Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

51. Roughly how many American adults have created an ad- 57. The opioids butorphanol, nalbuphine, and pentazocine, vance directive? are not recommended in cancer pain management because A. One in two ______. B. One in three A. They are likely to cause psychotomimetic effects C. One in four B. They are associated with an increased risk of pruritus D. One in five C. They commonly cause severe constipation D. Their metabolites may be neurotoxic in the context of chemo- 52. How accurate are physicians, generally, in predicting patient therapy preferences for end-of-life care? A. About 55% accurate 58. Unwarranted fear of what potential side effect of opioid B. About 65% accurate analgesics can lead to underprescribing by clinicians and/or C. About 75% accurate under use by patients? D. About 85% accurate A. Respiratory depression B. Sedation 53. In the United States, what term is generally used for care of C. Nausea people who are not expected to live more than 6 months? D. Constipation A. Palliative care B. Nursing home care 59. Which class of adjuvant analgesic has received increasing C. Hospice care attention in recent years as a possible way to control neuro- D. Terminal care pathic pain? A. Tricyclic antidepressants 54. The Karnofsky Scale may be useful for what clinical task? B. Cannabinoids A. Assessing patient’s cognitive ability C. Psychostimulants B. Determining level of adverse effects associated with chemo- D. Ketamine therapy C. Determining patient pain level 60. Which class of medications are first-line for treating dys- D. Determining patient life expectancy pnea in end-of-life settings? A. Corticosteroids 55. Which statement is true about the typical role of a referring B. Benzodiazepines physician relative to patients in hospice care? C. Bronchodilators A. Hospice staff are expected to be in charge of patient care, D. Opioids with a referring physician consulted only for prescription refills B. The referring physician is expected to remain in charge of care and be available by phone or other means C. The referring physician transfers responsibility for patient care to the hospice medical director D. The hospice team assumes responsibility for all patient care, including the ordering and administration of prescription medications as needed

56. What condition do many older well adults consider as being “worse than death”? A. Alzheimer Disease B. Severe pain C. Heart attack D. Stroke

89 MANAGING ACUTE PAIN Release Date: 09/2019 2 AMA PRA Enduring Material Exp. Date: 08/2022 Category 1 Credits™ (Self Study)

TARGET AUDIENCE

This course is designed for all physicians and health care providers involved in the treatment and monitoring of patients with pain. Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/ COURSE OBJECTIVE answer sheet, evaluation, and payment to InforMed by mail, phone, fax This program is designed to improve clinician competence in or complete online at course appropriately managing acute pain conditions so as to effectively website under NETPASS. alleviate patient pain while simultaneously reducing opioid risks of diversion, misuse, and addiction.

LEARNING OBJECTIVES

Completion of this course will better enable the course participant to: 1. Recognize how many patients might be at risk each year of developing dependence, abuse, or overdose as a result of being prescribed opioids for acute pain. 2. Compare opioid-induced hyperalgesia with opioid analgesia. 3. Identify 2 common tools for assessing patients’ risk of abusing opioids. 4. Describe 5 examples of non-pharmacologic pain management techniques. 5. Identify 3 examples of non-opioid pharmacologic treatments for acute pain.

ACCREDITATION STATEMENT InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

DESIGNATION STATEMENT InforMed designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

90 FACULTY

Paul J. Christo, MD, MBA Director, Multidisciplinary Pain Fellowship Program Associate Professor of Anesthesiology and Critical Care Medicine The Johns Hopkins University School of Medicine 2 Stephen Braun Pain Management Medical Writer and Terminally Braun Medical Communications Ill Patients

ACTIVITY PLANNER SPECIAL DESIGNATION

Michael Brooks This course satisfies two (2) CME credit Director of CME, InforMed hours on Pain Management and the Appropriate Treatment of the Terminally Ill.

DISCLOSURE OF INTEREST The Medical Board of California requires most physicians and surgeons to complete In accordance with the ACCME Standards for Commercial Support of a one-time mandatory 12 hours of CME in CME, InforMed implemented mechanisms, prior to the planning and the subjects of pain management and the implementation of this CME activity, to identify and resolve conflicts of treatment of terminally ill & dying patients. interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE

The following faculty and/or planning committee members The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to have indicated that they have relationship(s) with industry to disclose relative to the content of this CME activity: disclose: • Stephen Braun • Paul J. Christo, MD, MBA has received honoraria from • Michael Brooks GlaxoSmithKline, Daiichi Sankyo, and BTG International.

STAFF AND CONTENT REVIEWERS

InforMed staff, input committee and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

91 Introduction Ironically, despite generally liberal uses of for acute pain and for relatively short durations, opioids prescribed for acute pain, research shows are amplified among older adults, patients with A great deal of attention has been paid in the that, in fact, inadequate acute pain control is still impaired renal or hepatic function, those with COPD, past decade to the many problems associated common.19,20 Some studies show that fewer than cardiopulmonary disorders, sleep apnea, or mental with the use of opioid analgesics to treat chronic half of postoperative patients receive adequate illness, and in anyone likely to combine opioids with pain, both in the professional literature and the lay pain relief.21 Patients presenting to emergency other respiratory depressants such as alcohol or press. Many guidelines for managing chronic pain departments with significant pain may also be under- benzodiazepines.26 (particularly chronic non-cancer pain) have been treated, with median pain scores for ED patients in This CME activity presents an evidence- created by such organizations as the Centers for one study ranging from 8-10 (on a 10-point scale), based review of both pharmacological and non- Disease Control and Prevention2 and the American a median score at discharge of 6, and almost 75% pharmacological strategies for managing acute pain Pain Society/American Academy of Pain Medicine.3 reporting moderate or severe pain at discharge.22 conditions, with opioids used only when necessary Numerous recent articles in the medical literature Important disparities exist in pain treatment as well. and then at the lowest dose and shortest duration have raised important questions about the relatively A study including 22,267 patients with inadequate deemed clinically beneficial. As with treating chronic low effectiveness of opioids for chronic pain and the analgesia found that older patients were more likely pain, the appropriate deployment of opioids correspondingly high risks for diversion, misuse, to suffer than younger patients: 43% of patients < for acute pain can be challenging, but it is not addiction, and overdose.4-7 65 years old reported uncontrolled pain compared inherently different from using any other medical And yet many of the problematic issues to 52% of patients > 75 years.20 Another study treatment that carries significant risks of harm. surrounding the use of opioids for chronic pain found that non-white patients were consistently With proper pain assessment, primary reliance on are equally compelling and urgent in the treatment undertreated for postoperative pain, chest and non-pharmacologic and non-opioid analgesics, and of acute pain. For example, a number of studies cancer pain, chronic low back pain, and acute pain a view that includes critical emotional, psychological, demonstrate increased risk of new persistent presenting in emergency departments.23 and social dimensions of pain, clinicians can both opioid use in opioid-naïve patients after having been Uncontrolled acute pain leads to more than just relieve immediate suffering and maximize their prescribed opioids for acute pain.8-11 Although the patient discomfort or suffering—it is associated patients’ long-term health. risk of opioid misuse in patients prescribed opioids with a host of “downstream consequences” for acute post-surgical or post-procedural pain is including24 Acute pain overview relatively small in absolute terms (approximately • delayed wound healing 0.4% to 0.7%), the volume of such procedures • sustained hyperadrenergic stress response No reliable estimates of the prevalence of acute (approximately 48 million ambulatory surgeries or • reduced quality of life pain in the general population exist, although pain procedures in 2010) translates into large numbers • poor sleep is one of the most common symptoms reported by of patients (i.e., approximately 160,000) at risk for • limited mobility or breathing patients seeking care in emergency departments dependence, abuse, or overdose every year.12-14 • increased hospital length of stay and is a frequent reason for unplanned visits to • higher rates of complications general practitioners.27 Acute pain in hospitalized • increased risk that acute pain will morph into patients, however, is known to be relatively common. Acute vs. Chronic Pain chronic pain According to a 2016 systematic review including Acute pain has an abrupt onset and is typically In summary, although the focus of much public 23,523 hospitalized patients, the prevalence of due to an obvious cause, such as an injury and professional attention in the past decade has any acute pain ranged from 38% to 84%, and the or surgical procedure. It generally lasts less been on problems related to opioid analgesics for prevalence of severe acute pain ranged from 7% than four weeks, improving with time. Acute chronic pain, the treatment and management of to 36%.28 pain is one of the most common presenting acute pain is an equally important topic because Unlike chronic pain, acute pain serves an complaints in ambulatory care. many of the same dynamics (e.g., prescribing important protective purpose: it signals internal or Chronic pain is defined as lasting more than opioids when non-opioids may be just as effective, external bodily damage or dysfunction. The patient three months or past the time of normal or prescribing higher doses/durations than needed) experience of acute pain can vary markedly. The tissue healing. It can result from an underlying are at work with acute pain as with chronic pain. intensity of pain can be influenced by psychological medical disease or condition, injury, medical The Food and Drug Administration recognized distress (depression/anxiety), heightened treatment, inflammation, or an unknown cause. these issues when it announced, in August, 2018, a illness concern, and ineffective coping strategies new initiative to assess the evidence on the impact regarding the ability to control pain and function A related issue with opioid prescription for acute of opioid prescribing for acute pain conditions in despite it.29 It may also be shaped by personality, pain is the risk of diversion or inappropriate use order to lay the groundwork for future treatment culture, attitudes, and beliefs. For example, injured from leftover pills. Approximately 40-50% of those guidelines.25 soldiers who had positive expectations of pain (e.g., who abuse opioids initially obtain the drugs from Properly and responsibly managing acute pain evacuation and safe recuperation) requested less family members or friends with pills remaining from is imperative not only because it relieves patient analgesic medication than civilians with comparable legitimate prescriptions.15 Many studies have found suffering, but also because it reduces the chances injuries who had more negative associations with excessive levels of routine opioid prescriptions that acute pain will morph into chronic pain and pain (e.g., loss of wages and social hardship).30 for a range of surgical procedures or emergency simultaneously may help stem the tide of opioid Acute pain can provoke a range of protective department visits for painful conditions.16,17 One diversion, misuse, and abuse. Opioids can play a reflexes (e.g., withdrawal of a damaged limb, study of 1,416 patients in a 6-month period valuable role in the management of moderate to immobilization, autonomic responses) that can help found that surgeons prescribed a mean of 24 pills severe acute pain, but opioids also carry important the body heal. Even brief episodes of acute pain, (standardized to 5 mg oxycodone) but that patients risks, and thus are generally viewed as second-line however, can induce suffering, neuronal remodeling, reported using a mean of only 8.1 pills (utilization agents or to be used only as part of a multi-modal and can set the stage for chronic pain.30 rate 34%).18 approach. The risks of opioids, even when used 92 Associated behaviors (e.g., bracing, abnormal the pregabalin, as well as from the reduced need volume, excessive stress response, or inability to postures, excessive reclining) may further contribute for opioid analgesics in the intervention group, comply with rehabilitation). to the development of chronic pain. An example of which “reduced the probability of opioid-induced Acute pain is more difficult to manage if permitted this phenomenon is persistent postsurgical pain, hyperalgesia.”33 to become severe, so prompt and adequate which is pain persisting beyond the expected treatment of acute pain is imperative, with the basic healing period. Many common operations (e.g., BEFORE MOVING ON, PLEASE COMPLETE CASE goals of: mastectomy, thoracotomy, hernia repair, coronary STUDY 1. • Early intervention, with prompt adjustments in artery bypass surgery) are associated with an the regimen for inadequately controlled pain incidence of persistent postsurgical pain of up In addition to the purely humanitarian value • Reduction of pain to acceptable levels to 30-50%.31 The intensity of perioperative and of reducing or eliminating acute pain, therefore, • Facilitation of recovery from underlying postoperative pain is estimated to contribute about effectively treating acute pain may reduce disease or injury 20% of the overall risk for transition from acute complications and progression to chronic pain Acute pain is typically defined as pain concordant pain to persistent postsurgical pain.32 states.34 Nearly all cases of chronic pain begin as with the degree of tissue damage and which A recent example of research suggesting how an acute pain.35 remits with resolution of the injury (Table 1). A aggressive and pre-emptive approach to acute pain Acute pain is a multidimensional experience more holistic definition is “a complex, unpleasant may reduce the risk of transition to chronic pain that usually occurs in response to tissue trauma, experience with emotional and cognitive, as well as was a 2019 randomized trial in which 200 women and although responses to acute pain may be sensory, features that occur in response to tissue having surgery for breast cancer were randomized adaptive, they can have adverse physiologic and trauma.”36 to perioperative pregabalin (an antiepileptic psychological consequences (e.g., reduced tidal medication with known analgesic properties) plus usual operative anesthesia vs. placebo plus usual Table 1. Common types of acute pain39 anesthesia.33 Pregabalin was given as 75 mg twice daily, starting 1 hour before surgery and Acute illness Appendicitis, renal colic, myocardial infarction for a week post-operatively. Three months later Perioperative • Head and neck surgery the incidence of neuropathic pain was 14% in the • Chest and chest wall surgery pregabalin group vs. 32% in the placebo group (p • Abdominal surgery = 0.002), and the incidence of post-mastectomy • Orthopedic and vascular surgery (back, extremities) pain syndrome was 11% vs. 29% (p < 0.001).33 Major trauma Motor vehicle accident The 7-day period of pregabalin treatment covered Minor trauma Sprain, laceration the postoperative hyperexcitability and excitatory neuroplasticity of the dorsal horn neurons that is Burns Fire, chemical exposure known to persist for 5-6 days after surgery. The Procedural Bone marrow biopsy, endoscopy, catheter placement, circumcision, chest tube place- authors suggest that the reduction in post-surgical ment, immunization, suturing chronic pain resulted both from the direct effects of Obstetrical Childbirth by vaginal delivery or Cesarean section

Case Study 1 Instructions: Review the case below and consider the questions that follow.

Doris, 56, had a right thoracotomy and lobectomy for stage I lung cancer 2 years ago. Because she was frightened of having a “needle in her back” Doris declined epidural analgesia as part of her perioperative pain management plan, against the advice of her surgeon and anesthesiol- ogist. The surgery was successful: no sign of cancer remained. But Doris still has significant pain in the area around the incision—tight-fitting clothing against her chest is uncomfortable and the area is extremely sensitive to temperature, such as from warm water from a shower hitting the area. In addition, she reports frequent stabbing, shock-like pain in her chest, which occurs unpredictably and seems unrelated to specific movements, activities, or other factors.

1. What type of pain do these symptoms suggest?

2. Could the lack of epidural analgesia be related to Doris’ symptoms?

Question 1 Commentary: Doris’ pain is characteristic of neuropathic pain, which develops from nerve damage in the peripheral or central nervous systems, or both.

Question 2 Commentary: Yes. Doris’ symptoms are consistent with chronic postsurgical pain syndrome, the risk for which has been shown in observational studies to be lower in patients who have thoracic epidural analgesia prior to thoracotomy. Case study adapted from: Jungquist CR, et al. Assessing and managing acute pain: a call to action. AJN. 2017;117(3):S4-S11.

93 This definition captures the multiple levels of b. What does the pain feel like? (i.e., dull, throb- Assessing for risk of opioid misuse effects that pain can have, as well as the fact that bing, sharp, pins-and-needles) As with patients in chronic pain, patients in cognitive and emotional factors can influence how c. Does the pain spread anywhere? acute pain being considered for treatment with an d. How severe is the pain? pain is perceived. The subjective experience of pain opioid analgesic should also be evaluated for risk e. Is the pain constant or does it come and go? (as opposed to the purely physical phenomenon of opioid dependence or abuse. Such assessment The answers to these questions can help of nociceptive nerve activation) varies widely in is not completely objective, and opinions differ determine if the pain is nociceptive (i.e., the result degree (from mild to severe) and quality (dull, about which patients should be assessed. Some of injury to bones and muscles) or neuropathic (i.e., sharp, stinging, burning, throbbing, etc.) and is favor a “universal precautions” approach, in which the result of injury to peripheral or central nerves). significantly modulated by such factors as: all pain patients are considered to have some (A helpful tool for differentiating nociceptive • Type of injury or surgical procedure degree of vulnerability to abuse and addiction and, from neuropathic pain is the Grading System for • Cultural or ethic factors hence, all patients are given the same screenings Neuropathic Pain, which was updated in 2016).41 • History of drug or alcohol use and diagnostic procedures.43 Some patient Making this determination is important because • History of anxiety or depression characteristics, however, do appear to be predictive neuropathic pain is not particularly responsive to • Anatomic location of a potential for drug abuse, misuse, or other non-steroidal anti-inflammatory drugs (NSAIDs) or Injuries or procedures involving bones and aberrant behaviors, particularly a personal or family opioids. Other medications such as anticonvulsants joints tend to be more painful than those involving history of alcohol or drug abuse.3 Some studies 18 or antidepressants may be more appropriate first- soft tissues. For example, in one study of also show that younger age and the presence line agents for neuropathic pain. 5,703 ambulatory surgical patients, those having of psychiatric comorbidities are associated with Reliance on one-dimensional assessments microdiscectomy were most likely to have severe higher risk of aberrant drug-related behaviors.3 In of pain intensity may be inadequate, however. pain, followed by laparoscopic cholecystectomy, addition, a single question “How many times in the Pain ratings with movement or activity are as shoulder surgery, elbow or hand surgery, ankle past year have you used an illegal drug or used a 37 important—if not more important—than pain procedures, hernia repair, and knee surgery. prescription medication for nonmedical reasons?” ratings at rest, although these are often not Variations in pain levels for different procedures was found to be 100% sensitive and 73.5% specific obtained or documented (Table 2)35. In addition, can also be seen in data about the amount of for the detection of a drug use disorder when the standard pain scales or rating systems do not opioids needed to control pain. In one study, in answer was 1 or more times.44 capture the impact pain can have on quality of which opioid doses were standardized to units of Relatively brief, validated tools can help life, psycho-social functioning, and emotional well- 5 mg pills of oxycodone, 5 pills were adequate for formalize assessment of a patient’s risk of having a being. For example, a systematic review and meta- patients having partial mastectomy, 10 pills for substance misuse problem (Table 3) and these can analysis of 29 studies involving 14 instruments to partial mastectomy with lymph node biopsy, and 15 be considered for routine clinical use.3 pills for laparoscopic cholecystectomy and inguinal measure anxiety and pain catastrophizing found a hernia repair.38 (Significantly, in this study, many significant association between those variables and patients used no opioids, ranging from 22% after the development of postsurgical pain syndromes.42 hernia repair to 82% after partial mastectomy.) Table 2. Tools for multidimensional assessment of pain-related outcomes35 Another study found that in the 3 days after surgery, patients having wrist or hand surgery used about 7 Patient-reported outcome Assessment tool/instrument pills, those having forearm or elbows procedures Pain interference with daily life Brief pain inventory, short form pain interference subscale used an average of 11 pills, and those having upper Patient Reported Outcomes Measurement Information System arm or shoulder procedures used an average of (PROMIS) 22 pills (all pills standardized to oxycodone or Anxiety Hospital Anxiety/Depression Scale hydrocodone 5 mg or codeine 30 mg).18 Pain Anxiety Symptoms Scale PROMIS anxiety subscale Multidimensional acute pain assessment Depression Hospital Anxiety/Depression Scale The etiology of acute pain, as opposed to PROMIS depression subscale chronic pain, is typically straightforward since it Sleep PROMIS sleep disturbance subscale is usually associated with some kind of obvious Insomnia Severity Index injury, disease process, surgery, or procedure. Pittsburgh Sleep Quality Index Patients can often localize acute pain, describe its Pain catastrophizing Pain Catastrophizing Scale quality and character (as sharp, dull, piercing, or cramping, for example) and verbalize its temporal Social health Brief Pain Inventory interference subscale item: relations with pattern (when it started, what seems to trigger it, other people or how it has changed over time).27 Nonetheless, PROMIS social health it can be helpful to systematically evaluate the pain Table 3. Tools for Patient Risk Assessment using validated scales (numerical, visual-analog, or questionnaire-based) to increase the precision Tool Who Administers? Length of a patient’s self-report and provide a baseline Diagnosis, Intractability, Risk, Efficacy (DIRE) Clinician 7 items against which to evaluate analgesia and/or healing Opioid Risk Tool (ORT) Clinician or patient self-report 5 yes/no over time. Consider the following steps in assessing questions acute pain:40 Ask the patient to describe the pain using 5 Screener and Opioid Assessment for Patients with Pain, Patient self-report 24 items characteristics: Version 1 (SOAPP) and Revised SOAPP a. What makes the pain more or less intense? (SOAPP-R) 94 Pain assessment and cognitive impairment By accessing a PDMP, clinicians can quickly Some potential benefits of multimodal analgesia Cognitive impairment and/or language deficits assess patterns of prescription drug use that can include earlier ambulation, earlier oral intake, can be major barriers to adequate pain assessment be helpful in confirming or refuting suspicions of and earlier hospital discharge (for postoperative and treatment in patients of any age.45 Patients with aberrant behaviors. Such information may also patients) as well as higher levels of participation head injuries or severe dementia may be unable reveal that a patient is being prescribed medications in activities necessary for recovery (e.g., physical to report or describe pain, nor request analgesia. whose combinations are contraindicated. Reviewing therapy).51 Some pain experts advocate revision of Asking the patient to point to the body part that the PDMP can also help prescribers identify other traditional postoperative care programs to include hurts can be useful in cognitively impaired older prescribers involved in the care of the patient. accelerated multimodal postoperative recovery adults. Pain maps have been used among adults programs.52 of all ages with both acute and chronic pain and Strategies for managing acute pain have been effectively used with cognitively impaired Ladder of pain 46 elderly patients in long-term care facilities. The World Health Organization advocates a Table 4. Examples of multimodal therapy Pain assessment can also be hampered by 3-step “pain relief ladder” model in which non- Combination of Agents delirium, which can produce symptoms overlapping pharmacologic or non-opioid approaches are Systemic NSAID plus systemic opioid with manifestations of pain in older patients. In some preferred as first-line pain treatment, followed by cases, poorly controlled pain may even precipitate low-dose or low-potency opioids with or without Systemic NSAID plus epidural opioid and local delirium or behavioral changes in patients with adjunctive pharmacological or non-pharmacological anesthetic cognitive impairment and increase symptoms therapies, and, for moderate to severe pain, Systemic NSAID plus local infiltration of anesthet- such as fast or loud speech, irritability, anger, or higher doses and/or more potent opioids with or ic plus systemic opioid 45 lethargy. In a prospective observational study of 48 without adjunctive treatment. Variations on this Regional block plus systemic NSAID plus epidural 333 patients who had elective non-cardiac surgical model include a “fast-track” approach that skips opioid and local anesthetic procedures, higher preoperative pain scores at directly to step 3 for controlling intense acute Ketamine plus opioid rest were associated with an increased risk of pain, incorporation of “movement” on the ladder delirium over the first three days after surgery (OR both up (when, for example, a disease process for moderate pain 2.2, 95% CI 1.2-4, and OR for worsens) as well as down (in response to healing or 47 severe pain 3.7, 95% CI 1.5-9). remission of symptoms), and adding a 4th step that BEFORE MOVING ONTO THE NEXT SECTION, Careful observation of pain behaviors may help includes invasive procedures such as nerve blocks, PLEASE COMPLETE CASE STUDY 2 ON THE identify treatable causes of pain. For example, the neurolysis, epidurals, and spinal cord stimulators.49 NEXT PAGE. Pain Assessment Checklist for Seniors with Severe Dementia (PACSLAC) is a checklist of six pain Multimodal approach Managing patient expectations 45 behavioral categories: Clinicians should bear in mind that the goal of It is common for patients in pain to be worried • Facial expressions (grimacing, closed eyes, pain treatment is not necessarily zero pain, but that their pain will persist or get worse. Clinicians rapid blinking) a level of pain that is tolerable and that allows can help reduce such fears and set realistic • Verbalization (moaning, calling out, verbal the patient maximum physical and emotional expectations for treatment effectiveness and healing abusiveness) functioning with the lowest risk of side effects, with clear, compassionate communication couched • Body movement (guarding, fidgeting, gait progression to chronic pain, or misuse or abuse.50 in terms that patients can easily understand. It can changes) This requires an adroit balancing of many factors be helpful, for example, to tell patients that most • Changes in interpersonal interaction (com- (both patient-related and drug-related). One way forms of acute pain (e.g., nonspecific low back bativeness) to operationalize this paradigm is with multimodal pain) are self-limited, subside within weeks, and do • Changes in activity patterns or routines analgesia, in which several therapeutic approaches not require invasive interventions. (In a systematic (cessation of common routines) are used, each acting at different sites of the pain review of 15 prospective cohort studies, 82% of • Changes in mental status (confusion, irrita- pathway, which can reduce dependence on a single people who stopped work due to acute low back 53 bility) medication and may reduce or eliminate the need pain returned to work within one month. 51 It may help to develop a structured way to Prescription drug monitoring programs for opioids. Using both pharmacological and non- communicate about pain. For example, a systematic (PDMPs) and acute pain pharmacological interventions, and, if warranted, review of 14 controlled trials of patient education A standard part of assessing any patient in acute opioid and non-opioid medications, can reduce interventions for low back pain showed that pain, even if opioid analgesics are not expected to overall opioid use as well as opioid-related adverse structured messaging by providers can reassure be immediately prescribed, should be accessing effects. patients with acute pain more than usual care/ a prescription drug monitoring program (PDMP) This approach involves the use of more than control education both in the short and long term.54 if one is available. This can help identify patients one modality of controlling pain (e.g., drugs Messaging was significantly more reassuring to at higher risk for opiate overdose or opiate use from two or more classes, or drug plus non-drug patients when delivered by physicians compared disorder, and help determine which patients may treatment) to obtain additive beneficial effects, to the messaging being delivered by other primary benefit from heightened caution and increased reduce side effects, or both. These modalities care practitioners, and such communication monitoring when risk factors are present. Research may operate through different mechanisms or reduced the frequency of primary care visits. indicates that incidents of fatal overdose are highly at different sites (i.e., peripheral versus central correlated with two pieces of information: multiple actions).51 One example of multimodal analgesia is prescribers and high total daily opiate dosage, the use of various combinations of opioids and local both of which are available to prescribers through anesthetics to manage postoperative pain. Table 4 PDMPs. summarizes some specific examples of multimodal therapy. 95 Case Study 2 Instructions: Review the case below and consider the questions that follow.

Lamar, 67, had severe bilateral degenerative osteoarthritis in his knees. The pain and limited mobility led to depressive symptoms. His primary care physician recommended simultaneous total knee arthroplasty with the following aggressive multimodal pain treatment plan: Preoperative: celecoxib 200 mg twice daily Intraoperative: regional ropivacaine delivered with bilateral femoral catheters Postoperative: • IV acetaminophen 1,000 mg/every 6 hours for 24 hours then oral acetaminophen 650 mg/every 6 hours • IV patient-controlled analgesia hydromorphone 0.2 mg demand dose with lockout interval 10 minutes for first 48 hours, then oral extended- release oxycodone 10 mg every 12 hours with short-acting oxycodone 5 mg. PRN • IV ketorolac 15 mg every 6 hours for 24 hours • Ice packs for 20 minutes every 2 hours • Repositioning lower extremities with elevation and limited range of motion for first 24 hours • Oral analgesics continued PRN after discharge for 2 weeks Although chronic post-surgical pain is reported in 10% to 34% of patients undergoing total knee arthroplasty, Lamar’s recovery was uneventful. He reported very low pain for first 18 hours (1-2 on 10-point scale) at rest and with movement. After that pain levels rose to 4 at rest and 5 with physical therapy. Lamar reported only mild pain during rehabilitation. After 6 months he was walking a half-mile every day with no discomfort or pain.

1. Is it reasonable to think that the multimodal pain approach was related to Lamar’s positive outcome?

Commentary: Yes. A randomized trial comparing multimodal pain treatment to usual care in patients having hip fracture repair or knee arthroplasy found significant reductions in pain during the first week postoperatively and at 24 weeks.1

Non-pharmacological treatments for acute pain Physical therapy/exercise therapy found that people with low back pain who took weekly Physical therapy may be useful for a range yoga classes for 12 weeks had less pain and greater When possible, non-pharmacologic methods of musculoskeletal issues and can be helpful in physical function compared to those who just got should be used, alone or in combination with recovering from acute pain-producing traumas information about how to deal with back pain.58 The analgesics, to manage acute pain.39 The degree to initially treated with other methods. A 2018 study yoga in the study emphasized strengthening back which this can be done obviously depends on the reported that patients with low back pain who first and core muscles. In addition to reducing pain, the severity of pain, but many non-pharmacological consulted a physical therapist were less likely to people in the yoga group were more likely to have approaches can be very effective and their use receive an opioid prescription compared to those stopped taking pain relievers at 1 year follow-up. A avoids the potential side effects and risks associated who first saw their primary care physician.55 Physical 2012 systematic review of high-quality trials found with pharmacological interventions. therapists typically create individualized exercise, moderate effect sizes for reductions in pain-related Physical methods of pain management can be stretches, and body alignment adjustments to help disability in meta-analyses, with evidence that even helpful in all phases of care, including immediately relax tight muscles, decrease back and joint pain, short-term interventions might be effective.59 after tissue trauma (e.g., rest, application of cold, and improve range of motion. compression, elevation) and late during the healing Exercise therapy can take many forms, including Massage period (e.g., exercises to regain strength and walking, swimming or in-water exercise, weight Massage therapy can help relieve muscular range of motion). Non-pharmacologic methods can training, or use of aerobic or strength-training pain as well as pain related to stress and anxiety. include:39 equipment. According to a CDC review, conditions Some massage therapists specialize in working with • Application of cold (generally within first 24 that may improve with exercise therapy include people recovering from injuries or surgeries, or they hours) or heat chronic low back pain, chronic neck pain, hip and may have focused training for treating particular • Compression knee osteoarthritis pain, fibromyalgia, and migraine conditions such as back or neck pain. A 2011 study • Elevation (as a preventative treatment).56 in Annals of Internal Medicine randomized people • Immobilization with chronic low back pain to 10 weekly treatments • Relaxation exercises Yoga with structural massage, relaxation massage, or • Distraction/guided imagery Rigorous evaluation of the effectiveness of yoga usual care.60 At the end of treatment 36% and 39% • Hypnosis for alleviation of pain has been hampered by the of the patients in the massage groups reported • Acupuncture variety of yoga styles and heterogeneity in the way “much better or completely gone” pain vs. 4% of • Massage it is delivered.57 Yoga classes tend to involve poses patients in the usual care group. Another study • Electroanalgesia (e.g., transcutaneous electri- with a range of extensions and challenge, which found that 30-minute massages given twice weekly cal nerve stimulation) can be tailored to an individual’s level of flexibility, for 5 weeks after breast cancer surgery reduced • Physical therapy strength, and conditioning. Several relatively high- pain, fatigue, tension, and anxiety levels.61 • Yoga quality randomized clinical trials, however, suggest • Botulinum toxin (Botox) the potential for benefit. A 2017 study, for example, 96 Meditation and relaxation relaxation technique involving deep-breathing and Pharmacological management of acute pain Mindfulness meditation (also known as concentration. The researchers found that these mindfulness-based stress reduction) is a secular patients required less than half the amount of Most acute pain is nociceptive and responds to form of Buddhist meditation increasingly used in analgesic drugs used by those receiving standard non-opioids and opioids. However, some adjuvant pain clinics as it is known to elicit the relaxation treatments. Procedures also took less time for the analgesics (e.g., local anesthetics) also are used to response and promote pain relief. A 2016 hypnosis group, and they had lower levels of anxiety manage acute pain and medications for neuropathic randomized trial of 342 adults with low back and pain at both one hour and four hours into the pain are also important agents in the analgesic pain found that 8 weekly training sessions in procedure.65 A 2007 review of studies evaluating armamentarium. In general, mild-to-moderate mindfulness meditation showed significantly higher hypnosis for acute pain or distress during medical acute pain responds well to oral non-opioids (e.g., levels of function and reduced pain compared to procedures found that hypnosis consistently acetaminophen, NSAIDs, and topical agents). adults in usual care (61% vs. 44%, p = 0.04).62 reduced pain and was more effective than physical Moderate to severe acute pain is more likely to The neural correlates of the analgesic effects of therapy or educational methods.66 require opioids, although, as mentioned earlier, mindfulness meditation were explored in a 2018 lower doses and short durations may be possible trial at Wake Forest University in which 76 healthy Summary when appropriate. A review of the major classes of volunteers were taught mindfulness meditation and This brief review of non-pharmacologic non-opioid analgesics follows. then monitored by MRI while a pain-inducing heat treatments for acute pain is not exhaustive or device was applied to their leg for six minutes.63 The inclusive of all such modalities being explored, NSAIDs and acetaminophen meditation reduced pain unpleasantness by more but it provides some illustrative evidence that NSAIDs, which include aspirin and other salicylic than half (57%) and pain intensity by 40%. The these techniques have potential for reducing or acid derivatives, and acetaminophen are used in study also showed that mindfulness meditation was alleviating a range of acute pain condition. In the management of both acute and chronic pain associated with deactivation of the “default mode addition, these kinds of treatments may encourage such as that arising from injury, arthritis, dental network,” a system of brain structures including active patient participation in care plans, address procedures, swelling, or surgical procedures. the primary somatosensory cortex, the anterior the psychological and social dimensions of pain, Although they are weaker analgesics than opioids, cingulate cortex, the anterior insula, and the and may support sustained improvements in pain acetaminophen and NSAIDs do not produce orbitofrontal cortex.63 and function with minimal risks. Unfortunately, tolerance, physical dependence, or addiction and A component of some mindfulness meditation these therapies are not always or fully covered by they do not induce respiratory depression or techniques, and a therapeutic approach in its own insurance, and access and cost can be barriers for constipation. Acetaminophen and NSAIDs are often right, is progressive relaxation therapy, in which patients. added to an opioid regimen for their opioid-sparing muscles are relaxed sequentially from toes to head But for many patients, non-pharmacologic effect. Since non-opioids relieve pain via different or vice versa. Muscles are alternatively contracted management can be used even with limited access mechanisms than opioids, combination therapy can and released, with breathing coordinated with the to specialty care. For example, professional provide improved relief with fewer side effects. alterations. The Lamaze technique used by women guidelines have strongly recommended aerobic, These agents are not without risk, however. in labor is an example of a well-known, pain- aquatic, and/or resistance exercises for patients Potential adverse effects of NSAIDs include reducing relaxation technique based on breathing. with osteoarthritis of the knee or hip67 and gastrointestinal problems (e.g., stomach upset, maintenance of activity for patients with low back ulcers, perforation, bleeding, liver dysfunction), Hypnosis therapy pain.68 A randomized trial found similar reductions bleeding (i.e., antiplatelet effects), kidney Clinical hypnosis is a procedure in which a trained in chronic low back pain intensity, frequency, or dysfunction, hypersensitivity reactions and clinician or therapist gives a patient a series of verbal disability comparing patients assigned to low-cost cardiovascular concerns, particularly in the 71 instructions with the goal of helping the patient enter group aerobics vs. individual physiotherapy and elderly. The threshold dose for acetaminophen a state of deep relaxation. In this relaxed state, the muscle reconditioning sessions.69 Low-cost options liver toxicity has not been established; however, the patient is aware of everything that is going on, but to integrate exercise include brisk walking in public Food and Drug Administration (FDA) recommends at the same time, becomes increasingly absorbed spaces or use of public recreation facilities for group that the total adult daily dose should not exceed in using his or her imagination as directed by the exercise. CBT addresses psychosocial contributors 4,000 mg in patients without liver disease (although 72 therapist. Therapists use a variety of techniques to pain and has been shown to improve function.70 the ceiling may be lower for older adults). to help their patients acquire the self-control and Primary care clinicians can integrate elements of The FDA currently sets a maximum limit of 325 confidence to visualize, realize, and achieve goals a cognitive behavioral approach into their practice mg of acetaminophen in prescription combination such as reducing sensations of pain. Therapists by encouraging patients to take an active role in products (e.g., hydrocodone and acetaminophen) in often teach their patients self-hypnosis methods their care plan, by supporting patients in engaging an attempt to limit liver damage and other potential 32 that they can employ on their own to reinforce and in beneficial activities such as exercise, or by ill effects of these products. continue the process at home. providing education in relaxation techniques and Topical agents Hypnosis has a long history of being used to coping strategies. Patients with more entrenched Topical capsaicin and salicylates can both be 64 relieve pain. Evidence-based research on the use anxiety or fear related to pain, or other significant effective for short term pain relief and generally of hypnosis to relieve acute pain remains somewhat psychological distress, can be referred for formal have fewer side effects than oral analgesics, but limited, but large, well-designed studies have been therapy with a mental health specialist. Multimodal their long-term efficacy is not well studied.73,74 conducted. A 2000 study in The Lancet in 2000, therapies should be considered for patients Topical aspirin, for example, is an effective analgesic study evaluated the effectiveness of hypnosis for not responding to single-modality therapy, and for acute herpes zoster infection.75 Topical NSAIDs easing pain and anxiety in people having minimally combinations should be tailored depending on and lidocaine have been reported to be effective invasive surgical therapies such as angiograms, patient needs, cost, and convenience. for short-term relief of superficial pain with minimal angioplasty, or liver biopsies, during which they side effects, although both are more expensive than 65 remain conscious. Patients used a self-hypnosis topical capsaicin and salicylates. 97 Topical agents can be simple and effective for less than, or comparable to, existing analgesics.81 If an opioid is deemed necessary to treat acute reducing pain associated with wound dressing An observational study of 242 patients with chronic pain, oxycodone, hydrocodone, or tramadol in changes, debridement of leg ulcers, and other prostatitis and/or pelvic pain syndrome found short-acting formulations are commonly used. sources of superficial pain.75 moderate evidence that smoked cannabis reduced Guidelines from the Centers for Disease Control pain and muscle spasms.82 and other organizations strongly recommend that Ketamine The evidence for a benefit of cannabis or only short-acting opioids be prescribed for acute Ketamine has been used as a general anesthetic cannabinoids on acute pain, however, is limited and pain because they reach peak effect more quickly since the 1960s, but its use in sub-anesthetic mixed. A small double-blind, cross-over study in than extended-release formulations and the risk concentrations for analgesia has grown rapidly 18 females and experimentally-induced mild acute of unintentional overdose is reduced.2 (One study in recent years, due, in part, to efforts to reduce pain found no significant analgesic effect of oral looking at the prescription of opioids in about the risks of chronic opioid use.76 Ketamine has cannabis extract.83 Another randomized, double- 840,000 opioid-naïve patients over 10 years found been successfully used to treat such acute pain blind study with 15 healthy volunteers using smoked that unintentional overdose was 5 times more likely conditions as sickle cell crises, renal colic, and cannabis found no analgesic effect with low doses in patients prescribed extended-release opioids trauma.76 Recently the American Society of Regional of cannabis, a modest effect with moderate doses, compared to immediate-release opioids.93) Anesthesia and Pain Medicine, the American and enhanced pain responses with high doses.84 Research shows general equivalency of Academy of Pain Medicine, and the American The authors of a 2017 review paper on cannabis efficacy and tolerability between different opioids. Society of Anesthesiologists released the first joint and pain conclude that cannabis may have a narrow Hydrocodone 5 mg, oxycodone 5 mg, and tramadol recommendations for sub-anesthetic ketamine for therapeutic window as a pharmacotherapy for pain 50 mg alone or in combination with acetaminophen acute pain with the following guidelines:76 but that much more research is needed to inform or ibuprofen have similar analgesic power to treat • Indications physician recommendations to patients regarding acute pain.94-96 Oxycodone and hydromorphone are ° Perioperative use in surgery with moder- the analgesic efficacy of cannabis.85 available as pure drugs, whereas hydrocodone (in ate to severe postoperative pain the United States) is only available co-formulated ° Perioperative use in patients with opioid Opioids for acute pain in opioid-naïve patients with acetaminophen or ibuprofen, therefore tolerance Opioids are commonly prescribed for pain, with oxycodone or hydromorphone might be preferred if ° Adjunct in opioid-tolerant patients with a patient is already taking acetaminophen or NSAIDs, sickle cell crisis approximately 20% of patients presenting with non- or if those drugs are prescribed simultaneously with ° Adjunct in patients with obstructive sleep cancer acute or chronic pain receiving an opioid in 86 the opioid as part of multi-modal therapy. Codeine apnea any given year, and nearly two thirds (64%) of is not preferred due to differential metabolism to • Dose the public reporting being prescribed an opioid for 87 the active metabolite, morphine. It is associated ° Bolus IV: up to 0.35 mg/kg pain at some point in their lives. However, opioids ° Infusion: up to 1 mg/kg/hour may not be as safe and effective as once thought, with a risk of both under-treatment in usual doses • Contraindications and high-dose prescriptions or prolonged use (due to CYP2D6 mutations) and overtreatment (in 97 ° Poorly-controlled cardiovascular disease not only increase the risk of misuse, addiction, or ultra-rapid metabolizers of CYP2D6). ° Pregnancy overdose, they may actually increase pain and pain Meperidine is associated with an increased risk ° Psychosis sensitivity.88,89 of post-operative delirium98 due to its long half-life ° Severe hepatic disease Recent evidence suggests that non-opioid pain and its active metabolite, normeperidine, which is a ° Elevated intracranial pressure regimens may be as effective for moderate to central nervous system stimulant.99 ° Elevated intraocular pressure severe pain as opioids.90,91 A randomized trial of Cannabis 416 patients with acute extremity pain found no BEFORE MOVING ONTO THE NEXT SECTION, In recent years, with increasing numbers of clinically important differences in pain reduction at PLEASE COMPLETE CASE STUDY 3 ON THE states legalizing both medical and recreational use two hours after single-dose treatment with ibuprofen NEXT PAGE. of cannabis, there has been a resurgence of interest and acetaminophen vs. three different combinations 90 Dose and duration of opioid therapy in the use of cannabis or cannabis derivatives (e.g., of opioid and acetaminophen analgesics. Only enough opioids should be prescribed cannabidiol [CBD]) for pain relief. Like opioids, Physical dependence can readily occur after use to address the expected duration and severity cannabinoids produce their pharmacological effects of opioids for just a few days. In addition, side effects of pain from an injury or procedure (or to cover via specific receptors in the body designed for of opioid use include constipation, confusion/gait pain relief until a follow-up appointment). Several endogenously produced compounds with normal instability, respiratory depression, pruritus, erectile 77 guidelines about opioid prescribing for acute pain regulatory, homeostatic properties. The CB1 and dysfunction, and fractures, all of which may be more from emergency departments100,101 and other CB2 receptors have been shown to mediate the problematic in older patients and occur at higher 26,102 78 settings have recommended prescribing ≤ 3 analgesic effects of cannabinoids. Unlike opioids, rates than with non-opioid analgesics. days of opioids in most cases, whereas others have however, there has never been a documented A cross-sectional study compared common recommended ≤ 7 days,103 or ≤ 14 days.104 CDC case of death from cannabis overdose—indeed, side effects experienced during the first week of 79 guidelines suggest that for most painful conditions cannabis has no known lethal dose. treatment with opioid analgesics vs. non-opioid (barring major surgery or trauma) a 3-day supply A 2017 report by the National Academies of analgesics in patients over age 65 with acute should be enough, although many factors must be Science concluded that “conclusive or substantial musculoskeletal pain. The intensity of six common taken into account (for example, some patients in evidence” supports a beneficial role for cannabis or opioid-related side effects were significantly higher 80 92 very rural areas might live so far away from a health cannabinoids for treating chronic pain, and a 2018 with opioids. (A limitation of this study is that it care facility or pharmacy that somewhat larger Cochrane review of the existing literature evaluating could not assess severe but less common adverse supplies might be justified).2 cannabinoids (cannabis, CBD, or combinations) events associated with NSAIDs and acetaminophen, suggests that these agents are moderately effective including gastrointestinal bleeding, acute kidney for neuropathic pain with adverse effects that are injury, and hepatotoxicity.) 98 Case Study 3 Instructions: Review the case below and consider the questions that follow.

Mirella is a 70-year-old woman with a history of osteoporosis. Three months ago, Mirella slipped and fell on a tile floor, resulting in significant bruising and a hairline hip fracture, diagnosed after she was admitted to the hospital. Asked to rate her pain at the hospital on a 0-10 scale, Mirella reported a 10, which she said was the worst pain she’s experienced. She was prescribed morphine 5 mg IV every 4 hours, with an additional 3 mg morphine every hour PRN. The morphine reduced, but did not eliminate, her pain and she reported feeling dizzy and having difficulty breathing. After discharge, Mirella was prescribed extended-release oxycodone for pain. At a follow-up visit one week later, Mirella reported painful constipation and continuing pain.

1. What other pain management options might have been tried instead of morphine for Mirella’s pain in the hospital?

2. What analgesic options might be tried in response to Mirella’s experience of adverse effects of ER oxycodone?

Question 1 Commentary: A regional nerve block with a local anesthetic (e.g., bupivacaine) might have provided equal pain relief compared to morphine without the risk of dizziness, delirium, or respiratory depression.

Question 2 Commentary: A combination of acetaminophen and ibuprofen might provide as much relief as ER oxycodone, and would be indicated as long as Mirella had no unusual risks for bleeding or kidney or liver dysfunction. Use of injectable methylnaltrexone (or equivalent) could help reverse her opioid-induced constipation. Based on: Agency for Healthcare Research and Quality. Pain Management Interventions for Hip Fracture. https://effectivehealthcare.ahrq.gov/topics/hip-fracture-pain/slides. Accessed: July 23, 2019.

Clinician discretion in choosing an opioid and Opioid-induced hyperalgesia is different Calculating morphine equivalents deciding how much to prescribe is always necessary pharmacologically from the phenomenon of opioid Calculating a patient’s total daily dose of opioids because so many factors influence how a patient will tolerance, although both can lead to an increased is important to appropriately and effectively respond to both pain and an analgesic (Table 5). need for opioids and disentangling the two, can be prescribe, manage, and taper opioid medications These factors include: challenging in clinical situations. use for both acute and chronic pain. • Age • Hepatic or renal impairment • Genetic polymorphisms Table 5. Opioid dose recommendations for post-procedural pain105 • Comorbid conditions Procedure Number of oxycodone 5 mg • History of substance abuse tablets (or equivalent) • Potential drug-drug interaction Dental extraction 5 • Co-administration with other central nervous system depressants Breast biopsy or lumpectomy 5 • Co-existing chronic pain condition Lumpectomy plus sentinel lymph node biopsy 5 Hernia repair (minor or major) 10 Opioid-induced hyperalgesia Sleeve gastrectomy 10 An under-appreciated fact about opioids is that although they typically reduce pain, they can Prostatectomy 10 also result in patients becoming more sensitive to Open cholecystectomy 15 painful stimuli.89 This opioid-induced hyperalgesia Cesarean delivery 15 is probably due to upregulation of pro-nociceptive Hysterectomy (all types) 15 pathways in the peripheral and central nervous systems.106 Although hyperalgesia has traditionally Cardiac surgery via median sternotomy 15 been associated with chronic pain, it can also occur Open small bowel resection 20 after intraoperative or postoperative administration Simple mastectomy with or without sentinel lymph node biopsy 20 of high-dose opioids as well as in low-dose or Total hip arthroplasty 30 maintenance-dose regimens.107 Total knee arthroplasty 50

99 This can be done with printed or online equianalgesic • Consider whether cognitive limitations might drug options are generally safe, although spinal charts, which provide conversion factors and dose interfere with management of opioid therapy, manipulation may rarely produce stiffness, spasms, equivalents of all available opioid medications and if so, determine whether a caregiver can or increased pain.111,112 Although bed rest and relative to a standard dose of morphine. responsibly co-manage the therapy back-extension exercises are often prescribed for Care must be taken in using such charts because In addition, whenever an opioid is prescribed, patients with acute LBP, they have not been found to dose is not the only relevant variable. Clinicians the patient should be educated about the safe be more effective than continuing regular activities. must also consider the route of administration, storage and disposal of the medications. This One trial randomized 186 patients with nonspecific cross tolerance, half-life, and the bioavailability of can be done by a non-physician, if desired, and acute LBP to bed rest for two days, back-mobilizing a drug. In addition, the patient’s existing level of the key points can also be included in patient- exercises, or continuation of ordinary activities.113 opioid tolerance must be taken into account. Printed provider agreements or treatment plans. Safe use At three-weeks and 12-weeks follow-up, patients equianalgesic charts are common, and online means following clinician instructions about dosing, who continued ordinary activities had statistically calculators are also freely available (a common avoiding potentially dangerous drug interactions, significant reductions in pain duration and pain one can be accessed at clincalc.com/Opioids). The and preventing diversion. Remind patients that intensity, improved lumbar flexion, and returned CDC provides a helpful guide to opioid conversions opioid pain medications are sought after by many to work more quickly compared to the other two available at: www.cdc.gov/drugoverdose/pdf/ people, and that opioids should be stored in a groups. calculating_total_daily_dose-a.pdf locked cabinet or other secure storage unit. If a A Cochrane review of 61 randomized trials locked unit is not available, patients should, at least, involving 6,390 patients with acute and chronic Pain medicine specialists not keep opioids in an open place easily accessed LBP comparing a variety of exercise regimens Integrated pain management requires by others, since theft by friends, relatives, and to no exercise found that exercise was slightly coordination of medical, psychological, and social guests is a known route by which opioids become more effective for reducing pain and improving aspects of health care and includes primary diverted.108 Storage areas should be cool, dry, and function, particularly when patients were in some care, mental health care, and specialist services out of direct sunlight. kind of healthcare setting.114 The pooled mean when needed. Consultation with a pain medicine Proper disposal methods should be explained:109 improvement in pain with exercise vs. no exercise specialist, addiction medicine specialist, or • Follow any specific disposal instructions on the was 7.3 points (0-100 scale), 95% CI: 3.7-10.9 psychiatrist may be necessary if an episode of prescription drug labeling or patient informa- points, and the mean improvement in function was acute pain involves complicating variables (such as tion that accompanies the medication 2.5 points (out of 100) 95% CI: 1-3.9 points. In multiple comorbidities) or if opioids are needed but • Do not flush medicines down the sink or toilet another review of 20 head-to-head trials of different the patient is already using an opioid for chronic unless the prescribing information specifically exercise programs for LBP, there were no significant pain and/or opioid maintenance therapy. instructs to do so differences in outcomes between regimens.115 • Return unused medications to a pharmacy, Heat and cold treatments are often used to Patient education health center, or other organization with a relieve symptoms of low back pain, most frequently Before prescribing an opioid for acute pain, take-back program heat wraps or hot water bottles, rice bags, or heated providers should discuss the known risks and • Mix the medication with an undesirable sub- blankets.116 However, the evidence to support these benefits of such therapy in order to arrive at stance (e.g., coffee grounds or kitty litter) and practices is limited. informed decisions about opioid therapy. Here are put it in the trash Heat wrap therapy has been found by a small some suggestions from the CDC:2 number of trials to provide a minor short-term • Be explicit and realistic about expected Managing common acute pain conditions reduction in pain and disability in a population benefits, including the fact that complete pain with a mix of acute and subacute LBP. One trial of Acute low back pain relief is unlikely and not necessarily desired 100 patients found that adding exercise to heat Most low back pain (LBP) is non-specific with • Emphasize improved function as a primary wraps provided significantly more pain relief at no evidence of underlying disease, is usually self- goal and that function can improve even when day seven and also led to greater improvements limited, and resolves within weeks. A systematic some pain is present in function than either heat or exercise alone.116,117 review of 15 trials evaluating a range of treatments • Advise patients about potential serious The evidence for cold treatments for LBP is even for LBP found rapid pain reductions within a month, adverse effects including respiratory more limited—a 2017 review concluded that there regardless of treatment used.53 Rarely, low back depression, constipation, and development of is insufficient evidence for using such treatments.116 pain may indicate an underlying or systemic medical an opioid use disorder Only one study has looked at the effect of illness or condition, such as sciatica or herniated • Review common effects such as dry mouth, massage on patients with acute LBP (n=51), and disc. Red-flag symptoms include severe progressive nausea, vomiting, drowsiness, confusion, it suggested a short-term benefit of massage vs. neurologic deficits such as urinary or fecal tolerance, physical dependence, and inactive control (standard mean difference [SMD] incontinence, saddle anesthesia, or osteomyelitis. withdrawal symptoms when stopping opioids -1.24, 95% CI -1.85 to -0.64). However, massage Imaging for acute low back pain is rarely indicated • Discuss effects that opioids might have on had no benefit on function (SMD -0.50, 95% CI because image findings are poorly associated with ability to operate a vehicle, particularly when -1.06 to 0.06).118 A 2015 Cochrane review of symptoms.110 Imaging of the lower spine before opioids are first stared, when dosages are 25 trials comparing massage to active or inactive six weeks does not improve outcomes but does increased, or when other central nervous controls in 3,096 patients with acute, subacute, increase costs.110 system depressants, such as benzodiazepines or chronic LBP found low-quality evidence that or alcohol, are used concurrently massage modestly reduced pain and improved Non-pharmacologic treatment options • Discuss risks to household members and function in the short-term (0-6 months), but not Non-pharmacologic treatment with heat, other individuals if opioids are intentionally or long-term (6-12 months).119 massage, acupuncture, or spinal manipulation are unintentionally shared with others from whom Myofascial trigger points (MTrPs) are palpable often recommended to treat acute LBP. Most non- they are not prescribed. hyperirritable nodules in skeletal muscle that

100 are associated with chronic musculoskeletal improvement in disability scores (between-group used to treat spasticity from upper motor neuron pain.120 Pressure massage targeting compression difference -3.2 points on 0-100 scale; 95% CI: -5.9 syndromes and muscular pain or spasms from of MTrPs has been thought to reduce symptoms to -0.47 points), which was less than the author- peripheral musculoskeletal conditions. Their associated with acute LBP. A small randomized, defined minimum clinically important difference for efficacy in the management of non-specific acute unblinded study of 63 patients with acute LBP this outcome.126 At 1 year, there were no significant LBP is debated, however, and there are concerns randomized to MTrP massage, non-MTrP massage between-group differences. about potential adverse effects. A 2003 Cochrane (compression at non-trigger points), or effleurage Review found that skeletal muscle relaxants (both (massage of superficial areas) showed that MTrP Pharmacologic options of LBP benzodiazepines and non-benzodiazepines) were massage significantly reduced pain intensity (0- Several systemic pharmacologic therapies are more effective than placebo for short-term relief 100 scale), pressure pain threshold, and range of available for low back pain and are associated of acute LBP after two to four days. The pooled motion compared to either non-MTrP or effleurage with small to moderate, mostly short-term effects relative risk for non-benzodiazepines vs. placebo massage.121 on pain. The most commonly-used medications for was 0.80 (95% CI: 0.71-0.89) for pain relief and Low-quality evidence from five randomized LBP are NSAIDs, acetaminophen, skeletal muscle 0.49 (95% CI: 0.25-0.95) for global efficacy. 133 controlled trials (RCTs) showed that acupuncture relaxants, and opioids. However, research has However, a 2018 RCT of 240 patients with may improve symptoms of acute LBP to a greater found only limited evidence to support use of these LBP presenting to emergency rooms found that extent than (RR 1.11; 95% CI: 1.06-1.16) compared medications for LBP.127 adding the muscle relaxants orphenadrine or to control.122 Additionally, evidence from two RCTs Evidence for the analgesic efficacy of methocarbamol to naproxen was no better than showed that acupuncture may more effectively acetaminophen for acute LBP is mixed. The American naproxen alone for improving function at one week.134 relieve pain compared with sham acupuncture, College of Physicians Clinical Practice Guidelines In addition, a 2019 RCT of 320 patients with acute resulting in a small decrease in pain intensity (mean found no difference between acetaminophen and LBP randomized to ibuprofen or ibuprofen and difference -9.38 points; 95% CI: -17.00 to -1.76 NSAIDs in reducing pain intensity (SMD 0.21; 95% one of three skeletal muscle relaxants (baclofen, points), but there were no significant effects on CI: -0.02 to 0.43) at three weeks or less and a metaxalone, or tizanidine) found no significant function/disability.122 lower risk of adverse events with acetaminophen differences between groups in pain or functional Randomized trials and meta-analyses have vs. NSAIDs (RR 0.57; 95% CI: 0.36-0.89).127,128 impairment at one-week follow-up.135 Common provided conflicting conclusions about the Observed improvements in pain with acetaminophen side effects of skeletal muscle relaxants include effectiveness of spinal manipulation in treating may, however, be strongly influenced by the placebo dizziness, dry mouth, drowsiness, and somnolence, acute LBP, suggesting either no effect or small effect. For example, an RCT of 1,652 patients necessitating cautious use, particularly if taken with effect on pain and function. Spinal manipulation of compared acetaminophen 4000 mg/day in two other sedating medications such as opioids. the cervical spine has been associated with rare different regimens vs. placebo and found no Oral steroids are commonly used to treat acute adverse events, such as stroke, headache, and differences between either regimen and placebo in sciatica and may provide some analgesic effect vertebral artery dissection.112 days to recovery, or mean pain scores.129 due to their anti-inflammatory activity. However, A 2017 systematic review and meta-analysis of A Cochrane review of 65 RCTs of oral NSAIDs evidence suggests that non-epidural steroids do 26 randomized trials found a modest improvement for non-specific acute LBP with or without sciatica not improve pain in patients with acute nonspecific in both pain and function at up to six weeks after found that NSAIDs were associated with significantly LBP.115 One RCT of 269 patients with acute radicular the procedure (SMD -0.39; 95% CI: -0.71 to -0.07) more pain relief vs. placebo but also significantly LBP due to herniated lumbar disk found a small in patients with acute LBP who underwent spinal more side effects.128 In an analysis of 4 trials, mean improvement in function with a three-week course manipulation. Minor, transient musculoskeletal pain reduction with NSAIDs was 8.39 points (0-100 of oral prednisone (mean difference 6.4 points on adverse events such as increased pain, stiffness, scale); 95% CI: -12.68 to -4.10 points). There was a 100-point scale vs. placebo) but no significant and headache were reported in more than half of no significant improvement in function with NSAIDs improvement in pain.136 patients.111 in a single 7-day trial.128,130 A meta-analysis of 2 trials comparing TENS vs. COX-2 selective NSAIDs do not seem to be Opioids for LBP placebo in 121 patients with acute LBP found no more effective than traditional NSAIDs for pain Almost all RCTs of opioids have been conducted significant differences in analgesic efficacy (mean relief but are associated with fewer side effects, for chronic, rather than acute, LBP. One RCT in 107 difference on 100-point scale -15 points, 95% CI particularly gastrointestinal bleeding.128 An RCT of patients with acute LBP found that opioids may be -40 points to 10 points).123 A randomized trial of 24,081 patients with arthritis pain examined the no more effective than a combination of ibuprofen 74 patients with acute LBP being transported to safety of celecoxib, compared with nonselective and acetaminophen.137 The trial compared a hospital compared enroute TENS vs. sham TENS NSAIDs.131 Esomeprazole (20-40 mg) was provided functional outcomes and pain at one week and three and found significant differences in mean pain to all patients for gastric protection. Patients months after randomization to naproxen, naproxen scores upon arrival (49 mm on a 100 mm scale were randomized to celecoxib (mean daily dose plus cyclobenzaprine, or naproxen plus oxycodone/ with TENS vs. 77 mm with sham, P<0.01) and mean 209 mg), naproxen (mean daily dose 852 mg), acetaminophen. Results showed that adding anxiety scores (69 mm on 100 mm scale vs. 84 mm, or ibuprofen (mean daily dose 2,045 mg). There cyclobenzaprine or oxycodone/acetaminophen to P<0.01).124 were no differences among the three treatments in naproxen did not improve functional outcomes or The effect of early physical therapy on acute cardiovascular outcomes, but celecoxib produced pain at 1-week follow-up more than naproxen alone. back pain is unclear, and some guidelines advise fewer gastrointestinal events than either naproxen There was also no difference in patient-reported delaying referral to physical therapy or other (p=0.01) or ibuprofen (p=0.002), and celecoxib satisfaction with treatment nor in time to return to specialists for a few weeks to allow for spontaneous was associated with fewer renal events compared usual activities between treatment groups.137 recovery.125 One trial randomized 220 patients to ibuprofen (p=0.004). A retrospective cohort study of workers’ with acute LBP to four sessions of early physical Skeletal muscle relaxants account for more than compensation claims from 8,443 patients with therapy or usual care.126 At three months, patients 45% of all prescriptions written for management acute disabling LBP evaluated the associations receiving early physical therapy had a small of musculoskeletal pain.132 These are commonly between early opioid prescription and outcomes.138

101 Mean disability duration, mean medical costs, and outcomes associated with the under-treatment of recovery, and improve long-term functional risk of surgery and late opioid use increased with perioperative pain, including thromboembolic and outcomes. increasing opioid dose measured in morphine pulmonary complications, additional time spent Non-pharmacological options equivalent units. Compared with those receiving no in an intensive care unit or hospital, hospital Non-pharmacological options for relief of post- opioids, the risk for subsequent surgery was three readmission for further pain management, needless operative pain include transcutaneous electrical times greater (RR 3, 95% CI 2.4–4.0) in those suffering, impairment of health-related quality of nerve stimulation (TENS), acupuncture, massage, receiving the highest dose of opioids, and the risk life, and development of chronic pain.139 cold therapy (with and without compression), of receiving late-term opioids (≥5 prescriptions In addition, the issue of opioid analgesic localized heat, continuous passive motion, and from 30 to 730 days) was six times greater over prescription is as important an issue in the immobilization or bracing. Although these are (95% CI, 4.9–7.7). These results suggest that perioperative arena as it is anywhere in medicine. A generally safe, their effectiveness as an adjunct the use of opioids to manage acute LBP may be November, 2018 article in JAMA Surgery reporting to post-operative pain management is variable, counterproductive to recovery.138 on a cohort study of 2,392 adults having a range and treatments may not be covered by health of surgeries in Michigan found that, overall, a insurance.142 BEFORE MOVING ONTO THE NEXT SECTION, median of 30 pills of hydrocodone/acetaminophen Acupuncture has been investigated as adjuvant PLEASE COMPLETE CASE STUDY 4. (5/325 mg) were prescribed for postsurgical pain, treatment for post-operative analgesia.143 A 2016 but patients only used a median of 9 pills.140 The Post- and perioperative pain systematic review of 13 trials (682 patients) of study also found that the strongest association with A full discussion of ways to manage perioperative post-operative acupuncture and acupuncture- higher use of opioids was not level of pain, but the pain is beyond the scope of this document because related techniques vs. sham acupuncture or control quantity of opioids prescribed: 0.53 more pills used it can involve a diverse array of pharmacological found reduced pain within 24 hours of surgery with for every additional pill prescribed.141 and invasive measures administered by hospital- acupuncture or related techniques (SMD -1.27; Post-operative pain can have a significant effect based anesthesiologists or pain specialists in order 95% CI: -1.83 to -0.71) and lower mean use of on patient recovery and healthcare burden. Among to relieve suffering, achieve early mobilization post- opioid analgesics (SMD -0.72; 95% CI: -1.21 to 411 older adults (mean age 82) with recent hip surgery, and reduce hospital stay. It is worth noting, -0.22).144 fracture, a prospective cohort study found that however, that a multimodal approach to acute pain A meta-analysis of 15 trials evaluating patients with higher post-operative pain scores had management is the primary model for dealing with acupuncture and related techniques as adjunctive increased lengths of hospital stay, more missed perioperative pain as it is, more generally, for the therapy for acute post-operative pain management, physical therapy sessions, delayed ambulation, treatment of acute pain in primary care settings. found that pain intensity (0–100 mm scale) was and impaired locomotion at six months.1 Poor Also, just as competent and responsible treatment significantly reduced in the acupuncture group vs. pain control can delay post-operative functional of acute pain in primary care can help prevent control at eight hours (WMD -14.57 mm; 95% CI: improvement, whereas improved pain control the development of chronic pain and attendant -23.02 to -6.13] and at 72 hours (WMD -9.75 mm; may decrease length of stay, enhance functional morbidities, research has shown an array of adverse 95% CI: -13.82 to -5.68).145

Case Study 4 Instructions: Review the case below and consider the questions that follow.

Roland is a 16-year-old high school student who presents to the school nurse with 1 month of lower back pain. He is a 275-pound football player and says his pain has been getting worse as the football season has progressed. He denies any pain radiating down the legs or bowel and bladder changes. He is referred to the local hospital for imaging. X-rays show no fractures, although MRI shows edema in the right pars region of L5 consistent with an acute impending spondylolysis.

1. Which of the following options would be best for this type of acute pain:

1. Physical therapy (PT) with avoidance of lumbar spine extension 2. Corset bracing, PT, and avoidance of lumbar spine flexion 3. Complete lumbar spine immobilization in corset brace

2. What analgesic options would be appropriate for this patient?

Question 1 Commentary: PT with avoidance of lumbar spine extension would be the most appropriate approach here because the prognosis with such conservative treatment is > 90%. Active lumbar extension should be avoided because it increases shear forces across the back and increases the risk of instability and spondylolisthesis.

Question 2 Commentary: Combination of acetaminophen and ibuprofen (e.g., 1000 mg/600 mg) could be recommended to relieve pain in the early phase of recovery, with tapering appropriate to the expected course of healing. Opioid analgesics would not be appropriate as first-line treatment due to the known risks for adverse effects as well as the possibility of diversion. Adapted from: Selhorst M, et al. Long-Term Clinical Outcomes and Factors That Predict Poor Prognosis in Athletes After a Diagnosis of Acute Spondylolysis. J Orthop Sports Phys Ther. 2016;46(12):1029-1036.

102 A reduction in opioid-related adverse events 0.07-0.58) and range of motion (mean difference mild to moderate acute pain and inflammation vs. was also seen in patients receiving acupuncture, 2.9 degrees, 95% CI; 0.61-5.2 degrees), but no acetaminophen (Number Needed to Treat (NNT) of including nausea, dizziness, sedation, pruritus, and significant differences in walking ability or quality of 2-3 to achieve a 50% reduction in acute post-op urinary retention. The relative reduction in opioid life. At one-year follow-up, there were no significant pain vs. placebo).158,159 use with acupuncture was 21%-29%. differences in any outcome measures between The combination of acetaminophen and NSAID Although older adults, who have higher rates of groups. may offer superior analgesia compared with either postoperative morbidity and mortality, might benefit Massage therapy appears safe in post-operative drug alone. In a systematic review of 21 studies from perioperative acupuncture, this option is patients, but evidence suggests it has little effect on (n=1,909), combining acetaminophen and NSAID rarely available, and acupuncture procedures and key outcomes such as pain or consumption of opioid was more effective than acetaminophen alone (85% regimens have not been standardized.146 analgesics. One trial randomized 605 veterans of studies) or NSAID alone (64% of studies). Pain A systematic review of 21 RCTs found that TENS undergoing sternotomy or major abdominal surgery intensity with combination treatment was reduced administered with a strong, subnoxious intensity to one of three groups: standard post-operative by 35% vs. acetaminophen alone, and by 39% vs. at an adequate frequency in the wound area was care; individual attention from a massage therapies NSAIDs alone.160 associated with a non-significant 26.5% reduction (without massage); or daily back massage for up Topical NSAIDs may be an effective option for (range -6 to +51%) in post-operative analgesic to five postoperative days.153 All three groups post-surgical pain. One trial randomized 120 use compared with no TENS.147 Despite the limited experienced reductions in pain, pain unpleasantness, women having laparoscopic gynecologic surgery evidence base, TENS is recommended by the 2016 and consumption of opioid analgesics, and at five- to diclofenac patch vs. placebo at all incisional American Pain Society guideline as an adjunct to day follow-up, there were no significant differences areas.161 Mean pain intensity was significantly lower other post-operative pain treatments.142 between groups in these outcomes. Another trial in the diclofenac group at 12 hours post-surgery Evidence for the analgesic benefits of exercise randomized 252 adults having cardiac surgery to (3.7 points vs. 5.7 points on 10-point scale, or stretching for post-operative pain is mixed. usual care or usual care plus two massages and P=0.002) and 24 hours post-surgery (2 points vs. A trial of 63 patients who had arthroscopic found no significant differences in pain or any other 4.6 points, P<0.001). Significantly fewer patients in shoulder surgery found that horizontal adduction outcomes.154 A 2019 structured review of evidence the diclofenac group required additional analgesics stretching twice daily for 48-72 hours post-surgery about massage for post-surgical outcomes found in the first 36 hours post-surgery (35% vs. 71.7%, significantly reduced posterior shoulder tightness weak methodologies among existing trials and P<0.001). compared to either standard care or supine sleeper high clinical heterogeneity, leading the authors to Anticonvulsants (e.g., gabapentin or pregabalin) stretching.148 A prospective observational study conclude that massage is not recommended as an may be prescribed with opioids as part of multimodal of 231 patients having total knee arthroplasty effective therapy at this time.155 opioid-sparing analgesic regimes to help reduce compared participation in group-based exercise central sensitization induced by surgery.162,163 programs plus usual ambulation and activities-of- Pharmacological options for post-operative Gabapentin, however, may also increase side daily-living exercises vs. a historical control group pain effects such as sedation, visual disturbances, and who did not do group-based exercise and found Acetaminophen is more effective than placebo at dizziness.164 Pain reduction with gabapentin or significant improvements in knee range-of-motion reducing post-procedural pain, and is associated pregabalin alone is inconsistent, with some studies and extension and quadriceps strength with group with mild, mostly transient, adverse events.156 In a showing benefit to 24 hours while others showing exercise.149 Cochrane review of 21 RCTs of acute pain following no difference vs. placebo. However, adjunctive use A non-randomized study in 30 patients with wisdom teeth extraction, acetaminophen provided a of gabapentin and pregabalin in the immediate total knee arthroplasty found that exercise/ statistically significant benefit vs. placebo for pain post-operative period has been shown to reduced mobilization on first post-operative morning (25 relief at both four hours (RR 2.85; 95% CI: 1.89- overall opioid doses.162,164,165 meter walking twice, with 20-min. interval) was 4.29) and six hours (RR 3.32; 95% CI: 1.88-5.87). A 2018 RCT randomized 422 surgical patients to associated with significantly less pain at rest and Higher doses gave greater benefit for each measure 1200 mg of preoperative gabapentin followed by during knee flexion at 5 minutes and 20 minutes at both time points. There was no difference 600 mg every eight hours for 72 hours vs. active after the exercise compared to baseline pain between groups in reported adverse events.157 placebo.166 Gabapentin did not significantly affect scores.150 Whether physical rehabilitation following A separate Cochrane review of 51 studies time to postoperative pain resolution (84 days total knee replacement occurs at home or in an assessed the efficacy of acetaminophen for vs. 73 days for placebo), but patients receiving inpatient setting may not matter, according to the treatment of acute post-operative pain and gabapentin had a marginally significant reduction results of the HIHO randomized trial.151 In total, found that about half of participants treated with in time to opioid cessation after surgery (25 days 165 patients were randomized to 10 days of acetaminophen at standard doses achieved at least vs. 32 with placebo, P=0.05). Adverse events were hospital inpatient rehabilitation followed by 8 weeks 50% pain relief over four to six hours, compared similar between the two groups. of clinician-monitored home-based exercises vs. with about 20% treated with placebo. Additionally, Topical lidocaine patches may help manage the home-based program alone. At 26 weeks of about half of participants using acetaminophen chronic neuropathic pain syndrome and post- follow-up, there were no significant differences needed additional analgesia over four to six hours, herpetic neuralgia and have potential for treating between groups in results from the 6-minute walk compared with about 70% with placebo.156 post-operative pain, however evidence is insufficient test, patient-reported pain and function, or quality An overview of 16 systematic reviews and meta- for recommendations of transdermal lidocaine for of life.151 analyses that directly and indirectly compared this indication.167 A systematic review of 6 trials compared ibuprofen and acetaminophen at standard doses Skeletal muscle relaxants are not currently focused physiotherapy exercise vs. standard care showed that ibuprofen was consistently superior included as therapeutic options in clinical guidelines or standard physiotherapy in 614 patients with to acetaminophen at conventional doses in acute on postoperative pain management,142 and evidence total knee arthroscopy.152 The meta-analyses of post-operative pain. Single-dose oral NSAIDs from clinical trials is limited. 5 trials found small effect sizes at 3-4 months for (ibuprofen 400mg, diclofenac 50mg, naproxen functional improvement (effect size 0.33; 95% CI: 500mg or celecoxib 400mg) were shown to reduce

103 One trial randomized 60 patients undergoing Functional treatment • When NSAIDs were compared with opioids (4 inguinal hernia repair to tizanidine 4 mg orally Several studies suggest that early movement, studies, involving 958 participants), there was 1 hour before surgery and twice daily in first including manual therapy techniques, may be better a lack of clinically important differences in pain postoperative week vs. placebo.168 At one-week for recovery from strains or sprains.173,175 An RCT at less than 24 hours, at days four through six, follow-up, pain scores at rest and during movement of 101 patients with mild ankle sprains found that and at day seven. Return to function at day were significantly lower in the tizanidine group, and functional treatment (moderate exercises during seven or later favored the NSAID group (low analgesic consumption was also lower with tizanidine the first week after ankle sprain) led to significant quality evidence), with fewer gastrointestinal (33% vs. 77% in placebo group, P<0.001). Skeletal improvements in short-term ankle function adverse events in those receiving selective muscle relaxants are not effective for reducing pain compared with patients who received standard RICE COX-2 inhibitor NSAIDs. in patients having third molar extractions.169,170 treatment.175 Activity levels were significantly higher • When NSAIDs were compared with the combi- in the exercise group than in the standard treatment nation of acetaminophen and an opioid (four Opioids for post-operative pain group, as measured by time spent walking (1.6 studies, involving 240 participants), there Due to their potent analgesic efficacy in hours vs. 1.2 hours, P=0.029), step count (7,886 was no difference in pain, swelling, return to moderate-to-severe post-operative pain, opioids steps vs. 5,621 steps, P=0.021), and time spent function at day seven, or in gastrointestinal are frequently prescribed after many types of doing light-intensity activity (76.2 minutes v. 53 adverse events. surgery and are often considered the gold standard minutes, P=0.047). Topical NSAIDs such as diclofenac gel or patch for reducing postoperative pain. However, as noted Supervised physical therapy, long thought to (Flector) can also provide effective initial pain previously, these drugs are not only associated speed up the recovery from sprains, may not be control for acute musculoskeletal pain resulting with risks for addiction, they can exert a number of better than usual care for mild ankle sprains. An from sprains and strains.181 These agents have undesirable side effects, such as nausea, vomiting, RCT of 503 patients with simple ankle sprains found been shown to be safe and effective for acute gastrointestinal ileus, immunosuppression, and that addition of early supervised physiotherapy to musculoskeletal pain, with fewer systemic adverse respiratory depression, which may delay patient RICE treatment did not lead to clinically important effects than oral NSAIDs.182 However, the long recovery.171 improvements in functional recovery up to six term impact of topical NSAID use has not been A systematic review of 20 RCTs (2,641 adults months after injury.176 determined.159 with moderate-to-severe post-operative pain) found An RCT in 584 patients with the most severe When the efficacy of acetaminophen or that single-dose oxycodone is an effective analgesic ankle sprains (unable to bear weight for three combination acetaminophen plus opioids was in acute post-operative pain at doses over 5 mg days) found that a short period of immobilization compared to NSAIDs for the treatment of acute soft (NNT 4.6 for ≥ 50% pain relief with oxycodone with below-the-knee cast or air cast may result in tissue injuries, no clinically important differences 15 mg). Efficacy increased when combined with better quality of ankle function at three months than were observed for pain or function. An Cochrane acetaminophen (NNT 2.7 for oxycodone 10 mg plus if the patient is only given a tubular compression analysis of nine studies (n=991) comparing acetaminophen 650 mg). 172 bandage. Improvements in pain, symptoms, and acetaminophen vs. NSAIDs found little difference in activity was also observed in the cast groups.177 pain at 24 hours, or in swelling, or function at seven Non-pharmalogical options for sprains, Insufficient evidence exists to recommend days, although the study authors downgraded the strains, fractures, and trauma massage, acupuncture, or TENS for the treatment evidence for these outcomes due to the possibility The optimal non-drug treatment for sprains and of strains or sprains.178,179 of suboptimal dosing of the analgesics.180 NSAIDs strains remains uncertain. Rest, ice, compression, were associated with a higher risk of gastrointestinal and elevation (RICE) is a foundational management Pharmacological options for sprains and bleeding (13 more events per 1000 people) than approach for musculoskeletal trauma, but these strains acetaminophen. techniques are supported by surprisingly little A Cochrane review of 16 trials involving 2,144 clinical evidence.173 patients with acute soft tissue injury compared Opioids A meta-analysis of 24 RCTs analyzed the oral NSAIDs with acetaminophen, opioids, A 2017 RCT found that opioid analgesics effectiveness of RICE therapy within 72 hours of acetaminophen plus opioid, or complementary were no more effective in patients with severe trauma for patients after ankle sprain and found and alternative medicine. These results showed no acute musculoskeletal pain than a combination moderate evidence for the benefit of immediate clinically important differences in analgesic efficacy of ibuprofen plus acetaminophen.90 In total, 416 posttraumatic mobilization to treat acute ankle between NSAIDs and other oral analgesics, with patients with acute extremity pain were randomized sprains, limited evidence for the benefits of ice and some very low-quality evidence of better function to one of the following four regimens: 1) ibuprofen compression, and no evidence to support the use and fewer adverse events with NSAIDs compared 400 mg and acetaminophen 1000mg; 2) oxycodone of elevation.173 with opioid-containing analgesics.180 5mg and acetaminophen 325mg; 3) hydrocodone Ice has been shown to be better than heat • When NSAIDs were compared with acetamin- 5mg and acetaminophen 300mg; or 4) codeine for sprains because it reduces swelling. In a ophen (nine studies, involving 991 partici- 30mg and acetaminophen 300mg.90 The mean pain comparison study of 37 patients with ankle sprains, pants), there was a lack of clinically important scores at two hours after ingestion decreased by cryotherapy (15 minutes, one to three times per differences in pain at less than 24 hours, at 4.3 points (95% CI: 3.6-4.9) with ibuprofen and day) was compared with heat therapy (15 minutes, days one through three, and at day seven or acetaminophen; by 4.4 points (95% CI: 3.7 to one to three times per day). Results showed that later. There was little difference between the 5.0) with oxycodone and acetaminophen; by 3.5 early cryotherapy was associated with shorter time two groups in return to function at day seven points (95% CI: 2.9-4.2) with hydrocodone and to complete recovery vs. heat therapy (30.4 days or later. There was slightly lower risk of gas- acetaminophen; and by 3.9 points (95% CI: 3.2- vs. 33.3 days, no P-value reported).174 trointestinal adverse events in the acetamin- 4.5) with codeine and acetaminophen. None of the ophen group (16 per 1000 participants for differences between analgesics were statistically acetaminophen vs. 13 more participants per significant. 90 1000 in the NSAID group).

104 Management of acute pain in patients already • Assess for opioid misuse or addiction using using opioids validated screening tools • Access PDMPs when available When caring for patients who are physically • Avoid long-acting or extended-release opioids dependent on opioids—whether because of • Refrain from refilling chronic opioid prescrip- ongoing chronic pain or opioids used as part of tions—refer to treating clinician who provided treating opioid use disorder (OUD)—clinicians original prescription must know the type and quantity of opioid the • Refrain from replacing lost, stolen, or de- patient is currently using so that an equivalent stroyed opioid prescriptions (equianalgesic) dose can be administered by an Understand that the federal Emergency Medical appropriate route to cover their baseline opioid Treatment and Labor Act (EMTALA) does not state requirement as well as the additional medication that severe pain is an emergency medical condition, required for the acute pain. and that EMTALA allows emergency medical Some clinicians mistakenly believe that the opioid providers to withhold opioid treatment if in their agonist therapy (methadone or buprenorphine) professional judgment such withholding is clinically used by people in treatment for OUD provides justified enough analgesia to “cover” acute pain.183 In fact, the doses of methadone and buprenorphine Conclusions typically used for OUD treatment do not provide sustained analgesic effects and are insufficient to Although the focus of much public and treat acute pain.141 professional attention in the past decade has Patients on opioid agonist therapy also develop been on the problems related to opioid analgesic cross-tolerance, which means they require higher prescribing for chronic pain, this module has and more frequent doses of short- or long- demonstrated that the treatment and management acting opioids to provide analgesia for episodes of acute pain is an equally important topic because of acute pain. Because buprenorphine binds to many of the same dynamics are at work with acute mu-receptors with much higher affinity than other pain as with chronic pain. opioid agonists, pain management in patients using Properly and responsibly managing acute pain buprenorphine can be complicated. Several types is desirable not only because it relieves patient of regimens using both buprenorphine and other suffering, but also because it reduces the chances opioids for acute pain have been described in the that acute pain will transform into chronic pain, and literature with choices of regimen guided by the responsible prescribing can help stem the tide of specifics of a patient’s existing regimen, presence opioid diversion, misuse, and abuse. Opioids do of comorbid conditions, setting, and degree of play an invaluable role in the pain management acute pain.183 armamentarium, but they carry important risks, Emergency room considerations as well, and thus should be generally viewed as second-line agents or as part of a multi-modal Although emergency departments prescribe approach. The risks of opioids, even when used only a fraction of opioid analgesics prescribed for acute pain and for relatively short durations, nationwide, ED prescriptions for opioids are are amplified among older adults, patients with reported to account for about 45% of the opioids impaired renal or hepatic function, those with COPD, diverted for non-medical use.101 Guidelines from cardiopulmonary disorders, sleep apnea, or mental the American Academy of Emergency Medicine illness, and in anyone likely to combine opiates with and other groups have attempted to reduce the other respiratory depressants such as alcohol or variability in pain management and prescribing benzodiazepines. practices that has been evident in past decades. This learning activity has presented evidence- These guidelines mirror recommendations by the based recommendations for treating acute CDC and other organizations, with the following key pain with a range of pharmacological and non- provisions:101 pharmacological strategies to be administered • Give short-acting opioids as second-line treat- usually in a step-like fashion, with opioids only ment to other analgesics unless there is clear used when necessary and then at the lowest dose indication for opioid (e.g., acute abdominal and shortest duration deemed clinically beneficial. pain or long bone fracture) As with treating chronic pain, the appropriate • Start with lowest effective dose deployment of opioids for acute pain can be • Prescribe no more than a 3-day course of opi- challenging, but with proper pain assessment, oid for most acute pain conditions primary reliance on non-pharmacologic and non- • Address exacerbations of chronic pain with opioid analgesics, and a view that includes the non-opioid analgesics, non-pharmacological emotional, psychological, and social dimensions of therapies, or referral to pain specialists for pain, clinicians can relieve immediate suffering and follow-up maximize their patients’ long-term health.

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Diclofenac epolamine topical patch BMJ. 2007;335(7624):812. 2018;153(4):303-311. relieves pain associated with ankle sprain. Journal 153. Mitchinson AR, Kim HM, Rosenberg JM, et al. Acute 167. Bai Y, Miller T, Tan M, Law LS, Gan TJ. Lidocaine of pain research. 2011;4:47-53. postoperative pain management using massage as patch for acute pain management: a meta-analysis 182. Shinde VA, Kalikar M, Jagtap S, et al. Efficacy an adjuvant therapy: a randomized trial. Arch Surg. of prospective controlled trials. Current medical and Safety of Oral Diclofenac Sustained release 2007;142(12):1158-1167; discussion 1167. research and opinion. 2015;31(3):575-581. Versus Transdermal Diclofenac Patch in Chronic 154. Albert NM, Gillinov AM, Lytle BW, Feng J, Cwynar 168. Yazicioglu D, Caparlar C, Akkaya T, Mercan U, Musculoskeletal Pain: A Randomized, Open Label R, Blackstone EH. A randomized trial of massage Kulacoglu H. Tizanidine for the management of Trial. J Pharmacol Pharmacother. 2017;8(4):166- therapy after heart surgery. Heart Lung. acute postoperative pain after inguinal hernia 171. 2009;38(6):480-490. repair: A placebo-controlled double-blind trial. Eur J 183. Acute pain management for inpatients with opioid 155. Grafton-Clarke C, Grace L, Roberts N, Harky A. Anaesthesiol. 2016;33(3):215-222. use disorder. Am J Nursing. 2015;115(9):24-32. Can postoperative massage therapy reduce pain and anxiety in cardiac surgery patients? Interact Cardiovasc Thorac Surg. 2018. 109 Managing Acute Pain Self-Assessment Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

61. Roughly how many people every year are at risk for 66. During which phase of healing from acute conditions opioid misuse or addition due to their being prescribed are non-pharmacologic methods most appropriate? opioid analgesics for acute pain conditions? A. Immediately after tissue trauma A. 260,000 B. > 48 hours after tissue trauma B. 160,000 C. Late healing phase for recovery of function C. 60,000 D. Immediately after tissue trauma as well as in late healing D. 6,000 phase

62. Opioid-induced hyperalgesia is most likely the result of 67. Combination products for pain control join an opioid ______? with a ______. A. Upregulation of pro-nociceptive pathways in peripheral A. Non-opioid co-analgesic and central nervous systems B. Non-opioid controlled substance B. Downregulation of nociceptive pathways in dorsal horn C. Opioid antagonist to prevent abuse neurons D. Caffeine C. Increased release of substance-P in neuronal synapses of peripheral and central nervous system neurons 68. Which of the following is not an example of multimodal D. Disinhibition of neuropathic pain pathways in central therapy for acute pain? nervous system A. Systemic NSAID plus systemic opioid B. Systemic NSAID plus epidural opioid and local anesthetic 63. DIRE, ORT, and SOAPP are examples of tools for C. Immediate-release opioid plus extended-release opioid assessing what patient characteristic? D. Ketamine plus opioid A. Risk for opioid-induced hyperalgesia B. Neuropathic pain levels 69. For which type of pain should long-acting or C. Risk for opioid misuse or addiction extended-release opioid analgesics not be used D. Health-related quality of life ______? A. Treating cancer pain 64. A study found that surgeons prescribed a mean of 24 B. Treating acute pain pills (standardized to 5 mg oxycodone) for post-surgical C. Treating end-of-life pain pain. How many pills did patients actually use? D. Treating chronic non-cancer pain A. 4 pills B. 8 pills 70. Which of the following is not a topic that should be C. 16 pills routinely covered as part of patient education about D. 20 pills opioid analgesics? A. Background information about acute vs. chronic pain 65. What amount of opioid analgesic has been recommended B. Safe storage by the Centers for Disease Control and Prevention as C. Safe disposal appropriate for most painful conditions? D. Timing of medication use A. 2-day supply B. 3-day supply C. 5-day supply D. 7 day supply

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SPECIALTY BOARD: ID NUMBER: DATE OF BIRTH:

ABA, ABIM, ABO, ABOHNS, ABPath, ABP MM / DD / YYYY

EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, COMPASSIONATE CARE AT MANAGING ACUTE PAIN EFFECTIVE MANAGEMENT, AND THE END OF LIFE (P. 110) HARM REDUCTION (P. 32-33) (P. 89) 1. 14. 27. 38. 51. 61. 2. 15. 28. 39. 52. 62. 3. 16. 29. 40. 53. 63. 4. 17. 30. 41. 54. 64. 42. 5. 18. CDC OPIOID PRESCRIBING 55. 65. GUIDELINES FOR CHRONIC PAIN 6. 19. (P. 69-70) 43. 56. 66. 7. 20. 31. 44. 57. 67. 8. 21. 32. 45. 58. 68. 9. 22. 33. 46. 59. 69. 10. 23. 34. 47. 60. 70. 11. 24. 35. 48. 12. 25. 36. 49. 13. 26. 37. 50. $135.00 PROGRAM PRICE

CA21CME

112 LEARNER RECORDS: EVALUATION You must complete the program evaluation and applicable activity evaluation(s) in order to earn AMA PRA Category 1 CreditTM, MOC points, or participation in MIPS. For each of the objectives determine if the activity increased your: COURSE 1 - EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTION: A B C D 1. Describe the scope of current use and abuse of controlled substances in the U.S...... 2. Interpret regulatory and legal framework for prescribing controlled substances...... 3. Explain best practices for prescribing controlled substances...... 4. Respond to addiction treatment & diversion...... 5. Please identify a specific change, if any, you will make in your practice related to safe prescribing of controlled substances.

6. What do you see as a barrier to making these changes?

COURSE 2 - CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN: A B C D 7. Determining when to initiate or continue opioids for chronic pain ...... 8. Discussing known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. . . . . 9. Clinical treatment when opioids are started, including selection, dosage, duration, follow-up, tapering and discontinuation ...... 10. Assessing risk and addressing harms of opioid use ...... 11. Please identify a specific change, if any, you will make in your practice related to improving the safety and effectiveness of pain treatment.

12. What do you see as a barrier to making these changes?

COURSE 3 - COMPASSIONATE CARE AT THE END OF LIFE: A B C D 13. Manage patients at the end-of-life in ways consistent with their stated preferences and appropriately manage patients in hospice. . 14. Use both non-pharmacological and pharmacological treatment modalities to manage pain and other symptoms common in patients at the end-of-life...... 15. Please identify a specific change, if any, you will make in your practice related caring for patients at the end-of-life.

16. What do you see as a barrier to making these changes?

COURSE 4 - MANAGING ACUTE PAIN: A B C D 17. Assess patient’s risk for potential harms from using opioids to treat acute pain ...... 18. Apply non-pharmacological and non-opioid approaches to manage acute pain ...... 19. Please identify a specific change, if any, you will make in your practice related to managing acute pain.

20. What do you see as a barrier to making these changes?

OVERALL PROGRAM: Yes No If no, please explain: 21. The program was balanced, objective & scientifically valid ...... 22. Do you feel the program was scientifically sound & free of commercial bias or influence? . . 23. How can this program be improved?

24. Based on your educational needs, please provide us with suggestions for future program topics & formats?

25. For which activities would you like to use your participation as a clinical practice improvement activity (CPIA) for MIPS? Section 3 Section 4 None

CA21CME 113 CUSTOMER SERVICE

We maintain a fully-staffed educational service center that course participants can contact Monday through Friday, 8:30 AM to 5:00 PM (EST) by calling toll-free at 1-800-237-6999. You can speak directly with our educational support personnel to request course materials, have tests graded, receive interactive training and interpretation of course materials, request duplicate certificates and resolve problems.

EMAIL MAIL PHONE/FAX [email protected] 1015 Atlantic Blvd #301 P: 1-800-237-6999 Jacksonville, FL 32233 F: 1-800-647-1356

“I’ve been using InforMed to satisfy my “The course is 100% relevant to my “Open access to all the course materials CME for over 15 years. They provide practice. InforMed offers real life make it convenient and easy for me to first-rate content at an unbeatable cost.” scenarios that I can apply to my daily satisfy my CME requirements.” performance.” - Ashley Holmstead - Joseph Alasi - Christina Gomez

OPEN CME EDUCATION FOR THE FUTURE

OPEN ACCESS SELF-PACED Enjoy free access to all course materials. Our content is available on demand Whether you’re at home or on the go, all for your convenience and can be course materials are readily available. completed entirely at your own pace.

TARGETED SERIES Our CME is geared towards helping you VERIFIED CERTIFICATE Claim & Receive a verified certificate advance your professional career while upon successful course completion. focusing on refining your practice. 1015 Atlantic Blvd #301 | Jacksonville, FL 32233 2021 CALIFORNIA MEDICAL LICENSURE PROGRAM SATISFIES 12 CREDITS OF CME IN PAIN MANAGEMENT AND THE APPROPRIATE TREATMENT OF THE TERMINALLY ILL

PROGRAM INCLUDES:

12CREDITS PAIN MANAGEMENT AND APPROPRIATE TREATMENT OF TERMINALLY ILL

CALIFORNIA PHYSICIANS MANDATORY CME REQUIREMENT: Must complete one-time requirement within the minimum established time period.