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Primary Care Management in Pennsylvania: Optimizing Treatment, Minimizing Risk

PRACTICAL CONSIDERATIONS IN SELECTION FOR CHRONIC NONCANCER PAIN

MARY LYNN MCPHERSON, PHARMD, MA, BCPS, CPE

UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY

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LEARNING OBJECTIVES

1. Given an actual or simulated patient with chronic noncancer pain, demonstrate consideration of patient- and -related variables in selecting . 2. Demonstrate competence in basic opioid conversion calculations and opioid dosage titration. 3. Given an actual or simulated patient with chronic noncancer pain, recommend appropriate coanalgesic. WHAT IS PAIN?

¡ “Total” Pain (Dame Cicely Saunders) ¡ Physical (due to disease or treatments) ¡ Psychological (anger, fear of , , past experience of illness) ¡ Social (loss of role, status, job; financial concerns, worries about future/ family, dependency) ¡ Spiritual (anger, loss of faith, finding meaning, fear of the unknown ¡ An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP). ¡ “Pain is whatever the person experiencing it says it is” (McCaffery). www.iasp-pain.org/AM/Template.cfm?Secon=Home&Template=/CM/ContentDisplay.cfm&ContentID=8705 PATHOGENESIS OF PAIN

Pain

Nocicepve Neuropathic

Central or Visceral c Peripheral Type of pain How patient’s describe it Analgesics Nociceptive • May be sharp or dull, often aching in nature Responds well to somatic pain • Familiar pain (e.g., ) primary analgesics • May be exacerbated by movement (incident pain) such as NSAIDs • Well localized and consistent with underlying lesion and • Examples include metastatic pain, postsurgical pain, musculoskeletal pain, arthritis pain

Nociceptive • Arises from distention of a hollow organ Responds well to • Usually poorly localized, deep, squeezing and crampy primary analgesics • Often associated with autonomic sensations such as , such as opioids, , diaphoresis possibly non- • May be referred (heart pain to shoulder or jaw; gallbladder opioids. pain to scapula; pain to back) • Examples include pancreatic cancer, intestinal obstruction, intraperitoneal metastasis

Neuropathic • Patient struggle to describe it; it’s unfamiliar Adjuvant agents pain • They use words such as burning, electrical, numb such as • Innocuous stimuli may bring on pain () , • Patients may complain of paroxysms of electrical sensation (lancinating or lightning ) are primary • Examples include trigeminal , postherpetic intervention. neuralgia, painful WHO Pain Relief Ladder (1996)

hp://www.who.int/cancer/palliave/painladder/en/ • Non-opioid Analgesics

• Adjuvant Analgesics

• Opioid Analgesics ACETAMINOPHEN

¡ Other names – , APAP, ¡ APAP (N-acetyl-para-aminophenol) ¡ Analgesic, ¡ Widely available in US ¡ Legend prescription combinations – 228 ¡ OTC monotherapy and combinations – > 60 ¡ 31,580 individual NDC codes for mono and combo prescription and OTC products ¡ 28 billion doses purchased yearly in US ¡ Single ingredient OTC 8 billion doses ¡ Combination OTC 9.7 billion doses ¡ Acetaminophen / opioid combos 11 billion doses

Retrieved from National Drug Code Directory database: (http://www.fda.gov/Drugs/InformationOnDrugs/ucm142438.htm) IMS Health, IMS National Sales Perspectives™, Year 2005, Extracted 9/06. ACETAMINOPHEN MECHANISM OF ACTION

¡ Active metabolite of ¡ Not clearly understood; centrally active ¡ Weak COX-1 and COX-2 inhibitor ¡ Equivalent to ASA as an analgesic and antipyretic agent ¡ Lacks anti-inflammatory properties ¡ Does not affect uric acid levels ¡ Does not inhibit function ¡ Role in ¡ Minimal role in OA of knees; no role in low

Smith HS. Potenal analgesic mechanisms of acetaminophen. Pain Physician; 2009;12:269-280. ¡ Hepatotoxicity ¡ Skin reactions ¡ Drug-Drug ¡ Age-related metabolic changes ¡ Pregnancy ¡ Asthma LET’S PUT YOU TO WORK!

¡ Mr. Smith is a 74 year old man who presents in your pharmacy requesting assistance purchasing a product for his newly diagnosed of the knees. ¡ His physician suggested he start acetaminophen. ¡ During the conversation it comes up that Mr. Smith drinks 3-4 beers per day, and occasionally has a shot of whiskey for good luck (once or twice a week), and he has liver impairment. ¡ Under what circumstances would you be comfortable recommending acetaminophen for this patient? A. If he stops the whiskey shots once or twice a week B. If he reduces the beer consumption to no more than 2 a day C. If he “pinky swears” he will never drink again D. You would not recommend acetaminophen at this time NONSTEROIDAL ANTI-INFLAMMATORY (NSAIDS) AGENTS

• * ¡ • Indomethacin ¡ Analgesic Antipyretic • ¡ Anti-inflammatory • ¡ *** Antiplatelet • ** ¡ • Meclofenamate ¡ • ¡ • Nambumetone ¡ • ¡ *** www.online.factsandcomparisons.com *Available as topical; **COX-2 selective; ***Available as injectable NSAID TOXICITY

¡ Gastrointestinal ¡ Perforation, ulcers, bleeding ¡ Cardiovascular/cerebrovascular ¡ MI, heart failure, CVA ¡ Renal adverse effects ¡ Decreased GFR, progression of CKD ¡ Other adverse effects • Non-opioid Analgesics

• Adjuvant Analgesics

• Opioid Analgesics WHO’S UP FOR AN ADJUVANT ANALGESIC?

Adjuvant

hp://www.who.int/cancer/palliave/painladder/en/ WHAT IS AN ADJUVANT?

¡ What is an adjuvant? ¡ “Serving to help or assist; auxiliary.” ¡ “Serving to aid or contribute.” ¡ What is an adjuvant analgesic? ¡ “Drugs with a primary indication other than pain that have analgesic properties in some painful conditions.” ¡ “ whose primary indication is the treatment of a medical condition, with secondary effects of analgesia.” ¡ Also referred to as “co-analgesics” www.ask.com; www.merriam-webster.com; hp://theoncologist.alphamedpress.org/content/9/5/571.full Am J Hospice Pall Med 2012:29(1):70-79 ADJUVANT ANALGESICS

• Mulpurpose Analgesics • An, CCS, NSAIDs, α-2 adrenergic agonists, neurolepcs

• Adjuvants for • Anconvulsants, Na+ channel blockers, NMDA antagonists,

• Topical Analgesics • , local anesthecs, NSAIDs

• Adjuvants for • CCS, NSAIDs, calcitonin/, Radiopharmaceucals

• Other • Adjuvants for bowel obstrucon, musculoskeletal pain

Portenoy, Ahmed. hp://www.futuremedicine.com/doi/abs/10.2217/ebo.11.340 HOLD THE PHONE!

¡ Which of the following antidepressants is LEAST likely to provide pain relief? A. B. (Cymbalta) C. Sertraline (Zoloft) D. (Effexor) PRINCIPLES OF ADJUVANT ANALGESIC USE

¡ Assess complaint of pain, determine relationship to underlying disease, consider comorbidities ¡ Depression? ¡ Avoid initiating several adjuvant analgesics concurrently ¡ Initiate treatment with low doses and titrate gradually according to analgesic response and ¡ Select adjuvant analgesics based on knowledge of , evidence base, with other drugs, and potential adverse effects

Portenoy, Ahmed. hp://www.futuremedicine.com/doi/abs/10.2217/ebo.11.340 PRINCIPLES OF ADJUVANT ANALGESIC USE

¡ General principles of adjuvant analgesic use: ¡ Multiple pathways of pain transmission provide multiple targets of pain relief ¡ Use specific adjuvant for specific condition ¡ Titrate only one drug at a time ¡ May take several days-weeks to notice improvement in pain ¡ Adjuvants usually do not provide full pain relief ¡ Educate patients about trial-and-error nature of adjuvant use ¡ Select rational combinations of analgesics/adjuvant analgesics

Portenoy, Ahmed. hp://www.futuremedicine.com/doi/abs/10.2217/ebo.11.340 • Non-opioid Analgesics

• Adjuvant Analgesics

• Opioid Analgesics WHO LET THE OPIOIDS OUT?

Opioids

hp://www.who.int/cancer/palliave/painladder/en/ OPIOID CATEGORIES

Category Examples Phenanthrenes • • • • • • • • • • • Phenylpiperidines • , , • Meperidine Diphenylheptanes • • (Propoxyphene) – off market

Pain Physician 2008;11:S133-S153. ATYPICAL OPIOIDS

¡ and ¡ Indicated for the management of moderate to severe acute or ¡ Tramadol: Weak mu opioid agonist, increases serotonin and norepinephrine levels ¡ Tapentadol: Mu opioid agonist and primarily inhibits reuptake of norepinephrine OPIOID INDICATIONS AND USES

¡ Analgesia ¡ Moderate to severe pain ¡ ¡ Cough ¡ Detoxification ¡ ¡ Dyspnea OPIOIDS FOR

¡ Are all painful conditions amenable to opioid treatment? ¡ Consider benefits and burdens of therapy ¡ If an opioid is appropriate, should it be monotherapy? Which opioid? When should an adjuvant be used? ¡ If an opioid is appropriate, should a tamper-resistant formulation be used? ¡ If the patient doesn’t respond to the first opioid, or has an adverse outcome, should we switch to a different opioid? ¡ Are there special considerations when switching to methadone? ¡ What is the role for adjuvant analgesics? ORAL MORPHINE FOR

¡ Effectiveness of oral morphine in treating moderate to severe cancer pain. ¡ 62 studies with 4241 participants ¡ > 9/10 had pain that went from moderate or severe before taking morphine to pain that was < mild pain ¡ > 6/10 were very satisfied with morphine treatment; results very good or excellent ¡ 1 in 20 DC’ed therapy due to side effects (N, V, C)

Wiffen PJ, Wee B, Moore RA. Oral morphine for cancer pain. Cochrane Database of Systemac Reviews 2013, Issue 7. Art. No.: CD003868. DOI: 10.1002/14651858.CD003868.pub3. OPIOIDS IN CHRONIC NON- CANCER PAIN?

¡ Unl laer part of the 1990’s, long-term opioid therapy for CNCP was prohibited in most US states. ¡ Data on long-term safety emerged; advocacy groups lobbied to li the relave prohibion on opioid use in CNCP

Franklin GM. AAN; 2014; 83(14):1277-1284. OPIOIDS IN CHRONIC NON- CANCER PAIN?

¡ Data on efficacy for opioid use in CNCP lacking ¡ Increasing mortality from accidental poisoning, concomitant with dramacally increasing average daily morphine equivalent doses developed quickly

Franklin GM. AAN; Neurology, 2014; 83(14):1277-1284. AHQR

¡ The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain ¡ “Evidence on long-term opioid therapy for chronic pain is very limited but suggests an increased risk of serious harms that appears to be dose-dependent. More research is needed to understand long-term benefits, risk of abuse and related outcomes, and effectiveness of different opioid prescribing methods and risk mitigation strategies.” hp://www.ahrq.gov/research/findings/evidence-based-reports/opoidstp.html OPIOID RESPONSIVENESS

¡ Pseudo-resistant ¡ Opioid-resistant pain ¡ Dose too low, patient not ¡ Some neuropathic pain, muscle absorbing opioid, genetic variation ¡ Chronic visceral or central pain ¡ Semi-opioid resistant pain syndromes ¡ Bone metastases, some ¡ Abdominal or ; neuropathic pain, activity- pancreatic pain related (some musculoskeletal ¡ pain) ¡ ¡ Skin ulceration, bladder and ¡ Chronic rectal tenesmus

http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_215.htm; Am Fam Phys 2012;86(3):252-258. AMERICAN ACADEMY OF NEUROLOGY

! Opioids for chronic noncancer pain: A position paper of the American Academy of Neurology ¡ Franklin GM. Neurology 2014; 83(14):1277-1284. ¡ Opioids are not recommended for treating: ¡ Tension-type headaches ¡ Fibromyalgia ¡ Chronic low back pain I SCREAM, YOU SCREAM, WE ALL SCREAM FOR MORPHINE!

¡ For which patient populations have opioids been shown to be consistently, conclusively effective? A. Cancer pain B. Non-cancer pain C. Both A and B D. Neither A nor B WHICH OPIOID?

¡ Eenie-Meenie Miney Mo’phine: Why morphine isn’t ALWAYS the answer to cancer pain.”

hp://www.greekmyths-greekmythology.com/morpheus-the-god-of-dreams/ FIRST LINE OPIOIDS

¡ Morphine ¡ Oxycodone ¡ Hydromorphone ¡ Methadone ¡ Buprenorphine ¡ Fentanyl

So what? Pick any opioid?

Pain Pract 2008;8:287-313. CONSIDERATIONS IN OPIOID SELECTION?

¡ Patient-related variables ¡ Assessment information about patient’s pain complaint ¡ Specific information about the patient’s pre-existing conditions that may alter the expected dosing and effects (both therapeutic and toxic) prior to selection of pharmacotherapy

History of codeine allergy? CONSIDERATIONS IN OPIOID SELECTION?

¡ Agent/Drug-related variables ¡ Characteristic properties of a that affects it use in a given situation, including pharmacodynamic and pharmacokinetic parameters, dosage formulations or routes of administration, adverse effects, and costs (cost of medication, administration and ).

Cross-allergenicity with codeine? YOU BE THE JUDGE…

¡ You are seeing Mr. Stockton in your primary care clinic for chronic non-cancer pain. You have exhausted all therapeutic options and now mention morphine. ¡ “No way,” she responds. “That’s for cancer patients! I don’t have cancer!” ¡ What kind of variable is this? ¡ A. Patient related variable ¡ B. Agent related variable MORPHINE

¡ Agonist at mu and kappa opioid receptors ¡ Metabolized in the liver to morphine-3-glucuronide (M3G, 55%) and morphine-6-glucuronide (M6G, 10%). 10% eliminated unchanged. ¡ Both pharmacologically active ¡ M6G analgesic; both can cause toxicity ¡ Accumulated in renal impairment and may cause toxicity ¡ Reduce dose/avoid in renal impairment ¡ Use cautiously with hepatic impairment ¡ Oral morphine may become more bioavailable ¡ May require increase in dosing interval ¡ Available as: ¡ SA tablets, capsules, oral solution, oral intensol ¡ LA tablets, capsules; Rectal suppositories; Injectable formulation BUPRENORPHINE

¡ at the mu , antagonist at the kappa opioid receptor ¡ Metabolized to norbuprenorphine (weak mu agonist) and buprenorphine-3-glucuronide ¡ No dosage adjustment needed in renal impairment/failure or mild to moderate hepatic impairment (Not evaluated in severe hepatic impairment) ¡ Available as sublingual tablets and injection ¡ SL tablets with and without naloxone ¡ Available as transdermal formulation ¡ 5 mcg/hour, 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, 20 mcg/hour ¡ May be started in opioid-naïve patients FENTANYL

¡ Agonist at the mu opioid receptor ¡ Metabolized by the liver to inactive metabolites; little parent drug excreted unchanged ¡ Bolus doses require no dosage adjustment ¡ Continuous infusion and transdermal fentanyl (TDF) doses should be reduced in severe renal impairment ¡ Avoid TDF in severe hepatic disease, , cachexia ¡ Available as injectable, transmucosal, intranasal and transdermal formulations ¡ All but injectable may ONLY be used in opioid-tolerant patients ¡ Oral morphine > 60 mg/day for > 7 days or equivalent opioid ¡ Fentanyl is approximately 100 times more potent than morphine HYDROMORPHONE

¡ Agonist at the mu and kappa opioid receptors ¡ Metabolized in the liver to hydromorphone-3-glucuronide, which is pharmacologically active ¡ Moderate to severe renal failure increases hydromorphone area under the curve and half-life of elimination 2-4 fold, respectively ¡ Reduce dose or avoid in renal impairment ¡ Use cautiously with hepatic impairment ¡ Oral hydromorphone may become more bioavailable with severe hepatic impairment ¡ May require longer dosing interval ¡ Available as oral tablets, long-acting tablets, oral solution, injectable formulation and rectal suppository METHADONE

¡ Agonist at the mu receptor, antagonist at the N-methyl-D-aspartate receptor (NMDA) ¡ Metabolized to inactive metabolites ¡ No dosage adjustment is needed in renal impairment but use caution with end-stage renal disease ¡ Half-life may be prolonged with hepatic impairment; allow extra time to achieve steady-stage and dose with caution ¡ Available as oral tablets, oral solution, concentrated oral solution and injectable formulation ¡ Caution when switching from other opioids to methadone ¡ Allow 4-7 days or longer to achieve steady state; do not adjust dose before OXYCODONE

¡ Agonist at the mu opioid receptor ¡ Metabolized in the liver to ¡ Threefold greater affinity for mu receptor than oxycodone but poorly penetrates CNS ¡ Oxymorphone ¡ Ten percent of oxycodone excreted unchanged ¡ Parent drug and active metabolites accumulate with renal impairment ¡ Use with caution and at lower doses • Consider SA formulations in hepatic impairment • Available as SA tablets, capsules, oral solution, oral intensol, long-acting tablet ¡ Frequently given in combination with acetaminophen (e.g., Percocet), and to a lesser extent with (e.g., Percodan) PATIENT-RELATED VARIABLES

¡ Age, ethnicity, body habitus ¡ Opioid-use history (naïve, tolerant?) ¡ Ability to use/manipulate dosage formulation ¡ Renal and hepatic function ¡ History of opioid responsiveness in past (therapeutic or toxic; allergic) ¡ Patient’s lifestyle and dosing interval considerations ¡ Patient health care beliefs, cognitive status ¡ Patient febrile, pregnant, breast-feeding ¡ History of , medical conditions worsened by opioid adverse effects

OPIOID-INDUCED ADVERSE EFFECTS

¡ Gastrointestinal adverse effects ¡ Nausea and vomiting ¡ ¡ CNS adverse effects ¡ Sedation, mental clouding, impaired psychomotor function ¡ Cardiorespiratory ¡ Cardiac effects of opioids (methadone, buprenorphine??) ¡ Respiratory depression ¡ Other adverse effects (pruritus, immunologic effects, hormonal change, , bladder dysfunction)

Benyamin R et al. Pain Physician 2008;11:S105-S120. Swegle JM et al. Am Fam Physician 2006;74:1347-1354 REASONS FOR CHANGING OPIOIDS

¡ Lack of therapeutic response ¡ Development of adverse effects ¡ Change in patient status ¡ Other considerations ¡ Opioid/formulation availability ¡ Formulary issues ¡ Patient/family health care beliefs ¡ , substitution, switching ¡ Opioid Conversion Calculations! OPIOID DOSING

Equianalgesic Doses (mg) Drug Parenteral Oral Morphine 10 30 Buprenorphine 0.3 0.4 (sl) Codeine 100 200 Fentanyl 0.2-0.3 NA Hydrocodone NA 30 Hydromorphone 1.5 7.5 Meperidine 100 300 Oxycodone 10* 20 Oxymorphone 1 10 Tramadol 100* 120 *Not available Adapted from: McPherson ML. in the US Demysfying Opioid Conversion Calculaons: A Guide For Effecve Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2010. Copyright ASHP, 2010. Used with permission. NOTE: Learner is STRONGLY encouraged to access original work to review all caveats and explanaons pertaining to this chart. 5-STEP OCC PROCESS

1. Globally assess pain complaint (PQRSTU) 2. Determine TDD current opioid (LA and SA) 3. Decide which opioid analgesic will be used for the new agent and consult established conversion tables to determine new dose 4. Individualize dosage based on assessment information gathered in Step 1 5. Patient follow-up and continual reassessment (7-14 days)

Gammaitoni AR, et al. Clinical J Pain 2003;19:286-297 SETTING UP THE CONVERSION EQUATION

“x” mg new opioid/route = equivalent mg new opioid/route mg of current opioid/route equivalent mg current opioid/route

“x” mg oral oxycodone = 20 mg oral oxycodone 135 mg oral morphine 30 mg oral morphine

(x)(30) = (20)(135) X = 90 mg oral oxycodone per day

SOLVING THE EQUATION

¡ Individualize dose for patient ¡ Pain controlled; developed adverse effect; reduce 25-50% ¡ Calculated oxycodone 90 mg po qd ¡ Reduce to 45-65 mg oxycodone po qd ¡ Decide how many times per day you’re going to dose the new opioid; divided by the appropriate dosing interval, and select a dosage that is available in that strength. ¡ SA oxycodone 10 mg po q4h ¡ LA oxycodone 20 mg po q12h

PUTTING IT ALL TOGETHER…

Topiramate, , Beydoun A, Backonja MM. Journal of Pain Symptom Management 2003;25(5S):S18-S30. MORPHINE, , OR BOTH

¡ 41 paents with Group Pain Rating (0-10) neuropathic pain Baseline 5.72 randomized to four 4.49 groups (x 5 weeks) SR morphine 4.15 ¡ SR morphine Gabapentin 4.15 ¡ Gabapenn MS + Gabapentin 3.06 ¡ SR morphine + • Morphine + gabapenn doses were gabapenn lower than the morphine or gabapenn arms, with beer pain ¡ Placebo () relief.

• Combinaon treatment had more NEJM 2005;352:1324-1334 conspaon and dry mouth. USING OPIOIDS SAFELY IN CNCP

Opioid Responsive Pain / Minimize Use

Minimize Dose / Combination Therapy

Stay Safe (Corresponding Responsibility)

Show Functional Improvement

Exit Strategy POINTS TO TAKE HOME…

¡ Evaluate the utility of non-opioids (risks and benefits; acetaminophen and NSAIDs) ¡ Maximize the use of lifestyle modification for chronic non-cancer pain ¡ Maximize the use of adjuvant analgesics and other non-pharmacologic interventions ¡ Carefully consider the appropriateness of starting or continuing an opioid ¡ Monitor pain ratings, and more importantly, functional status ¡ Begin any pain management regimen with the end in mind (develop an exit strategy). SAVE THE DATE : PART II COMING SOON

¡ Wednesday, November 11, 2015 Noon to 1pm ¡ Part II: Case Studies and Practical Prescribing Information for Pain Management ¡ Remember to work on the Homework Cases prior to webinar. ¡ Submit any cases that you would like discuss with Dr. McPherson by Friday, November 6, 2015. ¡ Email cases to patricia,[email protected] ¡ You will receive an email with a link to the CME Post-test. REQUIRED FOR CME CREDIT for today’s webinar. Questions