Pain Physician. 2006;9:1-40, ISSN 1533-3159 Opioid Guidelines

Opioid Guidelines in the Management of Chronic Non-Cancer Pain

Andrea M. Trescot, MD, Mark V. Boswell, MD, Sairam L. Atluri, MD, Hans C. Hansen, MD, Timothy R. Deer, MD, Salahadin Abdi, MD, Joseph F. Jasper, MD, Vijay Singh, MD, Arthur E. Jordan, MD, Benjamin W. Johnson, MD, Roger S. Cicala, MD, Elmer E. Dunbar, MD, Standiford Helm II, MD, Kenneth G. Varley, MD, P.K. Suchdev, MD, John R. Swicegood, MD, Aaron K. Calodney, MD, Bentley A. Ogoke, MD, W. Stephen Minore, MD, and Laxmaiah Manchikanti, MD

Background: Opioid abuse has in- lation of the essentials of guidelines, a series analysis of the literature, the authors uti- creased at an alarming rate. However, avail- of potential evidence linkages representing lized two systematic reviews, two narrative re- able evidence suggests a wide variance in conclusions, followed by statements regard- views, 32 studies included in prior systematic the use of opioids, as documented by differ- ing relationships between clinical interven- reviews, and 10 additional studies in the syn- ent medical specialties, medical boards, ad- tions and outcomes. thesis of evidence. The evidence was limited. vocacy groups, and the Drug Enforcement Methods: Consistent with the Agency Conclusion: These guidelines evaluat- Administration (DEA). for Healthcare Research and Quality (AHRQ) ed the evidence for the use of opioids in the Objectives: The objective of these opi- hierarchical and comprehensive standards, management of chronic non-cancer pain and oid guidelines by the American Society of In- the elements of the guideline preparation recommendations for management. These terventional Pain Physicians (ASIPP) is to pro- process included literature searches, litera- guidelines are based on the best available vide guidance for the use of opioids for the ture synthesis, systematic review, consen- scientifi c evidence and do not constitute in- treatment of chronic non-cancer pain, to bring sus evaluation, open forum presentations, fl exible treatment recommendations. Be- consistency in opioid philosophy among the formal endorsement by the Board of Direc- cause of the changing body of evidence, this many diverse groups involved, to improve the tors of the American Society of Intervention- document is not intended to be a “standard treatment of chronic non-cancer pain, and to al Pain Physicians (ASIPP), and blinded peer of care.” reduce the incidence of drug diversion. review. Evidence was designated based on Key Words: Chronic pain, persistent Design: A policy committee evaluated a scientifi c merit as Level I (conclusive), Level pain, controlled substances, substance systematic review of the available literature II (strong), Level III (moderate), Level IV (lim- abuse, dependency, prescription account- regarding opioid use in managing chronic ited), or Level V (indeterminate). ability, opioids, prescription monitoring, di- non-cancer pain. This resulted in the formu- Results: After an extensive review and version, guidelines

CONTENTS 2.0 CHRONIC PAIN 3.7 Drug Diversion 2.1 Defi nitions 3.8 Controlling Diversion and Abuse 1.0 INTRODUCTION 2.2 Prevalence 3.8.1 Drug Enforcement 1.1 Purpose 2.3 Chronicity Administration (DEA) 1.2 Rationale and Importance 2.4 Health and Economic Impact 3.8.2 State Laws and Regulations 1.3 Objectives and Benefi ts 3.8.3 Prescription Drug Monitoring 1.4 Population and Preferences 3.0 OPIOIDS IN CHRONIC PAIN Programs 1.5 Implementation and Review 3.1 General Considerations 1.6 Application 3.2 Response to Undertreatment 4.0 PHARMACOLOGICAL CONSIDERATIONS 1.7 Focus 3.3 Opioid Use in Chronic Pain 4.1 Opioid Pharmacology 1.8 Methodology 3.4 Non-Medical Use of Prescription 4.1.1 Opioid Receptors Drugs 4.1.2 Opioid Categories 3.4.1 Center on Addiction and 4.1.3 Opioid Metabolism From: American Society of Interventional Pain Phy- 4.2 Pharmacology of Specifi c Opioids sicians, Paducah, KY Substance Abuse (CASA) Address Correspondence: Findings 4.2.1 Laxmaiah Manchikanti, MD 3.4.2 Physician Survey Highlights 4.2.2 Chief Executive Offi cer, ASIPP 3.4.3 Pharmacist Survey Highlights 4.2.3 81 Lakeview Drive, Paducah, KY 42001 3.4.4 Substance Abuse and 4.2.4 E-mail: [email protected] Mental Health Services 4.2.5 Disclaimer: There was no external funding in the Administration (SAMHSA) 4.2.6 preparation of this manuscript. Survey 4.2.7 Confl ict of Interest: None 3.4.5 Drug Abuse Warning Network 4.2.8 Funding: Internal funding was provided by the (DAWN) Reports 4.2.9 Meperidine American Society of Interventional Pain Physicians 3.5 Substance Abuse in Chronic Pain 4.2.10 and was limited to travel and lodging expenses for 3.6 Economic Impact 4.2.11 Propoxyphene the authors. 4.2.12 2 Trescot et al • Opioid Guidelines

4.3 Adverse Effects 6.0 CLINICAL EFFECTIVENESS 8.0 PRINCIPLES OF OPIOID USAGE 4.4 Drug Interactions 6.1 Introduction 8.1 Introduction 4.5 Drug Conversions 6.2 Systematic Reviews 8.2 Basic Philosophy 4.6 Opioid Therapy and Side Effects 6.3 Other Controlled Trials 8.3 Evaluation 4.6.1 Long-term opioid therapy 6.4 Infl uence of Psychopathology on 8.3.1 History 4.6.2 Opioid Induced Immunologic Opioid Effectiveness 8.3.2 Effect on Functional Status Effects 6.5 Summary of Evidence 8.3.3 Drug History 4.6.3 Opioid Induced Hormonal 8.4 Physical Examination 7.0 ADHERENCE MONITORING Changes 8.5 Laboratory Studies 7.1 Introduction 4.6.4 Opioid Induced Hyperalgesia 8.6 Psychological Evaluation 7.2 Screening for Opioid Abuse 4.6.5 Psychomotor Performance In 8.7 Medical Decision Making and 7.3 Urine Drug Testing Opioid Therapy Treatment Plan 7.4 Periodic Review and Monitoring 4.6.6 Breakthrough Pain 8.8 Consultation Management 7.4.1 Periodic Review 8.9 Informed Consent and Controlled 7.4.2 Periodic Monitoring Substance Agreement 5.0 TERMINOLOGY OF ABUSE AND ADDICTION 7.4.3 Prescription Drug Monitoring 5.1 Introduction 9.0 DOCUMENTATION AND MEDICAL RECORDS 7.4.4 Periodic Education 5.2 History 7.4.5 Pill Counts 10.0 KEY POINTS

dently or in conjunction with other mo- essary management. This management 1.0 INTRODUCTION dalities of treatments. Multidisciplinary may include, or be independent of, inter- or comprehensive pain management dif- ventional techniques. 1.1 Purpose fers among specialties and may elicit con- Guidelines for the use of opioids in fusion. An interventionalist perceives 1.5 Implementation and Review the treatment of chronic non-cancer pain comprehensive treatment programs as The dates for implementation and are statements developed by the Ameri- programs with interventional techniques review were established: can Society of Interventional Pain Physi- as the primary treatment modality, with ♦ Effective date – February 1, 2006 cians (ASIPP) to improve quality and ap- physical therapy, medical therapy, and ♦ Scheduled review − July 1, 2007 ♦ propriateness of care, improve patient ac- psychological management as supple- Expiration date – January 31, 2008 cess, improve patient quality of life, im- mentary. prove efficiency and effectiveness, min- 1.6 Application imize abuse and diversion, and achieve 1.3 Objectives and Benefi ts These guidelines are primarily in- cost containment by improving the cost- The objectives of these guidelines are tended for use by interventional pain phy- benefit ratio. to bring consistency in opioid prescrib- sicians. Others managing chronic pain ing to the many diverse groups involved; patients with opioids may also find these 1.2 Rationale and Importance to provide analysis of evidence to treat a guidelines useful. Available evidence documents a wide chronic pain patient with opioids, thus, These guidelines do not constitute degree of variance in the prescribing pat- maintaining reasonable patient access inflexible treatment recommendations. It terns of physicians in regard to opioids while reducing the risk of drug diversion; is expected that a provider will establish a for chronic pain, as suggested by differ- to provide practical prescribing guidelines plan of care on a case-by-case basis, taking ent specialties, medical boards, advocacy for physicians to reduce the risk of legal into account an individual patient’s medi- groups, and the Drug Enforcement Ad- and regulatory sanctions; and to empha- cal condition, personal needs, and prefer- ministration (DEA). size the need for systematic evaluation ences, as well as the physician’s experience. Opioids are commonly used in man- and ongoing care of patients with chronic Based on an individual patient’s needs, aging chronic non-cancer pain, even or persistent pain. treatment different from that outlined though this practice is controversial (1- The perceived benefits of these here could be warranted. These guidelines 3). However, documented abuse of opi- guidelines include: do not represent a “standard of care.” oids is increasing at an alarming rate (4- ♦ Improved patient compliance 11). While speaking at ASIPP’s 2004 an- ♦ Improved patient care with appropriate 1.7 Focus nual meeting in Washington, DC, Patricia medical management These guidelines focus on the effec- Good of the DEA’s Drug Diversion Con- ♦ Reduced misconceptions among tive management of chronic non-cancer trol division, stated that the United States, providers and patients about opioids pain as well as the multiple issues related to ♦ with 4.6% of the world’s population, uses Improved ability to manage patient opioid administration. It is recognized that expectations management of chronic non-cancer pain 80% of the world’s opioids. ♦ Reduced abuse and diversion Interventional pain management, as ♦ Improved cooperation among patients, takes place in a wide context of healthcare defined by the National Uniform Claims providers, and regulatory agencies. involving multiple specialists and multiple Committee (NUCC), is the discipline of techniques. Consequently, the decision to medicine devoted to the diagnosis and 1.4 Population and Preferences implement a particular management ap- treatment of pain and related disorders, The population covered by these proach should be based on a comprehen- with the application of interventional guidelines includes all patients suffering sive assessment of the patient’s overall techniques to manage subacute, chronic, with chronic non-cancer pain who may health status, disease state, patient prefer- persistent, and intractable pain, indepen- be eligible for appropriate, medically-nec- ence, and physician training and skill.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 3

1.8 Methodology ter the publication date of the systematic 2.0 CHRONIC PAIN In developing these guidelines, evi- reviews were evaluated. dence-based approaches were given the While an evidence-based approach 2.1 Defi nitions highest priority. If evidence-based ap- may seem to enhance the scientific rigor Chronic pain has numerous defi- proaches failed to give acceptable levels of of guideline development, recommenda- nitions. Consequently, a combination of information consensus, expert opinions tions may not always meet the highest sci- multiple definitions can be utilized (12): were utilized. These approaches are de- entific standards (13-15). Evidence-based ♦ Pain that persists beyond the usual scribed in separate publications (12-16). medicine is defined as the conscientious, course of an acute disease or a reason- A policy committee was convened explicit, and judicious use of current best able time for any injury to heal that is and included a broad representation of evidence in making decisions about the associated with chronic pathologic pro- academic and clinical practitioners rec- care of individual patients (16). cesses that cause continuous pain or ognized as experts in one or more as- In the preparation of these guide- pain at intervals for months or years ♦ pects of opioids, and representing a va- lines, it is recognized that at the core of Persistent pain that is not amenable to routine pain control methods riety of practices and geographic areas. an evidence-based approach to clinical or ♦ Pain where healing may never occur This committee formalized the essen- public health issues is, inevitably, the ev- Pain is a highly disagreeable sensa- tials of the guidelines. This was followed idence itself, which needs to be carefully tion that results from an extraordinarily by the formulation of a series of poten- gathered and collated from a systematic complex and interactive series of mecha- tial evidence linkages representing con- literature review of the particular issues. nisms integrated at all levels of the neur- clusions and statements about relation- Consequently, the process by which the axis, from the periphery to higher corti- ships between clinical interventions and strength of scientific evidence is evaluat- cal structures. outcomes. The elements of the guideline ed in the development of evidence-based preparation process included literature medicine recommendations and guide- 2.2 Prevalence searches, literature syntheses, systematic lines is crucial. The practice of evidence- The prevalence of chronic pain in the review, consensus evaluation, open forum based medicine requires the integration of adult population ranges from 2% to 40%, presentations, formal endorsement by the individual clinical expertise with the best with a median point prevalence of 15% ASIPP Board of Directors and blinded available clinical evidence from systemat- (12,20,21). Persistent pain was report- peer review. ic research. ed with an overall prevalence of 20% of In synthesizing the evidence, system- Systems for grading the strength of a primary care patients, with approximate- atic reviews, randomized clinical trials, body of evidence are much less uniform ly 48% reporting back pain (22). The lit- and observational studies were evaluat- and consistent than are those for rating erature also has consistently described the ed utilizing reporting criteria and quality study quality. Consequently, the guide- high prevalence of chronic pain in chil- evaluation criteria (13,14, 17-19). Details line committee designed levels of evi- dren and the elderly (23-28). In addition, of evidence synthesis are escribed in mul- dence from Level I through Level V, mod- chronic pain with involvement of multi- tiple publications (13,16,17). If the avail- ified from various publications (Table 1) ple regions is a common occurrence in able systematic reviews met the criteria of (13,17). over 60% of patients (24). inclusion, only those studies published af- 2.3 Chronicity Table 1. Designation of levels of evidence Duration of pain and its chronici- ty have been topics of controversy. Con- Level I Conclusive: Research-based evidence with multiple relevant and high-quality ventional beliefs are that most episodes scientifi c studies or consistent reviews of meta-analyses of low back pain will be short-lived, with 80% to 90% of attacks resolving in about Level II Strong: Research-based evidence from at least one properly designed random- ized, controlled trial; or research-based evidence from multiple properly de- 6 weeks irrespective of the administra- signed studies of smaller size; or multiple low quality trials. tion or type of treatment, and with 5% to 10% of patients developing persistent Level III Moderate: a) Evidence obtained from well-designed pseudorandomized con- back pain. However, this concept has been trolled trials (alternate allocation or some other method); b) evidence obtained questioned as the condition tends to re- from comparative studies with concurrent controls and allocation not random- lapse and most patients will experience ized (cohort studies, case-controlled studies, or interrupted time series with a control group); c) evidence obtained from comparative studies with historical recurrent episodes. Modern evidence control, two or more single-arm studies, or interrupted time series without a has shown that chronic persistent low parallel control group. back pain and neck pain in children and Level IV Limited: Evidence from well-designed nonexperimental studies from more than adults are seen in up to 60% of patients, one center or research group; or confl icting evidence with inconsistent fi ndings 5 years or longer after the initial episode in multiple trials (12,23,29-35). Level V Indeterminate: Opinions of respected authorities, based on clinical evidence, descriptive studies, or reports of expert committees. 2.4 Health and Economic Impact Chronic non-cancer pain is associ- Reproduced from Boswell et al (12) Interventional techniques in the management of chronic spinal ated with significant economic, societal, pain: Evidence-based practice guidelines; with permission from the authors and the American and health impact (36-49). The cost of Society of Interventional Pain Physicians. uncontrolled chronic pain is enormous

Pain Physician Vol. 9, No. 1, 2006 4 Trescot et al • Opioid Guidelines both, to individuals and to society as it Table 2. Retail sales of opioid medications (grams of medication) 1997-2002 leads to a decline in quality of life and dis- ability (39,41-49). Estimates and patterns 1997 2002 % change of direct healthcare expenditures among Morphine 5,922,872 10,264,264 73.3 individuals with back pain in the United States reached $90.7 billion for the year Hydrocodone 8,669,311 18,822,618 117.1 1998 (39). On average, individuals with back pain generate healthcare expendi- Oxycodone 4,449,562 22,376,891 402.9 tures about 60% higher than do individ- uals without back pain ($3,498 per year Methadone 518,737 2,649,559 410.8 versus $2,178). It was estimated that the cost of healthcare for patients with chron- ic pain might exceed the combined cost of veloped, even though none of them have claims for , with 68% of those treating patients with coronary artery dis- been developed using evidence-based claimants receiving an opioid (96). ease, cancer, and AIDS (45). In the Unit- medicine. Further, Medicaid patients were more ed States, it was estimated that the cost In 1998 and 2004, to alleviate physi- likely to receive prescription drugs, par- of treatment in the first year after failed cian uncertainty about opioid use and to ticularly opioids (73% Medicaid vs. 40% back surgery for pain was approximately encourage better pain control, the Feder- commercial insurance), for 30 days or $18,883 in 1997 (46). Even further, annual ation of State Medical Boards (FSMB) is- longer and to visit the emergency room healthcare cost incurred by chronic pain sued model guidelines or policies for the more frequently (97). Multiple other re- patients, excluding cost for surgical pro- use of controlled substances for the treat- ports (98-114) revealed widespread use cedures, may range from $500 to as high ment of pain (73). Over half of the state of opioids in the management of chron- as $35,400, with averages ranging from medical boards either adapted or modi- ic pain. Finally, the increasing retail sale of $12,900 to $18,883 annually (46,47). fied these guidelines and implemented opioid medications is the proof that opi- them in their states. In addition, based oids are used much more frequently (Ta- 3.0 OPIOIDS IN CHRONIC PAIN on the influence of advocacy groups, over ble 2). Retail sales of opioid medications one-third of the state legislatures have in- represented as grams of medication in- 3.1 General Considerations stituted intractable pain treatment acts creased significantly from 1997 to 2002 Considerable controversy exists that provide immunity from discipline for (106-108). Illicit drug use and dose esca- about the use of opioids for treatment of physicians who prescribe opioids within lations have been demonstrated in a simi- chronic pain of non-cancer origin. Inade- the requirements of the statute. Howev- lar proportion of patients on long-acting quate treatment of pain has been attribut- er, the guidelines, policies, and legislative and short-acting opioids (78,79). ed to a lack of knowledge about pain man- actions sometimes have been criticized as agement options, inadequate understand- having created new barriers to appropri- 3.4 Non-Medical Use of Prescription ing of addiction, or to fears of investiga- ate pain management. Drugs tion or sanction by federal, state, and local 3.4.1 Center on Addiction and Substance regulatory agencies (2,3,50-73). Many au- 3.3 Opioid Use in Chronic Pain Abuse (CASA) Findings thors contend that drug therapy with opi- In pain management settings, as Joseph A. Califano, Jr., Chairman and oid analgesics plays an important role in many as 90% of patients have been re- President of the National Center on Ad- pain management and should be avail- ported to receive opioids for chronic pain diction and Substance Abuse at Columbia able when needed for the treatment of all management (74-93). A prospective eval- University (CASA), in a July 2005 edito- kinds of pain, including non-cancer pain uation (74) showed that 90% of the pa- rial on the Diversion and Abuse of Con- (50,52-55,64-69). The DEA also took the tients were on opioids and 42% were on trolled Prescription Drugs in the United position that clinicians should be knowl- benzodiazepines prior to presenting to States (4) noted the following: edgeable about using opioids to treat pain, an interventional pain management cen- “While America has been congratu- and should not hesitate to prescribe them ter. Many of the patients also received lating itself in recent years on curbing in- when opioids are the best clinical choice more than one type of opioid, most com- creases in alcohol and illicit drug abuse of treatment (70). monly one for sustained release and one and in the decline in teen smoking, abuse for breakthrough pain. The frequency of and addiction of controlled prescription 3.2 Response to undertreatment overall opioid use among patients with drugs − opioids, central nervous system The alleged undertreatment of pain back pain was reported as approximately depressant and stimulants − have been as a major health problem in the United 12% (94). It was found that rheumatolo- stealthily, but sharply, rising. Between States led to the development of initiatives gists, family practitioners, and internists 1992 and 2003, while the U.S. popula- to address the multiple alleged barriers re- were much more likely to prescribe opi- tion increased 14%, the number of peo- sponsible for the undertreatment of pain oids for patients with chronic pain than ple abusing controlled prescription drugs (50). Patient advocacy groups and profes- were surgeons and neurologists (48,95). A jumped 94% − twice the increase in the sional organizations have been formed cross-sectional analysis of use by number of people abusing marijuana, five with a focus on improving the manage- patients with low back pain, showed that times in the number abusing cocaine and ment of pain (50). Consequently, numer- in 2001, 55.5% of insurance plan mem- 60 times the increase in the number abus- ous clinical guidelines also have been de- bers with low back pain had insurance ing . Controlled prescription drugs

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 5 like OxyContin®, Ritalin®, and Valium® Table 3. Past use of illicit drugs and illicit pain relievers among persons age 12 or are now the fourth most abused substanc- older; 2003 survey es in America behind only marijuana, al- cohol, and tobacco.” Number (Percentage) The CASA report (4) presented 12-17 18-25 >26 Total alarming statistics including a 212% in- years of age years of age years of age >=12 years crease from 1992 to 2003 in the number U.S. Population 24,995,000 31,728,000 180,958,000 237,682,000 of 12- to 17-year-olds abusing controlled prescription drugs, and the increasing 5,448,000.9 10,977,000.8 18,638,000.7 34,993,000 Any illicit drug number of teens trying these drugs for (21.8%) (34.6%) (10.3%) (14.7%) the first time. The report also illustrat- Non-medical ed that new abuse of prescription opioids use of any 2,229,000.5 4,600,000.6 8,143,000 14,986,000 among teens is up an astounding 542%, psychotherapeutic (9.2%) (14.5%) (4.5%) (6.3%) more than four times the rate of increase drug among adults. Furthermore, disturbing Non-medical use 1,924,000.6 3,807,000.4 5,971,000.6 11,671,000 statistics also show that teens who abuse of pain relievers (7.7%) (12.0%) (3.3%) (4.9%) opioids are likely to use other drugs in- Source: 2003 SAMHSA Survey (112) cluding alcohol, marijuana, heroin, ecsta- sy, and cocaine at rates respectively of 2, 5, term basis. HIPPA regulations have made rious problems. A study evaluating se- 12, 15, and 21 times that of teens who do this step much more diffi cult. vere dependence on oral opioids illus- not abuse such drugs. ♦ 74.1% have refrained from prescribing trated that the majority of patients with As per the CASA report (4), the bot- controlled drugs during the past 12 severe dependence (39%) obtained opi- months because of concern that a patient tom line is that the United States is in the oids by going to different physicians (11). might become addicted to them. throes of an epidemic of controlled pre- Another frequent form of obtaining opi- scription drug abuse and addiction with 3.4.3 Pharmacist Survey Highlights oids included “street” purchase by 26% 15.1 million people admitting to abusing A CASA survey of 1,303 pharmacists of the patients. This study also showed prescription drugs − more than the com- regarding diversion and abuse of con- that many patients used more than one bined number of those who admit abus- trolled prescription drugs showed the fol- method of acquiring the drugs. In eval- ing cocaine (5.9 million), hallucinogens (4 lowing: uating prescription opioid abuse in pa- ♦ million), inhalants (2.1 million), and her- When a patient presents a prescription for tients presenting for methadone mainte- oin (0.3 million). a controlled drug: nance treatment (10), at admission most • 78.4% of pharmacists become patients (83%) had been using prescrip- 3.4.2 Physician Survey Highlights “somewhat or very” concerned A CASA survey of 979 physicians re- about diversion or abuse when a tion opioids with or without heroin. This garding the diversion and abuse of con- patient asks for a controlled drug study showed that 24% had used prescrip- trolled prescription drugs showed the fol- by its brand name; tion opioids only, 24% used prescription • lowing: 26.5% “somewhat or very often” opioids initially and heroin later, 35% ♦ Physicians perceive the three main think it is for purposes of diversion used heroin first and prescription opi- mechanisms of diversion to be: or abuse. oids subsequently, and 17% had used her- ♦ • Doctor shopping (when patients 51.8% believe that patients account for oin only. Subjects reported regular use of the bulk of the diversion problem. obtain controlled drugs from prescription opioids at higher than ther- ♦ Only about half of the pharmacists multiple doctors) (96.4%) apeutic doses. In 2001, prescription drug • Patient deception or manipulation surveyed received any training in abuse and misuse was estimated to im- of doctors (87.8%) identifying prescription drug diversion • Forged or altered prescriptions (48.1%) or abuse or addiction (49.6%) pose approximately $100 billion annu- (69.4%). since pharmacy school. ally in health care costs (9,110,111). The ♦ ♦ 59.1% believe that patients account for 61% do not regularly ask if the patient is abuse of prescription medications has in- the bulk of the diversion problem. taking any other controlled drugs when creased steadily over the last 10 years, and ♦ 47.1% said that patients often try dispensing a controlled medication; every year more and more Americans try 25.8% rarely or never do so. to pressure them into prescribing a them for the first time. The abuse of con- ♦ 28.9% have experienced a theft or robbery controlled drug. trolled prescription drugs was foreshad- ♦ Only 19.1% of surveyed physicians of controlled drugs at their pharmacy owed by dramatic increases in their man- received any medical school training in within the last fi ve years; 20.9% do not identifying prescription drug diversion. stock certain controlled drugs in order to ufacture and distribution and the number ♦ Only 39.6% received any training in prevent diversion. of prescriptions written and filled (106- ♦ medical school in identifying prescription 28.4% do not regularly validate the 108). Between 1992 and 2002, while the drug abuse and addiction. prescribing physician’s DEA number population of the United States increased ♦ 43.3% of physicians do not ask about when dispensing controlled drugs; one in by 13% and the number of prescriptions 10 (10.5%) rarely or never do so. prescription drug abuse when taking a written for non-controlled drugs in- ♦ 83.1% have refused to dispense a patient’s health history. creased by 57%, the number of prescrip- ♦ 33% do not regularly call or obtain controlled drug in the past year because tions filled for controlled drugs increased records from the patient’s previous of suspicions of diversion or abuse. (or other treating) physician before Increasing abuse and diversion of by 154%. During this same period, there prescribing controlled drugs on a long- prescription drugs “on the street” are se- was a 90% increase (from 7.8 million to

Pain Physician Vol. 9, No. 1, 2006 6 Trescot et al • Opioid Guidelines

14.8 million) in the number of people by 42%. ther, it has been reported that 77.3% of who admitted abusing controlled pre- During the same time period, the suicide attempts involved benzodiaze- scription drugs (4). percentage of increase mentioned by the pines (114). 3.4.4 Substance Abuse and Mental Drug Abuse Warning Network (DAWN) Multiple investigators (81-85,116- Health Services Administration for prescription pain relievers has been 119) have shown a prevalence of drug (SAMHSA) Survey greater than the percentage of increase for abuse in 18% to 41% in patients receiv- The SAMHSA 2003 survey of drug marijuana, cocaine, and heroin. ing opioids for chronic pain. A study eval- abuse (112) revealed that 6.3% of the U.S. uating the prevalence, comorbidities and 3.5 Substance Abuse in Chronic Pain populace over 12 years of age (14,986,000 utilization of opioid abuse in a cohort of individuals) used psychotherapeutic drugs It has been reported that the princi- managed care patients with matched con- for non-medical purposes; of these, 4.9% ple drug of abuse for nearly 10% of youths trols showed that opioid abuse rose from of the U.S. population (11,671,000 indi- in drug treatment programs is a prescrip- 2000 to 2002 (105). The authors conclud- viduals) over 12 years of age used pain tion drug (115). In a comprehensive re- ed that opioid abuse was 6.7 per 10,000 relievers for non-medical purposes dur- view (80), between 3.2% and 18.9% of pa- patients in 2002. Opioid abusers also pre- ing the past year (Table 3, p 5). The num- tients were found to have been diagnosed sented with higher prevalence of opioid ber of individuals abusing pain medica- with a substance abuse disorder. In addi- prescriptions and comorbidities as com- tions for the first time grew from 628,000 tion, it was also concluded that diagnoses pared to controls. in 1990 to nearly 3 million in 2000 (Fig. 1). of abuse, drug dependency, and drug ad- Illicit drug use is also a common First-time use of stimulants and tranquiliz- diction occur in a significant proportion phenomenon in chronic pain patients. Ta- ers is also on the rise. Increases for specific of chronic pain patients. ble 4 illustrates the prevalence of prescrip- opioids are illustrated in Table 3, with the While opioids are by far the most tion drug abuse in a typical intervention- highest increase that of oxycodone at 345% abused drugs, other controlled sub- al pain management practice setting. Illic- (106-108). stances such as benzodiazepines, sedative it drug use without controlled substance hypnotics, and central nervous system abuse was found in 14% to 16% of pa- 3.4.5 Drug Abuse Warning Network stimulants, though described as having tients, and illicit drug use in patients with (DAWN) Reports less potential for abuse, are also of ma- controlled substance abuse was present in Drug-related emergency department jor concern to interventional pain spe- 34% of the patients (120,121). Based on visits also reveal that prescription drug cialists as they appear to be widely used their type of insurance, the prevalence of abuse is on the rise (Fig. 2) (107,108). for non-medical purposes as well (106- illicit drug use among individuals with From 1994 to 2002, mentions of pain 108,112). This is exemplified by the fact chronic pain was shown to be highest in medications during emergency depart- that benzodiazepine-related emergency patients on Medicaid (86) (Table 5). Oth- ment visits increased by 168%, while department visits increased from 71,609 ers (87,122) also showed significant illic- mentions of benzodiazepines increased in 1995 to 100,784 in 2002 (108). Fur- it drug use in patients with chronic non-

3,000

2,500 All Ages

2,000

1,500 Aged 18 or older

1,000

Aged under 18

500

0

1965 1907 1975 1980 1985 1990 1995 2000 Fig. 1. Annual numbers of new non-medical users of pain relievers: 1965-2002 Adapted from Ref. 112.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 7 malignant pain treated with opioids. Table 4. Prevalence of controlled prescription drug abuse in an interventional pain Overall use and abuse of opioids and practice other controlled substances in conjunc- tion with illicit drug use appears to be Total of 500 patients Proportion prevalent in pain management settings (86,87,120-124). Advocacy and unproven Grade ‘0’ – No abuse 444 72.2% Joint Commission standards may be lead- Grade I – Low grade abuse 47 9.4% ing to the overuse of opioids and subse- quent abuse. At the same time Americans Grade II – Moderate abuse – 3 or more physicians 30 6% continue to be dissatisfied with their pain – Receiving Schedule II drugs relief options. – Abusing Schedule II drugs

3.6 Economic Impact Grade III – High grade abuse– 12 2.4% In 1995, the Center on Addiction Traffi cking– Overdose and Substance Abuse (CASA) estimat- Total Abuse 89 17.8% ed the costs of substance abuse to feder- al entitlement programs and found that Modifi ed from Manchikanti et al (84)

Table 5. Prevalence of illicit drug use in an interventional pain practice

Group II Group III Group I Group IV (100) (100) (100) (100) P Value Medicare with or Medicare & Third party Medicaid without third party Medicaid Cocaine 7% 4% 6% 8% 0.684 95% CI 2% -12% 0% - 8% 1% - 11% 3% - 13% Marijuana (THC) 11% 8% 20%b 34%a,b,c 0.0000 95% CI 5% - 17% 3% - 13% 12% - 28% 25% - 43%

Methamphetamine/Amphetamine 3% 2% 4% 3% 0.876

95% CI 0% - 6% 0% - 5% 0% - 8% 0% - 6%

Total 17% 10% 24%b 39%a,b,c 0.0000

95% CI 10% - 24% 4% - 6% 16% - 32% 29% - 49%

Totals may not correlate as some patients were included in more than one category CI = Confi dence Interval a: Indicates signifi cant difference with Group I b: Indicates signifi cant difference with Group II c: Indicates signifi cant difference with Group IIII Adapted from Manchikanti et al (86)

108,320

Narcotic Analgesics Benzodiazepines 98,881 100,784 90,232 86,595 85,884 83,223 77,568 75,837 71,609 73,441 64,534

54,516 50,584

42,857 44,028

1995 1996 1997 1998 1999 2000 2001 2002 Fig. 2. Drug abuse related emergency department visits involving narcotic analgesics and benzodiazepines Adapted from Ref. 107, 108

Pain Physician Vol. 9, No. 1, 2006 8 Trescot et al • Opioid Guidelines health care and disability costs alone were ing from their relatives or buying from Soma have been implicated. Prescription $77.6 billion, representing nearly 20% of classmates who sell their legitimate pre- forgery is also fairly common, either by al- the $430 billion health care budget (125). scriptions. tering the prescription or stealing blank A study by the Office of Management and “Doctor shopping” is one of the prescription pads in order to write fake Budget estimated drug abuse costs to the most common methods of obtaining pre- prescriptions (4,9,125,135,139). Prescrip- United States government at $300 bil- scription drugs for legal and illegal use tion forgery may occur in two ways, either lion a year, including government anti- (9,11,78,79,83,84,86,87,121,122,128,129). by stealing blank prescription pads or by drug programs and the costs of the crime, The majority of physicians perceive “doc- making false prescription blanks or pads healthcare (public and nonpublic), acci- tor shopping” as the major mechanism of in order to write fake prescriptions (9). dents, and lost productivity (126). In the diversion (4). Doctor shopping typically However, legitimate prescriptions may Aid to Families with Dependent Children involves an individual going to several dif- be altered typically to increase the quan- (AFDC), Medicaid and food stamp pro- ferent doctors complaining of a wide array tity of controlled substances. Similar- grams, the incidence of drug abuse varies of symptoms in order to get prescriptions. ly, pharmacists may get involved in pre- from 9.4% to 16.4% (127). This type of diversion can also involve in- scription drug diversion, first by selling dividuals who use people with legitimate the controlled substances and then, using 3.7 Drug Diversion medical needs, like cancer patients, to their database of physicians and patients Drugs can be diverted from their go to various physicians in several cities to write and forge prescriptions to cover lawful purpose to illicit use at any point to get prescription medications. Patients their illegal sale. However, the vast major- in the pharmaceutical manufacturing and practicing doctor shopping may target ity of prescription forgery is from non- distribution process. The diversion of pre- physicians who readily dispense prescrip- healthcare professionals. scription drugs among adults is typically tions without thorough examinations or Illicit prescriptions written by phy- described to occur through one of the fol- screening. Some patients with a legitimate sicians, though rare, are a real phenom- lowing: doctor shopping, illegal Internet medical condition may get prescriptions enon. Making the headlines are criminal pharmacies, drug theft, prescription forg- from multiple physicians in various states cases involving physicians who become in- ery, and illicit prescriptions by physicians. or in the same state (9). It has been report- volved in diverting prescription drugs for Youths typically acquire drugs by steal- ed that individuals may collect thousands huge profits (9,140-143). However, mal- of pills during a one year period and sell prescribing, either due to lack of knowl- 765 783 them on the street (9). edge or due to prescribing inappropriate- (0.09%) (0.09%) 698 Since 1999, illegal Internet pharma- ly through “pill mills,” is more common (0.08%) cies have provided a convenient alterna- (141-147). Malprescribing often represents 568 (0.06%) tive for individuals wishing to fill their a lack of knowledge rather than a deliberate 411 prescriptions (9,130-132). In 2003, the attempt to profit from writing these trans- (0.05%) Federal Drug Administration (FDA) es- actions. Adverse actions taken by the DEA timated the number of Internet phar- against physician prescribers has, in fact, macies selling drugs illegally to be about decreased from 0.9% in 1999 to 0.05% in 400, with approximately 50% of the phar- 2003 (Fig. 3). However, actions by medical macies located outside the United States licensure boards have been increasing (Fig. (130). Rogue sites, many under the guise 4). Figure 4 illustrates all types of actions, 1999 2000 2001 2002 2003 of a legitimate pharmacy, provide con- where as Figure 3, illustrates actions related trolled substances to people without pre- to controlled substances. Fig. 3. Drug Enforcement Admin- scriptions. This is particularly troubling istration (DEA) actions against with respect to the 30 million youth na- 3.8 Controlling Diversion and Abuse physicians tionwide with Internet access (9). There Federal, state, and local govern- are numerous concerns regarding rogue ments, as well as professional associations Internet pharmacies, such as the abili- and pharmaceutical companies, share re- 6,265 ty to evade state licensing requirements sponsibility for preventing diversion and and standards, dispensing controlled sub- abuse of controlled prescription drugs 4,617 stances without a prescription; and pro- (4). However, the challenge is to eliminate viding fake substandard or inappropriate or significantly curtail diversion and abuse medication (130). However, state and fed- of controlled prescription drugs while as- eral laws governing traditional pharmacy suring proper treatment of patients who stores apply to Internet sales, regardless of can be helped by these medications. Gaps the method used by an Internet pharmacy exist between current efforts to control di- 36% to dispense the medication. version and efforts to maintain access to increase Prescription drug theft can occur at patient care. These gaps involve interna- 2000 2004 any point from manufacturer to the pa- tional law, federal laws and regulations, Fig. 4. Actions by state boards of tient. Thefts are on the rise, largely due activities of the DEA and FDA, schedul- medical licensure to drastic increases in prescription drug ing drugs, drug refills, state laws and reg- Source FSMB (145) abuse and high street prices (9,131-138). ulations, and existing prescription drug Several drugs ranging from OxyContin to monitoring programs.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 9

3.8.1 Drug Enforcement Administration agencies, health care and regulatory agen- forcement identify and prevent prescrip- The DEA, as an agency within the cies, and in some states, health care prac- tion drug diversion, state programs may United States Department of Justice, is titioners, to help identify inappropriate or include educational objectives to pro- the lead federal law enforcement agency illegal activities involving controlled pre- vide information to physicians, pharma- responsible for enforcing the Controlled scription drugs. It has been stated that the cies, and the public. The programs are also Substance Act. In cooperation with state scrutiny of professional boards and mon- highly variable with regards to monitor- authorities and other federal agencies, the itoring programs has, in some cases, cre- ing scheduled substances from Schedule DEA is responsible for preventing the di- ated fear that legal action will be taken II to Schedule IV. Only four states − Utah, version of controlled substances for illicit against physicians and pharmacists re- Nevada, Kentucky, and Idaho − monitor purposes. However, the DEA must comply garding their prescribing and dispensing Schedule II to IV drugs, while the major- with international treaties to the extent practices. As a result, practitioners may ity monitor only Schedule II drugs. Also, that they are not in conflict with constitu- under-treat patients or use less appropri- the majority of these programs are retro- tional provisions; it must also work close- ate medications that are not covered by a active with after-the-fact identification of ly with foreign, state, and local govern- monitoring program. abuse as reported by public health depart- ments. The DEA has increased its moni- The United States Government Ac- ments, pharmacy boards, and law enforce- toring of Internet prescription drug sales. countability Office (GAO) conducted a ment; few are available to practitioners in DEA investigations, enforcement, and in- study on state monitoring programs of real time and are useful as a prescribing telligence programs have started to work prescription drugs (7). They concluded decision tool. The major disadvantage of more closely with other federal, state, and that state monitoring programs provide a the programs is lack of interstate commu- local agencies to target individuals and useful tool to reduce diversion. nication. Consequently, only a few pro- organizations involved in diversion and The first prescription drug monitor- grams operate proactively, while most op- abuse of controlled prescription drugs. ing program (PDMP) was established in erate reactively. California in 1940. The number of states A few states routinely analyze pre- 3.8.2 State Laws and Regulations with PDMPs has grown only slightly over scription data collected by PDMPs to Every state has professional oversight the past decade, from 10 in 1992 to 15 in identify individuals, physicians, or phar- boards that license and discipline mem- 2002 (Table 6). These 15 programs cover macies that have unusual use, prescribing, bers within each profession. Further, the 47% of the nation’s population and DEA- or dispensing patterns that may suggest licensing boards for each health care pro- registered practitioners, and about 45% of potential drug diversion, abuse, or doctor fession have a designated national orga- the nation’s pharmacies. Since the GAO shopping. However, only three states pro- nization. However, many of these associ- report on state monitoring systems was vide this information proactively to physi- ations have not been proactive in address- published, PDMPs have been increasing cians. The GAO report cited many advan- ing the problems of prescription drug di- gradually (5). tages, as well as disadvantages, to PDMPs. version and abuse (4). Prescription drug monitoring pro- States with PDMPs experience consider- 3.8.3 Prescription Drug Monitoring grams vary as to objectives, design, and able reductions in the time and effort re- Programs operation, even though the primary ob- quired by law enforcement and regulatory Prescription drug monitoring pro- jective of PDMPs is to assist law enforce- investigators to explore leads and the mer- grams (PDMPs) capture information ment in detecting and preventing drug its of possible drug diversion cases. How- that may be shared with law enforcement diversion. In addition to helping law en- ever, while the presence of a PDMP may

Table 6. Prescription drug monitoring programs Year Controlled substance State Type of monitoring system Administrative agency implemented schedule(s)monitored California 1940 II Electronic and triplicate form Pharmacy and law enforcement Hawaii 1943 II Electronic Law enforcement Idaho 1967 II, III and IV Electronic Pharmacy board Illinois 1961 II Electronic Public health Indiana 1995 II Electronic Law enforcement Kentucky 1999 II, III, IV and V Electronic Public health Massachusetts 1992 II Electronic Public health Michigan 1989 II Single form Commerce Pharmacy board and law Nevada 1997 II, III, and IV Electronic enforcement New York 1977 II Electronic Public health Oklahoma 1991 II Electronic Law enforcement Rhode Island 1979 II, III Electronic Public health Texas 1982 II Electronic Law enforcement Utah 1997 II, III, IV, and V Electronic Commerce’s Licensing Division Washington 1987 Determined by disciplinary authority Triplicate form Public health Source: National Alliance for Model State Drug Laws. Information current through February 4, 2002. Adapted from Ref. 7

Pain Physician Vol. 9, No. 1, 2006 10 Trescot et al • Opioid Guidelines

effect, enacted by the U.S. Senate and 122,469 House of Representatives (6). This leg- 109,442 islation, named the National All Sched- ules Prescription Electronic Reporting 95,032 Act (NASPER), provides for the estab- lishment of a controlled substance mon- itoring program in each state, with com- 71,381 munication between state programs. It tasks the Public Health Service to require the United States Secretary of Health and Human Services to award 1-year grants to 36,172 each state with an approved application in order to establish, or improve, a state con- trolled substance monitoring program (1). NASPER was introduced into Con- 3,105 gress by the American Society of Inter- 1999 2000 2001 2002 2003 2004 ventional Pain Physicians with three ma- jor and important goals: Fig. 5. Increase of KASPER use in Kentucky 1) Physician and pharmacist access to Source: Ref. 138. monitoring programs 2) Monitoring of Schedule II to IV drugs 3) Information sharing across state lines NASPER was modeled on the high- ly successful state monitoring program in Kentucky (KASPER) (1). Licensure Board 2% 4.0 PHARMACOLOGICAL CONSIDERATIONS Law Enforcement 6% 4.1 Opioid Pharmacology Pharmacists 4% Opioids are analgesics affecting no- Physicians 87% ciception by modulation of ascending Others 1% and descending pathways. Opioids may be classified by their function as agonists, mixed agonists-antagonists, or antago- nists, as well as by their actions at various opioid receptors. The poppy was cultivated as early as 3400 BC in Mesopotamia. The Fig. 6. Use of Kentucky’s KASPER program term opium refers to a mixture of alka- Source: Ref. 138. loids from the poppy seed. Opiates are naturally occurring alkaloids such as mor- help one state reduce its illegal drug di- KASPER system was designed to produce phine or codeine. Opioid is the term used version, diversion activities may actually 2,000 reports per year at its inception in broadly to describe all compounds that increase in contiguous states that do not 1999; in 2004, however, it produced in ex- work at the opioid receptors. The term have PDMPs. All three of the states pro- cess of 2,500 reports per week (138). Even narcotic (from the Greek word for stu- viding access to physicians − Kentucky, then, it is estimated that only 50% of the por), originally was used to describe med- Nevada, and Utah − have helped reduce physicians who prescribe controlled sub- ications for sleep, then was used to de- the unwarranted prescribing and subse- stances in the Commonwealth of Ken- scribe opioids, but now is a legal term for quent diversion of abused drugs in their tucky are using the KASPER system. Fur- drugs that are abused. states. In both Kentucky and Nevada, an ther, in Kentucky, 87% of the reports are Morphine (the archetypal opioid) increasing number of PDMP reports are requested by physicians and 4% by phar- consists of five rings with a phenolic hy- being used by physicians to check the pre- macists. Further, only 6% were request- droxyl group at Position 3 and an alcohol- scription drug utilization history of cur- ed by law enforcement, and 2% by licen- ic hydroxyl group at Position 6 and at the rent and prospective patients to deter- sure boards (Fig. 6), dispelling the myth nitrogen atom. Both hydroxyl groups can mine whether it is necessary to prescribe that law enforcement and other regulato- be converted to ethers or esters. For exam- certain drugs that are subject to abuse. ry agencies use PDMPs for “witch hunt- ple, codeine is morphine O-methylated at The success of a prescription drug ing” physicians. position 3, while heroin is morphine O- monitoring program can be demonstrat- In addition to multiple state mon- acetylated at positions 3 and 6. Morphine ed by its use by physicians and other pro- itoring programs, on August 11, 2005, is optically active, and only the levorota- fessionals in Kentucky (Fig. 5). Kentucky’s President Bush signed a new law into tory isomer is an analgesic. The tertiary

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 11

Table 7. Analgesic effects at opioid receptors

Mu (µ) Delta (δ) Kappa (κ) • Mu 1 – Analgesia • Analgesia, spinal • Analgesia, sedation, dyspnea, psychomimetic • Mu 2 – Sedation, vomiting, respiratory analgesia effects, miosis, respiratory depression, depression, pruritus, euphoria, euphoria, dysphoria, dyspnea, physical anorexia, urinary retention, physical dependence dependence Endogenous Peptides Enkephalin Agonist Agonist β endorphin Agonist Agonist Agonist Agonist Agonists Morphine Agonist Weak agonist Codeine Weak agonist Weak agonist Fentanyl, Agonist Meperidine Agonist Agonist Methadone Agonist Oxycodone Agonist Agonist Agonist-antagonists Partial agonist Antagonist Pentazocine Partial agonist Agonist Antagonist Agonist Partial agonist Antagonist Antagonist Agonist Antagonists Antagonist Weak Antagonist Antagonist Antagonist Weak Antagonist Antagonist form of the nitrogen appears to be cru- Kappa (κ) (agonist ketocyclazocine) − These targets alter protein phosphoryla- cial to the analgesia of morphine; mak- Kappa receptors found in limbic and tion and/or gene transcription. Opioids ing the nitrogen quaternary greatly de- other diencephalic areas, brain stem and endogenous opioids activate presyn- creases the analgesia, since it cannot pass and spinal cord are responsible for aptic receptors on GABA neurons, which spinal analgesia, sedation, dyspnea, into the central nervous system. Changes inhibit the release of GABA in the ventral dependence, dysphoria, and respiratory tegmental area. This allows dopaminer- to the methyl group on the nitrogen will depression. decrease analgesia as well, creating antag- Delta (δ) (agonist delta-alanine-delta- gic neurons to fire more vigorously, and onists such as nalorphine. leucine-enkephalin) − Delta receptors the extra dopamine in the nucleus accum- restricted largely to the brain are not bens is intensely pleasurable. The varying 4.1.1 Opioid Receptors well studied. They may be responsible for effects of opioids may therefore be related There are opioid receptors within the psychomimetric and dysphoric effects. to varying degrees of affinity for the vari- σ central nervous system (CNS) as well as Sigma ( ) (agonist N-allylnormetazocine) ous receptors. − Sigma receptors are responsible for throughout the peripheral tissues. These The opioid receptors were discov- psychomimetic effects, dysphoria, ered in 1972, and the first endogenous receptors are normally stimulated by en- stress-induced depression. They are no dogenous peptides (endorphins, enkeph- longer considered opioid receptors, but opioid (enkephalin) was discovered in alins, and dynorphins) produced in re- rather the target sites for 1975. Their location in the CNS allows sponse to noxious stimulation. Greek let- (PCP) and its analogs. them to function as neurotransmitters, ters name the opioid receptors, based on These opioid receptors, concentrat- and they may play a role in hormone se- their prototype agonists (Table 7). ed in the ventral tegmental and periaq- cretion, thermoregulation, and cardiovas- Mu (µ) (agonist morphine) − Mu receptors ueductal grey areas, presynaptically in- cular control. found primarily in the brainstem and hibit the transmission of excitatory path- Enkephalins are derived from pro-en- medial thalamus. Mu receptors are re- ways: acetylcholine, catecholamine, sero- kephalin and are relatively selec- sponsible for supraspinal analgesia, re- tonin, and substance P. Activation of the tive δ ligands. spiratory depression, euphoria, seda- inhibits adenylate cy- Endorphins are derived from pro-opi- tion, decreased gastrointestinal motili- omelanocortin (also the precursor ty, and physical dependence. Subtypes clase. All opioid receptors are G protein- include Mu1 and Mu2, with Mu1 relat- linked structures embedded in the plasma for ACTH and MSH), and bind to ed to analgesia, euphoria, and serenity, membrane of neurons; activation releases the µ receptor. while Mu2 is related to respiratory de- a portion of the G protein, which moves Dynorphins are derived from pro-dyn- pression, pruritus, prolactin release, de- in the membrane until it reaches its tar- orphins, and are highly selective at pendence, anorexia, and sedation. get (either an enzyme or an ion channel). the µ receptors.

Pain Physician Vol. 9, No. 1, 2006 12 Trescot et al • Opioid Guidelines

Nociceptin (orphanin), identifi ed in Table 8. DEA schedules of controlled drugs 1995, may have potent hyperalgesic effects. It has little affi nity for the µ, Schedule Criteria Examples δ, or κ receptors. antag- No medical use: high addiction I Heroin, marijuana. PCP onists may be antidepressants and potential Medical use: high addiction Morphine, oxycodone, methadone, analgesics. II potential fentanyl, amphetamines Pure opioid agonists (e.g., morphine, Medical use; moderate addiction III Hydrocodone, codeine, anabolic steroids hydromorphone, fentanyl) stimulate µ re- potential ceptors and are the most potent analge- Benzodiazepines, meprobamate, IV Medical use; low abuse potential sics. As the dose is increased, analgesia oc- butorphanol, pentazocine, propoxyphene curs in a log linear fashion; the degree of V Medical use; low abuse potential Buprenex, Phenergan with codeine analgesia induced is limited only by intol- erable dose-related adverse effects. In con- trast, opioid agonists/antagonists and opi- Naltrexone is used orally in high dos- CYP1A2, CYP2C8 and CYP2C9 make up oid partial agonists (buprenorphine, pen- es to detoxify opioid addicts. Its primary ef- about 10% of the enzymes, CYP2D6 and tazocine, nalbuphine, butorphanol, nalor- fect is from its metabolite, 6-β-naltrexol. CYP2E1 each around 5%, and CYP2C19 phine) exhibit a ceiling effect on the de- around1%. CYP2D6 is entirely absent in gree of analgesia that they can produce. Opioid agonist-antagonists some populations, for example, 6-10% of Opiate agonist/antagonists and partial ag- Opioid agonist-antagonists are clas- Caucasians are 2D6 deficient (150) while onists can precipitate opioid withdrawal sified into two types: other persons have high levels of this en- reactions. The respiratory depressant ef- Partial agonists at µ receptor, such as zyme, leading to rapid metabolism of fects of partial agonists are not completely buprenorphine, have a high affinity but the medicines. Because of genetic poly- reversed with naloxone. low efficacy at the µ receptor. morphism and variant alleles of the cy- Agonist/partial agonist at κ recep- tochrome P-450 genes, patients may be 4.1.2 Opioid categories tor, such as nalorphine, pentazocine, na- either rapid or slow metabolizers of opi- The Drug Enforcement Agency lbuphine, and butorphanol, act as κ ag- oids. The possibility exists that genotyp- (DEA) classifies opioids into schedules as onists but are competitive µ antagonists, ing will allow identification of these pa- illustrated in Table 8. with a high affinity but no efficacy at the tients, with the ability to titrate their doses The phenanthrenes are the prototyp- µ receptor. and alvimo- appropriately. ical opioids. The presence of a 6-hydroxyl pan have poor oral absorption and are un- may be associated with a higher incidence der investigation for use as oral agents to 4.2 Pharmacology of Specifi c Opioids of nausea and hallucinations. For exam- reverse the decreased GI motility of opi- 4.2.1 Morphine ple, morphine and codeine (both with 6- oid agonists. Morphine is a strong Schedule II an- hydroxl groups) are associated with more These agonist-antagonists are potent algesic, indicated for severe acute pain, or nausea than are hydromorphone and oxy- analgesics with ceiling effect and therefore moderate to severe chronic pain. The pri- codone (which do not have 6-hydroxyl potentially decreased abuse potential. It mary site of action is the CNS. The oral groups). Opioids in this group include must be remembered that their antagonist form is available in immediate-release morphine, codeine, hydromorphone, le- properties may precipitate withdrawal. vorphanol, oxycodone, hydrocodone, and extended-release dosage forms. The parenteral forms of morphine contain , buprenorphine, nalbu- 4.1.3 Opioid metabolism sulfites that may cause anaphylactic or life phine, and butorphanol. Many of the side effects of opioids, as threatening, allergic-type reactions in in- The lone member of the benzomor- well as their effects, may be related to the dividuals with sulfa allergies. phan class is pentazocine. It is an agonist/ opioid metabolites. It is generally assumed Morphine is a phenanthrene deriva- antagonist with a high incidence of dys- that most of the metabolism occurs in the tive and is the prototype µ receptor opi- phoria. liver. The basal rate of metabolism is de- oid agonist. The absorption of morphine Phenylpiperidines include fentanyl, termined by genetic makeup, gender, age, after oral administration varies from 20% , sufentanil, and meperidine. Fen- as well as environment including diet, dis- to 30%. Morphine is a relatively long-last- tanyl has the highest affinity for the mu re- ease state, and concurrent use of medica- ing opioid with analgesic effects lasting 4- ceptor. tions. There is no clear evidence of renal 5 hours. Its elimination half-life is 2 hours Diphenylheptanes include propoxy- metabolism, though the kidney is an im- which is actually less than shorter acting phene and methadone. portant site of excretion. Most opioids are opioids such as fentanyl. Morphine is rel- Tramadol does not fit in the standard metabolized by glucuronidation or by the atively water soluble. This discrepancy is opioid classes (Fig. 7). P450 (CYP) system. In humans, 57 cyto- explained by the low lipid solubility of chrome P-450 genes have been identi- morphine and its slower elimination from Opioid antagonists fied (148). the brain compartment in relation to the Naloxone is a pure competitive an- CYP3A4 is the most abundant en- plasma concentration, which also may be tagonist at µ, κ, and δ receptors (strongest zyme in the body at 25% (149). Lev- associated with its existence in an ioniz- at µ). It rapidly reverses opioids, but the els of CYP3A4 may vary as much as 30- able state in the relatively acid brain com- action is short lived, therefore has the po- fold between individuals (149), lead- partment. The relatively long analgesic ac- tential for “re-narcotizing.” ing to large variability in blood levels.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 13 tivity of morphine may be associated with Codeine is a pro-drug, and has no is available as Synalgos-DC (163). Most the presence of the active morphine me- effect until metabolized by CYP2D6 to of dihydrocodeine is conjugated to inac- tabolites, which have half-lives of elimina- morphine (159, 160). Genetic deficiencies tive dihydrocodeine-6-glucuronide. Less tion longer than morphine itself. As with and multiple drugs interactions can lead than 10% of dihydrocodeine is metabo- other strong opioid analgesics, there is to its ineffectiveness (151). lized to nordihydrocodeine and to dihy- no ceiling to the analgesic effect. Howev- Codeine is also metabolized by gluc- dromorphine (DHM). DHM has stron- er, significant side effects, particularly se- uronidation to codeine-6-glucuronide ger affinity to µ opiate receptor than mor- dation and confusion, may interfere with (C6G). Minor metabolic pathways result phine itself, and it is also conjugated fur- achieving optimal analgesia (151). in other metabolites including nor-co- ther to the next active metabolite, DHM- Approximately 50% to 80% of the deine and morphine (161). C6G has been 6-glucuronide and inactive DHM-3-gluc- dose administered is typically recovered shown to be antinociceptive in rats (162). uronide (164). Dihydrocodeine has a half- as glucuronide metabolites, mostly mor- Doses of codeine greater than 65 mg are life of about 4 hours. phine-3-glucuronide (M3G) and mor- not well tolerated. Codeine has a half-life 4.2.4 Hydrocodone phine-6-glucuronide (M6G), whereas ap- of 3 hours, and >80% of the dose is ex- Hydrocodone is a mild opioid ago- proximately 2% to 8% of the dose typi- creted in 24 hours. nist and is indicated for moderate to mod- cally is found in urine as unmetabolized 4.2.3 Dihydrocodeine erately severe pain as well as symptomatic morphine. Morphine is also metabolized Dihydrocodeine is similar to codeine relief of nonproductive cough. Hydroco- to codeine, normorphine-3, 6-diglucuro- and also has a pharmacokinetic pattern done is the most commonly used opioid. nide, and morphine-3-sulfate. The liver similar to it. In the commercial form it Hydrocodone in its pure form is a Sched- is the major site of metabolism of mor- phine, even though extrahepatic gluc- uronidation has been reported. Mor- Opioid categories Chemical Structure phine glucuronides are eliminated from the body by urinary secretion. During long-term morphine administration, cir- culating concentrations of M3G and M6G Morphine markedly exceed those of morphine itself Phenanthrenes because hepatic metabolism converts ap- proximately 70% of morphine into M3G (60%) and M6G (10%). M6G and nor- morphine are both opioid agonists; M6G is 3-4 times more potent than morphine when injected subcutaneously, and 45 times more potent after intracerebroven- tricular injections in mice (152). M3G has a low affinity for the opioid recep- Benzomorphans tor, and may be responsible for the side Pentazocine effects of hyperalgesia, and myoclonus (153-155). Hepatic (156) and renal (157) disease may significantly prolong the ef- fect of morphine. Accumulation of mor- phine metabolites (especially M6G) be- comes significant as creatinine clearance declines below 50 ml/min (158). A steady Phenylpiperidines state for long acting preparations is usu- Fentanyl ally reached in 1-2 days. In adults, long- term oral administration of morphine produces variable plasma ratios of M3G and M6G, with reported mean ratios be- tween 10:1 and 5:1. 4.2.2 Codeine Codeine, first isolated in 1832, is the prototype of the weak opioid analgesics Diphenylheptanes Methadone with weak affinity to µ opioid receptor. Codeine in its pure form is a Schedule II substance, but in combination with other analgesics, it is Schedule III. Its analgesic potency is approximately 50% of the mor- phine with a half-life of 2.5 to 3 hours. Fig. 7. Opioid classifi cation

Pain Physician Vol. 9, No. 1, 2006 14 Trescot et al • Opioid Guidelines ule II substance; however it is only avail- in oral dosage, with a half-life of 2.5 to muscular, and subcutaneous routes. able for pain control as an oral, combi- 3 hours. It undergoes extensive hepat- Hydromorphone is metabolized pri- nation product with non-opioid analge- ic conjugation and oxidative degradation marily to hydromorphone-3-glucuronide sics, such as ibuprofen and acetamino- to a variety of metabolites excreted main- (H3G), which, similar to the correspond- phen. As a combination product, hydro- ly in urine. Oxycodone is metabolized by ing M3G, is not only devoid of analgesic codone is a Schedule III substance because glucuronidation to noroxycodone (which activity but in animal models also evokes the amount of hydrocodone is limited to has less than 1% of the analgesia poten- a range of dose-dependent excited behav- a maximum 15 mg per dosage unit. The cy of oxycodone), and by 2D6 to oxymor- iors, including allodynia, myoclonus and maximum recommended daily dose of phone. Oxycodone has activity at multi- seizures. hydrocodone is 37.5 mg when combined ple receptors, but oxymorphone has high 4.2.7 Methadone with ibuprofen or 60 mg when combined affinity for the µ receptor with negligible κ δ Methadone is a synthetic µ opioid with acetaminophen (165). interaction with and receptors (167). receptor agonist Schedule II drug (157). Hydrocodone bioavailability after Oxymorphone is about 10 times more po- Methadone, in addition to its opioid re- oral administration is high and its effec- tent than morphine. Oxymorphone is not ceptor activity, is an antagonist of N- tiveness is similar to that of morphine affected by CY2D6 or CY3A4. Oxycodone methyl-D-aspartate (NMDA) receptors. with oral administration. The half-life of is conjugated extensively in the liver, rang- Methadone is a racemic mixture of two hydrocodone is 2.5 to 4 hours. Hydroco- ing from 15% to 80% of the total dose. enantiomers; R-methadone accounts for done undergoes extensive hepatic conju- However, a minority of the dosage under- most of its opioid effect while L-meth- gation and oxidative degradation to a va- goes via hepatic pathways into noroxyco- adone is the NMDA antagonist. The in- riety of metabolites excreted mainly in the done, oxymorphone, oxycodols and their herent NMDA antagonistic effects make urine. Two major metabolites of hydroco- respective oxides. Less than 10% of un- it potentially useful in severe neuropath- done excreted in the urine are dihydroco- changed oxycodone is excreted in the ic and “opioid-resistant” pain states. The L done and nordihydrocodone, both con- urine. Significant individual variation in isomer also inhibits reuptake of serotonin jugated to approximately 65%. Hydroco- oxycodone metabolism may account for and norepinephrine, which should be rec- done is also metabolized to dihydromor- abnormal responses (168). ognized when using selective serotonin phone (DHM). DHM is produced only in 4.2.6 Hydromorphone reuptake inhibitors (SSRIs). minor amounts and is conjugated further Hydromorphone is a Schedule II Methadone is metabolized by 3A4 to 85%. Only about 25% of the dose is ex- semi-synthetic opioid agonist and a hy- primarily, and 2D6 secondarily (173, 174, creted in 72 hours. Some of the hydroco- drogenated ketone of morphine (169, 175). CYP182 is possibly involved, and a done metabolites including DHM, hydro- 170). It has been widely used for acute newly proposed enzyme CYP2B6 may be morphone, and dihydrocodone are phar- pain, chronic cancer pain, and to a less- emerging as an important enzyme inter- macologically active on the opioid recep- er extent in chronic non-malignant pain. mediary metabolic transformation. The tors. They may contribute in various de- Hydromorphone is structurally very sim- potential differences in enzymatic meta- grees to analgesic activity of hydrocodone ilar to morphine (171). Like morphine, bolic conversion of methadone may ex- or produce unexpected side effects when it acts primarily on µ opioid receptors plain the inconsistency of observed half- their excretion is impaired, and may show and to a lesser degree on delta receptors life. up on urine drug screens, leading to false (172). Methadone has several advantages in accusations of abuse. On the other hand, Hydromorphone is significantly more the treatment of chronic pain. It has excel- patients who are CYP2D6 deficient, or potent than morphine, with estimates of lent oral bioavailability (up to 100% ab- patients who are on CYP2D6 inhibitors, a relative potency of 7:1 up to 11:1 com- sorbed), though it is highly variable (from may not produce these analgesic metabo- pared to morphine. It is highly water solu- 40% to 100%). It can be crushed or dis- lites, and may have less than expected an- ble which allows for very concentrated for- solved to deliver down a nasogastric (NG) algesia. mulations. In patients with renal failure it tube. It can be used in patients with a true 4.2.5 Oxycodone may be preferred over morphine due to morphine allergy. Methadone is metabo- Oxycodone is considered as a mod- morphine’s risk of toxic metabolite accu- lized in the liver and intestines, and is ex- erate to strong opioid agonist and is a mulation. creted almost exclusively in feces, an ad- Schedule II substance whether alone or Hydromorphone is available in var- vantage in patients with renal insufficien- in combination with aspirin or acet- ious formats: powder, solution, interme- cy or failure. It may also cause less consti- aminophen. It is used orally for moder- diate release tablet and modified-release pation than morphine, and it is very inex- ate to moderately severe pain and postop- tablet. Hydromorphone is extensively me- pensive (176). erative, post exertional, and post partum tabolized in the liver with approximately The plasma levels decline following a pain (166). In recent years, extended-re- 62% of the oral dose being eliminated by biexponential model − 2 to 3 hours of ini- lease preparations have been extensively the liver on the first pass, partly account- tial phase followed by a 15 to 60 hours of used for moderate-to-severe chronic ma- ing for oral bioavailability in the range of terminal phase. This may partly explain lignant and nonmalignant pain. The ad- 1:2 to 1:8 (173). For orally administered its difference in analgesic action and accu- verse effects of oxycodone are milder than immediate release preparations, the on- mulation of the drug with repeated dos- those of morphine, but the addiction po- set of action is approximately 30 minutes ing. Most would agree that the analge- tential of oxycodone may be the same or with a duration of action of 4 hours (173). sic capacity of methadone is significant- higher than morphine. Hydromorphone can also be adminis- ly shorter than its known half-life. Eight Bioavailability of oxycodone is high tered parenterally by intravenous, intra- hours of analgesic relief may be overshad-

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 15 owed by the up to 120-hour half-life of the local anesthetic properties, and with an fective analgesia of 3 to 5 hours. It is me- drug. Methadone has the potential to ini- oral-to-parental ratio of 4:1. The half-life tabolized in the liver to norpropoxyphene, tiate Torsade de Points, a potentially fatal of meperidine is approximately 3 hours. It which has a long half-life of 30 to 60 hours arrhythmia caused by a lengthening of the is metabolized in the liver to normeperi- and is considered to have cardiac toxicity. QT interval. dine, which has a half-life of 15-30 hours Further, propoxyphene itself can produce Plasma levels of methadone are in- as well as significant neurotoxic proper- seizures (naloxone-reversible) after over- creased by concomitant administration of ties. Meperidine must not be given to pa- dose. In addition to being a µ receptor ago- cimetidine, erythromycin, ketoconazole, tients being treated with monoamine ox- nist, propoxyphene is a weak and noncom- and fluvoxamine. Conversely, plasma lev- idase inhibitors (MAOI); combination petitive N-methyl-D-aspartate (NMDA) els are decreased by concomitant adminis- with MAOIs may produce severe respira- receptor antagonist. tration of barbiturates, phenytoin, carba- tory depression, hyperpyrexia, CNS exci- 4.2.12 Tramadol mazepine, isoniazid, rifampin, ritonavir, tation, delirium, and seizures. Tramadol is a synthetic opioid that nevirapine, and possibly efavirenz. Meperidine is metabolized by gluc- inhibits norepinephrine and serotonin Methadone may be unique in its lack uronidation to normeperidine, which reuptake and produces some central opi- of profound euphoria, and patient self-di- causes CNS stimulation and seizures, es- oid receptor activity (179). The M1 deriv- rected redosing and long half-life may re- pecially with high doses or renal insuffi- ative (O-demethyl tramadol) produced by sult in accumulation, with ultimate ad- ciency. Normeperidine has a terminal half CYP2D6, has a higher affinity for the µ re- verse outcomes including respiratory de- life of 8-12 hours so significant amounts ceptor than the parent compound. Tram- pression and death. Even when prescribed can accumulate in only 2 days. Adverse ef- adol is a racemic mixture of two enantio- in low doses, and used appropriately by fects of normeperidine are not reversible mers − one form is a selective µ agonist individuals experienced with opioids, the by naloxone. and inhibits serotonin reuptake, while long half-life of methadone may be un- 4.2.10 Pentazocine the other mainly inhibits norepinephrine. derestimated while dosing is titrated to Pentazocine is a semisynthetic deriv- Maximum dose is 400 mg/day. Toxic doses analgesic effect. Furthermore, the list of ative of the benzomorphans, a Schedule cause CNS excitation and seizures. drug interactions with methadone is ex- IV substance. It interacts with µ receptors Tramadol is a non-scheduled drug tensive, and further alteration in metabo- and κ receptors. It is considered a mixed according to federal standards. State reg- lism may occur innocently and unexpect- opioid agonist-antagonist. It is manufac- ulations may vary. Tramadol is absorbed edly, without the prescribing physician’s tured as a racemic mixture (L:R 50:50), rapidly and extensively after oral doses, awareness. but only the L-isomer possesses analgesic and is equal to the analgesic potency of 4.2.8 Fentanyl activity. It is well absorbed after oral ad- codeine. Fentanyl is a strong opioid agonist, a ministration. The half-life of pentazocine Schedule II substance, available in paren- is about 4 hours. It is metabolized almost 4.3 Adverse Effects teral, transdermal, and transbuccal prepa- exclusively in the liver to inactive glucuro- The majority of the adverse effects rations (157). Fentanyl is the oldest syn- nides and oxidation of the terminal meth- of opioids reflect the effects of opioids at thetic piperidine opioid agonist, interact- yl groups. multiple organ systems (180). ing primarily with µ receptors. It is ap- ♦ Central nervous system 4.2.11 Propoxyphene • proximately 80 times more potent than A sense of emotional well being Propoxyphene is a mild, opioid ag- and euphoria morphine and is highly lipophilic and onist used in mild to moderate pain and • Drowsiness, sedation, or binds strongly to plasma proteins. is a Schedule IV substance. Propoxyphene hallucinations Fentanyl undergoes extensive metab- has CNS effects such as dizziness, seda- • Potential for diminished olism in the liver. When administered as a tion, weakness and falls, mild visual dis- psychomotor performance lozenge for oral transmucosal absorption, • Dysphoria, agitation, and seizures turbances, agitation, paradoxical excite- a portion is swallowed and is subject to ♦ Respiratory system ment, and insomnia. These effects be- first-pass metabolism in the liver and pos- • Respiratory depression is the come more common and can result in sibly the small intestine. It is metabolized major adverse effect and may drug-related deaths when propoxyphene result from toxicity. to hydroxyfentanyl and norfentanyl. is used in combination with other drugs • Diminution of pain or pain Fentanyl is metabolized by 3A4, but that can cause drowsiness (166,177). The relief by other modalities may to inactive and nontoxic metabolites. The GAO, after two studies conducted in 1991 exacerbate respiratory depression transdermal formulation has a lag time of and 1995, recommended that propoxy- (181). 6-12 hours to onset of action after appli- ♦ Ocular system phene not be used in elderly patients be- cation, and typically reaches steady state • Miosis stimulation occurs through cause of the existence of other analgesic in 3-6 days. When a patch is removed, a the parasympathetic ganglion. medications that are more effective and ♦ subcutaneous reservoir remains, and drug Gastrointestinal system safer (177, 178). Propoxyphene is a syn- • Constipation, nausea and clearance may take up to 24 hours. thetic analgesic that is structurally relat- vomiting 4.2.9 Meperidine ed to methadone and has an opioid dose • Delayed gastric emptying Meperidine is a Schedule II, relatively equipotency similar to codeine. The anal- ♦ Genitourinary • Urinary retention weak opioid µ agonist with only approxi- gesic activity is confined to its d-stereoiso- • mately 10% of the effectiveness of mor- mer () with a half- Sexual dysfunction ♦ Cardiovascular phine with significant anticholinergic and life of 6 to 12 hours, with duration of ef- • Reduction in systemic vascular

Pain Physician Vol. 9, No. 1, 2006 16 Trescot et al • Opioid Guidelines

resistance ♦ A patient taking Tamoxifen (a CY2D6 neric medications may have significant • Decreased blood pressure but substrate) was noted to get poor relief differences in bioavailability, and metabo- potentially increased cardiac with oxycodone (which is metabolized lism of medications may be influenced by by CY2D6) but excellent relief with output genetic polymorphism and drug interac- • Bradycardia due to vagal morphine (168). tions. It is therefore important to recog- stimulation Methadone has multiple drug in- nize that “equipotent” doses of medica- ♦ Musculoskeletal system teractions. Phenytoin, carbamazepine, ri- • tions may have very different degrees of Muscle rigidity and myoclonus fampin, erythromycin, barbiturates, and analgesia and side effects. In general, to (182) several anti-retrovirals induce methadone ♦ Immune system switch between medications, the clinician metabolism, resulting in decreased blood • Itching is common due to a direct must calculate a rough equivalent 24 hour levels and the potential for withdrawal. histamine release (especially by dose, divide by the dosing schedule, and The azole antifungals, the SSRIs, and tri- morphine) then “under-dose,” with subsequent titra- • Not an allergic reaction (183, 184) cyclic antidepressants may increase meth- tion to effect. ♦ Pregnancy adone levels (189). Methadone may also Most authors agree that oral mor- • All opioids cross the placenta increase TCA levels. Overmedication oc- • phine intravenous (IV) morphine: in- Neonatal depression can occur if curring within a few days is usually due to trathecal morphine equivalency is 30:10: opioids are used during labor P450 (CYP) inhibition, while withdrawal • No teratogenic effects have been 1. Hydromorphone is approximately five reactions taking a week or more are usu- observed times more potent than morphine. Ten ♦ ally due to CYP induction (190). Metha- Tolerance mg to 20 mg of IV morphine is roughly • done also has the potential to cause car- Decreased duration of analgesia equivalent to 25 mcg of transdermal fen- and then decreased effectiveness. diac arrhythmias, specifically prolonged tanyl. Oral oxycodone is about two-thirds ♦ Physical dependence QTc interval and/or torsade de pointes as potent as morphine. Although meth- • Withdrawal symptoms include under certain circumstances. Combining adone has been described as equipotent runny nose, shivering, “goosefl esh,” methadone with a CYP3A4 inhibitor such to morphine, it is now clearer that dos- diarrhea, and mydriasis as ciprofloxin (191), and even grapefruit, ing methadone on a milligram-for-mil- can increase that risk (192). It is recom- 4.4 Drug Interactions ligram basis will lead to life-threatening mended that a switch to methadone from overdose. For doses of morphine under A drug interaction occurs when the another opioid be accompanied by a large 100 mg, a ratio of 3:1 may be appropri- amount or the action of a drug are altered (50% to 90%) decrease in the calculated ate, while for higher doses of morphine a by the administration of another drug equipotent dose (193). or multiple drugs (185). Multiple hepat- ratio of 20 mg of morphine for each mg ic drug interactions may influence opi- 4.5 Drug Conversions of methadone may be appropriate (194). It cannot be too strongly emphasized that oid drug levels (118, 188), as illustrated While there have been multiple opi- the dosing of methadone can be poten- in Table 9. oid conversion charts developed, none ♦ There have been isolated reports of tially lethal and must be done with knowl- are reliable and none take into consider- interactions between opioid and H2 edge and caution. blockers (cimetidine and ranitidine) ation the vast individual differences in ef- fect and metabolism between patients and causing breathing diffi culties, confusion, 4.6 Opioid Therapy and Side Effects and muscle twitching. within medications. Brand name and ge- 4.6.1 Long-term opioid therapy While advocacy for appropriate opi- Table 9. Drug interactions of opioids oid usage in chronic pain continues, it is Inhibit morphine glucuronidation leading to ⇑ blood levels well known that prolonged use of opi- oids may result in adverse consequenc- Tricyclic antidepressants − inhibits non-competitively es, including tolerance, hyperalgesia, hor- − and clomipramine inhibit competitively monal effects, and immunosuppression (195). However, the clinical relevance of ⇓ Methadone and morphine metabolism of , leading to toxicity these problems is only known for opioid Quinine ⇓ conversion of codeine to morphine leading to ⇓ analgesia tolerance. It is postulated that prolonged use of high doses of opioids is likely to Metoclopramide Earlier peak plasma levels with controlled-released opioids be more toxic than short-term use of low Meperidine MAO inhibitors trigger hyperpyrexia doses, and hormonal effects are most like- ⇑ carbamazepine, doxepin, metoprolol, propranolol levels ly to occur in patients with chronic pain Propoxyphene ⇓ excretion of benzodiazepines, leading to accumulation and who receive high dose opioid therapy overdose (89). The essential aim of a multitude of Erythromycin ⇑ opioid effects available guidelines is to protect patients from the adverse effects of opioid thera- ⇓ Rifampin opioid effects py in addition to providing access. Para- ⇑ tramadol levels CY2D6 inhibitors doxically, opioid treatment may be offered ⇓ analgesia from hydrocodone/codeine in an attempt to reduce pain and improve CY2D6 substrates ⇑ tramadol levels because of competition for metabolism function, and thereby reduce the burden

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 17 of care, but the treatment may actually thalamic-pituitary-gonadal access (216, escalation during opioid therapy – that is, increase the burden of care, because the 223, 224). While there are no studies to the development of “afferent” opioid tol- management of opioid therapy in patients address multiple hormonal issues related erance – may result from pharmacologic with complex problems is time consum- to chronic pain and opioid therapy, tes- opioid tolerance, opioid-induced abnor- ing and difficult (89). tosterone depletion has been demonstrat- mal pain sensitivity, or disease progres- The adverse effects of long-term opi- ed in patients on methadone maintenance sion. The potential use of NMDA antago- oid therapy for the treatment of chronic therapy (217-219, 223-225). The effect of nists in the treatment of neuropathic pain, pain may be avoided or reduced by multi- testosterone depletion may result in hy- opioid tolerance, and opioid-induced hy- ple means. These include limiting the opi- pogonadism, decreased libido, aggression, peralgesia is the subject of multiple inves- oid dose, changing the drug formulation, and drive; amenorrhea or irregular men- tigations. opioid rotation, and understanding that ses; and galacturia (220, 221). In fact, clin- 4.6.5 Psychomotor Performance In despite all the changes and strategies, es- ically relevant testosterone depletion has Opioid Therapy calation of the opioid dose may fail (89). been reported to develop in the majority The negative effects of opioids on of men receiving intrathecal opioid ther- 4.6.2 Opioid Induced Immunologic psychomotor performance in the opi- apy for chronic pain, and they benefited Effects oid-naïve patient are well known (239- from testosterone-replacement therapy Opioids are known to effect immune 242). In addition, some believe that once (221, 222), with an increase in analgesia as function in many ways that are measur- opioids are added to the management of well as a decrease in testosterone deficien- able (196-212). It is accepted that acute pain, a patient’s ability to operate heavy cy symptoms. administration of opioid agonists is im- equipment is diminished and they should munosuppressive (197-199). The animal 4.6.4 Opioid Induced Hyperalgesia not be allowed to drive an automobile studies have shown that the prototypi- Hyperalgesia or abnormal pain sen- (243). However this view is contradicted cal opioid morphine suppresses natural sitivity manifests as increased pain from by others who believe that patients on sta- killer cell activity (NKCA), inflammato- noxious stimuli and as pain from previ- ble doses of opioid medications should be ry cytokine production, and mitogen-in- ously non-noxious stimuli. Long-term use allowed to drive vehicles (244). The only duced lymphocyte proliferation (196, 200, of opioids may be associated with the de- direct evidence provided in a subset of pa- 201). The human studies provided similar velopment of hyperalgesia (227-230). Ex- tients with chronic pain on a stable opioid results with morphine and fentanyl (205, perimental and clinical studies describe analgesic regimen (240) shows that these 206). Repeated and chronic opioid inges- that cellular mechanisms of neuropath- patients are capable of safely operating tion in the absence of pain appears to re- ic pain may be similar to opioid-induced an automobile during daytime, in nor- sult in significant consequences including hyperalgesia (229-232). In an experimen- mal weather conditions. On virtually ev- high infectious disease prevalence (196, tal setting, NMDA-receptor-mediated ery dependent measure tested, this study 207). However, in the presence of acute changes that cause abnormal pain sen- showed no significant difference among pain, there is evidence that opioid admin- sitivity have been shown to occur in an- patients with chronic pain without opi- istration in analgesic doses is protective, imals in the spinal cord dorsal horn cells oids, healthy patients or volunteers, and since pain, in and of itself, has been shown of animals after repeated exposure to opi- chronic pain patients on opioids. How- to be immunosuppressive (196, 199, 208, oids (233). Similarly, these changes have ever, in another study evaluating the ef- 209). However, much less is known re- been observed in the spinal cord in an- fects of immediate-release morphine garding the immune and disease implica- imal models of neuropathic pain. Con- and cognitive functioning in patients re- tions related to chronic opioid treatments sequently, interactions between neural ceiving chronic opioid therapy (245), the for chronic pain states. Despite exhibiting mechanisms of opioid tolerance and neu- study suggested that immediate release normal circulating levels of immunoglob- ropathic pain involving spinal and supra- morphine, when taken on top of sus- ulins throughout, pain patients exhibited spinal neural circuits may have important tained release opioid, produced transient reduced in vitro production of immuno- clinical implications (227, 234). anterograde and retrograde memory im- globulins, both before therapy initiation Repeated administration of opioids pairments and a decrement in two-target and throughout (210). not only results in the development of tol- tracking, leading the authors to conclude 4.6.3 Opioid Induced Hormonal erance but also hyperalgesia. In fact, opi- that these impairments may have impact. oid-induced abnormal pain sensitivity Changes 4.6.6 Breakthrough Pain Management has been observed in patients treated for Opioids influence the hypothalamic- Breakthrough pain and its manage- both pain and addiction (23, 235-239). It pituitary-adrenal axis and hypothalamic- ment is a controversial issue. A prospec- also has been postulated that there may be pituitary-gonadal axis, along with others tive study (246) of breakthrough pain and correlation between tolerance which is a (213-226). Morphine has been reported its clinical applications defined break- desensitization process, and hyperalgesia to cause a strong, progressive decline in through pain as a transitory flare of pain which is a pro-nociceptive process or sen- the plasma cortisol levels in laboratory beyond moderate intensity in the set- sitization. In prolonged opioid therapy, animals and humans (213-215). The ma- ting of chronic pain stabilized by opi- desensitization and sensitization togeth- jor effects of opioids include an increase oid therapy. Evaluation of opioid thera- er may contribute to tolerance or an affer- in prolactin and a decrease in luteinizing py in 63 cancer pain patients showed that ent decrease in analgesia, regardless of the hormone, follicle-stimulating hormone, 64% of them experienced breakthrough progression of the pain (238). Ballantyne testosterone, and estrogen by modula- pain. However, except for the applica- and Mao (89) stated that the need for dose tion of hormonal release involving hypo- tion of cancer pain patient data to non-

Pain Physician Vol. 9, No. 1, 2006 18 Trescot et al • Opioid Guidelines cancer pain patients, there have not been tee of experts on the addiction-produc- crease or discontinue use, a great deal of systematic evaluations. Indications for ing drugs convened by the WHO intro- time lost in obtaining the substance, us- breakthrough pain may be abused for ad- duced the terms psychological depen- ing the substance, or recovering from its ditional opioid therapy in chronic non- dence and physical dependence (248). Ad- effects, important activities given up be- cancer pain. diction was characterized by the presence cause of use, continued use despite phys- of both physical and psychological depen- ical or psychological problems caused by 5.0 TERMINOLOGY OF ABUSE AND dence and was viewed as primarily drug use, and continued use of a substance. ADDICTION induced. In 1964, WHO stopped using the Considering that there is significant terms addiction and habituation altogeth- confusion among all the definitions, sev- 5.1 Introduction er and introduced the term drug depen- eral organizations have also defined and The terminology related to abuse dence in their place, noting that depen- clarified various terms. These definitions and addiction of opioids and other con- dence is either psychological or physio- are related to tolerance, physical depen- trolled substances is considered confusing logic or both, and is a common feature of dence, and addiction. and reflects a lack of understanding of the both conditions (249). In 1969, the WHO Tolerance is the need for an increased multiple issues related to abuse and addic- re-conceptualized the definition of drug dosage of a drug to produce the same lev- tion. Savage et al (247) described the sci- dependence to include significant behav- el of analgesia that previously existed. Tol- entific basis of addiction-related terms. ioral criteria and to explicitly acknowl- erance is also suspected when a reduced They provided three fundamental con- edge that drug dependence is due to both physiologic effect is observed with con- cepts related to addiction in order for it to host and drug factors (250). In 1993, the stant dosing. Analgesic tolerance is not reflect current scientific and clinical un- WHO expert committee on drug depen- always evident during opioid treatment, derstanding: 1) criteria determination of dence noted the potential for confusion and is not to be confused with addiction, addiction rests with the user even though between the terms physical dependence which occurs as a dysfunctional craving some drugs produce pleasurable reward; and drug dependence and substituted of a drug action by physiologic action and 2) addiction is a multidimensional disease the term withdrawal syndrome for physi- psychologically driven factors. with neurobiological and psychosocial di- cal dependence (251). In 1998, the expert Physical dependence is a state of ad- mensions; and 3) addiction is a phenom- committee replaced the term drug depen- aptation manifested by a drug class spe- enon distinct from physical dependence dence with dependence syndrome, but re- cific withdrawal syndrome that can be and tolerance. affirmed its 1993 definition without revi- produced by drug cessation, rapid dose sions (252). Consequently, the 1998 term reduction, decreasing blood level of the 5.2 History “dependence syndrome” and the 1993 drug, and/or administration of an an- Historically terminology has not term “withdrawal syndrome” represent tagonist. Physical dependence is a normal clearly reflected the above-mentioned es- the current WHO nomenclature (252). adaptation to the drug, reinforced by con- sential elements and despite significant The Controlled Substance Act de- tinued use. Physical dependence is most growth in understanding of the scientif- fined addiction as a term meaning any in- commonly associated with withdrawal ic basis of addiction, definitions and di- dividual who habitually uses any narcot- symptoms when the substance is abruptly agnostic criteria persist that are based on ic drug so as to endanger the public mor- discontinued. obsolete conceptualizations of addiction. als, health, safety, or welfare or who is so Addiction by contrast, is compul- The terms have been defined by the World far addicted to the use of narcotic drugs as sive use of a drug despite physical harm, Health Organization (WHO), the Diag- to have lost the power of self-control with and the terms tolerance and addiction nostic and Statistical Manual of Mental reference to his or her addiction (70). are not interchangeable. The terminol- Disorders, fourth edition (DSM-IV) and DSM-IV defines substance abuse ogy may share similar characteristics, as United States federal and state policies, as and dependence. Substance abuse is a many addicts do become tolerant of their well as other organizations by means of maladaptive pattern of substance use chosen drug, which can be expected with consensus statements. leading to significant impairment or dis- regular use. Addiction is a dysfunctional In 1952, in connection with its role tress in the last 12 months with one (or use behavior that includes one or more in the international control of drugs, the more) events such as failure to fulfill ma- of the following: impaired control over WHO used two terms: “addiction” and jor role obligations, using inappropriate drug use, compulsive use, continued use “habituation.” Addiction was viewed pri- substances, participating in hazardous sit- despite harm and craving; however, tol- marily as the direct effect of certain drugs, uations, being involved in recurrent sub- erance is a physiologic alteration of me- and secondly as due to the psycholog- stance related legal problems and/or con- tabolism. ic make-up of the drug taker. In con- tinuing use in the face of adverse con- In a chronic pain state, a patient may trast, habituation was viewed as occur- sequences. In contrast, DSM-IV defines be exposed to a controlled substance for a ring in response to other drugs which substance dependence as a maladaptive prolonged period of time, developing tol- never produce compulsive craving, yet pattern of substance use leading to signif- erance and physical dependence. Addic- their pharmacologic action is found de- icant impairment or distress in the last 12 tion may occur, but is an unlikely event. sirable by some individuals to the point months, meeting the criteria for substance Dependence does not foreshadow harm, that they readily form a habit of admin- abuse plus three or more of the following or intent at self-destructive behavior. It istration (248). The distinction between seven criteria during the same 12 month is therefore, incumbent upon the pain the two terms lacked clarity and confused period: tolerance, withdrawal, inability to management physician to determine that most professionals. In 1957, a commit- control use, unsuccessful attempts to de- these definitions and their physiolog-

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 19 ic undertones are well understood, and long-acting opioid to another (253,254). up to 2 years. They included seven stud- that the overlap of these definitions does Seven trials (255-261) compared a long- ies (254, 256, 262, 264-266, 268) in the re- not necessarily define a controlled sub- acting opioid to a short-acting opioid, view, which were also included by Chou et stance risk, or an inappropriate patient. and seven trials (262-268) compared a al (90). Patients in most studies had previ- In other words, tolerance and dependence long-acting opioid to a non-opioid or pla- ously used opioids. Six of the studies dealt share many common physiologic charac- cebo. The trials ranged in size from 12 pa- with neuropathic pain, four with muscu- teristics, and addiction may be associat- tients to 295 patients, with an average en- loskeletal pain, and one with mixed pain. ed with, but not be defined by, either or rollment of 79 patients. The trials were fo- Of 1,025 randomized patients, 674 com- both. Physical dependence, addiction, and cused on multiple pain problems: five on pleted the studies. Adverse effects and lack tolerance are physiologic, social, and psy- back pain; five on osteoarthritis; two on of efficacy were the most frequent reasons chological considerations with prolonged neuropathic pain; one on phantom limb for discontinuation during both opioid substance management. pain; and three on heterogenous chronic and placebo treatments. They conclud- non-cancer pain. All of the trials were of ed that opioids alleviated nociceptive and 6.0 CLINICAL EFFECTIVENESS relatively short duration, ranging from 5 neuropathic pain, but trials reported large days to 16 weeks. In head-to-head com- individual variations. The mean pain re- 6.1 Introduction parisons, the results showed poor evi- lief with opioid was about 30%. The low- Controversy over the prescription dence that one or more long-acting opi- est maximum doses, morphine 30 mg of opioids for chronic non-malignant oids were superior to other long-acting and oxycodone 20 mg daily were used in pain continues despite the growing ac- opioids in reducing pain and improving musculoskeletal pain and were not effec- ceptance of this practice and claims that functional outcomes when used for treat- tive. About 80% of patients experienced pain is undertreated. The use of opioids ment of adults with chronic non-can- at least one adverse event, with constipa- has been endorsed by multiple societies cer pain. The evidence was poor in com- tion (41%), nausea (32%), and somno- and advocacy organizations as appropri- paring long-acting opioids to other types lence (29%) being most common. Only ate treatment for refractory chronic non- of drugs or to placebo in suggesting that 44% of the 388 patients on open label cancer pain in the general population as one long-acting opioid was more effec- treatments were still on opioids between well as in older patients, when used judi- tive than another. Evidence was also poor 7 and 24 months after therapy. The con- ciously and according to guidelines simi- with regards to long-acting opioids being clusions were that the short-term efficacy lar to those used for cancer patients. While superior to short-acting opioids in reduc- of opioids was good in both neuropath- all agree that opioids are indicated in can- ing pain and improving functional out- ic and musculoskeletal pain conditions. cer pain, questions continue to arise about comes when used for treatment in adults However, only a minority of patients in opioid usage in non-cancer pain on a long with chronic non-cancer pain. Finally, the these studies went on to long-term man- term basis. evidence was also poor as to the effective- agement with opioids. ness or fewer adverse effects of one long- A narrative review by Ballantyne 6.2 Systematic Reviews acting opioid versus another in evaluated and Mao (89) also reviewed clinical stud- Extensive review of the literature was subpopulations, or patients with chronic ies. They concluded that a cautious ap- presented by two systematic reviews and non-cancer pain. The authors were con- proach must be used in dose escalation two narrative and analytic reviews. cerned over a lack of high-quality evi- and further recommended discontinua- A systematic review by Chou et al dence comparing long-acting opioids to tion of opioid if treatment goals are not (90) evaluated the comparative efficacy one another, and to short-acting opioids, met. They also recommended that it is and safety of long-acting oral opioids for in patients with chronic non-cancer pain. imperative physicians make every effort the treatment of chronic non-cancer pain. They felt that data was inadequate to de- to control indiscriminate prescribing even This systematic review had a broad scope termine whether long-acting opioid prep- when they are under pressure by patients and key questions including evaluation arations, either compared to each other or to increase the opioid dose. They reviewed of the population, drugs, outcomes, and to short-acting opioids, have different ef- 16 randomized trials (254, 259, 262, 263, study types. The methodology included ficacy and safety profiles. 266-268, 270, 271, 273-279). Of these, 15 an extensive search of literature published The second systematic review by Kal- showed significant analgesic efficacy for between 1980 and 2001, study selection, so et al (91) included in their methodol- periods of one week to several months. data abstraction, quality assessment, and ogy section the search criteria, inclusion However, beneficial effects on function- data synthesis. Results gave an overview criteria and reporting, data extraction, ing were observed less consistently (253, of included trials, answers to key question and analysis. They provided results of in- 254, 259, 260, 262, 266, 267). Ballantyne outcomes, and a summary of evidence. cluded studies, quality and validity, de- and Mao (89) included seven studies (254, They identified 16 randomized trials with scription of the patient population, oral 256, 259, 262, 263, 267, 268) from Chou 1,427 enrolled patients that evaluated opioid dosing, and open label follow-up et al (90). They also reviewed two studies long-acting opioids in a chronic non-can- studies. They included 18 randomized, (270, 271) from Kalso et al (91). cer pain population. They included con- double-blind, placebo-controlled trials Bloodworth (88) reviewed and ana- trolled clinical trials to evaluate efficacy, which met inclusion criteria. In this sys- lyzed multiple issues in opioid manage- and they also included observational tri- tematic review, 11 studies (254, 256, 262, ment. She performed a review of pub- als to evaluate adverse event rates. In this 264-266, 268-272) compared oral opioids lished trials and identified 26 citations systematic review, the results showed that with placebo, over periods ranging from 4 that evaluated the effects of short- or only two of the 16 trials compared one days to 8 weeks, with open follow-ups of long-term opioids in adults experiencing

Pain Physician Vol. 9, No. 1, 2006 20 Trescot et al • Opioid Guidelines chronic, non-malignant pain (253, 254, Of the 10 additional trials found since the cussed indications and controversies of 260, 262, 263, 266, 267, 270, 275, 277, 279- publication of the above systematic re- the use of opioids in treating chronic non- 293). She included not only randomized views, five studies evaluated tramadol, cancer pain. Breivik reported that in some trials but also observational reports (286- two evaluated oxycodone, one evaluated well selected patients with long-lasting or 289). She included eight studies from transdermal buprenorphine, one com- recurrent pain that is severe enough to Chou et al (90), four studies from Kalso et pared transdermal fentanyl to long-act- markedly reduce their quality of life, and al (91), and nine studies from Ballantyne ing morphine, and one study evaluated for whom no other more effective and less and Mao (89). The average change in pain extended-release oxymorphone. Of these, risky therapies are available, opioid anal- intensity from baseline was 27.8% for pa- four studies included patients with chron- gesics may reduce the intensity of pain, in- tients receiving opioids versus 6.8% for ic low back pain, two studies included pa- crease functioning, and improved quality patients receiving placebo. Over one-third tients with chronic non-specific pain and of life for prolonged periods. of patients receiving a trial of opioids re- four studies included patients with osteo- jected the trial because of adverse effects. arthritis. None of the studies lasted more 7.0 ADHERENCE MONITORING Bloodworth also reported that, based on than 12 weeks, and therefore have limited the results, long-term use of opioid ther- applicability to chronic pain patients. 7.1 Introduction apy is not associated with fine motor or Important issues in opioid therapy cognitive impairment in the majority of 6.4 Infl uence of Psychopathology on for the treatment of chronic pain revolve patients with chronic back pain. Opioid Effectiveness around the appropriate use of prescrip- The four reviews described above, Psychopathology in pain patients tion opioids. Consequently, adherence two systematic and two narrative, evalu- is very common, with major depression monitoring is crucial to avoid abuse of the ated a total of 32 controlled studies (Ta- and anxiety seen in as high as 80% of the drugs and at the same time to encourage ble 10). All the reviews provided only lim- patients, a factor that may have a nega- appropriate use. Adherence monitoring ited strength of evidence with regards to tive affect on opioid analgesia in patients is achieved by screening tests, urine drug the clinical effectiveness of opioids on a with chronic pain (116, 302-315). Depres- testing, and periodic monitoring. long-term basis. sion, anxiety, and neuroticism are disor- Confusion surrounding a specific There was also one systematic litera- ders of negative affect, which often co-oc- operational definition of opioid misuse ture review of reasons for administration, cur in some combination in patients with among chronic pain patients has compli- prescription patterns, effectiveness, and chronic pain (300). Consequently, disor- cated the process of effectively assessing side effects of oral methadone for chron- ders of negative affect have been shown and predicting its occurrence (236,316- ic non-cancer pain (290). The authors of to correlate with increased pain intensi- 318). this study found a total of 21 papers, one ty and poorer function, regardless of the of which was a small randomized tri- treatment modality. It was shown that 7.2 Screening for Opioid Abuse al (291), 13 were case reports, and sev- psychopathology predicts poor opioid an- Even though several investigators en were case series involving 545 patients algesia in patients with chronic low back have described multiple screening instru- under treatment for multiple non-can- pain (302). ments in detecting opioid abuse or mis- cer pain conditions. Methadone was ad- use in chronic pain patients, there is no ministered primarily when previous opi- 6.5 Summary of Evidence widely used screening instrument in cur- oid treatment was ineffective or produced As listed in Table 10, there were rent practice (319-325). Chabal et al (81) intolerable side effects. Starting dos- 43 studies included in the evaluation. developed a prescription abuse “check- es ranged from 0.2 mg to 80 mg per day As described in the systematic reviews, list” consisting of five criteria as listed in and maximum doses ranged from 20 mg the quality of the studies was generally Table 11. Compton et al (319) identified to 930 mg per day. Meaningful outcomes low with regards to chronic pain. Con- three items which were particularly use- in pain were reported in 59% of the pa- sequently, despite multiple randomized ful in identifying misuses of opioids (Ta- tients in the uncontrolled studies. The sin- double-blind trials, the evidence was con- ble 11). Passik et al (320) evaluated a ques- gle randomized trial (291) demonstrated sidered as limited due to lack of long-term tionnaire among a small group of cancer a statistically significant improvement in studies, either comparative or placebo and HIV patients, evaluating medication neuropathic pain with methadone (20 mg controlled. use, present and past drug use, patients per day) as compared to placebo. Side ef- In an editorial titled Potent opioids for beliefs about addiction risk, and aber- fects were considered to be minor. How- chronic musculoskeletal pain: flying blind?, rant drug-taking attitudes and behaviors. ever, the authors cautioned that the figure Von Korff and Deyo (92) discussed vari- Atluri and Sudarshan (324) developed a of 59% effectiveness of methadone should ous issues related to opioid prescriptions. screening tool to detect the risk of inap- be interpreted very cautiously, as it seems They concluded that the studies were in- propriate prescription opioid use in pa- overrated due to the poor quality of the adequate in evaluating effectiveness and tients with chronic pain, with identifica- uncontrolled studies and their tendency risks of opioids in chronic non-cancer tion of six clinical criteria as shown in Ta- to report positive results. pain, prescription opioid abuse is increas- ble 11. Manchikanti et al (322) evaluated ing, caution must be applied in utilizing Atluri and Sudarshan’s (324) assessment 6.3 Other Controlled Trials consensus recommendations as they are tool with identification of three particu- Since the publication of the above not practical in the real world, and there larly useful factors (Table 11, p 22). Ad- reviews, our search yielded 10 additional should be no short cuts around rigorous ams et al (316) developed a pain medica- references as shown in Table 10 (292-301). effectiveness research. Breivik (93) dis- tion questionnaire based on a 26-item in-

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 21

Table 10. Analysis of controlled trials of opioids Chou et al Kalso et al Ballantyne Bloodworth Authors (90) (91) and Mao (89) (88) Drug(s) Tested Condition Evaluated Caldwell et al (254) Yes Yes Yes Yes Morphine vs placebo Osteoarthritis Oxycodone–CR vs Oxy Caldwell et al (256) Yes Yes Yes No Osteoarthritis with acetaminophen Morphine-CR vs Harke et al (264) Yes Yes No No Neuropathic pain carbamazepine Huse et al (265) Yes Yes No No Morphine Phantom-limb pain Moulin et al (266) Yes Yes Yes Yes Morphine Chronic pain Roth et al (262) Yes Yes Yes Yes Oxycodone-CR vs placebo Osteoarthritis Allan et al (253) Yes No No Yes Fentanyl, morphine Chronic pain Codeine-CR vs Codeine Hale et al (255) Yes No No No Chronic low back pain with acetaminophen Osteoarthritis & Gostik et al (257) Yes No No No Dihydrocodeine-CR vs IR chronic back pain Jamison et al (259) Yes No Yes Yes Morphine, oxycodone Chronic low back pain Dihydrocodeine-CR vs Lloyd et al (260) Yes No No Yes propoxyphene Osteoarthritis Salzman et al (261) Yes No No No Oxycodone-CR vs IR Back pain Arkinstall et al (263) Yes No Yes Yes Codeine-CR vs placebo Chronic pain Peloso et al (267) Yes No Yes Yes Codeine-CR Osteoarthritis Watson and Babul (268) Yes Yes Yes No Oxycodone Neuropathic pain Moran (276) Yes Yes Yes No Morphine Rheumatoid arthritis Gimbel et al (269) No Yes No No Oxycodone Diabetic neuropathy Maier et al (270) No Yes Yes Yes Morphine Chronic pain Opioids vs anti- Post-herpetic Raja et al (271) No Yes Yes No depressants neuralgia Watson et al (272) No Yes No No Oxycodone Diabetic neuropathy Oxycodone, Haythornthwaite No No Yes No propoxyphene, codeine, or Chronic pain et al (273) hydrocodone Rowbotham et al (274) No No Yes No Neuropathic pain Kjaersgaard-Andersen Codeine + paracetamol vs No No Yes Yes Osteoarthritis et al (275) paracetamol Sheather-Reid and Cohen Neck pain, No No Yes Yes Codeine vs ibuprofen (277) fi bromyalgia Methadone, levorphanol, Schofferman (278) No No Yes No morphine Low back pain de Craen et al (279) No No No Yes Tramadol Chronic pain Messick (280) No No No Yes Propoxyphene vs APAP Musculoskeletal pain Codeine + paracetamol vs Muller et al (281) No No No Yes tramadol Chronic back pain Codeine + APAP vs Mullican and Lacy (282) No No No Yes tramadol Chronic back pain Palangio et al (283) No No No Yet Hydrocodone vs codeine Musculoskeletal pain Salzman and Brobyn No No No Yes Suprofen vs propoxyphene Osteoarthritis (284) Tramadol SR vs Wilder-Smith et al (285) No No No Yes dihydrocodeine SR Osteoarthritis Morley et al (291) No No No No Methadone Neuropathic pain Malonne et al (292) No No No No Tramadol SR Osteoarthritis Babul et al (293) No No No No Tramadol SR Osteoarthritis Tramadol + Ruoff et al (294) No No No No acetaminophen Chronic low back pain Schnitzer et al (295) No No No No Tramadol Chronic low back pain Transdermal Sittl et al (296) No No No No buprenorphine Chronic pain Oxycodone + Gammaitoni et al (297) No No No No acetaminophen Chronic pain Tramadol + Pelosos et al (298) No No No No acetaminophen Chronic low back pain Markenson et al (299) No No No No Oxycodone-CR Osteoarthritis Allan et al (300) No No No No Fentanyl, morphine Chronic low back pain Matsumoto et al (301) No No No No Oxymorphone Chronic Osteoarthritis

Pain Physician Vol. 9, No. 1, 2006 22 Trescot et al • Opioid Guidelines strument. They concluded that the high- of function despite appropriate analgesia, In principle, urine drug tests er prevalence scores were associated with and frequent requests for medication be- can detect the parent drug and/or its increased disability and patients were at fore renewal is due. metabolite(s) and, therefore, demonstrate greater risk for opioid misuse. Based on the multiple criteria uti- recent use of prescription medications While similarities exist in all the cri- lized and their validation, the following and illegal substances. For most clinical teria described, they differ to a great ex- may be used to indicate potential abuse applications, initial testing is done with tent. The criteria developed by Atluri or inappropriate use of opioids in clinical class-specific immunoassay drug pan- and Sudarshan (324) and evaluated by practice: 1) excessive opioid needs; 2) de- els that typically do not identify individ- Manchikanti et al (322, 323) consistent- ception or lying to obtain controlled sub- ual drugs within a class. However, this ly showed three criteria to be diagnostic stances; 3) doctor shopping; 4) nonfunc- may be followed by a more specific tech- of opioid misuse or abuse, including: ex- tional status; 5) exaggeration of pain; and nique such as a gas chromatography/mass cessive opiate needs, deception or lying to 6) prescription forgery. spectometry (GC/MS) to identify, or con- obtain controlled substances, and doctor firm the presence, or absence, of a spe- shopping. In an elaborate evaluation by 7.3 Urine Drug Testing cific drug and/or its metabolite(s). Nu- Atluri and Sudarshan (324), six criteria Drug testing may be performed by merous differences exist between various were identified which included focus on either testing the urine, serum, or hair. tests and even among the testing labora- opioids, opioid overuse, other substance However, urine is considered to be the tories and manufacturers of various rap- use, nonfunctional status, exaggeration of best biologic specimen for detecting the id drug screen tests, including the number pain, and unclear pain etiology. Howev- presence or absence of certain drugs due of drugs tested, cross-reactivity patterns, er, all screening instruments do not agree. to specificity, sensitivity, ease of adminis- cut-off concentrations, and drug interfer- Portenoy (317) compiled a list of aber- tration, and cost. However, controversies ences. Consequently, clinicians should re- rant drug-related behaviors, which were exist regarding the clinical value of urine member that the cut-off concentrations divided into two risk categories. Among drug testing, partly because the most cur- used for drugs in federally-regulated test- the strongly predictive behaviors identi- rent methods are designed for, or adapted ing, particularly opioids, are too high to fied were forging prescriptions, stealing or from, forensic or occupational deterrent- be of value in clinical practice. Federally- borrowing drugs from others, frequently based testing for illicit drug use and are regulated testing includes the five drugs or losing prescriptions, and resisting chang- not necessarily optimized for clinical ap- drug classes tested for in federal employ- es to pain treatment despite adverse ef- plications in chronic pain management. ees and employees of federally-regulated fects. Less predictive behaviors were ag- However, in chronic pain management, industries. The five include marijuana, gressive complaining about the need for when used with an appropriate level of cocaine, opiates, PCP, and amphetamines/ more drugs, drug hoarding, and unsanc- understanding, urine drug testing can im- methamphetamines, with pre-determined tioned dose escalation or other forms of prove a physician’s professional ability to cut-off levels with mandatory reconfirma- noncompliance. With a similar list, Sav- manage therapeutic prescription drugs tion of results by GC/MS, along with split age (318) suggested that opioid addiction with controlled substances, and to diag- sample in chain of custody requirements. might be revealed through such behaviors nose substance abuse or appropriate in- In contrast, non-regulated testing is used as unwillingness to taper opioids or try al- take of drugs, thereby leading to proper for many purposes, including monitoring ternative pain treatments, decreased levels treatment. patients clinically.

Table 11. Summary description of key criteria in the literature

Criteria by Atluri and Criteria by Chabal et al (81) Criteria by Criteria by Criteria by Sudarshan (324) Compton et al (319) Manchikanti et al (322) Savage (235) Overwhelming focus on opiate issues Belief of addiction Unwillingness to Focused on opioids during pain clinic visits, persistent Excessive opiates needs by the patient taper opioids beyond the third clinic treatment session Effective The pattern of early refi lls (3 or more) or Deception or lying Increasing analgesic analgesia, but Opioid overuse escalating drug use in the absence of an to obtain controlled dose or frequency decreased acute change in the medical condition substance function Multiple telephone calls or visits with Route of requests for more opiates, early refi lls, Other substance use administration Doctor shopping Early refi lls or problems associated with the opiate preference prescription Prescription problems, including lost Non-functional medications, spilled medications, or stolen medications Opiates obtained from multiple Exaggeration of pain providers, emergency rooms, or illegal sources

Etiology of pain unclear

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 23

In clinical practice, urine drug test- Table 12. Typical detection times for urine drug testing of common drugs of abuse ing is used for accurate record keeping, to identify use of undisclosed substanc- Detection Time Cutoff Level Drug es, to uncover diversion or trafficking, in Urine (ng/mL) and to determine appropriate intake of Morphine 1 to 3 days (2 wks) 300 prescribed substances. There are typically two types of urine drug testing. These ap- Methadone 2 to 4 days ( 2 wks) 300 proaches used in proper combination can Hydrocodone 2 to 4 days ( 2 wks) 50 reduce cost, ensure accuracy, and improve Oxycodone 2 to 4 days ( 2 wks) 100 efficiency. The two main types of urine Benzodiazepines Up to 30 days 300 drug testing methods are: 1) Immunoassay drug testing, either Barbiturates (short-acting) 2 to 4 days 300 laboratory based or by rapid drug Barbiturates (long-acting) Up to 30 days 300 testing 2) Laboratory-based specifi c drug Marijuana (chronic use) Up to 30 days 50 identifi cation with GC/MS, high- Cocaine (benzoylecgonine-cocaine metabolite) 1 to 3 days 300 performance liquid chromatography (HPLC), etc. Amphetamine or methamphetamine 2 to 4 days 1000 Immunoassays, which are based on the principle of competitive binding, use antibodies to detect the presence of a par- agement settings a panel for rapid drug pected. Physicians not familiar with the ticular drug or metabolite in a urine sam- screening should include not only opi- opioid metabolites have wrongly accused ple. Immunoassay drug testing is provid- ates, but also oxycodone and methadone. too many patients of drug abuse. ed either in the laboratory or by means In addition, the panel should include co- of rapid drug testing at the point of ser- caine, marijuana, amphetamines and 7.4 Periodic Review and Monitoring vice. An immunoassay’s ability to de- methamphetamines for illicit drugs, and 7.4.1 Periodic Review tect drugs will vary according to the drug benzodiazepines and barbiturates for oth- Periodic reviews should assess: the concentration in the urine and the as- er controlled substances. If a custom pan- medical diagnoses; psychological diagno- say’s cut-off concentration. Any response el is not available, multiple tests may have ses; informed consent; treatment agree- above the cut-off is deemed positive and to be performed as rapid drug screening. ment; appropriate opioid therapy with any response below the cut-off is nega- Since false-negatives and false-positives or without adjuvant medications or with tive. Further, immunoassays are subject are possible, when questions arise, prior or without interventional techniques; pre to cross-reactivity. For example, tests for to taking any actions, a confirmatory test and post intervention assessment of pain cocaine are highly predictive of cocaine or no-threshold test must be performed in level and function; and reassessment of use. By contrast, tests for amphetamine/ the laboratory. pain score and level of function. methamphetamine are highly cross-re- Note that detection times can vary Regular assessment of the patient active and are unreliable. They may de- considerably, depending upon acute ver- along with the periodic review of the di- tect other sympathomimetic amines sus chronic use, the particular drug used agnosis is extremely important. Routine such as ephedrine and pseudoephed- within a class, individual characteristics of assessment of the “4 As” (analgesia, activ- rine and, therefore, are not very predic- the patient, and the method used to test ity, aberrant behavior, and adverse effects) tive for amphetamine/methamphetamine for a substance. will help to direct therapy and support the use. Further, standard tests for opiates are Physicians should establish a policy pharmacologic actions taken. very responsive for morphine and co- regarding their response to a positive drug Further assessment should be per- deine, but do not distinguish which is screen. This may include referral to an ad- formed by periodic monitoring, utilizing present. They also show a lower sensitivity dictionologist or psychologist, or may re- drug screening tests, and urine drug testing. for semisynthetic/synthetic opioids such sult in the refusal to prescribe opioids. as oxycodone, fentanyl, methadone, and However, it usually does not warrant dis- 7.4.2 Periodic Monitoring buprenorphine – a negative response does missal of the patient. Furthermore, a poli- At reasonable intervals, depending not exclude use of these opioids. Specif- cy regarding inappropriate use of prescrip- on the specific circumstances of a given ic immunoassay tests for semisynthetics/ tion drugs provided by the physician, as patient, the physician should review the synthetic opioids may be available. well as doctor shopping, also should be ad- course of treatment and any new infor- In contrast to immunoassays or rap- dressed systematically and consistently. In- mation about the etiology of the pain. id drug testing, laboratory-based specific terpretation of drug screens must include Continuation or modification of therapy drug identification is more sophisticated knowledge of the opioid metabolites. For should depend on the physician’s evalu- and expensive. Laboratory-based specific example, a urine screen positive for hydro- ation of progress towards stated treat- drug identification is needed to specifi- morphone in a patient receiving hydroco- ment goals, such as a reduction in a pa- cally confirm the presence of a given drug done reflects not drug abuse but the appro- tient’s pain scores and improved physical and to identify drugs not included in a priate metabolism of hydrocodone. In the and/or psychosocial function (i.e., ability screening test. Table 12 illustrates cut-off same way, since codeine is metabolized to to work, utilization of healthcare resourc- levels for various drugs detected by urine morphine, a screen positive for morphine es, activities of daily living, and quality of analysis. Ideally, in chronic pain man- in a patient taking codeine would be ex- social life). If treatment goals are not be-

Pain Physician Vol. 9, No. 1, 2006 24 Trescot et al • Opioid Guidelines ing achieved despite medication adjust- copy of the prescription form is sent to a drug abuse (4, 9). A 1999 survey of prima- ments, the physician should reevaluate state regulatory agency. However, in recent ry care physicians found there was a gen- the appropriateness of continued treat- years these programs have increasingly eral lack of training in medical schools ment with the current medications. The been replaced by electronic variations about addiction and the signs of substance physician should monitor patient com- that require pharmacists to transmit abuse (327). This survey revealed that pliance in medication usage and related prescription information via computer to 46.6% of physicians had difficulty dis- treatment plans. a designated state agency. cussing prescription drug abuse with pa- 7.4.3 Prescription Drug Monitoring Physicians can use these prescription tients, and only 32.1% carefully screened Prescription monitoring programs programs to their advantage in monitor- their patients for substance abuse (327). are changing as the result of recently ing patients. Monitoring can be achieved This leads to difficulty discussing sub- enacted NASPER legislation that will assist by initial assessment followed by intermit- stance abuse with patients and an inabili- physicians and pharmacists in identifying tent assessment of a patient’s drug profile. ty to recognize the signs of addiction. Fig- controlled substance abuse (1,2,5-9). However, if abuse is suspected or the phy- ure 8 shows that the majority of the phy- While some existing monitoring programs sician’s office receives complaints from sicians surveyed did not feel “very pre- intend to support state laws to ensure family, friends, neighbors, law enforce- pared” to diagnose substance abuse. legitimate access to drugs, while preventing ment, appropriate action should be taken, The educational aspects have been illegal diversion (7,9), many represent along with frequent monitoring. improving gradually. The American So- ciety of Interventional Pain Physicians information collected to assist state 7.4.4 Periodic Education (ASIPP) assists in preventing diversion law enforcement and regulatory agents Drug education for physicians, pro- while maintaining the availability of pre- in identifying and investigating illegal viders, and patients is crucial. While it ap- scription drugs for medical treatment. practices related to controlled substances. pears that certain medications have revo- ASIPP has devised guidelines for the use NASPER legislation will allow lutionized the treatment of chronic pain of controlled substances in the manage- for electronic sharing of information in the United States, physicians must bal- ment of pain, which include informa- across state lines, with physicians and ance medical need with the possibility of tion on how to conduct a comprehen- pharmacists as primary users of the system. abuse and diversion, as well as the necessi- sive evaluation to select patients for drug State by state development of NASPER ty to comply with state and federal regula- therapy and how to use a “controlled sub- programs will allow for electronic sharing tions. It is obvious that healthcare practi- stance agreement” as part of patient care. of information across state lines and will tioners are not only expected to prescribe Other ASIPP activities have included ac- ultimately replace most of the current medications when there is medical need tions and support leading to the passage prescription monitoring programs. and document appropriately, but they are of the National All Schedules Prescrip- Current programs generally involve also expected to prevent illegal diversion tion Electronic Reporting Act (NASPER) either use of multiple-copy prescriptions and identify drug abuse. Consequently, for uniform drug monitoring programs or electronic transmission. Multiple- education is a critical component of any across the states with interstate commu- copy prescription programs require program to control the diversion of pre- nication and physician access to the mon- physicians to use state-issued duplicate scription drugs (326). itoring programs. In addition, the Amer- copy prescription pads that contain serial However, data shows that many phy- ican Board of Interventional Pain Physi- numbers. After a prescription is fi lled, one sicians get little to no training regarding cians has made a competency certification available for interested physicians. Other organizations involved in substance abuse Hypertension 82.8% training include the American Acade- my of Family Physicians which has taken Diabetes 82.3% steps to make physicians aware of practic- es such as doctor shopping, and the Amer- ican Society of Addiction Medicine which Depression 44.1% conducts seminars and also provides cer- tification in addiction management. Prescription Drug Misuse 30.2% Additionally, several states have tak- en steps to educate physicians about pre- scription drugs. Alcoholism 19.9% 7.4.5 Pill Counts Random pill counts, along with urine Illegal Drug Use 16.9% drug testing and prescription monitoring, 0% 20% 40% 60% 80% would greatly reduce controlled substance abuse and diversion. Pill counts are essen- tial in patients suspected of abuse. How- Conditions that physicians feel “very prepared” to diagnose, 1999 Fig. 8. ever, these can also be performed ran- Source: The National Center on Addiction and Substance Abuse at Columbia University, Missed domly on high risk patients. Opportunity: National Survey of Primary Care Physicians and Patients on Substance Abuse (New York: CASA, 2000) (327) A pill count is performed by notifying the patient a day before or on the day of the

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 25 patient’s appointment that they are request- may be prescribed at lower doses to main- tocol and algorithmic approach for opi- ed to bring any unused pills to the appoint- tain functional status in conjunction with oid therapy. ment. Inability to provide pills, or provid- interventional techniques. It has also been Model guidelines for the use of opi- ing a reduced number, will indicate use be- shown that interventional techniques re- oids for the treatment of pain by the Fed- yond the prescription. Pill counts above ex- duce psychological distress significantly eration of Medical Boards, adapted by pected ranges would indicate inappropriate once the pain improves. More likely than several states also provide guidance in the intake. Recently, it has been reported that not, the requirement for opioids and ad- principles of opioid management (73). unsuspecting elderly patients may be selling juvant drugs may be reduced (329-336). their prescriptions of controlled substances Hence, interventional pain physicians 8.2 Basic Philosophy to supplement their incomes (328). probably should not compare the patients Principles for prescribing opioids in their settings who are undergoing in- must require a comprehensive evaluation 8.0 PRINCIPLES OF OPIOID USE terventional techniques with others who (mandatory physical and optional psycho- are receiving drug therapy as a mainstay. logical), appropriate documentation at reg- 8.1 Introduction Monotherapy, particularly with opioids, ular intervals to assess the efficacy of ther- In interventional pain management, may be appropriate for only a small sub- apy, with specific evaluation of the impact patients may receive not only opioid an- group of those with chronic pain. on functional status, degree of pain relief, algesics, but also other controlled or non- Gourlay et al (336) described a ratio- identification and treatment of undesirable controlled drugs. Further, patients may be nal approach to the treatment of chronic side effects, and monitoring for abuse be- receiving controlled substances as an ad- pain with opioids. They described a pain haviors. In addition, there must be adher- junct to interventional techniques, as well and addiction continuum of substance ence to a controlled substance agreement as to manage comorbid psychiatric and use in pain patients leading to implemen- and with regulatory guidelines promul- psychological disorders. Thus, the effec- tation of “universal precautions” in pain gated by various agencies. Figure 9 shows tiveness studies published may not apply medicine. Ballantyne and Mao (89) also an algorithmic approach to patient evalu- in the majority of cases in intervention- described the potential adverse conse- ation and management. Table 13 (page 26) al pain management. Indeed, controlled quences of prolonged opioid therapy, the shows an algorithmic approach for chronic substances, particularly opioid analgesics, clinical implications, and a suggested pro- opioid therapy.

Evaluation and Management

History Assessment Pain History Physical Medical History Functional Psychosocial History Psychosocial Diagnostic testing

Impression

Management Plan

Alternatives Diagnostic Interventions Therapeutic Interventional Management

Re-evaluation

Persistent Pain Adequate Pain Relief and New Pain improvement in functional status Worsening Pain

Repeat Comprehensive Discharge or Maintain Evaluation

Fig 9. A suggested algorithm for comprehensive evaluation and management of chronic pain.

Pain Physician Vol. 9, No. 1, 2006 26 Trescot et al • Opioid Guidelines

8.3 Evaluation Table 13. Ten step process: An algorithmic approach for long-term opioid therapy in Appropriate history, physical exam- chronic pain ination, and medical decision-making based on the initial evaluation of a pa- STEP I Comprehensive initial evaluation tient’s presenting symptoms are essen- STEP II Establish diagnosis tial. Guidelines by the Centers for Medi- ♦X-rays, MRI, CT, neuro-physiological studies care and Medicaid Services (CMS) pro- ♦Psychological evaluation vide various criteria for five levels of ser- ♦Precision diagnostic interventions vice (337-339). The three crucial com- STEP III Establish medical necessity (lack of progress or as supplemental therapy) ponents of evaluation and management ♦Physical diagnosis services are: history, physical examina- ♦Therapeutic interventional pain management tion, and medical decision-making. Oth- ♦Physical modalities ♦ er components include counseling, coor- Behavior therapy dination of care, nature of the presenting STEP IV Assess risk-benefi t ratio problem, and time required for face-to- ♦Treatment is benefi cial face evaluation. While there are numer- STEP V Establish treatment goals ous techniques to evaluate a chronic pain patient, and these vary from physician STEP VI Obtain informed consent and agreement to physician, institution to institution, STEP VII Initial dose adjustment phase (up to 8-12 weeks) and textbook to textbook, following the ♦Start low dose guidelines established by CMS will assist a ♦Utilize opioids, NSAIDs and adjuvants physician in performing a comprehensive ♦Discontinue due to  Lack of analgesia and complete evaluation while complying  with regulations. Side effects  Lack of functional improvement 8.3.1 History STEP VIII Stable phase (stable – moderate doses) The history includes the chief com- ♦ Monthly refi lls plaint, history of the present illness, re- ♦ Assess for four As view of systems, and past, family, and/or  Analgesia social history (337-339).  Activity History of the present illness is a  Aberrant behavior chronological description of the de-  Adverse effect ♦ velopment of a patient’s present illness Manage side effects from the first sign and/or symptom. It in- STEP IX Adherence monitoring cludes multiple elements: location; quali- ♦ Prescription monitoring programs ♦ ty, severity, duration, timing, context, and Random drug screens ♦ modifying factors; and associated signs Pill counts and symptoms. STEP X Outcomes Review of systems is an inventory of ♦Successful – continue body systems obtained through a series of  Stable doses  questions seeking to identify signs and/or Analgesia, activity  symptoms that the patient may be experi- No abuse, side effects ♦ Failed – discontinue if encing or has experienced.  Dose escalation Past, family, and/or social history is  No analgesia crucial for chronic pain patients who may  No activity be treated with opioids. It consists of a re-  Abuse view of the past history of the patient, in-  Side effects cluding past experiences, illnesses, opera-  Non-compliance tions, injuries, and treatment; family his- tory, including a review of medical events in the patient’s family, hereditary diseases, thematosus; drug dependency, alcohol- psychological disorders such as depres- and other factors; and social history ap- ism, or drug abuse; and psychological dis- sion, anxiety, schizophrenia, and suicid- propriate for age reflecting past and cur- orders such as depression, anxiety, schizo- al tendencies, etc., specifically in first de- rent activities. phrenia, suicidal tendencies, etc. gree relatives. Past history in interventional pain Family history is also important, and Social history is also of crucial im- management includes history of past pain should include not only the history of dif- portance in administering opioids, in- problems; motor vehicle, occupational, or ferent pain problems, including degener- cluding environmental information, ed- non-occupational injuries; history of var- ative disorders, but also should include ucation, marital status, children, habits, ious pain problems; disorders such as ar- familial disorders, drug or chemical de- hobbies, occupational history, family sup- thritis, fibromyalgia, systemic lupus ery- pendency, alcoholism, or drug abuse and port system, and recreational drug usage.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 27

8.3.2 Effect on Functional Status fering. Relief of the underlying causes of agement and functional improvement. Some of the aspects specific in con- suffering, as well as the pain, will lead to The effectiveness of various intervention- trolled substance abuse and chronic pain optimal treatment and utilization of con- al techniques has been evaluated in sys- include evaluation of effect of pain on trolled substances. tematic reviews (12,341,346-350). physical and psychological function, such A written treatment plan should as activities of daily living. 8.7 Medical Decision Making and document objectives that will be used to Treatment Plan 8.3.3 Drug History evaluate treatment success, including pain It is important to obtain a patient Medical decision making refers to relief and improved physical and psycho- drug profile, including drug history and the complexity of establishing a diagno- social function, and should indicate if ad- family history of drugs, and other chronic sis and/or selecting a management option, ditional diagnostic tests, consultations, pain patients in the patient’s social circles. including providing controlled substanc- or treatments are planned. After starting It is also important to obtain a pre-drug es to a patient, and is measured by three treatment, the physician should carefully screening prior to embarking on opioid components: diagnosis/management op- adjust the drug therapy to the individual therapy in conjunction with obtaining a tions with a number of possible differ- medical needs of each patient. In the con- patient’s opinion with regards to the doses ential diagnoses and/or the number of tinuum of treatment, other modalities in- of controlled substances, the importance management options; review of records/ cluding interventional techniques, reha- of adherence, and its monitoring. investigations, with number and/or com- bilitation, and psychological therapy may plexity of medical records, diagnostic be necessary depending on the etiology of 8.4 Physical Examination tests, and other information that must pain and the extent to which pain is asso- Physical examination involves gen- be obtained, reviewed, and analyzed; and ciated with physical, functional, and psy- eral, musculoskeletal, and neurological risks of significant complications, mor- chosocial impairment. examinations. Examination of other sys- bidity and mortality, as well as comor- 8.8 Consultation tems, specifically cardiovascular, lymphat- bidities associated with the patient’s pre- ic, skin, eyes and cranial nerves is recom- senting problem(s), the diagnostic proce- To achieve treatment objectives, phy- mended based on the presenting symp- dures, and/or the possible management sicians should be willing to refer a patient tomatology (337-339). options (337-339). for additional evaluation as clinically in- Prior to embarking on a regimen of dicated. Special attention should be given 8.5 Laboratory Studies opioids, the physician must determine, to those patients who are at risk of mis- To complement the history and through actual clinical trial or through using their medications and those whose physical examination, a review of the re- patient records and history, that non-ad- living arrangements create a risk for med- cords, either previous records or various dictive medication regimens and/or in- ication misuse or diversion. The manage- investigations, must be obtained or new terventional techniques have been inade- ment of patients with a history of sub- investigations must be ordered as appro- quate or are unacceptable for solid, clin- stance abuse or with a coexisting psy- priate. These include multiple radiologi- ical reasons. If this information is not chiatric disorder may require extra care, cal studies such as x-rays, MRIs, CT, bone available entirely through the patient, a monitoring, documentation, and consul- scan, etc.; electrophysiologic studies such family conference may be helpful to eval- tation with, or referral to, an addictionol- as EMG and nerve conduction studies; uate the patient’s integrity. However, be- ogist. The lack of well-trained psycholo- and blood work. cause of HIPPA regulations, the ability gists and psychiatrists in many regions of to have family conferences may be lim- the country may make this referral diffi- 8.6 Psychological Evaluation ited. An extensive drug utilization his- cult to obtain. In many locations there are Psychological evaluation is an exten- tory of the patient must be documented no clinically trained addiction specialists sion of the evaluation process similar to through previous medical records, state with whom to collaborate. the laboratory evaluation, imaging tech- drug monitoring programs, and multiple 8.9 Informed Consent and the Controlled niques, electromyography and nerve con- other avenues. Substance Agreement duction studies. Diagnostic interventional techniques By definition, pain is a subjective de- will assist in making the proper diagno- At the outset, the physician should scription of the patient’s perception of sis by following an algorithmic approach discuss the risks and benefits of the use actual or potential tissue damage. The (12). It has been shown that in approxi- of controlled substances with the patient distinction between pain and suffering mately 70% to 85% of patients with spi- or surrogate, including the risk of toler- should be established. A patient may suf- nal pain an accurate diagnosis may not be ance and drug dependence. It is advis- fer due to pain, but may have other rea- determined in spite of the available histo- able to employ the use of a written agree- sons for suffering as well. The assessment ry, physical examination, EMG nerve con- ment between physician and patient out- of a patient’s overall condition should be duction studies, and radiological evalu- lining patient responsibilities. Agreements made at the initial evaluation and fre- ation. With precise diagnostic interven- are helpful, specifically if the patient is de- quently thereafter. It is the goal of the tional techniques, the chances of diagnosis termined to be at high risk for medication physician to assist in the relief of suffer- may be improved substantially, and proper abuse or has a history of substance abuse. ing, no matter the cause. Financial, emo- treatment may be offered (12,340-345). Possible items of a controlled substance tional, mental, physical, and spiritual fac- Therapeutic interventional tech- agreement between a physician and pa- tors may contribute to the patient’s suf- niques also may be used as a monotherapy tient include: rather than using opioids for pain man- 1. One prescribing doctor and one

Pain Physician Vol. 9, No. 1, 2006 28 Trescot et al • Opioid Guidelines

designated pharmacy Physicians, under all circumstanc- 10.0 KEY POINTS 2. Urine/serum drug screening when es, except for unavoidable emergencies, 1. Opioid guidelines for the treatment requested should not prescribe scheduled drugs for of chronic non-cancer pain are de- 3. No early refi lls and no medications can themselves, immediate family, or staff. be called in. If medications are lost or veloped to improve quality and ap- The following criteria should be con- stolen, then a police report could be propriateness of care, improve pa- sidered carefully in providing controlled required before considering additional tient access, improve patient quality substances: prescriptions. of life, improve efficiency and effec- 1. Complete initial evaluation, including The reasons for which opioid drug tiveness, and achieve cost contain- therapy may be discontinued should be history and physical examination 2. Psychological evaluation ment by improving the cost-benefit delineated, such as violation of a docu- 3. Physiological and functional assess- ratio. mented doctor/patient agreement. Addi- ment, as necessary and feasible 2. Rationalization and importance of tional items to be included in an agree- 4. Definition of indications and medical these guidelines derives from the fact ment are listed in Figure 10. necessity: that most available evidence docu- ♦ Pain of moderate-to-severe degree ments a wide degree of variance in 9.0 DOCUMENTATION AND MEDICAL ♦ Suspected organic problem the prescribing patterns of opioids RECORDS ♦ Failure to respond to non- for chronic pain. The strength of The physician should keep accurate controlled substances, adjuvant agents, physical therapy, and available evidence for the use of opi- and complete medical records which in- interventional techniques oids for chronic non-cancer pain re- clude all aspects of interventional pain ♦ Patients with interventional mains Limited, Level IV. management and medical care. These techniques as primary modality 3. Opioids are extensively used in man- comprise, but are not limited to: and controlled substance drugs as aging chronic pain. ♦ The medical history and physical a second line treatment. 4. There is significant evidence of opi- examination ♦ Responsiveness to prior oid abuse in conjunction with or ♦ Diagnostic, therapeutic, and laboratory interventions with improvement results in physical and functional status without illicit drugs. ♦ Evaluations and consultations for continued management, with 5. Abuse terminology is variable. This ♦ Treatment objectives or without interventions, must be document attempts to standardize ♦ Discussion of risks, benefi ts, and documented. and provide common sense defini- limitations of treatments ♦ For non-opioid controlled sub- tions. ♦ Details of different treatments and stances, appropriate documenta- 6. Opioid pharmacology is variable but medications, including date, type, dosage, tion of psychological disorders understanding it is essential to prop- and quantity prescribed should be maintained. er management of patients. ♦ Instructions to the patient ♦ Continued opioid prescriptions ♦ Periodic reviews of outcomes, including require monitoring of: 7. Among the rules of opioid admin- documentation of functional status, • Analgesia istration, comprehensive evaluation preferably using validated tools • Activity and diagnostic assessment are cru- Records should remain current and • Aberrant behavior cial, including diagnosis by interven- be maintained in an accessible manner • Adverse effects tional techniques. and readily available for review, not only 5. Adherence to the controlled sub- 8. Establishing goals of treatment and for the physician and other members of stance agreement with the patient using a controlled substance agree- the practice, but also the authorities. understanding the risks and benefits ment are essential in the practice of To be in compliance with con- of controlled substances and the pol- pain management with opioids. trolled substance laws and regulations icy and regulations of the practitio- 9. Periodic review of the patient on required to prescribe, dispense, or ad- ner, including controlled substances opioids is essential, using appropri- minister controlled substances, the phy- being prescribed by only one practi- ate adjustments, with routine assess- sician must have an active license in the tioner and being obtained from only ment of analgesia, activity, aberrant state and comply with applicable federal one pharmacy. behavior, and adverse effects. and state regulations. Various boards have 6. Monitoring for drug abuse or diver- 10. Documentation is essential, includ- published regulations and recommenda- sion should be routine and, if con- ing the need to keep accurate and tions for prescribing controlled substanc- firmed, referral to rehabilitation cen- complete medical records with all es. Physicians are advised to refer to these ters may be made, along with ter- the essential elements to provide regulations for their respective state. mination of prescriptions for con- proper patient care and also meet trolled substances. regulatory and legal requirements.

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 29

We are committed to doing all we can to treat your chronic pain condition. In some cases, controlled substances are used as a therapeutic option in the management of chronic pain, which is strictly regulated by both state and federal agencies. This agreement is a tool to protect both you and the physician by establishing guidelines, within the laws, for proper and controlled substance use. The words “we” and “our” refer to the facility and the words “I,” “you,” “me,” or “my” refer to you, the patient.

1. All controlled substances must come from the physician whose signature appears below or, during his/her absence, by the covering physician, unless specifi c authorization is obtained for an exception. I understand that I must tell the physician whose signature appears below or, during his/her absence, the covering physician, all drugs that I am taking, have purchased, or have obtained, even over-the-counter medications. Failure to do so may result in drug interactions or overdoses that could result in harm to me, including death. I will not seek prescriptions for controlled substances from any other physician, healthcare provider, or dentist. I understand it is unlawful to be prescribed the same controlled medication by more than one physician at a time without each physician’s knowledge. I also understand that it is unlawful to obtain or to attempt or obtain a prescription for a controlled substance by knowingly misrepresenting facts to a physician, or his/her staff, or knowingly withholding facts from a physician or his/her staff (including failure to inform the physician or his/her staff of all controlled substances that I have been prescribed).

2. All controlled substances must be obtained at the same pharmacy, where possible. Should the need arise to change pharmacies, our offi ce must be informed. The pharmacy that you have selected is:

______phone: ______

3. You may not share, sell, or otherwise permit others, including spouse or family members, to have access to any controlled substances that you have been prescribed.

4. Unannounced urine or serum toxicology specimens may be requested from you, and your cooperation is required. Presence of unauthorized substances in urine or serum toxicology screens may result in your discharge from this facility.

5. I will not consume excessive amounts of alcohol in conjunction with controlled substances. I will not use, purchase, or otherwise obtain any other legal drugs except as specifi cally authorized by the physician whose signature appears below or, during his/her absence by the covering physician, as set forth in Section 1 above. I will not use, purchase or otherwise obtain any illegal drugs, including marijuana, cocaine, etc. I understand that driving while under the infl uence of any substance, including a prescribed controlled substance, or any combination of substances (e.g., alcohol and prescription drugs) which impairs my driving ability, may result in DUI charges.

6. Medications or written prescriptions may not be replaced if they are lost, stolen, get wet, are destroyed, left on an airplane, etc. If your medication has been stolen it will not be replaced unless explicit proof is provided with direct evidence from authorities. A report narrating what you told authorities is not enough.

7. Early refi lls will not be given. Renewals are based upon keeping scheduled appointments. Please do not phone for prescriptions after hours or on weekends.

8. In the event you are arrested or incarcerated related to legal or illegal drugs (including alcohol), refi lls on controlled substances will not be given.

9. I understand that failure to adhere to these policies may result in cessation of therapy with controlled substances prescribed by this physician and other physicians at the facility and that law enforcement offi cials may be contacted.

10. I affi rm that I have full right and power to sign and be bound by this agreement, and that I have read it and understand and accept all of its terms. A copy of this document has been given to me.

______Patient’s full name

______Patient’s signature Date

______Physician’s signature Date

Fig 10. Sample Controlled Substance Agreement Adapted from Pain Management Center of Paducah, Paducah, KY (Courtesy of Laxmaiah Manchikanti, MD)

Pain Physician Vol. 9, No. 1, 2006 30 Trescot et al • Opioid Guidelines

AUTHOR AFFILIATION

Andrea M. Trescot, MD Vijay Singh, MD Praveen K. Suchdev, MD Medical Director Medical Director Medical Director The Pain Center Pain Diagnostics Associates Pain Solutions 1564 Kingsley Ave. 1601 Roosevelt Rd. Centers for Pain Solutions- Orange Park, FL 32073 Niagara, WI 54151 Ambulatory Surgery Center E-mail: [email protected] E-mail: [email protected] 280 Main Street, Suite 420 Nashua, NH 03060 Mark V. Boswell, MD, PhD Arthur E. Jordan, MD E-mail: [email protected] Professor of Anesthesiology Director, Pain Management Center Division of Pain Medicine Carolina Health Specialists John R. Swicegood, MD Texas Tech University Health Sciences 945 82nd Parkway Medical Director Center Myrtle Beach, SC 29572 Advanced Interventional Pain and 3601 4th Street, MS 8182 E-mail: [email protected] Diagnostics of Western Arkansas Lubbock, TX 79430 P. O. Box 10206 Benjamin W. Johnson, MD E-mail: [email protected] Fort Smith, AR 72917 Director, Vanderbilt Pain Control E-mail: [email protected] Sairam L. Atluri, MD Center Medical Director Associate Professor of Anesthesiology Aaron K. Calodney, MD Tri-State Pain Management Institute Vanderbilt University Medical Center Director and Research Coordinator 7655 Five Mile Road, Suite 117 Vanderbilt University School of Implantable Therapies Cincinnati, OH 45230 Medicine NeuroCare Network E-mail: [email protected] Nashville, Tennessee P. O. Box 130459 Tyler, TX 75713-0459 Hans C. Hansen, MD Roger S. Cicala, MD E-mail: [email protected] Medical Director Physician Pain Relief Centers Semmes-Murphey Neurosurgical Bentley A. Ogoke, MD 1224 Commerce Street SW Institute Medical Director Conover, NC 28613 Associate Professor of Anesthesiology Northern Pain Management Center E-mail: [email protected] University of Tennessee Center for 125 Liberty Street, Suite 100 Health Sciences Springfi eld, MA 01103 Timothy R. Deer, MD 8940 Meaghan Drive E-mail: [email protected] Director Memphis, TN 38018 The Center for Pain Relief and E-mail: [email protected] W. Stephen Minore, MD Clinical Professor, Anesthesiology President, Rockford Anesthesiologists West Virginia University Elmer E. Dunbar, MD Associated Chairman, Committee on Pain Medical Director 2202 Harlem Road, Suite 200 Medicine Pain Control Network Loves Park, IL 61111 The American Society of 6400 Dutchman Parkway, Suite 60 and Clinical Assistant Professor Anesthesiology Louisville, KY 40205 University of Illinois College of 400 Court Street, Suite 304 E-mail: [email protected] Medicine Charleston, WV 25301 Rockford, IL Standiford Helm II, MD E-mail: [email protected] E-mail: [email protected] Medical Director Salahadin Abdi, MD, PhD Pacifi c Coast Pain Management Center Laxmaiah Manchikanti, MD Director, Massachusetts General 23792 Rockfi eld Blvd., Suite 101 Medical Director Hospital Pain Center Lake Forest, CA 92630 Pain Management Center of Paducah Department of Anesthesiology and E-mail: [email protected] 2831 Lone Oak Road Critical Care Paducah, KY 42003 Associate Professor of Anesthesiology Kenneth G. Varley, MD Medical Director Associate Clinical Professor of Harvard Medical School Anesthesiology and Perioperative 15 Parkman Street, Suite 333B Southern Pain Specialists 7500 Hugh Daniel Drive, #360 Medicine Boston, MA 02114 University of Louisville School of E-mail: [email protected] Birmingham, AL 35242 and Clinical Associate Professor Medicine Joseph F. Jasper, MD Dept. of Anesthesiology Louisville, KY 40292 Medical Director School of Medicine E-mail: [email protected] Advanced Pain Medicine Physicians University of Alabama at Birmingham 1628 South Mildred Street, Suite 105 E-mail: [email protected] Tacoma, WA 98465-1613 E-mail: [email protected]

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 31

REFERENCES Manchikanti L. Interventional techniques elderly. A systemic review of the literature. in the management of chronic spinal pain: Spine 1999; 24:1813-1819. 1. Manchikanti L, Whitfi eld E, Pallone F. Evidence-based practice guidelines. Pain 27. Lawrence RC, Helmick CG, Arnett FC. Es- Evolution of the national all schedules Physician 2005; 8:1-48. prescription electronic reporting act timates of the prevalence of arthritis and (NASPER): A public law for balancing 13. Manchikanti L, Abdi S, Lucas LF. Evidence selected musculoskeletal disorders in the treatment of pain and drug abuse and di- synthesis and development of guidelines United States. Arthritis Rheum 1998; 41: version. Pain Physician 2005; 8:335-347. in interventional pain management. Pain 778-799. Physician 2005; 8:73-86. 2. Manchikanti L, Brown K, Singh V. National 28. Mallen C, Peat G, Thomas E, Croft P. Se- All Schedules Prescription Electronic Re- 14. West S, King V, Carey T, Lohr K, McKoy verely disabling chronic pain in young porting Act NASPER: Balancing substance N, Sutton S, Lux L. Systems to rate the adults: prevalence from a population- abuse and medical necessity in interven- strength of scientifi c evidence. Evidence based postal survey in North Stafford- tional pain management. Pain Physician Report/Technology Assessment No. 47 shire. BMC Musculoskeletal Disords 2005, 2002; 5:294-319. University of North Carolina: Agency for 6:42. Healthcare Research and Quality. AHRQ 29. Enthoven P, Skargren E, Oberg B. Clinical 3. Atluri S, Boswell MV, Hansen HC, Trescot Publication No. 02-E016; April 2002. AM, Singh V, Jordan AE. Guidelines for the course in patients seeking primary care use of controlled substances in the man- 15. Tunis SR, Stryer DB, Clancy CM. Practical for back or neck pain: A prospective 5-year agement of chronic pain. Pain Physician clinical trials: Increasing the value of clini- follow-up of outcome and health care con- 2003; 6:233-257. cal research for decision making in clinical sumption with subgroup analysis. Spine and health policy. JAMA 2003; 290:1624- 2004; 29:2458-2465. 4. Bollinger LC, Bush C, Califano JA, Chenault 1632. KI, Curtis JL, Dimon J, Dolan PR, Ganzi 30. Sjolie AN. Persistence and change in non- VF, Fisher M, Kelmenson LA, Keough 16. Sackett D, Richardson WS, Roseberg W, specifi c low back pain among adoles- DR, Kessler DA, Malloy EA, Pacheco MT, Haynes RB. Evidence Based Medicine. cents: A 3-year prospective study. Spine Plumeri II JJ, Redstone SE, Rosenwald Jr Churchill Livingstone, Philadelphia, 1996. 2004; 29:2452-2457. EJ, Schulhof MP, Sullivan LW, Sweeney JJ, 17. O’Brien P, Silagy C, McCallum J, O’Connell, 31. Brattberg G. Do pain problems in young Wiener MA. Under the counter. The diver- D, Glasziou P, Hill A. How to use the evi- school children persist into early adult- sion and abuse of controlled prescription dence: Assessment and application of sci- hood? A 13-year follow-up. Eur J Pain drugs in the U.S. The National Center on entifi c evidence. National Health and Med- 2004; 8:187-199. Addition and Substance Abuse at Colum- ical Research Council, Canberra, Common- 32. Elders LA, Burdorf A. Prevalence, inci- bia University (CASA), July 2005. wealth of Australia, 2000, pp 1-84. dence, and recurrence of low back pain 5. Prescription Drug Monitoring: Strategies 18. Stroup DF, Berlin JA, Morton SC, Olkin I, in scaffolders during a 3-year follow-up to Promote Treatment and Deter Prescrip- Williamson GD, Rennie D, Moher D, Beck- study. Spine 2004; 29:E101-E106. tion Drug Abuse. Hearings of Subcommit- er BJ, Sipe TA, Thacker SB. Meta-analysis 33. Hoving JL, de Vet HC, Twisk JW, Deville WL, tee on Health House Energy and Com- of observational studies in epidemiology: van der Windt D, Koes BW, Bouter LM. merce Committee, March 4, 2004. A proposal for reporting. JAMA 2000; 283: Prognostic factors for neck pain in general 6. Public Law No: 109-60. H.R. 1132 signed 2008-2012. practice. Pain 2004; 110:639-645. by President George W. Bush on 8/11/05. 19. Moher D, Schulz KF, Altman D, for the CON- 34. Smith BH, Elliott AM, Hannaford PC, Cham- http://frwebgate.access.gpo.gov/cgi-bin/ SORT Group. The CONSORT statement: re- bers WA, Smith WC. Factors related to the getdoc.cgi?dbname=109_cong_public_ vised recommendations for improving the onset and persistence of chronic back pain laws&docid=f:publ060.109 quality of report of parallel-group random- in the community: Results from a general 7. GAO Report. GAO-02-634 Prescription ized trials. JAMA 2001; 285:1987-1991. population follow-up study. Spine 2004; drugs. State monitoring programs pro- 20. Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, 29:1032-1040. vide useful tool to reduce diversion. Bensing JM. Prevalence of chronic benign 35. Cote P, Cassidy JD, Carroll LJ, Kristman V. May 2002. http://searching.gao.gov/ pain disorder among adults: A review of The annual incidence and course of neck query.html?col=+&qt=+GAO-02- the literature. Pain 1998; 77:231-239. pain in the general population: A popula- 634&charset=iso-8859-1&ql=&x=9&y=14. 21. Blyth FM, March LM, Brnabic AJ, Jorm LR, tion-based cohort study. Pain 2004; 112: (Accessed December 29, 2005) Williamson M, Cousins MJ. Chronic pain in 267-273. 8. Drug Traffi cking in the United States. DEA Australia: A prevalence study. Pain 2001; 36. Daffner SD, Hilibrand AS, Hanscom BS, Briefs and Background, Drugs and Drug 89:127-134. Brislin BT, Vaccaro AR, Albert TJ. Impact of Abuse. www.usdoj.gov/dea/concern/ 22. Gureje O, Von Korff M, Simon GE, Gater R. neck and arm pain on overall health sta- drug_traffi cking.html. (Accessed Decem- Persistent pain and well-being: A World tus. Spine 2003; 28:2030-2035. ber 29, 2005) Health Organization study in primary care. 37. Latza U, Kohlmann T, Deck R, Raspe H. Can 9. Kraman P. Drug abuse in America – pre- JAMA1998; 280:147-151. health care utilization explain the associ- scription drug diversion. The Coun- 23. Elliott AM, Smith BH, Hannaford PC, Smith ation between socioeconomic status and cil of State Governments. April 2004. WC, Chambers WA. The course of chronic back pain? Spine 2004; 29:1561-1566. www.csg.org pain in the community: Results of a 4-year 38. Dionne CE, Chenard M. Back-related func- 10. Brands B, Blake J, Sproule BA, Gourlay D, follow-up study. Pain 2002; 99:299-307. tional limitations among full-time home- Busto UE. Prescription opioid abuse in pa- 24. Yeung SS, Genaidy A, Deddens J, Alhe- makers: A comparison with women em- tients presenting for methadone mainte- mood A, Leung PC. Prevalence of musculo- ployed full-time outside the home. Spine nance treatment. Drug Alcohol Depend skeletal symptoms in single and multiple 2004; 29:1375-1382. 2004; 73:199-207. body regions and effects of perceived risk 39. Luo X, Pietrobon R, Sun SX, Liu GG, Hey 11. Busto UE, Sproule BA, Knight K, Romach of injury among manual handling workers. L. Estimates and patterns of direct health MK, Sellers EM. Severe dependence on Spine 2002; 27:2166-2172. care expenditures among individuals with oral opioids. Can J Clin Pharmacol 1998; 5: 25. Menefee LA, Cohen MJ, Anderson WR, back pain in the United States. Spine 23-28. Doghramji K, Frank ED, Lee H. Sleep dis- 2004; 29:79-86. 12. Boswell MV, Shah RV, Everett CR, Seh- turbance and nonmalignant chronic pain: 40. Reyes-Gibby CC, Aday L, Cleeland C. Im- gal N, Mckenzie-Brown AM, Abdi S, Bow- A comprehensive review of the literature. pact of pain on self-rated health in the man RC, Deer TR, Datta S, Colson JD, Spill- Pain Med 2000; 1:156-172. community-dwelling older adults. Pain ane WF, Smith HS, Lucas-Levin LF, Burton 26. Bressler HB, Keyes WJ, Rochon PA, Badley 2002; 95:75-82. AW, Chopra P, Staats PS, Wasserman RA, E. The prevalence of low back pain in the 41. Leigh JP, Markowitz SB, Fahs M, Shin C,

Pain Physician Vol. 9, No. 1, 2006 32 Trescot et al • Opioid Guidelines

Landrigan PJ. Occupational injury and ill- 2002. J Pain Symptom Manage 2004; 28: 71. Lebovits AH, Florence I, Bathina R, Hunko ness in the United States. Estimates of 176-188. V, Fox MT, Bramble CY. Pain knowledge costs, morbidity, and mortality. Arch In- 55. Fleming DA. Relieving pain: What are to- and attitudes of healthcare providers: tern Med 1997; 157:1557-1568. day’s ethical and legal risks? Mo Med Practice characteristic differences. Clin J 42. Freedman VA, Martin LG, Schoeni RF. Re- 2002; 99:560-565. Pain 1997; 13:237-243. cent trends in disability and functioning 56. Marlowe KF, Chicella MF. Treatment of 72. Weinstein SM, Laux LF, Thornby JI, Lorimor among older adults in the United States. sickle cell pain. Pharmacotherapy 2002; RJ, Hill CS Jr, Thorpe DM, Merrill JM. Med- JAMA 2002; 288:3137-3146. 22:484-491. ical students’ attitudes toward pain and the use of opioid analgesics: Implications 43. Hurwitz EL, Morgenstern H, Yu F. Cross- 57. Kutner JS, Kassner CT, Nowels DE. Symp- for changing medical school curriculum. sectional and longitudinal associations of tom burden at the end of life: Hospice pro- Southern Med J 2000; 93:472-478. low-back pain and related disability with viders’ perceptions. J Pain Symptom Man- psychological distress among patients en- age 2001; 21:473-480. 73. Model Policy for the Use of Controlled rolled in the UCLA low-back pain study. J Substances for the Treatment of Pain.The 58. Weiss SC, Emanuel LL, Fairclough DL, Clin Epidemiol 2003; 56:463-471. Federation of State Medical Boards of the Emanuel EJ. Understanding the experi- United States. Inc., May 2004. 44. Turner JA, Franklin G, Heagerty PJ, Wu R, ence of pain in terminally ill patients. Lan- Egan K, Fulton-Kehoe D, Gluck JV, Wickizer cet 2001; 357:1311-1315. 74. Manchikanti L, Damron KS, McManus CD, TM. The association between pain and dis- Barnhill RC. Patterns of illicit drug use and 59. Teno JM, Weitzen S, Wetle T, Mor V. Persis- ability. Pain 2004; 112:307-314. opioid abuse in patients with chronic pain tent pain in nursing home residents (re- at initial evaluation: A prospective, obser- 45. Hough J. Estimating the health care utili- search letter). JAMA 2001; 285:2081. zation costs associated with people with vational study. Pain Physician 2004; 7: 60. Tolle SW, Tilden VP, Rosenfeld AG, Hick- disabilities: Data from the 1996 Medical 431-437. man SE. Family reports of barriers to opti- Expenditure Panel Survey (MEPS). Annu- 75. Gajraj N, Hervias-Sanz M. Opiate abuse or mal care of the dying. Nurs Res 2000; 49: al meeting of the Association for Health undertreatment? Clin J Pain 1998; 14:90- 310-317. Services Research, Los Angeles, Califor- 91. 61. Bernabei R, Gambassi G, Lapane K, Landi nia, 2000. 76. Simon S, Bennett D, Rauck R, Taylor D, F, Gatsonis C, Dunlop R, Lipsitz L, Steel K, 46. Bell G, Kidd D, North R. Cost-effectiveness Shoemaker S. Prevalence and characteris- Mor V. Management of pain in elderly pa- analysis of spinal cord stimulation in treat- tics of breakthrough pain in noncancer pa- tients with cancer. JAMA1998; 279:1877- ment of failed back surgery syndrome. J tients with chronic neuropathic pain. Pain 1882. Pain Symp Manage 1997; 13:286-295. Med 2005; 6:192. 62. Institute of Medicine Committee on Care 47. de Lissovoy G, Brown RE, Halpern M, Has- 77. Bennett D, Simon S, Rauck R, Taylor D, at the End of Life. Approaching death: im- senbusch SJ, Ross E. Cost-effectiveness of Shoemaker S. Prevalence and character- proving care at the end of life. Washing- long-term intrathecal morphine therapy istics of breakthrough pain in noncancer ton, DC: National Academy Press, 1997. for pain associated with failed back sur- patients with chronic back pain. Pain Med Available at books.nap.edu/catalog/ gery syndrome. Clin Ther 1997; 19:96-112. 2005; 6:193. 5801.html. 48. Turk DC. Clinical effectiveness and cost-ef- 78. Manchikanti L, Manchukonda R, Pampati 63. SUPPORT Study Principal Investigators. A fectiveness of treatments for patients with V, Damron KS. Evaluation of abuse of pre- controlled trial to improve care for seri- chronic pain. Clin J Pain 2002; 18:355-365. scription and illicit drugs in chronic pain ously ill hospitalized patients: the Study patients receiving short-acting (hydroco- 49. Walker BF, Muller R, Grant WD. Low back to Understand Prognoses and Preferenc- done) or long-acting (methadone) opioids. pain in Australian adults: The economic es for Outcomes and Risks of Treatments Pain Physician 2005; 8:257-261. burden. Asia Pac J Public Health 2003; 15: (SUPPORT). JAMA 1995; 274:1591–1598. 79-87. 79. Manchikanti L, Damron KS, Pampati V, Mc- 64. Hill CS. When will adequate pain treat- Manus CD. Prospective evaluation of pa- 50. Fishman SM, Papazian JS, Gonzalez S, ment be the norm? JAMA 1995; 274:1881- tients with increasing opiate needs: Pre- Riches PS, Gilson A. Regulating opioid 1882. prescribing through prescription monitor- scription opiate abuse and illicit drug use. 65. Dahl JL. Improving the practice of pain ing programs: Balancing drug diversion Pain Physician 2004; 7:339-344. management. JAMA 2000; 284:2785. and treatment of pain. Pain Med 2004; 5: 80. Fishbain DA, Rosomoff HL, Rosomoff RS. 309-324. 66. Joranson DE, Gilson AM, Dahl JL, Haddox Drug abuse, dependence, and addiction in JD. Pain management, controlled sub- 51. Cowan DT. Wilson-Barnett J, Griffi ths P, Al- chronic pain patients. Clin J Pain 1992; 8: stances, and state medical board policy: lan LG. A survey of chronic noncancer pain 77-85. a decade of change. J Pain Symptom Man- patients prescribed opioid analgesics. 81. Chabal C, Erjavec MK, Jacobson L, Mariano age 2002; 23:138-147. Pain Med 2003; 4:340-351. A, Chaney E. Prescription opiate abuse in 67. Gilson AM, Joranson DE. Controlled sub- 52. Joranson DE, Carrow GM, Ryan KM, Schae- chronic pain patients: Clinical criteria, inci- stances and pain management: Changes fer L, Gilson AM, Good P, Eadie J, Peine S, dence, and predictors. Clin J Pain 1997; 13: in knowledge and attitudes of state med- Dahl JL. Pain management and prescrip- 150-155. ical regulators. J Pain Symptom Manage tion monitoring. J Pain Symptom Manage 82. Katz NP, Sherburne S, Beach M, Rose RJ, 2001; 21:227-237. 2002; 23:231-238. Vielguth J, Bradley J, Fanciullo GJ. Behav- 68. Gunnarsdottir S, Serlin RC, Ward S. Pa- 53. National Institutes of Health Consensus ioral monitoring and urine toxicology test- tient-related barriers to pain manage- Development Program. Symptom man- ing in patients receiving long-term opioid ment: The Icelandic barriers questionnaire agement in cancer: Pain, depression and therapy. Anesth Analg 2003; 97:1097- II. J Pain Symptom Manage 2005; 29:273- fatigue. Statement prepared following a 1102. 285. National Institutes of Health State-of-the- 83. Manchikanti L, Pampati V, Damron K, Fel- Science Conference on Symptom Manage- 69. Glajchen M. Chronic pain: Treatment bar- lows B, Barnhill RC, Beyer CD. Prevalence ment in Cancer; Bethesda, MD, July 15-17, riers and strategies for clinical practice. J of opioid abuse in interventional pain 2002. Available at consensus.nih.gov/ta/ Am Board Fam Pract 2001; 14:211-218. medicine practice settings: A randomized 022/022_intro.htm. 70. Drug Enforcement Administration. Physi- clinical evaluation. Pain Physician 2001; 4: 54. Gilson AM, Ryan KM, Joranson DE, Dahl JL. cian’s manual: An informational outline of 358-365. A reassessment of trends in the medical the Controlled Substances Act of 1970. US 84. Manchikanti L, Pampati V, Damron K. Prev- use and abuse of opioid analgesics and Department of Justice, Washington, DC, alence of prescription drug abuse and de- implications for diversion control: 1997- 1990. pendency in patients with chronic pain in

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 33

western Kentucky. J KY Med Assoc 2003; drochloride controlled-release among pa- 115. Batten HL, Prottas JM, Horgan CM, Prottas 101:511-517. tients with chronic nonmalignant pain. J JM, Simon LJ, Larson MJ, Elliott EA, Bowden 85. Kell M. Monitoring compliance with Oxy- Manag Care Pharm 2003; 9:223-231. ML, Lee MT. Drug Services Research Sur- Contin prescriptions in 14,712 patients 102. Hermos JA, Young MM, Gagnon DR, Fio- vey. Phase II Final Report. Submitted to treated in 127 outpatient pain centers. re LD. Characterizations of long-term the National Institute on Drug Abuse. In- Pain Med 2005; 6:186-187. oxycodone/acetaminophen prescriptions stitute for Health Policy, Brandeis Univer- sity, Waltham, MA February 12, 1993. 86. Manchikanti L, Damron KS, Pampati V, in veteran patients. Arch Intern Med 2004; McManus CD. Prevalence of illicit drug use 164:2361-2366. 116. Polatin PB, Kinney RK, Gatchel RJ, Lillo E, among individuals with chronic pain in the 103. Ziegler DK. Opioids in headache treat- Mayer TG. Psychiatric illness and chronic commonwealth of Kentucky: An evalua- ment. Is there a role? Neurol Clin 1997; 15: low back pain: The mind and the spine – tion of patterns and trends. J KY Med As- 199-207. which goes fi rst? Spine 1993; 18:66-71. soc 2005; 103:55-62. 104. Reid MC, Engles-Horton LL, Weber MB, 117. Maruta T, Swanson DW, Finlayson RE. Drug 87. Atluri S, Sudarshan G. Evaluation of ab- Kerns RD, Rogers EL, O’Connor PG. Use of abuse and dependency in patients with normal urine drug screens among patients opioid medications for chronic noncancer chronic pain. Mayo Clin Proc 1979; 54:241- with chronic non-malignant pain treated pain syndromes in primary care. J Gen In- 244. with opioids. Pain Physician 2003; 6:407- tern Med 2002; 17:173-179. 118. Hoffmann NG, Olofsson O, Salen B, Wick- 409. 105. Sikirica V, Vallow S, Schein J, Doshi D, Katz strom L. Prevalence of abuse and depen- 88. Bloodworth D. Issues in opioid manage- N, White A, Stang P. Prevalence, comorbid- dency in chronic pain patients. Int J Addict ment. Am J Phys Med Rehabil 2005; 84: ities, and utilization of services of opioid 1995; 30:919-927. S42-S55. abusers in a managed care pain. Pain Med 119. Jinks MJ, Raschko RR. A profi le of alcohol 89. Ballantyne JC, Mao J. Opioid therapy for 2005; 6:190. and prescription drug abuse in a high- chronic pain. N Engl J Med 2003; 349: 106. Novak S, Nemeth WC, Lawson KA. Trends risk community based elderly population. 1943-1953. in medical use and abuse of sustained- DICP 1990; 24:971-975 90. Chou R, Clark E, Helfand M. Comparative release opioid analgesics: A revisit. Pain 120. Manchikanti L, Pampati V, Damron K, effi cacy and safety of long-acting oral opi- Med 2004; 5:59-65. Beyer CD, Barnhill RC. Prevalence of illic- oids for chronic non-cancer pain: A sys- 107. US Department of Health and Human it drug use in patients without controlled tematic review. J Pain Symptom Manage Services. Offi ce of Applied Studies, Sub- substance abuse in interventional pain 2003; 26:1026-1048. stance Abuse and Mental Health Servic- management. Pain Physician 2003; 6:173- 178. 91. Kalso E, Edwards JE, Moore RA, McQuay es Administration (SAMHSA). Drug Abuse HJ. Opioids in chronic non-cancer pain: Warning Network. The DAWN Report. Nar- 121. Manchikanti L, Beyer C, Damron K, Pam- Systematic review of effi cacy and safety. cotic analgesics, 2002 update. September pati V. A comparative evaluation of illicit Pain 2004; 112:372-380. 2004. drug use in patients with or without con- trolled substance abuse in interventional 92. Von Korff M, Deyo RA. Potent opioids 108. US Department of Health and Human pain management. Pain Physician 2003; for chronic musculoskeletal pain: Flying Services. Offi ce of Applied Studies, Sub- 6:281-285. blind? Pain 2004; 109:207-209. stance Abuse and Mental Health Servic- es Administration (SAMHSA). Drug Abuse 122. Atluri S, Sudarshan G. A screening tool to 93. Breivik H. Opioids in chronic non-cancer Warning Network. The DAWN Report. Ben- determine the risk of prescription opioid pain, indications and controversies. Eur J zodiazepines in drug abuse-related emer- abuse among patients with chronic non- Pain 2005; 9:127-130. gency department visits: 1995-2002. April malignant pain. Pain Physician 2002; 5: 94. Luo X; Pietrobon R, Hey L. Patterns and 2004. 447-448. trends in opioid use among individuals 109. Sproule BA, Busto UE, Otton SV, Zhong 123. Lentner S. Drug abuse. Winer Zeitschrift with back pain in the United States. Spine XH, Sellers EM. Abuse and dependence on fur Suchforschung 1991; 14:65-68. 2004; 29:884-891. prescription opiates. Clin Pharmacol Ther 124. Hurwitz W. The challenge of prescription 95. Turk DC, Brody MC, Okifuji EA. Physicians’ 1995; 57:161. drug misuse: A review and commentary. attitudes and practices regarding the long- 110. McCaskill C. Oversight Controls in the Pain Med 2005; 6:152-161. term prescribing of opioids for non-cancer State’s Medicaid Prescription Drug Pro- 125. Center on Addiction and Substance Abuse. pain. Pain 1994; 59:201-208. gram, 18 April 2002, Performance Audit Substance abuse and federal entitlement 96. Vogt MT, Kwoh CK, Cope DK, Osial TA, Cu- Report No. 2002-29, 4. programs. Columbia University, New York, lyba M, Starz TW. Analgesic usage for low 111. National Community Pharmacists Associa- 1995. back pain: Impact on health care costs and tion, NCPA Position Statements, Medicare 126. Feder J, Rowland D, Holahan J, Heslam service use. Spine 2005; 30:1075-1081. Reform: JCPP Statement, August 10, 1999. D. The Medicaid Cost Explosion: Causes 97. Pembrook L. Medicaid patients receive www.ncpanet.org/about/ncpa_position_ and Consequences. Henry J. Kaiser Family more medications, less alternative care. statements/m.shtml#10. (Accessed De- Foundation. Menlo Park, CA, 1993, pp 18- Pain Med News May/June 2005; 20. cember 29, 2005.) 22. 98. Caudill-Slosberg MA, Schwartz LM, Wo- 112. Substance Abuse and Mental Health Ser- 127. Held G. Linkages between substance loshin S. Offi ce visits and analgesic pre- vices Administration. (2004). Overview of abuse prevention and other human servic- scriptions for musculoskeletal pain in US: Findings from the 2003 National Survey es. LiteratureReview June 1998, Part A. 1980 vs. 2000. Pain 2004; 109:514-519. on Drug Use and Health (Offi ce of Applied 128. GAO Report. United States General Ac- Studies, NSDUH Series H-24, DHHS Publi- 99. Ytterberg SR, Mahowald ML, Woods SR. counting Offi ce. Prescription drugs. Oxy- cation No. SMA 04-3963). Rockville, MD. Opioid use by patients in an orthopedics Contin Abuse and Diversion and Efforts to spine clinic. Arthritis Rheum 2005; 52:6- 113. Simoni-Wastila L, Tompkins C. Balancing Address the Problem. GAO Publication No. 10. diversion control and medical necessity: GAO-4-110, December 2003. The case of prescription drugs with abuse 100. Katz N, Benoit C. Opioids for neuropathic 129. Gitchel GT. “Existing Methods to Identify potential. Substance Use & Misuse 2001; pain. Curr Pain Headache Rep 2005; 9:153- Retail Drug Diversion,” Impact of Prescrip- 36:1275-1296. 160. tion Drug Diversion Control Systems on 101. Ackerman SJ, Mordin M, Reblando J, Xu 114. Lewin ICF. Analysis of Prescription Moni- Medical Practice and Patient Care, NIDA X, Schein J, Vallow S, Brennan M. Patient- toring Programs. Prepared for Hoffman- Research Monograph 131, Rockville, MD, reported utilization patterns of fentanyl LaRoche by Lewin ICF. Washington DC, 1993, p 135. April 26, 1991. transdermal system and oxycodone hy- 130. U.S. General Accounting Offi ce. Internet

Pain Physician Vol. 9, No. 1, 2006 34 Trescot et al • Opioid Guidelines

Pharmacies: Adding Disclosure Would Aid Engl J Med 2005; 352:2211-2221. Karlix J, Sloan K, Tebbett I. Analgesic and State and Federal Oversight, GAO Publica- 149. Breimer DD. Genetic polymorphism in immunomodulatory effects of codeine and tion No. GAO-01-69, October 2000, 3. drug metabolism: clinical implications and codeine 6-glucuronide. Pharm Res 1996; 131. Cole N. “Rx Roulette on the Internet.” Wall consequences in ADME studies. In Walker 13:296-300. Street Journal, June 17, 2004, p A18. S. et al (eds.), The Relevance of Ethnic Fac- 163. Janicki PK, Parris WC. Clinical 132. Caywood T. “Online Drug Buying Can Turn tors in the Clinical Evaluation of Medicine. pharmacology of opioids. In Smith H (ed). Into a Nasty Habit; Deals are Illegal, Dan- Kluwer Academic Publishers, Dor-drecht/ Drugs for Pain. Hanley & Belfus, Inc., gerous,” The Boston Herald, 14 December Boston, 1994, pp 13-26. Philadelphia, 2003, pp 97-118. 2003, sec. news. 150. Evans DA, Mahgoub A, Sloan TP, Idle JR, 164. Aderjan RE, Rolf E, Skopp G. Formation 133. “The Pharmacy Theft Prevention Pro- Smith RL. A family and population study and clearance of active and inactive me- gram,” On-Line with Industry, DEA, Of- of the genetic polymorphism of debriso- tabolites of opiates in humans. Ther Drug fi ce of Diversion Control, 2 (Winter 2002/ quine oxidation in a white British popula- Monit 1998; 20:561-569. 2003), 10. tion. J Med Genet 1980; 17:102-105. 165. McEvoy GK. In AHFS Drug Information 134. U.S. Department of Justice, Drug Enforce- 151. Poulsen L, Brosen K, Arendt-Nielsen L, 2004 CD. American Society of Health-Sys- ment Administration, DEA Congressional Gram LF, Elbaek K, Sindrup SH. Codeine tem Pharmacists, Bethesda, MD. testimony, Statement of Asa Hutchinson, and morphine in extensive and poor me- 166. McLeod CM. A pharmacologic overview House Committee on Appropriations, 11 tabolizers of sparteine: Pharmacokinetics, of pain management. An online December 2001. analgesic effect and side effects. Eur J Clin program for pharmacists available at: Pharmacol 1996; 51:289-295. 135. Offi ce of National Drug Control Policy, ashpadvantage.com Drug Facts: OxyContin http://www.whiteh 152. Woolf CJ. Intrathecal high dose morphine 167. Metzger TG, Paterlini MG, Ferguson DM, ousedrugpolicy.gov/drugfact/oxycontin/ produces hyperalgesia in the rat. Brain Portoghese PS. Investigation of the se- index.html (6 September 2005). Res 1981; 209:491-495. lectivity of oxymorphone-and naltrex- 136. “Five Ogden-Layton Pharmacies Robbed 153. Shimomura K, Kamata O, Ueki S, Ida S, onederived ligands via site-directed muta- for OxyContin,” The Associated Press Oguri K, Yoshimura H, Tsukamoto H. An- genesis of opioid receptors: exploring the State and Local Wire, 28 November 2002, algesic effect of morphine glucuronides. ‘address’ recognition locus. J Med Chem sec. state and regional. Tohoku J Exp Med 1971; 105:45-52. 2001; 44:857-862. 137. “Crime Stoppers Pharmacy Burglary,” Co- 154. Lotsch J, Skarke C, Schmidt H, Grosch S, 168. Heiskanen TE, Ruismaki PM, Seppala TA, lumbus Dispatch, 24 November 2003, sec. Geisslinger G. The transfer half-life of mor- Kalso EA. Morphine or oxycodone in can- D8. phine-6-glucuronide from plasma to ef- cer pain? Acta Oncol 2000; 39:941-947. fect site assessed by pupil size measure- 138. Overview and Demonstration of Enhanced 169. Murray A, Hagen NA. Hydromorphone. ment in healthy volunteers. Anesthesiolo- KASPER (eKASPER) Program. Cabinet for J Pain Symptom Manage 2005; 29:S57- gy 2001; 95:1329-1338. Health and Family Services Offi ce of the S66. Inspector General, March 16, 2005. 155. Lotsch J, Kobal G, Stockmann A, Brune K, 170. Quigley C. Hydromorphone for acute and 139. Pulse Check: Trends in Drug Abuse, Of- Geisslinger G. Lack of analgesic activity of morphine-6-glucuronide after short-term chronic pain. Cochrane Database Syst Rev fi ce of National Drug Control Policy, NCJ 2002; 1:CD003447. 191248, Washington, D.C, November 2001, intravenous administration in healthy vol- 93. unteers. Anesthesiology 1997; 87:1348- 171. Babul N, Darke AC, Hagen N. Hydromor- 1358. phone metabolite accumulation in renal 140. Voris BV. “OxyContin Maker Not Yet Feel- 156. Twycross RG, Lack S. Symptom Control in failure. J Pain Symptom Manage 1995; 10: ing Much Pain; Some Lawyers Wary of Ad- 184-186. dicted Clients,” The National Law Journal, Far Advanced Cancer Pain Relief. Pitman, 24 (29 April 2002): A1. London, 1983. 172. Benedetti CB, Butler SH. Systemic analge- sics. In Bonica JJ (ed.), The Management of 141. Estep B. “Doctor Guilty of Drug Count,” 157. Bodd E, Jacobsen D, Lund E, Ripel A, Mør- land J, Wiik-Larsen E. Morphine-6-glucuro- Pain, 2nd edition. Lea & Febiger, Philadel- Lexington Herald-Leader, 8 April 2003, phia, 1990, pp 1640-1675. sec. A8. nide might mediate the prolonged opioid effect of morphine in acute renal failure. 173. Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, 142. Mueller L. “Drug Doctor Caught Fleeing,” Hum Exp Toxicol 1990; 9:317-321. Honigberg IL. Pharmacokinetics and bio- Lexington Herald-Leader, 1 August 2003, availability of hydromorphone following sec. B1. 158. Kaiko RF, Wallenstein SL, Rogers AG, Gra- binski PY, Houde RW. Narcotics in the el- intravenous and oral administration to hu- 143. “Prescription Fraud, Abuse Costs Taxpay- derly. Med Clin North Am 1982; 66:1079- man subjects. J Clin Pharmacol 1981; 214: ers, Patients,” The Associated Press & Lo- 1089. 152-156. cal Wire, 3 December 2003, sec. State and 174. Oda Y, Kharasch ED. Metabolism of meth- Regional. 159. Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine O-demethylation co- adone and levo-alpha-acetylmethadol 144. Richard J, Reidenberg MM. The risk of dis- segregates with polymorphic debrisoquine (LAAM) by human intestinal cytochrome ciplinary action by state medical boards hydroxylation. Br J Clin Pharmacol 1989; P450 3A4 (CYP3A4): Potential contribu- against physicians prescribing opioids. J 28:639-645. tion of intestinal metabolism to presys- Med Licens Discipl 2005; 91:14-19. temic clearance and bioactivation. J Phar- 160. Eckhardt K, Li S, Ammon S, Schanzle G, macol Exp Ther 2001; 298:1021-1032. 145. Federation of State Medical Boards Re- Mikus G, Eichelbaum M. Same incidence leases Annual Physician Discipline Report, of adverse drug events after codeine 175. Eap CB, Buclin T, Baumann P. Interindi- For Immediate Release: April 18, 2005. administration irrespective of the vidual variability of the clinical pharma- http://www.fsmb.org/pub_news-2005- genetically determined differences in cokinetics of methadone: Implications for 04-18.html (Accessed September 2005). morphine formation. Pain 1998; 76:27-33. the treatment of opioid dependence. Clin Pharmacokinet 2002; 41:1153-1193. 146. Kentucky Board of Medical Licensure 161. Yue QY, Hasselstrom J, Svensson JO, Newsletter, Summer 2005. http://ky.gov/ Sawe J. Pharmacokinetics of codeine 176. Moolchan ET, Umbricht A, Epstein D. Ther- agencies/kbml/newsletters.html (Ac- and its metabolites in Caucasian healthy apeutic drug monitoring in methadone cessed September 2005) volunteers: Comparisons between maintenance: Choosing a matrix. J Addict 147. DEA News Release. The myth of the “chill- extensive and poor hydroxylators of Dis 2001; 20:55-73. ing effect.” October 30, 2003. debrisoquine. Br J Clin Pharmacol 1991; 177. Offi ce of Inspector General. Memorandum 148. Wilkinson GR. Drug metabolism and vari- 31:635-542. to the Under Secretary of Health. Review ability among patients in drug response. N 162. Srinivasan V, Wielbo D, Simpkins J, of prescribing practices for elderly out-

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 35

patients. Department of Veterans Affairs, 192. De Bels D, Staroukine M, Devriendt J. in humans. Anesth Analg 2002; 94:94-99. 1996. Available at http:// www.va.gov/ Torsades de pointes due to methadone. 207. Alonzo NC, Bayer BM. Opioids, immunolo- oig/52/reports/1997/7R1-A28-008— Ann Intern Med 2003; 139:58. gy, and host defenses of intravenous drug prescrib.pdf. Accessed June 25, 2004. 193. Gazelle G, Fine PG. Methadone for the abusers. Infect Dis Clin North Am 2002; 16: 178. U.S. General Accounting Offi ce. Prescrip- treatment of pain. J Palliat Med 2003; 6: 553-569. tion drugs and the elderly. GAO, Washing- 621-622. 208. Gaspani L, Bianchi M, Limiroli E, Panerai ton, DC, 1995. 194. Mancini I, Lossignol DA, Body JJ. Opioid AE, Sacerdote P. The analgesic drug tram- 179. Dayer P, Desmeules J, Collart L. Pharma- switch to oral methadone in cancer pain. adol prevents the effect of surgery on nat- cology of tramadol. Drugs 1997; 53:18-24. Curr Opin Oncol 2000; 12:308-313. ural killer cell activity and metastatic col- 180. Harvard-MIT division of Health Scienc- 195. Andersen G, Sjogren P, Hansen SH, Jensen onization in rats. J Neuroimmunol 2002; es and Technology, HST.151 Principles of NH, Christrup L. Pharmacological conse- 129:18-24. Pharmacology (Opioid Pharmacology), quences of long-term morphine treatment 209. Nelson CJ, Lysle DT. Severity, time, and Spring 2003. in patients with cancer and chronic non- beta*adrenergic receptor involvement in http://mitocw.hitce.net/OcwWeb/Health- malignant pain. Eur J Pain 2004; 8:263- surgery-induced immune alterations. J Sciences-and-Technology/HST-151Prin- 271. Surg Res 1998; 80:115-122. ciples-of-PharmacologySpring2003/ 196. Page GG. Immunologic effects of opioids 210. Palm S, Lehzen S, Mignat C, Steinmann J, CourseHome/index.htm in the presence or absence of pain. J Pain Leimenstoll G, Maier C. Does prolonged 181. Hanks GW, Twycross RG, Lloyd JW. Unex- Symptom Manage 2005; 29:S25-S31. oral treatment with sustained-release pected complication of successful nerve 197. Shavit Y, Terman GW, Martin FC, Lewis JW, morphine tablets infl uence immune func- block. Anaesthesia 1981; 36:37-39. Liebeskind JC, Gale RP. Stress, opioid pep- tion? Anesth Analg 1998; 86:166-172. 182. Ferris DJ. Controlling myoclonus after tides, the immune system, and cancer. J 211. Gomez-Flores R, Weber RJ. Differential ef- high-dosage morphine infusions. Am J Immunol 1985; 135:834-837. fects of buprenorphine and morphine on Health Syst Pharm 1999; 56:1009-1010. 198. Shavit Y, Terman GW, Lewis JW, Zane CJ, immune and neuroendocrine functions following acute administration in the rat 183. Kam P, Tan K. Pruritus-itching for a cause Gale RP, Liebeskind JC. Effects of foot- mesencephalon periaqueductal gray. Im- and relief? Anaesthesia 1996; 51:1133- shock stress and morphine on natural kill- munopharmacology 2000; 48:145-156. 1138. er lymphocytes in rats: studies of toler- ance and crosstolerance. Brain Res 1986; 212. Tsai YC, Won SJ, Lin MT. Effects of mor- 184. Kuraishi Y, Yamaguchi T, Miyamoto T. Itch- 372:382-385. phine on immune response in rats with scratch responses induced by opioids sciatic constriction injury. Pain 2000; 88: through central mu opioid receptors in 199. Shavit Y, Martin FC, Yirmiya R, Ben-Eliyahu 155-160. mice. J Biomed Sci 2000; 7:248-252. S, Terman GW, Weiner H, Gale RP, Liebe- skind JC. Effects of single administration 213. Bartolome MB, Kuhn CM. Endocrine ef- 185. Bochner F. Drug interactions with meth- of morphine or footshock stress on natu- fects of methadone in rats: Acute effects adone: pharmacokinetics. In Humme- ral killer cell cytotoxicity. Brain Behav Im- in adults. Eur J Pharmacol 1983; 95:231- niuk R, Ali R, White J, Hall W, Farrell M mun 1987; 1:318-328. 238. (eds.), Proceeding of Expert Workshop on the Induction and Stabilization of Pa- 200. Lysle DT, Coussons ME, Watts VJ, Bennett 214. Rolandi E, Marabini A, Franceschini R, tients Onto Methadone. Monograph Se- EH, Dykstra LA. Morphine-induced altera- Messina V, Bongera P, Barreca T. Chang- ries 39. Canberra: Commonwealth of Aus- tions of immune status: Dose dependen- es in pituitary secretion induced by an ag- tralia; 2000: 93-110. Available at: http:// cy, compartment specifi city and antago- onist-antagonist opioid drug, buprenor- www.health.gov.au. nism by naltrexone. J Pharmacol Exp Ther phine. Acta Endocrinol (Copenh) 1983; 1993; 265:1071-1078. 104:257-260. 186. Jackson, KC, Lipman AG. Opioid Analesics. In Talison CD, Satterwaite JR, Tollison JW 201. Band LD, Pert A, Williams W, DeCosta BR, 215. Banki CM, Arato M. Multiple hormonal re- (eds.). Practical Pain Management, 3rd edi- Rice KC Weber R. Central µ-opioid recep- sponses to morphine: Relationship to di- tion. Lippincott Williams & Wilkins, Phila- tors mediate suppression of natural killer agnosis and dexamethasone suppression. delphia, 2001:216-231. activity in vivo. Prog Neuro Endocrin Im- Psychoneuroendocrinology 1987; 12:3-11. munol 1992; 5:95-101. 187. Bergendal L, Friberg A, Schaffrath AM, hol- 216. Malaivijitnond S, Varavudhi P. Evidence for mdahl M, Landahl S. The clinical relevance 202. Shavit Y, Depaulis A, Martin FC, Terman morphine-induced galactorrhea in male of the interaction between carbamazepine GW, Pechnick RN, Zane CJ, Gale RP, Liebe- cynomolgus monkeys. J Med Primatol and dextropropoxyphene in elderly pa- skind JC. Involvement of brain opiate re- 1998; 27:1-9. tients in Gothenburg, Sweden. Eur J Clin ceptors in the immune suppressive effects 217. Mendelson JH, Mendelson JE, Patch VD. Pharmacol 1997; 53:203-206. of morphine. Proc Nat Acad Sci USA 1986; Plasma testosterone levels in heroin ad- 83:7114-7117. 188. Abernethy DR, Greenblatt DJ, Morse DS, diction and during methadone mainte- Shader RI. Interaction of propoxyphene 203. Weber RJ, Pert A. The periaqueductal gray nance. J Pharmacol Exp Ther 1975; 192: with diazepam, alprazolam and loraze- matter mediates opiate-induced immuno- 211-217. pam. Br J Clin Pharmacol 1985; 19:51-57. suppression. Science 1989; 245:188-190. 218. Mendelson JH, Meyer RE, Ellingboe J, Mir- 189. Iribarne C, Picart D, Dreano Y, Berthou F. 204. Mellon RD, Bayer BM. Evidence for central in SM, McDougle M. Effects of heroin and In vitro interactions between fl uoxetine or opioid receptors in the immunomodulato- methadone on plasma cortisol and testos- fl uvoxamine and methadone or buprenor- ry effects of morphine: Review of potential terone. J Pharmacol Exp Ther 1975; 195: phine. Fundam Clin Pharmacol 1998; 12: mechanism(s) of action. J Neuroimmunol 296-302. 194-199. 1998; 83:19-28. 219. Rasheed A, Tareen IA. Effects of heroin on 190. Wolff K, Rostami-Hodjegan A, Hay AWM, 205. Yeager MP, Colacchio TA, Yu CT, Hildeb- thyroid function, cortisol and testosterone Raistrick D, Tucker G. Population based randt L, Howell AL, Weiss J, Guyre PM. Mor- level in addicts. Pol J Pharmacol 1995; 47: pharmacokinetic approach for methadone phine inhibits spontaneous and cytokine- 441-444. monitoring of opiate addicts: potential enhanced natural killer cell cytotoxicity in 220. Malik SA, Khan C, Jabbar A, Iqbal A. Hero- clinical utility. Addiction 2000; 95:1771- volunteers. Anesthesiology 1995; 83:500- in addiction and sex hormones in males. J 1783. 508. Pak Med Assoc 1992; 42:210-212. 191. Herrlin K, Segerdahl M, Gustafsson LL, 206. Yeager MP, Procopio MA, DeLeo JA, Arruda 221. Finch PM, Roberts LJ, Price L, Hadlow NC, Kalso E. Methadone, ciprofl oxacin, and JL, Hildebrandt L, Howell AL. Intravenous Pullan PT. Hypogonadism in patients treat- adverse drug reactions. Lancet 2000; 356: fentanyl increases natural killer cell cyto- ed with intrathecal morphine. Clin J Pain 2069-2070. toxicity and circulating CD16 lymphocytes 2000; 16:251-254.

Pain Physician Vol. 9, No. 1, 2006 36 Trescot et al • Opioid Guidelines

222. Abs R, Verhelst J, Maeyaert J, Van Buyten 1978; 45:233-237. ized crossover trial of transdermal fentan- JP, Opsomer F, Adriaensen H, Verlooy J, Van 236. Savage SR. Long-term opioid therapy: As- yl and sustained-release oral morphine for Havenbergh T, Smet M, Van Acker K. Endo- sessment of consequences and risks. J treating chronic non-cancer pain. Br Med J crine consequences of long-term intrathe- Pain Symptom Manage 1996; 11:274-286. 2001; 322:1154-1158. cal administration of opioids. J Clin Endo- 237. Compton MA. Cold-pressor pain tolerance 254. Caldwell JR, Rapoport RJ, Davis JC, Offen- crinol Metab 2000; 85:2215-2222. in opiate and cocaine abusers: Correlates berg HL, Marker HW, Roth SH, Yuan W, 223. Roberts LJ, Finch PM, Pullan PT, Bhagat CI, of drug type and use status. J Pain Symp- Eliot L, Babul N, Lynch PM. Effi cacy and Price LM. Sex hormone suppression by in- tom Manage 1994; 9:462-473. safety of a once-daily morphine formula- trathecal opioids: a prospective study. tion in chronic, moderate-to-severe osteo- 238. Mao J. Opioid-induced abnormal pain sen- Clin J Pain 2002; 18:144-148. arthritis pain: results from a randomized, sitivity: Implications in clinical opioid ther- placebo-controlled, double-blind trial and 224. Bhansali A, Velayutham P, Sialy R, Sethi B. apy. Pain 2002; 100:213-217. Effect of opiates on growth hormone se- an open-label extension trial. J Pain Symp- 239. Compton P, Charuvastra VC, Ling W.. Pain cretion in acromegaly. Horm Metab Res tom Manage 2002; 23:279-291. intolerance in opioid-maintained for- 2005; 37:425-427. 255. Hale M, Speight K, Harsanyi Z, Iwan T, Sla- mer opiate addicts: effect of long-acting gle N, Lacouture P, Darke AC. Effi cacy of 12 225. Rajagopal A, Vassilopoulou-Sellin R, Palm- maintenance agent. Drug Alcohol Depend hourly controlled-release codeine com- er JL, Kaur G, Bruera E. Hypogonadism and 2001; 63:139-146. sexual dysfunction in male cancer survi- pared with as required dosing of acet- 240. Byas-Smith MG, Chapman SL, Reed B, Cot- vors receiving chronic opioid therapy. J aminophen plus codeine in patients with sonis G. The effect of opioids on driving Pain Symptom Manage 2003; 26:1055- chronic low back pain. Pain Res Manage and psychomotor performance in patients 1061. 1997; 2:33-38. with chronic pain. Clin J Pain 2005; 21:345- 256. Caldwell JR, Hale ME, Boyd RE, Hague JM, 226. Hangaard J, Andersen M, Grodum E, Kold- 352. kjaer O, Hagen C. The effects of endoge- Iwan T, Shi M, Lacouture PG. Treatment of 241. Ramaekers JG. Antidepressants and driv- nous opioids and cortisol on thyrotropin osteoarthritis pain with controlled- release er impairment: Empirical evidence from a and prolactin secretion in patients with oxycodone or fi xed combination oxycodo- standard on-the-road test. J Clin Psychia- Addison’s disease. J Clin Endocrinol Metab ne plus acetaminophen added to nonste- try 2003; 64:20-29. 1999; 84:1595-1601. roidal anti-infl ammatory drugs: a double 242. Zacny JP, Lichtor JL, Flemming D, Coalson blind, randomized, multicenter, placebo 227. Mao J, Price DD, Mayer DJ. Mechanisms of DW, Thompson WK. A dose-response anal- controlled trial. J Rheumatol 1999; 26:862- hyperalgesia and opiate tolerance: a cur- ysis of the subjective, psychomotor and 869. rent view of their possible interactions. physiological effects of intravenous mor- Pain 1995; 62:259-274. 257. Gostick N, Allen J, Cranfi eld R. A compari- phine in healthy volunteers. J Pharmacol son of the effi cacy and adverse effects of 228. Mao J, Price DD, Mayer DJ. Thermal hyper- Exp Ther 1994; 268:1-9. controlled-release dihydrocodeine and algesia in association with the develop- 243. Meijler WJ. Driving ban for patients on immediate-release dihydrocodeine in the ment of morphine tolerance in rats: Roles chronic opioid therapy unfounded. Ned Ti- treatment of pain in osteoarthritis and of excitatory amino acid receptors and jdschr Geneeskd 2000; 144:1644-1645. chronic back pain. In Twycross RG (ed.), protein kinase C. J Neurosci 1994; 14:2301- Proceedings of the Edinburgh Symposium 2312. 244. Hanks GW. Morphine sans morpheus. Lan- cet 1995; 346:652-653. on Pain Control and Medical Education. 229. Angst MS, Koppert W, Pahl I, Clark DJ, 1989:137-143. Schmelz M. Short-term infusion of the 245. Kamboj SK, Tookman A, Jones L, Curran 258. Hale ME, Fleischmann R, Salzman R, Wild mu-opioid agonist in humans HV. The effects of immediate-release mor- J, Iwan T, Swanton RE, Kaiko RF, Lacouture causes hyperalgesia during withdrawal. phine on cognitive functioning in patients PG. Effi cacy and safety of controlled-re- Pain 2003; 106:49-57. receiving chronic opioid therapy in pallia- tive care. Pain 2005; 117:388-395. lease versus immediate-release oxycodo- 230. Wilson GR, Reisfi eld GM. Morphine hyper- 246. Portenoy RK, Hagen NA. Breakthrough ne: Randomized, double blind evaluation algesia: A case report. Am J Hosp Palliat in patients with chronic back pain. Clin J Care 2003; 20:459-461. pain: Defi nition, prevalence and charac- teristics. Pain 1990; 41:273-281. Pain 1999; 15:179-183. 231. Kissin I. Tolerance to opioid analgesia: 247. Savage SR, Joranson DE, Covington EC, 259. Jamison RN, Raymond SA, Slawsby EA, Ne- Why do we differ from rats? Anesth Anal deljkovic SS, Katz NP. Opioid therapy for 2005; 101:1727-1729. Schnoll SH, Heit HA, Gilson AM. Defi ni- tions related to the medical use of opi- chronic noncancer back pain. A random- 232. Van Elstraete AC, Sitbon P, Trabold F, Max- oids: Evolution towards universal agree- ized prospective study. Spine 1998; 23: oit J, Benhamou D. A single dose of intra- ment. J Pain Symptom Manage 2003; 26: 2591-2600. thecal morphine in rats induces long-last- 655-667. 260. Lloyd RS, Costello F, Eves MJ, James IG, ing hyperalgesia: The protective effect of 248. World Health Organization. Expert Com- Miller AJ. The effi cacy and tolerability of prior administration of . Anesth controlled-release dihydrocodeine tablets Analg 2005; 101:1750-1756. mittee on Addiction-Producing Drugs. 7th report. Geneva, Switzerland: WHO 1957. and combination dextropropoxyphene / 233. Mao J, Price DD, Mayer DJ. Experimental paracetamol tablets in patients with se- 249. World Health Organization. WHO Expert mononeuropathy reduces the antinoci- vere osteoarthritis of the hips. Curr Med Committee on Addiction-Producing Drugs. ceptive effects of morphine: Implications Res Opin 1992; 13:37-48. for common intracellular mechanisms in- 13th report. Geneva, Switzerland: WHO 1964. 261. Salzman RT, Roberts MS, Wild J, Fabian volved in morphine tolerance and neuro- C, Reder RF, Goldenheim PD. Can a con- 250. World Health Organization. WHO Expert pathic pain. Pain 1995; 61:353-364. trolled release oral dose form of oxycodo- Committee on Drug Dependence. 16th re- 234. Mao J, Sung B, Ji RR, Lim G. Chronic mor- ne be used as readily as an immediate-re- port. Geneva, Switzerland: WHO 1969 phine induces downregulation of spinal lease form for the purpose of titrating to glutamate transporters: implications in 251. World Health Organization. WHO Expert stable pain control? J Pain Symptom Man- morphine tolerance and abnormal pain Committee on Drug Dependence. 28th re- age. 1999; 18:271-279. port. Geneva, Switzerland: WHO 1993 sensitivity. J Neurosci 2002; 22:8312- 262. Roth SH, Fleischmann RM, Burch FX, Di- 8323. 252. World Health Organization. WHO Expert etz F, Bockow B, Rapoport RJ, Rutstein 235. Brodner RA, Taub A. Chronic pain exac- Committee on Drug Dependence. 30th re- J, Lacouture PG. Around-the-clock, con- erbated by long-term narcotic use in pa- port. Geneva, Switzerland: WHO 1998 trolled-release oxycodone therapy for os- tients with non-malignant disease: Clinical 253. Allan L, Hays H, Jensen NH, de Waroux teoarthritis-related pain: Placebo con- syndrome and treatment. Mt Sinai J Med BL, Bolt M, Donald R, Kalso E. Random- trolled trial and long-term evaluation. Arch

Pain Physician Vol. 9, No. 1, 2006 Trescot et al • Opioid Guidelines 37

Intern Med. 2000; 160:853-860. jerg PE. Codeine plus paracetamol versus 197-204. 263. Arkinstall W, Sandler A, Goughnour B, Ba- paracetamol in longer-term treatment of 288. Jamison RN, Anderson KO, Peeters-Asdou- bul N, Harsanyi Z, Darke AC. Effi cacy of chronic pain due to osteoarthritis of the rian C, Ferrante FM. Survey of opioid use controlled-release codeine in chronic non- hip. A randomised, double-blind, multi- in chronic nonmalignant pain patients. malignant pain: a randomized, placebo- centre study. Pain 1990; 43:309-318. Reg Anesth 1994; 19:225-230. controlled clinical trial. Pain 1995; 62:169- 276. Moran C. MST continuous tablets and pain 289. Zenz M, Strumpf M, Tryba M. Long-term 178. control in severe rheumatoid arthritis. Br J oral opioid therapy in patients with chron- 264. Harke H, Gretenkort P, Ladleif HU, Rah- Clin Res 1991; 2:1-12. ic nonmalignant pain. J Pain Symptom man S, Harke O. The response of neuro- 277. Sheather-Reid RB, Cohen M. Effi cacy of Manage 1992; 7:69-77. pathic pain and pain in complex region- analgesics in chronic pain: a series of N-of- 290. Sandoval JA, Furlan AD, Mailis-Gagnon A. al pain syndrome I to carbamazepine and 1 studies. J Pain Symptom Manage 1998; Oral methadone for chronic non-cancer sustained-release morphine in patients 15:244-252. pain: a systematic literature review of rea- pretreated with spinal cord stimulation: a 278. Schofferman J. Long-term opioid analgesic sons for administration, prescription pat- double-blinded randomized study. Anesth therapy for severe refractory lumbar spine terns, effectiveness, and side effects. Clin Analg 2001; 92:488-495. pain. Clin J Pain 1999; 15:136-140. J Pain 2005; 21:503-512. 265. Huse E, Larbig W, Flor H, Birbaumer N. The 279. de Craen AJ, Lampe-Schoenmaeckers AJ, 291. Morley JS, Bridson J, Nash TP, Miles JB, effect of opioids on phantom limb pain Kraal JW, Tijssen JG, Kleijnen J. Impact of White S, Makin MK. Low-dose metha- and cortical reorganization. Pain 2001; 90: experimentally-induced expectancy on the done has an analgesic effect in neuropath- 47-55. analgesic effi cacy of tramadol in chronic ic pain: a double-blind randomized con- 266. Moulin DE, Iezzi A, Amireh R, Sharpe WK, pain patients: A 2 x 2 factorial, random- trolled crossover trial. Palliat Med 2003; Boyd D, Merskey H. Randomized trial of ized, placebo-controlled, double-blind tri- 17:576-587. oral morphine for chronic noncancer pain. al. J Pain Symptom Manage 2001; 21:210- 292. Malonne H, Coffi ner M, Sonet B, Sereno Lancet 1996; 347:143-147. 217. A, Vanderbist F. Effi cacy and tolerability 267. Peloso PM, Bellamy N, Bensen W, Thom- 280. Messick RT. Evaluation of acetaminophen, of sustained-release tramadol in the treat- son GT, Harsanyi Z, Babul N, Darke AC. propoxyphene, and their combination in ment of symptomatic osteoarthritis of the Double blind randomized placebo control offi ce practice. J Clin Pharmacol 1979; 19: hip or knee: A multicenter, randomized, trial of controlled-release codeine in the 227-230. double-blind, placebo-controlled study. treatment of osteoarthritis of the hip or 281. Muller FO Odendaal CL, Muller FR, Clin Ther 2004; 26:1774-1782. knee. J Rheumatol 2000; 27:764-771. Raubenheimer J, Middle MV, Kummer M. 293. Babul N, Noveck R, Chipman H, Roth SH, 268. Watson CP, Babul N. Effi cacy of oxycodone Comparison of the effi cacy and tolerability Gana T, Albert K. Effi cacy and safety of in neuropathic pain a randomized trial in of a paracetamol/codeine fi xed-dose com- extended-release, once-daily tramadol in postherpetic neuralgia. Neurology 1998; bination with tramadol in patients with re- chronic pain: A randomized 12-week clini- 50:1837-1841. fractory chronic back pain. Arzneimittel- cal trial in osteoarthritis of the knee. J Pain 269. Gimbel JS, Richards P, Portenoy RK. Con- forschung 1998; 48:675-679. Symptom Manage 2004; 28:59-71. trolled-release oxycodone for pain in di- 282. Mullican WS, Lacy JR. TRAMAP-ANAG-006 294. Ruoff GE, Rosenthal N, Jordan D, Karim abetic neuropathy. Neurology 2003; 60: Study Group. Tramadol/acetaminophen R, Kamin M; Protocol CAPSS-112 Study 927-934. combination tablets and codeine/ Group. Tramadol/acetaminophen combi- 270. Maier C, Hildebrandt J, Klinger R, Henrich- acetaminophen combination capsules for nation tablets for the treatment of chron- Eberl C, Lindena G. Morphine responsive- the management of chronic pain: a com- ic lower back pain: a multicenter, random- ness, effi cacy and tolerability in patients parative trial. Clin Ther 2001; 23:1429- ized, double-blind, placebo-controlled with chronic non-tumor associated pain 1445. outpatient study. Clin Ther 2003; 25:1123- - results of a double-blind placebo-con- 283. Palangio M, Damask MJ, Morris E, Doyle RT 1141. trolled trial (MONTAS). Pain 2002; 97:223- Jr, Jiang JG, Landau CJ, de Padova A. Combi- 295. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. 233. nation hydrocodone and ibuprofen versus Effi cacy of tramadol in treatment of chron- 271. Raja SN, Haythornthwaite JA, Pappagallo combination codeine and acetaminophen ic low back pain. J Rheumatol 2000; 27: M, Clark MR, Travison TG, Sabeen S, Royall for the treatment of chronic pain. Clin Ther 772-778. RM, Max MB. Opioids versus antidepres- 2000; 22:879-892. 296. Sittl R, Griessinger N, Likar R. Analgesic ef- sants in postherpetic neuralgia: A ran- 284. Salzman RT, Brobyn RD. Long-term com- fi cacy and tolerability of transdermal bu- domized placebo-controlled trial. Neurol- parison of suprofen and propoxyphene in prenorphine in patients with inadequate- ogy 2002; 59:1015-1021. patients with osteoarthritis. Pharmacolo- ly controlled chronic pain related to can- 272. Watson CPN, Moulin D, Watt-Watson J, gy 1983; 27:S55-S64. cer and other disorders: a multicenter, Gordon A, Eisenhoffer J. Controlled-re- 285. Wilder-Smith CH, Hill L, Spargo K, Kalla A. randomized, double-blind, placebo-con- lease oxycodone relieves neuropath- Treatment of severe pain from osteoarthri- trolled trial. Clin Ther 2003; 25:150-168. ic pain: A randomized controlled trial in tis with slow-release tramadol or dihydro- 297. Gammaitoni AR, Galer BS, Lacouture P, Do- painful diabetic neuropathy. Pain 2003; codeine in combination with NSAID’s: A mingos J, Schlagheck T. Effectiveness and 105:71-78. randomized study comparing analgesia, safety of new oxycodone/acetaminophen 273. Haythornthwaite JA, Menefee LA, Quatra- antinociception and gastrointestinal ef- formulations with reduced acetamino- no-Piacentini AL, Pappagallo M. Outcome fects. Pain 2001; 91:23-31. phen for the treatment of low back pain. of chronic opioid therapy for non-cancer 286. Rangel-Guerra R. An open evaluation of Pain Med 2003; 4:21-30. pain. J Pain Symptom Manage 1998; 15: oral butorphanol as long-term therapy in 298. Peloso PM, Fortin L, Beaulieu A, Kamin M, 185-194. out-patients suffering from moderate to Rosenthal N; Protocol TRP-CAN-1 Study 274. Rowbotham MC, Twilling L, Davies PS, Re- severe chronic pain. J Int Med Res 1981; 9: Group. Analgesic effi cacy and safety of isner L, Taylor K, Mohr D. Oral opioid ther- 120-123. tramadol/ acetaminophen combination apy for chronic peripheral and central neu- 287. Milligan K, Lanteri-Minet M, Borchert K, tablets (Ultracet) in treatment of chronic ropathic pain. N Engl J Med 2003; 348: Helmers H, Donald R, Kress HG, Adri- low back pain: a multicenter, outpatient, 1223-1232. aensen H, Moulin D, Jarvimaki V, Haazen L. randomized, double blind, placebo con- trolled trial. J Rheumatol 2004; 31:2454- 275. Kjaersgaard-Andersen P, Nafei A, Skov Evaluation of long-term effi cacy and safe- 2463. O, Madsen F, Andersen HM, Kroner K, ty of transdermal fentanyl in the treatment Hvass I, Gjoderum O, Pedersen L, Braneb- of chronic noncancer pain. J Pain 2001; 2: 299. Markenson JA, Croft J, Zhang PG, Richards

Pain Physician Vol. 9, No. 1, 2006 38 Trescot et al • Opioid Guidelines

P. Treatment of persistent pain associated agement setting: A prospective evalua- Substance Abuse at Columbia University, with osteoarthritis with controlled-release tion. Pain Physician 2001; 4:131-142. Missed Opportunity: National Survey of Pri- oxycodone tablets in a randomized con- 314. Davis PJ, Reeves JL, Hastie BA, Graff-Rad- mary Care Physicians and Patients on Sub- trolled clinical trial. Clin J Pain 2005; 21: ford SB, Naliboff BD. Depression deter- stance Abuse (New York: CASA, 2000): iii. 524-535. mines illness conviction and pain impact: 328. “Some seniors sell prescriptions to get 300. Allan L, Richarz U, Simpson K, Slappendel A structural equation modeling analysis. by.” The Paducah Sun, Paducah, KY, De- R. Transdermal fentanyl versus sustained Pain Med 2000; 1:238-246. cember 31, 2005. release oral morphine in strong-opioid na- 315. Manchikanti L, Fellows B, Pampati VS, 329. Santillan R, Hurle MA, Armijo JA, de los Mo- ive patients with chronic low back pain. Damron KS, Beyer CD, Barnhill RC. Com- zos R, Florez J. Nimodipine-enhanced opiate Spine 2005; 30:2484-2490. parison of psychological status of chron- analgesia in cancer patients requiring 301. Kabata T, Kubo T, Matsumoto T, Nishino M, ic pain patients with general population. dose escalation: A double-blind, placebo- Tomita K, Katsuda S, Horii T, Uto N, Kita- Pain Physician 2002; 5:40-48. controlled study. Pain 1998; 76:17. jima I Apoptotic cell death in steroid in- 316. Adams LL, Gatchel RJ, Robinson RC, Pola- 330. Manchikanti L, Rivera J, Pampati V, Dam- duced osteonecrosis: An experimental tin P, Gajraj N, Deschner M, Noe C. Devel- ron KS, MCManus CD, Brandon DE, Wilson study in rabbits. J Rheumatol 2000; 27: opment of a self-report screening instru- SR. One day lumbar epidural adhesiolysis 2166-2171. ment for assessing potential opioid med- and hypertonic saline neurolysis in treat- 302. Wasan AD, Davar G, Jamison R. The asso- ication misuse in chronic pain patients. J ment of chronic low back pain: A random- ciation between negative affect and opioid Pain Symptom Manage 2004; 27:440-459. ized double blind trial. Pain Physician. analgesia in patients with discogenic low 317. Portenoy RK. Opioid therapy for chronic 2004; 7:177-186. back pain. Pain 2005; 117:450-461. nonmalignant pain: A review of the critical 331. Manchikanti L, Pampati VS, Bakhit C, Ri- 303. Rivera JJ, Singh V, Fellows B, Pampati V, issues. J Pain Symptom Manage 1996; 11: vera JJ, Beyer CD, Damron KS, Barnhill Damron KS, McManus CD. Reliability of 203-217. RC. Effectiveness of lumbar facet joint psychological evaluation in chronic pain 318. Savage SR. Opioid therapy of chronic nerve blocks in chronic low back pain: A in an interventional pain management set- pain: assessment of consequences. Acta randomized clinical trial. Pain Physician ting. Pain Physician 2005; 8:375-383. Anaesth Scand 1999; 43:909-917. 2001; 4:101-117. 304. Dersh J, Gatchel RJ, Polatin P. Chronic spi- 319. Compton P, Darakjian MA, Miotto K. 332. Manchikanti L, Pampati VS, Fellows B, Ri- nal disorders and psychopathology: Re- Screening for addiction in patients with vera JJ, Beyer CD, Damron KS. Role of one search fi ndings and theoretical consider- chronic pain and "problematic" substance day epidural adhesiolysis in management of ations. Spine 2001; 1:88-94. use: evaluation of a pilot assessment tool. chronic low back pain: A randomized clinical 305. Bair MJ, Robinson RL, Katon W, Kroenke K. J Pain Symptom Manage 1998; 16:355- trial. Pain Physician 2001; 4:153-166. Depression and pain comorbidity: A liter- 363. 333. Manchikanti L, Manchikanti KN, Damron ature review. Arch Intern Med 2003; 163: 320. Passik SD, Kirsh KL, McDonald MV, Ahn S, KS, Pampati V. Effectiveness of cervical 2433-2445. Russak SM, Martin L, Rosenfeld B, Breit- medial branch blocks in chronic neck pain: 306. Katon W. The impact of major depression bart WS, Portenoy RK. A pilot survey of A prospective outcome study. Pain Physi- on chronic medical illness. Gen Hosp Psy- aberrant drug-taking attitudes and be- cian 2004; 7:195-201. chiatry 1996; 18:215-219. haviors in samples of cancer and AIDS pa- 334. Manchikanti L, Boswell MV, Rivera JJ, 307. McWilliams LA, Goodwin RD, Cox BJ. De- tients. J Pain Symptom Manage 2000; 19: Pampati V, Damron KS, McManus CD, pression and anxiety associated with 274-286. Brandon DE, Wilson SR. A randomized, three pain conditions: results from a na- 321. Robinson RC, Gatchel RJ, Polatin P, Desch- controlled trial of spinal endoscopic ad- tionally representative sample. Pain 2004; ner M, Noe C, Gajraj N. Screening for prob- hesiolysis in chronic refractory low back 111:77-83. lematic prescription opioid use. Clin J Pain and lower extremity pain. BMC Anesthe- siol 2005; 5:10. 308. Rush AJ, Polatin P, Gatchel RJ. Depression 2001; 17:220-228. and chronic low back pain. Spine 2000; 322. Manchikanti L, Singh V, Damron KS, Bey- 335. Manchikanti L, Staats PS, Singh V, Schultz 25:2566-2571. er CD, Pampati V. Screening for controlled DM, Vilims BD, Jasper JF, Kloth DS, Trescot AM, Hansen HC, Falasca TD, Racz GB, Deer 309. Fishbain DA, Cutler R, Rosomoff HL, Ro- substance abuse in interventional pain T, Burton AW, Helm S, Lou L, Bakhit CE, somoff RS. Chronic pain associated de- management settings: Evaluation of an Dunbar EE, Atluri SL, Calodney AK, Has- pression: Antecedent or consequence of assessment tool. Pain Physician 2003; 6: senbusch S, Feler CA. Evidence-based chronic pain? A review. Clin J Pain 1997; 425-433. practice guidelines for interventional tech- 13:116-137. 323. Manchikanti L, Pampati V, Damron KS, Mc- niques in the management of chronic spi- Manus CD. Evaluation of variables in illic- 310. Macfarlane GJ, Morris S, Hunt IM, Benja- nal pain. Pain Physician 2003; 6:3-80. min S, McBeth J, Papageorgiou AC, Silman it drug use: Does a controlled substance 336. Gourlay DL, Heit HA, Almahrezi A. Univer- AJ. Chronic widespread pain in the com- abuse screening tool identify illicit drug sal precautions in pain medicine: a ratio- munity: The infl uence of psychological use? Pain Physician 2004; 7:71-75. nal approach to the treatment of chronic symptoms and mental disorder on health- 324. Atluri SL, Sudarshan G. Development pain. Pain Med 2005; 6:107-112. care seeking behavior. J Rheumatol 1999; of a screening tool to detect the risk of 26:413-419. inappropriate prescription opioid use in 337. Manchikanti L. Documentation for eval- uation and management services. In 311. Von Korff M, Le Resch L, Dworkin S. First patients with chronic pain. Pain Physician Manchikanti L (ed.), Interventional Pain onset of common pain symptoms: A pro- 2004; 7:333-338. Management: Principles and Practice spective study of depression as a risk fac- 325. Michna E, Ross EL, Hynes WL, Nedeljkovic of Documentation, Billing, Coding, and tor. Pain 1993; 55:251-258. SS, Soumekh S, Janfaza D, Palombi D, Practice Management. ASIPP Publishing, Jamison RN. Predicting aberrant drug be- 312. McWilliams LA, Cox BJ, Enns MW. Mood Paducah, KY, 2004; pp 31-46. and anxiety disorders associated with havior in patients treated for chronic pain: 338. 1997 Documentation Guidelines for Evalu- chronic pain: an examination in a national- importance of abuse history. J Pain Symp- ation and Management Services. http:// ly representative sample. Pain 2003; 106: tom Manage 2004; 28:250-258. www.cms.gov/medlearn/emdoc.htm 127-133. 326. National Institute of Drug Abuse Research 339. 1995 Documentation Guidelines for Evalu- 313. Manchikanti L, Pampati VS, Fellows B, Report Series, Prescription Drugs: Abuse ation and Management Services. http:// Beyer CD, Damron KS, Barnhill RC, Burks and Addiction, NIH Publication No. 01- www.cms.gov/medlearn/emdoc.htm T. Characteristics of chronic low back pain 4881, 2001, 7. in patients in an interventional pain man- 327. The National Center on Addiction and 340. Sehgal N, Shah RV, McKenzie-Brown A, Ev-

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erett CR. Diagnostic utility of facet (zyg- pain. Pain Physician 2001; 4:308-316. nal pain: Systematic review of the evi- apophysial) joint injections in chronic spi- 344. Shah RV, Everett CR, McKenzie-Brown AM, dence. Pain Physician 2002; 5:405-418. nal pain: A systematic review of evidence. Sehgal N. Discography as a diagnostic test 348. Abdi S, Datta S, Lucas LF. Role of epidural Pain Physician 2005; 8:211-224. for spinal pain: A systematic and narrative steroids in the management of chronic spi- 341. McKenzie-Brown AM, Shah RV, Sehgal N, review. Pain Physician 2005; 8:187-209. nal pain: a systematic review of effective- Everett CR. A systematic review of sacro- 345. Everett CR, Shah RV, Sehgal N, McKen- ness and complications. Pain Physician iliac joint interventions. Pain Physician zie-Brown AM. A systematic review of di- 2005; 8:127-143. 2005; 8;115-125. agnostic utility of selective nerve root 349. Boswell MV, Hansen HC, Trescot AM, 342. Boswell MV, Singh V, Staats PS, Hirsch JA. blocks. Pain Physician 2005; 8:225-233. Hirsch JA, Epidural steroids in the man- Accuracy of precision diagnostic blocks in 346. Boswell MV, Colson JD, Spillane WF. Ther- agement of chronic spinal pain and the diagnosis of chronic spinal pain of fac- apeutic facet joint interventions in chronic radiculopathy. Pain Physician 2003; 6: et or zygapophysial joint origin. Pain Phy- spinal pain: A systematic review of effec- 319-334. sician 2003; 6:449-456. tiveness and complications. Pain Physi- 350. Chopra P, Smith HS, Deer TR, Bowman RC. 343. Manchikanti L, Singh V, Pampati V, Dam- cian 2005; 8:101-114. Role of adhesiolysis in the management of ron KS, Barnhill RC, Beyer CD, Cash KA. 347. Manchikanti L, Singh V, Vilims BD, Hansen chronic spinal pain: A systematic review Evaluation of the relative contributions HC, Schultz DM, Kloth DS. Medial branch of effectiveness and complications. Pain of various structures in chronic low back neurotomy in management of chronic spi- Physician 2005; 8:87-100.

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Pain Physician Vol. 9, No. 1, 2006