The nexus of opioids, pain, and addiction: Challenges and solutions.

Pain and addiction are complex disorders with many commonalities. Beneficial outcomes for both disorders can be achieved through similar principles such as individualized medication selection and dosing, comprehensive multi-modal therapies, and judicious modification of treatment as indicated by the patient's status. This is implicit in the term "medication assisted treatment" (MAT) for opioid use disorders (OUD), and is equally important in pain management; however, for many OUD and pain patients, medication is central to the treatment plan and should neither be denied nor withdrawn if critical to patient well-being. Most patients prescribed opioids for pain do not develop OUD, and most people with OUD do not develop it as a result of appropriately prescribed opioids. Nonetheless, concerns about undertreatment of pain in the late 20th century likely contributed to inappropriate prescribing of opioids. This, coupled with a shortfall in OUD treatment capacity and the unfettered flood of inexpensive heroin and fentanyl, behavioral economics and other factors facilitated the 21st century opioid epidemic. Presently, injudicious reductions in opioid prescriptions for pain are contributing to increased suffering and suicides by pain patients as well as worsening disparities in pain management for ethnic minority and low-income people. Many of these people are turning to illicit opioids, and no evidence shows that the reduction in opioid prescriptions is reducing OUD or overdose deaths. Comprehensive, science-based policies that increase access to addiction treatment for all in need and better serve people with pain are vital to addressing both pain and addiction.

Commentary On The 40th Anniversary of AMERSA: AMERSA at 40: How It All Began And How It Survived.

The question at hand for the 40th anniversary of AMERSA is how an organization with such a small membership devoted to substance use disorder medical education actually survived for 40 years. There were many obstacles. AMERSA had limited resources and only modest outside support. It was surrounded by large addiction specialty medical organizations with large budgets, some with membership in the thousands. Further, the missions of these larger organizations included medical education. Our longevity can be ascribed to these four critical periods and events. The Career Teacher Program (1972-1981), The decision by AMERSA in 1983 to remain an independent national organization, The AMERSA standard setting conference of 1985, AMERSA's Strategic Plan for Interdisciplinary Faculty Development and Project Mainstream (1999-2003).

Identification of prescription opioid misuse and abuse behaviors and risk factors in chronic pain patients using the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ).

OBJECTIVES: To identify patient risk factors associated with prescription opioid misuse and abuse as well as groupings of misuse and abuse behaviors as measured by the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ). METHODS: Adults with chronic pain requiring long-term treatment with opioids completed the POMAQ and other study questionnaires. Latent class analysis (LCA) was used to examine underlying subgroups exhibiting particular risk profiles. Patient demographic and clinical characteristics were examined as covariates and the concordance between the identified latent classes at-risk classifications and the POMAQ clinical scoring algorithm was assessed. RESULTS: Analysis of data from 809 patients revealed four classes: "chronic pain, low risk" (n = 473, low to no prevalence of POMAQ behaviors), "chronic pain, comorbid condition" (n = 152, high prevalence of anti-anxiety, sleeping pill, and antihistamine use), "at risk" (n = 154, taking more opioids than prescribed and drinking alcohol with opioids more frequently than other groups), and "high risk" (n = 30, highest prevalence of each behavior). The "high risk" group was associated with being younger, less educated, and unemployed compared to other groups. When examining the LCA classes by groups defined by the original POMAQ clinical scoring algorithm, the "high risk" class had the highest proportion of participants identified with abuse behaviors (46.7%), compared to just 4.7% in the "chronic pain, low risk" group. CONCLUSIONS: Findings suggest there are four distinct subgroups of patients defined by chronic opioid misuse and abuse behaviors and support the use of the POMAQ to identify risk factors associated with prescription opioid misuse and abuse.

Do prescription monitoring programs impact state trends in opioid abuse/misuse?

OBJECTIVE: Prescription monitoring programs (PMPs) are statewide databases containing prescriber and patient-level prescription data on select drugs of abuse. These databases are used by medical professionals or law enforcement officials to identify patients with prescription drug use patterns indicative of abuse or providers engaging in illegal activities. Most states have implemented PMPs in an attempt to curb prescription drug abuse and diversion. However, assessment of their impact on drug abuse is only beginning. This study aimed to evaluate the relationship between PMPs and opioid misuse over time in two drug abuse surveillance data sources. METHODS: Data from the RADARS® System Poison Center and Opioid Treatment surveillance databases were used to obtain measures of abuse and misuse of opioids. Repeated measures negative binomial regression was applied to quarterly surveillance data (from 2003 to mid-2009) to estimate and compare opioid abuse and misuse trends. PMP presence was modeled as a time varying covariate for each state. RESULTS: Results support an association between PMPs and mitigated opioid abuse and misuse trends. Without a PMP in place, Poison Center intentional exposures increased, on average, 1.9% per quarter, whereas opioid intentional exposures increase 0.2% (P = 0.036) per quarter with a PMP in place. Opioid treatment admissions increase, on average, 4.9% per quarter in states without a PMP vs 2.6% (P = 0.058) in states with a PMP. In addition to the time trend, population and a measure of drug availability were also significant predictors. A secondary analysis that classified PMP based upon ideal characteristic showed consistent though not significant results. CONCLUSIONS: Two observational data sources offer preliminary support that PMPs are effective. Future efforts should evaluate what PMP characteristics are most effective and which opioids are most impacted.

Clinical scoring algorithm for the prescription opioid misuse and abuse questionnaire (POMAQ).

OBJECTIVE: The Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) was developed to identify prescription opioid misuse and abuse among patients with chronic pain. A clinical scoring algorithm was developed and refined to align with the patient experience. METHODS: This study utilized data from the POMAQ validation study (3033-4, NCT02660606) conducted on a sample of patients with chronic pain living in the United States. The study was carried out in two phases. Two purposefully enriched patient samples, one for each phase, were created based on patient responses to select POMAQ items and the availability of urine and hair samples. Two clinical experts (SHS, SFB) reviewed patient data to classify prescription opioid use behavior. Classification differences were adjudicated by a third clinical expert (JTF). Comparisons were made between the final clinical classification determined by the experts and the proposed classification based on the POMAQ algorithm. RESULTS: Sixty patients were included in Phase I (only POMAQ data) and 52 in Phase II (including POMAQ and ancillary sources [e.g. electronic medical records, urine toxicity screen]). Refinements were made to the POMAQ scoring algorithm following discussions with clinical experts to ensure it was clinically relevant. For both phases, classifications were reviewed and discussed to achieve maximal concordance of classifications across experts. The proposed scoring algorithm was then modified to maximize agreement with the expert interpretation of clinically relevant patient experiences. CONCLUSION: The clinical scoring algorithm for the POMAQ was developed and refined to reflect clinically relevant patient behaviors identified by expert review. Future testing is needed to determine the sensitivity and specificity of this measure.

An analysis of the root causes for opioid-related overdose deaths in the United States.

OBJECTIVE: A panel of experts in pain medicine and public policy convened to examine root causes and risk factors for opioid-related poisoning deaths and to propose recommendations to reduce death rates. METHODS: Panelists reviewed results from a search of PubMed and state and federal government sources to assess frequency, demographics, and risk factors for opioid-related overdose deaths over the past decade. They also reviewed results from a Utah Department of Health study and a summary of malpractice lawsuits involving opioid-related deaths. RESULTS: National data demonstrate a pattern of increasing opioid-related overdose deaths beginning in the early 2000s. A high proportion of methadone-related deaths was noted. Although methadone represented less than 5% of opioid prescriptions dispensed, one third of opioid-related deaths nationwide implicated methadone. Root causes identified by the panel were physician error due to knowledge deficits, patient non-adherence to the prescribed medication regimen, unanticipated medical and mental health comorbidities, including substance use disorders, and payer policies that mandate methadone as first-line therapy. Other likely contributors to all opioid-related deaths were the presence of additional central nervous system-depressant drugs (e.g., alcohol, benzodiazepines, and antidepressants) and sleep-disordered breathing. CONCLUSIONS: Causes of opioid-related deaths are multifactorial, so solutions must address prescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures. Clinical strategies to reduce opioid-related mortality should be empirically tested, should not reduce access to needed therapies, should address risk from methadone as well as other opioids, and should be incorporated into any risk evaluation and mitigation strategies enacted by regulators.

Establishing the content validity of the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) among chronic pain patients.

OBJECTIVES: Content validation is essential in the development of patient-reported instruments to ensure relevancy and understandability. The aim was to evaluate patient understanding of the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) using cognitive interviewing among adults with chronic moderate to severe pain. METHODS: This qualitative study involved a one-time in-clinic visit to conduct one-on-one cognitive interviews among participants with chronic moderate to severe pain from four groups: (1) Known Opioid Abuse; (2) Known Abuse of Other Substances (e.g. alcohol, benzodiazepines); (3) Opioid Non-abuse; and (4) No Chronic Opioid Use. Patients were recruited from 6 US clinical centers. Concept elicitation questions regarding misuse and abuse were asked at interview start; the POMAQ was completed via a web interface followed by a cognitive interview regarding POMAQ items and response options. RESULTS: 56 patients were enrolled. Mean age was 48.7 ± 12.3 years; 57% female; 80% Caucasian; mean duration of chronic pain was 11.2 ± 8.2 years with lower back pain predominating at 75%. Overall, the POMAQ was well-understood and received positive feedback. A few (n = 6, 11%) expressed concerns about completing the POMAQ using a secure internet site as they either indicated they were not computer savvy (n = 3, 5%) or were concerned about internet security (n = 3, 5%). Minor wording modifications were made to the POMAQ to enhance clarity and understanding of the POMAQ. CONCLUSIONS: The POMAQ demonstrated content validity among patients with moderate to severe chronic pain and is undergoing psychometric evaluation among a larger cohort of patients.

Construct validity and reproducibility of the Prescription Opioid Misuse And Abuse Questionnaire (POMAQ).

OBJECTIVE: The Prescription Opioid Misuse and Abuse Questionnaire was developed to identify prescription opioid abuse and misuse among patients with chronic pain, however, evidence of construct validity and reproducibility is needed. METHODS: Chronic pain patients were recruited from five Department of Defense Military Health System clinics across the United States. Construct validity was examined using subjective clinician-reported and patient-reported measures as well as objective information (e.g. hair/urine drug screens and electronic medical records). Test-retest reliability was assessed across 2 timepoints among a subgroup of patients with stable chronic pain. RESULTS: Of 3,263 screened patients, 938 (28.7%) met eligibility and were enrolled; 809 (86.2%) completed the Prescription Opioid Misuse and Abuse Questionnaire. Construct validity was supported by comparison to other validated questionnaires and hair and urine screens which yielded high agreements with patient reports on the Prescription Opioid Misuse and Abuse Questionnaire. Electronic medical record data supported patients' Prescription Opioid Misuse and Abuse Questionnaire responses regarding physician and emergency room visits and opioid refills. The Prescription Opioid Misuse and Abuse Questionnaire had excellent test-retest reliability; the percentage agreement between the two Prescription Opioid Misuse and Abuse Questionnaire administrations was high (>90%) for most questions. DISCUSSION: Results suggest that the Prescription Opioid Misuse and Abuse Questionnaire is a valid and reproducible tool that can be used to assess the presence of prescription opioid misuse and abuse among patients with chronic pain.

Insight into chronic pain in the United States: descriptive results from the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) validation study.

OBJECTIVE: A chronic pain patient sample living in the United States who participated in a cross-sectional study to evaluate the validity and reproducibility of the Prescription Opioid Misuse and Abuse Questionnaire is characterized. METHODS: Patients with chronic pain identified through electronic medical records as refilling at least one opioid prescription within the prior 3 months were recruited from five United States Department of Defense Military Health System clinics. Patients completed the Prescription Opioid Misuse and Abuse Questionnaire, Brief Pain Inventory-Short Form, Medical Outcomes Study: 36-item Short Form, and sociodemographic questions online. Clinical characteristics and electronic medical records for 1 year prior to consent were collected. RESULTS: 809 (86.2%) participants completed the Prescription Opioid Misuse and Abuse Questionnaire. Mean (± standard deviation) age was 55.4 ± 12.7 years; the majority female (55.5%) and white (74.8%). Mean duration of chronic pain was 14.7 ± 10.5 years; the most common pain conditions were lower back pain (76.6%), neck or shoulder pain (60.3%), and osteoarthritis (38.7%). The most commonly prescribed opioids were oxycodone (35.7%), tramadol (34.5%), and hydrocodone (26.9%); 54.8% took one opioid, 44.9% took 2 or more opioids. DISCUSSION: Participants' health status was poor; pain severity and interference were moderate. Electronic medical record data revealed high healthcare resource utilization. This chronic pain population was severely impacted by their pain condition(s).

Assessment of Amphetamine Withdrawal Symptoms of Lisdexamfetamine Dimesylate Treatment for Adults With Binge-Eating Disorder.

OBJECTIVE: To determine whether physical dependence developed during lisdexamfetamine dimesylate treatment, as evidenced by presence of withdrawal symptoms after treatment cessation in adults with binge-eating disorder (BED) treated for up to 38 weeks. METHODS: Three studies enrolled adults with DSM-IV-TR-defined BED. In two 12-week, randomized, double-blind, placebo-controlled studies conducted from November 2012 to September 2013, participants were treated with placebo or dose-optimized lisdexamfetamine (50 or 70 mg). In a double-blind, placebo-controlled, randomized-withdrawal maintenance-of-efficacy study conducted from January 2014 to April 2015, participants categorized as responders after 12 weeks of open-label lisdexamfetamine (50 or 70 mg) were randomized to continued lisdexamfetamine or placebo for 26 weeks. The Amphetamine Cessation Symptom Assessment (ACSA), a 16-item self-report instrument (total score: 0-64), assessed withdrawal experiences. Mean ± SD ACSA scores and medians are presented for study completers. RESULTS: In the short-term efficacy studies, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine (pooled data) were 7.0 ± 7.60 (n = 275) and 4.9 ± 6.41 (n = 271), respectively, on the day of the last dose at week 12/early termination (ET) and 4.8 ± 6.82 (n = 234) and 5.5 ± 7.50 (n = 221) on day 7 after the last dose. In the maintenance-of-efficacy study, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine were 4.8 ± 6.67 (n = 44) and 4.7 ± 7.78 (n = 85) on the day of the last dose at week 38/ET and 3.9 ± 5.75 (n = 37) and 5.2 ± 7.93 (n = 71) on day 7 after the last dose. CONCLUSIONS: Study results suggest that abrupt lisdexamfetamine termination was not associated with amphetamine withdrawal symptoms at the exposure durations and therapeutic doses analyzed. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01718483, NCT01718509, and NCT02009163.

Real-world misuse, abuse, and dependence of abuse-deterrent versus non-abuse-deterrent extended-release morphine in Medicaid non-cancer patients.

OBJECTIVE: Opioids with abuse-deterrent properties may reduce widespread abuse, misuse, and diversion of these products. This study aimed to quantify misuse, abuse, dependence, and health resource use of extended-release morphine sulfate with sequestered naltrexone hydrochloride (ER-MSN; EMBEDA®), compared with non-abuse-deterrent extended-release morphine (ERM) products in Medicaid non-cancer patients. METHODS: Administrative medical and pharmacy claims data were analyzed for 10 Medicaid states from 1 January 2015, to 30 June 2016. Patients were included if they received a prescription for ER-MSN or any oral, non-abuse-deterrent ERM. Index date was the date of first prescription for an ER-MSN or ERM. Abuse/dependence, non-fatal overdose, emergency department (ED) visits, and ED/inpatient readmissions were determined for each participant. An overall measure of misuse and abuse was also calculated. To account for differences in follow-up, all counts are expressed per 100 patient-years. RESULTS: There were 4,857 patients who received ER-MSN and 10,357 who received an ERM. The average age in the two cohorts was approximately 45 years old. From pre-index to follow-up, the number of patients per 100 patient-years with a diagnosis code indicating abuse or dependence increased by 0.91 (95% confidence interval [CI]: 0.85, 0.97) in the ER-MSN cohort and 2.23 (95% CI: 2.14, 2.32) in the ERM cohort. The number of patients per 100 patient-years with an opioid-related non-fatal overdose increased by 0.05 (95% CI: 0.04, 0.06) in the ER-MSN cohort compared with 0.11 (95% CI: 0.09, 0.13) in the ERM cohort. The opioid abuse overall composite score increased by 1.36 (95% CI: 1.24, 1.48) in the post-index period in the ER-MSN cohort compared to 3.21 (95% CI: 3.10, 3.32) in the ERM cohort. CONCLUSION: Misuse, abuse, and dependence events were numerically lower in patients receiving ER-MSN compared with those receiving ERM products.

Behavioral economic demand metrics for abuse deterrent and abuse potential quantification.

INTRODUCTION: Behavioral economics provides a framework for quantifying drug abuse potential that can inform public health risk, clinical treatment, and research. Hypothetical purchase task (HPT) questionnaires may provide a low-cost and sensitive method by which to measure and predict the appeal of pharmaceutical drugs that differ by formulation. However, the validity of this type of analysis must be empirically established by comparing the "essential value" (EV) of different drugs across subgroups. PROCEDURES: This pilot study used HPT assessments and the Exponential Model of Demand to quantify the EV of opioid medications-specifically, easily tampered formulations versus (vs.) abuse-deterrent formulations-in patients with a history of opioid abuse. MAIN FINDINGS: Participants had more inelastic demand for opioid pills than for cigarettes and alcohol. Participants with experience manipulating pills (M group) had more inelastic demand for standard pills vs. participants with no manipulation experience (NM group), and the M group had a more elastic demand for the abuse-deterrent opioid pill than for the standard pill. There was no effect of formulation in the NM group and there was no difference in demand elasticity for abuse-deterrent pills between the two groups. There was a positive correlation between the EVs of different drugs, and between some behavioral economic indices and treatment variables. CONCLUSIONS: Our results suggest that HPTs may provide a sensitive measure of abuse potential that can distinguish between different formulations in at-risk populations.

Misconceptions and Realities of the Prescription Opioid Epidemic.

The abuse of opioids in the US is not a new problem. In 1973 David Musto published his book, The American Disease: Origins of Narcotic Control, which described the problem as dating back to the time of the Civil War. Continued attempts to address it through legislation, law enforcement, prevention, treatment, and the development of less abuseable pain relievers have shown limited success.

Prescription opioid abuse among enrollees into methadone maintenance treatment.

A multi-state survey of 5663 opioid dependent persons enrolling in 72 methadone maintenance treatment programs (MMTPs) was conducted to determine the prevalence of prescription opioid (PO) abuse, factors associated with PO abuse and sources for POs. Regions where PO abuse was believed to be prevalent were oversampled; primary opioid was defined as the drug used the most before coming to the MMTP. Among primary heroin abusers, 69% reported abusing POs. Opioid abuse frequencies among primary PO abusers were oxycodone (79%), hydrocodone (67%), methadone (40%), morphine (29%), heroin (13%), hydromorphone (16%), fentanyl (9%) and buprenorphine (1%). Correlates (p < or = .01) of PO abuse, using general estimating equations, were: low urbanicity (MMTPs located in comparatively low population density counties), white ethnicity, no history of injecting primary drug, no previous methadone treatment, younger age, chronic pain, and pain as a reason for enrollment. The most frequent sources of POs were dealer, friend or relative, and doctor's prescription; least frequent were Internet and forged prescription. One-third of PO abusers reported a history of injecting their primary drug. PO abuse is highly prevalent among MMTP patients. Future studies should describe HIV/HCV needle injection practices, characteristics that predict treatment outcomes, and factors that contribute to higher prevalence of persistent pain among PO abusers.

Challenges in the development of prescription opioid abuse-deterrent formulations.

Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics--if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.

Prescription drug abuse among prisoners in rural Southwestern Virginia.

Non-medical use of prescription medications is on the rise across the U.S., particularly in rural areas. In this study of 233 prisoners and probationers in southwestern Virginia, we add to an emerging profile of individuals abusing prescription medications. In this retrospective review of 2000-2004 augmented Addiction Severity Index data, those abusing prescription medications reported increased illicit drug and alcohol abuse, poly-drug abuse, psychiatric problems, and arrests for property crimes. Forty percent reported abuse of OxyContin, a drug implicated in a number of deaths in this region. Compared to non-users, OxyContin users were younger, more likely to be female, and more likely to abuse benzodiazepines, methadone, cocaine, and heroin. Longevity of abuse of these other drugs belies suggestions that OxyContin was acting as a "gateway" drug leading naïve users into addiction and risk of death.

Women physicians and addiction.

Nine hundred and sixty-nine impaired physicians (125 women and 844 men) enrolled in one of four state physician health programs were evaluated with comprehensive psychosocial, psychiatric and substance abuse/dependence profiles. When compared to male impaired physicians at time of entry to physician health programs, the 125 female impaired physicians were younger (39.9 vs. 43.7 years; p < .0001), reported more medical (48.7% vs. 34.4%; OR = 1.81) and psychiatric (76.5% vs. 63.9%; OR = 1.84) problems at intake. They were more likely to report past (51.8% vs. 29.9%; OR = 2.51) or current (11.4% vs. 4.8%; OR = 2.54) suicidal ideation, and more likely to have made a suicide attempt under the influence (20.0% vs. 5.1%; OR = 4.64) or not under the influence (14.0% vs. 1.7%; OR = 9.67) of a substance. Although alcohol was the primary drug of abuse for all physicians studied, women physicians were more likely to abuse sedative hypnotics than men (11.4 vs. 6.4; OR = 1.87). There were no gender differences in employment problems (65.3% vs. 67.5%; ns) or legal problems (15% vs. 21%; OR = .66) due to addiction. These findings suggest different characteristics between male and female impaired physicians which may have implications for identification and treatment of this population.

Do abuse deterrent opioid formulations work?

OBJECTIVE: We performed a systematic review to answer the question, "Does the introduction of an opioid analgesic with abuse deterrent properties result in reduced overall abuse of the drug in the community?" DESIGN: We included opioid analgesics with abuse deterrent properties (hydrocodone, morphine, oxycodone) with results restricted to the metasearch term "delayed onset," English language, use in humans, and publication years 2009-2016. All articles that contained data evaluating misuse, abuse, overdose, addiction, and death were included. The results were categorized using the Bradford-Hill criteria. RESULTS: We included 44 reports: hydrocodone (n = 7), morphine (n = 5), or oxycodone (n = 32) with Food and Drug Administration-approved Categories 1, 2, or 3 abuse deterrent labeling. The data currently available support the Hill criteria of strength (effect size), consistency (reproducibility), temporality, plausibility, and coherence. There was insufficient or no information available for the criteria of biological gradient, experiment, and analogy. We also assessed confounding factors and bias, which indicated that both were present and substantial in magnitude. CONCLUSIONS: Our analysis found that only oxycodone extended release (ER) had information available to evaluate abuse deterrence in the community. In Australia, Canada, and the United States, reformulation of oxycodone ER was followed by marked reduction in measures of abuse. The precise extent of reduced abuse cannot be calculated because of heterogeneous data sets, but the reported reductions ranged from 10 to 90 percent depending on the measure and the duration of follow-up.

Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report.

A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions. There was overwhelming consensus that formulation does play a role in prescription drug abuse, i.e., a formulation of an abused substance can be developed that will decrease its abuse potential, and several examples were cited. Nevertheless, it is imperative that new formulations have similar efficacy and in no way compromise medication access to doctors and patients. However, there was also consensus that a great deal of research and discussion was needed to fully implement a program of risk management through reformulation of existing products or tailoring the formulation of new products to retain clinical efficacy and safety while minimizing potential for abuse. Those who need to take part in this discussion include scientific groups, pharmaceutical companies, as well as governmental and regulatory agencies. The areas where more research is needed include development of standards for assessing tamper-resistance, improved animal models that can address formulation-related variables (e.g., onset, duration), the redesign of human laboratory studies providing appropriate models for comparing formulations, and improved post-marketing surveillance. Finally, knowledge and experience are needed to translate scientific work into a predictable, transparent and reliable regulatory process.

A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain.

Concern about abuse/dependence in chronic pain patients taking opioid analgesics may lead to undertreatment of pain, yet little is known about the prevalence of abuse/dependence in these patients and how it differs among analgesic agents. The objective of this study was to assess the prevalence of tramadol abuse compared to nonsteroidal anti-inflammatory drugs (NSAIDs) and hydrocodone-containing analgesics in patients with chronic noncancer pain (CNP). The study had three arms. The first arm consisted of subjects prescribed tramadol alone; the second of subjects randomized to either NSAIDs or tramadol; and the third of subjects randomized to hydrocodone or tramadol. Each investigator received two boxes of prescriptions randomized so that one in every four prescriptions was for tramadol. Upon deciding on the therapeutically appropriate arm, the physician selected the appropriate box, opened the next envelope and completed the enclosed prescription. After the initial randomization, physicians could prescribe whatever medication was therapeutically appropriate. A total of 11,352 subjects were enrolled. Up to nine interviews using a structured questionnaire were conducted over a 12-month period. An algorithm called the "Abuse Index" was developed to identify subjects who were abusing the drug. The primary components of the index were increasing dose without physician approval, use for purposes other than intended, inability to stop its use, and withdrawal. The percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone.