Michelle R. Lofwall

The Relative Abuse Liability of Oral Oxycodone, Hydrocodone and Hydromorphone Assessed in Prescription Opioid Abusers

Abuse of prescription opioids has risen precipitously in the United States. Few controlled comparisons of the abuse liability of the most commonly abused opioids have been conducted. This outpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential and potency of oral oxycodone (10, 20 and 40 mg), hydrocodone (15, 30 and 45 mg), hydromorphone (10, 17.5 and 25mg) and placebo. Healthy adult volunteers (n=9) with sporadic prescription opioid abuse participated in 11 experimental sessions (6.5h in duration) conducted in a hospital setting. All three opioids produced a typical mu opioid agonist profile of subjective (increased ratings of liking, good effects, high and opiate symptoms), observer-rated, and physiological effects (miosis, modest respiratory depression, exophoria and decrements in visual threshold discrimination) that were generally dose-related. Valid relative potency assays revealed that oxycodone was roughly equipotent to or slightly more potent than hydrocodone. Hydromorphone was only modestly more potent (less than two-fold) than either hydrocodone or oxycodone, which is inconsistent with prior estimates arising from analgesic studies. These data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids.

Individual and Network Factors Associated With Prevalent Hepatitis C Infection Among Rural Appalachian Injection Drug Users

OBJECTIVES We determined the factors associated with hepatitis C (HCV) infection among rural Appalachian drug users. METHODS This study included 394 injection drug users (IDUs) participating in a study of social networks and infectious disease risk in Appalachian Kentucky. Trained staff conducted HCV, HIV, and herpes simplex-2 virus (HSV-2) testing, and an interviewer-administered questionnaire measured self-reported risk behaviors and sociometric network characteristics. RESULTS The prevalence of HCV infection was 54.6% among rural IDUs. Lifetime factors independently associated with HCV infection included HSV-2, injecting for 5 or more years, posttraumatic stress disorder, injection of cocaine, and injection of prescription opioids. Recent (past-6-month) correlates of HCV infection included sharing of syringes (adjusted odds ratio = 2.24; 95% confidence interval = 1.32, 3.82) and greater levels of eigenvector centrality in the drug network. CONCLUSIONS One factor emerged that was potentially unique to rural IDUs: the association between injection of prescription opioids and HCV infection. Therefore, preventing transition to injection, especially among prescription opioid users, may curb transmission, as will increased access to opioid maintenance treatment, novel treatments for cocaine dependence, and syringe exchange.

Individual and network factors associated with non-fatal overdose among rural Appalachian drug users

BACKGROUND Fatal overdoses involving prescription opioids have increased significantly in recent years in the United States--especially in rural areas. However, there are scant data about non-fatal overdose among rural drug users. The purpose of this study is to examine the prevalence and correlates of non-fatal overdose and witnessed overdose among rural Appalachian drug users. METHODS Rural drug users were participants in a longitudinal study of social networks and HIV transmission. An interviewer-administered questionnaire elicited information in the following domains: sociodemographic characteristics, drug use (including lifetime overdose and witnessed overdose), psychiatric disorders, HIV risk behaviors and social networks (support, drug and sex networks). Negative binomial regression was used to model the number of lifetime overdoses and witnessed overdoses. RESULTS Of the 400 participants, 28% had ever experienced a non-fatal overdose, while 58.2% had ever witnessed an overdose (fatal or non-fatal). Factors independently associated with a greater number of overdoses included having ever been in drug treatment, past 30-day injection of prescription opioids, meeting the criteria for post-traumatic stress disorder and/or antisocial personality disorder and having more members in ones support network. CONCLUSIONS Rural drug users with history of overdose were more likely to have injected with prescription opioids--which is different from urban heroin users. However, the remaining correlates of non-fatal overdose among this cohort of rural drug users were similar to those of urban heroin users, which suggests current overdose prevention strategies employed in urban settings may be effective in preventing fatal overdose in this population.

A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world.

Outpatient opioid addiction treatment with sublingual buprenorphine pharmacotherapy has rapidly expanded in the United States and abroad, and, with this increase in medication availability, there have been increasing concerns about its diversion, misuse, and related harms. This narrative review defines the behaviors of diversion and misuse, examines how the pharmacology of buprenorphine alone and in combination with naloxone influence its abuse liability, and describes the epidemiological data on buprenorphine diversion and intravenous misuse, risk factors for its intravenous misuse, and the unintended consequences of misuse and diversion. Physician practices to prevent, screen for, and therapeutically respond to these behaviors, which are a form of medication nonadherence, are discussed, and gaps in knowledge are identified. Outpatient opioid addiction treatment with sublingual buprenorphine pharmacotherapy experiences from other countries that have varied health care systems, public policies, and access to addiction treatment are shared to make clear that diversion and misuse occur across the world in various contexts, for many different reasons, and are not limited to buprenorphine. Comparisons are made with other opioids with known abuse liability and medications with no known abuse. The objective was to facilitate understanding of diversion and misuse so that all factors influencing their expression (patient and provider characteristics and public policy) can be appreciated within a framework that also recognizes the benefits of addiction treatment. With this comprehensive perspective, further careful work can help determine how to minimize these behaviors without eroding the current benefits realized through improved addiction treatment access and expansion.

Abuse liability and reinforcing efficacy of oral tramadol in humans

BACKGROUND Tramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist. METHODS Nine healthy, non-dependent prescription opioid abusers (6 male and 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample and 7 self-administration). During each sample session, an oral dose of tramadol (200 and 400 mg), oxycodone (20 and 40 mg), codeine (100 and 200 mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money. RESULTS All active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs. CONCLUSIONS This study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation.

Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults.

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Given the purported role of the NMDA receptor in long-term potentiation, the primary purpose of the present study was to further understand the dose-related effects of ketamine on memory. The study was also designed to provide information about the relative effects of ketamine on memory versus nonmemory effects and to more fully characterize ketamines overall pattern and time course of effects. Single intramuscular injections of ketamine (0.2 mg/kg, 0.4 mg/kg) were administered to 18 healthy adult volunteers using a double-blind, placebo-controlled, crossover design. Word lists were used to evaluate episodic memory (free recall, recognition memory, source memory) and metamemory. Working memory, time estimation, psychomotor performance, and subjective effects were assessed repeatedly for 5 hours after drug administration. Ketamine selectively impaired encoding (as measured by free recall) while sparing retrieval, working memory while sparing attention, and digit symbol substitution task speed while sparing accuracy. Ketamine did not significantly impair recognition or source memory, metamemory, or time estimation. There were no hallucinations or increases in mystical experiences with ketamine. Memory measures were less sensitive to ketamine effects than subjective or psychomotor measures. Subjective effects lasted longer than memory and most psychomotor impairments. Ketamine produces selective, transient, dose- and time-related effects. In conjunction with previous studies of drugs with different mechanisms of actions, the observed selectivity of effects enhances the understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience.

Changing Profile of Abused Substances by Older Persons Entering Treatment

This study evaluated whether there were increasing admissions for illicit drug abuse treatment among older persons from 1992 to 2005 in the United States and describes the characteristics, number, and type of substances most commonly abused in this population over this 14-year period. Analyses used public data files from the Treatment Episode Data Set, which tracks federally and state funded substance abuse treatment admissions. From 1992 to 2005, admissions for illicit drug abuse increased significantly; in 2005, 61% of admissions age 50 to 54 years old and 45% of admissions age 55 years and older reported some type of illicit drug abuse, most commonly heroin or cocaine abuse. Criminal justice referrals for drug abuse admissions have increased over time and daily substance use remains high. Efforts to determine best practices for prevention, identification, and treatment of illicit drug abuse in older persons are indicated.

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis

Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ9-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30–5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of ‘High’, ‘Good Effect’, ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.

The Safety, Tolerability, and Subject-Rated Effects of Acute Intranasal Cocaine Administration During Aripiprazole Maintenance

Although cocaine dependence remains a significant public health concern, efforts to identify a pharmacotherapy have been unsuccessful. The purpose of this study was to assess the safety, tolerability, and subject-rated effects of intranasal cocaine during maintenance on aripiprazole, a novel antipsychotic with partial agonist activity at monoamine receptors implicated in the effects of cocaine. To this end, eight cocaine dependent subjects were maintained on 10 mg oral aripiprazole and placebo in counterbalanced order prior to assessing the physiological and subject-rated effects of intranasal cocaine (4, 20, 40, and 60 mg). Aripiprazole was generally devoid of effects, but did alter temperature-increasing and subject-rated effects of cocaine as a function of cocaine dose.

Abuse and Diversion of Gabapentin Among Nonmedical Prescription Opioid Users in Appalachian Kentucky

Gabapentin (Neurontin®) is FDA-approved as an adjunctive anti-epileptic for refractory partial seizures and as an analgesic for post-herpetic neuralgia. It is presumed to interact with calcium channels to regulate various neurotransmitter release (1) and is commonly prescribed off-label for other pain syndromes as well as mood and anxiety disorders (2), with few reports of abuse (2–5). However, with decreasing availability of commonly abused prescription opioids, it has been suggested that non-medical users of prescription opioids are substituting other licit (6) and illicit (7) drugs for abuse.