Risk of death associated with kratom use compared to opioids.

Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to "narcotic-like opioids" (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is >1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.

Eluxadoline Demonstrates a Lack of Abuse Potential in Phase 2 and 3 Studies of Patients With Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a locally acting mixed µ-opiod and κ-opioid receptor agonist and δ-opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. METHODS: One Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS-D. Patients received oral twice-daily double-blind treatment with eluxadoline or placebo for 12, 26, or 52 weeks. The primary end point of these studies was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of days. Safety data were pooled, and specific adverse event terms potentially related to abuse were assessed descriptively. Adverse events reported during a 2-week post-treatment period (IBS-3001) and a 4-week single-blind washout period (IBS-3002) were assessed for signs of opioid withdrawal. Potential withdrawal effects were assessed by using the Subjective Opiate Withdrawal Scale. RESULTS: Overall, 807 and 1032 patients received 1 or more doses of eluxadoline (75 or 100 mg, respectively), and 975 patients received placebo. The overall incidence of adverse events potentially related to abuse did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (2.8%, 2.7%, and 4.3%, respectively). The most common adverse events potentially related to abuse were anxiety and somnolence, which occurred in less than 2% of patients in each group. Median overall Subjective Opiate Withdrawal Scale scores did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (3.0, 2.0, and 3.0, respectively). CONCLUSIONS: In an analysis of data from Phase 2 and Phase 3 trials of eluxadoline (75 or 100 mg) for patients with IBS-D, data revealed no signs of abuse potential for eluxadoline. ClinicalTrials.gov numbers: NCT01130272, NCT01553591, NCT01553747.

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.

REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats.

REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical "extinction burst" pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

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.

Pharmacotherapy for tobacco dependence.

Pharmacotherapy can provide effective treatment of tobacco dependence and withdrawal, and thereby facilitate efforts to achieve and sustain tobacco abstinence. Currently approved medications for smoking cessation are nicotine replacement medications (NRT), including nicotine patch, gum, lozenge, sublingual tablet, inhaler and nasal spray, the antidepressant bupropion, and the nicotinic partial agonist varenicline. This review discusses the pharmacological basis for the use of these medications, and the properties that might contribute to their efficacy, safety, and abuse liability. The review also discusses how pharmacological principles can be used to improve existing medications, as well as assist in the development of new medications.

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.

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status.

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research.

RATIONALE: Consideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. OBJECTIVE: The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. RESULTS: Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. CONCLUSIONS: Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use.

Assessment of the abuse liability of three menthol Vuse Solo electronic cigarettes relative to combustible cigarettes and nicotine gum.

RATIONALE: We previously reported that following a short-term product use period, use of non-menthol Vuse Solo electronic cigarettes (ECs) resulted in product effect-related subjective responses and nicotine uptake between those of combustible cigarettes (high-abuse liability comparator) and nicotine gum (low-abuse liability comparator); the results were generally closer to those of nicotine gum. OBJECTIVE: Using a similar design to the previous study, we evaluated the abuse liability of three menthol-flavored Vuse Solo ECs with the same nicotine contents (14, 29, and 36 mg) in a group of EC-naïve, menthol cigarette smokers, relative to comparator products. METHODS: Six-hour nicotine uptake and ratings of subjective effects were used to determine abuse liability and pharmacokinetics. RESULTS: Use of menthol Vuse Solo resulted in significantly lower responses to subjective measurements (product liking, intent to use product again, and liking of positive product effects), higher urge to smoke responses, and a lower peak (Cmax) and overall extent (AUC0-360) of nicotine uptake compared to smoking the usual brand menthol cigarette. When compared with use of nicotine gum, subjective responses to use of menthol Vuse ECs were in the same direction as those resulting from smoking cigarettes but were more similar to nicotine gum use in magnitude than they were to cigarettes. CONCLUSION: These findings are concordant with our previous results and provide evidence that menthol Vuse Solo ECs have abuse liability that is lower than menthol cigarettes and potentially greater than that of nicotine gum. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02664012.

Pharmacodynamic and pharmacokinetic assessment of electronic cigarettes, combustible cigarettes, and nicotine gum: implications for abuse liability.

RATIONALE: Electronic cigarettes (ECs) are becoming popular alternatives for smokers, but there has been limited study of their abuse liability. OBJECTIVES: The objective of this study was to evaluate the abuse liability of three Vuse Solo ECs, ranging from 14 to 36 mg in nicotine content, relative to high- and low-abuse liability comparator products (usual brand combustible cigarettes and nicotine gum, respectively) in a group of 45 EC-naïve smokers. METHODS: Enrolled subjects' ratings of subjective effects and nicotine uptake over 6 h were used to measure abuse liability and pharmacokinetics following in-clinic use of each EC. RESULTS: Use of Vuse Solo resulted in subjective measures and nicotine uptake that were between those of combustible cigarettes and nicotine gum, although generally closer to nicotine gum. Compared to combustible cigarettes, use of Vuse Solo resulted in significantly lower scores in measures of product liking, positive effects, and intent to use again. These pharmacodynamic findings were consistent with the pharmacokinetic data, showing that cigarettes produced substantially faster and higher levels of nicotine uptake as compared to Vuse Solo and nicotine gum. Vuse Solo resulted in more rapid initial uptake of nicotine compared to nicotine gum, but peak concentration and long-term extent of uptake were not different or were lower with Vuse. CONCLUSIONS: Collectively, these findings suggest that Vuse Solo likely has an abuse liability that is somewhat greater than nicotine gum but lower than cigarettes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02269514.

Nicotine self-administration research: the legacy of Steven R. Goldberg and implications for regulation, health policy, and research.

BACKGROUND AND RATIONALE: Steven R. Goldberg was a pioneering behavioral pharmacologist whose intravenous drug self-administration studies advanced the understanding of conditioned stimuli and schedules of reinforcement as determinants of pattern and persistence of drug-seeking behavior, and in particular, the importance of nicotine in tobacco use. His passing in 2014 led to invitations to contribute articles to psychopharmacology dedicated to his work. OBJECTIVES: The objectives of this review are to summarize and put into historical perspective Goldberg's contributions to elucidate the reinforcing effects of nicotine and to summarize the implications of his research for medication development, tobacco regulation, and potential tobacco control policy options. This includes a review of intravenous nicotine self-administration research from the 1960s to 2016. RESULTS: Goldberg's application of behavioral pharmacology methods to investigate nicotine reinforcement and the influence of schedule of reinforcement and conditioned stimuli on nicotine administration contributed to the conclusions of the US National Institute on Drug Abuse, and the Surgeon General, that nicotine met the criteria as a dependence-producing drug and cigarette smoking as a prototypic drug dependency or "addiction." Equally important, this work has been systematically extended to other species and applied to address a range of factors relevant to tobacco use, medication development, regulation, and public health policy. CONCLUSIONS: Steven R. Goldberg was a pioneering scientist whose systematic application of the science of behavioral pharmacology advanced the understanding of tobacco and nicotine use and contributed to the scientific foundation for tobacco product regulation and potential public health tobacco control policy development.

Nicotine delivery systems.

Over the past 20 years, medicinal nicotine has been used to aid smoking cessation, and has led to a significant increase in the number of smokers who successfully quit. This review describes currently available medicinal nicotine products, which include nicotine patch, gum, lozenge, nasal spray, inhaler and sublingual tablet, including their pharmacokinetics and recommended dosing. New developments in nicotine delivery that could further increase cessation rates include high-dose patches, rapid release gum, combined patch and acute forms, and several novel channels for nicotine delivery, such as nicotine drink, straw, lollipop and a pulmonary inhaler. New applications of existing and novel medicinal nicotine products may include relapse prevention, nicotine maintenance, temporary withdrawal management, reduced smoking and gradual quitting.

Placebo cigarettes in a spaced smoking paradigm.

Existing evidence supports the notion that nicotine delivery and recentness of smoking mediate the effects of smoking, including decreases in tobacco craving. However, smoking placebo (denicotinized) cigarettes decreases tobacco craving after overnight abstinence. The present study tested whether the recentness of smoking was an important determinant in the ability of a placebo cigarette to reduce tobacco craving. Placebo (0.07 mg nicotine) and conventional (1.1 mg nicotine) cigarettes were used in a spaced smoking paradigm. In six experimental sessions lasting 240 min, subjects smoked either a placebo or conventional nicotine cigarette in intervals of either 30, 60, or 240 min. Heart rate (HR), exhaled carbon monoxide (CO) levels, and subjective (Schuh-Stitzer, QSU) measures of tobacco craving were obtained throughout the spaced smoking paradigm. HR and CO levels increased after smoking both types of cigarettes. Increasing the interval since the last cigarette significantly (p<0.001) increased the baseline values of tobacco craving. Smoking either the placebo or the conventional cigarette caused a significant (p<0.01) reduction in the craving score after smoking. However, the nicotine yield of the cigarette did not influence these patterns. It is concluded that acute tobacco cravings can be repeatedly diminished with cigarettes that do not deliver nicotine.

Flavor improvement does not increase abuse liability of nicotine chewing gum.

Because the taste of nicotine gum has impeded compliance with dosing recommendations, nicotine gum with improved taste (mint, orange) was developed and marketed. Prior to marketing, the Food and Drug Administration (FDA) required a rigorous abuse liability assessment to examine whether enhanced palatability of nicotine gum would increase its abuse liability. Subjective, physiological, and psychomotor effects of mint flavor and original nicotine gum were tested in adult smokers (22-55 years old); a group of younger subjects (18-21 years old) was also included to allow for assessment of abuse liability in young adults specifically. Amphetamine and confectionery gum served as positive controls for abuse liability and palatability. Subjects rated palatability of mint gum higher than original nicotine gum, but substantially lower than confectionery gum. Palatability decreased with increasing dose of nicotine. Neither original nor mint gum increased ratings of traditional abuse liability predictors [Good Effect, Like Effect, Morphine-Benzedrine Group (MBG) scales of Addiction Research Center Inventory (ARCI)], while amphetamine increased ratings of all these measures. Both flavors of nicotine gum decreased craving during 2 h of abstinence. These effects were more pronounced in the adult group and mint gum was more effective than original gum. Younger subjects reported fewer withdrawal symptoms and lower ratings for drug effects and flavor. Improved flavor of nicotine gum does not increase abuse liability, but may be associated with enhanced craving reduction.

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions.

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 microg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 microg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 microg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 microg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 microg/mL (N = 90) as compared to 1.64 microg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions.

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple drug-induced deaths compared to single (OXC only) drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple drug-induced deaths, OxyContin identified, 0.93 mg/mL (N = 167); multiple drug-induced deaths, OxyContin not identified, 0.73 mg/mL (N = 579); single (OXC) drug-induced deaths, OxyContin identified, 1.55 mg/mL (N = 12); and single (OXC) drug-induced deaths, OxyContin not identified, 1.70 mg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC), drug-induced, drug abuse deaths > multiple, drug-induced drug abuse deaths > drug-related drug abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 mg/mL (N = 90) as compared to 1.64 mg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Oxycodone involvement in drug abuse deaths: a DAWN-based classification scheme applied to an oxycodone postmortem database containing over 1000 cases.

An oxycodone postmortem database was created from 1243 solicited cases from Medical Examiner and Coroner (ME/C) offices in 23 states in the United States over the period from August 27, 1999, through January 17, 2002. The request for cases was specific to only those cases in which the ME/C opined that the death involved oxycodone. Each case was evaluated to determine the role of oxycodone and the specific drug product OxyContin tablets in the death. Oxycodone identification was based on toxicology testing, and OxyContin identification was based on evidence found at the scene, credible witness reports, or identification of tablets in gastrointestinal contents. A system of case categorization was developed for this study based on the Drug Abuse Warning Network (DAWN) system for reporting drug abuse mortality data in the United States, using the same standardized, well-understood terminology. Of the 1243 cases, 79 cases were incomplete and could not be evaluated. There were an additional 150 cases submitted in which oxycodone was not identified by the originating ME/C. Of the remaining 1014 cases, 919 (90.6%) were related to drug abuse, whereas 95 (9.4%) cases were categorized as not involving drug abuse. Only 30 (3.3%) of the drug abuse cases involved oxycodone as the single reported chemical entity; of these, 12 cases had OxyContin identified as a source of oxycodone. Of the 919 drug abuse cases, the vast majority (N = 889, 96.7%) were multiple drug abuse deaths in which there was at least one other plausible contributory drug in addition to oxycodone. The most prevalent drug combinations were oxycodone in combination with benzodiazepines, alcohol, cocaine, other narcotics, marijuana, or antidepressants. Using the DAWN definitions, drug abuse cases were further categorized as drug-induced or drug-related. A total of 851 (92.6%) cases met the criteria for classification as being drug-induced, and the remaining 68 (7.4%) cases were categorized as drug-related. Cause of death (COD) statements from the originating ME/C indicated a general recognition of the role of abuse of multiple drugs in causing fatalities. Approximately 70% of the 889 cases in the multiple-drug-induced categories were listed in the COD or contributing COD statements as multiple-drug deaths. A variety of terms were employed in the COD statements to indicate multiple drug involvement such as "polydrug toxicity", "polypharmacy", "multiple drug poisoning", and "polypharmaceutical overdose". The system for death classification employed in this study recognizes the problems inherent in COD attribution when multiple drugs are involved. Use of this new system for reporting mortality data in future studies involving opioids is recommended.

Pharmacotherapy for nicotine dependence.

Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on cancer, cardiovascular disease, lung disease, or other illness. This risk can be substantially reduced by smoking cessation, with greater benefits occurring the earlier in the smoking career that cessation occurs. However, cessation provides benefits at any stage, including after the onset of smoking-related disease, by improving the prognosis and quality of life. Clinicians can have a significant impact on reducing tobacco use by their patients by following the US Public Health Service Clinical Practice Guidelines. Proven strategies include structured methods of advising cigarette smokers to quit and guidance to facilitate their efforts, as well as the use of various pharmacotherapies. Pharmacotherapies for tobacco dependence include nicotine replacement medications in the form of gum, transdermal patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler formulations. The only nonnicotine medication that has been approved by the US Food and Drug Administration is bupropion. Combination therapies, long-term medication therapies, and harm reduction strategies may further improve outcome with approved medications. Further, new medications such as varenicline and rimonabant are likely to reach tobacco users who are refractory to current treatments. Increasing the treatment options, increasing availability, and reducing the perceived cost of these medications may have an additional public health impact.

EEG effects of conventional and denicotinized cigarettes in a spaced smoking paradigm.

Although there is a documented association between plasma nicotine levels and smoking behavior, recent studies indicate that denicotinized cigarettes reduced craving and symptoms of tobacco withdrawal. Denicotinized cigarettes (that deliver tar but insignificant amounts of nicotine) and conventional cigarettes were compared in a within-subject spaced smoking study. In six sessions, subjects (n=10) smoked denicotinized cigarettes or conventional cigarettes every 30, 60 or 240 min (8, 4 or 1 cigarette(s)). EEG effects of the last cigarette of each session were deduced by comparisons with EEG recordings collected before smoking. Conventional cigarettes increased spectral edge EEG frequency, decreased theta power and increased beta1 power. Denicotinized cigarettes decreased spectral frequency. The EEG effects of both cigarettes depended upon the recentness of smoking. The results indicate that nicotine delivery, recentness and the process of smoking importantly influence the EEG; other, non-nicotine components of tobacco smoke may also exert EEG effects.