Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

A preliminary investigation of rapid smoking as a lapse-responsive treatment for tobacco dependence.

Lapses within the first 2 weeks of a smoking cessation attempt are strongly associated with a return to regular smoking (S. L. Kenford et al., 1994). Unfortunately, little is known about how to prevent an initial lapse from progressing to a full relapse, and presently there are no validated lapse-responsive therapeutic interventions. The present study tested the efficacy and feasibility of rapid smoking plus counseling as a novel lapse-responsive intervention. Sixty-seven participants enrolled in a smoking treatment program involving brief counseling and a 9-week course of bupropion. Beginning on the quit day, participants' smoking behavior was tracked daily for 14 days. Once an early smoking lapse was identified, participants were randomly assigned to receive either 3 sessions of rapid smoking plus counseling or no intervention (usual care). Consistent with previous research, participants who smoked during the first 2 weeks of the quit attempt had significantly poorer 6-month outcomes (3% abstinent) than did those who did not smoke (64% abstinent). Compared with early abstainers, early lapsers were more nicotine dependent and reported greater cravings and lower confidence in their ability to abstain from smoking during the first 48 hours of abstinence. As expected, rapid smoking produced a variety of aversive effects, including increased nausea, dizziness, and vomiting as well as sharply decreased cravings to smoke. However, rapid smoking did not improve abstinence outcomes relative to usual care. Although rapid smoking has been shown to be an effective treatment for initial smoking cessation, in this preliminary study the authors failed to demonstrate its effectiveness as a lapse-responsive treatment.

Experimental evidence for a causal relationship between smoking lapse and relapse.

In this study, the authors prospectively evaluated the impact of a smoking lapse on relapse probability. After 4 days of smoking abstinence, 60 smokers were randomly assigned to smoke 5 nicotine-containing or 5 denicotinized cigarettes, or to remain abstinent (no lapse) during a 4-hr time period. Afterward, smoking abstinence was encouraged with monetary incentives, and smoking behavior was tracked for 6 days. Relative to the no-lapse condition, exposure to either of the cigarette types more than doubled the probability of subsequent smoking. Smoking outcomes did not differ between nicotine-containing and denicotinized cigarettes. The data suggest that stimulus factors may play an important role in lapse to relapse processes.

Alcohol effects during acamprosate treatment: a dose-response study in humans.

BACKGROUND: Acamprosate (calcium acetyl homotaurinate) reduces alcohol intake in animals and increases abstinence rates in alcohol-dependent persons. Acamprosate's mechanism of action, however, remains poorly understood. In order to examine whether acamprosate/alcohol interactions contribute to acamprosate's efficacy, the present double-blind, placebo-controlled human laboratory study examined effects of acamprosate on the pharmacokinetics and subjective, psychomotor, and physiological effects of alcohol in heavy drinkers. METHODS: In a six-week within-subject design, participants were maintained on acamprosate (0, 2, and 4 g, p.o., double-blind, in counterbalanced order) for 11 days at each dose. Physiological, subjective, and psychomotor measures were collected daily during each dosing cycle. During each acamprosate dose condition, subjects were challenged with 0, 0.5, and 1.0 g/kg ethanol (p.o., counterbalanced order) during three separate laboratory sessions. Subjective, physiological, and psychomotor effects of alcohol, and breath alcohol levels were collected at baseline and at 30-min intervals for a 3-hr post-administration period. RESULTS: Acamprosate alone did not substantially affect subjective, physiological, or psychomotor performance measures. Acamprosate did not alter alcohol pharmacokinetics, or alcohol-induced behavioral impairment or tachycardia, and most subjective alcohol effects were also unaltered by acamprosate as well. Although a trend appeared for acamprosate to increase subjective ratings of intoxication following the lower (0.5 g/kg) alcohol dose, adjustment for individual differences in blood alcohol level eliminated this effect, suggesting the trend was not due to a central effect of acamprosate. CONCLUSIONS: Acamprosate does not alter alcohol pharmacokinetics, acute physiological or psychomotor alcohol effects, or most subjective alcohol effects.

Transdermal selegiline and intravenous cocaine: safety and interactions.

RATIONALE: Because the dopamine system appears to be involved in both acute and chronic effects of cocaine, medication development efforts for cocaine addiction have focused largely on agents that interact with the dopamine system. Selegiline, a selective monoamine oxidase B inhibitor, indirectly modulates dopamine levels, and research suggests selegiline may modify subjective effects of cocaine. OBJECTIVES: To evaluate further the safety and potential of transdermal selegiline as a treatment for cocaine dependence, interactions between transdermal selegiline and intravenous cocaine were studied in cocaine-dependent volunteers. METHODS: Pharmacokinetics and subjective, physiological, and endocrinological effects of intravenous cocaine (0,20 and 40 mg) were evaluated both before and during transdermal selegiline treatment (20 mg/day, 10 days) in 12 cocaine-dependent subjects. A transdermal selegiline formulation was used to avoid the risks associated with oral administration of MAO inhibitors. RESULTS: Selegiline attenuated some physiological (systolic blood pressure and heart rate) and subjective (good effects, liking, stimulated, high, desire for cocaine) effects of cocaine. Selegiline did not affect cocaine's pharmacokinetics or cocaine-induced prolactin decrease and growth hormone increase. CONCLUSIONS: The combined administration of the transdermal selegiline patch and up to 40 mg cocaine was well tolerated. Selegiline may reduce physiological and subjective effects of cocaine. A randomized trial is needed to evaluate the efficacy of selegiline for cocaine abuse.

Subjective effects of the nicotine lozenge: assessment of abuse liability.

RATIONALE: A nicotine lozenge was developed as a novel smoking cessation aid. Abuse liability, which in this context refers to use by novices not addicted to tobacco, may be expected to be low for the lozenge due to the relatively slow route of nicotine absorption. However, its resemblance to commercially marketed lozenges and its palatability, intended to increase medication compliance, may increase its abuse liability, especially among younger individuals. OBJECTIVES: The present study evaluated the abuse liability of the nicotine lozenge. Effects of the lozenge on cigarette craving were also measured. METHODS: Subjective and physiological effects of the nicotine lozenge were tested in healthy adult smokers ( n=12, 22-55 years old); a group of younger subjects ( n=12, 18-21 years) was also included to allow for assessment of abuse liability of the lozenge in young adults specifically. Amphetamine and a confectionery lozenge were included in the study conditions as positive controls for abuse liability and palatability, respectively, and nicotine gum was included to allow for comparison with a marketed oral nicotine replacement product with low abuse liability. RESULTS: The nicotine lozenge did not increase ratings of traditional abuse liability predictors (good effect, like effect, MBG scale of the ARCI), while amphetamine significantly increased ratings on these measures. The lozenge dose dependently decreased craving for cigarettes after 70 min of abstinence, but only in the older group. Palatability of the lozenge was rated lower than a confectionery lozenge, but not lower than nicotine mint gum. CONCLUSIONS: Results suggest that the nicotine lozenge has low abuse liability, both in adults and young adults. The lozenge reduces craving to smoke, although craving reduction may not apply to young adults (18-21 years). Subjective effects of the lozenge are consistent with utility as a smoking cessation aid and are comparable to those of nicotine gum.

Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking.

RATIONALE: The relative contribution of sensory and pharmacological variables in regulating craving and smoking remains unclear. Rapid smoking procedures and denicotinized cigarettes can be used to further disentangle these factors, and to explore the relationship between craving and smoking. OBJECTIVE: The present study examined the role of nicotine and sensory cues in mediating craving and smoking, and the relationship between craving and smoking. METHODS: Participants ( n=15) engaged in one session each of rapid smoking (up to nine cigarettes with puffs taken every 6 s) and normal paced smoking with nicotinized and denicotinized cigarettes (total of four sessions). During the next 3 h, craving and withdrawal assessments and smoking opportunities were scheduled every 15 min. Plasma nicotine levels were measured at baseline, immediately and 15 min after the smoking interventions, and subsequently at the time when the participant first chose to smoke. RESULTS: Craving ratings were equally suppressed immediately after all conditions. After self-paced conditions, both types of cigarettes produced equivalent effects on latency to smoke. Latency to smoke was significantly longer after rapid smoking of nicotinized cigarettes compared to all other conditions. Finally, changes in craving were associated with choices to smoke. CONCLUSIONS: The sensory cues associated with smoking suppressed craving ratings regardless of the smoking pace or nicotine content. Only at high doses did nicotine levels play an additional role in acutely suppressing smoking behavior. Small elevations in craving ratings were associated with choices to smoke.

Effects of selegiline (L-deprenyl) during smoking and short-term abstinence.

RATIONALE: Changes in dopamine level are thought to play an important role in both smoking reward and withdrawal symptoms during abstinence. Medications that modulate dopamine levels may have beneficial effects on both withdrawal symptom levels and on response to smoking lapses during abstinence. OBJECTIVES: To examine the effects of the selective MAO-B inhibitor selegiline on withdrawal symptoms, smoking behavior and smoking satisfaction ratings. METHODS: Fifteen smokers received selegiline (10 mg/day) and placebo (in counterbalanced order) on Monday through Thursday of 2 study weeks, separated by a 2-week washout. During each study week, ad lib smoking sessions were scheduled to assess smoking behavior both before and after a brief period of abstinence. Subjective withdrawal symptoms and mood were measured daily, and a modified Stroop test sensitive to withdrawal was scheduled during the period of abstinence. RESULTS: Selegiline decreased craving, especially during abstinence, and impaired performance on the modified Stroop test during subjects' attempts to abstain. Medication also reduced number of cigarettes smoked and smoking satisfaction ratings during the smoking sessions both before and after the brief abstinence attempt. CONCLUSION: These results are consistent with an important role of dopamine in smoking behavior and abstinence. They suggest that pharmacological reduction of MAO-B levels during the early part of a quit attempt may aid in smoking cessation.

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.