Continuous Abstinence During Early Alcohol Treatment is Significantly Associated with Positive Treatment Outcomes, Independent of Duration of Abstinence.

AIMS: Neither the predictive value of early continuous abstinence in alcohol use disorder (AUD) or the point at which this effect may emerge has been evaluated. This analysis of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) clinical trial evaluated whether abstinence early in treatment was a predictor of longer term abstinence. METHODS: Participants who stated a goal of total abstinence (N = 954) were dichotomized into Early Abstainer vs. Nonabstainers and were compared on a variety of drinking outcome measures that are frequently used in clinical trial evaluations of alcohol treatment strategies, as a function of duration of early continuous abstinence. RESULTS: Significant differences existed for every outcome. Early Abstinence was significantly associated with fewer drinks per drinking day, number of drinking and number of heavy drinking days, and longer time to first drinking and first heavy drinking day. Effects were evident within the first week. The magnitude of all effects increased as the duration of early abstinence (1-4 weeks) increased, though the size of increase varied across the outcomes. CONCLUSIONS: These data provide evidence that drinking at the beginning of alcohol treatment is significantly and robustly associated with drinking throughout and at the end of a clinical trial treatment for AUD. Early drinking may be a useful early index to identify whether patients are responding positively to a treatment strategy, and provides a useful method for tailoring treatment to patients that is consistent with a personalized medicine approach.

Recruitment techniques for alcohol pharmacotherapy clinical trials: A cost-benefit analysis.

OBJECTIVES: Alcohol use disorders (AUDs) represent a large public health burden with relatively few efficacious pharmacotherapies. Randomized controlled trials (RCTs) for new AUD therapies can be hampered by ineffective recruitment, leading to increased trial costs. The current analyses examined the effectiveness of recruitment efforts during two consecutive outpatient RCTs of novel AUD pharmacotherapies conducted between 2009 and 2012. METHODS: During an initial phone screen, participants identified an ad source for learning about the study. Qualified persons were then scheduled for in-person screens. The present analyses examined demographic differences amongst the eight ad sources utilized. Recruitment effectiveness was determined by dividing the number of persons meeting criteria for an in-person screen by the total number of callers from each ad source. Cost-effectiveness was determined by dividing total ad source cost by number of screens, participants randomized, and completers. RESULTS: 1,813 calls resulted in 1,005 completed phone screens. The most common ad source was TV (34%), followed by print (29%), word-of-mouth (11%), flyer (8%), internet (5%), radio (5%), bus ad (2%), and billboard (1%). Participants reporting bus ads (46%), billboard (44%), or print ads (34%) were significantly more likely than the other sources to meet criteria to be scheduled for in-person screens. The most cost-effective ad source was print ($2,506 per completer), while bus ad was the least cost-effective ($13,376 per completer). CONCLUSIONS: Recruitment in AUD RCTs can be successful using diverse advertising methods. The present analyses favored use of print ads as most cost-effective.

Opioid detoxification via single 7-day application of a buprenorphine transdermal patch: an open-label evaluation.

RATIONALE: Managed withdrawal (i.e., detoxification) from opioid dependence is a widespread clinical procedure that is a necessary step for those pursuing abstinence. Buprenorphine is one effective detoxification treatment, however, consensus regarding effective detoxification procedures is lacking. OBJECTIVES: This study evaluated the efficacy of a buprenorphine transdermal formulation (i.e., patch) in suppressing opioid withdrawal, its safety and tolerability, and its biodelivery when applied for 7 days. METHODS: Physically dependent opioid (heroin) users (n = 12) completed a 10-day opioid detoxification in a residential research unit. Each received a single patch application that remained in place for 7 days. Blood samples were drawn prior to patch application and once daily thereafter. Assessments, four times daily, included: the amount of rescue medications ordered to treat withdrawal discomfort; self-report and observer ratings of opioid withdrawal and agonist effects; and vital sign measures. RESULTS: Overall, the patch appeared safe and well-tolerated. Buprenorphine plasma levels peaked 48 h after patch application at 0.59 ng/ml. Indices of withdrawal (self-reports, observer ratings, rescue medication) were significantly reduced within 24 h of patch application, continued to decline thereafter, and did not reappear following patch removal. CONCLUSIONS: This study confirms that transdermal buprenorphine is safe and clinically effective, and suggests that a 7-day application may provide an effective and comfortable means of detoxification. This patch formulation would appear to be a useful opioid detoxification treatment by reducing compliance concerns, and administering buprenorphine in a formulation less likely to be diverted to illicit use.

Evaluation of a transdermal buprenorphine formulation in opioid detoxification.

AIMS: Buprenorphine is marketed in a sublingual formulation for treatment of opioid dependence. A transdermal formulation has been developed that may provide extended relief from opioid withdrawal, reduce required clinic visits and improve adherence, while having less potential for diversion and abuse. This study evaluated the safety and biodelivery (blood levels) of this transdermal buprenorphine formulation (i.e. buprenorphine patch), and its apparent efficacy in suppressing the opioid withdrawal syndrome. DESIGN: Open-label, first-in-humans trial. SETTING: A residential research facility. PARTICIPANTS: Nine physically dependent opioid-users completed the 10-day opioid detoxification study. INTERVENTION: Each volunteer received a single patch application that remained in place for 3 days. The formulation has shown an average delivery of 1.9 mg/day of buprenorphine over 3 days in pre-clinical evaluation. MEASURES: Physiological, behavioral, subjective and observer ratings of opioid withdrawal and opioid agonist effects were collected. FINDINGS: Overall, the patch appeared safe and well tolerated. There were no serious adverse events, and no opioid intoxication following patch application. Oxygen saturation, heart rate, blood pressure, skin temperature and pupil diameter remained well within normal ranges. Buprenorphine blood levels peaked 48 hours after patch application at a concentration of 0.60 ng/ml. Volunteers' self-reports of the presence and severity of withdrawal symptoms were reduced by approximately 50% on the 3 days of patch application. Withdrawal symptoms increased marginally upon patch removal. Administration of opioid rescue medication was eliminated within 6 hours of patch application, and increased slightly upon patch removal. CONCLUSIONS: The significant biodelivery of buprenorphine and the suppression of the opioid withdrawal syndrome during patch application and its reappearance after patch removal indicate clinically useful pharmacodynamic activity. Transdermal buprenorphine may be a useful opioid detoxification treatment that reduces compliance concerns, and delivers buprenorphine in a formulation less likely to be diverted to illicit use.

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential.

RATIONALE: Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects. OBJECTIVES: This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route. METHODS: Placebo, inhaled alprazolam (0.5, 1, and 2 mg), and oral alprazolam (1, 2, and 4 mg) were administered under double-blind, double-dummy conditions using a crossover design in 14 healthy participants with histories of drug abuse. Participant and observer ratings and behavioral and cognitive performance measures were assessed repeatedly during 9-h sessions. RESULTS: Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer-lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 min after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose-response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., "drug liking") were similar across the two routes. On other measures (e.g., sedation and performance), the routes were equipotent. CONCLUSIONS: The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low.

Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

RATIONALE: Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. OBJECTIVE: Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. MATERIALS AND METHODS: This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. RESULTS: The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. CONCLUSIONS: The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.

INTRODUCTION: The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. METHOD: Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. RESULTS: Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearson's correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbach's alpha for the COWS was 0.78, indicating good internal consistency (reliability). DISCUSSION: COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal.