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1.  Opioid Challenge Evaluation of Blockade by Extended-Release Naltrexone in Opioid-Abusing Adults: Dose-Effects and Time-Course 
Drug and alcohol dependence  2011;123(0):10.1016/j.drugalcdep.2011.10.018.
Background
Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans.
Methods
Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-hr intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) Visual Analog Scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade.
Results
Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150 and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing.
Conclusions
These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.
doi:10.1016/j.drugalcdep.2011.10.018
PMCID: PMC3880792  PMID: 22079773
naltrexone; opioid blockade; opioid challenge; extended-release naltrexone; depot naltrexone; injectable naltrexone; Vivitrol; hydromorphone
2.  Risk-Taking Propensity as a Predictor of Induction onto Naltrexone Treatment for Opioid Dependence 
The Journal of clinical psychiatry  2012;73(8):e1056-e1061.
Objective
Heroin addiction is a chronic relapsing disorder that has devastating social, medical, and economic consequences. Naltrexone is an antagonist that blocks opioid effects and could be an effective medication for the treatment of opioid dependence. However, its clinical utility has been limited partly because of poor adherence and acceptability. Given the importance of compliance to naltrexone treatment for opioid dependence, the goal of the current study was to examine predictors involved in successful induction onto naltrexone treatment.
Method
Parametric and nonparametric statistical tests were performed on data from a sample of 64 individuals entering treatment who met DSM-IV criteria for opioid dependence. The relationship between naltrexone induction (i.e., inducted- vs. not-inducted onto naltrexone) and risk-taking propensity, as indexed by riskiness on the Balloon Analogue Risk Task (BART) was examined. Participants were recruited from local detoxification programs, inpatient drug treatment, and other Baltimore programs that provided services to opioid dependent adults (e.g., Baltimore Needle Exchange Program) during the period from August 2007 to September 2008.
Results
Positive association between risk-taking propensity and odds of naltrexone induction. Specifically, each five point increase in the total BART score was associated with a 25% decrease in odds of naltrexone induction (OR=0.76, 95% CI: 0.58–0.99, p = .041). This association remained statistically significant even after adjusting for potential confounds, including injection drug use and cocaine positive urine results (p = .05). After adjusting for the covariates, each five point increase in BART score was associated with 28% decrease in the odds of achieving the maintenance dose (AOR=0.73, 95% CI: 0.54–0.99, p = .046).
Conclusions
Risk taking propensity was predictive of induction onto naltrexone treatment, above and beyond injection drug use and cocaine-positive urine samples.
doi:10.4088/JCP.09m05807
PMCID: PMC3985274  PMID: 22967782
Risk taking propensity; naltrexone; opioid dependence; substance abuse treatment
3.  Employment-Based Reinforcement of Adherence to Oral Naltrexone Treatment in Unemployed Injection Drug Users 
Naltrexone has high potential for use as a relapse prevention pharmacotherapy for opiate dependence; however suffers from notoriously poor adherence when prescribed for oral self-administration. This study evaluated whether entry to a therapeutic workplace could be used to reinforce adherence with oral naltrexone. Opiate-dependent and cocaine-using injection drug users were detoxified, inducted onto oral naltrexone, and randomly assigned to a Contingency (n=35) or Prescription (n=32) group for a 26-week period. Contingency participants were required to ingest naltrexone under staff observation to gain access to the therapeutic workplace. Prescription participants received a take-home supply of naltrexone and could access the workplace independent of naltrexone ingestion. Primary outcome measures were percent of urine samples positive for naltrexone at 30-day assessments and negative for opiates and cocaine at 30-day assessments. Contingency participants provided significantly more urine samples that were positive for naltrexone compared to Prescription participants (72% vs. 21%, P<.01), however no effect of experimental group was observed on percent opiate-negative (71% vs. 60%, P=.19.) or cocaine-negative (56% vs. 53%, P=.82) samples in the Contingency and Prescription groups, respectively. Opiate-positive samples were significantly more likely to occur in conjunction with cocaine (P<.001), and when not protected by naltrexone (P<.02), independent of experimental group. Overall, these results show that contingent access to a therapeutic workplace significantly promoted adherence to oral naltrexone, and that the majority of opiate use occurred in conjunction with cocaine use, suggesting that untreated cocaine use may limit the effectiveness of oral naltrexone in promoting opiate abstinence.
doi:10.1037/a0030743
PMCID: PMC3641088  PMID: 23205722
naltrexone; contingency management; therapeutic workplace; incentive; injection drug use
4.  Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations 
Pain  2012;153(12):2315-2324.
A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL has the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided and then those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are discussed. These outcome measures include: (1) subjective effects (some of which comprise the primary outcome measures, including drug liking); (2) physiological responses; (3) drug self-administration behavior; and (4) cognitive and psychomotor performance. Prior to presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.
doi:10.1016/j.pain.2012.07.035
PMCID: PMC3494795  PMID: 22998781
opioids; opioid analgesics; abuse; abuse liability; abuse potential
5.  Comparison of cognitive performance in methadone maintenance patients with and without current cocaine dependence 
Drug and Alcohol Dependence  2012;124(1-2):167-171.
Background
There is evidence for psychomotor and cognitive performance impairment in methadone maintenance patients (MMP), as well as in individuals with current cocaine dependence. It is unknown whether MMP with concurrent cocaine dependence perform worse on tests of cognitive function than MMP without cocaine dependence.
Methods
Performance was compared between MMP with and without current cocaine dependence (MMP/CD+; N=53 and MMP/CD−; N=24) on a standard battery of tasks designed to measure psychomotor performance, attention, episodic and working memory, and executive function.
Results
Participant characteristics were mostly similar across groups. However, the MMP/CD+ group had a shorter duration of methadone treatment, and a larger percentage of participants with self-reported 30-day poly-substance abuse and positive urine drug tests on the day of cognitive testing. There were no differences between the groups on measures of balance, psychomotor coordination, divided attention, working memory, most measures of episodic memory, or executive function. Relative to MMP/CD−, MMP/CD+ showed significant impairment on select measures of psychomotor performance/attention (simple reaction time and trail-making test A) and episodic memory (higher false alarm rates on recognition memory).
Conclusions
The absence of differences between MMP/CD+ and MMP/CD− on measures of higher order cognitive functions, and the relatively small magnitude between-group differences on other measures suggest that current cocaine dependence, in the absence of cocaine intoxication, is unlikely to be associated with clinically meaningful increases in performance impairment in MMP.
doi:10.1016/j.drugalcdep.2011.12.009
PMCID: PMC3351542  PMID: 22266090
Methadone Maintenance; Cocaine; Dependence; Cognition; Performance
6.  Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials 
Addiction (Abingdon, England)  2011;107(4):694-708.
Aims
Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials.
Methods
A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated.
Results
Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials.
Conclusions
We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them.
doi:10.1111/j.1360-0443.2011.03473.x
PMCID: PMC3537825  PMID: 21781202
Clinical trials; drug dependence; end-points; primary outcome; self-report; toxicology; treatment research
7.  Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: A randomized controlled trial 
Drug and alcohol dependence  2011;120(1-3):48-54.
Background
Naltrexone provides excellent opioid blockade, but its clinical utility is limited because opioid-dependent patients typically refuse it. An injectable suspension of naltrexone for extended release (XR-NTX) was recently approved by the FDA for treatment of opioid dependence. XR-NTX treatment may require concurrent behavioral intervention to maximize adherence and effectiveness, thus we sought to evaluate employment-based reinforcement as a method of improving adherence to XR-NTX in opiate dependent adults.
Methods
Opioid-dependent adults (N = 38) were detoxified and inducted onto oral naltrexone, then randomly assigned to contingency or prescription conditions. Participants received up to six doses of XR-NTX at four-week intervals. All participants could earn vouchers for attendance and performance at a therapeutic workplace. Contingency participants were required to accept XRNTX injections to access the workplace and earn vouchers. Prescription participants could earn vouchers independent of their acceptance of XR-NTX injections.
Results
Contingency participants accepted significantly more naltrexone injections than prescription participants (87% versus 52%, p = .002), and were more likely to accept all injections (74% versus 26%, p = .004). Participants in the two conditions provided similar percentages of samples negative for opiates (72% versus 65%) and for cocaine (58% versus 54%).Opiate positivity was significantly more likely when samples were also cocaine positive, independent of naltrexone blockade (p = .002).
Conclusions
Long-term adherence to XR-NTX in unemployed opiate dependent adults is low under usual care conditions. Employment-based reinforcement can maintain adherence to XRNTX. Ongoing cocaine use appears to interfere with the clinical effectiveness of XR-NTX on opiate use.
doi:10.1016/j.drugalcdep.2011.06.023
PMCID: PMC3245785  PMID: 21782353
contingency management; incentives; therapeutic workplace; heroin; opioid pharmacotherapy; extended-release naltrexone
8.  A Randomized Clinical Trial of a Therapeutic Workplace for Chronically Unemployed, Homeless, Alcohol-Dependent Adults 
Aims: To assess the efficacy of the Therapeutic Workplace, a substance abuse intervention that promotes abstinence while simultaneously addressing the issues of poverty and lack of job skills, in promoting abstinence from alcohol among homeless alcoholics. Methods: Participants (n = 124) were randomly assigned to conditions either requiring abstinence from alcohol to engage in paid job skills training (Contingent Paid Training group), offering paid job skills training with no abstinence contingencies (Paid Training group) or offering unpaid job skill training with no abstinence contingencies (Unpaid Training group). Results: Participants in the Contingent Paid Training group had significantly fewer positive (blood alcohol level ≥ 0.004 g/dl) breath samples than the Paid Training group in both randomly scheduled breath samples collected in the community and breath samples collected during monthly assessments. The breath sample results from the Unpaid Training group were similar in absolute terms to the Contingent Paid Training group, which may have been influenced by a lower breath sample collection rate in this group and fewer reported drinks per day consumed at intake. Conclusion: Overall, the results support the utility of the Therapeutic Workplace intervention to promote abstinence from alcohol among homeless alcoholics, and support paid training as a way of increasing engagement in training programs.
doi:10.1093/alcalc/agr057
PMCID: PMC3156886  PMID: 21622676
9.  Employment-Based Reinforcement of Adherence to Depot Naltrexone in Unemployed Opioid-Dependent Adults: A Randomized Controlled Trial 
Addiction (Abingdon, England)  2011;106(7):1309-1318.
Aims
Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence.
Design
Participants who were inducted onto oral naltrexone were randomly assigned to Contingency (n=18) or Prescription (n=17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace weekdays for 26 weeks where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independent of whether they accepted injections.
Setting
The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment.
Participants
Opioid-dependent unemployed adults.
Measurements
Depot naltrexone injections accepted and opiate-negative urine samples.
Findings
Contingency participants accepted significantly more naltrexone injections than Prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate positive samples were more likely when samples were also positive for cocaine.
Conclusions
Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone.
doi:10.1111/j.1360-0443.2011.03400.x
PMCID: PMC3107896  PMID: 21320227
depot naltrexone; contingency management; heroin; substance abuse; employment-based reinforcement
10.  A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients 
Background
Cocaine abuse and dependence continue to be widespread. Currently there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence.
Methods
A 33-week outpatient clinical trial of fluoxetine (60 mg/day, p.o.) for cocaine dependence was conducted that incorporated abstinence-contingent voucher incentives. Participants (n=145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing.
Results
The PV group had the longest treatment retention (mean of 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were: 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group.
Conclusions
Fluoxetine was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids.
doi:10.1016/j.jsat.2010.11.010
PMCID: PMC3078567  PMID: 21266301
Cocaine; Contingency management; Fluoxetine; Methadone
11.  Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble films 
A sublingual soluble film formulation of buprenorphine and naloxone (B/N) has been approved by the Food and Drug Administration. This preparation provides unit dose child resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has potentially preferred taste versus tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid dependent volunteers.
Methods
Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone induced opioid withdrawal. Subjects were randomized onto either B (16mg, n=18) or B/N (16/4 mg, n=16) soluble films for five days. Primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score.
Results
Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between groups.
Conclusions
Results support use of B and B/N soluble films as safe and effective delivery methods for opioid induction.
doi:10.1038/clpt.2010.352
PMCID: PMC3225026  PMID: 21270789
buprenorphine; buprenorphine/naloxone; precipitated withdrawal; soluble film
12.  Effects of repeated tramadol and morphine administration on psychomotor and cognitive performance in opioid-dependent volunteers 
Drug and alcohol dependence  2010;111(3):265-268.
Tramadol is an atypical, mixed mechanism analgesic used to treat moderate to severe pain. Based on evidence that tramadol has relatively low abuse potential and can relieve opioid withdrawal, tramadol may be useful for treating opioid dependence. The purpose of this study was to assess the performance side-effect profile of tramadol. Nine opioid-dependent volunteers completed a performance battery following 5–7 days of subcutaneous morphine (15 mg, 4 times/day) and two doses of oral tramadol (50, 200 mg, 4 times/day) in a within subject cross-over design. Morphine was always the first condition, and the order of the two tramadol doses was randomized and double blind. Performance was significantly worse in the morphine condition relative to one or both tramadol doses on measures of psychomotor speed/coordination (circular lights task), psychomotor speed/pattern recognition (DSST speed measure) and psychomotor speed/set shifting (trail-making tasks). There were no significant differences among conditions in DSST accuracy, simple reaction time, divided attention, working memory, episodic memory, metamemory, or time estimation. Neither tramadol dose was associated with worse performance than morphine on any measure. Although practice sessions were conducted prior to the first session to reduce order effects, the possibility that residual practice effects contributed to the differences between tramadol and morphine cannot be ruled out. The high tramadol dose produced worse performance than the low dose only on the balance measure. These findings suggest that tramadol is generally a safe medication with respect to cognitive and psychomotor measures and support tramadol’s further evaluation as an opioid dependence treatment.
doi:10.1016/j.drugalcdep.2010.05.002
PMCID: PMC2950255  PMID: 20538418
tramadol; morphine; opioid; dependence; performance; cognitive
13.  Physical dependence potential of daily tramadol dosing in humans 
Psychopharmacology  2010;211(4):457-466.
Rationale
Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence.
Objectives
The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol.
Methods
Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices.
Results
Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions.
Conclusions
Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.
doi:10.1007/s00213-010-1919-3
PMCID: PMC3028382  PMID: 20589494
Tramadol; Opioid; Dependence; Withdrawal; Naloxone; Treatment; Hydromorphone; Blockade; Abuse
14.  Measurement of self-reported HIV risk behaviors in injection drug users: Comparison of standard versus timeline, follow-back administration procedures 
The present study compares the frequencies of retrospective self-reported HIV high risk drug use and sexual behaviors in 127 out-of-treatment injection drug users using the HIV Risk Questionnaire (HRQ) across two administration methods: 1) a brief standard quantity-frequency approach covering the past 30-days, and 2) a lengthier timeline followback (TLFB) procedure for improving recall. The two procedures produced similar frequencies of risk behavior across most items (80%) and good intra- and interclass correlation coefficients. The TLFB, however, resulted in higher frequencies for two risk behavior questions - sharing of any drug injection equipment and having any type of unprotected sex. The TLFB is a well-established procedure for retrospective assessment of HIV risk behavior and a good choice when precision in measuring these behaviors is a primary focus of the work. In contrast, the brief HRQ-Standard interview procedure appears to be a reasonable choice for clinical, research and health related surveys where the primary focus is broader than HIV risk behavior.
doi:10.1016/j.jsat.2009.06.004
PMCID: PMC2789860  PMID: 19717270
HIV risk behavior; injection drug use; sexual behavior; assessment; timeline follow-back
15.  Cocaine Abuse Versus Cocaine Dependence: Cocaine Self-Administration and Pharmacodynamic Response in the Human Laboratory 
Drug and alcohol dependence  2009;106(1):28.
Cocaine has high abuse liability but only a subset of individuals who experiment with it develop dependence. The DSM-IV (APA, 2000) provides criteria for diagnosing cocaine abuse and cocaine dependence as distinct disorders- the latter characterized by additional symptoms related to loss of control over drug use. In this study, two groups of cocaine users (n=8/group), matched on demographic factors and length of cocaine use history and meeting criteria for either cocaine abuse (CocAb) or cocaine dependence (CocDep), were compared on 1) measures related to impulsivity and sensation seeking, 2) response to experimenter-administered cocaine (0, 12.5, 25 and 50 mg/70 kg, iv), and 3) cocaine self-administration using a Relapse Choice and a Progressive Ratio Procedure (0, 12.5 and 25 mg/70 kg, iv). Groups did not differ on impulsivity or sensation seeking scores. After experimenter-administered cocaine, the CocAb group reported feeling more suspicious and observers rated them significantly higher on unpleasant effects (e.g., irritability, difficulty concentrating). In contrast, the CocDep group reported significantly greater desire for cocaine, which was sustained over the course of the study, and gave higher street value estimates for cocaine (p< .05). While cocaine self-administration was dose-related and generally comparable across the two procedures, the CocDep users chose to take significantly more cocaine than the CocAb users. These data suggest that, while regular long-term users of cocaine with cocaine abuse or dependence diagnoses cannot be distinguished by trait measures related to impulsivity, they do exhibit significant differences with regard to cocaine-directed behavior and response to cocaine administration.
doi:10.1016/j.drugalcdep.2009.07.011
PMCID: PMC2815181  PMID: 19717246
cocaine; self-administration; DSM-IV diagnosis; abuse; dependence; humans
16.  Concurrent Validation of the Clinical Opiate Withdrawal Scale (COWS) and Single-Item Indices against the Clinical Institute Narcotic Assessment (CINA) Opioid Withdrawal Instrument 
Drug and alcohol dependence  2009;105(1-2):154-159.
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 minutes post-injection of naloxone. Mean COWS and CINA scores 30 minutes after placebo injection were 1.3 and 18.9, respectively. The Pearson 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.
doi:10.1016/j.drugalcdep.2009.07.001
PMCID: PMC2774236  PMID: 19647958
opioid withdrawal; opioid dependence; Clinical Opiate Withdrawal Scale; Clinical Institute Narcotic Assessment; naloxone; precipitated withdrawal
17.  Repeated Dosing with Oral Cocaine in Humans: Assessment of Direct Effects, Withdrawal and Pharmacokinetics 
Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n=9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses [875 mg/day]) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) 2- to 3-fold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects [liking, high, good effects] and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.
doi:10.1037/a0016469
PMCID: PMC2811070  PMID: 19653786
cocaine; withdrawal; pharmacokinetics; stimulants
18.  Sublingual Buprenorphine/Naloxone Precipitated Withdrawal in Subjects Maintained on 100 mg of Daily Methadone* 
Drug and alcohol dependence  2007;90(2-3):261-269.
Rationale
Acute doses of buprenorphine can precipitate withdrawal in opioid dependent persons. The likelihood of this withdrawal increases as a function of the level of physical dependence.
Objectives
To test the acute effects of sublingual buprenorphine/naloxone tablets in volunteers with a higher level of physical dependence. The goal was to identify a dose that would precipitate withdrawal (Phase 1), then determine if withdrawal could be attenuated by splitting this dose (Phase 2).
Methods
Residential laboratory study; subjects (N=16) maintained on 100 mg per day of methadone. Phase 1: Randomized, double blind, triple dummy, within subject study. Conditions were sublingual buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg), intramuscular naloxone (0.2 mg), oral methadone (100 mg), or placebo. Medication conditions were randomized, but buprenorphine/naloxone doses were ascending within the randomization. Phase 2: Conditions were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1 (full dose), and 50% of this dose administered twice in a session (split dose). Analyses covaried by trough methadone serum levels.
Results
Six subjects did not complete the study. Of the ten who completed, three tolerated up to 32/8 mg of buprenorphine/naloxone without evidence of precipitated withdrawal. For the seven completing both phases, split doses generally produced less precipitated withdrawal compared to full doses.
Conclusions
There is considerable between subject variability in sensitivity to buprenorphine's antagonist effects. Low, repeated doses of buprenorphine/naloxone (e.g., 2/0.5 mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical dependence.
doi:10.1016/j.drugalcdep.2007.04.006
PMCID: PMC2094723  PMID: 17517480
19.  Contingency Management in Cocaine Abusers: A Dose–Effect Comparison of Goods-Based Versus Cash-Based Incentives 
Goods-based contingency management interventions (e.g., those using vouchers or prizes as incentives) have demonstrated efficacy in reducing cocaine use, but cost has limited dissemination to community clinics. Recent research suggests that development of a cash-based contingency management approach may improve treatment outcomes while reducing operational costs of the intervention. However, the clinical safety of providing cash-based incentives to substance abusers has been a concern. The present 16-week study compared the effects of goods-based versus cash-based incentives worth $0, $25, $50, and $100 on short-term cocaine abstinence in a small sample of cocaine-dependent methadone patients (N=12). A within-subject design was used; a 9-day washout period separated each of 8 incentive conditions. Higher magnitude ($50 and $100) cash-based incentives (checks) produced greater cocaine abstinence compared with the control ($0) condition, but a magnitude effect was not seen for goods-based incentives (vouchers). A trend was observed for greater rates of abstinence in the cash-based versus goods-based incentives at the $50 and $100 magnitudes. Receipt of $100 checks did not increase subsequent rates of cocaine use above those seen in control conditions. The efficacy and safety data provided in this and other recent studies suggest that use of cash-based incentives deserves consideration for clinical applications of contingency management, but additional confirmation in research using larger samples and more prolonged periods of incentive delivery is needed.
doi:10.1037/1064-1297.15.4.338
PMCID: PMC2043576  PMID: 17696680
contingency management; abstinence incentives; contingent reinforcement; cocaine dependence
20.  The effects of a cooperation contingency on behavior in a continuous three-person environment1 
Five groups of three subjects resided for 10 or 15 days within a continuously programmed environment. Subjects followed a programmatic arrangement of required and optional private and social activities that determined the individual and group baseline behaviors into which experimental operations were introduced and withdrawn. A cooperation condition was in effect when all three subjects were required to select simultaneous access to a group area before it became available for use. A noncooperation condition was in effect when access to a group area could be selected by individual subjects, without regard to the other subjects' selections. For all groups, the effects of these two conditions on individual and group behaviors were investigated in reversal designs where several successive days occurred under each condition. Groups 1, 4, and 5 had the noncooperation condition interposed between cooperation conditions. Groups 2 and 3 had the cooperation condition interposed between noncooperation conditions. Durations of triadic activities, per cent of time in triadic activities, intercom use, and intersubject program synchronization were greater during cooperation conditions than during noncooperation conditions. These data show that a cooperation contingency within the behavioral program affected both social behavior and the collateral individual behavior necessary to execute the cooperation response.
doi:10.1901/jeab.1976.25-293
PMCID: PMC1333467  PMID: 16811912
cooperation contingency; social behavior; behavioral program; continuously programmed environment; social systems; humans
21.  Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone 
Psychopharmacology  2010;210(4):471-480.
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.
doi:10.1007/s00213-010-1838-3
PMCID: PMC2878387  PMID: 20386884
Abuse liability; Ultra-low-dose naltrexone; Oxytrex; OPIOID; PTI-801

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