Cross-validation of a new procedure for early screening of smoking cessation medications in humans.

Brief procedures for evaluating medication efficacy may reveal which candidate drugs warrant further testing in clinical trials and which do not. We previously carried out a study of smoking abstinence, involving the nicotine patch, and established the sensitivity of our procedure. In this study, we sought to cross-validate our earlier work by comparing short-term smoking abstinence due to varenicline (relative to placebo) in smokers with high intrinsic quit interest (n = 57) and those with low intrinsic quit interest (n = 67). All the subjects were randomly assigned to either abstinence reinforcement ($12/day) or no reinforcement. In a crossover design, all the subjects participated in two 3-week phases: ad libitum smoking (week 1), dose run-up of varenicline (1.0 mg b.i.d.) or placebo (week 2), and quit attempt on medication verified daily by carbon monoxide <5 ppm (week 3). As with the nicotine patch in the previous study, varenicline (relative to placebo) increased abstinence more effectively in those with high intrinsic quit interest than in those with low quit interest but did not affect abstinence due to reinforcement. These data confirm the feasibility of a brief, sensitive test of the efficacy of cessation medications in smokers with high quit interest.

Contingency management: utility in the treatment of drug abuse disorders.

Contingency management (CM) is a strategy that uses positive reinforcement to improve the clinical outcomes of substance abusers in treatment, especially sustained abstinence from drugs of abuse. Further, CM has been adopted to improve methodology and interpretation of outcomes in clinical trials testing new pharmacotherapies and to improve adherence to efficacious medications in substance abuse patients. Thus, CM has proven to be widely useful as a direct therapeutic intervention and as a tool in treatment development.

Smoking during pregnancy and intention to quit: a profile of methadone-maintained women.

The present study characterized cigarette smoking patterns (self-report, carbon monoxide, and cotinine), health-risk perceptions, attitudes, and quitting intentions among pregnant methadone-maintained women (n = 50) enrolled in comprehensive perinatal drug treatment. At baseline, women expressed only moderate motivation and self-efficacy for smoking cessation, and 60% were in the precontemplation stage of change for quitting. Follow-up assessment during pregnancy (n = 40) showed no change in self-reported cigarettes per day or cotinine values. Despite recognition of the personal and fetal health risks of smoking and high social support for quitting, none of the women stopped smoking and few demonstrated reduction. Compared to other pregnant smokers, this sample is characterized by many of the factors associated with difficulty in quitting. Innovative harm-reduction strategies and nicotine replacement medications deserve scientific attention in this high-risk group of tenacious smokers.

Voucher-based reinforcement of opiate plus cocaine abstinence in treatment-resistant methadone patients: effects of reinforcer magnitude.

The study tested a voucher-based abstinence reinforcement procedure for reducing opiate and cocaine use in a population of treatment-resistant opiate- and cocaine-abusing methadone patients. Vouchers exchangeable for goods and services were contingent on abstinence from both opiates and cocaine. In two conditions, participants could earn up to $374 or $3,369 in vouchers for providing opiate- and cocaine-free urine samples. Participants received a daily 60-mg dose of methadone. The dose was increased in a second phase, and the voucher conditions were replicated. Analyses of both phases revealed trends toward greater abstinence under the high voucher condition and suggested that higher doses may enhance the efficacy of voucher reinforcement. The results show that reinforcement for abstinence from 2 drugs simultaneously can be effective even in a treatment-resistant population.

MMPI-2 typology of pregnant drug-dependent women in treatment.

The present study examined the validity of Minnesota Multiphasic Personality Inventory-2 (MMPI-2) typology for pregnant drug-dependent women. A 3-cluster solution based on 7 MMPI-2 clinical scales emerged as the best model and was replicated across split-half samples and different primary substance-use diagnoses and treatment modalities. The 3 subtypes identified included Type I (n = 40, 24%) with no clinical elevation, Type II (n = 72, 42%) with elevated psychopathic deviate scale, and Type III (n = 58, 34%) with elevations on all 7 scales. Analyses with interview and self-report measures showed good concurrent validity. Type II had higher retention than Type I and Type III across methadone and medication-free treatments, showing some predictive validity. An a priori method for classifying new cases on the basis of the proposed typology was developed and validated. Study findings support MMPI-2's use with pregnant drug-dependent women for assessment and possibly treatment planning.

A reinforcement-based therapeutic workplace for the treatment of drug abuse: six-month abstinence outcomes.

This study evaluated a novel drug abuse treatment, the Therapeutic Workplace. In this treatment, patients are paid to perform jobs or to participate in job training. Salary is linked to abstinence by requiring patients to provide drug-free urine samples to gain access to the workplace. Pregnant and postpartum drug abuse patients (N = 40) were randomly assigned to a Therapeutic Workplace or usual care control group. Therapeutic Workplace participants were invited to work 3 hr every weekday for 6 months and could earn up to $4,030 in vouchers for abstinence, workplace attendance, and performance. On average, 45% of participants attended the workplace per day. Relative to controls, the Therapeutic Workplace nearly doubled patients' abstinence from opiates and cocaine (33% vs. 59% of thrice-weekly urine samples drug negative, respectively, p < .05). The Therapeutic Workplace can effectively treat heroin and cocaine abuse in pregnant and postpartum women.

Gradual dose taper following chronic buprenorphine.

This paper describes the time course of withdrawal and relapse in opioid-dependent volunteers (n = 8) who completed a gradual outpatient buprenorphine dose taper (28 days). Compliance with treatment was very high, as evidenced by clinic attendance (96-100%). Urinalysis showed that 6 of the 8 volunteers had relapsed to opiates by the end of the dose taper, even though reports of withdrawal were generally low. Relapse may have been triggered by a desire to re-experience the drug's positive subjective effects, craving, or low motivation to remain drug-free. A longer taper combined with an expanded range of treatments may improve prognosis.

One-, three-, and six-month outcomes after brief inpatient opioid detoxification.

The purpose of this study was to investigate short-term outcomes of a 3-day inpatient medical detoxification. Heroin abusers (n = 116; 66% male, 77% African-American, X = 38 years old), completed the Addiction Severity Index during detoxification, and at 1, 3, and 6 months after detoxification; 94.5% of the postdetoxification interviews were completed. During the 30 days before detoxification, mean days of self-reported use for heroin was 28, for cocaine 19, and for alcohol 14; a mean of $1,975 was spent on drugs. Across the postdetoxification interviews, mean days of reported heroin use ranged from 11 to 14; 21-30% of patients reported no heroin use, whereas 25-36% reported almost daily use. Reported use of cocaine and alcohol showed similar reductions from pre- to postdetoxification. Reports of heroin and cocaine abstinence were generally verified through urine tests. Other psychosocial factors improved as well from pre- to postdetoxification (e.g., employment increased and needle use decreased). During the 6-month evaluation, at least 41% reported engaging in formal inpatient or outpatient treatment; another 25-33% reported attending self-help groups. Engaging in formal treatment (at least 7 days duration) was associated with significantly better outcome. Nevertheless, pre- to postdetoxification changes were significant and robust for the entire study sample. These findings demonstrate that brief inpatient detoxification is followed by reduced drug use over several months and is accompanied by substantial treatment-seeking behavior. Thus brief detoxification may serve as an effective harm-reduction intervention.

Reinforcement-based outpatient treatment for opiate and cocaine abusers.

A reinforcement-based intensive outpatient treatment was delivered to 37 recently detoxified, inner city, heroin and/or cocaine abusers who did not want methadone treatment. Attendance was scheduled and urine collected daily for the first 2 weeks, four times weekly for the next 2 weeks, and then thrice weekly for the final 8 weeks. As attendance incentives, patients received transportation assistance (bus tokens), and $28-$30 per week in vouchers to be spent on activities/items chosen and agreed upon with their counselor. As abstinence incentives, patients received weekend supported recreational activities, lunches, $42-$45 per week in vouchers, and rent or utilities payment ($150 over 4 weeks). Total potential earnings was $1,435 per patient; actual mean earnings was $583. Forty-three percent (n=16) completed 10 or more weeks of treatment. These 16 long-stay patients submitted 92% (SD=19) opiate- and cocaine-negative urines during their enrollment compared with 56% (SD=42) drug-negative urines submitted by 21 drop-outs, F(1,35)=9.99, p=0.003. Overall, 32% of clients became employed during their treatment episode; 94% of long-stay patients were employed at the end of their treatment episode. Patients who were drug-positive at intake were highly likely to drop out. Treatment outcomes compare favorably with those reported in the literature for outpatient nonmethadone treatment of opiate and cocaine abusers. Continued evaluation of this new treatment appears warranted.

Effects of urine testing frequency on outcome in a methadone take-home contingency program.

We examined the effects of urine testing frequency on treatment outcome in a contingent methadone take-home program. Study patients who submitted<80% opiate and/or cocaine positive urines during a 5-week baseline received 60 mg methadone throughout the study, submitted urine samples on Monday, Wednesday, and Friday, and were randomized into one of three take-home incentive conditions. Study patients could receive three take-home doses per week if one urine sample randomly selected each week (Weekly; n=16) or each month (Monthly; n=18) was negative for opiates and cocaine. Take-homes for Random Drawing control patients (n=19) were determined weekly independent of urine test results. Subjects in the Weekly group showed an immediate increase from baseline in percentage of drug-free urines; those in the Monthly group showed a gradual increase over the first 3 months; and those in Random Drawings showed a decline in percentage of drug-free urines over time. The percentage of patients with sustained (8 or more weeks) opiate and cocaine abstinence was 56.6, 38.9 and 10.5% for Weekly, Monthly and Random Drawing groups, respectively (P<0.002). These results confirm that methadone take-homes contingent on drug-free urines prevent a decline in treatment performance over time and suggest that abstinence can be sustained with urine testing conducted as infrequently as once a month.

Methods for enhancing transition of substance dependent patients from inpatient to outpatient treatment.

This study examined methods for increasing transition of substance dependent patients from inpatient detoxification to outpatient aftercare. One hundred and ninety-six patients were randomly assigned to, (1) standard referral (standard); (2) standard referral with an incentive (incentive); or (3) staff escort from detoxification to aftercare with an incentive (escort+incentive). Incentives (worth US$13.00) were dispensed for completing aftercare intake procedures on the day of discharge from detoxification. More escort+incentive participants (76%) than those in the incentive (44%) or standard conditions (24%) completed intake. The escort+incentive procedure may be useful for improving transition from detoxification to aftercare.

A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.

BACKGROUND: Opioid dependence is a chronic, relapsing disorder with important public health implications. METHODS: In a 17-week randomized study of 220 patients, we compared levomethadyl acetate (75 to 115 mg), buprenorphine (16 to 32 mg), and high-dose (60 to 100 mg) and low-dose (20 mg) methadone as treatments for opioid dependence. Levomethadyl acetate and buprenorphine were administered three times a week. Methadone was administered daily. Doses were individualized except in the group assigned to low-dose methadone. Patients with poor responses to treatment were switched to methadone. RESULTS: There were 55 patients in each group; 51 percent completed the trial. The mean (+/-SE) number of days that a patient remained in the study was significantly higher for those receiving levomethadyl acetate (89+/-6), buprenorphine (96+/-4), and high-dose methadone (105+/-4) than for those receiving low-dose methadone (70+/-4, P<0.001). Continued participation was also significantly more frequent among patients receiving high-dose methadone than among those receiving levomethadyl acetate (P=0.02). The percentage of patients with 12 or more consecutive opioid-negative urine specimens was 36 percent in the levomethadyl acetate group, 26 percent in the buprenorphine group, 28 percent in the high-dose methadone group, and 8 percent in the low-dose methadone group (P=0.005). At the time of their last report, patients reported on a scale of 0 to 100 that their drug problem had a mean severity of 35 with levomethadyl acetate, 34 with buprenorphine, 38 with high-dose methadone, and 53 with low-dose methadone (P=0.002). CONCLUSIONS: As compared with low-dose methadone, levomethadyl acetate, buprenorphine, and high-dose methadone substantially reduce the use of illicit opioids.

Improving treatment outcomes for pregnant drug-dependent women using low-magnitude voucher incentives.

The aim of this study was to examine the effectiveness of low-magnitude behavioral incentives in improving attendance for abstinence-treated patients and sustaining illicit-drug abstinence for methadone-treated patients. Subjects were randomly assigned to either incentive or control conditions, with target behaviors differing for the two patient groups (attendance for abstinence-treated and abstinence for methadone-treated patients). Controls received no incentives, whereas incentive subjects could earn $5/day in vouchers during the first 7 days of an intensive outpatient treatment. Results showed that $5/day did not significantly improve attendance in abstinence-treated patients or impact drug abstinence in methadone-treated patients. The data suggest that low-magnitude voucher incentives enhanced treatment attendance by methadone-treated subjects. Although modest monetary incentives had some utility in improving attendance in methadone-treated patients, more potent interventions are needed to improve attendance and maintain abstinence in this high-risk population.

Antinociceptive, subjective and behavioral effects of smoked marijuana in humans.

The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and, if so, whether endogenous opiates modulate this effect. A total of five male regular marijuana users participated in three test sessions during which they smoked cigarettes containing 0% (placebo) and 3. 55% Delta(9)-tetrahydrocannabinol (Delta(9)-THC) (active). Each of four controlled smoking bouts per session, spaced at 40-min intervals, consisted of nine puffs from active and placebo cigarettes (three cigarettes, three puffs per cigarette, one puff per min). During successive bouts, participants smoked 0, 3, 6 and 9 (0, 3, 9 and 18 cumulative) puffs from active marijuana cigarettes, with the remainder of puffs from placebo cigarettes. Test sessions were identical, except for naltrexone 0, 50 or 200 mg p.o. (randomized, double-blind) administration 1 h before the first smoking bout on the different days. Before smoking, between smoking bouts and postsmoking, participants completed an assessment battery that included antinociceptive (finger withdrawal from radiant heat stimulation), biological, subjective, observer-rated signs and performance measures. Marijuana produced significant dose-dependent antinociception (increased finger withdrawal latency) and biobehavioral effects. Naltrexone did not significantly influence marijuana dose-effect curves, suggesting no role of endogenous opiates in marijuana-induced antinociception under these conditions.

The brief abstinence test: voucher-based reinforcement of cocaine abstinence.

This study assessed the effectiveness of a brief abstinence reinforcement procedure for initiating cocaine abstinence in methadone maintenance patients. On Monday of the test week, 72 cocaine-abusing methadone patients were offered a $100 voucher if urine samples collected on Wednesday indicated that they had abstained from cocaine across that 2-day period. A patient was considered abstinent and the voucher delivered if the urine benzoylecgonine concentration decreased by 50% from Monday to Wednesday (quantitative criterion) or if the concentration of Wednesday's urine sample was < or = 300 ng/ml. Overall, 79% of study patients showed urinalysis evidence of abstention from cocaine between Monday and Wednesday of the test week. In a subsample with complete data (n = 50), significantly more patients abstained from cocaine from Monday to Wednesday of the test week (84%) than from Monday to Wednesday of the week before (36%) or after (32%) the test week. Furthermore, while almost all patients (94%) decreased their benzoylecgonine concentration from Monday to Wednesday of the test week, significantly fewer patients' benzoylecgonine concentrations decreased from Monday to Wednesday of the week before (56%) or after (48%) the test week. This highly efficacious procedure may have clinical application where reliable abstinence initiation is desired, either on a temporary basis (e.g. sobriety sampling) or at the start of longer-term interventions. It may also be possible to use the brief abstinence test as an experimental model to assess the effects of other therapeutic interventions on abstinence initiation in treatment settings.

Reinforcement-based intensive outpatient treatment for inner city opiate abusers: a short-term evaluation.

We evaluated 3-month outcomes for reinforcement-based intensive outpatient treatment (RBT), a new relapse prevention behavior therapy for inner city opiate abusers. The therapy provides abstinence-contingent partial support of housing, food and recreational activities, abstinence-contingent access to social skills and job finding group therapy and non-contingent individual counseling, all in the context of a day treatment program. Heroin abusers (n = 52), contacted at a 3-day detoxification unit, were randomly assigned to RBT (n = 28) or referred to community treatment resources (n = 24) after a staff escort from the detoxification unit. For RBT patients, treatment began on the day of discharge; 61% received partial rent support in a recovery house based on the need for drug-free housing; the remainder were eligible for partial support of utility payments where they lived. Abstinence-based contingencies were in effect for 1 month with three times per week counseling available for an additional 2 months. One month after detoxification, 61% of RBT versus 17% of referral patients were enrolled in outpatient treatment (P < 0.01); RBT patients were significantly less likely than controls to have returned to any drug use; and 50% of RBT versus 21% of controls reported 30 days of abstinence from heroin and cocaine with confirmatory negative urine (P < 0.05). RBT patients had significantly lower scores on the Beck Depression Inventory at 1 month (M = 9.0 versus 17.6 for controls; P < 0.05) and showed evidence of less alcohol use and higher rates of employment. These results establish the short-term efficacy for RBT and support continued development and evaluation of this new outpatient behavioral treatment.

Voucher-based reinforcement of cocaine abstinence in treatment-resistant methadone patients: effects of reinforcement magnitude.

Voucher-based reinforcement of cocaine abstinence has been one of the most effective means of treating cocaine abuse in methadone patients, but it has not been effective in all patients. This study was designed to determine if we could promote cocaine abstinence in a population of treatment-resistant cocaine abusing methadone patients by increasing the magnitude of voucher-based abstinence reinforcement. Participants were 29 methadone patients who previously failed to achieve sustained cocaine abstinence when exposed to an intervention in which they could earn up to $1155 in vouchers (exchangeable for goods/services) for providing cocaine-free urines. Each patient was exposed in counterbalanced order to three 9-week voucher conditions that varied in magnitude of voucher reinforcement. Patients were exposed to a zero, low and high magnitude condition in which they could earn up to $0, $382, or $3480 in vouchers for providing cocaine-free urines. Analyses for 22 patients exposed to all three conditions showed that increasing voucher magnitude significantly increased patients' longest duration of sustained cocaine abstinence (P<0.001) and percent of cocaine-free urines (P<0.001), and significantly decreased patients' reports of cocaine injections (P=0.024). Almost half (45%) of the patients in the high magnitude condition achieved >/=4 weeks of sustained cocaine abstinence, whereas only one patient in the low and none in the zero magnitude condition achieved more than 2 weeks. Reinforcement magnitude was a critical determinant of the effectiveness of this abstinence reinforcement intervention.

Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans.

RATIONALE: One therapeutic benefit of mu opioid agonist or antagonist maintenance is the resultant attenuation of the effects of illicit opioids. It is important to characterize the development and duration of opioid blockade produced by buprenorphine, a novel opioid dependence pharmacotherapy. OBJECTIVE: This study characterized the ability of buprenorphine to attenuate opioid effects during treatment initiation and discontinuation compared to naltrexone and placebo. METHODS: Opioid-experienced volunteers (n = 8) participated in this 10-week, inpatient, double-blind, within-subject, crossover study. Five randomized conditions [buprenorphine (2 and 8 mg, sublingually), naltrexone (25 and 100 mg, PO) and placebo] were each examined during a 2-week period; the test drug was given for 7 days followed by a 7-day placebo wash-out. Cumulative doses of hydromorphone (0, 2 and 4 mg, IM, 45 min apart) were administered thrice-weekly corresponding with treatment and wash-out days 1, 3, and 5; behavioral, physiological and pharmacokinetic measures were collected. RESULTS: Buprenorphine alone produced dose-related prototypic agonist effects during induction (i.e., positive mood, respiratory depression, miosis); tolerance developed only to the subjective effects. Buprenorphine 2 mg partially attenuated the effects of hydromorphone, while nearly complete attenuation was observed with 8 mg that lasted up to 72 h after discontinuation. Both naltrexone doses produced complete hydromorphone blockade after a single dose; blockade of the behavioral, but not physiological, effects persisted for 5 days after discontinuation of 100 mg. CONCLUSIONS: These data suggest that 2 mg buprenorphine is a sub-therapeutic maintenance dose, both buprenorphine 8 mg and naltrexone produce immediate and efficacious opioid blockade, and adequate protection against illicit opioids may be achieved with less-than-daily dosing.

Predictors of discharges against medical advice from a short-term hospital detoxification unit.

The primary goal of this study was to identify factors associated with patients leaving a 3-day hospital detoxification unit against medical advice (AMA). Medical records of 302 patients who were admitted for alcohol or other drug withdrawal were reviewed. Variables examined were: demographics, reported history of drug use, urine toxicology at admission, medication received during the detoxification, and admission day. Data were analyzed using a case-control design. Logistic regression was used to identify independent predictors. We found that being younger, having a shorter history of cocaine abuse, being admitted on a Friday and being an opiate dependent patient treated with clonidine only during the detoxification, were significantly associated with leaving AMA. These findings may provide information that can help clinicians identify those patients who are most at risk for leaving AMA. This will in turn allow them the opportunity to initiate preventive measures to decrease unnecessary attrition and improve utilisation of treatment resources.

Relative potency of levo-alpha-acetylmethadol and methadone in humans under acute dosing conditions.

levo-alpha-Acetylmethadol (LAAM) and methadone are full mu-opioid agonists used to treat opioid dependence. Current labeling indicates that LAAM is less potent than methadone. Clinical studies have not determined the relative potency of these drugs. This study compared the effects of acute doses of LAAM and methadone and also examined the ability of naloxone to reverse their effects. Five occasional opioid users received once weekly doses of either placebo, LAAM, or methadone (15, 30, or 60 mg/70 kg p.o.) in agonist exposure sessions and then received naloxone (1.0 mg/70 kg i.m.) 24, 72, and 144 h after agonist exposure. Subject-rated, observer-rated, and physiological measures were assessed regularly. Comparisons of physiological and subjective measures collected in agonist exposure sessions indicate that LAAM is not less potent than methadone under acute dosing conditions. For some measures, LAAM was significantly more potent. Three subjects who entered the study were withdrawn for safety reasons due to greater than anticipated and clinically relevant respiratory depression after receiving 60 mg of LAAM. Naloxone did not fully reverse the pupil constriction produced by 60 mg of LAAM. Acute agonist effects suggest that LAAM may be more potent than methadone and more potent than current labeling indicates. An accurate LAAM:methadone relative potency estimate will aid determination of adequate doses for opioid-dependent patients inducted onto LAAM and for methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM.