Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment.

OBJECTIVE: The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients' stress to test hypotheses about clonidine's behavioral mechanism of action. METHOD: The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5-6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data were examined with generalized linear mixed models. RESULTS: In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7]; Cohen's d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% CI=0.45-1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors' hypothesized mechanism for clonidine's benefits. CONCLUSIONS: Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life.

A randomized investigation of methadone doses at or over 100 mg/day, combined with contingency management.

BACKGROUND: Methadone maintenance for heroin dependence reduces illicit drug use, crime, HIV risk, and death. Typical dosages have increased over the past few years, based on strong experimental and clinical evidence that dosages under 60 mg/day are inadequate and that dosages closer to 100mg/day produce better outcomes. However, there is little experimental evidence for the benefits of exceeding 100 mg/day, or for individualizing methadone dosages. We sought to provide such evidence. METHODS: We combined individualized methadone dosages over 100 mg/day with voucher-based cocaine-targeted contingency management (CM) in 58 heroin- and cocaine-dependent outpatients. Participants were randomly assigned to receive a fixed dose increase from 70 mg/day to 100mg/day, or to be eligible for further dose increases (up to 190 mg/day, based on withdrawal symptoms, craving, and continued heroin use). All dosing was double-blind. The main outcome measure was simultaneous abstinence from heroin and cocaine. RESULTS: We stopped the study early due to slow accrual. Cocaine-targeted CM worked as expected to reduce cocaine use. Polydrug use (effect-size h=.30) and heroin craving (effect-size d=.87) were significantly greater in the flexible/high-dose condition than in the fixed-dose condition, with no trend toward lower heroin use in the flexible/high-dose participants. CONCLUSIONS: Under double-blind conditions, dosages of methadone over 100mg/day, even when prescribed based on specific signs and symptoms, were not better than 100mg/day. This counterintuitive finding requires replication, but supports the need for additional controlled studies of high-dose methadone.

Opioid challenge evaluation of blockade by extended-release naltrexone in opioid-abusing adults: dose-effects and time-course.

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-h 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.

Tobacco, cocaine, and heroin: Craving and use during daily life.

BACKGROUND: Relationships among tobacco smoking, tobacco craving, and other drug use and craving may have treatment implications in polydrug-dependent individuals. METHODS: We conducted the first ecological momentary assessment (EMA) study to investigate how smoking is related to other drug use and craving during daily life. For up to 20 weeks, 106 methadone-maintained outpatients carried PalmPilots (PDAs). They reported their craving, mood, behaviors, environment, and cigarette-smoking status in 2 to 5 random-prompt entries/day and initiated PDA entries when they used cocaine or heroin or had a discrete episode of craving for cocaine or heroin. RESULTS: Smoking frequency increased linearly with random-prompt ratings of tobacco craving, cocaine craving, and craving for both cocaine and heroin. Smoking frequency was greater during discrete episodes of cocaine use and craving than during random-prompt reports of low craving for cocaine. This pattern was also significant for dual cocaine and heroin use and craving. Smoking and tobacco craving were each considerably reduced during periods of urine-verified abstinence from cocaine, and there was a (nonsignificant) tendency for morning smoking to be especially reduced during those periods. CONCLUSIONS: This EMA study confirms that smoking and tobacco craving are strongly associated with the use of and craving for cocaine and heroin. Together with prior findings, our data suggest that tobacco and cocaine may each increase craving for (and likelihood of continued use of) themselves and each other. Treatment for tobacco dependence should probably be offered concurrently with (rather than only after) initiation of treatment for other substance-use disorders.

Cocaine craving and use during daily life.

RATIONALE: Craving is often assumed to cause ongoing drug use and relapse and is a major focus of addiction research. However, its relationship to drug use has not been adequately documented. OBJECTIVES: The aim of this study was to investigate the relationship between craving and drug use in real time and in the daily living environments of drug users. METHODS: In a prospective, longitudinal, cohort design (ecological momentary assessment), 112 cocaine-abusing individuals in methadone maintenance treatment rated their craving and mood at random times (two to five times daily, prompted by electronic diaries) as they went about their everyday activities. They also initiated an electronic diary entry each time they used cocaine. Drug use was monitored by thrice-weekly urine testing. RESULTS: During periods of urine-verified cocaine use, ratings of cocaine craving increased across the day and were higher than during periods of urine-verified abstinence. During the 5 h prior to cocaine use, ratings of craving significantly increased. These patterns were not seen in ratings of heroin craving or mood (e.g., feeling happy or bored). CONCLUSIONS: Cocaine craving is tightly coupled to cocaine use in users' normal environments. Our findings provide previously unavailable support for a relationship that has been seriously questioned in some theoretical accounts. We discuss what steps will be needed to determine whether craving causes use.

Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study.

STUDY OBJECTIVE: To determine the electrocardiographic effects of coadministration of lofexidine and methadone. DESIGN: Prospective, double-blind study. SETTING: Outpatient drug treatment research clinic. PARTICIPANTS: Fourteen adults (mean +/- SD age 34.9 +/- 5.3 yrs) with physical dependence on opioids. INTERVENTION: Participants were stabilized on methadone maintenance therapy, reaching a target dose of 80 mg/day. After 3 weeks of methadone stabilization, participants received lofexidine 0.4 mg or placebo once/day, each for 1 week, administered at the same time as methadone. From weeks 3-8, all subjects received lofexidine, with the dose escalated each week in 0.2-mg increments so that by week 8, participants were receiving lofexidine 1.6 mg/day. Electrocardiograms (ECGs) were obtained at baseline (before methadone), after stabilization with methadone, and after lofexidine coadministration during peak plasma lofexidine levels. MEASUREMENTS AND MAIN RESULTS: Prespecified outcome measures of mean and maximal changes in heart rate, and PR, QRS, and QTc intervals were obtained after stabilization with methadone and after lofexidine 0.4 mg coadministration. Repeated-measures regression showed no significant changes in heart rate or PR, QRS, or QTc interval after methadone stabilization, but a significant decrease in heart rate (mean +/- SD -8.0 +/- 7.3 beats/min, p=0.0006) after starting lofexidine. When data were analyzed by using maximal ECG response, again, no significant changes were noted during methadone induction compared with baseline, but significant changes did occur in all four ECG parameters when lofexidine was coadministered: decreased heart rate (mean +/- SD -9.6 +/- 5.8 beats/min, p<0.0001) and increased PR interval (+11.1 +/- 19.8 msec, p=0.026), QRS interval (+3.7 +/- 4.3 msec, p=0.002), and QTc interval (+21.9 +/- 40.8 msec, p=0.018). In three female participants, the change in QTc interval from baseline was clinically significant (> 40 msec). CONCLUSION: Our preliminary data suggest that coadministration of lofexidine and methadone induces QTc interval prolongation. This drug combination should be prescribed cautiously, with ECG monitoring. Furthermore, because the participants with the largest changes in QTc interval in our study were female, women may be at highest risk.

Promoting abstinence from cocaine and heroin with a methadone dose increase and a novel contingency.

To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 x 3 (dosexcontingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. They were randomly assigned to methadone dose (70 or 100mg/day, double-blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or "split"). The "split" contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was "split" between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin, cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required.

Hepatitis C and human immunodeficiency virus risk behaviors in polydrug users on methadone maintenance.

We examined the impact of methadone maintenance treatment (MMT) on risk behaviors for transmission of blood-borne diseases in polydrug users who had tested positive or negative for hepatitis C virus (HCV). At intake, HCV-positive participants (n=362) engaged in more human immunodeficiency virus (HIV) risk behaviors (as measured by the HIV Risk-Taking Behavior Scale) than HCV-negative participants (n=297; p< .001). This difference was specific to injection-related behaviors and decreased significantly within the first few weeks of MMT (p< .0001). Where needles continued to be used, HCV-positive participants became more likely over time to engage in safer injecting practices. Furthermore, HCV-positive participants became more likely to use condoms than HCV-negative participants. These findings demonstrate that both drug- and sex-related risk behaviors decrease during MMT and emphasize the benefits of methadone programs for public health and HIV/HCV prevention.

Randomized trial comparing two treatment strategies using prize-based reinforcement of abstinence in cocaine and opiate users.

We compared two strategies of prize-based contingency management (CM) in methadone-maintained outpatients. Urine was tested thrice weekly for 5 weeks pre-CM, 12 weeks CM, and 8 weeks post-CM. Participants were randomly assigned to a cocaine contingency (four prize draws for each cocaine-negative urine, N=29) or an opiate-cocaine contingency (one draw for each urine negative for opiates or cocaine, four draws if negative for both, N=38). There were no group differences in cocaine abstinence during CM or post-CM and no differences in opiate abstinence during CM. Opiate abstinence was greater in the opiate-cocaine group post-CM, and heroin craving was reduced in this group during and post-CM. Draws earned per cocaine-negative urine (four vs. one) did not affect cocaine use.

Effect of reinforcement probability and prize size on cocaine and heroin abstinence in prize-based contingency management.

Although treatment outcome in prize-based contingency management has been shown to depend on reinforcement schedule, the optimal schedule is still unknown. Therefore, we conducted a retrospective analysis of data from a randomized clinical trial (Ghitza et al., 2007) to determine the effects of the probability of winning a prize (low vs. high) and the size of the prize won (small, large, or jumbo) on likelihood of abstinence until the next urine-collection day for heroin and cocaine users (N=116) in methadone maintenance. Higher probability of winning, but not the size of individual prizes, was associated with a greater percentage of cocaine-negative, but not opiate-negative, urines.

Physician awareness of the cardiac effects of methadone: results of a national survey.

BACKGROUND: Levacetylmethadol was withdrawn from the U.S. market as a treatment for opioid-dependent patients in 2003 due to QT prolongation, leaving methadone as the primary therapy for over 200,000 individuals. Methadone was subsequently shown to prolong the QT interval as well. We hypothesized that opioid treatment program physicians are unaware of these safety concerns. METHODS: To assess awareness of methadone's QT-prolonging properties, we conducted a national mail survey of physicians licensed as medical directors for accredited U.S. opioid treatment programs in 2006. The primary outcome was knowledge of methadone's QT-prolonging effects. Awareness of the cardiac effects of levacetylmethadol and buprenorphine were also assessed. RESULTS: The survey response rate was 66% (692 physicians) of whom 35% were family practitioners, 25% internists, 22% psychiatrists, and 8% self-identified as addiction specialists. While 75% (95% CI, 72-78) correctly identified levacetylmethadol as a QT-prolonging drug, only 41% (95% CI, 37- 45) were aware of methadone's QT-prolonging properties. Just 24% (95% CI, 21-27) were aware of methadone's association with torsade de pointes. In addition, 52% (95% CI, 48- 56) correctly reported the absence of an association between buprenorphine and QT prolongation. Larger program census and academic setting tended to predict greater awareness of methadone's QT-prolonging effects; yet even in these subgroups awareness did not exceed 54%. CONCLUSIONS: Scientific publication alone has been inadequate in raising awareness regarding methadone's QT-prolonging properties, even among those who most often prescribe the drug. Universal education initiatives for all accredited opioid treatment programs seem warranted to enhance the safety of this essential therapy.

Randomized trial of prize-based reinforcement density for simultaneous abstinence from cocaine and heroin.

To examine the effect of reinforcer density in prize-based abstinence reinforcement, heroin/cocaine users (N = 116) in methadone maintenance (100 mg/day) were randomly assigned to a noncontingent control group (NonC) or to 1 of 3 groups that earned prize draws for abstinence: manual drawing with standard prize density (MS) or computerized drawing with standard (CS) or high (CH) density. Probabilities (prizes/draw) were standard (50%) and high (78%); prize density was double blind. Mean prize values were CH, $286; CS, $167; MS, $139; and NonC, $171. Outcomes were % opioid/cocaine-negative urines during the 12-week intervention and then 8 weeks postintervention as well as diagnosis of dependence up to 6 months poststudy. CH had significantly more negative specimens than did NonC during intervention and had more than all groups during postintervention treatment: Mean % negative (95% confidence interval) during postintervention treatment adjusted for baseline drug use and dropout were CH, 55% (14%-90%); CS, 7% (1%-27%); MS, 4% (1%-12%); and NonC, 3% (1%-10%). Current cocaine dependence diagnoses after treatment were significantly lower in contingent compared with noncontingent groups. Computerized drawing with higher-density prizes enhanced reduction of cocaine use; abstinence reinforcement had long-term therapeutic benefits.

Hemodynamic and cognitive effects of lofexidine and methadone coadministration: a pilot study.

STUDY OBJECTIVE: To determine the hemodynamic and cognitive effects of lofexidine and methadone coadministration. DESIGN: Prospective, double-blind study. SETTING: Outpatient drug treatment research clinic. SUBJECTS: Fourteen participants (aged 18-45 yrs) with physical dependence on opioids. INTERVENTION: Subjects were stabilized on methadone maintenance therapy, starting with 30 mg/day and increasing by 10-mg/day increments, based on each subject's tolerability to achieve a target dose of 80 mg/day. After 3 weeks of methadone stabilization, lofexidine 0.4 mg/day or matching placebo were coadministered with methadone, in doses escalating by 0.2-mg/week increments, to achieve a target dose of 1.6 mg/day over the next 8 weeks. MEASUREMENTS AND MAIN RESULTS: Acute orthostatic vital signs and neuropsychological effects of lofexidine and methadone coadministration were monitored for 5 hours after the dose on the first day of each new lofexidine dose. Orthostatic vital signs and adverse events were assessed daily thereafter to determine the effects of repeated doses. Lofexidine significantly decreased sitting systolic and diastolic blood pressure (p=0.045 and p=0.033, respectively) compared with placebo (i.e., methadone alone). With lofexidine 0.4 mg/day, mean decreases in systolic and diastolic blood pressure were 27 +/- 17 and 15 +/- 16 mm Hg, respectively. No significant association was noted between changes in orthostatic vital signs and lofexidine dose. Decreased cognitive efficiency was associated with lofexidine administration, and higher lofexidine doses adversely affected performance on a mathematical task compared with placebo (p=0.0035). The rate of adverse events was no higher with lofexidine than with placebo; the majority (54.3%) were common adverse effects of lofexidine. CONCLUSION: Significant changes in hemodynamic and cognitive efficiency were observed with coadministration of lofexidine and methadone compared with methadone alone. When patients receiving methadone are prescribed lofexidine, they should be closely monitored for cardiovascular and cognitive changes.

Adverse events among patients in a behavioral treatment trial for heroin and cocaine dependence: effects of age, race, and gender.

Safety monitoring is a critical element of clinical trials evaluating treatment for substance dependence, but is complicated by participants' high levels of medical and psychiatric comorbidity. This paper describes AEs reported in a large (N = 286), 29-week outpatient study of behavioral interventions for heroin and cocaine dependence in methadone-maintained outpatients. A total of 884 AEs were reported (3.1 per patient, 0.12 per patient-week), the most common being infections (26.8%), gastrointestinal (20.5%), musculoskeletal (12.3%), and general (10%) disorders. Serious AEs were uncommon (1.6% of total). Female participants reported significantly higher rates of AEs (incidence density ratio, IDR = 1.38, p < 0.0001); lower rates of AEs were reported by African Americans (IDR = 0.73, p<0.0001) and participants over age 40 reported lower rates of AEs (IDR = 0.84, p = 0.0095). AE incidence was not associated with the study intervention or with psychiatric comorbidity. Further work is needed to adapt AE coding systems for behavioral trials for substance dependence; the standard Medical Dictionary for Regulatory Activities, International Federation of Pharmaceutical Manufacturers Associations (MedDRA) coding system used in this report did not contain a separate category for one of the most common types of AE, dental problems. Nonetheless, the data reported here should help provide a context in which investigators and IRBs can interpret the patterns of AEs they encounter.

Menstrual cycle length during methadone maintenance.

AIMS: While the menstrual disruption of heroin has been demonstrated, there are few published data concerning methadone maintenance and menstrual function. This study was conducted to evaluate whether cycle length was more regular during methadone maintenance. SETTINGS: An out-patient research treatment program in Baltimore, Maryland, USA. PARTICIPANTS: A total of 191 heroin and cocaine-using women from two clinical trials, lasting 25-29 weeks; each woman was maintained on 70-100 mg of methadone. MEASUREMENTS: Start/end dates of each menses were collected. DESIGN: Menstrual patterns were classified as regular, irregular, transient amenorrhea, persistent amenorrhea or cycle restart. Repeated-measures regression modeling determined correlates of cycle length and predictors of long cycles (> 40 days) and short cycles (< 20 days). Bleeding episodes were defined as 1 or more bleeding days, bound by at least 2 non-bleeding days. Correlates/predictors examined were body mass index, drug use, methadone dose and race. FINDINGS: In the 133 women for whom menstrual patterns could be determined, cycle-length irregularity was common: irregular, 62 (46.7%); regular, 37 (27.8%); cycle restart, 16 (12%); persistent amenorrhea, 11 (8.3%); transient amenorrhea, seven (5.3%). Each additional week on methadone maintenance was associated with decreased risk of long (OR = 0.96, P < 0.01 and short (OR = 0.92, P < 0.01) cycles. Of 27 women with secondary amenorrhea pre-study, 16 (59%) restarted menses. Positivity for opioids or cocaine was not significantly associated with short or long cycles. CONCLUSIONS: Cycle length begins to normalize during methadone maintenance. Menses resumption may occur. Methadone maintenance, despite interfering with menstrual function in an absolute sense, may interfere less than illicit heroin abuse.