Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade.

RATIONALE: Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans. OBJECTIVES: The aim of this study was to determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu vs kappa receptors. MATERIALS AND METHODS: Ten healthy adult inpatient volunteers (eight men, two women), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10, or 30 mg, p.o.) was administered 1 h before butorphanol (0, 6, or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, and subject- and observer-rated) measures was collected before and for 4 h after drug administration. RESULTS: Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., "liking," "good drug effects") and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanol-induced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of subjective responses. CONCLUSION: These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu vs kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.

Differential effects of diazepam and pentobarbital on mood and behavior.

The effects of administering moderately high doses of diazepam and pentobarbital sodium for five consecutive days to subjects with histories of sedative drug abuse were examined. The two drugs produced similar dose-related effects on psychomotor performance, daytime sleeping, and ratings of magnitude of drug effects. Diazepam, but not pentobarbital, produced dose-related decreases in staff ratings of subjects' mood and social interactions and increases in staff ratings of subjects' hostility, complaining, and unusual behavior. During the placebo washout periods that followed drug administration. diazepam, but not pentobarbital, was associated with carry-over effects. The diazepam-produced deterioration in mood and social behavior was a subtle effect observed in a population for which usual therapeutic indications were lacking and at higher than usual therapeutic doses. The syndrome may, however, occur with long-term diazepam use or misuse in therapeutic settings and, hence, warrants clinical awareness in monitoring the course of treatment.

Double-blind evaluation of reinforcing and anorectic actions of weight control medications. Interaction of pharmacological and behavioral treatments.

Within a behavioral self-management treatment program for overweight, 59 patients were randomly assigned to receive as an adjunct either dextroamphetamine sulfate, fenfluramine hydrochloride, or placebo in a double-blind procedure. Patients self-regulated their drug intake during a four-week medication period. Two types of behavioral-pharmacological interaction were observed: (1) drug assignment influenced participation in the behavioral treatment; and (2) drug assignment influenced the extent of medication self-administration. The dextroamphetamine group was superior in terms of behavioral treatment participation, extent of eating and exercise habit change, and weight loss. Self-administration of dextroamphetamine was most well-maintained--showing it to be a reinforcer--and self-administration of fenfluramine was suppressed below placebo levels. No patient taking either drug showed excessive drug intake, and all were, in fact, conservative in drug use. These data concerning relative reinforcing efficacy within a therapeutic medication setting are discussed in relation to data from animal models used to assess relative abuse liability of these drugs.

Psychiatric and substance use comorbidity among treatment-seeking opioid abusers.

BACKGROUND: Major studies of psychiatric comorbidity in opioid abusers reported rates of comorbidity that far exceeded general population estimates. These studies were published more than a decade ago and reported on few women and few substance use diagnoses. METHODS: Psychiatric and substance use comorbidity was assessed in 716 opioid abusers seeking methadone maintenance. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnostic assessment was conducted 1 month after admission. Rates of psychiatric and substance use disorder were compared by gender, and associations were assessed between psychiatric comorbidity and dimensional indexes of substance use severity, psychosocial impairment, and personality traits. RESULTS: Psychiatric comorbidity was documented in 47% of the sample (47% women and 48% men). Antisocial personality disorder (25.1%) and major depression (15.8%) were the most common diagnoses. Patients had at least 2 substance use diagnoses, most often opioid and cocaine dependence. Demographics, substance use history, and personality variables discriminated between patients with vs without comorbidity. Psychiatric comorbidity also was associated with a more severe substance use disorder. CONCLUSIONS: Psychiatric comorbidity, especially personality and mood disorder, was common in men and women. The positive associations between psychiatric comorbidity and severity of substance use and other psychosocial problems were most consistent among those with antisocial personality.

Induction with levomethadyl acetate: safety and efficacy.

BACKGROUND: Levomethadyl acetate hydrochloride (known as LAAM) is a mu-opioid agonist approved for the treatment of opioid dependence. Clinical trials comparing LAAM and methadone have reported lower patient retention rates during LAAM induction; however, this may reflect dose and schedule differences. Few studies have systematically examined LAAM dose induction. This study compared induction with 3 different LAAM dosage levels. METHODS: In a randomized, double-blind trial, male and female opioid-dependent patients (N = 180) were assigned to 1 of 3 LAAM doses. The low-dose (25 mg) induction was constant from the onset of treatment, the medium-dose (50 mg) induction lasted 7 days, and the high-dose (100 mg) induction lasted 17 days. Safety and efficacy were assessed on retention, urinalysis and self-reported drug use, symptoms, and patient ratings of medication adequacy. RESULTS: The high-dose group had significantly fewer illicit opioid-positive urine samples in weeks 3 and 4 as compared with the low-dose group. The high-dose group had significantly lower self-reported heroin craving in weeks 2 and 3. All groups demonstrated significant decreases in illicit drug use, withdrawal symptoms, and depression. There were no between-group differences in retention; however, there was a trend (P = .08) for lower retention and a greater number of agonist adverse effects were observed in the high-dose group. Overall, LAAM doses were well tolerated by most patients. CONCLUSION: Induction with low and medium LAAM doses can be safely and effectively achieved within 7 days. Induction with higher LAAM doses can be safely achieved within 17 days, but may result in greater rates of patient dropout and opioid agonist adverse effects. Therefore, higher doses should be approached more slowly.

Short-term effects of oral methadone in methadone maintenance subjects.

In two experiments the physiologic and subjective status of methadone maintenance patients was assessed during the presumed peak (0 to 6 hr postmethadone) and during the presumed nadir of the daily methadone effect (18 to 30 hr postmethadone). In the first experiment physiologic and subjective responses were measured in seven ambulatory subjects at 2, 4, and 6 hr after a regular daily dose of methadone or placebo. In the second, physiologic measures were continuously monitored for 4 hr in six inactive seated subjects. In both studies, pupil diameter decreased after moderate to high methadone doses (35 to 80 mg). In the second experiment, heart rate fell and skin temperature rose significantly after methadone. Responses to the morphine-benzedrine group scale of the Addiction Research Center Inventory were elevated after methadone for most subjects in both studies, although there were individual differences in the magnitude and time course of this effect. Finally, low methadone maintenance doses of 10 and 20 mg/day had little or no effect on physiologic or subjective responses in two subjects. These studies showed that short-term effects of oral methadone can be readily detected during a 24-hr dosing regimen. The changes in function after the regular maintenance dose may result both from short-term opiate effects and relief of mild withdrawal.

Single-day methadone dose alteration: detectability and symptoms.

Three experiments were conducted in which detectability and symptomatic effects of acute (single-day) increases and decreases in the methadone dose of subjects on methadone maintenance were examined. Altered doses ranged from 0% to 200% of the stable methadone dose, which was typically 50 mg. In an initial experiment, explicit information was provided to subjects (N = 10) about the occurrence and size of altered doses. No explicit information was provided in a second experiment, but subjects (N = 14) could detect altered doses on the basis of taste. In the third experiment, subjects (N = 2) received no information about the direction, size, or schedule of altered doses. Large dose alterations (75% to 100% of stable dose) were reliably detected by subjects on methadone maintenance, although marked individual differences in sensitivity were apparent. With taste cues available, subjects underestimated the magnitude of dose decreases and increases by 50% and 75%. Without taste cues, subjects could reliably detect only decreased doses. Symptomatic effects related to direction and size of altered doses but not to information conditions. Withdrawal symptom checklist scores were elevated after large (75% to 100%) dose decreases under all information conditions, but few symptomatic effects were reported after dose increases under any information condition.

Self-administration of clonidine, oxazepam, and hydromorphone by patients undergoing methadone detoxification.

The extent to which hydromorphone, clonidine, and oxazepam alleviate the symptoms of opioid withdrawal and the extent and pattern of self-administration of these drugs during methadone detoxification were examined within a residential laboratory in three groups of patients dependent on methadone. Six times over the course of detoxification, acute effects of orally administered placebo and a single active drug (hydromorphone HCl, 3 mg, clonidine HCl, 0.3 mg, or oxazepam, 30 mg, all given twice daily) were tested, followed by an opportunity for subjects to self-administer the drug and dose of their choice. Hydromorphone significantly decreased opioid withdrawal symptoms and was more preferred for self-administration than the placebo. Clonidine and oxazepam did not significantly decrease withdrawal symptoms, nor was either drug self-administered significantly more than placebo. Clonidine, however, did induce side effects.

Pupillary response to methadone challenge in heroin users.

The relationship between self-reported illicit heroin use and pupillary response to a low-dose methadone challenge was examined in 28 men beginning methadone therapy for opiate dependence. Pupil diameter was assessed before and 60, 90, and 120 minutes after a 20 mg methadone dose on day 1 of treatment. Self-reports of opiate drug effects were also taken at these times. There was a significant negative correlation (r = -0.53) between pupillary constriction 120 minutes after drug dosing and the average dollar value of subjects' reported heroin use per week. In other words, those who showed the least pupillary constriction generally reported the highest amount of illicit heroin use. Total years since first opiate use was also a significant predictor of pupillary response (r = -0.46). Self-reported amount of heroin use and years since first opiate use together accounted for 60% of the total variance in pupillary response to the challenge (Mult r = 0.77). Pupillary response to a low-dose methadone challenge appears to be a clinically practical and objective method for determining opiate tolerance levels in applicants for methadone therapy.

Clinical pharmacology of buprenorphine: ceiling effects at high doses.

OBJECTIVE: The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial mu-agonist, across a wide range of doses in comparison to methadone. METHOD: Healthy adult male volunteers, who had experience with but were not physically dependent on opioids, participated while residing on a closed research unit. Four subjects received buprenorphine (0, 1, 2, 4, 8, 16, and 32 mg sublingually and five subjects received methadone (0, 15, 30, 45, and 60 mg orally) in ascending order at 1-week intervals. Physiologic, subjective, and behavioral measures were monitored for 96 hours after drug administration. RESULTS: Both drugs produced typical opioid agonist effects (positive mood, sedation, respiratory depression, and miosis), some of which persisted for 24 to 48 hours. A plateau was observed for the dose effects of buprenorphine on subjective measures and respiratory depression. Pharmacokinetic data revealed that plasma concentrations of buprenorphine were linearly related to dose, indicating no limits on sublingual absorption in this dose range. CONCLUSIONS: This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent humans.

Opioid antagonist effects of dezocine in opioid-dependent humans.

Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.

Oral methadone self-administration: effects of dose and alternative reinforcers.

We examined the efficacy of oral methadone as a reinforcer by offering methadone maintenance patients the chance to self-administer extra doses of methadone occasionally in addition to their regular dose. Seven maintenance patients received twice-weekly choices between methadone doses or money. Doses were 0, 1, 5, 10, 25, or 50 mg methadone; the alternative money option was $1 or $5. Extra methadone doses were reliably self-administered by maintenance patients, and percent of dose choices rose as the size of the dose offered increased. Thus extra methadone doses functioned as reinforcers in this situation. Further, across the entire dose range, more dose choices were selected when $1 was offered than when $5 was offered as an alternative. Thus methadone self-administration was influenced by the alternative reinforcers available for drug refusal. Neither reports of subjective withdrawal symptoms nor reduction of symptoms after extra methadone predicted methadone self-administration, but dose selections were more likely when urinalysis results indicated recent illicit opiate use. The reinforcing effects of oral methadone in methadone-tolerant patients may be an important factor in the popularity of this treatment among drug abusers and in the long-term treatment retention generally observed during methadone maintenance.

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts.

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.

Antisocial personality disorder and HIV infection among intravenous drug abusers.

OBJECTIVE: Antisocial personality disorder in drug abusers has been associated with poor treatment outcome. The authors examined the relationship between diagnosis of antisocial personality and HIV infection. METHOD: Subjects were 272 intravenous drug abusers, 140 (52%) of whom were in methadone treatment. Subjects were given an HIV risk behavior interview before diagnostic interviewing and HIV testing. RESULTS: Using the DSM-III-R definition, the authors found that 119 (44%) of the subjects met criteria for antisocial personality. Significantly more of the subjects with antisocial personality (18% [N = 21] than of the subjects without antisocial personality (8% [N = 12]) had HIV infection. The diagnosis of antisocial personality disorder was associated with a significantly higher odds ratio of infection independent of ethnicity, gender, and treatment status. CONCLUSIONS: Antisocial personality is a risk factor for HIV infection among intravenous drug abusers.

Comparison of buprenorphine and methadone in the treatment of opioid dependence.

OBJECTIVE: This study compared the efficacy of buprenorphine and methadone in the treatment of opioid dependence. METHOD: Participants (N = 164) were relatively treatment-naive, opioid-dependent applicants to a 26-week treatment program who were randomly assigned to either methadone or buprenorphine treatment. Dosing was double-blind and double-dummy. Patients were stabilized on a regimen of either methadone, 50 mg, or buprenorphine, 8 mg, with dose changes possible through week 16 of treatment. Urine samples were collected three times a week, and weekly counseling was provided. RESULTS: Buprenorphine (mean dose = 8.9 mg/day) and methadone (mean dose = 54 mg/day) were equally effective in sustaining retention in treatment, compliance with medication, and counseling regimens. In both groups, 56% of patients remained in treatment through the 16-week flexible dosing period. Overall opioid-positive urine sample rates were 55% and 47% for buprenorphine and methadone groups, respectively; cocaine-positive urine sample rates were 70% and 58%. Evidence was obtained for the effectiveness of dose increases in suppressing opioid, but not cocaine, use among those who received dose increases. CONCLUSIONS: The results of this study provide further support for the utility of buprenorphine as a new medication in the treatment of opioid dependence and demonstrate efficacy equivalent to that of methadone when used during a clinically guided flexible dosing procedure.

Antisocial behavior of intravenous drug abusers: implications for diagnosis of antisocial personality disorder.

OBJECTIVE: A pattern of chronic adult antisocial behavior is not sufficient for the DSM-III-R diagnosis of antisocial personality disorder unless the early-onset criteria are satisfied, even if the adult criteria are met. The utility of the early-onset requirement for the diagnosis was examined in intravenous drug abusers, a population known to have high rates of irresponsible, aggressive, and criminal behavior. METHOD: The subjects were 237 drug abusers who had volunteered for an outpatient study of psychopathology and HIV risk behavior and infection. They completed a structured psychiatric interview as part of their participation in that study. The adult antisocial behavior of the group that met both the early-onset and the adult criteria for antisocial personality disorder, the group that met only the adult criteria, and the group that met neither the early-onset nor the adult criteria was then compared. RESULTS: Antisocial personality disorder (meeting the early-onset and adult criteria) was diagnosed in 44% of the sample; an additional 24% met only the adult criteria. The group with the diagnosis of antisocial personality disorder reported a more pervasive and more serious pattern of adult antisocial behavior than did the other groups, although antisocial behavior was commonplace in all three groups. CONCLUSIONS: Early onset of multiple antisocial behaviors identified a subset of drug abusers with important differences in the extent and severity of their adult antisocial behavior. The antisocial behavior of the group that met only the adult criteria suggests the possibility of a late-onset and less severe form of antisocial personality disorder.

Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects.

OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid agonists differently: mu agonists produce mainly euphoria, while kappa agonists are more likely to produce dysphoria. This study tested the hypothesis that these subjective effects would be associated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid abusers participated in the study. In the first phase of the study, the participants were acclimated to effects of the study drugs. In the second phase they underwent repeat challenges with the study drugs followed by an assessment of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol (which has a kappa agonist component of activity), and saline placebo. RESULTS: Subjective effects of the drugs were distinctly different. Hydromorphone produced increased ratings of "good effects," while butorphanol led to more "bad effects." Hydromorphone significantly increased regional CBF in the anterior cingulate cortex, both amygdalae, and the thalamus--all structures belonging to the limbic system. Butorphanol caused a less distinct picture of regional CBF increases, mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates that opioids with different subjective effects also produce statistically significant patterns of change in regional CBF from baseline, and the regions of statistical significance appear in different brain regions. In addition, these results demonstrate the applicability of SPECT functional neuroimaging in the study of medications with potential abuse liability.

Buprenorphine reduces cerebral glucose metabolism in polydrug abusers.

Buprenorphine is a mixed opioid agonist-antagonist, which acts as a partial mu agonist and a kappa antagonist. The present study evaluated the acute effects of buprenorphine on cerebral glucose metabolism (CMRglc) in six human substance abusers using a double-blind, placebo-controlled, counterbalanced, crossover design. Each subject participated in two positron emission tomographic (PET) studies, 1 week apart, following the injection of buprenorphine (1 mg, intramuscularly) and placebo. Buprenorphine significantly reduced CMRglc and the regional cerebral metabolic rate for glucose (rCMRglc) by up to 32% in all but three of 22 bilateral and in 4 midline regions (p < .05). No region showed an increase in rCMRglc. Buprenorphine also produced miosis, respiratory depression, and subjective ratings of euphoria and sedation in comparison to placebo (p < .05). These observations extend previous findings of reduced CMRglc following acute treatment with morphine and other nonopioid euphorigenic drugs.

Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans.

RATIONALE: It is commonly accepted that the relative abuse liability of drugs is positively related to the rate of delivery to the central nervous system; however, few controlled studies have tested this hypothesis in humans. OBJECTIVES: The aims of this study were to evaluate systematically the effects of modifying intravenous infusion speed on the pharmacodynamic responses related to abuse liability and toxicity of intravenous cocaine and hydromorphone. METHODS: Twelve experienced opiate and cocaine users completed this 3-week inpatient study. After completing a safety session, participants were tested on 9 separate test days with intravenous cocaine (30 mg/70 kg), hydromorphone (3 mg/70 kg), and placebo, each administered under double-blind and randomized conditions at infusion rates of 2, 15, and 60 s. Dependent outcome measures included a range of physiological, subjective, and observer-rated measures, and continuous electrocardiographic monitoring was conducted for safety monitoring. RESULTS: Subjective responses to cocaine (for example, "high," "liking") were significantly greater when cocaine was infused more rapidly. Physiological responses to cocaine were largely unaltered with no evidence of increased toxicity with faster infusion speeds. None of the effects of hydromorphone were altered by varying the speed of infusion. CONCLUSIONS: This study provides empirical evidence for the commonly accepted belief that the abuse liability of cocaine can be enhanced by increasing the rate of the intravenous infusion; this principal may not hold true for opioids but further work would be required to rule this out. The data also indicate that moderate doses of cocaine can be administered over a range of infusion speeds commonly used in experimental settings without appreciably altering the apparent medical risks.