Association between use of specific drugs and antiretroviral adherence: findings from MACH 14.

To determine the association between individual substances of abuse and antiretroviral adherence, analyses require a large sample assessed using electronic data monitoring (EDM). In this analysis, EDM data from 1,636 participants in 12 US adherence-focused studies were analyzed to determine the associations between recent use of various substances and adherence during the preceding 4 weeks. In bivariate analyses comparing adherence among patients who had used a specific substance to those who had not, adherence was significantly lower among those who had recently used cocaine, other stimulants or heroin but not among those who had used cannabis or alcohol. In multivariate analyses controlling for sociodemographics, amount of alcohol use and recent use of any alcohol, cocaine, other stimulants and heroin each was significantly negatively associated with adherence. The significant associations of cocaine, other stimulants, heroin, and alcohol use with adherence suggest that these are important substances to target with adherence-focused interventions.

Consumer experience with payeeship provided by a community mental health center.

We surveyed 28 participants in a program in which the clinical therapist and money manager were different staff members. Patients reported strong therapeutic alliances with both the money manager and treating therapist as assessed by the Working Alliance Inventory. Alliance scores for the two providers were highly correlated (p = .68) and not significantly different from each other. Most patients endorsed overall satisfaction with the money management service, and report program-related benefits in housing, achieving abstinence, avoiding financial predators and budgeting arrangements. A significant minority endorsed some feeling of coercion, and coercion was associated with a weaker therapeutic alliance.

Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.

OBJECTIVE: To assess the feasibility and efficacy of two interventions for improving adherence to antiretroviral therapy regimens in HIV-infected subjects compared with a control intervention. DESIGN: Randomized, controlled, pilot study. SETTING: Department of Veterans Affairs HIV clinic and community-based HIV clinical trials site. PARTICIPANTS: Fifty-five HIV-infected subjects on stable antiretroviral therapy regimens. Subjects were predominantly male (89%) and African American (69%), and had histories of heroin or cocaine use (80%). INTERVENTIONS: Four weekly sessions of either nondirective inquiries about adherence (control group, C), cue-dose training, which consisted of the use of personalized cues for remembering particular dose times, and feedback about medication taking using Medication Event Monitoring System (MEMS) pill bottle caps, which record time of bottle opening (CD group), or cue-dose training combined with cash reinforcement for correctly timed bottle opening (CD+CR). MEASUREMENTS: Opening of the pill bottle within 2 hours before or after a predetermined time was measured by MEMS. RESULTS: Adherence to the medication as documented by MEMS was significantly enhanced during the 4-week training period in the CD+CR group, but not in the CD group, compared with the control group. Improvement was also seen in adherence to antiretroviral drugs that were not the object of training and reinforcement. Eight weeks after training and reinforcement were discontinued, adherence in the cash-reinforced group returned to near-baseline levels. CONCLUSIONS: Cue-dose training with cash reinforcement led to transient improvement in adherence to antiretroviral therapy in a population including mostly African Americans and subjects with histories of drug abuse. However, we were not able to detect any sustained improvement beyond the active training period, and questions concerning the timing and duration of such an intervention require further study. Randomized, controlled clinical studies with objective measures of adherence can be conducted in HIV-infected subjects and should be employed for further evaluation of this and other adherence interventions.

Effects of lamotrigine on behavioral and cardiovascular responses to cocaine in human subjects.

We evaluated the effects of acute pretreatment with lamotrigine, a putative glutamate release inhibitor, on the physiological and behavioral responses to intranasal cocaine in cocaine-dependent volunteers (N = 8). The study employed a double-blind, placebo-controlled, within-subject design. Subjects participated in six experimental sessions. On each study day, placebo, lamotrigine 125 mg, or lamotrigine 250 mg was administered orally in the morning, followed 2 hours later by intranasal cocaine 120 mg/70 kg or placebo. Measurements of heart rate and blood pressure were acquired, and subjects responded to mood state questionnaires at predetermined time intervals. Cocaine alone produced increases in heart rate, blood pressure, and several measures of pleasurable mood and drug effects. Lamotrigine alone produced a mild relaxing effect. Lamotrigine pretreatment altered neither the physiological responses nor the subjective ratings of cocaine's pleasurable or aversive mood effects.

Naloxone challenge in smokers. Preliminary evidence of an opioid component in nicotine dependence.

BACKGROUND: This study used an opioid antagonist challenge procedure to evaluate the responsivity of the endogenous opioid system in nicotine-dependent individuals, as evidenced by naloxone-induced alterations in both behavioral (withdrawal, craving) and neuroendocrine (cortisol levels) parameters. METHODS: Twenty subjects (9 smokers and 11 nonsmokers) participated in 4 laboratory sessions during which they were challenged with 0, 0.8, 1.6, or 3.2 mg/70 kg of naloxone and then monitored for 1 hour for subjective signs and symptoms of opiate-like withdrawal, nicotine craving, and alterations in cortisol levels. RESULTS: Nicotine-dependent subjects evidenced naloxone dose-dependent increases in withdrawal signs and symptoms. Lower doses of naloxone also produced increases in urges to smoke (craving) and tiredness in smokers. Smokers, when compared with nonsmokers, had lower prenaloxone baseline levels of cortisol and attenuated cortisol release in response to challenge with naloxone. CONCLUSIONS: These results provide preliminary evidence to suggest that long-term exposure to cigarette smoke is associated with alterations in the responsivity of the endogenous opioid system and the hypothalamic-pituitary-adrenal axis that may contribute to the development of nicotine dependence.

The effects of naltrexone maintenance on the response to yohimbine in healthy volunteers.

BACKGROUND: Preclinical research suggests that opiate antagonists may alter stress responsiveness. This study describes the effect of pretreatment with the opioid antagonist naltrexone on the response to a noradrenergic stressor, the alpha-2-receptor-antagonist, yohimbine, in healthy subjects. The current study was designed to compare the change in responses to yohimbine after 2 weeks of treatment with naltrexone to the response after at least 2 weeks of treatment with placebo. METHODS: After a week of placebo naltrexone treatment, ten subjects were randomized into a double-blind cross-over to placebo or active naltrexone (50 mg p.o. daily) on weeks 2 to 4, and the converse condition for weeks 5 to 7. Subjects received challenges in a random, fixed sequence with placebo and active yohimbine (i.v., 0.2 mg/kg) on weeks 1, 4, and 7. The active-active combination generally had the strongest drug effects. RESULTS: There were statistically significant (p < .05) interactions of naltrexone condition X yohimbine condition for subject ratings of "nervous," "not liking the drug effect," "talkative," and "urge to urinate," and a trend (p < .10) for cortisol levels. CONCLUSIONS: The results suggest that clinically used naltrexone doses alter sensitivity to yohimbine.

Interactions of cocaine with nimodipine: a brief report.

This double blind, placebo controlled study of acute calcium channel antagonist use during cocaine administration in five patients found that 60 mg of nimodipine treatment attenuated the systolic, but not diastolic, blood pressure effects of cocaine. In three subjects, a 90 mg dose of nimodipine showed a greater attenuation than that of 60 mg. Subjective effects of cocaine were not altered by either dose of nimodipine.

Substance use and assignment of representative payees.

Recent legislation prohibiting the awarding of Social Security Disability Insurance benefits to people whose disability is based on drug and alcohol abuse has effectively eliminated the Social Security Administration's practice of assigning representative payees to such persons. Currently no regulations exist for assigning representative payees to substance users who receive benefits based on non-substance-use disabilities. The authors suggest guidelines for determining when recipients with comorbid substance use disorders are incapable of managing their benefit funds. Representative payeeship is recommended for recipients who meet three criteria within the last 12 months: a maladaptive pattern of substance use; mismanagement of funds due to substance use, causing substantial harm to the recipient, unavailability of sufficient funds to meet basic needs, or victimization of the recipient; and availability of a representative payee whose efforts would increase the likelihood that the beneficiary's mismanagement of funds will be curtailed.

The effect of lamotrigine on naloxone-precipitated opiate withdrawal.

We hypothesized that lamotrigine, a putative glutamate release antagonist, would attenuate glutamate-mediated signs of opiate withdrawal. Seven heroin-dependent subjects were hospitalized, stabilized on oral levorphanol 6 mg three times daily, and thrice underwent withdrawal precipitated by naloxone 0.4 mg intravenously. Lamotrigine (placebo, 250 mg, and 500 mg) was randomly given as a pretreatment 6 h before naloxone. Lamotrigine did not significantly attenuate any measure of opiate withdrawal. Lamotrigine was well-tolerated in subjects, although one did develop an allergic rash.

Hydromorphone-naloxone combinations in opioid-dependent humans under a naloxone novel-response discrimination procedure.

Naloxone-hydromorphone combinations were tested in participants trained to discriminate naloxone from placebo under a novel-response drug discrimination procedure while maintained on methadone. Naloxone alone produced dose-related increases in naloxone-appropriate responding, little or no "novel"-appropriate responding, and increases in opioid antagonist adjective ratings (n = 5). Hydromorphone alone produced dose-related increases in novel-appropriate responding, little or no naloxone-appropriate responding, and increases in opioid agonist adjective ratings (n = 6). When combined with naloxone, hydromorphone produced dose-related decreases in naloxone-appropriate responding and antagonist adjective ratings (n = 6). These findings are consistent with nonhuman data and suggest that this procedure may be useful as a human laboratory model of opioid withdrawal.

Treatment of early AIDS dementia in intravenous drug users: high versus low dose peptide T.

This placebo-controlled, double blind, cross-over study tested the efficacy of two different doses of Peptide T in the treatment of nine intravenous drug users with early AIDS dementia who were also receiving methadone and AZT. Subjects received Peptide T doses of either 15 or 1.5 mg daily for four weeks. Neuropsychological performance improved in four of five patients treated with the high dose, but at the lower dose, three of four patients showed no improvement on Peptide T when compared with placebo. When subjects who received the high dose were compared with those who received the low dose, a significant dose effect was found only during the active phase of the trial even after correction for differences in level of functioning at baseline.

Dose dependent effects of yohimbine on methadone maintained patients.

Twelve methadone-maintained patients were randomized into a controlled crossover study with active and placebo yohimbine 20 mg once a day (n = 4), 5mg three times a day (n = 4) or 10 mg three times a day (n = 4) for seven days to evaluate the effect of yohimbine on naloxone precipitated opiate withdrawal. The yohimbine dose of 10 mg TID was well tolerated and was associated with an average decrease of 30% in precipitated withdrawal symptoms.

Effects of gamma-hydroxybutyric acid (GHB) in opioid-dependent patients.

Gamma-hydroxybutyric acid (GHB) is a GABA metabolite used clinically for sleep induction. The abuse liability of GHB is controversial. As part of a study of the effect of GHB pretreatment on naloxone-precipitated opiate withdrawal, eight opioid-stabilized subjects received a balanced, randomized, double-blind sequence of oral placebo, GHB 15 mg/kg and 30 mg/kg. GHB had no consistent physiological effects. After GHB and prior to naloxone, subjects rated "sluggish," "spaced," "carefree," and "good-mood" higher after GHB 30 mg/kg than after placebo. Subjects identified the 30 mg/kg dose as most similar to placebo (n = 3), benzodiazepine (n = 2), opiate (n = 2), and alcohol (n = 1).

Sustained-release methylphenidate for cognitive impairment in HIV-1-infected drug abusers: a pilot study.

Other investigators have reported clinical improvement from psychostimulant drugs in patients with HIV-1-related cognitive impairment. However, no previous research has substantiated this claim by using a controlled study design. We examined the efficacy of sustained-release methylphenidate (MSR) in a sample of substance abusers with HIV-1-related cognitive impairment. Eight HIV-1-infected methadone patients with impaired neuropsychological test performance participated in an inpatient double-blind placebo-controlled crossover trial of MSR 20-40 mg/day. On a composite neuropsychological measure, patients improved significantly from baseline during MSR but not placebo treatment. Nevertheless, MSR performance did not differ significantly from placebo performance. Patients appeared to improve as a function of time, regardless of sequence, with somewhat more improvement during MSR than placebo treatment.

Acute cocaine effects on absolute cerebral blood flow.

Cocaine use has been associated with vasoconstriction and stroke, and several studies have demonstrated that it decreases relative cerebral blood flow (rCBF) in humans. However, rCBF has not been quantitated. We compared 40 mg IV cocaine hydrochloride to placebo effects on absolute rCBF in four cocaine users using 99mTc-HMPAO SPECT with a modified microsphere model for CBF quantitation. Cocaine produced significant decreases in rCBF in all regions studied with a mean decrease of 30% in absolute whole brain blood flow (P = 0.002) which was 3-fold greater than relative blood flow changes.

A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal.

Dextromethorphan and its metabolite dextrophan antagonize N-methyl-D-aspartate (NMDA)-mediated activity in pre-clinical studies. We examined dextromethorphan's effects on naloxone-precipitated opiate withdrawal in opiate-dependent subjects stabilized on 25 mg of methadone. Subjects received challenges on three different days with 0.4 mg of intramuscular naloxone. Pretreatment 1 h before naloxone was with dextromethorphan in a double-blind, balanced, randomized design with either placebo, dextromethorphan 60 mg, or dextromethorphan 120 mg for six subjects; and placebo, dextromethorphan 120 mg, or dextromethorphan 240 mg for five subjects. There was considerable inter-individual variability in the response to dextromethorphan, but no net attenuation by dextromethorphan on any withdrawal measure assessed. Two of three subjects detoxified from methadone with dextromethorphan 60 mg orally every 4 h demonstrated considerable withdrawal.

The effect of gamma-hydroxybutyric acid on naloxone-precipitated opiate withdrawal.

Because gamma-hydroxybutyric acid (GHB), a GABA metabolite, attenuated spontaneous opiate withdrawal in a prior study, we studied GHB's effect on naloxone-precipitated opiate withdrawal. Eight opiate-dependent inpatients were stabilized on the opioid levorphanol, 18 mg daily. After an initial acclimatization challenge, subjects underwent three double-blind challenges on consecutive days. Pretreatment in a balanced randomization was with either placebo, GHB, 15 mg/kg, or GHB, 30 mg/kg, followed an hour later by intravenous naloxone, 0.4 mg/70 kg. GHB produced no significant attenuation of multiple withdrawal measures except for hot-cold feelings. GHB pretreatment slightly accelerated respiration prior to naloxone. Differences with prior studies may be due to (1) timing of GHB administration (giving postwithdrawal in prior studies), (2) direct reversal of GHB's anti-withdrawal effects by naloxone, or (3) differences between naloxone-precipitated and spontaneous opiate withdrawal.

Effect of clonidine pretreatment on naloxone-precipitated opiate withdrawal.

The purpose of this pilot study was to validate a methodology for testing the opioid withdrawal-attenuating effects of new medications using clonidine as a positive control. Seven heroin-dependent subjects stabilized on levorphanol received naloxone challenge tests on 4 consecutive days in a 2 x 2 design with placebo or clonidine (0.4-0.5 mg) pretreatment, followed by 0.2 or 0.4 mg of i.v. naloxone. The change in the area-under-the-curve from the preclonidine base line for various measures of withdrawal was analyzed in a two-factor (naloxone dose and clonidine condition) analysis of variance. Clonidine significantly (P < .05) attenuated systolic and diastolic blood pressure, pulse, lacrimation, nasal congestion and plasma cortisol, but not subject-rated withdrawal severity. There was a robust dose-dependent adrenocorticotropic hormone response to naloxone that was not changed by clonidine pretreatment. The consistency between these results and prior studies of clonidine's antiwithdrawal efficacy suggests the validity of the methodology for testing medications to treat opiate withdrawal. Studies with larger samples are needed to refine this methodology.

The severity of naloxone-precipitated opiate withdrawal is attenuated by felbamate, a possible glycine antagonist.

Recent studies indicate that an N-methyl-D-aspartate (NMDA) receptor system in the rostral medulla is involved in opiate withdrawal. Although NMDA antagonists attenuate naloxone-precipitated opiate withdrawal, they can cause phencyclidine (PCP)like effects that contraindicate clinical use. Because NMDA channels contain sites for the glutamate coagonist, glycine, we assessed the effects of glycinergic agents on naloxone-precipitated opiate withdrawal in rats. The putative antagonist, felbamate (100, 300 mg/kg), attenuated overall withdrawal severity in a dose-related manner and reduced occurrences of chews, teeth chatters, and penile grooming. The partial agonist, D-cycloserine (3, 10 mg/kg), attenuated withdrawal severity, but not in a dose-related manner. Conversely, the low dose of the partial agonist, (+/-)-HA-966 (3, 10 mg/kg), heightened the occurrences of some withdrawal signs. These results support a role for glycine in opiate withdrawal and suggest that these agents, which do not cause PCPlike effects, may be potential treatment for agents for opiate detoxification.