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.

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.

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.

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.

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 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.

Buprenorphine: duration of blockade of effects of intramuscular hydromorphone.

Six opioid-dependent in-patients were maintained on daily sublingual doses of buprenorphine at 2, 6, and 12 mg/day for five days at each dose in a randomized, balanced sequence. Placebo buprenorphine was substituted for the next three days, and challenge doses of the mu agonist hydromorphone were administered on the three days. Planned comparisons in a 3-factor ANOVA showed dose-dependent hydromorphone effects, significant blockade of 'high' by the 12 mg buprenorphine dose, and no differences on hydromorphone-induced 'high' across 72 h of active buprenorphine. The data suggest that the blockade by buprenorphine of 'high' persists for at least 72 h after the last dose of buprenorphine.

SPECT regional cerebral blood flow alterations in naltrexone-precipitated withdrawal from buprenorphine.

The effects of naltrexone-precipitated withdrawal from buprenorphine on behavior and regional cerebral blood flow (rCBF) were studied in 11 opiate-dependent patients. Patients initially received buprenorphine, 2 mg sublingually, every day for 7 days. They were then challenged sequentially with placebo and naltrexone, 25 mg orally, before single photon emission computed tomography with technetium-99m-d,l-hexamethyl-propylene amine oxime as tracer. Behavioral ratings of withdrawal severity were made before and after naltrexone/placebo administration. Naltrexone produced significantly greater signs and symptoms of opiate withdrawal than placebo. Analysis of variance revealed no significant regionally specific effect of naltrexone on rCBF ratios. Severity of withdrawal, however, showed a significant negative correlation with rCBF in the anterior cingulate cortex following naltrexone. These results are interesting as the anterior cingulate region has been implicated in the emotional component of pain and in opiate-induced analgesia.

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).

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.

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.

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.

Buprenorphine: beyond methadone?

This month's guest authors are affiliated with the substance abuse treatment and treatment research unit of the Connecticut Mental Health Center and the department of psychiatry at Yale University School of Medicine, where Dr. Rosen is instructor and Dr. Kosten is associate professor. They discuss a promising new treatment that may reduce abuse of cocaine by drug addicts who use intravenous heroin and may indirectly reduce risk-taking behavior associated with transmission of the human immunodeficiency virus.

Cocaine-associated panic attacks in methadone-maintained patients.

The incidence of panic attacks methadone-maintained patients has increased over a 10-year period from 1 to 6-13%. Cocaine use appears to be associated with this increase, although other environmental and constitutional factors may be contributory. Patients with cocaine-associated panic differ from other panic patients in rates of psychiatric hospitalization and medical illness, but not in depression, other drug use, or agoraphobia.

Discriminative stimulus, self-reported and cardiovascular effects of orally administered cocaine in humans.

This study evaluated whether an oral dose of cocaine can serve as a discriminative stimulus in humans. Four male and one female cocaine-abusing volunteers (ages 26-41 years) were trained to discriminate between cocaine HCl (80 mg/70 kg p.o.) and placebo. Once the criterion for discrimination was met (i.e., > or = 80% correct responding for four consecutive sessions), dose-effect curves were determined for orally administered cocaine (20, 40, 80 and 120 mg/70 kg), intranasally administered cocaine (20, 40, 80 and 120 mg/70 kg) and the benzodiazepine triazolam (0.25 and 0.50 mg/70 kg p.o.). All five subjects met the criterion for the cocaine-placebo discrimination within four to seven sessions. Novel cocaine doses by either the oral or intranasal route of administration generally produced dose-related increases in cocaine-appropriate responding, whereas triazolam produced predominantly placebo-appropriate responding. Cocaine by both routes produced qualitatively similar increases in stimulant-like self-reports, blood pressure and heart rate, whereas triazolam produced increases in sedative-like ratings and no changes in cardiovascular measures. Throughout dose-effect curve determinations, the training dose of cocaine and placebo continued to be identified correctly in four of five subjects (range, 75-100% correct responding). These results suggest that orally administered cocaine (80 mg/70 kg) is discriminable from placebo, has behavioral effects that are qualitatively similar to intranasal cocaine and does not show cross-generalization to a pharmacologically dissimilar compound.