Suspiciousness induced by four-hour intravenous infusions of cocaine. Preliminary findings.

Cocaine hydrochloride was administered to experienced users as an intravenous (IV) loading dose of 40 to 80 mg, followed by four-hour continuous IV infusions of either cocaine or placebo. Rates of cocaine infusion were individualized to maintain steady-state cocaine concentrations for the duration of the infusion. During the infusions, subjects rated themselves on questions that assessed their suspiciousness and paranoia, and nurse-observers took descriptive notes on the subjects' behavior; these notes were later scored on a scale for guarded, suspicious, and paranoid behavior. Nurses observed and rated moderately suspicious behavior when cocaine IV bolus loading doses were followed by cocaine infusions, but not when loading doses were followed by saline solution infusions; subjects did not rate themselves as suspicious during any of the study conditions. Suspiciousness during low-dose cocaine infusions significantly correlated with the amount of cocaine previously administered to the subjects. Suspiciousness during infusions was not related to plasma cocaine concentrations, preadmission drug use, or psychiatric symptoms and history. Cocaine infusions may be a useful tool to pursue the biology of stimulant psychoses.

Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy.

BACKGROUND: Chronic cocaine abuse remains a serious and costly public health problem. This study assessed the effectiveness of a voucher-based reinforcement contingency in producing sustained cocaine abstinence. METHODS: A randomized controlled trial compared voucher-based reinforcement of cocaine abstinence to noncontingent voucher presentation. Patients were selected from 52 consecutively admitted injecting heroin abusers in a methadone maintenance treatment program. Patients with heavy cocaine use during baseline period (N = 37) participated. Except where otherwise indicated, the term cocaine abuse is used in this article in a generic sense and not according to the DSM-III-R definition. Patients exposed to abstinence reinforcement received a voucher for each cocaine-free urine sample (ie, negative for benzoylecgonine) provided three times per week throughout a 12-week period; the vouchers had monetary values that increased as the number of consecutive cocaine-free urine samples increased. Control patients received noncontingent vouchers that were matched in pattern and amount to the vouchers received by patients in the abstinence reinforcement group. RESULTS: Patients receiving vouchers for cocaine-free urine samples achieved significantly more weeks of cocaine abstinence (P = .007) and significantly longer durations of sustained cocaine abstinence (P = .001) than controls. Nine patients (47%) receiving vouchers for cocaine-free urine samples achieved between 7 and 12 weeks of sustained cocaine abstinence; only one control patient (6%) achieved more than 2 weeks of sustained abstinence. Among patients receiving vouchers for cocaine-free urine samples, those who achieved sustained abstinence ( > or = 5 weeks) had significantly lower concentrations of benzoylecgonine in baseline urine samples than those who did not achieve sustained abstinence (P < or = .01). Patients receiving voucher reinforcement rated the overall treatment quality significantly higher than controls (P = .002). CONCLUSION: Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in injecting polydrug abusers.

Changes in mood, craving, and sleep during short-term abstinence reported by male cocaine addicts. A controlled, residential study.

We examined changes over 28 days in mood states, craving for cocaine, and sleep during short-term abstinence reported by 12 male, predominantly intravenous-using, cocaine-addicted subjects residing in a research facility. For comparison, we examined 10 nonaddicted control subjects. There were no significant differences between cocaine addicts and controls regarding demographics and selected DSM-III-R diagnoses other than psychoactive substance use disorder and antisocial personality disorder. There were significantly higher scores of psychiatric symptoms reported by cocaine addicts 1 week before admission. Mood-distress and depression scores recorded at admission and during short-term abstinence were significantly greater than those reported by controls. Addicts' mood-distress scores and craving for cocaine were greatest at admission and decreased gradually and steadily during the 28-day study. There were no significant differences between groups regarding reports of sleep other than difficulty falling asleep and clearheadedness on arising. Although there were significant differences in resting heart rate at admission and over time, there were no significant differences in weight gain or blood pressure. Given the absence of a classic "withdrawal" pattern, "short-term abstinence" may be a more appropriate classification of psychological and physical phenomena experienced by cocaine addicts who initiate abstinence in a controlled environment.

The association of hepatitis delta virus and hepatitis B virus in parenteral drug abusers. 1971 to 1972 and 1986 to 1987.

From 1971 to 1972 (N = 105) and 1986 to 1987 (N = 160), parenteral drug abusers seropositive for hepatitis B virus (HBV) markers were screened for antibodies to the hepatitis delta virus (anti-HD). In both time frames anti-HD was independently associated with the hepatitis B surface antigen. It was observed that 31% of those positive for hepatitis B surface antigen from the early sample and 20% of those from the latter sample had detectable anti-HD, as opposed to 10% and 7%, respectively, of those negative for hepatitis B surface antigen. Anti-HD seropositivity was unrelated to gender and ethnicity, and in the 1971 and 1972 nationwide sample, its presence was unrelated to geographic location. The probability of manifesting anti-HD increased with the more HBV markers detected, particularly the number of different HBV antibody markers. We conclude that anti-HD was wide-spread in parenteral drug abusers at least as early as 1971, and that its expression was associated with hepatitis B surface antigen and the intensity of the immune response to HBV as evidenced by the number of different circulating HBV antibodies.

Metabolism and Disposition of Prescription Opioids: A Review.

Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subjectto drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation.

Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke.

Five healthy men were passively exposed under pre- and postplacebo controlled conditions to sidestream smoke from four and 16 standard marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [delta-9-THC]) for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16-cigarette exposure conditions were similar to those observed after active smoking of one 2.8% delta-9-THC marijuana cigarette. Effects after the four-cigarette condition were less pronounced. Concurrent physiologic measurements showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of delta-9-THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16-cigarette condition. With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs, urines positive per subject under the four- and 16-cigarette passive exposure conditions were 4.6 +/- 2.2 and 35.2 +/- 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 +/- 0.8, respectively, for the EMIT 100 assay. From the results of these studies, caution is clearly indicated for individuals who might be substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting marijuana screening data.

Subjective and physiologic effects of intravenous buprenorphine in humans.

The pharmacologic profile of sublingual and subcutaneous buprenorphine, a partial opioid agonist, indicates it may be useful as a maintenance drug in the treatment of opioid dependence. However, illicit intravenous self-administration suggests that it may have a greater abuse potential by this route of administration. Physiologic and subjective effects of intravenous buprenorphine (0.0, 0.3, 0.6, and 1.2 mg) were determined in a dose-escalation study in six nondependent volunteers with histories of opioid use. Buprenorphine caused miosis and decreased respiratory rate, increased diastolic blood pressure, and transiently increased heart rate. Buprenorphine increased positive responses on a "feel drug" question and scores on scales of "liking," "good effects," euphoria, and apathetic sedation. Physiologic and subjective responses were not consistently dose related, a finding compatible with the pharmacologic profile of a partial agonist. The findings indicate that buprenorphine has substantial potential for abuse when administered intravenously.

Characterization of the absorption phase of marijuana smoking.

Rapid blood collection, a paced smoking protocol and timely collection of physiologic and behavioral measures were used to characterize the absorption phase of marijuana smoking. Six healthy males smoked a single marijuana cigarette (placebo, 1.75%, or 3.55% delta-9-tetrahydrocannabinol) in a double-blind, randomized, Latin square study design. Rapid blood sampling with a continuous withdrawal pump allowed simultaneous collection with concurrent physiologic and behavioral measures. Mean plasma levels of 7.0 and 18.1 ng/ml delta-9-tetrahydrocannabinol were observed after the first inhalation of a 1.75% and 3.55% delta-9-tetrahydrocannabinol cigarette, respectively. Blood levels increased rapidly and peaked at 9 minutes, before initiation of the last puff sequence at 9.8 minutes. Three of six subjects reported increases in drug "liking" scores after the first puff, and all subjects responded by the second puff of a high dose cigarette. Significant increases in heart rate and diastolic blood pressure occurred shortly after peak blood levels. Previous studies have indicated that there is a substantial time delay between peak plasma levels of delta-9-tetrahydrocannabinol and drug-induced effects. This study showed that behavioral and physiologic effects appear concurrently or within minutes after the rapid appearance of delta-9-tetrahydrocannabinol in blood during marijuana smoking.

Use of buprenorphine in the treatment of opiate addiction. I. Physiologic and behavioral effects during a rapid dose induction.

A new, rapid dose-induction procedure was used in the evaluation of buprenorphine hydrochloride (buprenorphine) as a treatment for opiate dependence. Nineteen heroin-dependent men were given buprenorphine sublingually in ascending daily doses of 2, 4, and 8 mg and then maintained on 8 mg daily. The observations of the transition from heroin to buprenorphine for the first 4 days are described. During this period, subjects reported significantly elevated ratings of "good effects" and feelings of "overall well-being" and decreased ratings of "overall sickness." Data from subscales of the Addiction Research Center Inventory indicated increasing euphoria and decreasing dysphoria and sedation after buprenorphine administration. Subjects and observers consistently identified buprenorphine as an opiate and not as an opiate antagonist. These findings indicate that a rapid dose induction with buprenorphine is acceptable to heroin-dependent persons and that it causes minimal withdrawal symptoms.

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.

Phencyclidine binding to striatal cocaine receptors.

PCP and related compounds inhibit 3H-mazindol binding to the cocaine receptor on dopamine transporters. The relative potencies of these compounds are such that some of the behavioral effects of PCP could be related to its action at the cocaine receptor; however, the affinity of PCP at the cocaine site (Ki = 1.59 microM) is less than its affinity at its own receptor (Ki about 0.12 microM). More data will be needed to conclusively implicate the cocaine receptor in the action of PCP.

Structure-activity relationships of the cycloalkyl ring of phencyclidine.

In order to investigate the structural requirements for a cycloalkyl moiety in the potent hallucinogen 1-(1-phenylcyclohexyl)piperidine (PCP, 1), a series of structural analogues was synthesized in which the size of the cycloalkyl ring was varied from three carbons to eight carbons. Biological activities of these compounds were assessed in an in vitro assay (phencyclidine binding assay) and an in vivo assay (discriminative stimulus assay). As the cycloalkyl ring size decreased from that of cyclohexane (PCP), PCP-like activity declined in both assays, but as the cycloalkyl ring size became larger than cyclohexane, a sharp decline in PCP-like activity was observed in the in vivo assay, while activity in the in vitro assay was only slightly less than that of PCP. 1-(1-Phenylcyclooctyl)piperidine (8) had potent competitive binding properties in the in vitro binding assay but produced no observable PCP-like effects in the in vivo assay. The importance of the cycloalkyl ring in the structure of PCP was demonstrated by testing benzylpiperidine (2), which had almost no measurable activity in either assay.

Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxy metabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol.

One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.

Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys.

The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered i.v. cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it.

Saliva testing for drugs of abuse.

Saliva testing for drugs of abuse can provide both qualitative and quantitative information on the drug status of an individual undergoing testing. Self-administration by the oral, intranasal, and smoking routes often produces "shallow depots" of drug that contaminate the oral cavity. This depot produces elevated drug concentrations that can be detected for several hours. Thereafter, saliva drug concentrations generally reflect the free fraction of drug in blood. Also, many drugs are weak bases and saliva concentrations may be highly dependent upon pH conditions. These factors lead to highly variable S/P ratios for many of the drugs of abuse. Table 3 provides a compilation of experimental and theoretical S/P (total) ratios determined for drugs of abuse. Estimations of the theoretical S/P (total) ratios for acidic and basic drugs were based on the Henderson-Hasselbalch equation. Saliva pH was assumed to be 6.8 unless reported otherwise by the investigators. Generally, there was a high correlation of saliva drug concentrations with plasma, especially when oral contamination was eliminated. Assay methodology varied considerably, indicating that saliva assays could be readily developed from existing methodology. There are many potential applications for saliva testing for drugs of abuse. Table 4 lists several general areas in which information from saliva testing would be useful. Clearly, saliva drug tests can reveal the presence of a pharmacologically active drug in an individual at the time of testing. Significant correlations have been found between saliva concentrations of drugs of abuse and behavioral and physiological effects. Results indicate that saliva testing can provide valuable information in diagnostics, treatment, and forensic investigations of individuals suspected of drug abuse. It is expected that saliva testing for drugs of abuse will develop over the next decade into a mature science with substantial new applications.

Assessment of cocaine use with quantitative urinalysis and estimation of new uses.

Qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use, possibly decreasing the ability of clinical trials to detect effective treatments. Quantitative urinalysis and newly developed criteria for identifying new cocaine use were evaluated as alternative measures of cocaine use. Urine specimens collected in a cocaine dosing study in non-treatment-seeking subjects (n = 5) and a cocaine treatment trial (n = 37) were analyzed for the cocaine metabolite, benzoylecgonine, with qualitative and quantitative methods. Pharmacokinetic criteria ('New Use' rules) were applied to quantitative data to identify occasions of new cocaine use. Results were compared to known cocaine administrations in the laboratory study and to self-reported drug use and qualitative urinalysis for subjects in the clinical trial. New Use criteria correctly identified cocaine administrations in the cocaine dosing study in all but a small number of specimens. In the clinical trial, quantitative urinalysis and estimated New Uses provided more information about patterns and frequency of use than qualitative urinalysis in the different treatment conditions in the clinical trial. Interpretation of quantitative urinalysis with New Use rules appears to be a useful method for monitoring treatment outcome and may be more accurate than traditional qualitative urinalysis in estimating frequency of cocaine use.

Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine.

AIMS: Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and withdrawal. DESIGN: Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52. SETTING: Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD. PARTICIPANTS: Eleven male, heroin-dependent volunteers participating in a research study. INTERVENTION: Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). MEASUREMENTS: Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. FINDINGS: The mean steady-state buprenorphine plasma concentration (24 hours) after daily administrations of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively. CONCLUSIONS: during daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.

Cocaine use early in treatment predicts outcome in a behavioral treatment program.

In this evaluation of baseline drug use as a predictor of treatment outcome, cocaine use during a 5-week baseline was compared in methadone maintenance patients who had < 5 (n = 10) versus > or = 5 (n = 9) weeks of abstinence during an experimental cocaine abstinence reinforcement treatment. Cocaine use was evaluated at the 1st and last visit and the 1st and last week of baseline and as a mean across the 5-week baseline treatment; response was calculated as a mean across 12 weeks of experimental treatment. Those who had successful outcomes (abstainers) used significantly less cocaine in the 5-week baseline than those with less successful outcomes (nonabstainers). Differences in cocaine use were not evident in the 1st baseline visit or week, but the abstainers used significantly less cocaine in the last visit and week of baseline compared with the nonabstainers. Cocaine use during baseline provided critical predictors of response to the experimental treatment.

Intravenous self-administration of fencamfamine and cocaine by beagle dogs under fixed-ratio and progressive-ratio schedules of reinforcement.

Catheterized beagle dogs were given access to response-contingent intravenous injections of fencamfamine (FEN) or cocaine (COC) injections under a fixed-ratio (FR) schedule of reinforcement. Both drugs maintained self-administration behavior considerably above saline levels; there was an inverted U-shaped relationship between the number of injections per daily session and the dose per injection. Presession treatment with the dopaminergic antagonist pimozide (PIM) appreciably altered both the FEN and COC dose-effect curves, suggesting a dopaminergic component in the reinforcing properties of these substances. When tested under a progressive-ratio (PR) schedule, both FEN and COC maintained nearly identical FR-values which were considerably above those seen for saline. It appears from these data that FEN may have a cocaine-like abuse potential.

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single 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). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.