Howard L. Kaplan

Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectiveness of supportive care.

The relative roles of supportive care and pharmacotherapy in the treatment of alcohol withdrawal are not established. A reliable and validated withdrawal severity assessment scale (Clinical Institute Withdrawal Assessment for Alcohol, CIWA-A) was developed to assess initially and then follow the clinical course of 38 hospitalized chronic alcoholics requiring hospitalization for withdrawal but without serious concurrent medical or surgical problems. Supportive care, consisting of standardized half-hourly patient assessment (CIWA-A) and nursing care, was used as the initial treatment for all patients. Twenty-eight (74%) patients with clinical supportive care successes within 8 hours, 75% within 4 hours. Two responding patients subsequently developed evidence of withdrawal at 48 hours (hallucinations) and 72 hours (seizure). Ten patients (26%) did not respond to supportive care and required drug therapy in addition. Responders to supportive care drink more by history and have less severe liver disease than nonresponders. There are no other apparent predictors of the patients who require drug therapy. Three quarters of hospitalized patients, without serious medical complications, in alcohol withdrawal respond to intensive supportive care. However, pharmacotherapy is essential for nonresponders and patients with hallucinations.

CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone

The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodones active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6‐B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O‐demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O‐demethylation in the three groups were 28.1 ± 10.3, 3.4 ± 2.4, and 5.0 ± 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more “good opiate effects” and fewer “bad opiate effects” than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.

Tables of d′ for variable-standard discrimination paradigms

Signal detection theory (SDT) allows a bias-free measure of sensitivity, d′, to be simply estimated from discrimination data when certain conditions are met. The computation is not straightforward, however, in several popular discrimination designs, such as two- and four-interval same-different designs and the ABX design. The present tables, derived from the SDT models of Macmillan, Kaplan, and Creelman (1977), make possible the estimation of d’ from these complex discrimination designs.

Effective random seeding of random number generators

To obtain different sequences of values from a random number generating algorithm, we must start with different seed values or discard a variable number of initial samples. For maximum independence among sequences, differences must include the lowest order seed bits, and some generators require one to wait many samples for differences to propagate to the significant bits. While it is straightforward to generate two statistically independent sequences, it is surprisingly difficult to generate three or more such sequences.

Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans

To assess the pharmacologie effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short‐term effects of diazepam and alprazolam over a range of doses.

Chlordiazepoxide and oxazepam disposition in cirrhosis

When disease impairs clearance of drugs, multiple‐dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy‐proven cirrhosis. In the normal subjects, mean (±SE) kinetic parameters were: t½β, 10.0 (±0.9) hr; Vd, 0.38 (±0.04) 1/kg; clearance, 0.54 (±0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = −0.63). Values in cirrhotic patients were: t½β, 34.9 (±8.7) hr; Vd, 0.34 (±0.024) 1/kg; and clearance, 0.185 (±0.034) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean tVifîfor oxazepam (7.1 ± 1.0 hr) was 27% longer than in control subjects (5.6 ± 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.

Comparative abuse liability of sertraline, alprazolam, and dextroamphetamine in humans

Sertraline is an effective antidepressant acting as a selective serotonin reuptake inhibitor. The subjective and behavioral effects of sertraline were studied and compared with the effects of alprazolam and dextroamphetamine in a within-subject, randomized, double-blind study in 20 volunteers aged 18 to 46 years. These subjects were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish secobarbital, 150 mg, from placebo and to report positive subjective effects of secobarbital in an experimental setting. The following drug conditions were tested: sertraline, 100 and 200 mg; alprazolam, 1 mg; dextroamphetamine, 10 mg; and placebo. Drug effects were assessed with an objective test of psychomotor performance, subject-rated questionnaires, and observer-rated scales. Both alprazolam and dextroamphetamine were distinguishable from placebo on most measures, but sertraline produced effects discernable from placebo on only a few measures. At 1 hour postdrug administration, dextroamphetamine and alprazolam produced positive effects on several measures of elation, euphoria, and drug liking greater than placebo and both doses of sertraline. In contrast, sertraline produced higher scores on measures of dysphoria and physical unpleasantness than did the other drug conditions. Observer ratings of satisfaction with the drug and other pharmacologic effects were consistent with these findings. Results from this study indicate that sertraline, at the doses tested, does not possess the behavioral effects profile considered to be indicative of abuse potential when compared with alprazolam and dextroamphetamine.

Diazepam tapering in detoxification for high‐dose benzodiazepine abuse

The clinical characteristics and management of patients who abuse high doses of benzodiazepines are not well described. In a prospective open study, 23 subjects who abused high doses of benzodiazepines were admitted for detoxification. Urine or blood test results confirmed benzodiazepine use in all but one subject and multiple drug use in eight (35%). Median benzodiazepine dose was 150 mg (range 40 to 500 mg) of diazepam equivalent. Initial plasma concentrations (diazepam: median = 1245 ng/ml; desmethyldiazepam: median = 2961 ng/ml) were 400% to 800% higher than usual therapeutic concentrations. For detoxification, subjects were given a loading dose of diazepam equal to approximately 40% their reported daily consumption. This was followed with daily tapering of diazepam by 10%. This regimen resulted in a slow and gradual decline in drug concentrations. Withdrawal symptoms were assessed daily. Sixteen subjects completed detoxification in the hospital without complications. One subject became paranoid and confused on day 7 of withdrawal. This was attributed to a too‐low initial loading dose and too‐rapid tapering, which resulted in rapid drug elimination. Gradual reduction of diazepam dose appears to be an effective and safe approach for detoxifying abusers of high doses of benzodiazepines.

Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism : A pilot study

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.

Evaluation of Zopiclone Physical Dependence Liability in Normal Volunteers

The potential of zopiclone, a non-benzodiazepine sedative hypnotic, to induce physical dependence in normal human volunteers was investigated. 9 male subjects (age range 21-39 years) participated in a 56-day double-blind study with random assignment to initial treatment A or B: (A) zopiclone 7.5 mg p.o. nightly for 21 days followed by placebo for 7 days, and (B) placebo nightly for 21 days followed by placebo for 7 days. Heart rate, blood pressure, hand tremor and auditory-evoked EEG were repeatedly measured during the withdrawal periods. No differences in any of these variables between phases were found (beta = 0.90 for mean differences of 16% between phases). Subjects slept longer (mean 28 min, p less than 0.013) on zopiclone than on placebo. Symptoms of state anxiety were greater on days 2 and 4 after discontinuing zopiclone compared to all other withdrawal days (p less than 0.0021). The mean relative increase on days 2 and 4 was 30%. Sleep depth (self-rating scale) was no deeper on drug than on placebo, but during the withdrawal phases, sleep was less deep on days 2 and 4 of withdrawal from zopiclone compared to all other withdrawal days (p less than 0.0001). Subjects were unable to identify the pattern of drug administration on withdrawal, and none reported important symptoms. Discontinuation of zopiclone (7.5 mg for 21 days) is associated with detectable increase in state anxiety and lighter sleep on days 2 and 4 of withdrawal. Quantitatively, similar changes occur with other hypnotic drugs of relatively low dependence liability.