Absence of cross-tolerance to heroin in morphine-tolerant mice.

Mice implanted with morphine pellets demonstrated a 30-fold increase in tolerance to subcutaneously administered morphine but showed no cross-tolerance to subcutaneously administered heroin. When given morphine intracerebroventricularly, the mice showed no tolerance to morphine or cross-tolerance to heroin. These observations depended on the presence of the morphine pellet. If the pellets were removed prior to determinations of potency, the expected responses--tolerance to morphine and cross-tolerance to heroin--were obtained. The blood-brain barrier may be a prime site for the expression of morphine tolerance in mice.

Doxpicomine in postoperative pain.

In a single-dose study the analgesic activity of 400 mg doxpicomine was compared with 4 and 8 mg morphine administered intramuscularly. Our subjects wee 43 men with moderate or severe postsurgical pain on the first postoperative day. Results of a double-blind trial indicate the analgesic activity of 400 mg intramuscular doxpicomine to be within the range of 8 mg morphine. There was no statistical significance between the effects of 400 mg doxpicomine and 8 mg morphine with the exception of half-hour data where doxpicomine was more effective than morphine. Doxpicomine has a rapid onset of analgesic action, the duration of which is equivalent to that of 8 mg morphine.

Hypnotic efficacy of lorazepam and flurazepam.

In a double-blind crossover study involving 15 insomniac subjects, the hypnotic efficacy of lorazepam, 2 and 4 mg, was compared with flurazepam, 15 and 30 mg, and placebo. Five subjective measures were used: onset, length, and depth of sleep, number of times awakened, and satisfaction with the hypnotic. Lorazepam in 2- and 4-mg doses was comparable in hypnotic efficacy to flurazepam, 30 mg, according to most parameters of measurement. Side effects were minor, although relatively numerous at the 4-mg doses.

Disulfiram and erythrocyte aldehyde dehydrogenase inhibition.

During disulfiram therapy erythrocyte aldehyde dehydrogenase (ALDH) was fully inhibited. The time for total loss of erythrocyte ALDH activity ranged from 36 to 120 hr. In contrast to the 85% recovery of in vitro disulfiram-inhibited ALDH activity, this in vivo disulfiram-ALDH inhibition could not be reversed by mercaptoethanol. It is proposed that the in vivo and in vitro mechanisms of ALDH inhibition by disulfiram differ. Erythrocyte ALDH activity can be readily monitored to determine patient compliance and is an accessible model for investigations of in vivo mechanisms of drug inhibition. Because the disulfiram-inhibited erythrocyte ALDH is not regenerated until new erythrocytes are made (120 days), a significant portion of the extrahepatic acetaldehyde metabolic capacity remains inhibited for long periods after disulfiram is discontinued. Thus, the recidivistic patient who discontinues disulfiram and waits several days (to regenerate liver ALDH activity) before drinking will be exposed to even higher ethanol-derived blood acetaldehyde levels than usual, which may induce further alcohol-associated organ damage and alcohol dependence.

Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome.

A methadone maintenance patient with a decreased plasma methadone level, possibly due to phenobarbital-induced acceleration of methadone biotransformation, experienced opioid withdrawal symptoms. This finding suggests that when phenobarbital is used with methadone the plasma methadone level must be monitored.

Hydrogen peroxide-induced glutathione depletion and aldehyde dehydrogenase inhibition in erythrocytes.

To study relationships between lipid peroxidation and aldehyde dehydrogenase (ALDH) inhibition, the Stocks and Dormandy model of H2O2-induced lipid peroxidation in erythrocytes was employed. Hydrogen peroxide treatment of erythrocytes and erythrocyte lysates caused a dose-dependent inhibition and depletion of ALDH and reduced glutathione (GSH) respectively. Complete ALDH inhibition and glutathione depletion occurred before significant lipid peroxidation was detected by HPLC analysis of malondialdehyde-thiobarbituric acid adducts. Hydroxyl radical scavengers did not antagonize the hydrogen peroxide-induced enzyme inhibition. Studies with the iron chelator desferrioxamine suggested that the hydrogen peroxide-induced ALDH inhibition was mediated by iron in erythrocyte lysates but not in semi-purified (and Chelex-treated) ALDH preparations. Glutathione peroxidase reduction of H2O2 exhibited an anomalous GSH dependence which was not in agreement with the accepted reaction mechanism. Reduced glutathione also antagonized the hydrogen peroxide-induced ALDH inhibition by possible complex formation with the enzyme. A hypothetical model is presented which accounts for the observed responses to hydrogen peroxide.

Reserpine and alpha-methyldopa in the treatment of tardive dyskinesia.

Thirty inpatients with evidence of tardive dyskinesia secondary to antipsychotic medications participated in this double-blind, controlled, randomized study comparing reserpine, alpha-methyldopa and placebo. Reserpine at doses of 0.75--1.5 mg daily, or alpha-methyldopa at doses of 750--1,500 mg daily, produced a statistically significant improvement in tardive dyskinesia symptomatology compared to the results obtained with placebo.

Propoxyphene napsylate compared to methadone for opiate dependence.

When high single doses of propoxyphene napsylate (PN) were given to patients on a methadone maintenance program, results indicated that, to avoid undesirable side effects, the dose should not exceed 600 mg. However, when PN was given in divided doses (800 mg/day in two equal doses), no significant adverse reactions were noted. In the double-blind comparison of 800 mg PN in two divided doses versus 20 mg methadone, 10 mg methadone, or placebo methadone, it was found that PN (1) did not alleviate withdrawal symptoms in patients previously maintained on 20 mg methadone, (2) produced a slightly overmedicated effect in the detoxified group of ex-methadone patients, and (3) compared favorably to 10 mg methadone in suppressing withdrawal symptoms without producing evidence of overmedication in those patients previously stabilized on a methadone maintenance dose of 10 mg. It is concluded that on a mg for mg basis, PN at a dose of 80-times that of methadone will relieve withdrawal symptoms in the treatment of mildly addicted patients requiring 10 mg methadone or less per day.

Value of chemical mixture in multiple supralethal X-irradiation of mice.

A chemical mixture containing 25 Amoles of MEA, 7 pmoles of AET, and 2 micromoles of 5-HT was found to be of significant value in protecting mice against repeated exposures of 800 R, 1100 R, or 1400 R given at intervals of 28 days. Dose-reduction factors of 2.17, 2.18, 1.95, 2.14, and 1.58 were obtained for the first five exposures. Following the first exposure there was no chemical mortality. The beneficial value of this mixture, however, was limited by the incidence of chemical toxicity which was more prevalent in mice with higher cumulative doses of radiation.

Further efficacy evaluation of doxpicomine for postoperative pain.

In this single-dose, double-blind study, the analgesic activity of 400 and 200 mg doxpicomine was compared with 100 and 50 mg meperidine and placebo when given intramuscularly in 102 subject patients experiencing severe postoperative pain. Results indicate that 400 mg doxicomine is similar to 100 mg meperidine in analgesic activity, onset, and duration of action. Side effects were of the same order as those produced by other centrally acting analgesics.

The clinical analgesic efficacy of oral nefopam hydrochloride.

The analgesic efficacy of 60 and 120 mg nefopam hydrochloride was compared to 650 mg aspirin and placebo in a double-blind single-dose study. Oral doses were administered to 120 patients suffering from acute postsurgical or fracture pain. All active medications demonstrated analgesic activity in comparison to placebo. Patients on 120 mg nefopam obtained the greatest degree of analgesia. Side effects were minor and did not interfere with the course of therapy. The incidence of side effects (sweating, nausea, and lightheadedness) was greater on 120 mg nefopam than on 650 mg aspirin).

Crossover and parallel study of oral analgesics.

Ten years ago, analgesics were studied using crossover designs. In recent years, analgesics have been studied only in parallel designs primarily because biostatisticians do not like crossover studies. The advantages of crossover studies are numerous: (1) patients serve as their own control; (2) there is less variability of responses among patients; and (3) a smaller number of patients is needed to provide statistically significant data. As long as crossover of treatment medications does not occur within 4 to 6 hours, the problem of carryover effect of the previous medication is insignificant or negligible. Two studies will be presented. One is a crossover study of Percodan with and without naloxone to placebo. The other is a parallel study comparing the effects of propoxyphene with naloxone to those of propoxyphene alone. The results of these studies reaffirm the value of the crossover method of evaluating analgesics.

A subjective and objective method assessing the efficacy of hypnotic medications in insomniacs.

The response of chronic insomniacs to 100 mg pentobarbital, 300 mg methyprylon, 500 mg glutethimide, and placebo was assessed using our previously described subjective and objective techniques. The purpose of the study was to examine (1) the presence or absence of the subjects' reported insomnia; (2) the subjects' ability to discriminate between active hypnotic drugs and placebo; and (3) whether any preference existed among active medications. Statistically significant findings included a high degree of correlation (P less than 0.001) between subjective and objective data and greater response to active medications as compared to placebo shown on all parameters except objective onset of sleep. In no case was there significant difference between the two nights of placebo. Although methyprylon was most frequently superior to placebo, there was no significant patient preference for any of the active medications.

A brief self-assessing depression scale.

The Wang-Self-Assessing Depression Scale (SADS) was devised to provide a brief self-rating form for measuring depressive symptomatology. The present study compares the SADS with the Zung Self-Rating Depression Scale (SDS) to assess reliability and relative ease of completion. Ninety-three ratings on each scale were obtained from a subject group that included normal volunteers and patients with differing degrees of depression. The paired t-test showed no significant difference between mean SDS scores and mean SADS scores for normal volunteers or subjects rated at any of the four depression levels. Positive correlation was demonstrated between tsds scores and SADS scores for depressed and normal subjects. The period of time required to complete the Wang SADS was found to be significantly shorter than for the Zung SDS, while the number of errors and requests for additional assistance were significantly lower. It was felt that these differences would constitute an advantage in the clinical use of the Wang SADS for diagnosing, evaluating, and monitoring the progress of depressed inpatients and outpatients.

Study of penfluridol and chlorpromazine in the treatment of chronic schizophrenia.

This study presents data on the use of penfluridol, a once-a-week orally administered, antipsychotic agent, in the treatment of chronic schizophrenic patients. Fifty-nine patients participated in the initial dose titration segment during which doses of penfluridol were adjusted weekly until the patients' condition became stabilized. The starting dose did not exceed 60 mg per week, and the maximum weekly dose did not exceed 140 mg. Forty-one of these patients continued on to participate in a double-blind comparison of penfluridol with chlorpromazine. Maximum doses did not exceed 140 mg per dose per week for penfluridol and 7350 mg per week for chlorpromazine in the double-blind segment. Patients were abruptly switched from their previous neuroleptic medication to penfluridol without loss of control. Side effects, mainly extrapyramidal in nature, were readily alleviated with benztropine mesylate. Penfluridol, administered orally once a week, appeared to be well tolerated; it was comparable to daily chlorpromazine in treating and maintaining schizophrenic patients.

The study of analgesics following single and repeated doses.

The efficacy and safety of 0.3 mg buprenorphine on single and repeated intramuscular administration (every 4 to 8 hours as needed) were compared to those of 10 mg intramuscular morphine. Fifty adult patients experiencing moderate to severe postoperative pain were evaluated up to three days following surgery. Results showed that 0.3 mg buprenorphine was as effective as 10 mg morphine, whether given as a single dose or on a repeat-dose schedule. The patterns of analgesia were similar and without indication of increasing dosage requirements with time. Minor side effects encountered were brief and minimal, including such conditions as drowsiness, dizziness, diaphoresis, flushing, and nausea.

A brief anxiety rating scale in evaluating anxiolytics.

The Wang Anxiety Rating Scale (WARS) was designed to evaluate degrees of anxiety in patients receiving anxiolytic medication. WARS contains 12 pertinent symptoms of anxiety: nervousness, restlessness, excitability, irritability, worrying, disturbed concentration, palpitation, insomnia, hostility, tremors, smoking, and excessive perspiration. Frequently encountered side effects of anxiolytic medications are excluded. The validity of the WARS was determined by correlation with the Hamilton Anxiety Rating Scale (HARS) in a single-blind study in which 20 chronically anxious patients consecutively received placebo (three days), 15 mg clorazepate dipotassium (two weeks), and 22.5 mg clorazepate dipotassium (two weeks). Both anxiety scales, a side effect scale, and a global assessment were completed at regular intervals (periods 0-6). Results show (1) highly significant correlation (P less than 0.001) between WARS and HARS for periods 1-6; (2) greater correlation between HARS and side effect scale than between WARS and side effect scale; (3) greater correlation between WARS and global assessment than between HARS and global assessment; correlated changes in scores for WARS, HARS, and global assessment demonstrate efficacy of active medication.

A method for evaluating anxiolytic sedatives.

Although anxiolytic sedatives are widely used in clinical practice, the methodology for assessing treatment effect of these compounds has not been well developed. The present double-blind study was designed to refine methodology for evaluating anxiolytics. Choice of rating scale, patient selection, maintenance of the double-blind status, the subjects' environment during the study, and the subjects' understanding of the study are discussed as considerations in reducing sources of variability and bias in the study of anxiolytics. After placebo prescreening, 14 subjects with diagnoses of anxiety recieved 3 to 6 mg lorazepam daily for four weeks, while 14 control subjects received placebo. The Hamilton Anxiety Rating Scale (HARS) and the Wang Anxiety Rating Scale (WARS), with its Anxiolytic Adjunct Scale (AAS), were used to assess changes in anxiety. The Wang and Hamilton ratings correlated well at both comparison periods. Lorazepam demonstrated significant superiority to placebo and produced no serious adverse effects. Anxiolytic efficacy did not differ significantly among the four weekly ratings.

The oral analgesic efficacy of bicifadine hydrochloride in postoperative pain.

The analgesic efficacy of 75 and 150 mg bicifadine hydrochloride was compared to 650 mg aspirin and placebo in a double-blind, single-dose study. Oral doses were administered to 100 patients suffering from moderate to severe postoperative pain. Significant analgesic activity was demonstrated with 650 mg aspirin and 150 mg bicifadine as compared to 75 mg bicifadine or placebo. No significant treatment difference was found between 75 mg bicifadine and placebo. Side effects were minor and did not interfere with the course of therapy.

Effects of acute and chronic morphine treatment on methadone analgesia and metabolism.

Morphine sulfate (5 mg/kg s.c.) given 30 min prior to administration of methadone prolonged methadone analgesia and increased the brain level of methadone measured 60, 120 and 180 min after administration of methadone. Rats rendered tolerant to morphine analgesia by subcutaneous implantation of two pellets, each containing 75 mg of morphine base, for 1-3 days showed cross-tolerance to methadone analgesia regardless of the presence or absence of morphine pellets. Decreases in the brain concentrations of methadone measured at 60 and 120 min time points accompanied the decreased analgesia. Neither acute nor chronic morphine pretreatment affects the biotransformation of methadone. The results suggest that the cross-tolerance to methadone analgesia seen in chronic morphine-implanted rats was partly associated with a decrease in the brain concentration of methadone occurring by a mechanism not directly related to a change in the biotransformation of methadone. In view of the known inhibitory effect of chronic morphine pretreatment on drug metabolism, our findings might demonstrate a unique phenomenon between morphine and methadone.