Biomedical subjects

K L Preston

Publications and source records attributed to K L Preston.

At least 73 records · Page 4Linked to original sources

PubMed1992

Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers.

Buprenorphine is an opioid agonist-antagonist being evaluated for treatment of opioid dependence. This study characterized the effects of buprenorphine in comparison to naloxone, hydromorphone and saline, in methadone-dependent volunteers. In a residential laboratory, 6 volunteer male opioid abusers maintained on 30 mg of methadone daily underwent pharmacological challenges 2 to 3 times per week. Pharmacological challenges consisted of a double-blind i.m. injection of: buprenorphine (dose range 0.5-8.0 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg) or saline. Injections were given 20 hr after the last dose of methadone. Measures included physiologic indices, and self-report and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively, on subjective, observer and physiologic indices. None of the doses of buprenorphine were consistently or systematically identified as an opioid agonist or antagonist on any of the measures. Thus buprenorphine produced minimal effects in methadone-dependent patients. The lack of agonist effects suggests buprenorphine has a low abuse potential in methadone-dependent patients. The lack of antagonist effects suggests buprenorphine can be administered safely to subjects dependent on a low dose of methadone. This lack of effect of buprenorphine distinguishes it from other mixed agonist antagonists previously tested, which produced antagonist effects in this procedure.

Adult↗

PubMed1992

Assessment of buprenorphine in a drug discrimination procedure in humans.

These studies indicate that buprenorphine shares stimulus effects with other opioid drugs and that in overall profile of effects buprenorphine is more similar to hydromorphone than are the other opioid mixed agonist-antagonists tested-pentazocine, butorphanol, and nalbuphine. This characterization is supported by the behavioral drug discrimination results and by the subjective effect self-report results. In the drug discrimination assessments buprenorphine showed a pattern of generalization that was different from that of the other opioid-mixed agonist-antagonists. It did not generalize completely to either pentazocine or butorphanol, but it did generalize to hydromorphone in two studies and partially in a third. Both nalbuphine and pentazocine showed at least partial generalization to butorphanol, but buprenorphine did not. Butorphanol showed little generalization to hydromorphone except in the two-choice hydromorphone vs. saline discrimination in which all the tested mixed agonist-antagonists generalized to hydromorphone. The subjective effect self-report data also revealed a pattern of response to buprenorphine that was different from that to the other mixed agonist-antagonists. In particular, buprenorphine's profile of acute subjective effects was similar to that of hydromorphone. There were dose-related increases on various scales reflecting positive subjective effects, with little evidence of the dysphoric effects that are characteristic of high doses of the other mixed agonist-antagonists. These data are compatible with the view that buprenorphine is a partial agonist at the mu-receptor. Although they do not demonstrate the ceiling on magnitude of pharmacological effects that would be characteristic of a partial agonist, they do demonstrate that buprenorphine's profile of activity--both stimulus effects and subjective effects--is similar to that of the pure mu-agonist hydromorphone.

Buprenorphine↗

PubMed1992

Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability.

The effects of orally administered placebo, diphenhydramine, lorazepam, methocarbamol and placebo were studied in volunteers with histories of recreational substance abuse including sedative/hypnotics. Placebo, diphenhydramine (100, 200 and 400 mg), lorazepam (1 and 4 mg) and methocarbamol (2.25 and 9 g) were tested in a randomized, double-blind crossover study using 14 subjects. Psychomotor and cognitive performance and subject- and observer-rated responses were measured daily before and for 5.5 hr after drug administration. The results showed that each of the drugs exhibited a different profile of effects on the test battery. Lorazepam produced significant increases in subjects' ratings of drug effect and liking, increases in measures of sedation and impairment of psychomotor performance. Methocarbamol also produced significant increases in subjects' ratings of drug effect and liking and measures of sedation, but it produced only minor impairment of psychomotor and cognitive performance. Diphenhydramine increased subjects' and observers' ratings of drug effect and measures of sedation, but it produced less psychomotor performance impairment and liking than lorazepam. Diphenhydramine produced the most side effects. The present study clearly differentiated the behavioral and subjective profiles of diphenhydramine, lorazepam and methocarbamol. Consistent with its recognized low abuse liability, diphenhydramine produced fewer increases in measures of positive mood and more adverse effects. The considerable overlap in subjective effect measures of positive mood make further differentiation with respect to abuse liability difficult.

Adult↗

PubMed1992

Effects of cocaine alone and in combination with bromocriptine in human cocaine abusers.

This study was conducted to determine whether the acute administration of bromocriptine, a dopamine agonist, modulates the acute pharmacologic effects of i.v. cocaine in humans. Eight current users of i.v. cocaine who were not seeking treatment for their cocaine abuse completed the study while they were inpatients on a research unit. Twelve drug conditions were tested in all subjects in randomized order under double-blind, double-dummy conditions and included cocaine (0, 12.5, 25 and 50 mg, i.v.) in combination with bromocriptine (0, 1.2 and 2.5 mg given orally 2 hr before the cocaine injection). Physiologic and subject- and observer-rated responses were measured. Cocaine alone significantly increased pupil diameter, heart rate and blood pressure, and ratings of drug effect, good effects, liking and rush. Bromocriptine alone significantly increased pupil diameter and heart rate, decreased blood pressure and had only minor effects on subjective measures. There were significant cocaine/bromocriptine interactions on diastolic and mean arterial blood pressure, with combinations producing significantly smaller increases compared to cocaine alone, and on heart rate, with combinations producing significantly larger increases compared to cocaine alone. The physiologic and subjective effects of cocaine were not modified by pretreatment with bromocriptine in any other way that might indicate either a therapeutic benefit or a safety concern. However, bromocriptine alone produced undesirable effects (fainting) that should be considered before administration to outpatient cocaine abusers. Any possible therapeutic benefits of acute administration of bromocriptine in cocaine abuse are not likely to be due directly to modulation of the acute effects of cocaine.

Adult↗

PubMed1991

Infant eye movements: quantification of the vestibulo-ocular reflex and visual-vestibular interactions.

The gain of the infant vestibulo-ocular reflex (VOR) was determined when infants were rotated either in total darkness or while they viewed visual targets consisting of a stationary spot or a full field of black and white stripes. The average VOR gain in the dark was 1.03 +/- 0.014 for 1-4-month-old infants and 0.59 +/- 0.03 for adult subjects tested with appropriate controls for psychological "set". Longitudinal studies showed no significant change in gain over the first 4 months of life. Although the presence of the spot or full-field striped background increased adult compensatory gains from 0.59 to 1.0, the same visual targets had no effect on infant gains. Thus, an infant's VOR gain of nearly 1.0 apparently reduces reliance on the poorly developed smooth pursuit and optokinetic systems that, in adults, help the VOR provide perfect ocular stabilization.

Adult↗

PubMed1991

Evaluation of the abuse potential of the novel analgesic flupirtine maleate.

To evaluate the psychopharmacological effects and potential abuse liability of the novel analgesic flupirtine maleate the subjective and behavioral effects of orally administered flupirtine, lorazepam and placebo were studied in polydrug abusers. Effects were measured before and for 6 h after drug administration under double-blind conditions. At therapeutic doses flupirtine was not differentiated from placebo. Lorazepam and higher doses of flupirtine produced increases in subject-rated liking, ARCI MBG scale scores, and sedative-like effects including impaired psychomotor performance. Flupirtine, but not lorazepam, increased ratings on measures indicating dysphoric effects. The results indicate that flupirtine has some sedative-like effects but that its abuse potential is probably modest.

Adult↗

PubMed1991

Abuse liability studies of opioid agonist-antagonists in humans.

Prediction of the abuse liability of a drug before it reaches the market is complicated by the fact that there are many factors that influence the actual abuse of a drug. Laboratory methods used in humans to assess the abuse liability of the opioids are reviewed and illustrative studies of morphine and the agonist-antagonist opioids, pentazocine, butorphanol, nalbuphine and buprenorphine, are presented. Three assessment methods, subjective effect measurement, self-administration and drug discrimination, provide information relevant to measuring reinforcing efficacy, a major determinant of the degree to which a drug is sought and self-administered by abusers. Physical dependence capacity, which can contribute to sustained drug use, is evaluated in direct addiction and substitution/suppression studies. Withdrawal precipitation studies measure antagonist activity which might limit abuse. The results of testing the agonist-antagonist opioids are generally consistent across these various methods and consistent with historical experience with these drugs, suggesting that these methods are useful in predicting abuse liability of novel opioids.

Arousal↗

PubMed1991

Abuse potential and pharmacological comparison of tramadol and morphine.

The purpose of the study was to assess the abuse potential of the opioid analgesic tramadol. Tramadol (75, 150 and 300 mg), morphine (15 and 30 mg) and placebo were tested intramuscularly in volunteer non-dependent opiate abusers. Subjective, behavioral and miotic changes were assessed prior to dosing and intermittently for 12 h after drug administration. Morphine produced typical subjective effects, opiate identifications and miosis. Tramadol 75 and 150 mg were not different from placebo. Although tramadol 300 mg was identified as an opiate, it produced no other morphine-like effects. These findings suggest that tramadol has a low abuse potential by the parenteral route.

Adult↗

PubMed1991

Drug discrimination methods in human drug abuse liability evaluation.

The drug discrimination paradigm, which is sometimes considered to provide an animal model of human subjective effects, has been adapted for use with human subjects. This procedure provides a direct measure of stimulus similarity between the test drug and a known standard drug, information that may be of value in predicting abuse liability of novel compounds. The present paper reviews the general methods used in human drug discrimination studies, some of the drugs that have been tested, factors to consider in designing drug discrimination studies in humans, and evidence concerning the utility of the procedure in abuse liability assessment. Further research is needed to validate this procedure and to determine the conditions under which it has the greatest value in abuse liability assessment.

Discrimination Learning↗

PubMed1991

Drug abstinence effects: opioids.

The capacity to produce physical dependence is an important factor in the abuse liability of the opioids, contributing both to their reinforcing efficacy and to the negative public health consequences of abuse. Validated methods for measuring the physical dependence capacity of opioids in humans are the Direct Addiction and Substitution/Suppression tests; however, both methods require that subjects be made physically dependent on morphine or on high doses of investigational drugs. New methods need to be developed. Possibilities include assessment of acute physical dependence and the modification of existing substitution test methods for use with subjects already dependent on therapeutic agents.

Dose-Response Relationship, Drug↗

PubMed1991

The reinforcing and subjective effects of morphine in post-addicts: a dose-response study.

The reinforcing and subjective effects of morphine were determined in five human volunteers with histories of i.v. heroin abuse. Subjects responded under a second-order schedule of i.m. injection. Under this schedule, every 100 lever presses produced a brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion of the FR 100 requirement turned on the light for 15 min and the subject received an i.m. injection of morphine [FR 30 (FR 100:s)]. Once each weekday morphine or placebo was available under this schedule. Each drug dose was available for 1 week. Under these conditions placebo did not maintain responding; 3.75 mg of morphine maintained responding in four of five subjects, and higher morphine doses (7.5, 15 and 30 mg) maintained responding in all five subjects. Subjective effects were measured concurrently: these included measures of drug liking, the Morphine Benzedrine Group scale of the Addiction Research Center Inventory, drug detection and identification. Subjects did not report subjective effects different from placebo for the lowest dose of morphine; the intermediate doses of morphine produced inconsistent effects, and the highest dose of morphine occasioned reports of drug liking and "dope" identifications. These results indicate that there can be a significant dissociation of the reinforcing and the subjective effects of opioids, which has implications for theories of opioid abuse, particularly those assuming that the reinforcing effects are causally related to the euphoric effects of opioids. Furthermore, these results confirm that measures of reinforcing effects and measures of subjective effects do not necessarily lead to identical predictions when used to assess the liability for abuse of a substance.

Analgesia, Patient-Controlled↗

PubMed1990

Obtaining a quantitative measure of eye movements in human infants: a method of calibrating the electrooculogram.

We have developed a calibration procedure that combines the measurement of the EOG voltage with the concurrent assessment of the actual direction of gaze as revealed by the corneal reflection of a target light. Using this method, we have been able to calibrate the eye-position signal recorded from 2- and 3-month-old infants. Our results show that in young infants (1) the EOG is linearly related to eye position to at least +/- 20 deg; (2) the slopes of the calibration lines measured early and late in the same test session were not significantly different at the 0.1 level; (3) at the most eccentric eye position, the calibration was accurate to within +/- 1 deg; and (4) an abbreviated calibration at 0 and +/- 15 deg, which took less than 2 min, produced essentially the same slope (t-test not significant at the 0.1 level) as a longer procedure that tested at every 5 deg between +20 and -20 deg.

Adult↗

PubMed1990

Discrimination of butorphanol and nalbuphine in opioid-dependent humans.

The purpose of the study was to evaluate the agonist and antagonist stimulus properties of the mixed opioid agonist antagonists butorphanol and nalbuphine in opioid-dependent subjects. Opioid-dependent volunteers (methadone 30 mg/day, PO) were trained in a three-choice drug discrimination procedure to discriminate between the effects of saline (2 ml), hydromorphone (10 mg/70 kg) and naloxone (0.15 mg/70 kg) administered IM. Subjects earned monetary reinforcement for correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were also collected. Hydromorphone and naloxone increased drug-appropriate responses and other characteristic subjective effects measures. Butorphanol and nalbuphine produced increases in naloxone-appropriate discrimination responding and in those subjective effect measures increased by naloxone. Butorphanol produced greater than 80% naloxone-appropriate responding at 1.05 mg/70 kg; nalbuphine produced 100% naloxone-appropriate responding at 2.1 mg/70 kg. Neither butorphanol nor nalbuphine showed opioid agonist-like effects in these subjects maintained at moderate levels of physical dependence. In opioid-dependent subjects, the stimulus effects of butorphanol and nalbuphine are antagonist-like.

Adult↗

PubMed1990

Effects of sublingually given naloxone in opioid-dependent human volunteers.

To determine whether sublingual naloxone could precipitate withdrawal in opioid-dependent subjects, naloxone was administered in increasing doses (0-8 mg in four or six sessions conducted over 2 days) to six heroin abusers and three methadone (30 mg/day, p.o.) maintenance patients. Two or three sessions were conducted per day with 2- to 2.5-h intervals between same-day sessions. Naloxone precipitated withdrawal in two of six heroin abusers and in all three methadone subjects. Naloxone is sufficiently absorbed sublingually to precipitate abstinence in dependent subjects, but naloxone doses up to 1-2 mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal.

Administration, Sublingual↗

PubMed1990