Biomedical subjects

I A Liebson

Publications and source records attributed to I A Liebson.

At least 37 records · Page 2Linked to original sources

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

Acute physical dependence in humans: repeated naloxone-precipitated withdrawal after a single dose of methadone.

This paper reports the intensity and duration of acute physical dependence precipitated by naloxone administration following a single pre-treatment with the opioid against methadone (30 mg/70 kg, i.m.) in six non-dependent human volunteers with histories of prior opioid abuse. In a within-subject cross-over design, challenges of the antagonist naloxone (0.5-1.0 mg, i.m.) were administered at 6, 30 and 54 h, or at only 54 h after methadone pre-treatment. Acute physical dependence, as indicated by physiologic, subjective, and observer rated withdrawal, was seen in all subjects following active naloxone administration, was of nearly uniform intensity for a period of 6-54 h after acute methadone administration, and was not attenuated by prior naloxone administration.

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

Acute opioid physical dependence in humans: effect of naloxone at 6 and 24 hours postmorphine.

Previous studies in our laboratory have documented the occurrence of naloxone-precipitated opioid abstinence from 45 minutes to 6 hours after acute morphine administration in humans. This study extended the morphine-naloxone interval to 24 hours and examined the effect of repeated naloxone challenges on withdrawal responses. Six male nondependent opiate users participated in eight experimental sessions in which they received single IM injections of morphine (18 mg/70 kg) followed 6 and 24 hours later by challenge sessions with IM placebo or naloxone (10 mg/70 kg). Naloxone challenge at 6 hours postmorphine reversed morphine-induced miosis and subjective reports of opiate symptoms, drug high, good drug effects, and drug liking. At 24 hours postmorphine, naloxone had no effect on these measures, which had returned to premorphine levels. However, at 6 and 24 hours postmorphine, naloxone precipitated subjective symptoms and observer-rated signs of opioid abstinence. When naloxone challenge at 24 hours was preceded by naloxone at 6 hours postmorphine, the magnitude of abstinence symptoms and signs was attenuated. These data suggest that morphine-induced adaptational changes underlying the development of physical dependence persist beyond other measureable agonist effects, and that these changes are disrupted or reversed by repeated antagonist administration.

Double-Blind Method↗

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↗

PubMed1989

Reinforcing effects of caffeine in coffee and capsules.

In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.

Adult↗

PubMed1989

Antagonist effects of nalbuphine in opioid-dependent human volunteers.

The subjective, physiological and behavioral effects of nalbuphine, an opioid mixed agonist/antagonist analgesic, naloxone and hydromorphone were studied on adult, male, methadone-dependent volunteers living on a clinical research ward. The purpose was to assess nalbuphine's agonist properties vs. antagonist properties relative to a standard agonist (hydromorphone) and a standard antagonist (naloxone) in opioid-dependent subjects. Drug conditions included saline placebo, nalbuphine hydrochloride (0.375, 0.75, 1.5, 3 and 6 mg), naloxone hydrochloride (0.1 and 0.2 mg) and hydromorphone hydrochloride (4 and 8 mg). Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5 hr experimental sessions. Physiologic measures were monitored continuously before and for 2 hr after drug administration: pupil diameter and subject- and observer-rated behavioral responses were measured intermittently over this same period. Hydromorphone increased ratings significantly on subjective measures typical of morphine-like effects. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Nalbuphine produced effects which were qualitatively similar to the effects of naloxone and showed no evidence of opioid agonist effects in these methadone-dependent subjects. The withdrawal syndrome precipitated by nalbuphine was indistinguishable from that produced by naloxone.

Adult↗

PubMed1989

Drug discrimination in human postaddicts: agonist-antagonist opioids.

To assess the stimulus properties of opioid mixed agonist-antagonist drugs in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. given saline (4 ml), hydromorphone (3 mg/70 kg) and pentazocine (45 mg/70 kg). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were also collected. After training, subjects were tested for their ability to discriminate between the three drugs; generalization curves for the training drugs and three mixed agonist-antagonist test drugs (butorphanol, nalbuphine and buprenorphine) were then determined. In generalization testing both hydromorphone and pentazocine produced dose-related increases in drug-appropriate responses and in characteristic subjective effects measures. Butorphanol produced dose-related increases in identifications as pentazocine and in those subjective effect measures increased by pentazocine. Nalbuphine was not consistently identified as either pentazocine or hydromorphone and produced relatively flat dose-response functions on most of the subjective effect measures. At the three highest doses tested buprenorphine was identified in 50% of trials as hydromorphone and in 50% of trials as pentazocine in the discrimination measures and increased subjective effect scales which were characteristic of both hydromorphone and pentazocine. The results are most consistent with butorphanol having the stimulus properties of a kappa agonist and both nalbuphine and buprenorphine having the stimulus properties of partial mu agonists although the profiles of observed drug effects were complicated and not entirely consistent with a simple mu/kappa opioid receptor model.

Adult↗

PubMed1989

Opioid drug discrimination in humans: stability, specificity and relation to self-reported drug effect.

Non-dependent volunteers with histories of opioid use were trained in a three-choice drug-discrimination procedure to discriminate the effects of i.m. saline, hydromorphone hydrochloride (3 mg/70 kg) and pentazocine lactate (45 mg/70 kg). In daily sessions, monetary reinforcement was contingent upon correctly identifying by letter code, the drug administered; measures of drug discrimination included an operant procedure and a qualitative and a quantitative choice procedure. Drug effects were assessed concurrently on self reports and physiological indices. After acquisition of the discrimination, subjects were tested for generalization to: 1) a range of doses of the training drugs, 2) p.o. doses of the training drugs and 3) novel drugs. The discrimination was readily learned and all three discrimination measures were comparable. Discrimination performance, as well as self reports and physiological effects, remained stable over the course of the study, suggesting that tolerance did not develop in the daily session procedure. Testing with a range of doses of the training drugs resulted in dose-related effects in discrimination performance, physiological effects and self-reported drug effect. Oral doses of the training drugs resulted in partial generalization to the i.m. training doses, compatible with the attenuated subjective effects of the p.o. doses. Novel drugs (d-amphetamine, 10-20 mg p.o.; Lorazepam, 2-4 mg p.o.; and secobarbital, 100-200 mg p.o.) did not generalize to hydromorphone, but showed partial generalization to both pentazocine and saline. In general, drug-discrimination performance paralleled the patterns of self reports.

Adult↗

PubMed1989

Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval. I.

Acute opioid physical dependence refers to the withdrawal symptoms precipitated by an opioid antagonist administered after a single dose or short-term infusion of an opioid agonist. This phenomenon is particularly interesting given that the abstinence syndrome has generally been thought to develop only after chronic exposure to opioid agonists. The purpose of this study was to determine the minimum time after agonist administration when antagonist-precipitated withdrawal could be observed. Naloxone (10 mg/70 kg) was administered i.m. either 0, 15, 45 or 90 min after single i.m. injections of morphine (18 mg/70 kg) in five nondependent male opiate users. Physiological and subjective report measures revealed no effect of morphine or naloxone at the 0 and 15 min morphine-naloxone interval conditions; however, before the naloxone challenge 45 and 90 min post-morphine, agonist effects (e.g., miosis, respiratory depression and good drug effect subjective ratings) were clearly evident. Naloxone reversed these effects to premorphine levels and simultaneously precipitated subjective symptoms and observer rated signs of opiate withdrawal. Thus, this study showed that antagonist-precipitated withdrawal in humans was first observed 45 min after agonist administration. Further, the onset of naloxone-precipitated withdrawal effects closely paralleled the onset of morphine agonist effects. The results of this study suggest that adaptational changes underlying the development of physical dependence begin within minutes after acute exposure to an opiate.

Humans↗

PubMed1989

Acute opioid physical dependence in postaddict humans: naloxone dose effects after brief morphine exposure.

Antagonist-precipitated withdrawal after acute opioid administration (acute physical dependence) is an interesting phenomenon in that the opioid abstinence syndrome is generally thought to develop only after prolonged exposure to opioid agonists. The purpose of this study was to examine further this phenomenon in humans by characterizing the antagonist dose-response function. The effects of i.m. naloxone (0, 0.1, 0.3, 1, 3, 10 and 30 mg/70 kg) were assessed 6 hr after single i.m. injections of morphine (18 or 30 mg/70 kg) in six subjects with a history of chronic opiate use. Naloxone reversed residual morphine effects, including miosis and respiratory depression. The degree of reversal was dose-related to 10 mg/70 kg of naloxone with no further increases at the highest naloxone dose. Simultaneously, observer ratings of withdrawal signs and subjective reports of withdrawal symptoms were increased in an orderly dose-related manner to 30 mg/70 kg of naloxone. Reversal of residual morphine effects and onset of precipitated withdrawal were evident by 5-min postnaloxone; peak effects occurred within 15 min. This study confirmed the occurrence of antagonist-precipitated withdrawal after brief opioid exposure in humans, demonstrated the rapid onset of withdrawal effects and characterized the naloxone dose-response function.

Adult↗

PubMed1988

Buprenorphine and naloxone alone and in combination in opioid-dependent humans.

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.

Adult↗

PubMed1988

Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users.

The subjective, psychomotor and cognitive effects of oral doses of lorazepam (0, 1.5, 3 and 6 mg) and diazepam (0, 10, 20 and 40 mg) were studied under double-blind conditions in 14 volunteers with histories of 'recreational' benzodiazepine use/abuse. For each subject, drug was administered over 4 test days in a 2 (drug) by 4 (dose level) mixed design. Drug was the between-groups factor while dose was the within-subjects factor. Test days were separated by at least 1 week. The results showed that subjective ratings of drug 'liking' and the psychomotor and cognitive effects of lorazepam were generally similar to those of diazepam over the range of doses studied. Lorazepam, however, tended to produce effects of longer duration than diazepam. Since previous studies have shown that diazepam has a relatively high abuse liability among the benzodiazepines, the present findings suggest that lorazepam shares this property with diazepam is subjects with a history of 'recreational' drug use/abuse.

Adult↗

PubMed1988

Contingency management in methadone maintenance: effects of reinforcing and aversive consequences on illicit polydrug use.

Treatment outcomes were compared for an intervention emphasizing reinforcement for abstinence from illicit drug use and an alternative intervention which combined the same reinforcement contingencies with aversive consequences for unauthorized drug use. Sixteen polydrug abusing methadone maintenance patients were randomly assigned to one of two treatment groups. Both groups received the opportunity to take methadone doses away from the clinic (take-home dose) as reinforcement for submitting urines testing negative for illicit substances. A regular weekly take-home dose of methadone could be earned for every 2 weeks of verified abstinence from unauthorized drugs, up to a maximum of three take-home doses per week. The combined intervention group had an additional contingency which involved a reduction in methadone dose as an aversive consequence for submitting urine samples testing positive for illicit substances. Specifically, 10% of the patient's daily methadone dose was lost for each week in which two of three urines tested positive for illicit drugs. An examination of the urinalysis results indicated no between group differences. Overall, 8% of the 12-week baseline urinalysis results tested negative for illicit substances while 42% tested negative for unauthorized substances during the 20 weeks of treatment intervention. At the end of the intervention period, nine subjects remained in treatment with three patients in each group receiving at least once weekly take-home privileges. Of the seven subjects no longer in treatment, five were in the combined intervention group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts.

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.

Adult↗

PubMed1988

Butorphanol-precipitated withdrawal in opioid-dependent human volunteers.

The subjective, physiological and behavioral effects of hydromorphone, naloxone and butorphanol, an opioid agonist/antagonist analgesic, were studied in adult, male, methadone-dependent volunteers living on a clinical research ward. Drug conditions included saline placebo, 4 and 8 mg of hydromorphone HCl, 0.375, 0.75, 1.5, 3 and 6 mg of butorphanol tartrate and 0.1 and 0.2 mg of naloxone HCl. Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5-hr experimental sessions. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 2 hr after drug administration. Hydromorphone decreased pupil diameter, and significantly increased ratings of "Good Effects" on the subjective measures. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Butorphanol produced effects which were generally similar to the effects of naloxone, indicating that butorphanol doses precipitate withdrawal signs and symptoms when administered to methadone-dependent humans. There were some differences in the withdrawal syndromes precipitated by naloxone vs. butorphanol, suggesting that multiple mechanisms may be involved in opioid withdrawal precipitation.

Adult↗

PubMed1988

Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans.

This study assessed the blockade of hydromorphone challenge effects (cumulative s.c. doses of 0, 6 and 18 mg) during chronic buprenorphine treatment of opioid dependent subjects. Buprenorphine was administered daily via the sublingual route in ascending doses of 2, 4, 8 and 16 mg. Hydromorphone challenges were conducted after 10 to 14 days of chronic administration of each buprenorphine dose and 24 h after the last buprenorphrine dose. Buprenorphrine itself only produced dose-related effects in respiration rate. While subjects were maintained on 2 mg of buprenorphine, the hydromorphone challenge produced dose-related changes in physiological and self-report measures. As the dose of buprenorphine was increased, hydromorphone effects on self-report measures were attenuated to a greater extent than was noted for pupil diameter. The results of this study confirm previous reports of buprenorphine blockade of opioid agonist effects in humans and extent those findings by demonstrating both a buprenorphine dose-effect function and a dissociation between the potency of buprenorphine's opioid blockade for self-report vs. physiological measures.

Adult↗

PubMed1988

Acute physical dependence in man: effects of naloxone after brief morphine exposure.

This study assessed the effects of i.m. naloxone (10 mg) 6 hr after acute i.m. injections of morphine (0, 1, 3, 5.6, 10 and 17 mg). Naloxone reversed residual morphine-produced respiratory depression, miosis and subjective reports of drug "high." In addition, naloxone precipitated signs and symptoms characteristic of opioid withdrawal. Subjective report measures of "bad" drug effects and specific opioid withdrawal symptoms increased as a function of morphine pretreatment dose, as did observer-rated signs of withdrawal. Yawning was the most prominent observed sign, whereas yawning and irritability were the most consistently reported subjective symptoms. Peak withdrawal effects were seen within 15 min post-naloxone. The results of this study confirm previous reports of acute physical dependence in man and extend those findings by demonstrating a morphine dose-response function.

Adult↗