Donald R. Jasinski

Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

An evaluation of the abuse potential of modafinil using methylphenidate as a reference

Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72 h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.

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.

Challenges in the development of prescription opioid abuse-deterrent formulations.

Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics—if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.

Morphine effects on human REM state, waking state and NREM sleep

SummaryAfter 4 adaptation nights, IM doses of morphine sulfate (7.5, 15, 30 mg/70 kg) and placebo were studied in 8 male postaddicts, using a cross-over design with randomized block analysis to demonstrate significant drug effect. Morphine decreased the number and duration of REM periods, delayed the onset of the first REM period, and possibly increased the time between REM period onsets. Thus, morphine significantly decreased REM state (REMS), but did not alter the pattern of maximum REMS in late night. Morphine significantly increased waking state (WS) but did not alter the pattern of maximum WS in early night. Morphine significantly increased tension, and shifted maximum tension from early night to middle night. Morphine altered EEG sleep patterns; although NREM definitions were thus less certain, morphine appeared to increase NREM light sleep (stages 1 and 2) and decrease NREM deep sleep (stages 3 and 4). After an initial decrease in REMS by 30 mg/70 kg of morphine, an increase in REMS was noted in the third night of the 2 pilot study subjects. The arousal response to morphine seen in post-addicts needs further study in other populations and during the course of chronic morphine use.

Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol

Assessment of abuse potential of opioid analgesics has a long history in both laboratory animals and humans. This article reviews the methods used in animals and in humans and then presents the data collected in the evaluation of tramadol, an atypical centrally acting opioid analgesic approved for marketing in the United States in 1998. Finally, data on the abuse of tramadol from postmarketing surveillance and case reports are presented. The consistency between animal and human study results and the predictive value of both are discussed. Overall, there was substantial agreement between animal and human data, with each having predictive value. Nonetheless, it is suggested that abuse-potential screening of new medications would benefit from an organized, integrated cross-species program.

Sublingual versus subcutaneous buprenorphine in opiate abusers

To compare the pharmacologic profiles of sublingually and subcutaneously administered buprenorphine, 10 healthy male subjects with histories of opiate abuse were given sublingually administered buprenorphine (1, 2, and 4 mg), subcutaneously administered buprenorphine (1 and 2 mg), and placebo in a double‐blind, double‐dummy, placebo‐controlled study. All active buprenorphine dosages produced a significant degree of miosis but no significant changes in body temperature, blood pressure, or respiratory or heart rate. Buprenorphine produced varying degrees of euphoria related to dose and route of administration but little dysphoria and sedation, as assessed by subscales of the Addiction Research Center Inventory. Subject “liking” for buprenorphine was reported by both observers and subjects. The relative potency of sublingually to subcutaneously administered buprenorphine was calculated for both physiologic and behavioral parameters and found to be approximately two thirds. The results indicated that both sublingual and subcutaneous buprenorphine have a similar profile of effects in opiate abusers.

Ritanserin in the treatment of alcohol dependence – a multi-center clinical trial

Abstract Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects’ QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

Investigation of the abuse liability of buspirone in alcohol-dependent patients

By use of the Addiction Research Center Inventory, the Amphetamine Self-Rating Scale, the Single-Dose Questionnaire, and selected physiologic measures (blood pressure, pulse and respiratory rates, oral temperature, and pupil diameter), the abuse liability of buspirone (10, 20, and 40 mg) was compared with that of diazepam (10 and 20 mg) and placebo in 19 subjects who were hospitalized for the treatment of alcohol dependency. Each treatment was given as a single dose at intervals of at least three days according to a double-blind, six-period, crossover Latin square design. Neither buspirone nor diazepam had any effect on blood pressure, pulse and respiratory rates, or body temperature. A small, transient pupillary constriction was evident in the 20- and 40-mg buspirone groups, but it dissipated within two hours after dosing. Both buspirone and diazepam had only a small stimulating effect on appetite. On the Pentobarbital-Chlorpromazine-Alcohol Group and Sedation subscales of the Addiction Research Center Inventory, the 40-mg dose of buspirone yielded effects suggestive of a mild sedative-type drug. Only the 20-mg dose produced a significant effect on the Euphoria scale. Diazepam appeared to be more active as a sedative-hypnotic type of drug, by virtue of its effects on both the Amphetamine and Euphoria subscales and its greater effects on the Morphine-Benzedrine Group, Pentobarbital-Chlorpromazine-Alcohol Group, and Sedation subscales, suggesting euphoria. Not only does the lack of effect of buspirone on the Amphetamine and Morphine-Benzedrine Group subscales indicate lack of a euphorigenic property, but the score on the Lysergic Acid Diethylamide subscale, especially in the 40-mg group, suggests a dysphorigenic property at high doses. On the Amphetamine Self-Rating Scale, buspirone and diazepam affected only the sleep factor and only the 40-mg buspirone dose was distinguishable from placebo. On the Single-Dose Questionnaire, both buspirone and diazepam tended to be rated more as sedative-type drugs, but buspirone was generally less well liked than diazepam. Overall, the results, which suggest a lack of euphoria and the presence of dysphoria at high doses, indicate that buspirone has only limited, if any, abuse liability.

Abuse liability assessment of atomoxetine in a drug-abusing population

BACKGROUND Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.