A method has been developed which permits monkeys to self-administer drug solutions, at will, through indwelling intravenous catheters. Psychological dependence on the effects of a drug occurs when a naive monkey voluntarily initiates and maintains self-administration of the drug. If, in addition to psychological dependence, the drug also produces psychotoxieity, either directly or upon abrupt withdrawal, it has a potential abuse liability. In the present study monkeys developedpsychological dependence on morphine, codeine, cocaine, d-amphetamine, pentobarbital, ethanol, and caffeine. All of these drugs except caffeine produced psychotoxicity. Monkeys did not develop psychological dependence on nalorphine, morphinc-nalorphine mixtures, chlorpromazine, mescaline or physiological saline.
Background: Our previous placebo-controlled, prospective, double-blind study demonstrated that a new opioid ĸ-receptor agonist, nalfurafine hydrochloride, effectively reduced treatment-resistant pruritus in 337 hemodialysis patients. Thus, we designed this study to evaluate prospectively the efficacy, safety, addiction liability, and pharmacokinetics of nalfurafine given orally for 1 year. Methods: This open-label study examined the effects and adverse drug reactions (ADRs) of 52-week oral administration of nalfurafine hydrochloride (5 µg/day) in 211 hemodialysis patients with a treatment-resistant itch. Results: Of 211 patients, 145 completed the study as scheduled. The mean pruritus value assessed by the visual analogue scale was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in week 2 and 52, respectively, indicating a long-lasting efficacy. ADRs occurred in 103 patients (48.8%). Frequent ADRs were insomnia (sleep disturbance, 19.4%), constipation (7.1%) and increased blood prolactin (3.3%), similar to previous reports. Regarding addiction liability, it appeared unlikely that nalfurafine hydrochloride was abused. After the start of treatment, plasma drug levels reached a steady state in week 2 with no apparent tendency of systemic accumulation. Conclusions: Nalfurafine hydrochloride, orally administered at 5 µg/day for 52 weeks to hemodialysis patients, produced a long-term suppression of pruritus without significant safety problems.
Nalfurafine (nalfurafine hydrochloride, TRK-820, Remitch®) was launched as an anti-pruritic for uremic pruritus in hemodialysis patients in Japan in 2009. Since the drug is an opioid that mainly binds to κ-receptors and possesses κ-agonistic pharmacological properties and also binds partially, but very weakly, to μ-receptors, the abuse liability of the drug was assessed by using questionnaires in patients enrolled in a clinical trial evaluating the efficacy and safety of the drug. The clinical trial was conducted for up to 52 weeks in patients subjected to regular hemodialysis. End-stage renal disease (ESRD) patients with uremic pruritus (n = 146) were administered nalfurafine 5 μg intravenously after each hemodialysis session. 81 ESRD patients without uremic pruritus served as non-treatment controls. All pruritus patients answered the 3 questionnaires of "the Addiction Research Centre Inventory (ARCI)", "modified Short Opiate Withdrawal Scale (SOWS)", which provides a range of signs and symptoms of opiate withdrawal, and Severity of Dependence Scale (SDS), which measures the dependence potential of the drug. The control patients were tested with the ARCI and modified SOWS questionnaires. There were no significant differences between the nalfurafine group and control group in the ARCI and modified SOWS scales. Thus, no evidence of abuse liability was indicated in the results. Also, no significant differences in the blood pressure, respiratory rate, body temperature and pupil diameter were shown between the two groups.
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