Search

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.

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.

The central mechanism mediating the discriminative effects of nicotine was studied using rats. Rats were trained to discriminate subcutaneously administered nicotine at 0.5 mg/kg from saline in a 2-lever operant chamber situation for food reinforcement. 1) Nicotine administered into the lateral ventricle at both 100 micrograms and 120 micrograms substituted for subcutaneously administered nicotine at 0.5 mg/kg. This result indicates that the discriminative effects of nicotine are mediated centrally. 2) Among the drugs, acetylcholine at 0.5-10 micrograms administered into the lateral ventricle and methamphetamine at 5-40 micrograms and dopamine at 1-10 micrograms administered into the nucleus accumbens, none substituted for subcutaneously administered nicotine. These results indicate that the discriminative effects of nicotine differ from those of the above drugs. 3) Nicotine at 100 micrograms administered into the nucleus accumbens almost completely substituted for subcutaneously administered nicotine. In addition, mecamylamine at 180 micrograms administered into the nucleus accumbens attenuated the discriminative effects of subcutaneously administered nicotine. These results suggest that nicotinic receptors in the nucleus accumbens may be involved in the discriminative effects of nicotine. However, further studies are needed, since the nucleus accumbens is regarded not to be a major site of action of nicotine for these effects because of its low susceptibility to nicotine and mecamylamine.

As a method for examining the psychological dependence potential of afloqualone, a centrally acting muscle relaxant, the subjective effects of the drug were studied in 8 healthy male volunteers under the double blind condition. The trial in each subject consisted of a 3-day afloqualone administration session and a 3-day control agent administration session with a 4-day interval between the two sessions. The subjects were hospitalized for the 3 days of each session and treated with oral daily doses of either afloqualone or control agents. In the afloqualone session, 2 capsules containing afloqualone (10 mg each) and 2 placebo capsules, 3 afloqualone capsules and 1 placebo capsule, and 4 afloqualone capsules were administered on the 1st, 2 nd, and 3 rd day respectively.In the control agent session, one capsule containing 5 mg of diazepam and 3 placebo capsules were administered on either the 1st or 3 rd day and 4 placebo capsules were administered on each of the other 2 days. Half of the subjects had the afloqualone session first while the rest had the control agent session first, and in the control agent sessions, half of the subjects received diazepam on the 1st day while the remaining half received it on the 3 rd day. In each session the subjective feelings of the subjects were examined using 4 types of questionnaires given 1 to 11/2 hours after administration. In addition, such psychological tests as the personality, tapping, and Uchida-Kraepelin tests were conducted both prior to and after each administration. As a result, while some statistically significant subjective effects were observed with diazepam, none were found with afloqualone even though the blood levels of the drug were sufficiently high in these subjects. Thus, within the above dose regimen, afloqualone was regarded to have no pharmacological property, productive of psychological dependence in man.

中枢性筋弛緩薬tizanidineにある程度の強化効果があることがサルの実験で観察されたため, ヒトにおける精神依存性の有無を検索する目的で健常人12名を対象として, 本薬およびdiazepamを用いて自覚効果に関する二重盲検比較試験を実施した.その結果, tizanidineは臨床常用1回最大量の3mgおよびその倍量の6mgが服用されても, placeboに比較して明らかな身体的および精神的自覚効果を示さなかった.一方, diazepam 10mgではplaceboやtizanidineに比較して, 有意に高い率で自覚効果に関する肯定回答が得られ, 「ねむい」, 「ぼんやり」等をはじめ, いくつかの項目で中枢抑制効果を示す肯定回答が高率にみられた.またdiazepamでは, その自覚効果を「好ましい」とするもの1例, 「うっとりとしたいい気分」とするもの2例, および「酔った感じ」5例など精神依存性があることを直接示唆する項目への肯定回答もみられた.なお, tizanidineのタッピングや血圧等に対する影響は6mgではdiazepamと同様に観察された.これらのことはtizanidine高用量投与による薬理作用が影響したと考えられる.また血中濃度の測定においても, 6mgでは3mgのときの約4倍の値が得られていることが確認された.

The drug dependence potential of viloxazine was tested in 5 experiments on rhesus monkeys. In gross behavioral observation of normal monkeys the acute CNS effects of the drug were found to be very weak. Decrement of spontaneous motor activity and occasional eye-closing were observed with single doses higher than 16 mg/kg IV, IM and 128 mg/kg PO, while convulsions and death occured at 64 mg/kg IV and IM. Viloxazine did not suppress the morphine and barbital withdrawal signs in monkeys that had been made physically dependent on these drugs and withdrawal. In the test for physical dependence by repeated administration of the drug at 16 mg/kg IM twice daily for 31 days in normal monkeys, no observable withdrawal sign was developed in the naloxone precipitation and natural withdrawal tests. In intravenous self-administration experiments, a weak reinforcing effect was demonstrated in some monkeys, but the effect was extremely weak. Thus, viloxazine was found to be physical dependence-free and its overall dependence potential was regarded as very low.

The relationship between minimum reinforcing doses and injection speed was investigated by using 2 levels of speeds in experiments on self-administration of cocaine or pentobarbital in 2 crab-eating monkeys each. The experiments were conducted under a fixed ratio (FR) 1 schedule with 30-min time-out after each drug injection, wherein the drugs and saline were made available for alternate 5-day periods. The minimum reinforcing doses at each injection speed were determined by the titration procedure in which the presence or absence of reinforcing effect at a particular drug dose was judged based on comparison of the self-administration rate at that dose with the rate in the preceding saline period. The results showed that the minimum reinforcing doses of cocaine and pentobarbital tended to be higher in inverse proportion to the injection speed of the drugs.

Risk assessment of dependence-producing drugs comprises assessment of two major risks: the risk that a drug is likely to be abused (abuse liability) and the harm that is likely to occur as a consequence of abuse (termed here as harm liability). Important determinants of these risks are the dependence-related pharmacological and toxicological properties of a drug. In this paper, the relationships of the drug properties to the abuse and harm liabilities are described. Next, a scoring system to assess the abuse and harm liabilities is introduced. Finally, an attempt to actually apply this system to several prototypic drugs of abuse and some agonist-antagonist analgesics is explained.

beta-Blocking actions of orally administered Ko 1400 and tiprenolol, new beta-blocking agents, were studied in unanesthetized rats and dogs, using a fall of blood pressure and an increase in heart rate produced by isoproterenol as a measure of beta-receptor activation. Blood pressure was recorded from the aorta of the dog and the caudal artery of rat via indwelling catheter, and heart rate of the dog was recorded by a cardiotachometer triggered by R waves of the lead II electrocardiogram. Mean resting blood pressure was 116 mmHg in rats and 93 mmHg in dogs, and heart rate was 99 beats/min in dogs. Isoproterenol (0.5 microgram/kg) was injected via indwelling venous catheter. Ko 1400, tiprenolol and propranolol inhibited the hypotension and tachycardia induced by isoproterenol at an oral dose level of 2 mg/kg or more. beta-blocking action in these preparations was found to be tiprenolol greater than Ko 1400 greater than propranolol. Pharmacological half life of tiprenolol was longer than that of propranolol, whereas that of Ko 1400 was shorter. No selectivity of beta-blocking actions was observed with all three beta-blockers. These findings are in agreement with the results obtained in isolated atrial and tracheal preparations of the guinea pig.

Drug depenence liabilty of 5 tricyclic antidepressants, imipramine, imipramine-N-oxide, protriptyline, maprotiline and iprindole, were examined using rhesus monkeys. In gross behavioral observations of acute central nervous system effects in normal monkeys, imipramine, protriptyline, maprotiline and iprindole produced a decrease of awareness, mydriasis, ataxia, tremor and convulsions, but imipramine-N-oxide did not. In cross intravenous self-administration of the drugs with a standard stimulant and saline, no meaningful reinforcing effect on monkeys' drug-seeking behavior was observed with any drug, with the exception of one of the 4 monkeys with iprindole. In the continuous self-administration test, positive self-administration was observed in 2 out of 4 monkeys with imipramine and in one monkey each with imipramine-N-oxide, protriptylin and iprindole. But the self-administration rates were considerably low in comparison with that of principle drugs of abuse and none of these monkeys manifested observable drug effects. No monkey showed positive self-administration of maprotiline. Thus, the amphetamine-like dependence liability was not found in these drugs.

In the drug dependence liability studies, 4 tests were conducted. In the test on acute CNS effects of the drug, normal monkeys did not show any meaningful or physical changes with single oral doses of the drug at 50, 100, 200, 400, and 500 mg/kg.In the test of substitution of Clonixin for morphine in morphine dependent and withdrawn monkeys, single oral doses of the drug at 20, 50, 100, and 200 mg/kg did not suppress morphine withdrawal signs, and thus did not support physical dependence on morphine.In the physical dependence producing test on Clonixin, repeated oral administration of the drug to naive monkeys at daily doses of 100, 200, and 400 mg/kg for 4 weeks did not produce any physical dependence as observed by naloxone tests.In the intragastric self-administration test in drug seeking behavior conditioned monkeys, Clonixin did not positively reinforce the drug seeking behavior. Thus, Clonixin was found to be dependence free.In the teratogenicity test, 2 pregnant monkeys received 30 mg/kg, 2 other pregnant monkeys received 200 mg/kg, and one pregnant monkey received the vehicle alone, daily by gavage for 7 days, from the 23rd to 29th day of pregancy. All fetuses were removed from the uteruses by cesarean section on 59th, 60th or 61 st day of gestation. Detailed examinations of the fetuses revealed no abnormalities at all in external morphological appearance, visceral organs, or skeletal structures.

Sedative-hypnotic type drug dependence liability of B 169, a new anticonvulsant, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects by single oral doses of 500 and 1000 mg/kg, no meaningful effect was observed. At 2000 mg/kg, a slight decrease of spontaneous motor activity and of awareness to outer stimuli was observed one hour after administration. The monkeys, however, reacted normally to man without any impairment of motor function.In the cross physical dependence test in monkeys made, physically dependent on barbital and then withdrawn, the drug did not support the dependence when it was substituted for barbital at single oral doses of 1000 or 2000 mg/kg.When drug seeking behavior conditioned monkeys were allowed to self-administer the drug intragastrically by pressing a lever switch in the cage without time or dose limitation, none of the animals voluntarily ingested the drug. Since they did not initiate self-administration, timer-programmed forced infusion of the drug into the stomach was conducted at a dose regimen of 20 mg/kg/infusion every 6 hours for 2 weeks. Initiation of self-administration was still not observed during or after the programmed administration period. No withdrawal signs were observed at the termination of programmed administration.Thus, B169 was found to be dependence free.

Barbiturate-like drug dependence liability of Calcium N-2-ethylhexyl-β-oxybutyramide semisuccinate (M-2), a new synthetic sedative-hypnotic agent, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects, the compound did not show as strong CNS depressant effects in monkeys as it had in small animals.A physical dependence producing test was conducted by oral administration of the compound 4 times a day, for 4 weeks at dose levels of 100, 200, or 400 mg/kg/day, with 2 naive monkeys for each dose level. At the end of 4 weeks, administration was terminated and a withdrawal test was conducted for 5 days. No meaningful withdrawal signs were observed. On the other hand, oral administration of barbital for 4 weeks produced intermediate to severe grade withdrawal signs in other monkeys.In cross intravenous self-administration of M-2, a CNS stimulant and saline in self-administration conditioned monkeys, the compound did not show drug seeking behavior reinforcing effects at unit doses of 0.25, 1.0, and 4.0 mg/kg/inj..Because of the lack of CNS depressant effects, ability of producing physical dependence and drug seeking behavior reinforcing effects, the potency of dependence liability of M-2 was concluded as practically none.

Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

Nicotine levels in four cigarette smoking rhesus monkeys were measured by gas-liquid chromatography and compared with levels similarly obtained for two human smokers.A range of 18.9-39.1 ng/ml was achieved by the monkeys during smoking, highter than that of the human smokers after smoking a cigarette.

In this chapter, the pharmacological factors involved in predicting the abuse liability of drugs are discussed with major emphasis on their psychological dependence potential. For prediction of drug abuse liability, it is important to find and compare the drug’s effects against those of prototypic drugs. The important pharmacological properties include the following: central nervous system (CNS) effects, including operant behavioral effects; tolerance; physical dependence potential; and psychological dependence potential. It is also important to consider such chemical and pharmacokinetic properties as water solubility and speeds of absorption and elimination. In particular, psychological dependence potential is most relevant to abuse liability. To evaluate psychological dependence potential from animal studies, the reinforcing and discriminative stimulus properties of drugs must be assessed in comparison with those of prototypic drugs. When human data are available, it is important to verify the animal results on such points as pharmacokinetics and CNS drug susceptibility which may differ across species.

The influence of diazepam treatment following prolonged ethanol administration was toxicologically examined in rhesus monkeys and rats. In the monkey, ethanol was intragastrically administered through a chronically implanted catheter by programmed infusions at doses of 1.5 g/kg 4 times daily every 6 hours over a period of 5 or 10 weeks and followed by intragastric administration of diazepam 4 mg/kg twice a day for 5 weeks. In the rat, ethanol was administered by gavage at doses of 8 g/kg once a day or 4 g/kg twice a day for 5 weeks after which diazepam 300 mg/kg was intragastrically administered once daily for 5 weeks. In the monkey, ethanol produced such toxic changes as hypertriglyceridaemia, fatty metamorphosis of the hepatocytes associated with megamitochondria, proliferation of smooth endoplasmic reticulum and vacuolation in the hepatocytes, and gastritis. Diazepam did not aggravate but mostly alleviated these changes. In the rat, on the contrary, the serum GPT level slightly elevated due to the ethanol administration, and remained at the elevated level with the diazepam treatment in contrast with the complete recovery with non-treatment for 5 weeks after the ethanol administration. However, such changes as increase of fat droplets in the hepatocytes and the triglyceride concentration in the liver which had been developed by ethanol administration recovered during the diazepam treatment period. In spite of the recovery, the elevation of the serum GPT level being remained by diazepam may indicate possible influence of diazepam on the liver function when the drug is administered after prolonged administration of ethanol.

In gross behavioral observation the minimum effective dose of zopiclone was intravenously 0.06-0.25 mg/kg and intragastrically 1-4 mg/kg in rhesus monkeys. Zopiclone suppressed barbital withdrawal signs of rhesus monkeys at a single dose of 16 mg/kg or more. The suppressing effect of zopiclone 32 mg/kg i.g. was comparable to diazepam 8 mg/kg. Crab-eating monkeys treated with zopiclone at doses up to 32 mg/kg twice daily for up to 8 weeks manifested intermediate-grade signs upon withdrawal (i.e., less severe than after treatment with diazepam and similar to nitrazepam). Zopiclone was self-administered by rhesus monkeys relatively frequently by the intravenous route; the infrequent intragastric rate was similar to or slightly higher than with diazepam.

Dependence potential of μ-agonists such as morphine and codeine is known to be very high both physically and psychologically. The reinforcing effect of these drugs is markedly intensified at withdrawal when subjects developed physical dependence. For example, final ratios obtained by the ingressive ratio method in intravenous self-administration of codeine inrhesus monkeys were 4,540 under a physical dependence-free state and 5,080 under a physically dependent state in average of 3 or 4 monkeys. Contrary to this, the dependence potentials of agonist/antagonist analgesics such as pentazocine, cyclazocine, buprenorphine, and propiram are infinitely lower than the opiates, with no significant intensification of the reinforcing effect at withdrawal. Especially the physical dependence potential of buprenorphine and psychological dependence potential of cyclazocine are extremely low in both animals and humans. In morphine dependent and withdrawn monkeys, these drugs did not suppress the withdrawal signs, but precipitated the signs in non-withdrawn monkeys. However, when physical dependence was maintained by low doses of morphine, pentazocine suppressed the morphine withdrawal signs, and buprenorphine and propiram were also reported to have suppressed the signs. These results may be attributable to the fact that these drugs are either μ-antagonists or partial μ-agonists. It has been reported that the dependence potential of highly selective κ-agonists such as ketocyclazocine is very low,and that of a σ-agonist, SKF-10047,is negligible. Thus, the strong dependence on opioids, particularly strong physical dependence, appears to be developed by a mechanism which involves the μ-receptors.

Normal rhesus monkeys were administered diazepam (DZ) twice daily for 14 weeks at doses of 8 mg/kg, i.g. for the first 2 weeks and 12 mg/kg, i.g., thereafter. Two monkeys were withdrawn after 4 weeks of administration of DZ, and such signs as apprehension, hyperirritability, tremor, muscle rigidity, and motor impairment were noted, with the severity reaching a peak on the 3rd withdrawal day. Generalized convulsions were also observed in 1 of the monkeys. The other 2 monkeys were administered 10 mg/kg, i.g., of a benzodiazepine (BD) antagonist, Rol5-1788, at 2.5 hr after the last DZ dose, and within several min, such signs as lying down, fighting, defecation, and frequent retching and vomiting were observed in addition to those seen in the naturally withdrawn monkeys, but without convulsions. After 10 weeks of administration of DZ, 4 monkeys were administered 10 mg/kg, i.g., of Rol5-1788 at 2.5 hr after the last DZ dose. In 2 monkeys, pretreatment with pentobarbital at 15 mg/kg, i.m., 5 min prior to administration of Rol5-1788 prevented the appearance of restlessness, muscle rigidity, and motor impairment and markedly attenuated the signs of retching, vomiting, and defecation,but showed no suppression of tremor; in contrast, the other 2 monkeys pretreated with saline showed approximately the same withdrawal signs as those precipitated by Rol5-1788 in the 4th week, while 1 of the monkeys manifested convulsions. Four weeks later, another experiment approximately identical with that described above was conducted7crossing over the animals, and similar results were obtained. Thus, BD receptors were considered to be involved in the physical dependence-producing mechanism of DZ.