morphinans and Substance-Withdrawal-Syndrome

Nalfurafine hydrochloride, a kappa-opioid receptor agonist, was approved in January 2009 and released to the market on March 2009 for the indication of "Improvement of pruritus in hemodialysis patients (only for cases resistant to conventional treatments)" in Japan (Brand Name: REMITCH CAPSULES 2.5 microg, Marketing Authorization Holder: Toray Industries, Inc., Distributed by Torii Pharmaceutical Co., Ltd., Co-developed by Japan Tobacco Inc.). In addition to antipruritic effect, nalfurafine hydrochloride showed ameliorating effects on pain, neuropathic pain, drug dependence, schizophrenia and dyskinesia in non-clinical studies. Therefore, nalfurafine hydrochloride may become a useful therapeutic agent for their diseases.

Topics: Analgesics; Animals; Antipruritics; Disease Models, Animal; Drug Tolerance; Dyskinesias; Humans; Mice; Morphinans; Rats; Receptors, Opioid, kappa; Schizophrenia; Spiro Compounds; Substance Withdrawal Syndrome

Nalbuphine is a potent analgesic with a low side effect and dependence profile in animals and man. Nalbuphine is distinguished from other agonist/antagonist analgesics in having greater antagonist activity and fewer behavioral effects at analgesic doses than pentazocine, butorphanol or buprenorphine. At equi-analgesic doses, nalbuphine is quantitatively similar to nalorphine in regard to its large ratio of antagonist to analgetic activity. Clinical studies have confirmed this balance of strong antagonist to analgesic activity. Nalbuphine has been shown to effectively antagonize the respiratory depressant activity of narcotic analgesics while concomitantly adding to their analgetic responses. Unlike nalorphine or pentazocine, nalbuphine produces few overt behavioral or autonomic effects in animals at doses over 300 times its analgesic range. These findings are confirmed by clinical results which show that nalbuphine produces few psychotomimetic effects, even at elevated dose levels, in contrast to nalorphine or pentazocine. Nalbuphine produces limited respiratory depression in animals and in man. Significant cardiovascular effects have not been found. Nalbuphine was found to produce significantly less inhibition of gastrointestinal activity than any of the clinically useful narcotic or agonist/antagonist analgesics tested in animals. Nalbuphine's analgetic effects are reversed by naloxone doses similar to those which reverse nalorphine's agonist effects. Results in this and other tests suggest that nalbuphine is primarily a kappa-agonist/mu-antagonist analgesic. Unlike pentazocine or buprenorphine, nalbuphine does not suppress the narcotic abstinence syndrome in partly-withdrawn morphine-dependent animals or man. Rather, due to nalbuphine's strong antagonist activity, analgesic-range doses of nalbuphine severely exacerbate the withdrawal syndrome in partly-withdrawn mice, monkeys and humans. Nalbuphine also precipitates a strong abstinence response in non-withdrawn morphine-dependent animals and man. In post-addict humans, analgesic-range doses of nalbuphine are perceived as minimally morphine-like, but higher doses are judged to be progressively more nalorphine-like (i.e. dysphoric), which further limits nalbuphine's abuse potential in drug-seeking individuals. Primary dependence studies have demonstrated that physical dependence is possible at high dose levels that produce marked side effects. Other studies show that dependence is unlikely to be of signi

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Depression, Chemical; Discrimination, Psychological; Dogs; Guinea Pigs; Haplorhini; Humans; Mice; Morphinans; Morphine; Nalbuphine; Naloxone; Rabbits; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiration; Self Administration; Sleep Stages; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Codeine; Drug Tolerance; Guinea Pigs; Half-Life; Haplorhini; Humans; Ileum; In Vitro Techniques; Meperidine; Mice; Molecular Conformation; Morphinans; Nalorphine; Narcotic Antagonists; Pentazocine; Rats; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders; Tail

Topics: Animals; Behavior, Animal; Cyclazocine; Cyclopropanes; Dose-Response Relationship, Drug; Facial Expression; Handling, Psychological; Haplorhini; Humans; Morphinans; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Species Specificity; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thebaine; Time Factors

Topics: Animals; Chlorpromazine; Codeine; Cyclazocine; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Lysergic Acid Diethylamide; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentobarbital; Rats; Receptors, Drug; Species Specificity; Substance Withdrawal Syndrome; Substance-Related Disorders; Surveys and Questionnaires

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.

Topics: Adult; Dose-Response Relationship, Drug; Humans; Hydromorphone; Male; Methadone; Morphinans; Nalbuphine; Naloxone; Opioid-Related Disorders; Substance Withdrawal Syndrome

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.

Topics: Adult; Butorphanol; Cognition; Double-Blind Method; Humans; Hydromorphone; Injections, Intramuscular; Male; Methadone; Morphinans; Naloxone; Opioid-Related Disorders; Psychomotor Performance; Substance Withdrawal Syndrome

Heroin-dependent out-patients who had been prescribed buprenorphine by general practitioners took part in a controlled study in which 2 mg or 4 mg of buprenorphine were administered by the sublingual route to assess its acceptability as a maintenance opiate and to determine the effects of its abrupt withdrawal and reintroduction a week later. Subjects who received 4 mg of buprenorphine reported being more intoxicated and having fewer symptoms of opiate withdrawal than did the subjects who received the 2-mg dose. Subjects who received the higher dose also abused opiate and benzodiazepine drugs less frequently. When buprenorphine was ceased abruptly, the subjects reported mild withdrawal discomfort for which many requested symptomatic treatment. The reintroduction of buprenorphine caused their condition to restabilize. The subjects' use of opiate drugs, as shown by urine assay, rose from a prevalence of around 15% of specimens at the beginning to about 50% of specimens at the end of the five-week study period. Sublingual buprenorphine was acceptable to opiate-addicted outpatients as a maintenance treatment. However, daily doses of greater than 4 mg will probably be required to suppress concurrent opiate abuse, and detoxification will need to be undertaken gradually.

Topics: Administration, Oral; Adult; Buprenorphine; Dose-Response Relationship, Drug; Female; Heroin Dependence; Humans; Male; Morphinans; Narcotics; Patient Dropouts; Random Allocation; Substance Withdrawal Syndrome; Surveys and Questionnaires

Buprenorphine was evaluated for its abuse potential and utility in treating narcotic addiction. The drug was morphine-like but was 25 to 50 times more potent than morphine and was longer-acting. Little if any physical dependence of clinical significance was produced by buprenorphine. The effects of morphine to 120-mg doses were blocked by buprenorphine, a blockade that persisted for 29 1/2 hours. In man, buprenorphine has less intrinsic activity than morphine, and as such, as a low abuse potential. Moreover, the drug has potential for treating narcotic addiction since it is acceptable to addicts, is long-acting, produces a low level of physical dependence such that patients may be easily detoxified, is less toxic than drugs used for maintenance therapy, and blocks the effects of narcotics.

Topics: Adult; Blood Pressure; Buprenorphine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Euphoria; Humans; Male; Methadone; Middle Aged; Morphinans; Morphine; Naloxone; Narcotics; Pulse; Pupil; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

The effects of etorphine, a potent morphine-like drug, were qualitatively and quantitatively compared to those of morphine. In nondependent subjects, etorphine in doses of 0.025, 0.050, and 0.100 mg produced pupillary constriction and morphine-like subjective effects and euphoria. Etorphine was 500 times as potent as morphine, with a very rapid onset and short duration of action. In morphine-dependent subjects, etorphine suppressed abstinence but for a shorter period than morphine. These studies indicate that in man etorphine is a morphine-like drug with a high abuse potential.

Topics: Clinical Trials as Topic; Euphoria; Humans; Morphinans; Morphine Dependence; Narcotics; Pentanols; Personality Inventory; Placebos; Pupil; Structure-Activity Relationship; Substance Withdrawal Syndrome; Surveys and Questionnaires; Time Factors

Topics: Animals; Aspirin; Brain; Cyclazocine; Drug Tolerance; Fenclonine; Humans; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Pargyline; Pentazocine; Phenylalanine; Physostigmine; Placebos; Serotonin; Substance Withdrawal Syndrome

Naloxegol is a new peripherally acting mu-opioid receptor antagonist to treat opioid-induced constipation with supposedly no effect on opioid analgesia. We present a patient with cancer-related pain who developed acute opioid withdrawal symptoms due to an interaction between the opioid antagonist naloxone and naloxegol. He was treated with oxycodone sustained release because of poor pain control. For opioid-related constipation, he had been receiving naloxegol. He complained about worsening pain and constipation and oxycodone was switched to oxycodone/naloxone. Shortly after intake, he experienced acute severe agitation, anxiety, sweating, tachycardia, disorientation and yawning without improvement after intravenous midazolam. Only after intravenous morphine administration, symptoms were controlled. He was switched back to the previous oxycodone dose without naloxone, with naloxegol being maintained. In the light of this case we suggest to avoid the use of naloxone and naloxegol in combination, or at least, to use it with extreme caution and monitorisation of tolerance.

Topics: Analgesics, Opioid; Constipation; Humans; Male; Morphinans; Naloxone; Narcotic Antagonists; Oxycodone; Polyethylene Glycols; Substance Withdrawal Syndrome

To observe the effect of alcohol extracts from orientivne and its effective component sinomenine on withdrawal syndromes and neurotransmitter of morphine-abstinent mice and on intracellular calcium level in morphine-dependent neuronal-cells line. To study the detoxification of alcohol extracts from orientvine and sinomenine on morphine-dependent animal and explore the mechanism of its effect.. The effect of alcohol extracts from orientivne and sinomenineon on abstinent syndromes was observed by experiment study on morphine-dependent ex vivo ileum from guinea pigs and morphine-dependent mice. The morphine-dependent model mice were established by injection on dosage increasing by degrees. The hypothalamic monomine neurotransmitters such as NA, DA, 5-HT were tested by fluorospectrophotometry. Morphine-dependent cell line was established by administering morphine at different doses into the culture medium. The cells were stained with fluo-3 and the intracellular calcium level was measured by flow cytometry.. Alcohol extracts from orientvine and sinomenine could alleviate withdrawal contractile response of morphine-dependent ex vivo ileum from guinea pigs and withdrawal syndromes of morphine-dependent mice, decrease the concentration of the neurotransmitters, and elevate the intracellular calcium level and inhibit the decreasing of Ca2+ induced by naloxone.. Alcohol extracts from orientvine and sinomenine have some effects on withdrawal syndromes which may be related to inhibiting neurotransmitters and the regulation of intracellular calcium concentration.

Topics: Animals; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Ethanol; Female; Guinea Pigs; Ileum; Male; Mice; Morphinans; Morphine; Morphine Dependence; Muscle Contraction; Neurons; Norepinephrine; Random Allocation; Rats; Rats, Sprague-Dawley; Sinomenium; Substance Withdrawal Syndrome

It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In naïve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.

Topics: Animals; Binding, Competitive; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Pain Measurement; Pyrroles; Receptors, Opioid, mu; Substance Withdrawal Syndrome

To explore the effect of sinomenine on the nitric oxide (NO)/neural nitric oxide synthase (nNOS) system in the cerebellum and spinal cord of morphine-dependent and morphine-withdrawal Kunming mice, mice were subjected to injection of morphine with an increasing dose for 5 d, and then were treated with sinomenine (40 mg/kg, i.p.) for another 5 d. Naloxone was used to develop acute withdrawal, and the withdrawal syndromes, including teeth chattering, twisting, straightening, sneezing and ptosis, were investigated. nNOS mRNA expressions in the cerebellum and spinal cord were determined by semi-quantitative RT-PCR. nNOS activity and NO level were determined by the chemistry-colorimetry and nitrate reductase-reduction, respectively. The results obtained were as follows: (1) Sinomenine restored the decrease in body weight and alleviated the signs of morphine-withdrawal in mice. (2) Sinomenine also reduced the increases in nNOS mRNA expression and nNOS activity resulting from morphine-dependence, and simultaneously attenuated the high level of NO in both tissues following morphine-withdrawal. (3) Administration of sinomenine alone did not develop physical dependence in mice. The results obtained indicate that sinomenine may attenuate morphine addiction and significantly alleviate morphine-withdrawal symptoms, and the mechanism may be associated with the effect of sinomenine on the NO/nNOS system in the cerebellum and spinal cord.

Topics: Animals; Body Weight; Cerebellum; Male; Mice; Morphinans; Nitric Oxide; Nitric Oxide Synthase Type I; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome

7-Hydroxymitragynine is a potent opioid analgesic alkaloid isolated from the Thai medicinal herb Mitragyna speciosa. In the present study, we investigated the opioid receptor subtype responsible for the analgesic effect of this compound. In addition, we tested whether development of tolerance, cross-tolerance to morphine and naloxone-induced withdrawal signs were observed in chronically 7-hydroxymitragynine-treated mice. Subcutaneous (s.c.) administration of 7-hydroxymitragynine produced a potent antinociceptive effect mainly through activation of mu-opioid receptors. Tolerance to the antinociceptive effect of 7-hydroxymitragynine developed as occurs to morphine. Cross-tolerance to morphine was evident in mice rendered tolerant to 7-hydroxymitragynine and vice versa. Naloxone-induced withdrawal signs were elicited equally in mice chronically treated with 7-hydroxymitragynine or morphine. 7-Hydroxymitragynine exhibited a potent antinociceptive effect based on activation of mu-opioid receptors and its morphine-like pharmacological character, but 7-hydroxymitragynine is structurally different from morphine. These interesting characters of 7-hydroxymitragynine promote further investigation of it as a novel lead compound for opioid studies.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Subcutaneous; Male; Mice; Mitragyna; Models, Molecular; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Reaction Time; Secologanin Tryptamine Alkaloids; Substance Withdrawal Syndrome; Thailand

To investigate the effects of sinomenine on morphine withdrawal response and acetylchline (Ach)-induced contracture in isolated guinea pig ileum.. The withdrawal contracture was elicited by subjecting isolated ileum incubated with morphine (3 micromol/L) at 37.5 degrees Celsius for 4 h to naloxone (1 micromol/L) treatment. Sinomenine (10, 50, 250 micromol/L) and nimodipine (Nim, 0.1 micromol/L) were administered 1 min before and after naloxone in morphine-dependent ilea bathed in Krebs solution containing morphine, to observe the changes in the withdrawal contracture of the ileum. The effect of sinomenine (10, 50, 250 micromol/L) on the contracture of untreated ileum in Krebs solution elicited by acetylcholine was also observed.. Naloxone-induced withdrawal contracture or acetylcholine-induced contracture of the ileum was significantly decreased in a dose-dependent manner, indicating that sinomenine can inhibit morphine withdrawal symptoms in guinea pigs.

Topics: Animals; Guinea Pigs; Ileum; Morphinans; Morphine; Morphine Dependence; Muscle Contraction; Naloxone; Nimodipine; Substance Withdrawal Syndrome

To study on the detoxification effect of sinamine in morphine-dependent rats.. Morphine-dependent rats were induced by injecting morphine on dosage increasing by degrees, then treated with medication. The withdrawal symptoms, body weight and NE, DA, 5-HT in the brain were tested.. Sinamine could alleviate withdrawal symptom, reablement body weight, inhibit neurotransmitter in the brain.. Sinamine have effects on morphine-dependent rats which may relate to modulating neurotransmitter.

Topics: Animals; Biogenic Monoamines; Body Weight; Brain; Dopamine; Male; Morphinans; Morphine Dependence; Norepinephrine; Rats; Serotonin; Substance Withdrawal Syndrome

The present study was designed to examine the modulation of the kappa-opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion. The nicotinic receptor antagonist mecamylamine, which is known to pass the blood-brain barrier, produced a place aversion in rats chronically treated with nicotine using an osmotic mini-pump. This effect was significantly attenuated by pretreatment with -opioid receptor agonists U50,488H (1.0 mg/kg, s.c.) and TRK-820 (0.03 mg/kg, s.c.). The attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by U50,488H was completely reversed by the combination with a selective -opioid receptor antagonist nor-binaltorphimine (10.0 mg/kg, i.p.). These results suggest that the activation of endogenous -opioidergic systems can suppress the mecamylamine-precipitated nicotine-withdrawal aversion.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Aversive Therapy; Conditioning, Psychological; Male; Mecamylamine; Morphinans; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spiro Compounds; Substance Withdrawal Syndrome

1. Although cholecystokinin octapeptide sulphate (CCK-8) activates the opioid system of isolated guinea-pig ileum (GPI) whether it activates the mu- or kappa-system, or both, remains unclear. Neither is it known whether CCK-8 influences the withdrawal responses in GPI preparations briefly exposed to opioid agonists. This study was designed to clarify whether CCK-8 activates mu- or kappa-opioid systems or both; and to investigate its effect on the withdrawal contractures in GPI exposed to mu- or kappa-agonists and on the development of tolerance to the withdrawal response. 2. In GPI exposed to CCK-8, the selective kappa-antagonist nor-binaltorphimine elicited contractile responses that were concentration-related to CCK-8 whereas the selective mu-antagonist cyprodime did not. 3. In GPI preparations briefly exposed to the selective mu-agonist, dermorphin, or the selective kappa-agonist, U-50, 488H, and then challenged with naloxone, CCK-8 strongly enhanced the withdrawal contractures. 4. During repeated opioid agonist/CCK-8/opioid antagonist tests tolerance to opioid-induced withdrawal responses did not develop. 5. These results show that CCK-8 preferentially activates the GPI kappa-opioid system and antagonizes the mechanism(s) that control the expression of acute dependence in the GPI.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphinans; Muscle Contraction; Naloxone; Naltrexone; Oligopeptides; Opioid Peptides; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Receptors, Opioid; Sincalide; Substance Withdrawal Syndrome

A case of opioid withdrawal precipitated in an opioid-dependent person by low plasma levels of naloxone is presented. In this patient, changes were observed in the hypothalamic-pituitary-adrenal (HPA) axis that preceded the clinical symptoms and adrenergic signs of withdrawal. Plasma naloxone levels were strongly correlated with plasma cortisol levels (P < .0001, R2 = .73, r = .85). In addition, these neuroendocrine changes persisted after adrenergic changes and clinical symptoms had been ameliorated by administration of a short-acting opioid agonist. It is suggested that the HPA axis is a more sensitive indicator of opioid withdrawal than the adrenergic system.

Topics: Drug Hypersensitivity; Female; Humans; Hypothalamo-Hypophyseal System; Middle Aged; Morphinans; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Substance Withdrawal Syndrome; Substance-Related Disorders

The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED50 values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal delta 2 opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED50 values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.

Topics: Animals; Enkephalin, Leucine; Isothiocyanates; Male; Mice; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Thiocyanates

Butorphanol has been known to act on mu-, delta-, and kappa-opioid receptors, mu- and possibly delta-receptors are thought to mediate morphine dependence. Relative to morphine, butorphanol has a higher affinity for mu- and delta-receptors. In the present study, beta-funaltrexamine (beta-FNA) and naltrindole (NTI) (nonequilibrium mu- and delta-antagonist, respectively) were used to precipitate withdrawal in butorphanol-dependent rats. It was found that beta-FNA (12, 24, 48, and 100 nM) did not elicit significant withdrawal behaviors, while NTI caused teeth-chattering (100 nM), wet shakes (100 nM), forepaw tremors (24 nM), yawning (48 and 100 nM), ejaculation (24 nM), and urination (100 nM). The present results indicate that delta-opioid receptors may be involved in mediating butorphanol dependence, while the involvement of mu-opioid receptors needs to be further investigated.

Topics: Animals; Behavior, Animal; Butorphanol; Indoles; Injections, Intraventricular; Male; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.

Topics: Animals; Body Weight; Indoles; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

Butorphanol precipitated a withdrawal syndrome in rats receiving continuous intracerebroventricular infusions of morphine for three days. However, the potency of butorphanol to induce defecation, urination, teeth chattering and escape behavior was one to two orders of magnitude less on a molar basis than that of naloxone. Wet shake behavior, a prominent feature of naloxone precipitated withdrawal, was absent in morphine dependent animals challenged with butorphanol. These data indicate qualitative as well as quantitative differences in the withdrawal syndromes induced by butorphanol and naloxone.

Topics: Animals; Butorphanol; Dose-Response Relationship, Drug; Male; Morphinans; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Topics: Butorphanol; Heart Rate; Humans; Hydromorphone; Male; Methadone; Morphinans; Naloxone; Opioid-Related Disorders; Pupil; Respiration; Skin Temperature; Substance Withdrawal Syndrome; Surveys and Questionnaires

The kappa opioid agonists, Mr 2033 and U-50, 488, or the mu opioid agonist, morphine, were administered chronically to three separate groups of rhesus monkeys. Tolerance developed to the overt signs of intoxication produced by each compound. Monkeys receiving morphine were not cross-tolerant to Mr 2033 or to U-50, 488, and monkeys receiving U-50, 488 were not cross-tolerant to morphine. Monkeys given Mr 2033 chronically were, however, cross-tolerant to morphine. When administration of U-50,488 was interrupted, or the monkeys receiving this compound were given an opioid antagonist, withdrawal behaviors were displayed that were qualitatively different from deprivation or antagonist-induced morphine withdrawal. These signs were suppressed by kappa agonists but not by morphine. Deprivation-induced withdrawal from Mr 2033 resulted in signs similar to those shown by U-50,488-dependent monkeys and some signs were observed in withdrawn morphine-dependent monkeys. Several antagonists, including the mu-selective antagonist beta-funaltrexamine, precipitated signs of withdrawal normally associated with morphine dependence in Mr 2033-dependent monkeys. Withdrawal from Mr 2033 was suppressed by kappa agonists in a stereoselective manner, and by morphine. The asymmetrical cross-tolerance and cross-dependence between Mr 2033 and morphine, and the appearance of morphine-like signs during precipitated withdrawal, suggest that Mr 2033 is kappa receptor selective but not specific. Dependence to U-50,488, however, was qualitatively and pharmacologically distinct from morphine-dependence and is apparently a consequence of specific activity at kappa receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Cyclazocine; Drug Tolerance; Endorphins; Ethylketocyclazocine; Macaca mulatta; Morphinans; Morphine; Narcotic Antagonists; Pentobarbital; Pyrrolidines; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Adult; Anesthesia, Epidural; Aspirin; Blood Pressure; Butorphanol; Caffeine; Cesarean Section; Codeine; Drug Combinations; Female; Humans; Morphinans; Nausea; Oxycodone; Phenacetin; Pregnancy; Reoperation; Substance Withdrawal Syndrome

Topics: Butorphanol; Humans; Male; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.

Topics: Animals; Behavior, Animal; Benzomorphans; Buprenorphine; Butorphanol; Codeine; Discrimination, Psychological; Humans; Macaca mulatta; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Narcotic Antagonists; Pentazocine; Piperidines; Substance Withdrawal Syndrome

Opioid agonist and antagonist properties of diastereoisomeric N-Tetrahydrofurfurylnoroxymorphones, Mr 2096 and Mr 2097 were examined in mice using the hot plate and tail flick tests and on acute dependence. Subcutaneous administrations of Mr 2096, the agonist diastereoisomer and Mr 2097, the antagonist diastereoisomer respectively produced analgesia and hyperalgesia in these tests, confirming the involvement of stereoselective opioid receptors in the regulation of thermonociception. Intracerebroventricular injection of Mr 2096 prolonged the tail flick latency, but that of Mr 2097 was without effect. The analgesic effect of Mr 2096 might be due to mimicking the descending inhibition of nociception and suppression of nociceptive reflexes at the level of spinal cord. The absence of hyperalgesia in the tail flick test following the central administration of Mr 2097 might arise from a rapid fall in concentration at relevant receptor sites and/or absence of a significant effect on the spinal reflex. In mice acutely dependent on morphine, Mr 2096 did not precipitate withdrawal. Mr 2097 behaved as an antagonist, precipitating withdrawal. These experiments indicate that stereoselective opioid receptors are involved in acute withdrawal syndrome. This study further confirms the importance of the steric properties of N-substituted moieties in Tetrahydrofurfurylnoroxymorphones.

Topics: Animals; Behavior, Animal; Humans; Injections, Intraventricular; Male; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Narcotics; Reaction Time; Stereoisomerism; Substance Withdrawal Syndrome

A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in position 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of the 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 were synthesized from oxymorphone (11), which was 3-O-benzylated, 6,14-bis-O-methylated with dimethyl sulfate, hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3, 4, 5, 7, 9, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous and oral administration. The most potent derivative in this series (15) showed a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analogue oxymorphone (11). The 14-OCH3 series also exhibited a considerably higher affinity to opioid receptors in binding studies using [3H]naloxone as ligand when compared to their 14-OH analogues.

Topics: Analgesia; Animals; Binding, Competitive; Biological Assay; Brain; Cell Membrane; Drug Evaluation, Preclinical; Humans; Indicators and Reagents; Mice; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Rabbits; Rats; Receptors, Opioid; Respiration; Structure-Activity Relationship; Substance Withdrawal Syndrome

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.

Topics: Analgesics; Animals; Benzomorphans; Catatonia; Constipation; Dose-Response Relationship, Drug; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Etorphine; Gastrointestinal Motility; Humans; Male; Morphinans; Morphine; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9 alpha-hydroxy racemate (II) whose phenolic analogue (III) is a strong antinociceptive agent, fully supportive of morphine dependence in rhesus monkeys. The di-O-acetyl derivative (VI) of III was similar to III in its profile of activity. The diastereoisomer of III (VII), obtained by hydrogenation of the methobromide of I (IV), extrusion of methyl bromide, and O-demethylation of the resultant free base (VIII), was almost inactive antinociceptively and did not suppress withdrawal symptoms in morphine-dependent monkeys. The orientation of the C-9 hydroxyl groups was deduced from spectral data and by analogy.

Topics: Analgesics; Animals; Benzoquinones; Chemical Phenomena; Chemistry; Humans; Macaca mulatta; Mice; Morphinans; Pain; Quinones; Reaction Time; Stereoisomerism; Substance Withdrawal Syndrome

Topics: Buprenorphine; Humans; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Buprenorphine is a powerful new analgesic agent with agonist and antagonist opiate receptor activity. Its withdrawal symptoms have been reported as being mild; however, its potential for abuse is not known. A case of buprenorphine abuse is reported, in which the patient's history and his response to naloxone suggest that important underlying factors were physical tolerance and dependence.

Topics: Adult; Buprenorphine; Humans; Male; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Animals; Etorphine; Female; Humans; Macaca mulatta; Male; Mice; Morphinans; Morphine Dependence; Opioid-Related Disorders; Substance Withdrawal Syndrome

The purpose of the study was to define possible self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Rats were prepared with permanent EEG and EMG electrodes and indwelling IV cannulae, made tolerant to and physically dependent on morphine, then trained to lever press for morphine IV self-injections on a fixed ratio (FR) 20 schedule of reinforcement. Rats were then spontaneously withdrawn from morphine. When these morphine post-addict rats were returned to the experimental cages three to four weeks later, they were found to reestablish self-administration of morphine as well as to establish self-administration of nalbuphine, butorphanol and pentazocine. Suppression of REM sleep for at least 30 min was apparent following self-injections of these agents. After the stabilization of self-injection patterns, withdrawal from nalbuphine and pentazocine was found to be associated with intense abstinence symptoms. However, withdrawal from morphine and butorphanol was not. It can be concluded that while drug-seeking behavior for the above narcotics in morphine post-addict rats was analogous as measured by self-administration, nalbuphine and butorphanol appeared to produce lower levels of physical dependence.

Topics: Animals; Butorphanol; Female; Humans; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Pentazocine; Rats; Rats, Inbred Strains; Self Administration; Sleep, REM; Substance Withdrawal Syndrome

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment or upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor - which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine - in comparison to pure agonists is limited, like that of other partial agonists.

Topics: Animals; Buprenorphine; Drug Tolerance; Humans; Male; Methadone; Morphinans; Morphine; Naloxone; Rats; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Substance Withdrawal Syndrome

Intravenous injections of buprenorphine, a partial opiate agonist and antagonist, maintained operant responding under second order schedule control (FR 3 VR 16:S) across a dose range of 0.005 to 0.10 mg/kg/inj. A drug naive monkey and four monkeys with a history of morphine self-administration all self-administered buprenorphine at all doses studied. Four monkeys showed dose-related increases in the total amount of buprenorphine (mg/kg) self-administered each day as the available dose increased from 0.01 to 0.10 mg/kg/inj. Injections per day remained equivalent to the number of injections at the lowest dose studied or increased significantly (p less than 0.05, 0.01), as the dose per injection increased in three monkeys. Even at high buprenorphine doses, there was no evidence of sedation. Monkeys consistently self-administered significantly more buprenorphine than saline in control studies (p less than 0.01). Buprenorphine's agonistic effects appear to persist for 24 to 48 hours. When saline and buprenorphine were available on alternate days, monkeys did not distinguish between them, but when 3 days of saline were alternated with 1 day of buprenorphine (0.03 mg/kg/inj), monkeys took significantly more buprenorphine than saline (p less than 0.02--0.001). Abrupt discontinuation of buprenorphine (0.10 mg/kg/inj) did not result in discernible withdrawal signs. The effects of buprenorphine on food intake were inconsistent, but there were no significant changes in body weight as a function of chronic buprenorphine self-administration or withdrawal. These data indicate that buprenorphine is a positive reinforcer in rhesus monkeys and maintains behavior leading to its administration on second order schedules over a wide dose range. Despite its opiate agonist properties, there was no evidence of physical dependence.

Topics: Animals; Buprenorphine; Drug Interactions; Food; Humans; Macaca mulatta; Morphinans; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome; Substance-Related Disorders

N-Ethyl-, N-(2-fluoroethyl)-, N-(2,2-difluoroethyl)-, and N-(2,2,2-trifluoroethyl)-substituted normeperidine (1b-e) and normetazocine (2b-e) derivatives were prepared. The analgesic activities of the compounds were determined in mice. Opiate receptor binding studies, in the presence and absence of sodium ion, were carried out. The antagonist activities of normetazocine derivatives were studied in monkeys. These were further examined in the isolated guinea pig ileum for relative agonist activity. The pKa values were measured; in vivo agonist acitivty was lost with weakly basic derivatives. For the normetazocine derivatives, opiate receptor binding data were consistent with guinea pig ileum agonist potency and mouse vas deferens antagonist potency but not with in vivo data. Opiate receptor binding was reduced for the less basic normetazocine derivatives. In the normeperidine series, there was no apparent direct relationship between pKa and opiate receptor binding. However, a relationship involving the hydrophobic character of the N-substituent is discussed. The N-(2-fluoroethyl) derivatives in both series were found to cause convulsions in rats at doses of 40-45 mg/kg ip. Elevated serum citrate levels were found in these rats, implicating in vivo oxidative deamination of the N-(fluoroalkyl) substituent to fluoroacetate.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Guinea Pigs; Haplorhini; Humans; Male; Meperidine; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Receptors, Opioid; Seizures; Structure-Activity Relationship; Substance Withdrawal Syndrome

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Topics: Acetates; Analgesics; Animals; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

3,6-Dimethoxy-7 beta, 17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinan (2) was converted to the 4-deoxy compound 4 and hydrolyzed to a mixture of the B/C-cis (C series) and B/C-trans (T series) isomers of 7,8-didehydromorphinan-6-one, 5. Hydrogenation of the separated isomers gave 7-methyl-6-oxo derivatives 6a. 7,8-Dimethyl-(6b) or 7-methyl-8-ethylmorphinan-6-one (6c) was prepared by reaction of 5 with lithium organocuprates. The analgesic N-methyl compounds 6 were converted to 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 10--13. Some of these compounds had mixed profiles of narcotic agonist-antagonist effects. Studies with drug-dependent monkeys indicated that several of these compounds with an analgesic-antagonist ratio of less than 0.4 substitute for morphine.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Humans; Morphinans; Morphine Dependence; Narcotic Antagonists; Substance Withdrawal Syndrome

Heroin-dependent men were given buprenorphine (a partial opiate agonist-antagonist) or a placebo under duoble-blind conditions on a clinical research ward where they could acquire heroin (21 to 40.5 milligrams per day, intravenously). Buprenorphine significantly (P less than .001) suppressed the self-administration of heroin over 10 days. Control subjects took between 93 and 100 percent of the available heroin. The effects of buprenorphine were dose-dependent; a dose of 8 milligrams per day reduced heroin use by 69 to 98 percent; a dose of 4 milligrams per day reduced heroin use by 45 percent. Termination of buprenorphie maintenance did not result in opiate withdrawal signs or symptoms. The subjects liked buprenorphine and indicated that it was preferable to methadone or naltrexone. Buprenorphine should be a safe and effective new pharmacotherapy for heroin dependence.

Topics: Adult; Buprenorphine; Double-Blind Method; Heroin Dependence; Humans; Informed Consent; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Drug Interactions; Haplorhini; Humans; Methods; Mice; Morphinans; Morphine; Naloxone; Quinones; Reaction Time; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome

Racemic 1,4-dimethyl- (1), 1,4,12 alpha-trimethyl- (2), and 1,4,12 beta-trimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine (3) have been optically resolved. The analgesic potency and physical-dependence capacity of the optical isomers and their racemic parents were determined. The levo isomers of compounds 2 and 3 were analgesically much more potent than the dextro isomers and were equipotent with morphine. Optical resolution gave no effect on the activity of compound 1. None of the optical isomers and the racemates suppressed the morphine-withdrawal syndrome in the monkey.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Macaca mulatta; Mice; Morphinans; Self Administration; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

An antagonist of morphine analgesia, N-cyclopropylmethylnorazidomorphine (CAM) inhibited the"wet shakes" appearing during spontaneous or nalorphine-precipitated morphine abstinence. CAM inhibited the pinna reflex more strongly than did morphine and selectively antagonized quipazine-induced head twitches; its inhibition of head twitches induced by 5-hydroxytryptophan or LSD seemed unspecific. The results suggest that the opiate receptors involved in the inhibition of some symptoms of morphine abstinence and of the pinna reflex differ from those involved in opiate analgesia.

Topics: 5-Hydroxytryptophan; Animals; Behavior, Animal; Drug Interactions; Humans; Lysergic Acid Diethylamide; Male; Morphinans; Morphine; Morphine Derivatives; Narcotic Antagonists; Quipazine; Rats; Reflex; Substance Withdrawal Syndrome; Time Factors

A homologous series of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the normetazocine, normorphine, and (-)-3-hydroxymorphinan series, the N-pentyl and N-hexyl derivatives do not have the analgesic potency of the parent N-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9 alpha-propylbenzomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the N-alkyl compounds are uniformly two- to threefold lower than those of the N-substituted normetazocines.

Topics: Analgesics; Animals; Benzomorphans; Brain; Haplorhini; Humans; In Vitro Techniques; Morphinans; Morphine; Narcotic Antagonists; Rats; Receptors, Opioid; Structure-Activity Relationship; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesics; Animals; Apomorphine; Behavior, Animal; Body Weight; Chlorpromazine; Dronabinol; Humans; Mice; Morphinans; Morphine; Pain; Pentobarbital; Rats; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone

Oxilorphan (levo-BC-2605) is a new, long-acting, narcotic antagonist that has agonist properties. Twenty-one (21) heroin addicts in Los Angeles were detoxified and given at least one oral dose of oxilorphan. Only three (14.3%) patients took daily doses for 14 days, which was the maximal time allowed for oxilorphan administration in this study. The remainder discontinued oxilorphan because of subjective side effects or for unknown reasons. Side effects most responsible for dropouts were dysphoria, insomnia, weakness, hallucinations, nausea, drowsiness and anorexia. Oxilorphan provided 24-hour protection with a single, oral dose, but subjective side effects encountered during inductiolinical trials with oxilorphan should be attempted with other addict populations to fully determine its potential therapeutic value.

Topics: Adult; Drug Evaluation; Female; Heroin Dependence; Humans; Male; Morphinans; Narcotic Antagonists; Substance Withdrawal Syndrome

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.

Topics: Analgesics; Animals; Behavior, Animal; Cyclobutanes; Dogs; Drug Tolerance; Female; Haplorhini; Hemodynamics; Histamine Release; Humans; Male; Mice; Morphinans; Motor Skills; Narcotic Antagonists; Oxymorphone; Pentylenetetrazole; Pupil; Rats; Reaction Time; Respiration; Saimiri; Substance Withdrawal Syndrome; Substance-Related Disorders

2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Male; Mice; Molecular Conformation; Morphinans; Morphine Dependence; Reaction Time; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome

Abstinence signs were precipitated in rats by naloxone (1 mg - kg-1 s.c.) injected at various times (from 1.5 to 16 h) after a single dose of morphine hydrochloride (15 or 50 mg - kg-1 s.c.) administered in aqueous solution. Increasing the dose of morphine increased the latency of the phenomena and the duration of the underlying state; "shifts" of signs as described by Bläsig et al. (1974) in chronically morphinized rats also occurred when increasing the dose of morphine and the time interval between the injections of morphine and of naloxone. Naltrexone and diprenorphine were also effective. These three antagonists, given before morphine, were able to prevent precipitated abstinence: however, naloxone was almost ineffective when the higher dose of morphine was used and when the time interval was long. In these latter conditions, naltrexone was definitely more effective and longer acting and diprenorphine still more so. The same characteristics were found for the protective action of the three antagonists in acutely morphinized mice and the same order for their potencies in precipitating abstinence in acutely morphinized mice. Like naloxone, naltrexone and diprenorphine facilitated a nociceptive reaction in normal mice. The abstinence signs precipitated in acutely morphinized rats or mice are probably not unmasked excitatory effects of morphine as such effects should have been increased rather than inhibited by previous administration of specific antagonists; they might correspond to potentiated effects of the antagonists themselves. The prevention by specific antagonists of the abstinence syndrome is most simply interpreted by antagonism (direct or indirect) of dependence induction, but other interpretations are not excluded.

Topics: Animals; Diprenorphine; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Naloxone; Naltrexone; Rats; Substance Withdrawal Syndrome; Time Factors

In rats made dependent on morphine by implantation of morphine pellets, withdrawal, as precipitated by intraventricular injection of morphine antagonists, was compared to withdrawal as precipitated by systemic antagonist application. The results, most clearly those obtained with a hydrophilic compound, diallyl-nor-morphinium-bromide, point to periventricularly located sites of action for the release of most withdrawal signs by antagonists. Jumping, reaching only low levels after i.ventr. injection of levallorphan and nalorphine, was very pronounced when the benzomorphane derivative SH 254, was used. In the case of writhing and diarrhea, the situation is more complicated. Possibly, central as well as peripheral mechanisms are involved in the expression of these signs.

Topics: Animals; Cerebral Ventricles; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Levallorphan; Male; Morphinans; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists; Rats; Receptors, Drug; Substance Withdrawal Syndrome

Topics: Adult; Alcoholism; Barbiturates; Cannabis; Diazepam; Drug Combinations; Drug Therapy, Combination; Female; Germany, West; Hospitals, General; Humans; Male; Methadone; Morphinans; Opium; Promethazine; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders; Thiazines

Topics: Aminopyrine; Analgesics; Animals; Behavior, Animal; Humans; Isonipecotic Acids; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Codeine; Dyspepsia; Female; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Morphinans; Phenobarbital; Substance Withdrawal Syndrome

Topics: Adult; Cyclopropanes; Drug Interactions; Female; Heroin Dependence; Humans; Infusions, Parenteral; Male; Methadone; Morphinans; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Analgesics; Animals; Humans; Lethal Dose 50; Macaca mulatta; Male; Mice; Morphinans; Optical Rotation; Phenols; Seizures; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Dogs; Dose-Response Relationship, Drug; Haloperidol; Hot Temperature; Humans; Morphinans; Morphine; Morphine Dependence; Naloxone; Propranolol; Pulse; Pupil; Reflex; Respiration; Skin; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesics; Animals; Cyclazocine; Female; Haplorhini; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentazocine; Stereotyped Behavior; Substance Withdrawal Syndrome; Substance-Related Disorders; Thebaine; Time Factors

Topics: Adult; Ataxia; Auditory Perception; Blepharoptosis; Cognition Disorders; Hallucinations; Humans; Hypertension; Hypotension; Male; Morphinans; Speech Disorders; Substance Withdrawal Syndrome; Thebaine; Tinnitus; Visual Perception

Naloxone hydrochloride, an opioid antagonist, was applied to several discrete brain regions of morphine-dependent rats to precipitate abstinence. Severe withdrawal signs were elicited after administration in the thalamus but not in neocortical, hippocampal, hypothalamic, or tegmental areas of the brain.

Topics: Animals; Brain; Cerebral Cortex; Diencephalon; Hippocampus; Humans; Hypothalamus; Male; Mesencephalon; Morphinans; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Stereotaxic Techniques; Substance Withdrawal Syndrome; Thalamus

Topics: Adolescent; Adult; Amphetamine; Barbiturates; Cannabis; Cocaine; Cognition Disorders; Factor Analysis, Statistical; Hallucinogens; Humans; Male; Morphinans; Perceptual Disorders; Psychological Tests; Socioeconomic Factors; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Brain Chemistry; Chromatography, Thin Layer; Drug Interactions; Humans; Lethal Dose 50; Levorphanol; Male; Mice; Mice, Inbred Strains; Morphinans; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome; Tartrates; Time Factors; Tritium

Topics: Animals; Drug Tolerance; Humans; Injections, Intraperitoneal; Levorphanol; Male; Mice; Morphinans; Morphine; Narcotic Antagonists; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

According to a recently proposed hypothesis, physical dependence upon alcohol is due to the formation of an endogenous opiate. We tested the hypothesis by determining whether or not ethanol-dependent mice would show typical opiate-dependent behavior (withdrawal jumping syndrome) when challenged with the opiate antagonist naloxone. Our results do not support the hypothesis.

Topics: Alcoholism; Animals; Dopamine; Ethanol; Humans; Isoquinolines; Male; Mice; Morphinans; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: American Medical Association; Female; Health Education; Heroin; Humans; Legislation, Drug; Methadone; Morphinans; Morphine; Morphine Dependence; Pain; Personality; Pregnancy; Pregnancy Complications; Socioeconomic Factors; Substance Withdrawal Syndrome; United States

Topics: Adolescent; Adult; Child, Preschool; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Maternal-Fetal Exchange; Methadone; Morphinans; Poisoning; Pregnancy; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Allyl Compounds; Carbamates; Cyclazocine; Ethers, Cyclic; Humans; Male; Methadone; Morphinans; Morphine Dependence; Narcotic Antagonists; Substance Withdrawal Syndrome; Time Factors; Tranquilizing Agents

Topics: Analgesics; Animals; Antitussive Agents; Arteries; Barium Sulfate; Blood Pressure; Body Weight; Cats; Codeine; Cough; Depression, Chemical; Dogs; Emetics; Ethers; Gastrointestinal Motility; Guinea Pigs; Humans; Mice; Morphinans; Phosphates; Rats; Respiration; Substance Withdrawal Syndrome

Topics: Analgesics; Azocines; Cyclazocine; Evaluation Studies as Topic; Heroin; Hospitalization; Hospitals, General; Hospitals, Teaching; Humans; Methadone; Morphinans; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; New York City; Outpatient Clinics, Hospital; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Brain; Brain Chemistry; Chlorine; Drug Tolerance; Humans; Hydroxyindoleacetic Acid; Male; Mice; Morphinans; Morphine; Morphine Dependence; Narcotic Antagonists; Pargyline; Phenylalanine; Placebos; Serotonin; Sodium Chloride; Substance Withdrawal Syndrome

Topics: Animals; Brain; Female; Humans; Mice; Morphinans; Morphine; Motor Activity; Narcotic Antagonists; Phenylalanine; Serotonin; Substance Withdrawal Syndrome