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Determinants of withdrawal in a methadone maintenance population
0-9 Addiction II
68 withdrawal periods (0, 3 or 14 days) after 10 days of treatment of Sprague-Dawley rats with cocaine (10 mg/kg, IP) and before a challenge injection of cocaine (10 mglkg , IP) on locomotor sensitization, on the relative concentration of dopamine bound to its D I-like and D2-like receptors in the nucleus accumbens, and on the relative concentration of serotonin on its cortical 5-HT2 receptors were investigated. Relative concentrations of neurotransmitters bound to their receptors were assessed using established receptor binding techniques after treatment with EEDQ, an agent that irreversibly denatures a variety of receptors. The degree of protection from EEDQ-den aturation is taken as a measure of ligands bound to the receptors. Receptor occupation of both DI -like and D2-like receptors in the nucleus accumbens is increased in rats exhibiting behavioural sensitization after 0 or 3 days withdrawal, but not after 14 days withdrawal. In contrast, occupation of cortical 5-HT2 receptors is increased only after 0 days of withdrawal. Neither increases in dopamine occupation of its receptors in the nucleus accumbens, nor cortical 5HT2 receptor occupation can account for behavioural sensitization at all withdrawal times.
I0-9-4 1 Smoked or I.V. Cocaine Binges in Humans: Is There a "Crash"? R.W Foltin, M.W. Fischman. Columbia University and NYS Psychiatric
Institute. New York, NY The clinical literature suggests that intermittent cycles of repeated cocaine dosing, i.e., binges, followed by abrupt cessation of cocaine use are associated with a distinct pattern of withdrawal symptoms and signs. Experienced cocaine users, including some maintained on methadone, completed a protocol investigating changes in behavior after the selfadministration of cocaine. During sessions, subjects could self-administer up to 6 doses of i.v, cocaine (32 mgn O kg), smoked cocaine (50 mg), or placebo. Both 2- and 3-binge cycle conditions were tested. During the 2-cvcle condition. a cocaine self-administration/choice session occurred in the afternoon and again in the evening on 2 consecutive days, while during the 3-cycle condition. choice sessions occurred on 3 consecutive days. Self-reported effects were obtained during each session as well as the morning after each choice day and 2 no-drug days following each binge cycle. Several patterns of maximal morning-after scores were evident I) Opiate Symptoms, abstinence symptoms, and Beck Depression scores were greater during 3-binge cycles compared to 2-binge cycles, 2) Opiate Symptoms. abstinence symptoms, sleep disturbance, and ratings of "Anxious" remained elevated following 3-binge cycles, i.e., "crash", and 3) although abstinence symptoms. sleep disturbance. and ratings of "Anxious" increased during 2-binge cycles. these effects did not persist after dosing. Methadone maintenance minimized the crash. Thus. the repeated self-administration of cocaine in a binge pattern over several days produces subjective effects after the cessation of cocaine use which may be described as a "crash". The cocaine crash is dose-dependent, affected by route of cocaine administration, and other drug dependence. Supported by NIDA grant DA-08105 and NIH grant MOI-RR-00645
I0 -9-51
Determinants of Withdrawal In a Methadone Maintenance Population
J.M. White, K.R. Dyer, F. Bochner, A. Menelaou, A.A. Somogyi. Department of Clinical & Experimental Pharmacology, Department of
Psychology, University of Adelaide. Australia Methadone maintenance reduces illicit opioid use and improves the health and social functioning of heroin users. However, one cause of poor compliance with the program is the failure of methadone to be effective over the whole 24-hour inter-dosing interval. A significant proportion of methadone maintenance patients report opioid withdrawal symptoms in the period prior to each dose. While these patients may be more sensitive to withdrawal symptomatology, a limited number of case studies suggests that they may have elevated rates of methadone clearance. The present study was designed to compare patients who experienced such symptoms with a group who did not, in order to determine whether they also differed in other measures of opioid effect. Eighteen methadone maintenance patients were admitted to an inpatient unit for a single 24-hour period. Measures were made of self-reported withdrawal severity, subjective
response, pain sensitivity. pupil diameter and respiratory rate . Blood samples were collected to determine plasma concentrations of methadone. All measures showed temporal patterns consistent with a maximal opioid effect approximately 3-4 hours post-dosing and maximal withdrawal immediately prior to each dose. Subjects with higher withdrawal intensity also showed greater degree of change in the other measures , as well as plasma methadone concentrations. These results indicate that failure of methadone to ' hold' over the full 24-hour period is associated with more pronounced rises and falls in methadone concentrations and effects and may be due to enhanced methadone clearance in this patient group. The common practice of using tough methadone concentrations to test the validity of self-reports of withdrawal symptomatology is inappropriate.
I0-9-6 \ A Rapid Discontinuation of Opiates and Benzodiazepines in Dependent Patients
E.H. Bennie, N. Poole. Department of Psychiatry, Levemdale Hospital,
Glasgow,
ux.
This is an open clinical report documenting the use of Zuclopenthixol (Z.A.) in two groups of drug dependent patients, those dependent on a high dose of maintenance Methadone and a second group dependent on a high dose of Benzodiazepines. All patients had expressed a desire to be withdrawn from the drug on which they had become dependent, and had consented to the experimental regime using Z.A. which had been explained to them in writing. Following out-patient assessment where the drug history was taken the patient was admitted to hospital and following pre-medication with Lorazepam they were given a 100 mg of Z.A. intramuscularly which was repeated within 72 hours. No further Methadone was given after the first injection of Z.A. Classical withdrawal signs were minimal and patients were relaxed and calm throughout the study period. Methadone abstinence was confirmed by a Naloxone challenge test. Benzodiazepine dependent patients were progressively withdrawn from their drug over a three day period, no significant withdrawal signs were observed. During the treatment with Z.A. the patients were able to take food and fluids orally, they were drowsy and contented, but readily arousable. Z.A. did not induce any adverse reactions in patients so far studied.
I0-9-7 1 Lofexidine in the Treatment of Heroin Withdrawal - A Comparative Studywith Clonidine S.K. Lin. L.W Su, c.r. Tsai, WH. Hu. Departmentof Addiction
Science, Taipei City Psychiatric Center, Taipei, Taiwan Lofexidine is an analogue of clonidine, an agonist of Cl'z noradrenergic receptor. There are some reports comparing clonidine and lofexidine in the treatment of opiate (mostly methadone) and alcohol withdrawal. In this study we compared lofexidine with clonidine in treating heroin withdrawal. Eighty hospitalized heroin addicts (male/female: 65115 ; age: 31.7 ± 7.0 yrs; body weight: 61.5 ± 8.9 kg; duration of addiction: 4.3 ± 5.3 yrs) were treated with lofexidine or clonidine during withdrawal period in a randomized double blind basis. Abstinence Symptom Rating Scale (ASRS) was used three times a day to monitor the acute opiate withdrawal syndrome. Blood pressure was checked four times a day before medication. The maximal daily dose was 1.6 mg for lofexidine, 0.6 mg for clonidine, respectively. The result showed that there was no significant difference in demographic data, changes in ASRS between two groups. Clonidine significantly decreased blood pressure than lofexidine (p < 0.05, by repeated measures). In conclusion, lofexidine is as effective as clonidine in treating heroin withdrawal syndrome, yet the side effect is much less in term of blood pressure decrease.
1 0-9-8
1 Neuropeptide Y Attenuates Naloxone-Precipitated Morphine Withdrawal In Rats
D.P.D. Woldbye, T.G. Bolwig. Lab.for Experimental Neuropsychiatry,
The National University Hospital. Dept. of Psychiatry, Copenhagen, Denmark Neuropeptide Y (NPY), a 36 amino acid polypeptide, is widely distributed in the e NS. NPY has been implicated in a number of medical disorders
68 withdrawal periods (0, 3 or 14 days) after 10 days of treatment of Sprague-Dawley rats with cocaine (10 mg/kg, IP) and before a challenge injection of cocaine (10 mglkg , IP) on locomotor sensitization, on the relative concentration of dopamine bound to its D I-like and D2-like receptors in the nucleus accumbens, and on the relative concentration of serotonin on its cortical 5-HT2 receptors were investigated. Relative concentrations of neurotransmitters bound to their receptors were assessed using established receptor binding techniques after treatment with EEDQ, an agent that irreversibly denatures a variety of receptors. The degree of protection from EEDQ-den aturation is taken as a measure of ligands bound to the receptors. Receptor occupation of both DI -like and D2-like receptors in the nucleus accumbens is increased in rats exhibiting behavioural sensitization after 0 or 3 days withdrawal, but not after 14 days withdrawal. In contrast, occupation of cortical 5-HT2 receptors is increased only after 0 days of withdrawal. Neither increases in dopamine occupation of its receptors in the nucleus accumbens, nor cortical 5HT2 receptor occupation can account for behavioural sensitization at all withdrawal times.
I0-9-4 1 Smoked or I.V. Cocaine Binges in Humans: Is There a "Crash"? R.W Foltin, M.W. Fischman. Columbia University and NYS Psychiatric
Institute. New York, NY The clinical literature suggests that intermittent cycles of repeated cocaine dosing, i.e., binges, followed by abrupt cessation of cocaine use are associated with a distinct pattern of withdrawal symptoms and signs. Experienced cocaine users, including some maintained on methadone, completed a protocol investigating changes in behavior after the selfadministration of cocaine. During sessions, subjects could self-administer up to 6 doses of i.v, cocaine (32 mgn O kg), smoked cocaine (50 mg), or placebo. Both 2- and 3-binge cycle conditions were tested. During the 2-cvcle condition. a cocaine self-administration/choice session occurred in the afternoon and again in the evening on 2 consecutive days, while during the 3-cycle condition. choice sessions occurred on 3 consecutive days. Self-reported effects were obtained during each session as well as the morning after each choice day and 2 no-drug days following each binge cycle. Several patterns of maximal morning-after scores were evident I) Opiate Symptoms, abstinence symptoms, and Beck Depression scores were greater during 3-binge cycles compared to 2-binge cycles, 2) Opiate Symptoms. abstinence symptoms, sleep disturbance, and ratings of "Anxious" remained elevated following 3-binge cycles, i.e., "crash", and 3) although abstinence symptoms. sleep disturbance. and ratings of "Anxious" increased during 2-binge cycles. these effects did not persist after dosing. Methadone maintenance minimized the crash. Thus. the repeated self-administration of cocaine in a binge pattern over several days produces subjective effects after the cessation of cocaine use which may be described as a "crash". The cocaine crash is dose-dependent, affected by route of cocaine administration, and other drug dependence. Supported by NIDA grant DA-08105 and NIH grant MOI-RR-00645
I0 -9-51
Determinants of Withdrawal In a Methadone Maintenance Population
J.M. White, K.R. Dyer, F. Bochner, A. Menelaou, A.A. Somogyi. Department of Clinical & Experimental Pharmacology, Department of
Psychology, University of Adelaide. Australia Methadone maintenance reduces illicit opioid use and improves the health and social functioning of heroin users. However, one cause of poor compliance with the program is the failure of methadone to be effective over the whole 24-hour inter-dosing interval. A significant proportion of methadone maintenance patients report opioid withdrawal symptoms in the period prior to each dose. While these patients may be more sensitive to withdrawal symptomatology, a limited number of case studies suggests that they may have elevated rates of methadone clearance. The present study was designed to compare patients who experienced such symptoms with a group who did not, in order to determine whether they also differed in other measures of opioid effect. Eighteen methadone maintenance patients were admitted to an inpatient unit for a single 24-hour period. Measures were made of self-reported withdrawal severity, subjective
response, pain sensitivity. pupil diameter and respiratory rate . Blood samples were collected to determine plasma concentrations of methadone. All measures showed temporal patterns consistent with a maximal opioid effect approximately 3-4 hours post-dosing and maximal withdrawal immediately prior to each dose. Subjects with higher withdrawal intensity also showed greater degree of change in the other measures , as well as plasma methadone concentrations. These results indicate that failure of methadone to ' hold' over the full 24-hour period is associated with more pronounced rises and falls in methadone concentrations and effects and may be due to enhanced methadone clearance in this patient group. The common practice of using tough methadone concentrations to test the validity of self-reports of withdrawal symptomatology is inappropriate.
I0-9-6 \ A Rapid Discontinuation of Opiates and Benzodiazepines in Dependent Patients
E.H. Bennie, N. Poole. Department of Psychiatry, Levemdale Hospital,
Glasgow,
ux.
This is an open clinical report documenting the use of Zuclopenthixol (Z.A.) in two groups of drug dependent patients, those dependent on a high dose of maintenance Methadone and a second group dependent on a high dose of Benzodiazepines. All patients had expressed a desire to be withdrawn from the drug on which they had become dependent, and had consented to the experimental regime using Z.A. which had been explained to them in writing. Following out-patient assessment where the drug history was taken the patient was admitted to hospital and following pre-medication with Lorazepam they were given a 100 mg of Z.A. intramuscularly which was repeated within 72 hours. No further Methadone was given after the first injection of Z.A. Classical withdrawal signs were minimal and patients were relaxed and calm throughout the study period. Methadone abstinence was confirmed by a Naloxone challenge test. Benzodiazepine dependent patients were progressively withdrawn from their drug over a three day period, no significant withdrawal signs were observed. During the treatment with Z.A. the patients were able to take food and fluids orally, they were drowsy and contented, but readily arousable. Z.A. did not induce any adverse reactions in patients so far studied.
I0-9-7 1 Lofexidine in the Treatment of Heroin Withdrawal - A Comparative Studywith Clonidine S.K. Lin. L.W Su, c.r. Tsai, WH. Hu. Departmentof Addiction
Science, Taipei City Psychiatric Center, Taipei, Taiwan Lofexidine is an analogue of clonidine, an agonist of Cl'z noradrenergic receptor. There are some reports comparing clonidine and lofexidine in the treatment of opiate (mostly methadone) and alcohol withdrawal. In this study we compared lofexidine with clonidine in treating heroin withdrawal. Eighty hospitalized heroin addicts (male/female: 65115 ; age: 31.7 ± 7.0 yrs; body weight: 61.5 ± 8.9 kg; duration of addiction: 4.3 ± 5.3 yrs) were treated with lofexidine or clonidine during withdrawal period in a randomized double blind basis. Abstinence Symptom Rating Scale (ASRS) was used three times a day to monitor the acute opiate withdrawal syndrome. Blood pressure was checked four times a day before medication. The maximal daily dose was 1.6 mg for lofexidine, 0.6 mg for clonidine, respectively. The result showed that there was no significant difference in demographic data, changes in ASRS between two groups. Clonidine significantly decreased blood pressure than lofexidine (p < 0.05, by repeated measures). In conclusion, lofexidine is as effective as clonidine in treating heroin withdrawal syndrome, yet the side effect is much less in term of blood pressure decrease.
1 0-9-8
1 Neuropeptide Y Attenuates Naloxone-Precipitated Morphine Withdrawal In Rats
D.P.D. Woldbye, T.G. Bolwig. Lab.for Experimental Neuropsychiatry,
The National University Hospital. Dept. of Psychiatry, Copenhagen, Denmark Neuropeptide Y (NPY), a 36 amino acid polypeptide, is widely distributed in the e NS. NPY has been implicated in a number of medical disorders