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Conference 2006
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3rd Berlin Stapleford
International Addiction Conference on:
Latest developments in effective
medical treatments for addiction.

Berlin March 18-19th 2006

(PP) after the title indicates Poster Presentation.

Since 1989, Stapleford international conferences have been the main forum for clinicians and researchers interested in the potential of naltrexone treatment and of the specialized techniques needed to transfer patients rapidly and effectively from opiates to naltrexone. We know that rapid transfer is best and the main argument now is about the level of sedation needed to complete the process comfortably and safely.This conference is especially timely because a very important technical advance in addiction treatment should soon become more generally available. Depot Naltrexone injections, lasting about a month, are due to receive their full US product licence as Vivitrol‘, initially for alcoholism, within the next few months. The speakers include most of the world‘s clinicians and researchers with significant experience of implant treatment. As well as papers on promising new developments, the conference also has a session on disulfi ram, now recognized as neglected but still important in alcoholism treatment (also with consistently useful effects in cocaine abuse) and on rapid benzodiazepine withdrawal - arguably the next big advance in addiction treatment. We look forward to fruitful and informative exchanges in Berlin.

C. Brewer L. Partecke





A RANDOMIZED, COMPARATIVE STUDY OF EVIDENCE-BASED ALCOHOL DEPENDENCE TREATMENTS: DISULFIRAM, NALTREXONE, AND ACAMPROSATE IN THE TREATMENT OF ALCOHOL DEPENDENCE.

Hannu Alho1,2 Esti Laaksonen1 MD

1National Public Health Inst., Dept. of Mental Health and Alcohol Research; 2Research Unit of Alcohol Diseases Unit, Univ. of Helsinki, Finland

There are several effective methods in treating alcoholism, currently several studies have shown the efficiency of disulfiram, naltrexone, and acamprosate pharmacotherapy for increasing the effectiveness of alcoholism treatment. Some studies have compared the effectiveness of these pharmacotherapies, indicating that there is no significant difference between these medications per se. However, there are no studies comparing the effect of these treatments when done with manual-based (evidence based) methods for each pharmacotherapy. Our study had two objectives: 1) To improve the quality and efficacy of the therapy by creating three cognitive evidence based manuals, and 2) to compare the efficiency of disulfiram, naltrexone, or acamprosate assisted manual based cognitive therapies. Our study was conducted as an open-label randomized multicenter trial on voluntary patients seeking help for alcoholism in occupational health services and A-clinics. Each drug group had 81 and thus a total of 243 patients. The treatment program lasted for 6 months after which patients had a 6 months follow-up period. In addition, one and half year after completing the study the assessment scales were sent to the patients again. The results showed that alcohol consumption, ALAT, GGT, AUDIT, SADD and BDI, depression scale and quality of life assessments showed significant improvement during the treatment and remained over the baseline on the follow-up period. In comparison between the three drug groups, disulfiram was significantly better than naltrexone in SADD, alcohol craving and very heavy drinking days during the weeks from the 1st to 52nd. There was no significant difference between naltrexone and acamprosate.



















METHADONE TOLERANCE TESTING: AUDIT OF A TECHNIQUE THAT CAN IMPROVE UPTAKE OF MAINTENANCE THERAPY. (PP)
Adam Bakker.
Lisson Grove Health Centre. London. NW8 [email protected]

Background: Oral methadone maintenance treatment (MMT) is a highly effective treatment for opiate addiction but in the first 2 weeks of MMT there is an increased risk of death even if the dosage is titrated slowly. Methadone tolerance testing is a technique that enables potentially fatal doses of methadone to be used from the beginning of treatment. The technique was adopted in 1995 at Lisson Grove Health Centre, an inner-city London general practice, for all admissions to MMT. Tolerance testing involves observing patients for 2 to 4 hours after administration of a test dose of methadone. Methods: A retrospective cohort study of all patients treated with methadone at LGHC in the last 10 years. Treatment files were reviewed to identify adverse events (the primary outcome) and retention in treatment (the secondary outcome). Results: One hundred and twenty-one patients underwent 141 test procedures, 119 with doses over 40mg and 22 with doses 100-150mg. There were no deaths in the first two weeks of treatment. The 121 patients accrued 360 treatment years. Average length of care was 3 years to 1/1/2005 with 66% still registered despite 71% of patients having no fixed abode. There were no serious adverse events while the treatment was able to attract and retain difficult-to-treat patients.


























PHARMACOLOGICAL STRATEGIES TO IMPROVE EFFECTIVENESS OF NALTREXONE TREATMENT FOR OPIOID DEPENDENCE (PP)

Adam Bisaga, Herbert Kleber, Edward Nuńes

Columbia University and NYS Psychiatric Institute, 1051 Riverside Dr.
New York, NY 10032, USA. [email protected]

Maintenance treatment with opioid agonists is the major pharmacological
strategy that is currently available for the treatment of opioid dependence.
However this treatment approach remains controversial and has several
limitations. An alternate pharmacological strategy, maintenance treatment
with an antagonist such as naltrexone, has several theoretical advantages.
However, naltrexone has currently limited usefulness due to poor compliance
and limited patient acceptability. Patients who discontinue naltrexone report
that while on it, they experienced persistent somatic withdrawal, mood and
anxiety symptoms, as well as heightened reactivity to drug-related cues and
stress, and intense craving for heroin. We hypothesize that targeting
these disturbances with an adjunct medication can improve tolerability
and adherence to naltrexone and provide an effective combination
treatment for opioid dependence. Several pharmacological strategies to
improve tolerability of naltrexone have been proposed. These include agents
targeting glutamatergic, adrenergic, serotonergic, or kappa opioidergic
neurotransmission. Studies supporting the use of such pharmacological
strategies will be reviewed. A controlled clinical trial has been initiated
to evaluate the efficacy of glutamatergic antagonist memantine in reducing
early attrition and improving outcome in opioid-dependent individuals
maintained on naltrexone. The design and preliminary results of this clinical
trial will be presented.





















NEWER STRATEGIES IN DE-ADDICTION – AN INDIAN PERSPECTIVE

Sanjay Chugh

S–132, Greater Kailash–11, New Delhi, India, 110048. [email protected]

Addiction is a biological disorder associated with several structural and physiological changes in different parts of the brain, especially in the area known as the Reward Centre. Failure to understand this and to apply its implications in the management of Addiction is primarily responsible for the high failure rates seen in this field in India. The Opiate addict dreads going in for Detoxification because of the intense discomfort experienced during withdrawal. With Ultra Rapid Opiate Detoxification (UROD), now done under light sedation without the use of any anesthesia, the entire procedure is over in a short time compared to conventional Detoxification. The addict’s fear of intense and prolonged withdrawal is removed and it is possible to move on the next stage of treatment, that is Antagonist Induction, smoothly. 756 Opiate addicts were detoxified using this protocol (till 15th January 2006) and in 100% cases, Naltrexone blockade was initiated. Oral Naltrexone has been used for several years in India with results incompatible with its potential. The Naltrexone implant makes relapse to the Opiate almost impossible. An implant can last for six weeks to one year. 512 addicts have so far received these implants (till 15th January 2006). The findings will be discussed in the paper. Disulfiram implants have been used alone or in conjunction with Naltrexone implants in 426 cases so far (till 15th January 2006). The experience with these implants will also be discussed.

























A PILOT STUDY OF ONCE DAILY SLOW RELEASE ORAL MORPHINE AS AN ALTERNATIVE TO METHADONE (PP)

Nicolas Clark, Katie Khoo, Nicholas Lintzeris, Alison Ritter, Gregory Whelan

Turning Point Alcohol & Drug Centre Inc. 54-62 Gertrude St, Fitzroy, Vic 3065 Australia. [email protected]

Recent formulations of morphine sulphate in polymer coated granules such as Kapanol™ allow for once daily dosing. An outpatient, open label trial was conducted comparing Kapanol™ with methadone using a randomised crossover design. Eleven stable methadone maintained patients using heroin on average once per week commenced the study. Morphine and methadone were administered once daily over a period for 6 weeks each. Heroin use was measured weekly by self report and in the last week of each treatment period by detection of 6-monoacetymorphine (6-mam) in hair and urine. Nine subjects completed the study. The mean morphine dose was 6.26 times the starting methadone dose. Morphine was generally well tolerated and was preferred by 7 out of 9 subjects. No subjects complained that morphine did not "hold" for the 24 hour dosing interval. Heroin use levels were similar throughout the study during periods of methadone and morphine treatment and there was a strong correlation between self reported heroin use and urinary 6-mam and to a lesser extent hair 6-mam. Opiate withdrawal symptoms between doses were initially higher in morphine patients in the first two weeks following transfer but then reduced to levels below that experienced with methadone. New formulations of morphine such as Kapanol™ are promising once daily alternatives to methadone for the treatment of heroin dependence.























TRANSFERING FROM HIGH DOSES OF METHADONE TO BUPRENORPHINE A RANDOMISED TRIAL OF THREE DIFFERENT BUPRENORPHINE SCHEDULES

Nicolas Clark, Nicholas Lintzeris, Damien Jolley, James Bell, Gregory Whelan, Amy Pennay

Turning Point Alcohol & Drug Centre Inc. 54-62 Gertrude St, Fitzroy, Vic 3065 Australia. [email protected],

Transferring from high doses of methadone to buprenorphine can precipitate severe opiate withdrawal symptoms, posing a dilemma for people on high doses of methadone considering alternative treatment options. We examined the severity of opiate withdrawal associated with three approaches to transferring from methadone doses between 40 and 100mg commencing with either 0.8mg, 4mg or 32mg buprenorphine and increasing to 32mg daily. Thirty participants were admitted to a residential detoxification unit and randomly allocated to one of the three different treatment approaches. All participants waited at least 2 days before commencing buprenorphine. Overall withdrawal symptoms were mild and only three patients did not complete the transfer. Higher methadone doses, a shorter time period between methadone and buprenorphine and female sex were associated with more severe withdrawal. The low and high buprenorphine dose schedules resulted in less opiate withdrawal. There were also differences in the pattern of opiate withdrawal following buprenorphine with the low dose group having less withdrawal following the first dose of buprenorphine and the high dose group having the shortest duration of opiate withdrawal. When taking withdrawal features, medication use and drop out into consideration, low doses and high doses appear to result in better outcomes than doses in between. Participants were followed up for three moths post transfer, at which time 18 patients were still taking buprenorphine. Overall, heroin use reduced and quality of life improved significantly as a result of the transfer, particularly in those who chose to remain on buprenorphine or cease OST completely.


















NEW TREATMENTS, NEW CHALLENGES. PERSISTENT INTRAVENOUS OPIATE ABUSE DESPITE ADEQUATE BLOCKADE WITH NALTREXONE.

Peter Coleman, Colin Brewer

The Stapleford Centre, London. SW1W 9NP [email protected]

Many patients who choose treatment with long-acting parenteral naltrexone (NTX) preparations never put the resultant opiate blockade to the test. If they do, it is often just a single episode, apparently motivated by a need to reassure themselves that the implants really do block heroin or, occasionally, other opiates. Patients who test-out in this way seem no more likely to relapse after the implant expires than patients who do not test-out. This behaviour is consistent with the considerable pharmacological sophistication, as well as the healthy curiosity and scepticism, characteristic of many heroin users. However, in several years experience of providing NTX implant treatment, we have encountered a small number of patients who continued to inject heroin despite the complete absence of opiate agonist activity, as shown by no objective signs of agonist action on supervised opiate challenge, supported, in some cases, by conventionally adequate NTX blood levels. These patients are different from those who inject buprenorphine (BPN) because at high levels, BPN may displace NTX from opiate receptors; and also from those who resume injecting heroin when they confirm their belief (or hope) that NTX levels have fallen below the minimal required for total blockade. We describe some cases and speculate on the psychological and pharmacological mechanisms, including needle addiction, which may lead to this rare behaviour that does not always lead to long-term relapse. One pharmacological mechanism may be opiate-provoked histamine release, providing a poor but sufficient substitute for heroin euphoria.























A COMPARISON OF ORAL AND IMPLANT NALTREXONE OUTCOMES AT 12 MONTHS

Ross Colquhoun, Donald Tan, Samantha Hull

Addiction Treatment and Psychology Services, Broadway Healthcare, Level 1, Broadway Shopping Centre, 1 Bay Street, Broadway, 2007, Australia. [email protected]

Naltrexone’s current use has been limited by compliance. Subcutaneous implants would seem to offer a solution to this problem and improve long-term outcomes. The aim of the present study was to compare groups of patients who had received oral naltrexone or a naltrexone implant after detoxification and to follow their progress. Forty-one patients received an implant, and 42 patients received oral naltrexone. They were surveyed at one, three, six, and 12 months after detoxification. Their designated support person was also contacted to confirm the self-reports of participants. Patients were compared on gender, age, and length of time since detoxification. Implant patients showed much higher abstinence rates, while those in both groups who were abstinent showed greater compliance to naltrexone (time spent in treatment) and attended more counselling sessions. Although the participants were not randomly allocated to each treatment condition, the preliminary evidence indicated that implants can improve compliance rates and outcomes.



























GENERAL ANAESTHESIA DOES NOT IMPROVE OUTCOME IN OPIOID ANTAGONIST DETOXIFICATION TREATMENT

Cor A.J. De Jong, Paul F.M. Krabbe

Novadic-Kentron, Schijndelseweg 46, 5491 TB St. Oedenrode, Netherlands. [email protected], [email protected]

Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. The EDOCRA study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without anaesthesia. In a randomised controlled open clinical trial from September 1999 to August 2001, 272 opioid-dependent patients whose previous attempts to abstain were unsuccessful were detoxified by means of rapid induction with naltrexone. Patients received rapid detoxification with general anaesthesia (RD-GA) or without general anaesthesia (RD) in an inpatient facility. The detoxification period was divided in a highly intensive detoxification programme of three days and a three days recovery period. Outcome was measured by means of urine screens and an interview (EuropASI) to assess opioid abstinence; two questionnaires (SOOS, OOWS) to measure withdrawal symptoms and several secondary outcome measures (craving, psychopathology and quality of life). All patients left the inpatient facility taking naltrexone. There were no differences between RD-GA and RD concerning withdrawal, craving, psychopathology or quality of life during the first week. One month after the intervention 62.8 % of the patients in the RD-GA group and 60.0 % in the RD group were abstinent for opioids (p=0.71). No adverse events or complications occurred during RD; however, in the RD-GA group, five adverse events necessitated admission to a general hospital. The average one-month cost for RD was € 2517 versus € 4439 for RD-GA. Conclusions: Rapid detoxification under general anaesthesia did not result in higher levels of opioid abstinence than rapid detoxification without anaesthesia. The cost of the former intervention was much higher.














RAPID OPIOID DETOXIFICATION UNDER GENERAL ANAESTHESIA: DOES THE BENEFIT OF GENERAL ANAESTHESIA OUTWEIGH THE RISK?

Catherine de Jong,

Anesthesiologist. Amsterdam. [email protected]

Rapid Opioid Detoxification under Anesthesia (RODA) has been a treatment option for opioid addicts since 1987. Unfortunately RODA was mainly done in private clinics and the anesthesiologists did not publish their data. Newspapers stories appeared where RODA was portrayed as a miracle cure for addiction. Then stories of patients dying after RODA appeared and this was blamed on the use of General Anaesthesia (GA). In anaesthesiology, developments have been impressive the last 20 years. With new monitoring and other equipment, it has become possible to keep a patient stable and safe under anaesthesia for long periods of time. New anaesthesic drugs have led to new possibilities. GA has a low patient-impact nowadays and is now used for medically unnecessary procedures such as liposuction or facelifts and for procedures that can easily be done under local anaesthesia such as operations on hands, feet or eyes. It is not uncommon nowadays for a patient to walk out of hospital one hour after waking up from GA. So what is the problem with validating GA for RODA? Publications on RODA and its complications show mainly one of the following items: giving GA despite a contra indication; an inadequate anaesthesia protocol; manifestations of underlying diseases, common in addicted patients, that appear after RODA; inadequate medical treatment of withdrawal symptoms. This paper will discuss the RODA literature and the complications that are usually incorrectly blamed on GA. A retrospective descriptive study of a group of patients undergoing RODA will be presented, as will an anaesthesiologist’s view of the decision process on whether or not to provide a GA for RODA.





















STUDIES OF FAMILY SUPERVISED DISULFIRAM, NALTREXONE & ACAMPROSATE IN THE INDIAN SETTING
Avinash De Sousa

Get Well Clinic and Nursing Home, Mumbai. India. [email protected]

Disulfiram (DSF) has been a rather neglected entity in the long term management of alcoholism. There has been off late a paucity of data on Disulfiram and its effectiveness when compared to naltrexone (NTX) and acamprosate (ACP). Studies comparing DSF to NTX and ACP have proven DSF to be significantly more effective than these drugs. In a one year trial in an Indian clinical setting comparing DSF and NTX, relapse occurred at a mean of 119 days with DSF compared to 63 days with NTX (p = 0.020). 86% of the patients remained abstinent throughout the year with DSF compared to just 44% with NTX (p = 0.0009). In an 8-month study comparing DSF and ACP, it was seen that relapse occurred at a mean of 123 days with DSF compared to 71 days with ACP (p = 0.0001). At the end of the study 88% of patients with DSF were abstinent compared to 46% with ACP (p = 0.0002). In both studies the patients on NTX and ACP had lower craving scores than the patients with DSF. Disulfiram is the drug of choice for the long-term management of alcoholism as it is the only agent that actually puts the brakes on the consumption of alcohol. The need for supervised therapy by family members is emphasized and reasons for the popularity and widespread use of DSF in India are discussed. Future research underway in these areas and some extraordinary cases are presented. Further studies between DSF and various agents used in the long-term management of alcoholism in varied clinical settings are warranted.























DOES NALTREXONE INFLUENCE CRAVING IN OPIOID-DEPENDENT PATIENTS AFTER DETOXIFICATION?

Boukje Dijkstra, Paul F.M. Krabbe, Cor A.J. DeJong

Novadic-Kentron, Rompertsebaan 28, 5231 GT ’s-Hertogenbosch, The Netherlands. [email protected]

Naltrexone is an opioid antagonist and is used for rapid detoxification. Naltrexone blocks the opioid receptors and blocks therefore the effects of heroin. It is primarily used in the management of alcohol and opioid dependence. Its use in alcohol dependence has shown to be effective. Patients reported lower craving levels, had fewer relapses and had less alcohol consumption than placebo. For opioid dependence, findings are less clear. Naltrexone reduces relapse in opioid use, only if high compliance is guaranteed. There are only a few studies on the effect of naltrexone on craving. Because of the opioid-induced euphoria mechanism and because of the modulation of the dopaminergic brain reward system, it is expected that craving should be decreased by taking naltrexone.
During the EDOCRA study, a randomised controlled trial in which the add-on effect of general anesthesia was examined during rapid detoxification induced by naltrexone, patients were followed during 16 months. Data about abstinence, relapse and naltrexone use are collected by means of urine specimens and self report . Craving is measured by the VAS craving, the Obsessive Compulsive Drug Questionnaire (OCDUS) and the Desires for Drug Questionnaire (DDQ). The course of experienced craving during and after detoxification is examined and the influence of administration of naltrexone was analysed.























HIGH EFFECTIVENESS OF LONG-TERM DISULFIRAM IN A STRUCTURED OUTPATIENT REHABILITATION PROGRAMME
Hannelore Ehrenreich, Henning Krampe
Division of Clinical Neuroscience, MPI of Experimental Medicine, Hermann-Rein-Str. 3 37075 Göttingen Germany. [email protected]

Objective: (1) To perform a 9-year study of abstinence, lapse and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as adjunct for maintenance of long-term abstinence. Method: This prospective open treatment study evaluates long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993-2002. Subsamples are compared regarding (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, (3) AD use for 13-20 versus >20 months. Results: In this 9-year study, cumulative probability of not having relapsed was 0.52, of not having consumed any alcohol 0.26. Despite long-term use, disulfiram/calcium carbimide were well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S=.86 versus S=.49, p=.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p<.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p<.001). The cumulative abstinence probability was S=.75 for patients with long-term intake compared to S=.50 for patients who stopped AD between months 13 and 20 (p<.001). Conclusions: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be employed as predominantly psychologically acting ingredient of successful alcoholism therapy.



















AN EFFECTIVE DISULFIRAM IMPLANT - BUT IS THIS THE WAY FORWARD?

Morris D. Faiman,

Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA [email protected]

Disulfiram (DSF) implants have been considered for alcoholism treatment. However, a DSF implant has significant limitations. First, the size of the implant may be too large, and secondly, DSF requires biotransformation to the active metabolite S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). No relationship exists between the plasma concentration of DSF or its metabolic intermediates and ALDH2 inhibition. Bioactivation is a complex oxidative process, using the cytochrome P450 (CYP) system. Inter-patient variation in CYP enzyme activity can affect the formation of sufficient active metabolite (DETC-MeSO), contributing to inter-patient variability in the dose of DSF required to produce the desired DER. We have formulated a DSF implant; however, the implant developed may be physically too large for appropriate use. A DETC-MeSO implant (significantly lower dose required than DSF) also has been formulated. DETC-MeSO is further oxidized to the sulfone (DETC-MeSO2) which then reacts with glutathione to form carbamathione [S-(N, N-diethylcarbamoyl) glutathione], a partial inhibitor of the NMDA receptor. The glutamatergic system has been implicated in alcohol craving. Carbamathione does not inhibit ALDH2. Using microdialysis techniques, carbamathione is found in the nucleus accumbens of the brain of rats after the administration of DSF. We propose that DSF has two effects, a peripheral effect (liver ALDH2 inhibition), and a central effect on the glutamatergic system. Implants can be made from either DETC-MeSO or carbamathione. To produce a DER, DETC-MeSO should be used, and for an anti-craving response carbamathione should be employed.




















VIVITROL: DEVELOPMENT, EFFECTIVENESS AND PROSPECTS OF INJECTABLE NALTREXONE

David Gastfriend.

Alkermes Inc. 88 Sydney St. Cambridge MA 02139-4137 USA [email protected]

Abstract not yet received.








































NALTREXONE AS ANTICRAVING TREATMENT:
A PSYCHOPHYSIOLOGICAL EVALUATION

Grüsser, S.M, Ziegler, S, Thalemann, C, Partecke, L.

Interdisciplinary Research Group on Addiction, Institute for Medical Psychology, Charité - University Medicine, Berlin, Germany

The present studies investigated psychophysiological aspects after different methods of withdrawal treatments in opiate addicts had been conducted. Two pharmacological strategies based on delivering an opioid agonist (Levomethadone) or antagonist (Naltrexone) were used for withdrawal in opioid addicts. After detoxification, the antagonist was delivered by pellet implanted subcutaneously. In a psychometric investigation four days after beginning the treatment several psychological variables such as craving, anxiety, depression, and mood were assessed and compared with data from actively consuming opiate addicts. In addition, 6 and 12 weeks later the relapse rates were assessed. Based on the assumption that addictive behavior is a learned behavior, in a second psychophysiological investigation, the emotional processing of opiate-relevant as well as opiate-irrelevant stimuli was assessed in treated opiate addicts as well as healthy controls using the cue-ractivity paradigm. Stimuli-induced physiological (EEG) as well as psychological (craving, mood, disorders) parameters were assessed. Data analyses of the psychometric investigation revealed that compared with addicts detoxified and treated with Levonmethadone as well as actively heroin consuming addicts, subjects treated with Naltrexone demontrated significantly higher positive psychological outcome concerning all assessed variables and significantly lower relapse rates. Naltrexone implants prove prevention of relapse during the most vulnerable period after detoxification. Compared with Levomethadone withdrawal, they lead to a significantly better condition in patients. In addition, results of the second psychophysiological assessment showed that electroencephalographic acitivities (late positive complex) differences between healthy controls and addicts appear to be influenced by the addiction state and choosen kind of treatment. Compared to Levomethadone treated patients subjects treated with Naltrexone showed a less emotional-motivational involvement when watching the opiate-relevant visual stimuli.














USE AND MISUSE OF BUPRENORPHINE AMONG HEROIN AND AMPHETAMINE ADDICTS IN MALMO, SWEDEN (PP)

Anders Hakansson, Alvaro Medvedeo, Mats Berglund, Magnus Andersson

Clinical Alcohol Research, Lund University, Malmo University Hospital, entrance 108, S-20502 Malmo, Sweden. [email protected] [email protected]

Studies have documented illicit and intravenous misuse of buprenorphine. This study investigates buprenorphine misuse among injecting drug users (IDUs) attending the Syringe Exchange Program (SEP) of Malmo, Sweden. A survey addressed 357 IDUs, asking about buprenorphine use, means of acquisition, purpose of intake and usual administration route. Data were treated anonymously. Respondents were amphetamine (57 %, n=204) or heroin addicts (42 %, n=150). Eighty-nine percent of heroin addicts (n=133) and 24% of amphetamine addicts (n=49) had used buprenorphine at some time during the last year. Most users obtained buprenorphine illegally: 87 % (n=116) in the heroin group, and 94 % (n=46) in the amphetamine group. Among heroin addicts reporting illicit buprenorphine use, eighty-seven percent (n=101) took buprenorphine only for treatment of withdrawal symptoms or self-detoxification, and only 10% for euphoria. Among amphetamine addicts, sixty-one percent (n=28) admitted euphoria seeking when taking illicit buprenorphine. Among illicit buprenorphine users altogether (heroin or amphetamine addicts), injection as a usual administration route was reported by 43% (n=69), and snorting by 30% (n=48). Using buprenorphine only sublingually was reported by 46% and 20% in the heroin and amphetamine groups, respectively. Use of illicit buprenorphine was widespread, mostly among heroin addicts for self-medication. Among illicit buprenorphine users, few heroin addicts, but a majority of amphetamine addicts, reported euphoria seeking. Consistently with previous studies, intravenous misuse was common. Snorting of illicit buprenorphine was also common.


















INFLUENCE OF PSYCHIATRIC COMORBIDITY ON ADDITIONAL ABUSE OF DRUGS IN MAINTENANCE TREATMENT WITH L- AND D/L-METHADONE

U. Havemann-Reinecke, D. Wedekind, S. Jacobs, I. Karg, C. Lüdecke, U. Schneider, K. Cimander, E. Rüther, W. Poser

University of Goettingen, Dept. of Psychiatry and Psychotherapy, von Siebold Str. 5, D37075 Goettingen, Germany, [email protected]

The influence of psychiatric comorbidity on additional abuse of drugs in maintenance treatment with either L- or D/L-Methadone was studied in a first explorative study. 60 methadone razemate (D/L) or L-methadone treated patients in maintenance therapy were interviewed with a questionnaire based on the EuropASI. Comorbidity was assessed using the Mini-DIPS. 51.7 % of subjects (75% male) had a comorbid axis-I disorder. Anxiety- (36.7%) and affective disorders (30%) were seen most frequently with a higher prevalence in female addicts (p = 0.05). Among the affective disorders dysthymia had the highest prevalence (23.4%). In axis-I-comorbid addicts a trend to earlier onset of regular substance consumption (p = 0.09) and to a higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin, was found. They received a significantly lower D/L-methadone (p < 0.05) and L-methadone dose (not significant) than non-comorbid patients. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (p < 0.01). Patients with additional heroin intake received a lower L- but not D/L-methadone dosage (p <0.05). To conclude, comorbid anxiety- and depressive disorders seem not to be correlated with higher intake of additional heroin, but with a more frequent abuse of benzodiazepines, alcohol, and cannabis. Higher dosages of D/L-methadone (and L-methadone) seem to decrease axis-I comorbidity. In the lower and middle dosage range L-, but not D/L- methadone seems to be more effective in reducing additional heroin abuse.



















TISSUE COMPATABILITY, BIODEGRADABILITY, BLOOD NALTREXONE LEVELS, AND HEROIN OVERDOSE FOLLOWING TREATMENT OF HEROIN DEPENDENT PERSONS WITH SUSTAINED RELEASE NALTREXONE-POLY(DL-LACTIDE) IMPLANTS

G K Hulse, V Low, V Stalenberg, N Morris, R Thompson, R J Tait,
D Arnold-Reed, D McCallum, W Smit, G O’Neil.

School of Psychiatry and Clinical Neurosciences, University of Western Australia. [email protected]

Four independent studies assessed in vivo human tissue compatibility, biodegradability, and blood naltrexone levels associated with different implant doses, and overdose in heroin dependent persons treated with the Australian subcutaneous naltrexone-poly(DL-lactide) implant. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue biopsy samples taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Ultrasound assessment of 139 clearly identifiable implant sites from 71 human subjects at various periods post-implant showed a significant decrease in mass and length of implant detectable from the time of implantation until total absence by ≥896 days. In humans blood naltrexone levels remained above 2ng/ml for 147 days compared to 164 days following 3.4g or 5.0g naltrexone implant insertion respectively, suggesting that no significant clinical efficacy is achieved by using the larger size implant mass. In a large cohort of heroin dependent persons (n=361; 218 males) no opioid overdose was observed in the six months post-treatment, with a reduced number observed seven to twelve months post-implant compared to pre-treatment levels. The results of these studies indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated, biodegradable, sustains blood naltrexone levels for extended periods, and prevents opioid overdose, suggesting it may have a role in the management of heroin dependence.

















A ‘BIORELEVANT’ APPROACH TO DRUG RELEASE TESTING OF A BIODEGRADABLE NALTREXONE IMPLANT

Sunil S. Iyer, H. Thomas Karnes, William H. Barr

School of Pharmacy, Box 980533, Virginia Commonwealth University, Richmond VA, USA 23298.

Characterization of the in vitro and in vivo release profiles of a drug from a long-acting implant dosage form constitutes an important step in developing and optimizing effective long acting delivery systems for naltrexone. Accelerated in vitro methods are also important to assure effectiveness of manufactured dosage forms. The Fédération Internationale Pharmaceutique/American Association of Pharmaceutical Scientists (FIP/AAPS) have provided Guidelines1 for drug release testing of modified release dosage forms using the modified USP Apparatus 4 (flow-through cell), but details on such studies are generally not found in the literature2,3. To incorporate ‘biorelevance’ to implant drug release studies, we have investigated an approach to apparatus design and media selection that is significantly different from the conventional dissolution studies involving oral dosage forms4,5. Biodegradable implants of naltrexone were obtained from Durect Corp., USA. A modified Hank’s Balanced Salts Solution6 has been used as a ‘biorelevant’ medium for drug release studies of this implant. Naltrexone was found to be sufficiently stable in the medium. A miniature, cell-culture, capillary system7 was tested as a ‘biorelevant’ alternative to the modified flow-through apparatus, to mimic significant barriers to drug release that would be expected in vivo. The in vitro release profiles generated up to 3 months using both devices indicate considerable (up to 2-fold) variation in rates, as can be expected from the difference in media flow characteristics. Scanning Electron Micrographs reveal the persistence of an intact, slightly swollen, membrane sheath around the implant; a careful examination however, reveals the formation of channels due to penetration of the medium. Research in progress includes a study to evaluate potential correlation with in vivo pharmacokinetic parameters of dog, and a method to accelerate drug release in vitro.

















MANAGED WITHDRAWAL FROM GHB: A PROPOSED DETOXIFICATION PROTOCOL (PP)

Mary E. Janssen van Raay, Cor A.J. de Jong, Renate Tillema, Hein de Haan

Novadic-Kentron, Schijndelseweg 46, 5491 TB St. Oedenrode, Netherlands.
[email protected]

Dependence on Gamma-hydroxybutyric acid (GHB), also in the forms of gamma-butyrolactone (GBL) or 1,4-Butanediol (1,4-BD) is an increasing problem in the Netherlands and other countries since its first appearance on the party scene during the early nineties of the last century. GHB dependent-patients will take a new dose every 2-4 hours also during the night, no longer for its pleasurable effects but to avoid withdrawal symptoms. One to six hours after the last dose of GHB a severe withdrawal syndrome starts with restlessness, anxiety, insomnia, hallucinations, and delirium.. This syndrome is preferably treated in an in-patient setting with heavy doses of benzodiazepines, pentobarbital, propofol or other general anaesthetics. In our addiction treatment centres a new detoxification strategy has been developed and tested in an open non-randomized design. Experience in our institution (data will be presented) has shown this to be a safe method. The next step is that the method will be evaluated in a randomized clinical trial in two of our facilities. Two groups of patients will be gradually tapered from GHB using a pharmaceutically made version of the substance itself to do so. The proposed study protocol is that after a titration phase to determine the correct starting dose, patients will receive either a tapering dosage or the same dosage with extending the time between the gifts. The rationale behind this latter method is a gradual desensitization for GHB.























MAINTENANCE TREATMENT WITH ORAL NALTREXONE FOR OPIOID DEPENDENCE – A SYSTEMATIC REVIEW AND META-ANALYSIS
Björn Axel Johansson, Mats Berglund and Anna Lindgren

Clinical Alcohol Research, Lund University, Malmö University Hospital, Sweden.
[email protected]

Aims: To study the effects of naltrexone for opioid dependence with a meta-analytical technique. Sample and Methods: Fifteen studies involving 1,071 patients were found. First, randomised controlled trials (RCTs) comparing the regimens of treatment using the opioid antagonist, naltrexone, with controls were analysed by meta-analysis for treatment effect (Software: Comprehensive Meta-Analysis, Biostat™, 1998) with regard to a range of outcome criteria. Degree of heterogeneity was also determined. Then the moderating effect of other interventions during naltrexone maintenance was estimated, particularly with regard to their effect on treatment retention. All available outcomes were analysed in 10 studies of naltrexone vs. control (7 placebo) and 6 studies of randomised psychosocial-psychopharmacological interventions. Results: Significant heterogeneity was found in the efficacy of naltrexone. Level of retention in treatment was found to be a moderator, explaining most of the heterogeneity found. Overall, naltrexone was significantly better than control conditions in reducing the number of opioid positive urines. This effect was only present in the high retention sub-group for differences in retention. Contingency management (CM) increased retention and naltrexone use, resulting in a reduced number of opioid positive urines. Conclusion: Retention is important to the effect of naltrexone in treating opioid dependence. Contingency management is a promising method of increasing retention.





















EFFECTS OF KETAMINE ON PRECIPITATED OPIATE WITHRAWAL (PP)

Tomas Jovaisa, Giedrius Laurinenas, Saulius Vosylius, Juratė Sipylaitė,
Robertas Badaras, Juozas Ivaškevičius

Vilnius University Clinic of Anaesthesiology and Intensive Care. Siltnamiu 29, Vilnius, Lithuania. [email protected]

NMDA antagonists were shown to be effective in suppressing the symptoms of opiate withdrawal. This study was designed to evaluate effects of sub-anaesthetic ketamine infusion, as little human data is available on ketamine in precipitated opiate withdrawal. 58 opiate dependent patients were enrolled in randomised, placebo controlled, double-blind study. Patients underwent rapid opiate antagonist induction under general anaesthesia. Prior to opiate antagonist induction patients were given either placebo (normal saline) or sub-anaesthetic ketamine infusion of 0.5 mg/kg/h. Further evaluations were split into three phases: anaesthetic, early post-anaesthetic (48 hours) and remote at 4 months after procedure. Cardiovascular, respiratory, renal and gastrointestinal responses to opiate antagonist induction were monitored during anaesthesia phase. Changes in plasma cortisol concentrations were measured as stress-response markers. Post-anaesthetic evaluations were based on Subjective and Objective Opiate Withdrawal Scales. Remote effects were assessed according to questionnaire based on Addiction Severity index. 50 patients were included in final analysis. ‘Ketamine group’ presented better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant differences between ketamine and control groups were noted in anaesthetic and early post anaesthetic phases. There were no differences in effects on outcome after 4 months. In this study sub-anaesthetic ketamine infusion was effective adjuvant in correction of acute precipitated opiate withdrawal, although had no long-term effects on treatment of opiate dependence.



CLINICAL TRIALS OF DEPOT NALTREXONE IN OPIATE ABUSERS

Herb Kleber.

Columbia University and NYS Psychiatric Institute, 1051 Riverside Dr.
New York, NY 10032, USA. [email protected]

Abstract not yet received


NALTREXONE IMPLANTS TO PREVENT RELAPSE AFTER INPATIENT TREATMENT FOR OPIOID ADDICTION: A RANDOMISED CONTROLLED TRIAL. (PP)

Nikolaj Kunře, Philipp Lobmaier & Helge Waal.

University of Oslo, Department of Psychiatry, Unit for Addiction Medicine, Kirkeveien 166, NO-0407 Oslo, Norway [email protected]

This trial investigates the efficacy and safety of O´Neill naltrexone double implants in preventing relapse for patients that are soon to complete treatment for opiate addiction in inpatient (or similarly controlled) settings. A maximum of 100 volunteers that complete inpatient treatment for opioid addiction in 2006 are included in the study in a trickle design. Patients complete standardised interviews and questionnaires on drug use, work and social integration, quality of life, depression, anxiety, as well as hair samples. Prior to discharge, they are randomized to an implant group or a waiting-list control for the duration of the first six months. All participants retain full social- and healthcare rights and -benefits while in the study, and have implants and implantations conducted free of charge. After six months, both groups will be reassessed and offered naltrexone implants for the remaining six months of the study. The initial waiting list control group will be offered reimplantation following the final reassessment at the end of the study at 12 months, giving all participants the opportunity of two implantation periods independent of their initial group randomisation. Main hypotheses are: 1.Quality of life will increase, depression and opioid use decrease, in the implant group compared to controls at 6-month follow-up. 2.Choosing reimplantation after six months will strengthen positive tendencies or reverse negative tendencies. 3. Implants will prevent opioid-related death for 4-6 months. Challenges are, among others, attrition in the waiting-list control group following randomisation, and attrition at the scheduled follow-up intervals.











A MATCHED CASE-CONTROL STUDY OF NALTREXONE IMPLANTS FOR RELAPSE PREVENTION IN DETOXIFIED OPIOID ADDICTS.

Nikolaj Kunře, Philipp Lobmaier & Helge Waal.

University of Oslo, Department of Psychiatry, Unit for Addiction Medicine, Kirkeveien 166, NO-0407 Oslo, Norway.
[email protected]

The Unit for Addiction medicine has gradually gained experience with naltrexone implant research, yielding valuable experiences regarding naltrexone serum analyses as well as a preference for the O’Neill implant. The positive experiences encouraged us to increase our research effort by initiating two controlled studies, one RCT with prison inmates, and the present study, which originally intended to recruit 100 patients about to complete inpatient treatment for opioid dependence. Patients volunteered for study participation, receiving an O’Neil double naltrexone implant prior to discharge, being offered reimplantation at 6 and 12 month followup. Participation was granted on condition that a control could be found, matching the implant candidate on gender, age (+/- five years), opioid type and mode of administration (i.e. injection, smoking). Controls were offered implants at 6 and 12-month followup, and were compensated 25€ for each interview. Recruiting control patients proved difficult, resulting in only 6 matched pairs being recruited in 2005 (n=12), of which half the controls had recently completed significantly more inpatient treatment than other participants. We decided to stop recruitment to the project and label it a pilot study, starting a new RCT study from january 2006. Still, all patients in the pilot study reached 6-month followup. Controls did better than implant patients on most measures of drug use, quality of life and mental health at baseline, but preliminary analyses suggest these differences are reversed after six months. This strongly suggests that naltrexone implants are an effective aid in preventing opioid relapse after completion of inpatient treatment for opioid addiction.


















NALTREXONE IMPLANTS VS METHYADONE MAINTENANCE TREATMENT FOR OPIOID DEPENDENCE AMONG PRISON INMATES IN NORWAY (PP)

Philipp Lobmaier, Nikolaj Kunře, Helge Waal

Unit for Addiction Medicine, University of Oslo, Kirkeveien 166, 0407 Oslo, Norway
mail to: [email protected]

Opioid dependence is closely related to criminal behaviour with a high prevalence of drug abuse among inmates. While incarcerated, most drug offenders abstain from regular use and are often motivated to begin treatment. Oral naltrexone, when systematically linked to incentives such as working programs or parole, has shown promising results in prison settings; implantable naltrexone may be an effective alternative. This open-label, crossover, randomized controlled trial evaluates the effects of implantable naltrexone for relapse prevention in a sample of opiate dependent inmates, compared to a control group treated with methadone maintenance. Participants are recruited from five prisons in the greater Oslo area. Poly drug users are included, if opioids can be considered the main drug of abuse. Random allocation is completed and medication started while incarcerated. All participants have monthly clinical follow-up meetings with staff from the home community's social services, including a GP. At follow-up 6 (12, 18) months after release, participants complete a EuropASI interview and a hair sample is taken for drug analysis. Study group crossover is optional at any follow-up; the study ends 18 months after prison release. Delinquency and relapse to opioid use are the study's primary outcome measures. Secondary outcome measures are dysphoria, use of other illicit drugs, satisfaction with and quality of life.























SUBJECTIVE SLEEP AND RESTLESS LEGS BEFORE, DURING AND AFTER OPIATE WITHDRAWAL

Ellis H.B. Magnée, Cor A.J. de Jong

Department GGZ-groep Noord- en Midden Limburg, Wanssumseweg 12, 5807 EA Oostrum, The Netherlands. [email protected]

Subjective sleep complaints are common during withdrawal from opiates. Although patients complain about poor sleep quality, fragmentation of sleep and Periodic Limb Movement Disorder (PLMD), hardly any research has been done to study these complaints. The EDOCRA study was designed to study the effects of withdrawal methods, which includes the use of naltrexone. During the EDOCRA study, the sleep of 14 subjects was studied, using sleep-logs and actigraphy. These data where completed with the same variables from 7 inpatients who were in the methadone detoxification program. The sleep-logs were used to study subjective sleep before, during and after opiate withdrawal. Actigraphy was used to objectify the complaint of PLMD. Furthermore a sleep specialist saw all subjects for a sleep diagnosis before and after detoxification. The results show that 29% of the subjects had difficulty falling asleep before withdrawal, whereas 45% showed the same complaints after withdrawal. Almost 20% complained about early awakenings during opiate use, but after withdrawal 65% had these complaints. Furthermore the results show a drastic raise of the number of subjects that was diagnosed with PLMD after opiate withdrawal. Although these results suggest a link between the opiate withdrawal and PLMD, further research is needed to study the long term effects of opiate withdrawal on PLMD and subjective sleep complaints.
























RAPID OPIATE DETOXIFICATION PRECIPITATED BY SUBCUTANEOUS NALTREXONE PELLET IMPLANTATION USING KETAMINE ANAESTHESIA.

Wayne Moran, E.Warne,

Hong Kong Detox. [email protected] www.hkdetox.com

Rapid opiate detoxification (ROD) is recognized as having a significantly higher success rate than conventional opiate withdrawal techniques as patient compliance is virtually 100%. If this is coupled with subcutaneous implantation of the opiate antagonist Naltrexone, relapse rates are also significantly reduced. Anaesthetic techniques for ROD generally involve the use of either general anaesthesia or heavy sedation. In order to achieve adequate levels of anaesthesia for pain and stress-free detoxification endotracheal intubation is considered, by many, to be essential to reduce the risk of aspiration. Ketamine is a dissociative anaesthetic which provides excellent analgesia without CNS depression. Indeed, its actions of cardiac & respiratory stimulation coupled with hyperreflexia has led to its extensive use as a safe anaesthetic by surgeons ‘in the field’ in situations when a qualified anaesthetist is unavailable. In ketamine anaesthesia endotracheal intubation is contraindicated and aspiration is rare due to the hyperactive cough reflex. We report a series of Naltrexone-induced ROD in a series of 77 opiate addicts in Hong Kong. Ages ranged from 15-62 and included 57 males and 20 females. Ketamine anaesthesia was used in 42 cases. Dosage of ketamine was titrated in accordance with level of withdrawal symptoms. None of the patients were intubated and there was no incidence of aspiration. All patients displayed tachycardia, tachypnoea & hypertension as an expected response to the ketamine and naltrexone induction and these did not require treatment. Most also had salivary hypersecretion easily managed with suction. A few patients exhibited bradycardia & hypotension 12-24 hours after stopping ketamine. These responded to medical intervention. Other minor complications and their management are also discussed. Emergence phenomena, a common complication of ketamine anaesthesia, was well tolerated by all the patients probably due to previous experience with hallucinogenics. Conclusion: Ketamine is a safe and effective method of anaesthesia for ROD and should be considered by physicians providing ROD without a qualified anaesthetist.















DEVELOPMENT OF THE PERIPHERAL OPIATE ANTAGONIST METHYLNALTREXONE: POTENTIAL USES IN ADDICTION

Jonathan Moss,

Department of Anesthesia and Critical Care, University of Chicago, [email protected]

Methylnaltrexone was developed to antagonize the peripheral adverse effects of opiates while preserving centrally mediated analgesia. MNTX is the quaternary derivative of the opioid antagonist naltrexone. MNTX is currently being evaluated to prevent or treat opiate-induced inhibition of GI motility in advanced medical illness (AMI), chronic pain, and postoperatively. In volunteer studies, oral, sq, and iv MNTX prevented the morphine-induced delay in oral-cecal transit time without affecting analgesia. The efficacy of MNTX in opiate-tolerant individuals was studied in a double-blind, placebo-controlled, randomized clinical trial of 22 chronic methadone maintenance subjects. Subjects received MNTX iv on an ascending dose schedule. All 11 subjects responded with laxation within one minute of MNTX injection but no subject showed psychological or physical signs of opiate withdrawal. Similar effects were noted with oral MNTX in 12 methadone maintenance subjects, but over hours. Two recently reported randomized, double-blind, placebo-controlled trials, in which 154 and 133 patients with AMI received sq MNTX (0.15 or 0.3 mg/kg) or placebo with either a single dose or over 2 weeks, followed by open label therapy demonstrated laxation in 50-60% of patients, usually within one hour, without evidence of pain reversal (p<0.0001 vs placebo). Other effects including nausea and vomiting, urinary retention, gastric emptying, dysphoria, and pruritis have been evaluated in volunteers. Importantly, unlike addicted subjects given naloxone, our subjects experienced none of the hemodynamic sequelae associated with acute withdrawal. We also established that the gut was supersensitive to MNTX, implying a change in µ opiate receptors in the gut with chronic exposure. Recent Phase 1 data using alvimopan in volunteers exposed to and withdrawn from morphine suggests that such changes in opiate receptors in the gut occur over 10 days. Therefore, a potential new therapeutic option to attenuate the severity of detoxification could be a phased approach in which MNTX is initially used to reset peripheral receptors prior to later use of tertiary antagonists. A second potential use of MNTX is to foster compliance with maintenance programs. Aside from improved gut function, there may be other benefits to MNTX in this population. For example, methadone facilitates replication of the CCR5 binding explaining the increased infectivity described in HIV-positive patients receiving opiates. In our in vitro study, doses of MNTX (10-10M ) block opiate induced increases in the CCR5 receptor, as well as viral replication and entry in this model system, suggesting a potential therapeutic role in the clinical setting of HIV positive patients receiving opiates for AIDS pain or addiction.









NMDA RECEPTOR ANTAGONISTS DURING RAPID INDUCTION OF NALTREXONE UNDER PROPOFOL SEDATION. (PP)

Mohamed Abdel Raouf Nasr

Dept of anesthesia, Cairo University, Cairo, Egypt. [email protected]

It has been shown that rapid opioid detoxification is associated with increased sympathetic activity (SYMP) and plasma catecholamine. This will lead to a lot of symptoms and signs (abdominal cramps, arthralgias, myalgias, muscle spasms, hypertension, tachycardia, tachypnea, agitation, anxiety, irritability, insomnia, lacrimation, diaphoresis, piloerection, diarrhea, rhinorrhea, nausea, vomiting, yawning, and dilated pupils) that may endanger life or make the technique unsatisfactory. The N-methyl-D-aspartate (NMDA) receptor is an excitatory amino acid receptor that has been implicated in the modulation of prolonged pain states both in animal and human models. Chronic morphine treatment significantly alters NMDA receptor-mediated synaptic transmission in the accumbens, and these effects persist 1 week after withdrawal. This study demonstrates the outcome using two different NMDA receptor antagonists as well as their combination during rapid induction of naltrexone under light propofol sedation. Patients in group I received intravenous magnesium sulfate (blocks NMDA receptor at normal resting membrane potential). Patients in group II received intravenous low-dose ketamine (a non-competitive NMDA receptor blocker acting on phencyclidine recognition site) Patients in group III received the combination in identical doses. Patients received first a bolus dose of the studied drug (5g magnesium over 30 minutes in group I, 10g.kg-1 ketamine in group II, and the combination in group III). This was followed by infusion of (1) 0.4mg naloxone every hour (2) 5-25 g. kg-1. min-1 Propofol infusion of the studied drug(s), 1g magnesium every hour in group I, ketamine 5g kg-1. h-1 in group II, and the combination in group III. After six hours another bolus of the studied drug was given with a bolus of 0.4mg naloxone. This was followed by naltrexone implant insertion. The results showed marked improvement in abdominal cramps, arthralgias, myalgias, muscle spasms, hypertension, tachycardia, tachypnea, agitation, anxiety, and irritability; minimal or no change in insomnia, lacrimation, diaphoresis, piloerection, diarrhea, rhinorrhea, nausea vomiting, yawning, and dilated pupils. The improvement was maximum in group III (combined) and least in group I (ketamine).















NALTREXONE IMPLANTS FOR AMPHETAMINE DEPENDENCE (PP)

George O’Neil, Zoe Parsons, Phil O’Neil, J X Xu, Gary Hulse

65 Townshend Rd, Subiaco, Perth WA 6008. Australia. [email protected]

13 of 53 patients were available for a telephone interview to review the effectiveness of naltrexone implants for amphetamine dependence. It is estimated that there are 60 million amphetamine addicts worldwide. Lindstrom has reported improvement in 11 amphetamine dependent patients (p-value <0.01) treated with oral naltrexone tablets. We have requests for treatment from a large population of amphetamine patients, many of whom have previously been dependent on amphetamines. To date there is no established pharmacotherapy for amphetamine dependence. 8 of 11 patients treated with naltrexone implants confirmed a decrease in amphetamine use in the three months after commencing treatment. The average number of injecting days in the 90 days before and after the implant changed from 67.1 to 29.8 (p<0.016). The average decrease in injecting days for the 8 patients who were responsive to treatment was 58.6 to 17.1 (p<0.000347). Of these patients, four (31%) had reported that they had not used amphetamines since their last implant, after an average of 249 days. The average number of years using amphetamines in the patients reviewed was 9.92 years. 27% appeared to be non-responders. The statistical significant decrease (P<0.000347) in number of using days amongst the responders deserves a prospective randomised controlled trial comparing the effect of active and placebo implants. This is the first work defining a possible place for naltrexone implants in managing amphetamine dependence.
























THE PROBLEM OF INTRAVENOUS BUPRENORPHINE INJECTION WITH NALTREXONE IMPLANTS.

George O’Neil, Zoe Parsons, Gary Hulse

65 Townshend Rd, Subiaco, Perth WA 6008. Australia. [email protected]

Buprenorphine is known to have a high affinity for the opiate receptor and is potentially one of the most difficult drugs to manage with diversion occurring frequently. In Western Australia we have managed abscess formations in the neck, limbs, groin, as well as vessel thrombosis including femoral and upper limb vessels. We have also noted bacterial endocarditis with valve replacement, associated with intravenous methamphetamine use in addition to subutex. One patient presented with septicaemia leading to meningitis with severe cerebral oedema which required three weeks ventilation in an intensive care unit. Patients with naltrexone implants may be only partially protected by their implants and even with serum levels of naltrexone above 4ng/mL the patients are at risk of intravenous buprenorphine addiction when large doses of buprenorphine (32mg dose) are given intravenously. One death occurred in a patient with an active implant from alcohol, benzodiazepines, amphetamines and buprenorphine. The withdrawal symptoms lead to intense craving and in some cases a severe withdrawal illness. In some patients we have found oral naltrexone 50mg daily or twice daily may be useful in shortening the withdrawal illness. Conclusion We should encourage formal research to test whether subutex or suboxone is equally acceptable to intravenous buprenorphine injectors. Until there is evidence that suboxone is less acceptable to intravenous buprenorphine injectors, dispensing buprenorphine should include as many precautions to eliminate diversion with suboxone as have been set up for subutex.























THE USE OF LONG ACTING NALTREXONE IMPLANTS FOR ALCOHOL ADDICTION (PP)

George O’Neil, Zoe Parsons, Elsie Tan, Philip O’Neil, Gary Hulse

65 Townshend Rd, Subiaco, Perth WA 6008. Australia. [email protected]

23 of 71 patients were available at the time of conducting a phone survey for a review of patients treated with a naltrexone implant for alcohol addiction. Most patients (73%) had consumed some alcohol following their implant procedure. The average length of time to the first post-implant drink was 49 days and the average duration of the first relapse was 32 days. Of the 19 patients who reported on craving, 9 (47%) claimed they had no craving for alcohol following their first implant. For all 23 patients, frequency of alcohol consumption decreased from an average of 21.7 drinking days per month to an average of 4.7 drinking days per month after treatment. Our patients averaged 20 standard drinks per day prior to treatment. The average age was 39 and the average age of commencing alcohol consumption was 18 years. The average number of years of drinking was 21 years. In response to a series of questions, the patients reported a marked improvement in their relationship with themselves, their community and their ability to deal with legal, educational and employment issues. In the event of a future relapse, 69% reported that they would immediately use another implant while 31% stated they would not. 21% stated that they would return for further implants to maintain naltrexone levels even if no return of craving or drinking occurred. In summary, our review of 23 alcohol patients confirmed a reduction in drinking days for the group (p > 0.0001). Larger prospective studies comparing active and placebo implants are required.























RAPID BENZODIAZEPINE DETOXIFICATION: AN OUTPATIENT SERVICE?

George O’Neil, Rebecca Moore, Zoe Parsons, Gary Hulse

65 Townshend Rd, Subiaco, Perth WA 6008. Australia. [email protected]

Flumazenil, a benzodiazepine antagonist, has been marketed for the treatment of benzodiazepine