Naltrexone Implant Research
Depot naltrexone: long-lasting antagonism of the effects of heroin in humans. Comer SD, Collins ED, Kleber HD, Nuwayser ES, Kerrigan JH, Fischman MW.Psychopharmacology (Berl). 2002 Feb;159(4):351-60.
Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA. sdc10@columbia.edu
RATIONALE: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. OBJECTIVE: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex).
Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA. sdc10@columbia.edu
RATIONALE: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. OBJECTIVE: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex).
METHODS: Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192 mg naltrexone base and six participants received 384 mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25 mg, i.v.) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. RESULTS: The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1 ng/ml for approximately 3 and 4 weeks after administration of 192 mg and 384 mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. CONCLUSIONS: These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin.
A pilot study to assess the impact of naltrexone implant on accidental opiate overdose in 'high-risk' adolescent heroin users. GK Hulse and RJ Tait. Addict Biol, September 1, 2003; 8(3): 337-42.
University School of Psychiatry and CLinical Neurosciences, QE II Medical Centre, Nedlands, Western Australia. ghulse@cyllene.uwa.edu.au
A pilot study to assess the impact of naltrexone implant on accidental opiate overdose in 'high-risk' adolescent heroin users. GK Hulse and RJ Tait. Addict Biol, September 1, 2003; 8(3): 337-42.
University School of Psychiatry and CLinical Neurosciences, QE II Medical Centre, Nedlands, Western Australia. ghulse@cyllene.uwa.edu.au
Morbidity and mortality rates for regular heroin users are much greater than those observed in the general population. In 'high-risk' heroin users implantable naltrexone has been used under Commonwealth Therapeutic Goods Administration Compassionate guidelines in Western Australia since August 2000. This pilot study compared the frequency of accidental opiate overdose and other morbidity resulting in hospital presentations in eight 'high-risk' dependent heroin using adolescents pre- and post-naltrexone implant treatment. We reviewed the hospital medical records retrospectively for t he participants across the four public hospitals in Perth. The review period was September 1999-October 2002. The eight adolescents (aged 15-19 years) initially underwent naltrexone implant treatment between September 2000 and September 2001.The data indicated a dramatic reduction in opiate overdose post-implantable naltrexone treatment, with a smaller reduction in opiate overdose during oral naltrexone treatment compared to the pre-oral/implant period. Implant treatment in the high-risk heroin user may provide an importantprophylaxis against mortality associated with accidental opiate overdose.
These encouraging findings now require validation using a larger cohort over an extended period
Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels.Addict Biol. 2003 Jun;8(2):211-7. Foster J, Brewer C, Steele T.
Department of Biochemistry, Kings College Hospital, London, UK.
Early relapse is common after opiate withdrawal and deprives addicts of important opportunities to develop new, opiate-free cognitive-behavioural habits. The oral opiate antagonist naltrexone (NTX) significantly reduces relapse only when rigorously supervised and/or probation-linked. Simple but effective NTX implants, containing 1G NTX and giving an average blockade of 6 - 7 weeks, have been available since 1997. We present outcome data for two cohorts. Group 1 were the first 55 consecutive implanted British patients (76% male, 51% unemployed, 64% in social classes III - V). Group 2 were a second consecutive group of 46. Implants were inserted subcutaneously mainly during rapid opiate detoxification under general anaesthesia or sedation. The follow-up rate for group 1 was 100%. At 12 weeks after first implantation, 21% of group 1 patients and 26% of group 2 patients had apparently resumed opiate use. Thirty per cent of patients tested-out the blockade in the first week. None reported any opiate effects at less than 5 weeks after insertion. In other patients, typical blood NTX levels 4 - 5 weeks post-insertion were in the range 3 - 5 ng/ml, which is evidently enough to block 500 mg of pure diamorphine. NTX implants provide considerable protection against early relapse and may increase the likelihood of therapeutically useful periods of abstinence after opiate withdrawal. Troublesome tissue reactions were infrequent. Improvements in implant technology and duration are already occurring. We stress that implants strengthen rather than replace the therapeutic alliance.
These encouraging findings now require validation using a larger cohort over an extended period
Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels.Addict Biol. 2003 Jun;8(2):211-7. Foster J, Brewer C, Steele T.
Department of Biochemistry, Kings College Hospital, London, UK.
Early relapse is common after opiate withdrawal and deprives addicts of important opportunities to develop new, opiate-free cognitive-behavioural habits. The oral opiate antagonist naltrexone (NTX) significantly reduces relapse only when rigorously supervised and/or probation-linked. Simple but effective NTX implants, containing 1G NTX and giving an average blockade of 6 - 7 weeks, have been available since 1997. We present outcome data for two cohorts. Group 1 were the first 55 consecutive implanted British patients (76% male, 51% unemployed, 64% in social classes III - V). Group 2 were a second consecutive group of 46. Implants were inserted subcutaneously mainly during rapid opiate detoxification under general anaesthesia or sedation. The follow-up rate for group 1 was 100%. At 12 weeks after first implantation, 21% of group 1 patients and 26% of group 2 patients had apparently resumed opiate use. Thirty per cent of patients tested-out the blockade in the first week. None reported any opiate effects at less than 5 weeks after insertion. In other patients, typical blood NTX levels 4 - 5 weeks post-insertion were in the range 3 - 5 ng/ml, which is evidently enough to block 500 mg of pure diamorphine. NTX implants provide considerable protection against early relapse and may increase the likelihood of therapeutically useful periods of abstinence after opiate withdrawal. Troublesome tissue reactions were infrequent. Improvements in implant technology and duration are already occurring. We stress that implants strengthen rather than replace the therapeutic alliance.
Naltrexone implants--a pilot project. H Waal, AS Christophersen, G Frogopsahl, LH Olsen, and J MorlandTidsskr Nor Laegeforen, June 12, 2003; 123(12): 1660-1.
Instituttgruppe for psykiatri, Seksjon for kliniske rusmiddelproblemer, Universitetet i Oslo, MARIO, Kirkeveien 166, 0407 Oslo. helge.waal@psykiatri.uio.no
BACKGROUND: An increasing number of Norwegian heroin addicts have had naltrexone implants abroad without proper documentation. The authors established a joint project to study duration and safety. MATERIAL AND METHODS: Methodology to measure naltrexone in plasma was developed. 10 patients had 21 implants. Plasma samples were collected before, one and three hours after implantation, daily for one week, then weekly. Patient satisfaction, side effects and unwanted medical events were recorded. RESULTS: Patients had a protective level of naltrexone for 35-80 days.
Side effects were few. Two patients had abstinence reactions caused by insufficient detoxification. Two patients had their repeat implants removed because of tissue reactions. One patient developed hepatitis C infection in the second week after implantation. One had transient increase in transaminases after heavy multi-drug use. The others were without signs of hepatic toxicity. INTERPRETATION: Use of implants secures
a prolonged period of naltrexone protection. Implants are mostly well tolerated, but tissue reactions to repeat implants could be a problem. Evaluation of the patients should be thorough and the treatment integrated in a competent follow up.
Maintenance treatment with depot opioid antagonists in subcutaneous implants: an alternative in the treatment of opioid dependence.
Carreño JE, Alvarez CE, Narciso GI, Bascaran MT, Diaz M, Bobes J.Addict Biol. 2003 Dec;8(4):429-38.
Clinica Medico Psicologica Asturias, C/Astrurias, 8 - 5a planta, 33206, Gijon, Spain. cmedico@telecable.es
A report is presented of treatment of 156 patients (male 98%) with opioid dependence (ICD-10 criteria) using a maintenance programme with depot opioid antagonists (naltrexone) as subcutaneous implants, started after an outpatient rapid antagonization regimen. The retention index in the treatment was from 80% in the sixth month, and 65% after one year. The patients were followed-up for 1 year after discharge. For 6 months after discharge 55.4% were still returning for follow-up visits and 20.8% after 1 year, all of them remaining abstinent to opioids. It is concluded that the programme is safe for the patients and shows a better retention index than programmes using oral antagonists, with an improved compliance (negative urine analysis) compared to the latter.
antagonization regimen. The retention index in the treatment was from 80% in the sixth month, and 65% after one year. The patients were followed-up for 1 year after discharge. For 6 months after discharge 55.4% were still returning for follow-up visits and 20.8% after 1 year, all of them remaining abstinent to opioids. It is concluded that the programme is safe for the patients and shows a better retention index than programmes using oral antagonists, with an improved compliance (negative urine analysis) compared to the latter.
Use of oral and implantable naltrexone in the management of the opioid impaired physician.Hulse GK, O'Neil G, Hatton M, Paech MJ.Anaesth Intensive Care. 2003 Apr;31(2):196-201.
School of Psychiatry and Clinical Neurosciences, University of Western Australia, QE II Medical Centre.
Doctors are at an increased risk for prescription drug use, particularly opioids and benzodiazpines. This use can interfere with work function and has major potential negative implications for patient safety. Oral naltrexone, an opioid antagonist, has been used as part of a management strategy for opioid dependent physicians. While some patients stabilize on oral naltrexone, others relapse to opioid use. An alternative method of naltrexone maintenance involves the injection or surgical insertion of a sustained release preparation of naltrexone. This approach dramatically improves compliance, removing the onus from the previously opioid impaired physician to use daily oral naltrexone. This article describes the cases of four opioid-impaired doctors who received naltrexone (either oral or implant) as part of their management. The authors conclude that monitoring daily oral naltrexone use and detecting early opioid relapse is difficult, placing both the opioid impaired physician and their patients at risk. In contrast, by using implantable naltrexone, compliance is assured and opioid abstinence can virtually be guaranteed for five months. It is argued that naltrexone implants offer a level of protection not achieved with any previous treatment. It is recommended that management should involve early and close collaboration between the treating doctor and the Medical Board, with initial treatment, ongoing monitoring and follow-up being a Medical Board requirement for registration.
Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage following sequential naltrexone implants. Addict Biol. 2004 Mar;9(1):67-72. Hulse GK, Arnold-Reed DE, O'Neil G, Chan CT, Hansson RC.
Unit for Research and Education in Drugs and Alcohol, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia.
The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2+/-15.67 days of the first implant. The mean length of follow-up was 307.2+/-18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin-dependent patient.
Determination of naltrexone and 6-beta-naltrexol in human plasma following implantation of naltrexone pellets using gas chromatography-mass spectrometry.J Pharm Biomed Anal. 2004 Apr 1;35(1):169-76.Toennes SW, Kauert GF, Grusser SM, Jakel W, Partecke G.
Center of Legal Medicine, Institute of Forensic Toxicology, University of Frankfurt, Kennedyallee 104, D-60596 Frankfurt/Main, Germany. toennes@em.uni-frankfurt.de
An alternative to detoxification by oral therapy with the narcotic antagonist naltrexone is the subcutaneous implantation of naltrexone pellets. From detoxified patients with naltrexone implants (1g) 26 blood samples were collected up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol in plasma was developed using automated mixed-mode solid-phase extraction, catalysed trimethylsilylation and gas chromatography-mass spectrometry in single ion monitoring mode with naloxone as internal standard. The analytical method was very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60 ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy 1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6 each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and 10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0 ng/ml, respectively. The simple analytical procedure described provided good sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone pellet implantation.
Instituttgruppe for psykiatri, Seksjon for kliniske rusmiddelproblemer, Universitetet i Oslo, MARIO, Kirkeveien 166, 0407 Oslo. helge.waal@psykiatri.uio.no
BACKGROUND: An increasing number of Norwegian heroin addicts have had naltrexone implants abroad without proper documentation. The authors established a joint project to study duration and safety. MATERIAL AND METHODS: Methodology to measure naltrexone in plasma was developed. 10 patients had 21 implants. Plasma samples were collected before, one and three hours after implantation, daily for one week, then weekly. Patient satisfaction, side effects and unwanted medical events were recorded. RESULTS: Patients had a protective level of naltrexone for 35-80 days.
Side effects were few. Two patients had abstinence reactions caused by insufficient detoxification. Two patients had their repeat implants removed because of tissue reactions. One patient developed hepatitis C infection in the second week after implantation. One had transient increase in transaminases after heavy multi-drug use. The others were without signs of hepatic toxicity. INTERPRETATION: Use of implants secures
a prolonged period of naltrexone protection. Implants are mostly well tolerated, but tissue reactions to repeat implants could be a problem. Evaluation of the patients should be thorough and the treatment integrated in a competent follow up.
Maintenance treatment with depot opioid antagonists in subcutaneous implants: an alternative in the treatment of opioid dependence.
Carreño JE, Alvarez CE, Narciso GI, Bascaran MT, Diaz M, Bobes J.Addict Biol. 2003 Dec;8(4):429-38.
Clinica Medico Psicologica Asturias, C/Astrurias, 8 - 5a planta, 33206, Gijon, Spain. cmedico@telecable.es
A report is presented of treatment of 156 patients (male 98%) with opioid dependence (ICD-10 criteria) using a maintenance programme with depot opioid antagonists (naltrexone) as subcutaneous implants, started after an outpatient rapid antagonization regimen. The retention index in the treatment was from 80% in the sixth month, and 65% after one year. The patients were followed-up for 1 year after discharge. For 6 months after discharge 55.4% were still returning for follow-up visits and 20.8% after 1 year, all of them remaining abstinent to opioids. It is concluded that the programme is safe for the patients and shows a better retention index than programmes using oral antagonists, with an improved compliance (negative urine analysis) compared to the latter.
antagonization regimen. The retention index in the treatment was from 80% in the sixth month, and 65% after one year. The patients were followed-up for 1 year after discharge. For 6 months after discharge 55.4% were still returning for follow-up visits and 20.8% after 1 year, all of them remaining abstinent to opioids. It is concluded that the programme is safe for the patients and shows a better retention index than programmes using oral antagonists, with an improved compliance (negative urine analysis) compared to the latter.
Use of oral and implantable naltrexone in the management of the opioid impaired physician.Hulse GK, O'Neil G, Hatton M, Paech MJ.Anaesth Intensive Care. 2003 Apr;31(2):196-201.
School of Psychiatry and Clinical Neurosciences, University of Western Australia, QE II Medical Centre.
Doctors are at an increased risk for prescription drug use, particularly opioids and benzodiazpines. This use can interfere with work function and has major potential negative implications for patient safety. Oral naltrexone, an opioid antagonist, has been used as part of a management strategy for opioid dependent physicians. While some patients stabilize on oral naltrexone, others relapse to opioid use. An alternative method of naltrexone maintenance involves the injection or surgical insertion of a sustained release preparation of naltrexone. This approach dramatically improves compliance, removing the onus from the previously opioid impaired physician to use daily oral naltrexone. This article describes the cases of four opioid-impaired doctors who received naltrexone (either oral or implant) as part of their management. The authors conclude that monitoring daily oral naltrexone use and detecting early opioid relapse is difficult, placing both the opioid impaired physician and their patients at risk. In contrast, by using implantable naltrexone, compliance is assured and opioid abstinence can virtually be guaranteed for five months. It is argued that naltrexone implants offer a level of protection not achieved with any previous treatment. It is recommended that management should involve early and close collaboration between the treating doctor and the Medical Board, with initial treatment, ongoing monitoring and follow-up being a Medical Board requirement for registration.
Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage following sequential naltrexone implants. Addict Biol. 2004 Mar;9(1):67-72. Hulse GK, Arnold-Reed DE, O'Neil G, Chan CT, Hansson RC.
Unit for Research and Education in Drugs and Alcohol, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia.
The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2+/-15.67 days of the first implant. The mean length of follow-up was 307.2+/-18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin-dependent patient.
Determination of naltrexone and 6-beta-naltrexol in human plasma following implantation of naltrexone pellets using gas chromatography-mass spectrometry.J Pharm Biomed Anal. 2004 Apr 1;35(1):169-76.Toennes SW, Kauert GF, Grusser SM, Jakel W, Partecke G.
Center of Legal Medicine, Institute of Forensic Toxicology, University of Frankfurt, Kennedyallee 104, D-60596 Frankfurt/Main, Germany. toennes@em.uni-frankfurt.de
An alternative to detoxification by oral therapy with the narcotic antagonist naltrexone is the subcutaneous implantation of naltrexone pellets. From detoxified patients with naltrexone implants (1g) 26 blood samples were collected up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol in plasma was developed using automated mixed-mode solid-phase extraction, catalysed trimethylsilylation and gas chromatography-mass spectrometry in single ion monitoring mode with naloxone as internal standard. The analytical method was very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60 ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy 1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6 each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and 10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0 ng/ml, respectively. The simple analytical procedure described provided good sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone pellet implantation.