528592 research-article2014
JOP0010.1177/0269881114528592Journal of PsychopharmacologyJhugroo et al.
Original Paper
Naltrexone implant treatment for buprenorphine dependence – Mauritian case series Anil Jhugroo1, Darmen Ellayah2, Amanda Norman3 and Gary Hulse3
Journal of Psychopharmacology 1–4 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114528592 jop.sagepub.com
Abstract Although substitution therapy with opiate agonist treatments such as methadone and buprenorphine has resulted in a reduction of illicit drug use related harm, such treatment has also resulted in severe problems in some countries where opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin. There is no approved treatment for buprenorphine dependence. Naltrexone is an opioid antagonist which has been used for the treatment of both alcohol and opioid dependencies. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. This paper presents observational case series data on the use of a sustained-release naltrexone implant for the treatment of buprenorphine dependence. To the authors’ knowledge this is the first use of sustained-release naltrexone for this indication.
Keywords Naltrexone, sustained release, buprenorphine, dependence
Background The only substantially effective treatment for opioid dependence has been the substitution of another opioid for the initial opioid of abuse (Veilleux et al., 2010). This approach aims to reduce harm by replacing intravenous use of heroin by orally administered methadone or buprenorphine. Although this kind of substitution therapy has resulted in a reduction of illicit drug use related harm, such as crime and spreading of HIV and C-hepatitis (Johnson et al., 2000; Oviedo-Joekes et al., 2009; Van den Brink and Haasen, 2006), this approach also has associated problems. For example, in a number of countries such as Finland, Georgia, and Mauritius, the vast majority of all opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin (INCB, 2012; Otiashvili et al., 2010; Simojoki et al., 2010). In Mauritius it has been estimated that approximately 80% of intravenous drug users are using buprenorphine. Buprenorphine is preferred over heroin as it is easier to get, it is less expensive, and is longer lasting. Naltrexone is an opioid antagonist, which has been used for the treatment of both alcohol and opioid dependencies (Garbutt et al., 2005; Gastfriend, 2011; Krystal et al., 2001; Rösner et al., 2010; Veilleux et al., 2010). However, oral naltrexone has proved ineffective in the treatment of opioid dependence, due to poor treatment adherence (Veilleux et al., 2010). Five recent randomized controlled trials indicate that a naltrexone implant (Hulse et al., 2009; Kunøe et al., 2009; Krupitsky et al., 2010) and depot injection (Comer et al., 2006; Krupitsky et al., 2011) may be the first effective, non-addictive pharmacological treatments for heroin dependence among patients without other co-existing drug dependence. The naltrexone implant has also been observed to be effective in the treatment of co-existing heroin and amphetamine
dependence, decreasing heroin and amphetamine use and improving clinical state of patients (Tiihonen et al., 2012). There is no treatment approved for buprenorphine dependence and little published data on the subject. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. A literature search using Medline database revealed only three relevant studies. Basu et al. (2000) studied the course and outcomes of 94 male patients who registered for treatment for buprenorphine dependence at an addiction clinic in northern India between 1987 and 1993. Over an average follow-up period of three years, the researchers found the majority of the patients at the end of followup ‘improved’ compared to their baseline conditions; however,
1Department
of Medicine, University of Mauritius, Reduit, Mauritius Centre for Drug and Alcohol Counselling and Community Rehabilitation, Roche Bois, Mauritius 3School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia 2APPEL
Corresponding authors: Gary Hulse, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, M521, D Block, QEII Medical Centre, Nedlands, W.A. 6009, Australia. Email: [email protected] Anil Jhugroo, Department of Medicine, University of Mauritius, Reduit, Mauritius. Email: [email protected]
Downloaded from jop.sagepub.com at UNIV OF GEORGIA LIBRARIES on May 28, 2015
2
Journal of Psychopharmacology
the treatment method was not mentioned. The second study, Ahmadi et al. (2003), compared treatment retention of 204 buprenorphine-dependent patients in Iran treated with a 50 mg/ day dose of methadone, or a 5 mg/day dose of buprenorphine, or a 50 mg/day dose of oral naltrexone, over a 24-week treatment period. Treatment retention in the methadone group was most superior, followed by that in the buprenorphine group, with the retention outcome in the naltrexone group being the most inferior. The third study by Singh et al. (2004), however, described a case of a young Indian male patient who injected 24 mg of buprenorphine per day in a dependent pattern, and who was successfully treated (i.e. remained abstinent) with naltrexone. It is possible that, as in heroin addiction, sustained-release preparations may prove more effective than oral medication in the treatment of buprenorphine dependence. Sustained-release preparations commonly involve using compressed naltrexone, or naltrexone/polymer/co-polymer base formulations administered subcutaneously or intramuscularly, and have been shown to maintain therapeutic blood levels of above 1–2 ng naltrexone for 3–5 weeks (Comer et al., 2007). Recently a 30-day injectable naltrexone formulation, Vivitrol, was approved by the US Food and Drug Administration (FDA) for the management of heroin dependence. Despite addressing issues of daily oral naltrexone non-compliance, these injectable sustained release formulations still rely on patients returning monthly for subsequent treatments over 4–6 months, with failure to return for subsequent treatment still remaining a potential problem. For example, when treated with a 30-day injectable naltrexone formulation of either 192 or 384 mg naltrexone, 40% and 32% of patients respectively failed to return for re-treatment by month two (Comer et al, 2006). An implantable formulation of naltrexone has been developed in Australia, which may provide longer-lasting blockade of opioid receptors, for approximately 145 days (Ngo et al., 2008). The implant formulation incorporates naltrexone loaded poly-(trans3,6-dimethyl-1,4-dioxane-2,5-dione) (DL)-lactide microspheres compressed into tablets and surrounded by a poly-(DL)-lactide coating to form an implant. The expected in vitro release rate of the tablets is 0.4–0.5% per day and each implant contains 1.1 g of naltrexone, with two implants commonly used as a treatment for heroin dependence (Hulse et al., 2009; Kunoe et al., 2009). Hulse et al. (2009) published results of a randomized double-blind controlled trial comparing the safety and efficacy of a single treatment of the Australian sustained-release naltrexone implant with daily oral naltrexone treatment. The naltrexone implant effectively reduced relapse to regular heroin use compared with oral naltrexone and was not associated with major adverse events. This paper presents observational case series data on the use of this Australian sustained release naltrexone implant for the treatment of buprenorphine dependence. To the authors’ knowledge this is the first use of sustained release naltrexone for this indication.
Method Clinical setting and treatment Between 2007–2010, 24 opiate dependent patients travelled to Australia from Mauritius to have the double naltrexone implant treatment (each implant containing 1.1 g of naltrexone). Patients went in batches of 4–6, accompanied by care workers. Surgical
implant treatment was performed at the Fresh Start Clinic, Perth. Prior to treatment participants underwent a medically supervised opiate withdrawal and were required to give an opioid-negative urine sample after which they received oral naltrexone (50 mg/ day) for one day. If opiate withdrawal was not observed the implant procedure proceeded the next day. Following treatment participants remained in Perth for a period of observation before returning to Mauritius. On return to Mauritius, patient follow-up was conducted at Centre d’Accueil de Terre Rouge, a Drug Rehabilitation Centre, north of Port Louis, the capital of Mauritius.
Design This study was based on an observational case series.
Participants Patients presenting for treatment who were buprenorphine dependent (in accordance with Diagnostic and Statistical Manual 4th Edition (DSMIV) criteria) and wishing to withdraw from and cease using buprenorphine were considered for treatment. At the time of treatment patients were aged between 19–28 years (mean=24 years, standard deviation=8.6 years). All had been injecting between 2 mg and 8 mg buprenorphine “sub lingual” tablets intravenously daily. The duration of buprenorphine use varied between 18 months and four years. Prior to naltrexone implant treatment these patients had been treated using the opiate agonist methadone. None had achieved more than three weeks opioid abstinence on the agonist treatment.
Review and follow-up Patients were required to attend the Centre d’Accueil de Terre Rouge for regular follow-up appointments. Post-treatment, patients were contacted by phone and requested to attend the clinic the following day. During follow-up visits patients received a brief 20 min counseling session. Drug use was assessed using a poly-drug test kit which included screening for buprenorphine, morphine and methadone. Regular follow-up data is available for two and a half years post initial treatment.
Results Initial treatment Table 1 presents the abstinence rates of the 24 patients initially treated with the naltrexone implant. All patients (100%) remained abstinent for six months. At one year, 83% were still abstinent. Eighteen months after treatment, 46% were abstinent, this figure remaining relatively stable at 42% for the following 12 months. Nineteen out of the 24 patients (79%) reported having tried unsuccessfully to override the naltrexone implant blockade by injecting either buprenorphine or heroin in the first four weeks following implant treatment. No major adverse events or complications were reported during active treatment.
Retreatment In the period between 6–18 months after the first implant three patients had repeat naltrexone implants. One patient remained
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3
Jhugroo et al. Table 1. Abstinence rates for patients treated with a naltrexone implant for buprenorphine dependence. Duration of abstinence
Number of opiate-abstinent patients
Total number of patients in study
% Abstinent
6 months 1 year 1½ years 2 years 2½ years
24 20 11 10 10
24 24 24 24 24
100 83 46 42 42
abstinent but returned twice for two subsequent implant treatments. Two patients returned following relapse. Other patients had expressed desire for further treatment but due to visa restrictions were unable to travel to Australia.
Discussion These results indicate that sustained-release naltrexone implant treatment may offer an excellent option for patients with buprenorphine dependence. Although the implant treatment only provides naltrexone blood levels above 1–2 ng/mL for 145 days above (Ngo et al., 2008) all 24 patients (100%) were buprenorphine/opiate abstinent at six months, with 83% abstinent at one year. As with all case series data, these results need to be interpreted cautiously and the generalizability of the outcomes is limited. The encouraging outcomes reported here need to be verified and replicated under controlled trial conditions. A clinical trial would also provide much needed safety and adverse event data. Extensive data has been published on the clinical efficacy and adverse event profile of sustained-release naltrexone for heroin addiction. However, given buprenorphine’s higher affinity to the mu opioid receptor, sustained-release preparations may be less effective in the management of buprenorphine-dependent patients especially as blood naltrexone levels decrease over time. This is consistent with the finding that two and a half years after initial treatment 14 out of 24 (59%) patients returned to use, indicating the need to consider follow-up or sequential treatment with some patients. However, notwithstanding these caveats, it would appear that, as with other indications, sustained-release naltrexone preparations offer hope of more effective treatment of buprenorphine dependence than oral naltrexone. Given that buprenorphine dependence is primarily a problem in developing rather than developed economies, a major limitation of sustained-release naltrexone treatment is cost. A single treatment (two implants) of the Australian product costs approximately $US1500. A six-month treatment of the injectable sustained-release treatment (Vivitrol) is more than $US6000 (at more than $1000 per treatment). The challenge for governments, health service providers and drug manufacturers is to make these promising treatment options available at an affordable price for those who need them most.
Conflict of interest The authors declare that there is no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
References Ahmadi J, Ahmadi K and Ohaeri J (2003) Controlled, randomized trial in maintenance treatment of intravenous buprenorphine dependence with naltrexone, methadone or buprenorphine: A novel study. Eur J Clin Invest 33: 824–829. American Psychiatric Association. Diagnostic and Statistical Manual, 4th Edition. Washington, DC: American Psychiatric Association. Basu D, Mattoo SK, Malhotra A, et al. (2000) A longitudinal study of male buprenorphine addicts attending an addiction clinic in India. Addiction 95: 1363–1372. Comer SD, Sullivan MA and Hulse GK (2007) Sustained-release naltrexone: Novel treatment for opioid dependence. Expert Opin Investig Drugs 16: 1285–1294. Comer SD, Sullivan MA, Yu E, et al. (2006) Injectable, sustained-release naltrexone for the treatment of opioid dependence: A randomized, placebo-controlled trial. Arch Gen Psychiatry 63: 210–218. Garbutt JC, Kranzler HR, O’Malley SS, et al.; Vivitrex Study Group. (2005) Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. JAMA 293: 1617–1625. Gastfriend DR (2011) Intramuscular extended-release naltrexone: Current evidence. Ann N Y Acad Sci 1216: 144–166. Johnson RE, Chutuape MA, Strain EC, et al. (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343: 1290–1297. Hulse GK, Morris N, Arnold-Reed D, et al. (2009) Improving clinical outcomes in treating heroin dependence: Randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry 66: 1108–1115. International Narcotics Control Board (2012) Report of the International Narcotics Control Board for 2012. Report no. E/INCB/2012/1. United Nations publication. Vienna: International Narcotics Control Board. Krupitsky E, Nunes EV, Ling W, et al. (2011) Injectable extendedrelease naltrexone for opioid dependence: A double-blind, placebo-controlled, multicentre randomised trial. Lancet 377: 1506–1513. Krupitsky E, Zvartau E and Woody G (2010) Use of naltrexone to treat opioid addiction in a country in which methadone and buprenorphine are not available. Curr Psychiatry Rep 12: 448–453. Krystal JH, Cramer JA, Krol WF, et al.; Veterans Affairs Naltrexone Cooperative Study 425 Group. (2001) Naltrexone in the treatment of alcohol dependence. N Engl J Med 345: 1734–1739. Kunøe N, Lobmaier P, Vederhus JK, et al. (2009) Naltrexone implants after in-patient treatment for opioid dependence: Randomised controlled trial. Br J Psychiatry 194: 541–546. Ngo HTT, Arnold-Reed DE, Hansson RC, et al. (2008) Blood naltrexone levels over time following naltrexone implant. Prog Neuropsychopharmacol Biol Psychiatry 32: 23–28. Otiashvili D, Zabransky T, Kirtadze I, et al. (2010) Why do the clients of Georgian needle exchange programmes inject buprenorphine? Eur Addict Res 16: 1–8. Oviedo-Joekes E, Brissette S, Marsh DC, et al. (2009) Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med 361: 777–786.
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Rösner S, Hackl-Herrwerth A, Leucht S, et al. (2010) Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 12: CD001867. Simojoki K, Lillsunde P, Lintzeris N, et al. (2010) Bioavailability of buprenorphine from crushed and whole buprenorphine (subutex) tablets. Eur Addict Res 16: 85–90. Singh J, Grover S and Basu D (2004) Very high-dose intravenous buprenorphine dependence: A case report. Ger J Psychiatry 7: 58–59.
Tiihonen J, Krupitsky E, Verbitskaya E, et al. (2012) Naltrexone implant for the treatment of polydrug dependence. Am J Psychiatry 169: 531–536. Van den Brink W and Haasen C (2006) Evidenced-based treatment of opioid-dependent patients. Can J Psychiatry 51: 635–646. Veilleux JC, Colvin PJ, Anderson J, et al. (2010) A review of opioid dependence treatment: Pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev 30: 155–166.
Downloaded from jop.sagepub.com at UNIV OF GEORGIA LIBRARIES on May 28, 2015
JOP0010.1177/0269881114528592Journal of PsychopharmacologyJhugroo et al.
Original Paper
Naltrexone implant treatment for buprenorphine dependence – Mauritian case series Anil Jhugroo1, Darmen Ellayah2, Amanda Norman3 and Gary Hulse3
Journal of Psychopharmacology 1–4 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114528592 jop.sagepub.com
Abstract Although substitution therapy with opiate agonist treatments such as methadone and buprenorphine has resulted in a reduction of illicit drug use related harm, such treatment has also resulted in severe problems in some countries where opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin. There is no approved treatment for buprenorphine dependence. Naltrexone is an opioid antagonist which has been used for the treatment of both alcohol and opioid dependencies. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. This paper presents observational case series data on the use of a sustained-release naltrexone implant for the treatment of buprenorphine dependence. To the authors’ knowledge this is the first use of sustained-release naltrexone for this indication.
Keywords Naltrexone, sustained release, buprenorphine, dependence
Background The only substantially effective treatment for opioid dependence has been the substitution of another opioid for the initial opioid of abuse (Veilleux et al., 2010). This approach aims to reduce harm by replacing intravenous use of heroin by orally administered methadone or buprenorphine. Although this kind of substitution therapy has resulted in a reduction of illicit drug use related harm, such as crime and spreading of HIV and C-hepatitis (Johnson et al., 2000; Oviedo-Joekes et al., 2009; Van den Brink and Haasen, 2006), this approach also has associated problems. For example, in a number of countries such as Finland, Georgia, and Mauritius, the vast majority of all opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin (INCB, 2012; Otiashvili et al., 2010; Simojoki et al., 2010). In Mauritius it has been estimated that approximately 80% of intravenous drug users are using buprenorphine. Buprenorphine is preferred over heroin as it is easier to get, it is less expensive, and is longer lasting. Naltrexone is an opioid antagonist, which has been used for the treatment of both alcohol and opioid dependencies (Garbutt et al., 2005; Gastfriend, 2011; Krystal et al., 2001; Rösner et al., 2010; Veilleux et al., 2010). However, oral naltrexone has proved ineffective in the treatment of opioid dependence, due to poor treatment adherence (Veilleux et al., 2010). Five recent randomized controlled trials indicate that a naltrexone implant (Hulse et al., 2009; Kunøe et al., 2009; Krupitsky et al., 2010) and depot injection (Comer et al., 2006; Krupitsky et al., 2011) may be the first effective, non-addictive pharmacological treatments for heroin dependence among patients without other co-existing drug dependence. The naltrexone implant has also been observed to be effective in the treatment of co-existing heroin and amphetamine
dependence, decreasing heroin and amphetamine use and improving clinical state of patients (Tiihonen et al., 2012). There is no treatment approved for buprenorphine dependence and little published data on the subject. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. A literature search using Medline database revealed only three relevant studies. Basu et al. (2000) studied the course and outcomes of 94 male patients who registered for treatment for buprenorphine dependence at an addiction clinic in northern India between 1987 and 1993. Over an average follow-up period of three years, the researchers found the majority of the patients at the end of followup ‘improved’ compared to their baseline conditions; however,
1Department
of Medicine, University of Mauritius, Reduit, Mauritius Centre for Drug and Alcohol Counselling and Community Rehabilitation, Roche Bois, Mauritius 3School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia 2APPEL
Corresponding authors: Gary Hulse, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, M521, D Block, QEII Medical Centre, Nedlands, W.A. 6009, Australia. Email: [email protected] Anil Jhugroo, Department of Medicine, University of Mauritius, Reduit, Mauritius. Email: [email protected]
Downloaded from jop.sagepub.com at UNIV OF GEORGIA LIBRARIES on May 28, 2015
2
Journal of Psychopharmacology
the treatment method was not mentioned. The second study, Ahmadi et al. (2003), compared treatment retention of 204 buprenorphine-dependent patients in Iran treated with a 50 mg/ day dose of methadone, or a 5 mg/day dose of buprenorphine, or a 50 mg/day dose of oral naltrexone, over a 24-week treatment period. Treatment retention in the methadone group was most superior, followed by that in the buprenorphine group, with the retention outcome in the naltrexone group being the most inferior. The third study by Singh et al. (2004), however, described a case of a young Indian male patient who injected 24 mg of buprenorphine per day in a dependent pattern, and who was successfully treated (i.e. remained abstinent) with naltrexone. It is possible that, as in heroin addiction, sustained-release preparations may prove more effective than oral medication in the treatment of buprenorphine dependence. Sustained-release preparations commonly involve using compressed naltrexone, or naltrexone/polymer/co-polymer base formulations administered subcutaneously or intramuscularly, and have been shown to maintain therapeutic blood levels of above 1–2 ng naltrexone for 3–5 weeks (Comer et al., 2007). Recently a 30-day injectable naltrexone formulation, Vivitrol, was approved by the US Food and Drug Administration (FDA) for the management of heroin dependence. Despite addressing issues of daily oral naltrexone non-compliance, these injectable sustained release formulations still rely on patients returning monthly for subsequent treatments over 4–6 months, with failure to return for subsequent treatment still remaining a potential problem. For example, when treated with a 30-day injectable naltrexone formulation of either 192 or 384 mg naltrexone, 40% and 32% of patients respectively failed to return for re-treatment by month two (Comer et al, 2006). An implantable formulation of naltrexone has been developed in Australia, which may provide longer-lasting blockade of opioid receptors, for approximately 145 days (Ngo et al., 2008). The implant formulation incorporates naltrexone loaded poly-(trans3,6-dimethyl-1,4-dioxane-2,5-dione) (DL)-lactide microspheres compressed into tablets and surrounded by a poly-(DL)-lactide coating to form an implant. The expected in vitro release rate of the tablets is 0.4–0.5% per day and each implant contains 1.1 g of naltrexone, with two implants commonly used as a treatment for heroin dependence (Hulse et al., 2009; Kunoe et al., 2009). Hulse et al. (2009) published results of a randomized double-blind controlled trial comparing the safety and efficacy of a single treatment of the Australian sustained-release naltrexone implant with daily oral naltrexone treatment. The naltrexone implant effectively reduced relapse to regular heroin use compared with oral naltrexone and was not associated with major adverse events. This paper presents observational case series data on the use of this Australian sustained release naltrexone implant for the treatment of buprenorphine dependence. To the authors’ knowledge this is the first use of sustained release naltrexone for this indication.
Method Clinical setting and treatment Between 2007–2010, 24 opiate dependent patients travelled to Australia from Mauritius to have the double naltrexone implant treatment (each implant containing 1.1 g of naltrexone). Patients went in batches of 4–6, accompanied by care workers. Surgical
implant treatment was performed at the Fresh Start Clinic, Perth. Prior to treatment participants underwent a medically supervised opiate withdrawal and were required to give an opioid-negative urine sample after which they received oral naltrexone (50 mg/ day) for one day. If opiate withdrawal was not observed the implant procedure proceeded the next day. Following treatment participants remained in Perth for a period of observation before returning to Mauritius. On return to Mauritius, patient follow-up was conducted at Centre d’Accueil de Terre Rouge, a Drug Rehabilitation Centre, north of Port Louis, the capital of Mauritius.
Design This study was based on an observational case series.
Participants Patients presenting for treatment who were buprenorphine dependent (in accordance with Diagnostic and Statistical Manual 4th Edition (DSMIV) criteria) and wishing to withdraw from and cease using buprenorphine were considered for treatment. At the time of treatment patients were aged between 19–28 years (mean=24 years, standard deviation=8.6 years). All had been injecting between 2 mg and 8 mg buprenorphine “sub lingual” tablets intravenously daily. The duration of buprenorphine use varied between 18 months and four years. Prior to naltrexone implant treatment these patients had been treated using the opiate agonist methadone. None had achieved more than three weeks opioid abstinence on the agonist treatment.
Review and follow-up Patients were required to attend the Centre d’Accueil de Terre Rouge for regular follow-up appointments. Post-treatment, patients were contacted by phone and requested to attend the clinic the following day. During follow-up visits patients received a brief 20 min counseling session. Drug use was assessed using a poly-drug test kit which included screening for buprenorphine, morphine and methadone. Regular follow-up data is available for two and a half years post initial treatment.
Results Initial treatment Table 1 presents the abstinence rates of the 24 patients initially treated with the naltrexone implant. All patients (100%) remained abstinent for six months. At one year, 83% were still abstinent. Eighteen months after treatment, 46% were abstinent, this figure remaining relatively stable at 42% for the following 12 months. Nineteen out of the 24 patients (79%) reported having tried unsuccessfully to override the naltrexone implant blockade by injecting either buprenorphine or heroin in the first four weeks following implant treatment. No major adverse events or complications were reported during active treatment.
Retreatment In the period between 6–18 months after the first implant three patients had repeat naltrexone implants. One patient remained
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3
Jhugroo et al. Table 1. Abstinence rates for patients treated with a naltrexone implant for buprenorphine dependence. Duration of abstinence
Number of opiate-abstinent patients
Total number of patients in study
% Abstinent
6 months 1 year 1½ years 2 years 2½ years
24 20 11 10 10
24 24 24 24 24
100 83 46 42 42
abstinent but returned twice for two subsequent implant treatments. Two patients returned following relapse. Other patients had expressed desire for further treatment but due to visa restrictions were unable to travel to Australia.
Discussion These results indicate that sustained-release naltrexone implant treatment may offer an excellent option for patients with buprenorphine dependence. Although the implant treatment only provides naltrexone blood levels above 1–2 ng/mL for 145 days above (Ngo et al., 2008) all 24 patients (100%) were buprenorphine/opiate abstinent at six months, with 83% abstinent at one year. As with all case series data, these results need to be interpreted cautiously and the generalizability of the outcomes is limited. The encouraging outcomes reported here need to be verified and replicated under controlled trial conditions. A clinical trial would also provide much needed safety and adverse event data. Extensive data has been published on the clinical efficacy and adverse event profile of sustained-release naltrexone for heroin addiction. However, given buprenorphine’s higher affinity to the mu opioid receptor, sustained-release preparations may be less effective in the management of buprenorphine-dependent patients especially as blood naltrexone levels decrease over time. This is consistent with the finding that two and a half years after initial treatment 14 out of 24 (59%) patients returned to use, indicating the need to consider follow-up or sequential treatment with some patients. However, notwithstanding these caveats, it would appear that, as with other indications, sustained-release naltrexone preparations offer hope of more effective treatment of buprenorphine dependence than oral naltrexone. Given that buprenorphine dependence is primarily a problem in developing rather than developed economies, a major limitation of sustained-release naltrexone treatment is cost. A single treatment (two implants) of the Australian product costs approximately $US1500. A six-month treatment of the injectable sustained-release treatment (Vivitrol) is more than $US6000 (at more than $1000 per treatment). The challenge for governments, health service providers and drug manufacturers is to make these promising treatment options available at an affordable price for those who need them most.
Conflict of interest The authors declare that there is no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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