Skip to main content
SpringerLink
Log in

The Development of Sustained-Release Naltrexone and Clinical Use in Treating Opiate Dependence

  • Chapter
Opiate Receptors and Antagonists

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

Heroin and related illicit opioid abuse continues to be a significant problem in the United States and globally, as measured by a variety of indicators. The ability of naltrexone to effectively antagonize heroin use is unequivocal. However, despite this pharmacological efficacy, noncompliance with oral naltrexone formu lae has been a significant impediment to its adoption as a treatment. Noncompliance is often associated with a patient' withdrawal from treatment and return to heroin use, although several recent studies specifically aimed at improving medication compliance have yielded promising results. An alternative method of naltrexone maintenance delivery involves the injection or surgical insertion of a sustained release preparation of naltrexone. This approach removes the onus on patients to use daily oral naltrexone. To date, a number of sustained release preparation of naltrexone have been developed for intramuscular or subcutaneous injection, or surgical insertion. Optimally, these products should be easy to administer, have no “major” adverse tissue reaction (biocompatible), be biodegradable, provide thera-peutically relevant blood naltrexone levels, and be clinically effective. This chapter reviews the history, development, and comments on the relative merits of different formulations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abrahams, RA & Ronel, SH 1975. Biocompatible implants for the sustained zero-order release of narcotic antagonists. Journal of Biomedical Materials Research, 9, 355–366.

    Article  CAS  PubMed  Google Scholar 

  2. Ahmadi, J 2003. Methadone versus buprenorphine maintenance for the treatment of heroin-dependent outpatients. Journal of Substance Abuse Treatment, 24, 217–220.

    Article  PubMed  Google Scholar 

  3. Anton, RE, Hogan, I, Jalali, B, Riordan, CE & Kleber, HD 1981. Multiple family therapy and naltrexone in the treatment of opiate-dependence. Drug and Alcohol Dependence, 8, 157–168.

    Article  CAS  PubMed  Google Scholar 

  4. Azarian, A, Papiasvilli, A & Joseph, H 1994. A study of the use of clonidine and naltrexone in the treatment of opiod addiction in the former USSR. Journal of Addictive Diseases, 13, 35–52.

    Article  Google Scholar 

  5. Bartus, RT, Emerich, DF, Hotz, J, Blaustein, M, Dean, RL, Perdomo, B & Basile, A 2003. Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats. Neuropsychopharmacology, 28, 1973–1982.

    CAS  PubMed  Google Scholar 

  6. Brewer, C 2001. Naltrexone implants for opiate addiction: new life for a middle aged drug. The Pharmaceutical Journal, 267, 260.

    Google Scholar 

  7. Brewer, C 2002. Serum naltrexone and 6-beta-naltrexol levels from naltrexone implants can block very large amounts of heroin: a report of two cases. Addiction Biology, 7, 321–323.

    Article  PubMed  Google Scholar 

  8. Callaghan, E, Rawson, R & McCleave, B 1980. The treatment of heroin addiction using naltrex-one alone and with behaviour therapy. International Journal of the Addiction, 15, 795–807.

    Google Scholar 

  9. Callahan, E, Rawson, R., Glazer, M., McCleave, B., & Arias, R 1980. In: Demetrios, J. & Renault, P. (Eds.). Comparison of two naltrexone treatment programs: naltrexone alone versus naltrexone plus behaviour therapy, pp. 150–157.

    Google Scholar 

  10. Carroll, KM, Ball, SA, Nich, C, O'Connor, PG, Eagan, DA, Frankforter, TL, Triffleman, EG, Shi, JM & Rounsaville, BJ 2001. Targeting behavioral therapies to enhance naltrexone treatment of opiod dependence: efficacy of contingency management and significant other involvement. Archives in General Psychiatry, 58, 755–761.

    Article  Google Scholar 

  11. Chan, KY 1996. The Singapore naltrexone community-based project for heroin addicts com pared with drugfree community-based program: the first cohort. Journal of Clinical Forensic Medicine, 3, 87–92.

    Article  CAS  PubMed  Google Scholar 

  12. Chiang, CN, Hollister, LE, Kishimoto, A & Barnett, G 1984. Kinetics of a naltrexone sustained-release preparation. Clinical Pharmacology and Therapeutics, 36, 704–708.

    Article  CAS  PubMed  Google Scholar 

  13. Chiang, CN, Hollister, LE, Gillespie, HK & Foltz, RL 1985. Clinical evaluation of a naltrex-one sustained-release preparation. Drug and Alcohol Dependence, 16, 1–8.

    Article  CAS  PubMed  Google Scholar 

  14. Comer, S, Sullivan, MA, Yu, E, Rothenberg, JL, Kleber, HD, Kampman, K, Dackis, C & O'Brien, CP 2006. Injectable, sustained-release naltrexone for the treatment of opioid depend ence: a randomized, placebo-controlled trial. Archives of General Psychiatry, 63, 210–218.

    Article  CAS  PubMed  Google Scholar 

  15. Comer, SD, Collins, ED, Kleber, HD, Nuwayser, ES, Kerrigan, JH & Fischman, MW 2002. Depot naltrexone: long-lasting antagonism of the effects of heroin in humans. Psychopharmacology (Berl), 159, 351–360.

    Article  CAS  PubMed  Google Scholar 

  16. Cornish, JW, Metzger, D, Woody, GE, Wilson, D, McLellan, AT, Vandergrift, B & Obrien, CP 1997. Naltrexone pharmacotherapy for opioid dependent federal probationers. Journal of Substance Abuse Treatment, 14, 529–534.

    Article  CAS  PubMed  Google Scholar 

  17. Crowley, TJ, Wagner, JE, Zerbe, G & Macdonald, MJ 1985. Naltrexone-induced dysphoria in former opioid addicts. American Journal of Psychiatry, 142, 1081–1084.

    CAS  PubMed  Google Scholar 

  18. Darke, S & Ross, J 1999. Heroin-related deaths in South Western Sydney, Australia, 1992–96. Drug and Alcohol Review, 18, 39–45.

    Article  Google Scholar 

  19. Darke, S, Sunjic, S, Zador, D & Prolov, T 1997. A comparison of blood toxicology of heroin-related deaths and current heroin users in Sydney, Australia. Drug and Alcohol Dependence, 47, 45–53.

    Article  CAS  PubMed  Google Scholar 

  20. Darke, S, Ross, J, Zador, D & Sunjic, S 2000. Heroin-related deaths in New South Wales, Australia, 1992–1996. Drug and Alcohol Dependence, 60, 141–150.

    Article  CAS  PubMed  Google Scholar 

  21. Dole, V, Nyswander, ME & Kreek, MJ 1966. Narcotic blockade. Archives of Internal Medicine, 118, 304–309.

    Article  CAS  PubMed  Google Scholar 

  22. Faggiano, F, Versino, E, Vigna-Taglianti, F & Lemma, P. 2000. Methadone maintenance at different dosages for opioid dependence. Cochrane Database systemic reviews.

    Google Scholar 

  23. Fals-Stewart, W & O'Farrell, TJ 2003. Behavioral family counseling and naltrexone for male opiod-dependent patients. Journal of Consulting and Clinical Psychology, 71, 432–442.

    Article  PubMed  Google Scholar 

  24. Galloway, GP, Koch, M, Gross, J & Smith, DE 2001. Safety, tolerability and pharmacokinetics of a sustained-release formulation of naltrexone in alcoholics. Drug and Alcohol Dependence, 63, S52.

    Google Scholar 

  25. Garbutt, JC, Kranzler, HR, O'Malley, SS, Gastfriend, DR, Pettinati, HM, Silverman, BL, Loewy, JW, Ehrich, EW & Vivitrex Study Group 2005. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA, 293, 1617–1625.

    Article  CAS  PubMed  Google Scholar 

  26. Gerostamoulos, J, Staikos, V & Drummer, OH 2001. Heroin-related deaths in Victoria: a review of cases for 1997 and 1998. Drug and Alcohol Dependence, 61, 123–127.

    Article  CAS  PubMed  Google Scholar 

  27. Grizzi, I, Garreau, H, Li, S & Vert, M 1995. Hydrolytic degradation of devices based on poly(d-l-lactic acid) size-dependence. Biomaterials, 16, 305–311.

    Article  CAS  PubMed  Google Scholar 

  28. Hamilton, RJ, Olmedo, RE, Shah, S, Hung, OL, Howland, MA, Perrone, J, Nelson, LS, Lewin, NL & Hoffman, RS 2002. Complications of ultrarapid opioid detoxification with subcutaneous naltrexone pellets. Academic Emergency Medicine, 9, 63–68.

    Article  PubMed  Google Scholar 

  29. Hando, J, Hall, W, Rutter, S & Dolan, K. 1998. An information document on the current state of research on illicit drugs in Australia. Sydney: University of New South Wales.

    Google Scholar 

  30. Harrigan, SE & Downs, DA 1981. Pharmacological evaluation of narcotic antagonist delivery systems in rhesus monkeys. NIDA Research Monograph, 28, 77–92.

    CAS  PubMed  Google Scholar 

  31. Hollister, LE, Johnson, K, Boukhabza, D & Gillespie, HK 1981. Aversive effects of naltrex-one in subjects not dependent on opiates. Drug and Alcohol Dependence, 8, 37–41.

    Article  CAS  PubMed  Google Scholar 

  32. Hulse, GK & Basso, MR 2000. The association between naltrexone compliance and daily supervision. Drug and Alcohol Review, 19, 41–48.

    Article  Google Scholar 

  33. Hulse, GK & O'Neil, G 2002. A possible role for implantable naltrexone in the management of the “high risk” pregnant heroin user. Australian and New Zealand Journal of Obstetrics and Gynaecology, 42, 93–94.

    CAS  PubMed  Google Scholar 

  34. Hulse, GK, English, DR, Milne, E & Holman, CDJ 1999. The quantification of mortality resulting from the regular use of illicit opiates. Addiction, 94, 221–229.

    Article  CAS  PubMed  Google Scholar 

  35. Hulse, GK, Arnold-Reed, DA, O'Neil, G, Chan, CT & Hansson, R 2004a. Achieving long-term continuous blood naltrexone and 6-β-naltrexol coverage following sequential naltrexone implants. Addiction Biology, 9, 67–72.

    Article  CAS  Google Scholar 

  36. Hulse, GK, Arnold-Reed, DE, O'Neil, G, Chan, CT, Hansson, R & O'Neil, P 2004b. Blood naltrexone and 6-β-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology, 9, 59–65.

    Article  CAS  Google Scholar 

  37. Hulse, GK, Stalenberg, V, McCallum, D, Smit, W, O'Neil, G, Morris, N & Tait, RJ 2005a. Histological changes over time around the site of sustained release naltrexone-poly(d-l-Lactide) implants in humans. Journal of Controlled Release, 108, 43–55.

    Article  CAS  Google Scholar 

  38. Hulse, GK, Tait, RJ, Comer, SD, Sullivan, MA, Jacobs, IG & Arnold-Reed, DE 2005b. Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. Drug and Alcohol Dependence, 79, 351–357.

    Article  Google Scholar 

  39. Johnson, BA, Ait-Daoud, N, Aubin, H-J, van den Brink, W, Guzzetta, R, Loewy, J, Silverman, B & Ehrich, E 2004. A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone [Vivitrex (R)] in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research, 28, 1356–1361.

    Article  CAS  Google Scholar 

  40. Julius, D. 1976. NIDA' naltrexone research program. In: Narcotic Antagonists: Naltrexone (NIDA Research Monograph No. 9), Julius, D. & Renault, P. (eds.), pp. 5–11. Rockville, MD: National Institute of Drug Abuse.

    Google Scholar 

  41. Kaplan, SA, Pouletty, P & Wesson, DR 2000. Pharmacokinetics of naltrexone from polylac-tide sustained-release naltrexone. Drug and Alcohol Dependence, 60, S107.

    Google Scholar 

  42. Kirchmayer, U, Davoli, M, Verster, AD, Amato, L, Ferri, A & Perucci, CA 2002. A systematic review on the efficacy of naltrexone maintenance treatment in opiod dependence. Addiction, 97, 1241–1249.

    Article  PubMed  Google Scholar 

  43. Kirchmayer, U, Davoli, M & Verster, A 2003. Naltrexone maintenance treatment for opioid dependence. Cochrane Database of Systematic Reviews, Issue 2, DOI: 10.1002/14651858. CD001333.

    Google Scholar 

  44. Kosten, TR & Kleber, HD 1984. Strategies to improve compliance with narcotic antagonists. American Journal of Drug and Alcohol Abuse, 10, 249–266.

    Article  CAS  PubMed  Google Scholar 

  45. Kranzler, HR, Modesto-Lowe, V & Nuwayser, ES 1998. Sustained-release naltrexone for alcoholism treatment: a preliminary study. Alcoholism: Clinical and Experimental Research, 22, 1074–1079.

    CAS  Google Scholar 

  46. Kranzler, HR, Wesson, DR, Billot, L and Drug Abuse Sciences Naltrexone Depot Study Group 2004. Naltrexone depot for treatment of alcohol dependence: a multicenter, rand omized, placebo-controlled clinical trial. Alcoholism: Clinical and Experimental Research, 28, 1051–1059.

    Article  CAS  Google Scholar 

  47. Krupitsky, EM, Zvartau, EE, Masalov, DV, Tsoi, M V, Burakov, AM, Egorova, VY, Didenko, TY, Romanova, TM, Ivanova, EB, Bespalov, AY, Verbitskaya, EV, Neznanov, NG, Grinenko, AY, O'Brien, CP & Woody, GE in press. Naltrexone for heroin dependence treat ment in St. Petersburg, Russia. Journal of Substance Abuse Treatment.

    Google Scholar 

  48. Lin, F-H, Chen, T-M, Lin, C-P & Lee, C-J 1999. The merit of sintered PDLLA/TCP compos ites in management of bone fracture internal fixation. Artificial Organs, 23, 186–194.

    Article  CAS  PubMed  Google Scholar 

  49. Maa, YF & Heller, J 1990. Controlled release of naltrexone pamoate from linear poly(ortho esters). Journal of Controlled Release, 14, 21–28.

    Article  CAS  Google Scholar 

  50. Martin, WR & Sandquist, VL 1974. A sustained release depot for narcotic antagonists. Archives of General Psychiatry, 30, 31–33.

    CAS  PubMed  Google Scholar 

  51. Navaratnam, V, Jamaludin, A, Raman, N, Mohamed, M & Mansor, SM 1994. Determination of naltrexone dosage for narcotic agonist blockade in detoxified Asian addicts. Drug and Alcohol Dependence, 34, 231–236.

    Article  CAS  PubMed  Google Scholar 

  52. Olmedo, R & Hoffman, RS 2000. Withdrawal syndromes. Emergency Medicine Clinics of North America, 18, 273–288.

    Article  CAS  PubMed  Google Scholar 

  53. Olsen, JL & Kincl, FA 1980. A review of parental sustained-release naltrexone systems. In: Naltrexone Research Monograph, Willette, R. E. & Barnett, G. (eds.), pp. 187–264: National Institute on Drug Abuse.

    Google Scholar 

  54. Oncken, C, Van Kirk, J & Kranzler, HR 2001. Adverse effects of oral naltrexone: analysis of data from two clinical trials. Psychopharmacology, 154, 397–402.

    Article  CAS  PubMed  Google Scholar 

  55. Preston, KL, Silverman, K, Umbricht, A, DeJesus, A, Montoya, ID & Schuster, CR 1999. Improvement in naltrexone treatment compliance with contingency management. Drug and Alcohol Dependence, 54, 127–135.

    Article  CAS  PubMed  Google Scholar 

  56. Reuning, RH, Liao, SHT, Staubus, AE, Ashcraft, SB, Downs, DA, Harrigan, SE, Wiley, JN & Wise, DL 1983. Pharmacokinetic quantitation of naltrexone controlled release from a copolymer delivery system. Journal of Pharmacokinetics and Biopharmaceutics, 11, 369–387.

    Article  CAS  PubMed  Google Scholar 

  57. Rothenberg, JL, Sullivan, MA, Church, SH, Seracini, A, Collins, E, Kleber, HD & Nunes, EV 2002. Behavioral naltrexone therapy: an integrated treatment for opiate dependence. Journal of Substance Abuse Treatment, 23, 351–360.

    Article  PubMed  Google Scholar 

  58. San, L, Pomarol, G, Peri, JM, Olle, JM et al. 1991. Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts. British Journal of Addiction, 86, 983–990.

    Article  CAS  PubMed  Google Scholar 

  59. Schwope, AD, Wise, DL & Howes, JF 1975. Lactic/glycolic acid polymers as narcotic antagonist delivery systems. Life Sciences, 17, 1877–1886.

    Article  CAS  PubMed  Google Scholar 

  60. Seaman, SR, Brettle, RP & Gore, SM 1998. Mortality from overdose among injecting drug users recently released from prison: database linkage study. British Medical Journal, 316, 426–428.

    CAS  PubMed  Google Scholar 

  61. Sharon, AC & Wise, DL 1980. Development of drug delivery systems for use in treatment of narcotic addiction. NIDA Research Monograph, 28, 194–213.

    Google Scholar 

  62. Sidman, CL, Bercovici, T & Gitler, C 1980. Membrane insertion of lymphocyte surface molecules. Molecular Immunology, 17, 1575–1583.

    Article  CAS  PubMed  Google Scholar 

  63. Tennant, FS, Rawson, RA, Cohen, AJ & Mann, A 1984. Clinical experience with naltrexone in suburban opioid addicts. Journal of Clinical Psychiatry, 45, 42–45.

    PubMed  Google Scholar 

  64. Therin, M, Christel, P, Li, SM, Garreau, H & Vert, M 1992. In vivo degradation of massive poly(a-hydroxyacids): validation of in vitro findings. Biomaterials, 13, 594–600.

    Article  CAS  PubMed  Google Scholar 

  65. Tucker, TK, Ritter, A, Maher, C & Jackson, H 2004. Natrexone maintenance for heroin dependence: uptake, attrition and retention. Drug and Alcohol Review, 23, 299–300.

    Article  PubMed  Google Scholar 

  66. Vereby, K, Volavka, J, Mule, SJ & Resnick, RB 1976. Naltrexone: disposition, metabolism, and effects after acute and chronic dosing. Clinical Pharmacology and Therapeutics, 20, 315–328.

    Google Scholar 

  67. Vert, M, Schwach, G, Engel, R & Coudane, J 1998. Something new in the field of PLA/GA bioresorbable polymers? Journal of Controlled Release, 53, 85–92.

    Article  CAS  PubMed  Google Scholar 

  68. Walsh, SL, Preston, KL, Stitzer, ML et al. 1994. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clinical Pharmacology and Therapeutics, 55, 569–580.

    Article  CAS  PubMed  Google Scholar 

  69. Washton, AM, Pottash, AC & Gold, MS 1984. Naltrexone in addicted business executives and physicians. Journal of Clinical Psychiatry, 45, 39–41.

    CAS  PubMed  Google Scholar 

  70. White, JM & Irvine, RJ 1999. Mechanisms of fatal opioid overdose. Addiction, 94, 961–972.

    Article  CAS  PubMed  Google Scholar 

  71. Willette, RE 1982. Narcotic antagonists. An alternative for treating opioid dependence. American Pharmacy, NS22, 44–46.

    CAS  PubMed  Google Scholar 

  72. Yamaguchi, K & Anderson, JM 1993. In vivo biocompatibility studies of medisorb 65/35 d,l-lactide/glycolide copolymer microspheres. Journal of Controlled Release, 24, 81–93.

    Article  CAS  Google Scholar 

  73. Yolles, S, Leafe, TD, Woodland, JHR & Meyer, FJ 1975. Long acting delivery systems for narcotic antagonists II: release rates of naltrexone from poly(lactic acid) composites. Journal of Pharmacological Science, 64, 348–349.

    Article  CAS  Google Scholar 

  74. Zacny, JP, Bigelow, GE, Compton, P, Foley, K, Iguchi, M & Sannerud, C 2003. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug and Alcohol Dependence, 69, 215–232.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit for Research and Education in Drugs and Alcohol, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, 35 Stirling Highway, Western Australia, 6009, Australia

    Gary K. Hulse

  2. Division on Substance Abuse, Department of Psychiatry, Columbia University, New York, NY, 10032

    Sandra D. Comer & Maria A. Sullivan

Authors
  1. Gary K. Hulse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra D. Comer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria A. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Life Sciences/Toxicology, Alkermes, Inc., Cambridge, MA, 02139, USA

    Reginald L. Dean III

  2. Department of Pharmacology, College of Osteopathic Medicine, University of New England, Biddleford, ME, 04005, USA

    Edward J. Bilsky

  3. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    S. Stevens Negus

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Hulse, G.K., Comer, S.D., Sullivan, M.A. (2009). The Development of Sustained-Release Naltrexone and Clinical Use in Treating Opiate Dependence. In: Dean, R.L., Bilsky, E.J., Negus, S.S. (eds) Opiate Receptors and Antagonists. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-197-0_36

Download citation

Publish with us

Policies and ethics

Search

Navigation