Skip to main content
SpringerLink
Log in

Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids

  • Chapter
Opiate Receptors and Antagonists

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

  • 1050 Accesses

Abstract

Ultra-low-dose opioid antagonist cotreatment was first shown parad oxically to enhance opioid analgesia and to reduce analgesic tolerance and physical dependence. In this chapter, we review data demonstrating that ultra-low-dose naloxone or naltrexone reduces several components of opioid dependence and addiction. While the reduction in opioid dependence, first demonstrated as a reduction in somatic withdrawal signs, might seem merely a correlate of the attenuation in tolerance, the data reviewed here show that ultra-low-dose naltrexone also reduces the “psychological” or negative affective aspect of acute opioid withdrawal. In addition, the acute rewarding properties of opioids are reduced by ultra-low-dose naltrexone. The attenuation of rewarding effects occurs in the same ultra-low dose ranges shown to enhance analgesia, thus dissociating the rewarding or addictive effects of opioids from their analgesic properties. Furthermore, in intravenous self-administration procedures in rats, ultra-low-dose opioid antagonists coadmin-istered with opioids reduced their rewarding potency, reduced motivation to obtain the drug, and reduced “drug-seeking” in the absence of drug availability. Finally, in a Phase III clinical trial, the ultra-low-dose naltrexone component of Oxytrex™ significantly reduced physical signs of opioid dependence after abrupt cessation of treatment, compared to withdrawal from oxycodone alone. Together, the data reviewed in this chapter suggest a reduced potential for opioid dependence and addiction by certain ultra-low-dose opioid antagonists combined with opioids, concurrent with the enhanced analgesia from these opioid agonist/antagonist cotreatments.

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. Azar MR, Jones BC, Shulteis G (2003) Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal. Psychopharmacology 170:42–50.

    Article  CAS  PubMed  Google Scholar 

  2. Ballantyne J, Mao J (2003) Opioid therapy for chronic pain. N Engl J Med 349:1943–1953.

    Article  CAS  PubMed  Google Scholar 

  3. Beardsley PM, Aceto MD, Cook CD, Bowman ER, Newman JL, Harris LS (2004) Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys. Exp Clin Psychopharmacol 12:163–172.

    Article  CAS  PubMed  Google Scholar 

  4. Bechara A, Nader K, van der Kooy D (1995) Neurobiology of withdrawal motivation: evidence for two separate aversive effects produced in morphine-naive versus morphine-dependent rats by both naloxone and spontaneous withdrawal. Behav Neurosci 109:91–105.

    Article  CAS  PubMed  Google Scholar 

  5. Beckman A, Matsumoto I, Wilce P (1995) Immediate early gene expression during morphine withdrawal. Neuropharmacology 34:1183–1189.

    Article  Google Scholar 

  6. Burns LH, Olmstead MC (2005) Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology 181:576–581.

    Article  PubMed  Google Scholar 

  7. Chen H, Yang Y, Yeh T, Cherng C, Hsu H, Hsiao S, Yu L (2003) Methamphetamine-induced conditioned place preference is facilitated by estradiol pretreatment in female mice. Chin J Physiol (China) 46:169–174.

    CAS  Google Scholar 

  8. Chindalore VL, Butera PG, Yu KP, Burns LH, Friedmann N (2005) Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: A randomized, controlled trial of Oxytrex. J Pain 6:392–399.

    Article  CAS  PubMed  Google Scholar 

  9. Compton WM, Volkow ND (2006) Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend 81:103–107.

    Article  PubMed  Google Scholar 

  10. Crain SM, Shen K-F (1995) Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic co-treatment. Proc Natl Acad Sci USA 92:10540–10544.

    Article  CAS  PubMed  Google Scholar 

  11. Fne P (2004) Opioid insights: opioid-induced hyperalgesia and opioid rotation. J Pain Palliat Care Pharmacother 18:75–79.

    Google Scholar 

  12. Franklin KB (1998) Analgesia and abuse potential: an accidental association or a common substrate? Pharmacol Biochem Behav 59:993–1002.

    Article  CAS  PubMed  Google Scholar 

  13. Frenois F, Cador M, Caille S, Stinus L, Le Moine C (2002) Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal. Eur J Neurosci 16:1377–1389.

    Article  PubMed  Google Scholar 

  14. Hamman S, Wala E, Rebel A, Lock R (2004) Selective antagonism of excitatory opioid receptors: A pilot clinical study demonstrating enhancement of morphine analgesia by low-dose naltrxone in female patients undergoing elective laparotomy. American Society of Anesthesiologists Annual Meeting, Las Vegas, NV

    Google Scholar 

  15. Joranson D, Ryan K, Gilson A, Dahl J (2000) Trends in medical use and abuse of opioid analgesics. J Am Med Assoc 283:1710–1714.

    Article  CAS  Google Scholar 

  16. Kogan MJ, Verebey K, Mule SJ (1977) Estimation of the systemic availability and other pharmacokinetic parameters of naltrexone in man after acute and chronic oral administration. Res Commun Chem Pathol Pharmacol 18:29–34.

    CAS  PubMed  Google Scholar 

  17. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58.

    Article  CAS  PubMed  Google Scholar 

  18. Koob GF, Stinus L, Le Moal M, Bloom FE (1989) Opponent process theory of motivation: neurobiological evidence from studies of opiate dependence. Neurosci Biobehav Rev 13:135–140.

    Article  CAS  PubMed  Google Scholar 

  19. Koob GF, Maldonado R, Stinus L (1992) Neural substrates of opiate withdrawal. Trends Neurosci 15:186–191.

    Article  CAS  PubMed  Google Scholar 

  20. Leri F, Burns LH (2005) Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats. Pharmacol Biochem Behav 82:252–262.

    Article  CAS  PubMed  Google Scholar 

  21. Mannelli P, Gottheil E, Peoples JF, Oropeza VC, Van Bockstaele EJ (2004) Chronic very low dose naltrexone attenuates opioid withdrawal expression. Biol Psychiatry 56:261–268.

    Article  CAS  PubMed  Google Scholar 

  22. Marlatt GA, Gordon JR (1985) Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behavior. New York: Guilford Press.

    Google Scholar 

  23. Nazarian A, Russo S, Festa E, Kraish M, Quinones-Jenab V (2004) The role of D(1) and D(2) receptors in the cocaine conditioned place preference of male and female rats. Brain Res Bull 63:295–299.

    Article  CAS  PubMed  Google Scholar 

  24. Olmstead MC, Burns LH (2005) Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology 181:576–581.

    Article  CAS  PubMed  Google Scholar 

  25. Olmstead MC, Franklin KBJ (1997) Development of a conditioned place preference to morphine: effects of microinjections into various CNS sites. Behav Neurosci 111:1324–2334.

    Article  CAS  PubMed  Google Scholar 

  26. Oxbro K, Trang T, Sutak M, Jhamandas K (2003) The effects of spinal ultra-low doses of an opioid receptor antagonist on systemic morphine dependence. Society for Neuroscience Annual Meeting, New Orleans, LA.

    Google Scholar 

  27. Powell KJ, Abul-Husn NS, Jhamandas A, Olmstead MC, Beninger RJ, Jhamandas K (2002) Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats. JPET 300:588–596.

    Article  CAS  Google Scholar 

  28. Rassmusen K, Beitner-Johnson B, Krystal J, Aghajanian G, Nestler E (1990) Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological and biochemical correlates. J Neurosci 10:2308–2317.

    Google Scholar 

  29. Roberts DC, Bennett SA (1993) Heroin self-administration in rats under a progressive ratio schedule of reinforcement. Psychopharmacology 111:215–218.

    Article  CAS  PubMed  Google Scholar 

  30. Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20.

    Article  CAS  Google Scholar 

  31. Shen KF, Crain SM (1997) Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice. Brain Res 757:176–190.

    Article  CAS  PubMed  Google Scholar 

  32. Shen K-F, Crain SM, Moate P, Boston R, de Kater AW, Schoenhard GL (2002a) PTI-801, a novel formulation of oxycodone, shows absence of tolerance, physical dependence and naloxone-precipitated withdrawal effects in mice. Pain 3:49.

    Google Scholar 

  33. Shen K-F, Crain SM, Moate P, Boston R, de Kater AW, Schoenhard GL (2002b) PTI-555, reverses and prevents morphine-induced tolerance and naloxone-precipitated withdrawal in mice chronically treated with morphine. Pain 3:50.

    Article  Google Scholar 

  34. Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–184.

    Article  CAS  Google Scholar 

  35. Stinus L, Caille S, Koob GF (2000) Opiate withdrawal-induced place aversion lasts for up to 16 weeks. Psychopharmacology 149:115–120.

    Article  CAS  PubMed  Google Scholar 

  36. Trang T, Sutak M, Quirion R, Jhamandas K (2002) The role of spinal neuropeptides and prostaglandins in opioid physical dependence. Br J Pharmacol 136:37–48.

    Article  CAS  PubMed  Google Scholar 

  37. Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress, and new issues. Prog Neurobiol 56:613–672.

    Article  CAS  PubMed  Google Scholar 

  38. Wang H-Y, Friedman E, Olmstead MC, Burns LH (2005) Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in Mu opioid receptor-G protein coupling and G²γ signaling. Neuroscience 135:247–261.

    Article  CAS  PubMed  Google Scholar 

  39. Webster LR, Butera PG, Moran LV, Wu N, Burns LH, Friedmann N (2006) Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low-back pain. J Pain 7:937–946.

    Article  CAS  PubMed  Google Scholar 

  40. Woods JH, Ko MC, Winger G, France CP, Traynor JR (2002) Evaluation of new compounds for opioid activity. In: NIDA Research Monograph (2003), 183 (Problems of Drug Dependence 2002), Dewey WL, Harris, LS (Eds.), pp 170–190. Baltimore, MD: National Institutes of Health.

    Google Scholar 

  41. Yokel RA, Wise RA (1975) Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward. Science 187:547–549.

    Article  CAS  PubMed  Google Scholar 

  42. Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology (Berl) 48:311–318.

    Article  CAS  Google Scholar 

  43. Zacny J, Bigelow G, 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 Alcohol Depend 69:215–232.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Preclinical Development, Pain Therapeutics, Inc., 2211 Bridgepointe Parkway, Suite 500, San Mateo, CA, 94404

    Lindsay H. Burns, Francesco Leri & Mary C. Olmstead

  2. Department of Psychology, University of Guelph, Guelph, ON, N1G2W1, Canada

    Francesco Leri

  3. Department of Psychology, Queen's University, Kingston, ON, K7L 3N6, Canada

    Mary C. Olmstead

Authors
  1. Lindsay H. Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Leri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary C. Olmstead
    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

Burns, L.H., Leri, F., Olmstead, M.C. (2009). Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids. 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_13

Download citation

Publish with us

Policies and ethics

Search

Navigation