, 200:521 | Cite as

Predicting response to opiate antagonists and placebo in the treatment of pathological gambling

  • Jon E. GrantEmail author
  • Suck Won Kim
  • Eric Hollander
  • Marc N. Potenza
Original Investigation



Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG.


We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists.

Materials and methods

Two hundred eighty-four subjects [137 (48.2%) women] with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) with positive response defined as ≥35% reduction in PG-YBOCS score for at least 1 month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response.


The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p = 0.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50 or 100 mg/day or naltrexone 100 or 150 mg/day), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p = 0.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p = 0.012).


A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.


Opiate antagonists Impulsivity Impulse control disorders Addiction Pharmacotherapy Placebo 



This research was supported in part by a Career Development Award (K23 MH069754-01A1) (JEG), a grant from NIMH (R21-MH065920) (SWK), an educational grant from BioTie Therapies Corporation, Turku, Finland, and support from the U.S. Department of Veterans Affairs (the VA Connecticut-Massachusetts Mental Illness Research, Education and Clinical Center (MIRECC)) (MNP).

All procedures comply with the current laws of the United States of America.

Conflict of interest statement

Dr. Grant has received research grants from Forest Pharmaceuticals, GlaxoSmithKline, and Somaxon Pharmaceuticals. Dr. Grant has also been a consultant to Pfizer Pharmaceuticals and Somaxon Pharmaceuticals and has consulted for law offices as an expert in pathological gambling.

Dr. Kim reports no competing interests.

Dr. Hollander has received a research grant from and served as a consultant to Somaxon.

Dr. Potenza consults for and is an advisor to Boehringer Ingelheim, receives research support from Mohegan Sun and Forest Laboratories, has consulted for Somaxon and BioTie/Oy Contral, has financial interests in Somaxon, and has consulted for law offices and the federal defender’s office as an expert in pathological gambling and impulse control disorders.


  1. Anton RF, Moak DH, Waid LR, Latham PK, Malcolm RJ, Dias JK (1999) Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry 156(11):1758–1764PubMedGoogle Scholar
  2. Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A, COMBINE Study Research Group (2006) Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295(17):2003–2017PubMedCrossRefGoogle Scholar
  3. Blanco C, Moreyra P, Nunes EV, Sáiz-Ruiz J, Ibáñez A (2001) Pathological gambling: addiction or compulsion? Sem Clin Neuropsychiatry 6(3):167–176CrossRefGoogle Scholar
  4. Brewer JA, Potenza MN (2008) The neurobiology and genetics of impulse control disorders: Relationships to drug addictions. Biochem Pharmacol 75(1):63–75 [Epub 2007 Jul 3 ahead of print]PubMedCrossRefGoogle Scholar
  5. Broekkamp CL, Phillips AG (1979) Facilitation of self-stimulation behavior following intracerebral microinjections of opioids into the ventral tegmental area. Pharmacol Biochem Behav 11(3):289–295PubMedCrossRefGoogle Scholar
  6. Chambers RA, Taylor JR, Potenza MN (2003) Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160(6):1041–1052PubMedCrossRefGoogle Scholar
  7. de la Fuente-Fernández R, Lidstone S, Stoessl AJ (2006) Placebo effect and dopamine release. J Neural Transm Suppl 70:415–418PubMedCrossRefGoogle Scholar
  8. Dell’Osso B, Altamura AC, Allen A, Marazziti D, Hollander E (2006) Epidemiologic and clinical updates on impulse control disorders: a critical review. Eur Arch Psychiatry Clin Neurosci 256(8):464–475PubMedCrossRefGoogle Scholar
  9. First MB, Spitzer RL, Gibbon M, Williams JBW (1995) Structured Clinical Interview for DSM-IV-Patient Edition (SCID-I/P, Version 2.0). New York Biometrics Research Department, New York State Psychiatric Institute, New YorkGoogle Scholar
  10. Grant JE, Potenza MN (2007) Treatments for pathological gambling and other impulse control disorders. In: Nathan PE, Gorman JM (eds) A guide to treatments that work, 3rd edition. Oxford University Press, New York, pp 561–571Google Scholar
  11. Grant JE, Potenza MN, Hollander E, Cunningham-Williams R, Nurminen T, Smits G, Kallio A (2006) A multicenter investigation of the opioid antagonist nalmefene in the treatment of pathological gambling. Am J Psychiatry 163(2):303–312PubMedCrossRefGoogle Scholar
  12. Grant JE, Kim SW, Hartman BK (2008) A double-blind, placebo-controlled study of the opiate antagonist, naltrexone, for the treatment of pathological gambling urges. J Clin Psychiatry 69(5):783–789PubMedCrossRefGoogle Scholar
  13. Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32(1):50–55PubMedGoogle Scholar
  14. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62PubMedGoogle Scholar
  15. Hollander E, DeCaria CM, Finkell JN, Begaz T, Wong CM, Cartwright C (2000) A randomized double-blind fluvoxamine/placebo crossover trial in pathological gambling. Biol Psychiatry 47(9):813–817PubMedCrossRefGoogle Scholar
  16. Hollander E, Pallanti S, Allen A, Sood E, Baldini Rossi N (2005) Does sustained-release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders? Am J Psychiatry 162(1):137–145PubMedCrossRefGoogle Scholar
  17. Kim SW, Grant JE, Adson DE, Shin YC (2001) Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biol Psychiatry 49(11):914–921PubMedCrossRefGoogle Scholar
  18. Kosten TR, Kleber HD, Morgan C (1989) Role of opioid antagonists in treating intravenous cocaine abuse. Life Sci 44(13):887–892PubMedCrossRefGoogle Scholar
  19. Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O’Malley SS (2007) Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol Psychiatry 62(6):694–697PubMedCrossRefGoogle Scholar
  20. Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA, Veterans Affairs Naltrexone Cooperative Study 425 Group (2001) Naltrexone in the treatment of alcohol dependence.. N Engl J Med 345(24):1734–1739PubMedCrossRefGoogle Scholar
  21. Lesieur HR, Blume SB (1987) The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers. Am J Psychiatry 144(9):1184–1188PubMedGoogle Scholar
  22. Martin WR, Jasinski DR, Mansky PA (1973) Naltrexone, an antagonist for the treatment of heroin dependence. Effects in man.. Arch Gen Psychiatry 28(6):784–791PubMedGoogle Scholar
  23. Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB (1999) A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56(8):719–724PubMedCrossRefGoogle Scholar
  24. Matthews RT, German DC (1984) Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine. Neuroscience 11(3):617–625PubMedCrossRefGoogle Scholar
  25. Monterosso J, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien CP, Volpicelli J (2001) Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict 10(3):258–268PubMedCrossRefGoogle Scholar
  26. Montgomery SA (1999) The failure of placebo-controlled studies. ECNP Consensus Meeting, September 13, 1997, Vienna, European College of Neuropsychopharmacology. Eur Neuropsychopharmacol 9(3):271–276PubMedCrossRefGoogle Scholar
  27. O’Brien CP (2005) Anti-craving (relapse prevention) medications: possible a new class of psychoactive medication. Am J Psychiatry 162:1423–1431PubMedCrossRefGoogle Scholar
  28. Oslin DW, Berrettini W, Krnazler H, Pettinati H, Gelernter J, Volpicelli J, O’Brien CP (2003) A functional polymorphism of the mu opioid receptor gene is associated with naltrexone response in alcohol dependent patients. Neuropsychopharmacol 28(8):1546–1552CrossRefGoogle Scholar
  29. Pallanti S, DeCaria CM, Grant JE, Urpe M, Hollander E (2005) Reliability and validity of the Pathological Gambling Modification of the Yale-Brown Obsessive-Compulsive Scale (PG-YBOCS). J Gambl Stud 21(4):431–443PubMedCrossRefGoogle Scholar
  30. Ray LA, Hutchison KE (2007) Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: a double-blind placebo-controlled study. Arch Gen Psychiatry 64(9):1069–1077PubMedCrossRefGoogle Scholar
  31. Rosner B (1995) Fundamentals of Biostatistics, 4th ed. Duxbury, BelmontGoogle Scholar
  32. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2007) Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55(2):325–336PubMedCrossRefGoogle Scholar
  33. Sheehan DV (1983) The anxiety disease. Scribner’s, New YorkGoogle Scholar
  34. Slutske WS, Eisen S, True WR, Lyons MJ, Goldberg J, Tsuang M (2000) Common genetic vulnerability for pathological gambling and alcohol dependence in men. Arch Gen Psychiatry 57:666–673PubMedCrossRefGoogle Scholar
  35. Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49(11):876–880PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jon E. Grant
    • 1
    Email author
  • Suck Won Kim
    • 1
  • Eric Hollander
    • 2
  • Marc N. Potenza
    • 3
    • 4
    • 5
    • 6
  1. 1.Department of PsychiatryUniversity of Minnesota School of MedicineMinneapolisUSA
  2. 2.Department of PsychiatryMount Sinai School of MedicineNew YorkUSA
  3. 3.Connecticut Mental Health CenterYale University School of MedicineNew HavenUSA
  4. 4.VA Connecticut Healthcare SystemYale University School of MedicineNew HavenUSA
  5. 5.Department of PsychiatryYale University School of MedicineNew HavenUSA
  6. 6.Child Study CenterYale University School of MedicineNew HavenUSA

Personalised recommendations