CNS Drugs

, Volume 19, Issue 8, pp 693–707 | Cite as

The Opioidergic-Alcohol Link

Implications for Treatment
Review Article

Abstract

Preclinical and clinical data implicate the endogenous opioid system in alcohol dependence. In vitro studies show that rodent pituitary and hypothalamic tissue responds to acute exposure to alcohol by releasing β-endorphins. In vivo studies suggest differential activity of endogenous opioid receptors in rodents with high and low alcohol preference. Similarly, humans with a family history of alcohol dependence also show a heightened endorphin response to an acute challenge of alcohol compared with those with no family history of alcohol dependence.

The effects of opioid agonists and antagonists on rodent and human alcohol consumption further support the opioid-alcohol link. In rodents and humans, small doses of opioid agonists increase alcohol consumption, while pretreatment with large doses decreases consumption. The opioid antagonist naltrexone decreases rodent alcohol consumption, particularly in low doses under acute and intermittent schedules.

Most clinical trials in patients with alcohol dependence support modest therapeutic effects of naltrexone in decreasing alcohol consumption. Efforts to identify subgroups of alcohol-dependent patients responsive to naltrexone, as well as psychosocial and pharmacological augmentation strategies, may further improve the clinical usefulness of the drug.

Notes

Acknowledgements

We acknowledge Drs Nancy Petry, Lance Bauer and Victor Hesselbrock for their comments, Dr Kranzler for his help, and Judy Herkimer and Vera Dynder for typing the manuscript. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Volpicelli JR. Alcohol abuse and alcoholism: an overview. J Clin Psychiatry 2001; 62Suppl. 20: 4–10PubMedGoogle Scholar
  2. 2.
    O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 1992; 49: 881–7PubMedCrossRefGoogle Scholar
  3. 3.
    Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 1992; 49: 876–80PubMedCrossRefGoogle Scholar
  4. 4.
    Chick J, Anton R, Checinski K, et al. A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol 2000; 35(6): 587–93PubMedGoogle Scholar
  5. 5.
    Volpicelli J, Rhines KC, Rhines, et al. Naltrexone and alcohol dependence: role of subject compliance. Arch Gen Psychiatry 1997; 54: 737–42PubMedCrossRefGoogle Scholar
  6. 6.
    Oncken C, Van Kirk J, Kranzler HR. Adverse effects of oral naltrexone: analyses of data from two clinical trials. Psychopharmacology 2001; 154(4): 397–402PubMedCrossRefGoogle Scholar
  7. 7.
    Davis VE, Walsh MJ. Alcohol, amines and alkaloids: a possible biochemical basis for alcohol addiction. Science 1970; 167: 1005–7PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science 1970; 167:1749–51PubMedCrossRefGoogle Scholar
  9. 9.
    Myers RD. Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms. Experientia 1989; 45: 436–42PubMedCrossRefGoogle Scholar
  10. 10.
    Swift RM. Effect of naltrexone on human alcohol consumption. J Clin Psychiatry 1995; 56Suppl. 7: 24–9PubMedGoogle Scholar
  11. 11.
    Gianoulakis C. Implications of endogenous opioids and dopamine in alcoholism: human and basic science studies. Alcohol Alcohol 1996; 31Suppl. 1: 33–42PubMedGoogle Scholar
  12. 12.
    Reisine T, Bell GI. Molecular biology of opioid receptors. Trends Neurol Sci 1993; 16: 506–10CrossRefGoogle Scholar
  13. 13.
    Terenius L. Alcohol addition (alcoholism) and the opioid system. Alcohol 1996; 13(1): 31–4PubMedCrossRefGoogle Scholar
  14. 14.
    Mucha RF, Herz A. Motivational properties of kappa and mu opioid receptor agonists studies with place and taste preference conditioning. Psychopharmacology 1985; 86: 274–80PubMedCrossRefGoogle Scholar
  15. 15.
    Di Chiara G, Acquas E, Tanda G. Ethanol as a neurochemical surrogate of conventional reinforcers: the dopamine-opioid link. Alcohol 1996; 13(1): 13–7PubMedCrossRefGoogle Scholar
  16. 16.
    Koob GF, Roberts AJ, Kieffer BL, et al. Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology. Recent Dev Alcohol 2003; 16: 263–81PubMedCrossRefGoogle Scholar
  17. 17.
    Herz A. Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl) 1997; 129(2): 99–111CrossRefGoogle Scholar
  18. 18.
    Gessa GL, Montoni F, Collo M, et al. Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Res 1985; 348: 201–3PubMedCrossRefGoogle Scholar
  19. 19.
    Brodie MS, Pesold C, Appel SB. Ethanol directly excites dopaminergic ventral tegmental reward neurons. Alcohol Clin Exp Res 1999; 23: 1848–52PubMedCrossRefGoogle Scholar
  20. 20.
    Wozniak KM, Pert A, Mele A, et al. Focal application of alcohols elevates extracellular dopamine in rat brain: a microdialysis study. Brain Res 1991; 540: 31–40PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshimoto K, McBride WJ, Lumeng L, et al. Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens. Alcohol 1991; 9: 17–22CrossRefGoogle Scholar
  22. 22.
    Hyytia P. Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats. Pharmacol Biochem Behav 1993; 45(3): 697–701PubMedCrossRefGoogle Scholar
  23. 23.
    Honkanen A, Vilamo L, Wegelius K, et al. Alcohol drinking is reduced by a mu 1-butnotbya delta-opioid receptor antagonist in alcohol-preferring rats. Eur J Pharmacol 1996; 304(1–3): 7–13PubMedCrossRefGoogle Scholar
  24. 24.
    Stromberg MF, Volpicelli JR, O’Brien CP. Effects of naltrexone administered repeatedly across 30 or 60 days on ethanol consumption using a limited access procedure in the rat. Alcohol Clin Exp Res 1998; 22(9): 2186–91PubMedCrossRefGoogle Scholar
  25. 25.
    Kim SG, Stromberg MF, Kim MJ, et al. The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice. Alcohol 2000; 22(2): 85–90PubMedCrossRefGoogle Scholar
  26. 26.
    Ciccocioppo R, Martin-Fardon R, Weiss F. Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology 2002; 27(3): 391–9PubMedCrossRefGoogle Scholar
  27. 27.
    June HL, McCane SR, Zink RW. The delta 2-opioid receptor antagonist naltriben reduces motivated responding for ethanol. Psychopharmacology (Berl) 1999; 147(1): 81–9CrossRefGoogle Scholar
  28. 28.
    Roberts AJ, McDonald JS, Heyser CJ, et al. mu-Opioid receptor knockout mice do not self-administer alcohol. J Pharmacol Exp Ther 2000; 293(3): 1002–8PubMedGoogle Scholar
  29. 29.
    Roberts AJ, Gold LH, Polis I, et al. Increased ethanol self-administration in delta-opioid receptor knockout mice. Alcohol Clin Exp Res 2001; 25(9): 1249–56PubMedGoogle Scholar
  30. 30.
    Spanagel R, Herz A, Shippenberg TS. The effects of opioid peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study. J Neurochem 1990; 55: 1734–40PubMedCrossRefGoogle Scholar
  31. 31.
    Gianoulakis C, Hutchison WD, Kalant H. Effects of ethanol treatment and withdrawal on biosynthesis and processing proopiomelanocortin by the rat neurointermediate lobe. Endocrinology 1988; 122(3): 817–25PubMedCrossRefGoogle Scholar
  32. 32.
    Gianoulakis C. Characterization of the effects of acute ethanol administration on the release of beta-endorphin peptides by the rat hypothalamus. Eur J Pharmacol 1990; 180(1): 21–9PubMedCrossRefGoogle Scholar
  33. 33.
    de Waele JP, Gianoulakis C. Effects of single and repeated exposures to ethanol on hypothalamic beta-endorphin and CRH release by the C57BL/6 and DBA/2 strains of mice. Neuroendocrinology 1993; 57(4): 700–9PubMedCrossRefGoogle Scholar
  34. 34.
    de Waele JP, Papachristou DN, Gianoulakis C. The alcohol-preferring C57BL/6 mice present an enhanced sensitivity of the hypothalamic beta-endorphin system to ethanol than the alcohol-avoiding DBA/2 mice. J Pharmacol Exp Ther 1992; 261(2): 788–94PubMedGoogle Scholar
  35. 35.
    Rasmussen DD, Bryant CA, Boldt BM, et al. Acute alcohol effects on opiomelanocortinergic regulation. Alcohol Clin Exp Res 1998; 22(4): 789–801PubMedCrossRefGoogle Scholar
  36. 36.
    Gianoulakis C, Barcomb A. Effect of acute ethanol in vivo and in vitro on the beta-endorphin system in the rat. Life Sci 1987; 40(1): 19–28PubMedCrossRefGoogle Scholar
  37. 37.
    Thiagarajan AB, Mefford IN, Eskay RL. Single-dose ethanol administration activates the hypothalamic-pituitary-adrenal axis: exploration of the mechanism of action. Neuroendocrinology 1989; 50(4): 427–32PubMedCrossRefGoogle Scholar
  38. 38.
    de Waele JP, Kiianmaa K, Gianoulakis C. Spontaneous and ethanol stimulated in vitro release of β-endorphin by the hypothalamus of AA and ANA rats. Alcohol Clin Exp Res 1994; 18: 1468–73PubMedCrossRefGoogle Scholar
  39. 39.
    Gianoulakis C, Hutchison WD, Kalant H. Effects of ethanol treatment and withdrawal on biosynthesis and processing of proopiomelanocortin by the rat neurointermediate lobe. Endocrinology 1988; 122(3): 817–25PubMedCrossRefGoogle Scholar
  40. 40.
    Seizinger BR, Bovermann K, Hollt V, et al. Enhanced activity of the beta-endorphinergic system in the anterior and neurointermediate lobe of the rat pituitary after chronic treatment with ethanol liquid diet. J Pharmacol Exp Ther 1984; 230(2): 455–61PubMedGoogle Scholar
  41. 41.
    Dave JR, Eiden LE, Karanian JW, et al. Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase activity, proopiomelanocortin biosynthesis, and plasma beta-endorphin levels in the rat. Endocrinology 1986; 118(1): 280–6PubMedCrossRefGoogle Scholar
  42. 42.
    Seizinger BR, Bovermann K, Maysinger D, et al. Differential effects of acute and chronic ethanol treatment on particular opioid peptide systems in discrete regions of rat brain and pituitary. Pharmacol Biochem Behav 1983; 18 Suppl. 1: 361–9CrossRefGoogle Scholar
  43. 43.
    Schulz R, Wuster M, Duka T, et al. Acute and chronic ethanol treatment changes endorphin levels in brain and pituitary. Psychopharmacology (Berl) 1980; 68(3): 221–7CrossRefGoogle Scholar
  44. 44.
    Adams ML, Cicero TJ. Effects of alcohol on beta-endorphin and reproductive hormones in the male rat. Alcohol Clin Exp Res 1991; 15(4): 685–92PubMedCrossRefGoogle Scholar
  45. 45.
    Angelogianni P, Gianoulakis C. Chronic ethanol increased proopiomelanocortin gene expression in the rat hypothalamus. Neuroendocrinology 1993; 57(1): 106–14PubMedCrossRefGoogle Scholar
  46. 46.
    Scanlon MN, Lazar-Wesley E, Grant KA, et al. Propiomelanocortin messenger RNA is decreased in the mediobasal hypothalamus of rats made dependent on ethanol. Alcohol Clin Exp Res 1992; 16: 1147–51PubMedCrossRefGoogle Scholar
  47. 47.
    Marinelli PW, Kiianmaa K, Gianoulakis C. Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats. Life Sci 2000; 66(20): 1915–27PubMedCrossRefGoogle Scholar
  48. 48.
    de Waele JP, Gianoulakis C. Enhanced activity of the brain beta-endorphin system by free-choice ethanol drinking in C57BL/6 but not DBA/2 mice. Eur J Pharmacol 1994; 258(1–2): 119–29PubMedCrossRefGoogle Scholar
  49. 49.
    Gianoulakis C, de Waele JP, Kiianmaa K. Differences in the brain and pituitary beta-endorphin system between the alcohol-preferring AA and alcohol-avoiding ANA rats. Alcohol Clin Exp Res 1992; 16(3): 453–9PubMedCrossRefGoogle Scholar
  50. 50.
    Jamensky NT, Gianoulakis C. Content of dynorphins and kappa-opioid receptors in distinct brain regions of C57BL/6 and DBA/2 mice. Alcohol Clin Exp Res 1997; 21(8): 1455–64PubMedGoogle Scholar
  51. 51.
    Froehlich JC. Genetic factors in alcohol self-administration. J Clin Psychiatry 1995; 56Suppl. 7: 15–23PubMedGoogle Scholar
  52. 52.
    Blum K, Briggs AH. Opioid peptides and genotypic responses to ethanol. Biog Amines 1988; 5: 527–33Google Scholar
  53. 53.
    Li X-W, Li T-K, Froelich JC. Enhanced sensitivity of the nucleus accumbens proenkephalin system to alcohol in rats selectively bred for alcohol preference. Brain Res 1998; 794: 35–47PubMedCrossRefGoogle Scholar
  54. 54.
    Nylander I, Hyytia P, Forsander O, et al. Differences between alcohol-preferring (AA) and alcohol-avoiding (ANA) rats in the prodynorphine and proenkephalin systems. Alcohol Clin Exp Res 1994; 18(5): 1272–9PubMedCrossRefGoogle Scholar
  55. 55.
    Ng GYK, O’Dowd BE, George SR. Genotypic differences in mesolimbic enkephalin gene expression in DBA/2J and C57BL/6J inbred mice. Eur J Pharmacol 1996; 311: 45–52PubMedCrossRefGoogle Scholar
  56. 56.
    Jamensky NT, Gianoulakis C. Content of dynorphins and kappa-opioid receptors in distinct brain regions of C57BL/6 and DBA/2 mice. Alcohol Clin Exp Res 1997; 21(8): 1455–64PubMedGoogle Scholar
  57. 57.
    de Waele JP, Kiianmaa K, Gianoulakis C. Distribution of the mu and delta opioid binding sites in the brain of the alcohol-preferring AA and alcohol-avoiding ANA lines of rats. J Pharmacol Exp Ther 1995; 275(1): 518–27PubMedGoogle Scholar
  58. 58.
    Learn JE, Chernet E, McBride WJ, et al. Quantitaive autoradiography of mu-opioid receptors in the CNS of high-alcohol-dromlomg (HAD) and low-alcohol-drinking (LAD) rats. Alcohol Clin Exp Res 2001; 25(4): 524–30PubMedGoogle Scholar
  59. 59.
    de Waele JP, Gianoulakis C. Characterization of the mu and delta opioid receptors in the brain of the C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. Alcohol Clin Exp Res 1997; 21(4): 754–62PubMedCrossRefGoogle Scholar
  60. 60.
    Fadda P, Tronci S, Colombo G, et al. Differences in the opioid system in selected brain regions of alcohol-preferring and alcohol-nonpreferring rats. Alcohol Clin Exp Res 1999; 23(8): 1296–305PubMedCrossRefGoogle Scholar
  61. 61.
    Soini SL, Ovaska T, Honkanen A, et al. Brain opioid receptor binding of [3H] CTOP and [3H] naltrindole in alcohol-preferring AA and alcohol-avoiding ANA rats. Alcohol 1998; 15(3): 227–32PubMedCrossRefGoogle Scholar
  62. 62.
    Soini SL, Honkanen A, Hyytia P, et al. Ethylketocyclazocine binding to brain opioid receptor subtypes in alcohol-preferring AA and alcohol-avoiding ANA rats. Alcohol 1999; 18(1): 27–34PubMedCrossRefGoogle Scholar
  63. 63.
    Soini SL, Hyytia P, Korpi ER. Brain regional mu-opioid receptor function in rat lines selected for differences in alcohol preference. Eur J Pharmacol 2002; 448(2-3): 157–63PubMedCrossRefGoogle Scholar
  64. 64.
    Gianoulakis C, Beliveau D, Angelogianni P, et al. Different pituitary beta-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism. Life Sci 1989; 45(12): 1097–109PubMedCrossRefGoogle Scholar
  65. 65.
    Froehlich JC, Zink RW, Li TK, et al. Analysis of heritability of hormonal responses to alcohol in twins: beta-endorphin as a potential biomarker of genetic risk for alcoholism. Alcohol Clin Exp Res 2000; 24(3): 265–77PubMedCrossRefGoogle Scholar
  66. 66.
    Sinclair JD. Morphine suppresses alcohol drinking regardless of prior alcohol access duration. Pharmacol Biochem Behav 1974; 2: 409–12PubMedCrossRefGoogle Scholar
  67. 67.
    Ho AKS, Chen RCA, Morrison JM. Interactions of narcotics, narcotic antagonists, and ethanol during acute, chronic, and withdrawal states. Ann N Y Acad Sci 1976; 281: 297–310PubMedCrossRefGoogle Scholar
  68. 68.
    Ross D, Hartmann RJ, Geller I. Ethanol preference in the hamster: effects of morphine sulfate and naltrexone, a long-acting morphine antagonist. Proc West Pharmacol Soc 1976; 19: 326–30PubMedGoogle Scholar
  69. 69.
    Reid LD, Hunter GA. Morphine and naloxone modulate intake of ethanol. Alcohol 1984; 1: 33–7PubMedCrossRefGoogle Scholar
  70. 70.
    Beaman CM, Hunter GA, Dunn LL, et al. Opioids, benzodiazepines and intake of ethanol. Alcohol 1984; 1(1): 39–42PubMedCrossRefGoogle Scholar
  71. 71.
    Hubbell CL, Czirr SA, Hunter GA, et al. Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administrations. Alcohol 1986; 3: 39–54PubMedCrossRefGoogle Scholar
  72. 72.
    Hubbell CL, Czirr SA, Reid LD. Persistence and specificity of small doses of morphine on intake of alcoholic beverages. Alcohol 1987; 4(3): 149–56PubMedCrossRefGoogle Scholar
  73. 73.
    Reid LD, Czirr SA, Bensinger CC, et al. Morphine and diprenorphine together potentiate intake of alcoholic beverages. Alcohol 1987; 4: 161–8PubMedCrossRefGoogle Scholar
  74. 74.
    Hubbell CL, Abelson ML, Burkhardt CA, et al. Constant infusions of morphine and intakes of sweetened ethanol solution among rats. Alcohol 1988; 5: 409–15PubMedCrossRefGoogle Scholar
  75. 75.
    Reid LD, Delconte JD, Nichols ML, et al. Tests of opioid deficiency hypotheses of alcoholism. Alcohol 1991; 8: 247–57PubMedCrossRefGoogle Scholar
  76. 76.
    Wild KD, Reid LD. Modulation of ethanol-intake by morphine: evidence for a central site of action. Life Sci 1990; 47(14): 49–54CrossRefGoogle Scholar
  77. 77.
    Reid LD. Endogenous opioids and alcohol dependence: opioid alkaloids and the propensity to drink alcoholic beverages. Alcohol 1996; 13: 5–11PubMedCrossRefGoogle Scholar
  78. 78.
    Volpicelli JR, Ulm RR, Hopson J. Alcohol drinking in rats during and following morphine injections. Alcohol 1991; 8: 289–92PubMedCrossRefGoogle Scholar
  79. 79.
    Anglin MD, Almog IJ, Fisher DG, et al. Alcohol use by heroin addicts: evidence for an inverse relationship: a study of metha-done maintenance and drug-free treatment samples. Am J Drug Alcohol Abuse 1989; 15(2): 191–207PubMedCrossRefGoogle Scholar
  80. 80.
    Hser YI, Anglin MD, Powers K. Longitudinal patterns of alcohol use by narcotics addicts. Recent Dev Alcohol 1990; 8: 145–71PubMedGoogle Scholar
  81. 81.
    Almog YJ, Anglin MD, Fisher DG. Alcohol and heroin use patterns of narcotics addicts: gender and ethnic differences. Am J Drug Alcohol Abuse 1993; 19(2): 219–38PubMedCrossRefGoogle Scholar
  82. 82.
    Stromberg MF, Rukstalis MR, Mackler SA, et al. A comparison of the effects of 6-beta naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats. Pharmacol Biochem Behav 2002; 72(1–2): 483–90PubMedCrossRefGoogle Scholar
  83. 83.
    Cramer CM, Gardell LR, Boedeker KL, et al. Isradipine combined with naltrexone persistently reduces the reward-relevant effects of cocaine and alcohol. Pharmacol Biochem Behav 1998; 60(2): 345–56PubMedCrossRefGoogle Scholar
  84. 84.
    Stromberg MF, Mackler SA, Volpicelli JR, et al. Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption. Alcohol 2001; 23(2): 109–16PubMedCrossRefGoogle Scholar
  85. 85.
    Stromberg MF, Sengpiel T, Mackler SA, et al. Effect of naltrexone on oral consumption of concurrently available ethanol and cocaine in the rat. Alcohol 2002; 28(3): 169–79PubMedCrossRefGoogle Scholar
  86. 86.
    Bienkowski P, Kostowski W, Koros E. Ethanol-reinforced behaviour in the fat: effects of naltrexone. Eur J Pharmacol 1999; 374(3): 321–7PubMedCrossRefGoogle Scholar
  87. 87.
    Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry 1994; 151(10): 1463–7PubMedGoogle Scholar
  88. 88.
    Volpicelli JR, Watson NT, King AC, et al. Effect of naltrexone on alcohol “high” in alcoholics. Am J Psychiatry 1995; 152(4): 613–5PubMedGoogle Scholar
  89. 89.
    Middaugh LD, Kelley BM, Cuison Jr ER, et al. Naltrexone effects on ethanol reward and discrimination in C57BL/6 mice. Alcohol Clin Exp Res 1999; 23(3): 456–64PubMedCrossRefGoogle Scholar
  90. 90.
    McCaul ME, Wand GS, Eissenberg T, et al. Naltrexone alters subjective and psychomotor responses to alcohol heavy drinking subjects. Neuropsychopharmacology 2000; 22: 480–92PubMedCrossRefGoogle Scholar
  91. 91.
    O’Malley SS, Krishnan-Aarin S, Farren C, et al. Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl) 2002; 160(1): 19–29CrossRefGoogle Scholar
  92. 92.
    Coonfield DL, Hill KG, Kaczmarek HJ, et al. Low doses of naltrexone reduce palatability and consumption of ethanol in outbred rats. Alcohol 2002; 26(1): 43–7PubMedCrossRefGoogle Scholar
  93. 93.
    Ross D, Hartmann RJ, Geller I. Ethanol preference in the hamster: effects of morphine sulfate and naltrexone, a long-acting morphine antagonist. Proc West Pharmacol Soc 1976; 19: 326–30PubMedGoogle Scholar
  94. 94.
    Nation JR, Horger BA, Pugh CK, et al. The effects of naltrexone on cadmium-induced increased in oral ethanol self-administration. Alcohol 1990; 7: 17–20PubMedCrossRefGoogle Scholar
  95. 95.
    Berman RF, Lee JA, Olson KL, et al. Effects of naloxone on ethanol dependence in rats. Drug Alcohol Depend 1984; 13: 245–54PubMedCrossRefGoogle Scholar
  96. 96.
    Holter SM, Spanagel R. Effects of opiate antagonist treatment on the alcohol deprivation effect in long-term ethanol-experienced rats. Psychopharmacology (Berl) 1999; 145(4): 360–9CrossRefGoogle Scholar
  97. 97.
    Cowen MS, Rezvani AH, Jarrott B, et al. Ethanol consumption by Fawn-Hooded rats following abstinence: effect of naltrexone and changes in mu-opioid receptor density. Alcohol Clin Exp Res 1999; 23(6): 1008–14PubMedGoogle Scholar
  98. 98.
    Phillips TJ, Wenger CD, Dorow JD. Naltrexone effects on ethanol drinking acquisition and on established ethanol consumption in C57BL/6J mice. Alcohol Clin Exp Res 1997; 21(4): 691–702PubMedCrossRefGoogle Scholar
  99. 99.
    Middaugh LD, Bandy AL. Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57BL/ 6 mice. Psychopharmacology (Berl) 2000; 151(4): 321–7CrossRefGoogle Scholar
  100. 100.
    Mason BJ, Ritvo EC, Morgan RO, et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nelmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18: 1162–7PubMedCrossRefGoogle Scholar
  101. 101.
    Mason BJ, Salvato FR, Williams LD, et al. A double-blind, placebo-controlled study of nalmefene for alcohol dependence. Arch Gen Psychiatry 1999; 56(8): 719–24PubMedCrossRefGoogle Scholar
  102. 102.
    Anton RF, Moak DH, Waid LR. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry 1999; 156(11): 1758–64PubMedGoogle Scholar
  103. 103.
    Kranzler HR, Modesto-Lowe V, Van Kirk J. Naltrexone vs nefazodone for treatment of alcohol dependence placebo-controlled trial. Neuropsychopharmacology 2000; 22(5): 493–503PubMedCrossRefGoogle Scholar
  104. 104.
    Monti PM, Rohsenow DJ, Swift RM, et al. Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes. Alcohol Clin Exp Res 2001; 25(11): 1634–47PubMedCrossRefGoogle Scholar
  105. 105.
    Heinala P, Alhol H, Kiianmaa K, et al. Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 2001; 21(3): 287–92PubMedCrossRefGoogle Scholar
  106. 106.
    Krystal JH, Cramer JA, Krol WF, et al. Naltrexone in the treatment of alcohol dependence. N Engl J Med 2001; 345: 1734–9PubMedCrossRefGoogle Scholar
  107. 107.
    Monterosso JR, Flannery BA, Pettinati HM, et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict 2001; 10(3): 258–68PubMedCrossRefGoogle Scholar
  108. 108.
    Morris PL, Hopwood M, Whelan G, et al. Naltrexone for alcohol dependence: a randomized controlled trial. Addiction 2001; 96(11): 1565–73PubMedCrossRefGoogle Scholar
  109. 109.
    Latt NC, Jurd S, Houseman J, et al. Naltrexone in alcohol dependence: a randomized controlled trial of effectiveness in a standard clinical setting. Med J Aust 2002; 176(11): 530–4PubMedGoogle Scholar
  110. 110.
    Gastpar M, Bonnet U, Boning J, et al. Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study. J Clin Psycopharmacol 2002; 22(6): 592–8CrossRefGoogle Scholar
  111. 111.
    Balldin J, Berglund M, Borg S, et al. A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence. Alcohol Clin Exp Res 2003; 23(7): 1142–9CrossRefGoogle Scholar
  112. 112.
    Kiefer F, Jaun H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003; 60(1): 92–9PubMedCrossRefGoogle Scholar
  113. 113.
    Kranzler HR, Van Kirk J. Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res 2001; 25(9): 1335–41PubMedCrossRefGoogle Scholar
  114. 114.
    Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol 2001; 36(6): 544–52Google Scholar
  115. 115.
    Pettinati HM, Volpicelli JR, Pierce Jr JD, et al. Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. J Addict Dis 2000; 19(1): 71–83PubMedCrossRefGoogle Scholar
  116. 116.
    Jaffe AJ, Rounsaville B, Chang G, et al. Naltrexone, relapse prevention, and supportive therapy with alcoholics: an analysis of patient treatment matching. J Consult Clin Psychol 1996; 64(5): 1044–53PubMedCrossRefGoogle Scholar
  117. 117.
    Kranzler HR, Modesto-Lowe V, Nuwayser ES. Sustained-release naltrexone for alcoholism treatment: a preliminary study. Alcoholism Clin Exp Res 1998; 22(5): 1074–9Google Scholar
  118. 118.
    Modesto-Lowe V. Naltrexone depot. IDrugs 2002; 5(8): 835–8.PubMedGoogle Scholar
  119. 119.
    Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial [published erratum appears in JAMA 2005 Apr 27; 293 (16): 1978 and JAMA 2005 Jim 15; 293 (23): 2864. JAMA 2005 Apr 27; 293(13): 1617–25PubMedCrossRefGoogle Scholar
  120. 120.
    Kranzler H, Liou S, Loewy J, et al. Effect of long-acting injectable naltrexone on quality of life [abstract]. American Psychiatric Association Annual Meeting 2005 May 21–26; Atlanta (GA)Google Scholar
  121. 121.
    O’Malley SS. Opioid antagonists in the treatment of alcohol dependence: clinical efficacy and prevention of relapse. Alcohol Alcohol 1996; Suppl. 1: 77–81Google Scholar
  122. 122.
    Holter SM, Spanagel R. Effects of opiate antagonist treatment on the alcohol deprivation effect in long-term ethanol-experienced rats. Psychopharmacology (Berl) 1999; 145(4): 360–9CrossRefGoogle Scholar
  123. 123.
    Kranzler HR, Armeli S, Tennen H, et al. Targeted naltrexone for early problem drinkers. J Clin Psychopharmacol 2003; 23(3): 294–304PubMedGoogle Scholar
  124. 124.
    Johnson BA, Ait-Daoud N, Prihoda TJ. Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence. Alcohol Clin Exp Res 2000; 24: 737–42PubMedCrossRefGoogle Scholar
  125. 125.
    De Witte P, Littleton J, Parot P, et al. Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 2005; 19(6): 517–37PubMedCrossRefGoogle Scholar
  126. 126.
    Johnson BA. Role of the seroteoergic system in the neurobiology of alcoholism: implications for treatment. CNS Drugs 2004; 18(15): 1105–18PubMedCrossRefGoogle Scholar
  127. 127.
    Michel ME, Bolger G, Weissman BA. Binding of a new opiate antagonist, nalmefene, to rat brain membrains. Methods Find Exp Clin Pharmacol 1985; 7: 175–7PubMedGoogle Scholar
  128. 128.
    The COMBINE Study Research Group. Testing combined pharmacotherapies and behavioural interventions for alcohol dependence: a pilot feasibility study. Alcohol Clin Exp Res 2003; 27(7): 1123–31CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Addiction Services, Connecticut Valley Hospital, Merrit HallMiddletownUSA
  2. 2.Department of PsychiatryUniversity of Connecticut School of MedicineFarmingtonUSA

Personalised recommendations