Abstract
Rationale
Upon discontinuation of chronic opioid treatment, withdrawal typically peaks in 1–3 days and decreases markedly within 1 week; however, persistent physiological changes have been reported long after other signs have waned.
Objective
The goal of this study was to compare the discriminative stimulus, directly observable signs, and physiological effects of withdrawal in morphine-treated monkeys.
Materials and methods
Monkeys received 5.6 mg/kg/12 h morphine and discriminated 0.0178 mg/kg naltrexone while responding under a fixed-ratio 5 schedule of stimulus–shock termination. Drug discrimination, behavioral observation, and telemetry were used to monitor the emergence of withdrawal, as well as any persistent changes, following discontinuation of morphine treatment.
Results
Naltrexone dose (0.001–0.032 mg/kg, s.c.) was positively related with indices of withdrawal. In the discrimination study, monkeys responded on the naltrexone lever 1–5 days following discontinuation of treatment; thereafter, they responded exclusively on the saline lever. After discontinuation of morphine, the frequency of observable signs peaked within 2–3 days and most were not significantly increased after 5 days. In contrast, increased heart rate and body temperature persisted for 14 days, returning to values obtained prior to discontinuation by 21 days.
Conclusions
To the extent that discriminative stimulus effects of withdrawal in nonhumans are predictive of subjective reports of withdrawal in humans, these data indicate that effective treatments for opioid dependence must address not only the short-term subjective components of withdrawal but also, and perhaps more importantly, lingering behavioral and physiological effects that might contribute to relapse long after chronic drug use is discontinued.
Similar content being viewed by others
References
Beswick T, Best D, Rees S, Bearn J, Gossop M, Strang J (2003) Major disruptions of sleep during treatment of the opiate withdrawal syndrome: differences between methadone and lofexidine detoxification treatments. Addict Biol 8:49–57
Brandt MR, France CP (1998) Chronic l-alpha acetylmethadol in rhesus monkeys: discriminative stimulus and other behavioral measures of dependence and withdrawal. J Pharmacol Exp Ther 287:1029–1037
Chan R, Irvine R, White J (1999) Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat. Eur J Pharmacol 368:25–33
France CP, Woods JH (1987) Morphine, saline and naltrexone discrimination in morphine-treated pigeons. J Pharmacol Exp Ther 242:195–202
France CP, Woods JH (1989) Discriminative stimulus effects of naltrexone in morphine-treated rhesus monkeys. J Pharmacol Exp Ther 250:937–943
Gellert VF, Holtzman SG (1979) Discriminative stimulus effects of naltrexone in the morphine-dependent rat. J Pharmacol Exp Ther 211:596–605
Gmerek DE, Woods JH (1985) Effects of b-funaltrexamine in normal and morphine-dependent rhesus monkeys: observation studies. J Pharmacol Exp Ther 235:296–301
Gmerek DE, Dykstra LA, Woods JH (1987) Kappa opioids in rhesus monkeys. III. Dependence associated with chronic administration. J Pharmacol Exp Ther 242:428–436
Gossop M, Stewart D, Browne N, Marsden J (2002) Factors associated with abstinence, lapse or relapse to heroin use after residential treatment: protective effect of coping responses. Addiction 97:1259–1267
Himmelsbach CK (1942) Clinical studies of drug dependence. Physical dependence, withdrawal and recovery. Arch Intern Med 69:766–772
Holtzman SG, Villarreal JE (1969) Morphine dependence and body temperature in rhesus monkeys. J Pharmacol Exp Ther 166:125–133
Holtzman SG, Villarreal JE (1971) Pharmacologic analysis of the hypothermic responses of the morphine-dependent rhesus monkey. J Pharmacol Exp Ther 177:317–325
Jasinski DR, Johnson RE, Kocher TR (1985) Clonidine in morphine withdrawal. Differential effects on signs and symptoms. Arch Gen Psychiatry 42:1063–1066
Katz JL (1986) Effects of clonidine and morphine on opioid withdrawal in rhesus monkeys. Pscyhopharmacology 88:392–397
Kleber HD, Gold MS, Riordan CE (1980) The use of clonidine in detoxification from opiates. Bull Narc 32:1–9
Li JX, Becker GL, Traynor JR, Gong ZH, France CP (2007) Thienorphine: receptor binding and behavioral effects in rhesus monkeys. J Pharmacol Exp Ther 321:227–236
Light AB, Torrance EG (1929) The effects of abrupt withdrawal followed by re-administration of morphine in human addicts, with special reference to composition of the blood, the circulation and the metabolism. Arch Intern Med 44:3–16
Martin WR, Jasinski DR (1969) Physiological parameters of morphine dependence in man-tolerance, early abstinence, protracted abstinence. J Psychiatr Res 7:9–17
McMahon L, Sell SL, France CP (2004) Cocaine and other indirect-acting monoamine agonists differentially attenuate a naltrexone discriminative stimulus in morphine-treated rhesus monkeys. J Pharmacol Exp Ther 308:111–119
Negus SS (2006) Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: effects of naloxone, buprenorphine, and methadone. J Pharmacol Exp Ther 317:711–723
Newlin DB, Wong CJ, Cheskin LJ (1992) Cardiovascular responses to naloxone challenge in opiate-dependent individuals. Pharmacol Biochem Behav 43:357–360
Paronis CA, Woods JH (1997) Ventilation in morphine-maintained rhesus monkeys. I: effects of naltrexone and abstinence-associated withdrawal. J Pharmacol Exp Ther 282:348–354
Preston KL, Bigelow GE (1998) Opioid discrimination in humans: discriminative and subjective effects of progressively lower training dose. Behav Pharmacol 9:533–543
Sell SL, France CP (2002) Cocaine and amphetamine attenuate the discriminative stimulus effects of naltrexone in opioid-dependent rhesus monkeys. J Pharmacol Exp Ther 301:1103–1110
Sell SL, McMahon LR, Koek W, France CP (2005) Monoaminergic drugs and directly observable signs of LAAM-withdrawal in rhesus monkeys. Behav Pharmacol 16:53–58
Walsh SL, Strain EC, Bigelow GE (2003) Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans. Addiction 98:427–439
Wikler A, Pescor FT (1967) Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats. Psychopharmacologia 10:255–284
Zhou W, Zhang F, Tang S, Liu H, Lai M, Yang G (2004) Low dose of heroin inhibits drug-seeking elicited by cues after prolonged withdrawal from heroin self-administration in rats. NeuroReport 15:727–730
Acknowledgements
The authors would like to thank Christopher Cruz, Blake Harrington, Maria Hernandez, Dawn Logan, and Ryan Luna for their expert technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
This project was supported by USPHS Grants DA05018 and DA17918 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.
Rights and permissions
About this article
Cite this article
Becker, G.L., Gerak, L.R., Koek, W. et al. Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys. Psychopharmacology 201, 373–382 (2008). https://doi.org/10.1007/s00213-008-1293-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-008-1293-6