Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys.
BACKGROUND
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.


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.
Becker
G L
GL
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Gerak
L R
LR
Koek
W
W
France
C P
CP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002940:Circadian Rhythm; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000188:drug therapy* / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009293:Opioid-Related Disorders; D012965:Sodium Chloride / Q000008:administration & dosage; D013239:Stereotyped Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000209:etiology*; D013997:Time Factors
D009292:Narcotic Antagonists; D012965:Sodium Chloride; D009271:Naltrexone; D009020:Morphine