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

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.

Fig. 1

Discriminative stimulus effects of naltrexone in three morphine-treated monkeys discriminating 0.0178 mg/kg naltrexone while responding under a fixed-ratio 5 schedule of SST. Saline was administered on the first cycle. Data shown are from five determinations of naltrexone dose–effect curves for each monkey (mean±SEM). The SEM does not appear if it was less than the radius of the data point. Ordinate: percentage of responses occurring on the naltrexone lever (%DR drug responding, top) and mean response rate expressed as percentage of control rate (saline training days, bottom). Abscissa: naltrexone dose in milligrams per kilogram of body weight (V vehicle)

Fig. 2

Selected behaviors observed every 15 s during a 2-min observation period. This occurred 30 min after the administration of vehicle (V) or naltrexone. Each data point represents the average (±SEM) number of times that a sign was observed (maximum possible score=8). One-factor repeated-measures ANOVA was followed by Dunnett's test to determine which points were significantly (*p<0.05) different from control (points above V). Ordinate: frequency of signs. See Fig. 1 for other details

Fig. 3

Heart rate (upper panel), body temperature (middle panel), and activity (bottom panel) after administration of vehicle (V) or naltrexone. Each symbol represents the average (±SEM) values for heart rate and body temperature at the time of the peak effect (20 min after injection) and for activity (40 min after injection). Two-factor repeated-measures ANOVA was followed by Dunnett's test to determine which points were significantly (*p<0.05) different from control (points above V). Ordinate: upper heart rate (beats per minute); middle body temperature (°C); bottom activity (counts per minute). See Fig. 1 for other details

Fig. 4

Discriminative stimulus effects after morphine discontinuation in three monkeys (represented by different panels for each subject). Twice daily injections of morphine were replaced with saline. Each data point represents the average (±SEM) percentage of responses occurring on the naltrexone lever for two cycles after receiving a saline injection. Abscissa: days since last injection. See Fig. 1 for other details

Fig. 5

Selected behaviors observed every 30 s during 2-min periods both before and after discrimination sessions, prior to (day 0–control), and after morphine discontinuation. Each data point represents the average (±SEM) number of times that a sign was observed (maximum possible score=8). For clarity, each point summarizes data over 3 days for each monkey (±SEM). Abscissa: days since last injection. See Fig. 2 for other details

Fig. 6

Heart rate (open squares), body temperature (open triangles), and overall activity (open diamonds) prior to and 1, 7, and 14 days after discontinuation of morphine treatment during the period when lights were on in the housing room and when the lights were off in the housing room (dark bars). Closed circles represent values obtained prior to discontinuing morphine treatment (and are the same for days 1 and 7) and open symbols represent values obtained after morphine treatment was discontinued. For clarity, each point summarizes data over 3 h for each monkey (±SEM). Two-factor repeated-measures ANOVA was followed by Dunnett's test to determine which points were significantly (*p<0.05) different from control (closed circles). For day 14, only data from two monkeys were included in both the control data and the data obtained after morphine treatment was discontinued and are analyzed separately from days 1 and 7. Ordinate: upper heart rate (beats per minute); middle body temperature (°C); bottom activity (counts per minute). Abscissa: time of day represented every 3 h