Physical dependence potential of daily tramadol dosing in humans

Abstract

Rationale: Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence.

Objectives: The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol.

Methods: Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices.

Results: Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions.

Conclusions: Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Conflict of interest statement

Disclosure Tramadol was developed by Grünenthal. Dr. Strain is a paid consultant to Grünenthal. This arrangement is being managed by the Johns Hopkins University in accordance with its conflict of interest policies. In recent years, Dr. Bigelow has received consulting payments from Abbott Laboratories, Takeda Pharmaceuticals, and Teva Pharmaceuticals and through his university has received research support from Titan Pharmaceuticals and Pain Therapeutics, Inc. Dr. Lanier is now an employee of Rock Creek Pharmaceuticals.

Figures

Fig. 1

Mean peak VAS drug effect scores. Results following IM placebo and naloxone challenges during SC morphine maintenance are shown on the left, and results following IM naloxone and hydromorphone challenges during 200 and 800 mg/day oral tramadol maintenance are shown on the right. Tramadol 200 mg/day is represented by circles, and tramadol 800 mg/day is represented by squares. A number sign indicates a significant difference from placebo following naloxone challenge during morphine maintenance. A darkened symbol indicates a significant difference from placebo during tramadol maintenance, and an asterisk indicates a significant difference between tramadol dosing conditions. Statistical significance was set at p<0.05. Vertical bars represent the SEM

Fig. 2

Mean peak scores on the BPRU opioid withdrawal scale (BOWS) and observer agonist adjective scale are shown in the top and middle panels, respectively. Mean peak increase (above abscissa) and decrease (below abscissa) from baseline in pupil diameter is shown in the bottom panel. Results following IM placebo and naloxone challenges during SC morphine maintenance are shown on the left, and results following IM naloxone and hydromorphone challenges during 200 and 800 mg/day oral tramadol maintenance are shown on the right. Tramadol 200 mg/day is represented by circles, and tramadol 800 mg/day is represented by squares. A number sign indicates a significant difference from placebo following naloxone challenge during morphine maintenance. A darkened symbol indicates a significant difference from placebo during tramadol maintenance, and an asterisk indicates a significant difference between tramadol dosing conditions. Statistical significance was set at p<0.05. Vertical bars represent the SEM