Altered antinociceptive efficacy of tramadol over time in rats with painful peripheral neuropathy

Abstract

Pain due to peripheral nerve injury or disease is a dynamic process, such that the mechanism that underlies it alters over time. Tramadol has been reported to be analgesic in clinical neuropathic pain, with varying levels of efficacy due to a patient population that has had neuropathic pain for a wide range of time. In order to address and examine the issue, the antinociceptive efficacy of tramadol over time was tested in rats with a chronic constriction injury (CCI) of the left sciatic nerve. Rats developed a robust hind paw hypersensitivity to innocuous mechanical stimulation ipsilateral to CCI surgery. Subcutaneous injection of tramadol in rats two weeks after CCI surgery dose-dependently attenuated mechanical hypersensitivity, which was abolished with the mu-opioid receptor antagonist naloxone but not the alpha(2)-adrenoceptor antagonist yohimbine. Systemic tramadol also attenuated mechanical hypersensitivity four weeks after CCI surgery, but the efficacy significantly diminished at this time point. In addition, the effect of tramadol at this later time point could be reduced with yohimbine as well as naloxone. These data demonstrate that the efficacy of tramadol depends in part on the duration of nerve injury-evoked nociception, and that its antinociceptive mechanism changes over time. Alteration in antinociceptive mechanism over time may explain the inconsistency in efficacy of this and other analgesic drugs in chronic pain patients.

Figure 1

Time course of the effect of tramadol in rats with a chronic constriction injury. The abscissa is time post-subcutaneous (s.c.) injection (in minutes) and the ordinate is withdrawal threshold (grams). The efficacy of s.c. tramadol was measured in rats with a chronic constriction injury (CCI) two weeks (A) and four weeks (B) after surgery. A dose-dependent increase in withdrawal threshold was observed in rats two weeks after CCI and a modest increase in threshold was observed in rats four weeks after CCI. The 50% analgesic dose of tramadol in rats 2 weeks after CCI was 8.2 mg/kg (95% C.L. = 5.1-13.4 mg/kg) and the 50% analgesic dose in rats 4 weeks after CCI was >30 mg/kg. Data are expressed as mean ± S.E.M. N = 6-7 rats/treatment group. * P<0.05 vs. baseline and vehicle.

Figure 2

Effect of antagonists on tramadol antinociception in rats two weeks following a chronic constriction injury. The abscissa is time post-subcutaneous (s.c.) injection (in minutes) after the antagonist and the ordinate is withdrawal threshold (grams). After baseline testing, rats were injected with either vehicle, naloxone (s.c. 5 mg/kg, A) or yohimbine (s.c. 2 mg/kg, B). Following the 30 min. testing time point, either vehicle or 30 mg/kg of tramadol was s.c. injected. Rats were tested 60 min following tramadol injection (90 min following antagonist injection). Data are expressed as mean ± S.E.M. N = 7 rats/treatment group. # P< 0.05 vs. vehicle/vehicle.

Figure 3

Effect of antagonists on tramadol antinociception in rats four weeks following a chronic constriction injury. The abscissa is time post-subcutaneous (s.c.) injection (in minutes) of the antagonist and the ordinate is withdrawal threshold (grams). After baseline testing, rats were injected with either vehicle, naloxone (s.c. 5 mg/kg, A) or yohimbine (s.c. 2 mg/kg, B). Following the 30 min. testing time point, either vehicle or 30 mg/kg of tramadol was s.c. injected. Rats were tested 60 min following tramadol injection (90 min following antagonist injection). Data are expressed as mean ± S.E.M. N = 8-9 rats/treatment group. # P<0.05 vs. vehicle/vehicle.