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Preclinical Research The current work evaluates the interaction between two commonly used drugs, tramadol (Tra) and gabapentin (Gbp). Dose-response curves (DRC) and isobolographic analysis were used to confirm their synergistic antihyperalgesic and anti-allodynic responses in a rat neuropathic pain model involving chronic constriction injury of the sciatic nerve and in von Frey and acetone tests. Tra and Gbp produced dose-dependent antihyperalgesic and anti-allodynic effects. Dose-response studies of combinations of Tra and Gbp in combination showed the DRC was leftward-shifted compared to the DRCs for each compound alone. One combination demonstrated both antihyperalgesic and anti-allodynic effects greater than those observed after individual administration. The remaining combinations demonstrated an additive effect. The Tra+Gbp combination demonstrated a potentiative effect with smaller doses of Tra. Additionally, it was determined lethal dose 50 (LD50 ) of Tra alone and tramadol + Gbp 10 using mice to 48 h post administration. The DRC (death) were similar for Tra alone and in Tra in combination, despite the improved effectiveness of Tra in the presence of GBP, 10 mg/kg. A combination of these drugs could be effective in neuropathic pain therapy because they can produce potentiative (at a low dose) or additive effects. Drug Dev Res 77 : 217-226, 2016.   © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In order to detect an anti-nociceptive interaction between morphine and gabapentin, the anti-allodynic and anti-hyperalgesic effects of these drugs, administered either separately or in combination, were determined using the von Frey and acetone tests in a rat model of neuropathic pain (Bennett model). Morphine and gabapentin individually induced moderate attenuation of mechanical hyperalgesia, whereas the morphine and gabapentin combination completely decreased hyperalgesia. Morphine showed its maximal effect at 30 min post-injection in the acetone test; however, this effect gradually returned to the baseline value. Gabapentin did not produce an anti-allodynic effect, whereas the morphine and gabapentin combination completely decreased allodynia behavior at 30 min post-injection, an effect that persisted until 120 min. The area under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the combinations were significantly greater than the theoretical sum of effects produced by each drug alone or similar to the theoretical sum. The analysis of the effect, expressed as the AUC of the time course, supports the hypothesis that the combination of these drugs is useful in neuropathic pain therapy.

Background: Neuropathic pain is associated with disease or injury to the peripheral or central nervous system, which is considered particularly difficult to treat due to its diverse etiology and underlying physiopathological mechanisms. Recent experimental and clinical data support the potential of pharmacotherapy using a combination of drugs for neuropathic pain., Methods: In order to assess a possible synergistic anti-hyperalgesic interaction, the anti-hyperalgesic effects of morphine and gabapentin, single-dose administered either separately or in combination, were determined using the von Frey test in a rat model of neuropathic pain (Bennett model)., Results: Time course analysis showed that morphine (3.2 mg/kg s.c.) and gabapentin (17.8 mg/kg s.c.) individually reached their maximum effect at 60 min after treatment, producing an anti-hyperalgesic effect of 51.7+/-10.5% and 55.0+/-11.7%, respectively, whereas the combination morphine + gabapentin (3.2+17.8 mg/kg s.c.) produced an almost total anti-hyperalgesic effect at 30 min (96.7+/-2.1%) and at 60 min showed 100% anti-hyperalgesia. This anti-hyperalgesic effect remained during 180 min of observation. Analysis of global effects as area under the curve of time course showed that the nature of the anti-hyperalgesic interaction of the analyzed dose had an additive effect. There was no significant difference observed in the theoretical sum of anti-hyperalgesic effect produced by each drug alone (225.4+/-29.1 area units, au) compared with the corresponding effects produced by the combination of drugs (263.33+/-3.3 au)., Conclusions: These findings are useful in determining the type of interaction that these drugs produce using this combination ratio in neuropathic pain.