BACKGROUND: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. METHODS: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. RESULTS: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. CONCLUSIONS: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.
Analgesics/pharmacology , Caffeine/pharmacology , Facial Neuralgia/drug therapy , Facial Pain/drug therapy , Piracetam/analogs & derivatives , Sumatriptan/pharmacology , Trigeminal Nerve Diseases/drug therapy , Animals , Behavior, Animal/drug effects , Caffeine/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Drug Therapy, Combination , Facial Neuralgia/chemically induced , Facial Neuralgia/physiopathology , Facial Neuralgia/psychology , Facial Pain/chemically induced , Facial Pain/physiopathology , Facial Pain/psychology , Formaldehyde , Levetiracetam , Male , Motor Activity/drug effects , Nociception/drug effects , Piracetam/pharmacology , Rats, Wistar , Time Factors , Trigeminal Nerve Diseases/chemically induced , Trigeminal Nerve Diseases/physiopathology , Trigeminal Nerve Diseases/psychology
