title: The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.
abstract: 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.
authors.affiliation: From the *Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; and †Faculty of Philosophy, University of Montenegro, Nikšić, Montenegro.
authors.forename: Maja A
authors.initials: MA
authors.lastname: Tomić
authors.forename: Uroš B
authors.initials: UB
authors.lastname: Pecikoza
authors.forename: Ana M
authors.initials: AM
authors.lastname: Micov
authors.forename: Božidar V
authors.initials: BV
authors.lastname: Popović
authors.forename: Radica M
authors.initials: RM
authors.lastname: Stepanović-Petrović
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005156:Facial Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D005157:Facial Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D005557:Formaldehyde; D000077287:Levetiracetam; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D059225:Nociception / Q000187:drug effects; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D017208:Rats, Wistar; D018170:Sumatriptan / Q000494:pharmacology*; D013997:Time Factors; D020433:Trigeminal Nerve Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology
chemical_list: D000700:Analgesics; D005557:Formaldehyde; D002110:Caffeine; D000077287:Levetiracetam; D018170:Sumatriptan; D010889:Piracetam