Low doses of tizanidine synergize the anti-nociceptive and anti-inflammatory effects of ketorolac or naproxen while reducing of side effects.
The aim of the present study was to determine whether tizanidine, an alpha2-adrenoceptor agonist, is able to increase the anti-inflammatory and anti-nociceptive effects of naproxen and ketorolac with a low incidence of gastric injury and spontaneous activity in rats. The anti-inflammatory effect was assayed in a carrageenan test, and oral administration of tizanidine (ED40=0.94±0.2mg/kg), naproxen (ED40=3.18±0.4mg/kg), and ketorolac (ED40=16.4±1.9mg/kg) showed a dose-dependent effect on inflammation. The anti-nociceptive effect was assayed in the formalin test, and administration of tizanidine (ED40=0.39±0.06mg/kg, p.o.), naproxen (ED40=33.9±3.9mg/kg, p.o.) or ketorolac (ED40=6.49±1mg/kg, p.o.) each showed a dose-dependent anti-nociceptive effect. The effects of combinations of tizanidine/naproxen and tizanidine/ketorolac were determined considering their ED40at a rate of 1:1. Additionally, the tizanidine/naproxen and tizanidine/ketorolac combinations showed anti-inflammatory and anti-nociceptive effects. The tizanidine/ketorolac combination was more potent than tizanidine/naproxen, in both inflammatory (interaction index=0.03 tizanidine/ketorolac and 0.07 tizanidine/naproxen) and nociceptive (interaction index=0.005 tizanidine/ketorolac and 0.01 tizanidine/naproxen) processes. In both cases, tizanidine improved naproxen and ketorolac gastrointestinal tolerability by 50%. Furthermore, co-administration of tizanidine with naproxen or ketorolac did not modify the spontaneous activity in the same way as individual tizanidine administration. Considering that tizanidine increases the anti-inflammatory and anti-nociceptive effects of naproxen or ketorolac, with an increase in gastric tolerability, tizanidine could provide therapeutic advantages in the clinical treatment of inflammation and pain.
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico; Centro de Investigación para el Desarrollo Industrial, Universidad Autónoma de Guadalajara, Jalisco, Mexico.
Selene I
SI
Patiño-Camacho
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico. Electronic address: myrnadeciga@hotmail.com.
Myrna
M
Déciga Campos
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico.
Karla
K
Beltrán-Villalobos
Facultad de Química, Universidad Autónoma de Yucatán. Yucatán, Mexico; Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California, Baja California, Mexico.
Dalia A
DA
Castro-Vidal
Centro de Investigación Biomédica del Sur, IMSS, Argentina No.1 Col. Centro Xochitepec, Morelos, Mexico.
Rosa M
RM
Montiel-Ruiz
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico; Unidad de Investigación en Farmacología Clínica, Instituto Nacional de Enfermedades Respiratorias, S.S.A., Ciudad de México, Mexico.
Francisco J
FJ
Flores-Murrieta
D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020910:Ketorolac / Q000009:adverse effects* / Q000494:pharmacology*; D008297:Male; D009288:Naproxen / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen; C023754:tizanidine; D003000:Clonidine; D020910:Ketorolac
Anti-inflammatory effect; Anti-nociception; Combination; Ketorolac; Naproxen; Synergism; Tizanidine