Tizanidine Increases Antinociceptive Effect and Prevents Gastric Damage Induced by Ketorolac in the Rat

Abstract

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) effective in the treatment of moderate to severe pain. Tizanidine, an a-2-adrenoceptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with NSAIDs. However, side effects may limit their use. As both drugs produce side effects that are dose dependent, a combination of these drugs appears in order to reduce the dose required for efficacy and, consequently, side effects. In this study, we evaluated the potential synergistic effect of these drugs in the thermal paw stimulation model and their effect on gastric ulcer production in response in the rat. Dose-response curves for ketorolac and tizanidine were constructed and from these, an ED40 value was obtained. Isobolographic analysis was carried out based on 0.5:0.5 proportions. In addition, protective effect of tizanidine against ketorolac-induced gastric damage was evaluated. A synergistic interaction in thermal hyperalgesia and gastroprotective activity was observed, suggesting a good therapeutic potential of this combination in the treatment of pain. Drug Dev Res 74 : 38-42, 2013.

Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac

“…Methyleugenol, diclofenac, and ketorolac administered individually herein produced dose-dependent antinociception (Figure 1B,D,F), in agreement with previous reports [16][17][18]. The results showed significantly reduced licking behavior time in phase II of the test.…”

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

“… 28 Rodriguez-Silverio et al observed the synergistic interaction between ketorolac and tizanidine in thermal hyperalgesia model and the gastroprotective activity of tizanidine against gastric damage induced by ketorolac in the rat. 29 …”

“…Studies in rats have shown that tizanidine could prevent the changes of glycoproteins in the gastric mucosa and gastric juice induced by NSAIDs, reduce central vagal activity and acid secretion, and increase mucosal blood flow by regulating central alpha-2-receptors. 29 , 50–52 …”

“…28 Rodriguez-Silverio et al observed the synergistic interaction between ketorolac and tizanidine in thermal hyperalgesia model and the gastroprotective activity of tizanidine against gastric damage induced by ketorolac in the rat. 29 Two clinical studies have examined tizanidine against the potential gastrointestinal damage caused by NSAIDS. Pareek et al evaluated the efficacy and safety of a fixed dose combination (aceclofenac 100 mg plus tizanidine 2 mg) versus aceclofenac (100 mg) alone twice daily for 7 days in patients with acute low back pain (LBP).…”

“…48,49 Studies in rats have shown that tizanidine could prevent the changes of glycoproteins in the gastric mucosa and gastric juice induced by NSAIDs, reduce central vagal activity and acid secretion, and increase mucosal blood flow by regulating central alpha-2-receptors. 29,[50][51][52] Alpha 2-Adrenoceptors and Side Effects When alpha-2 receptors are stimulated, the activity of the sympathetic nervous system decreases, thus potentially leading to a drop in blood pressure. Unlike clonidine, tizanidine had a significantly less adverse effect on blood pressure, which may be due to their differences in lipophilicity and systemic bioavailability.…”