Effect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac

doi:10.1016/0014-2999(96)00320-2

European Journal of Pharmacology

Volume 308, Issue 3, 25 July 1996, Pages 275-277

https://doi.org/10.1016/0014-2999(96)00320-2 Get rights and content

Abstract

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by N^G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. l-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the l-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.

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Effect of acute caffeine administration on PTZ-induced seizure threshold in mice: Involvement of adenosine receptors and NO-cGMP signaling pathway
2019, Epilepsy Research
Citation Excerpt :
In addition, the results of several studies demonstrate the modulatory role of the NO-cGMP pathway on the anticonvulsant effect of adenosine (Akula et al., 2008; Kaku et al., 2001). There is obvious evidence that caffeine can modulate NO production (Lopez-Munoz et al., 1996; Kayir and Uzbay, 2004). For example, NO production decreases as the result of A1Rs activation, whereas activation of A2ARs leads to elevation of NO generation (Bruce et al., 2002).
Caffeine is a non-selective antagonist of A₁ and A_2A adenosine receptors (ARs). In this regard, nitric oxide (NO) is partly involved in the central effects of caffeine. In this study, we examined the effect of acute caffeine administration on pentylenetetrazole (PTZ)-induced seizure threshold by focusing on A₁Rs, A_2ARs, and NO-cGMP signaling pathway.
NMRI male mice (25–30 g) received caffeine (5, 50, and 100 mg/kg) alone, whereas 8-CPT (1 and 5 mg/kg, a selective A₁Rs antagonist), SCH-442416 (5 and 10 mg/kg, a selective A_2ARs antagonist) or sildenafil (5 and 10 mg/kg, a phosphodiesterase 5 inhibitor) were administrated alone or as pre-treatment before caffeine. Seizure threshold was assessed by intravenous infusion of PTZ. Nitric oxide metabolites (NOx) were measured with the Griess method.
When administrated alone, caffeine (5 and 50 mg/kg) and 8-CPT (1 and 5 mg/kg) significantly decreased seizure threshold, while 100 mg/kg of caffeine, SCH-442416 or sildenafil did not change it. Only pre-treatment with SCH-442416 (5 and 10 mg/kg) or sildenafil (5 and 10 mg/kg) before 100 mg/kg of caffeine significantly decreased seizure threshold. Moreover, NOx levels significantly decreased following alone administration of caffeine (100 mg/kg) or 8-CPT (5 mg/kg).
The results of present study showed that 5 and 50 mg/kg of caffeine had a proconvulsant effect but caffeine at a dose of 100 mg/kg had no effect on seizure threshold. In addition, it seems that the effect caffeine on seizure threshold is partly mediated through ARs or modulation of the NO-cGMP signaling pathway.
Tramadol and caffeine produce synergistic interactions on antinociception measured in a formalin model
2010, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Clinically, caffeine has been used as an adjuvant for many years, both to eliminate sleepiness induced by antihistamines and to provide better analgesic efficacy. Combinations of non-steroidal anti-inflammatory drugs (NSAIDS) with caffeine have been analyzed in different animal models; caffeine with ibuprofen, aspirin, ketorolac in pain-induced functional impairment in the rat (PIFIR model) (Medina et al., 2006; López-Muñoz et al., 1996; Castañeda-Hernández et al., 1994), paracetamol + caffeine in hot plate (Engelhardt et al., 1997) and aspirin + caffeine in carrageenan-induced edema in the hind paw test (Vinegar et al., 1976). Misra et al. (1985) reported that the antinociceptive effect of morphine was potentiated by caffeine.
Drug combinations have been used in clinical practice for the main purpose of increasing therapeutic effect efficacy. The aim of this study was to determine the antinociceptive effect of tramadol and caffeine administered separately or in combination, as well as their synergistic interaction. The formalin test was used. Nociceptive behavior was evaluated by flinching response of the formalin-treated paw. Rats were divided into five groups and received tramadol alone (4.9–49.6 mg/kg, s.c.), caffeine alone (1–17.8 mg/kg, p.o.), or combinations of tramadol (4.9, 8.8, 15.6 and 20.8 mg/kg, s.c.) and caffeine (1, 3.16 and 10 mg/kg, p.o.). Tramadol showed dose-dependent antinociceptive effect in both phases of the formalin test. Caffeine only presented antinociceptive effect in the second phase and this effect was also dose-dependent. In Phase 1, combinations of tramadol and caffeine showed antinociceptive effect similar to that of tramadol alone. In Phase 2, the dose–response curve shifted to the left with the combination of tramadol and each dose of caffeine. Synergism analysis resulted in synergistic effect in ten combinations and antagonism in two combinations. In conclusion, the synergism observed in the majority of tramadol and caffeine combinations used in this study suggests that this drug combination is useful in the treatment of pain.
Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats
2006, European Journal of Pharmacology
It has been observed that caffeine improves antinociceptive efficacy of some non-steroidal antiinflammatory drugs (NSAIDs) in several experimental models, however, these effects have been questioned in humans. Controversy in clinical studies may be due to the use of different protocols as well as to high interindividual variability in patient response. In addition, the antinociceptive interaction of ibuprofen + caffeine has not been studied. To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ibuprofen, and caffeine administered either separately or in combinations were determined in a model of arthritic pain: “Pain-induced functional impairment in the rat (PIFIR model). The antinociceptive efficacies were evaluated using several dose–response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine or acetylsalicylic acid alone. The animals were administered with 0.05 ml intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received either acetylsalicylic acid, morphine, ibuprofen or caffeine, or a combination ibuprofen + caffeine (18 combinations). We report here that caffeine (17.8 and 31.6 mg/kg) is able to potentiate the antinociceptive effect of ibuprofen. This investigation showed that six combinations presented effects of potentiation and twelve combinations only showed antinociceptive effects not different from that of ibuprofen alone. The maximum antinociceptive effect was 270.7 ± 12.7 area units (au), produced by ibuprofen 100 mg/kg + caffeine 17.8 mg/kg; this effect was greater than the maximum produced by morphine 17.8 mg/kg (244.7 ± 22.9 au) in these experimental conditions. The maximum potentiation was 197 % produced with the combination of ibuprofen 17.8 mg/kg + caffeine 17.8 mg/kg. These results suggest that the antinociceptive effect of ibuprofen was significantly potentiated by doses of caffeine that by themselves are ineffective in this model.
The NO-cGMP-K<sup>+</sup> channel pathway participates in the antinociceptive effect of diclofenac, but not of indomethacin
2003, Pharmacology Biochemistry and Behavior
The aim of this study was to examine if the peripheral antinociceptive effects of diclofenac and indomethacin involve the sequential participation of NO and cGMP synthesis followed by potassium channel opening. The peripheral antinociceptive effects of diclofenac, indomethacin, pinacidil (a potassium channel opener) and atrial natriuretic peptide (ANP, which increases cGMP content in a NO-independent manner) were assayed using the formalin test in the rat. All compounds produced significant local antinociception. Diclofenac effect was reverted by N^G-l-nitro-arginine methyl ester (l-NAME, an inhibitor of NO synthesis), by 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and by the potassium channel blockers glibenclamide, tolbutamide, charybdotoxin and apamin. Pinacidil effect was blocked by glibenclamide, tolbutamide, charybdotoxin and apamin, strongly suggesting that potassium channel opening results in antinociception. ANP effect was inhibited by the potassium channel blockers, but not by l-NAME, suggesting that potassium channel opening is a consequence of an increased cGMP content. Indomethacin was effective, but at doses higher than those of diclofenac, and could not be blocked by l-NAME nor by potassium channel blockers. The present results suggest that the l-arginine–NO–cGMP–potassium channel pathway is involved in the peripheral antinociceptive effect of diclofenac, but not of indomethacin, and thus provide evidence for differences in mechanisms of action among nonsteroidal antiinflammatory drugs (NSAIDs).
Effects of caffeine as an adjuvant to morphine in advanced cancer Patients: A randomized, double-blind, placebo-controlled, crossover study
2001, Journal of Pain and Symptom Management
Psychomotor abnormalities are one of the complications of opioid therapy in advanced cancer patients. Caffeine has potential properties to counteract the central effects of morphine. Twelve patients receiving stable doses of slow release morphine with adequate pain relief were scheduled for this double-blind placebo-controlled crossover trial. The treatment consisted of an intravenous dose of 1/6 of the daily morphine dose, using an intravenous/oral conversion ratio of 1:3. The dose calculated was administered in 5 minutes. Patients were randomly divided to received in a double-blind manner an infusion of 200 mg of caffeine or saline solution intravenously over one hour. A crossover took place after 2–3 days. Patients were assessed immediately before the infusion and once at the end (one hour after). Each assessment included pain, nausea, confusion, and drowsiness intensity. Psychomotor tests, including tapping speed with 10–30 seconds trials, arithmetic tests, memory for digits, and visual memory were also performed. Caffeine infusion induced a significant decrease in pain intensity (from 25.3 to 16.3, p =0.003), but this was no different from the placebo. Caffeine increased both tapping speed tests (p = 0.041 and 0.010, respectively) in comparison with placebo treatment. No other significant differences were found in the other parameters examined. Caffeine showed a partial effect on the cognitive performance of advanced cancer patients on chronic morphine treatment who received a bolus of intravenous morphine. Further studies are necessary to evaluate whether higher doses of caffeine may be more effective and to establish the role of tolerance to caffeine in this group of patients.
Effect of caffeine on antinociceptive action of ketoprofen in rats
2001, Archives of Medical Research
To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain.
Antinociceptive activity was assayed using “… pain-induced functional impairment in the rat” (PIFIR model). The antinociceptive efficacies were evaluated using several dose–response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations).
ASA (ED₅₀ 465.2 ± 1.5 mg/kg), MOR (ED₅₀ 71.0 ± 1.6 mg/kg), and KET (ED₅₀ 7.2 ± 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 ± 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 ± 10.3 au. The median effective dose (ED₅₀) of KET alone was 7.2 ± 1.4 mg/kg, whereas the ED₅₀ of KET + CAF 17.8 mg/kg was 0.4 ± 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF.
These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.

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Short communicationEffect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac

Abstract

Eur. J. Pharmacol.

Pain

Eur. J. Pharmacol.

Pain

Ethics of Animal Investigation

Potentiation by caffeine of the analgesic effect of aspirin in the pain-induced functional impairment model in the rat

Can. J. Physiol. Pharmacol.

Short communication
Effect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac