Selective inhibitors of cyclo-oxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation

1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non-inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4. In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.     

Endogenous opioids mediate the hypoalgesia induced by selective inhibitors of cyclo-oxygenase 2 in rat paws treated with carrageenan

Mechanical hyperalgesia induced in rat paws by carrageenan (250microg) was modified by pre-treatment with three selective inhibitors of cyclo-oxygenase-2 (COX-2); celecoxib, rofecoxib and SC236. These inhibitors raised the nociceptive threshold above the normal, non-inflamed, level, inducing a state of hypoalgesia. Such hypoalgesia was observed in different strains of rat (Holtzman, Wistar and Sprague-Dawley) and after different modes of administration of the COX-2 inhibitor (locally, in the paw, or systemically). A selective inhibitor of COX-1 (SC 560; 1-10mg kg(-1)) decreased hyperalgesia but did not induce hypoalgesia. Pre-treatment with naltrexone (3mg kg(-1)), an opioid receptor antagonist, did not affect carrageenan-induced hyperalgesia but abolished the hypoalgesic effects of COX-2 inhibitors, without diminishing the anti-hyperalgesic effect of indomethacin. In rats made tolerant to the anti-nociceptive effects of morphine, all anti-nociceptive effects of SC236 were abolished but the anti-hyperalgesic effects of indomethacin or SC 560 were unaffected. We conclude that, in our model of inflammatory hyperalgesia, the anti-nociceptive effect of selective COX-2 inhibitors involved the participation of endogenous opioids.     

Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced hyperalgesia

Lipopolysaccharide (LPS) is known to increase the expression and release of various pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and produce hyperalgesia. It is also well known that prostaglandins (PGs), synthesised both in the periphery and centrally by COX isoforms, play a key role in sensitisation of nociceptors and nociceptive processing. To investigate the role of COX-2 in LPS-induced hyperalgesia, parecoxib, a selective COX-2-inhibiting pro-drug, was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS (50 g/mouse or 25 g/paw of rat, respectively). Acetic acid-induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of COX-2 on LPSinduced hyperalgesia. Animals showed significant hyperalgesic behavior 8 h after LPS injection. Parecoxib (up to 20 mg/kg, i.v.) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS-pretreated mice. Similarly, parecoxib reversed the hyperalgesia in the LPS-injected paw but not in the contralateral paw of rats. Pre-treatment with dexamethasone, an inhibitor of COX-2 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats. These findings suggest that inducible COX-2 derived PGs are involved in central nociceptive processing, which resulted in hyperalgesic behavior following LPS administration and inhibition of COX-2 or its expression attenuated LPS-induced hyperalgesia.     

Differential effects of dipyrone, ibuprofen, and paracetamol on experimentally induced pain in man.

In a double-blind cross-over study on 22 healthy subjects the analgesic efficacies of the antipyretic analgesic drugs ibuprofen, dipyrone and paracetamol were tested against placebo using a model of experimentally induced pain. To this purpose interdigital webs were pinched repeatedly for 2 min periods. The painfulness of these stimuli was assessed by the subjects on an electronically controlled visual analogue scale at 10 sec intervals. In addition to the subjective pain ratings the stimulus induced reflex diminution of the blood flow in the stimulated hand was measured with photoplethysmography and laser Doppler flow analysis. The flare response around the stimulated area was assessed with infrared thermography. In this assay system ibuprofen and dipyrone, but not paracetamol, showed statistically significant analgesic effects by preventing hyperalgesia which is normally induced by the repeated stimulation of a skin site. This hypoalgesic effect was not related to the subjective impression of the subjects of the analgesic potency of the respective drug. Sympathetic reflex vasoconstriction was not quantitatively related to the drug induced hypoalgesia. Ibuprofen and, to a minor extent, the other antipyretic analgesic drugs also diminished the stimulus induced flare reaction around the stimulated skin sites.     

Analgesia by direct antagonism of nociceptor sensitization involves the arginine-nitric oxide-cGMP pathway.

We tested the hypothesis that activation of the nitric oxide (NO)-cGMP pathway is involved in the mechanism of two directly acting non-opiate peripheral analgesics, myrcene and dipyrone, using our modification of the Randall-Selitto test. The NO inhibitor, NG-monomethyl-L-arginine (50 micrograms/paw) and methylene blue (500 micrograms/paw) abolished the analgesic effect of dipyrone and myrcene. Dibutyryl cyclic adenosine monophosphate (DbcAMP) caused a dose-dependent hyperalgesia (20, 50 and 100 micrograms/paw). Only responses to low doses of DbcAMP were inhibited by the two analgesics. Pretreatment with MY5445 (50 micrograms/paw) resulted in potentiation of the effects of both analgesics. These results support our hypothesis that the sensitivity of nociceptors may be controlled by the balance between the levels of cAMP and cGMP. Stimulation of the NO-cGMP pathway is probably the common denominator for the mode of action of peripheral analgesics which block hyperalgesia directly.     

Involvement of ATP-sensitive K(+) channels in the peripheral antinociceptive effect induced by dipyrone

We evaluated the effect of several K(+) channel blockers on the peripheral antinociception induced by dipyrone using the rat paw pressure test, in which sensitivity is increased by intraplantar injection (2 micro g) of prostaglandin E(2). Dipyrone administered locally into the right hindpaw (50, 100 and 200 micro g) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. The specific blockers of ATP-sensitive K(+) channels glibenclamide (40, 80 and 160 micro g/paw) and tolbutamide (80, 160 and 320 micro g/paw) antagonized the peripheral antinociception induced by dipyrone (200 micro g/paw). Charybdotoxin (2 micro g/ paw), a blocker of large conductance Ca(2+)-activated K(+) channels, and dequalinium (50 micro g/paw), a selective blocker of small conductance Ca(2+)-activated K(+) channels, did not modify the effect of dipyrone. This effect was also unaffected neither by intraplantar administration of non-specific voltage-dependent K(+) channel blockers tetraethylammonium (1700 micro g) and 4-aminopyridine (100 micro g) nor cesium (500 micro g), a non-specific K(+) channel blocker. These results suggest that the peripheral antinociceptive effect of dipyrone may result from activation of ATP-sensitive K(+) channels, while other K(+) channels appear not to be involved in the process.     

Evidence for a peripheral mechanism of action for the potentiation of the antinociceptive effect of morphine by dipyrone

The potentiation of the antinociceptive effect of morphine by dipyrone (metamizol) and the possible participation of a peripheral mechanism on such synergism were studied with the use of the formalin test in the rat. Nociception was induced by the intraplantar injection of diluted formalin (1%) in the right hind paw. Local administration of either dipyrone or morphine in the site of injury produced a dose-dependent antinociceptive effect. When combined, noneffective doses of morphine (1.25 microg/paw) and dipyrone (100 microg/paw) produced a significantly greater antinociceptive effect compared with either drug alone or saline. The opioid antagonist naloxone partly reversed the effect of the dipyrone-morphine combination. On the other hand, the inhibitor of nitric oxide (NO) synthesis, N(G)-L-nitro-arginine methylester (L-NAME), but not its inactive isomer, D-NAME, completely antagonized the effect of the dipyrone-morphine combination. These results suggest that the potentiation of morphine-induced antinociception by dipyrone in the formalin test requires an important participation of local release of NO, activating the NO-cyclic GMP pathway at the peripheral level.     

The dose-related effects of paracetamol on hyperalgesia and nociception in the rat.

1. We have studied the effects of 3 low doses of paracetamol (25, 50 and 100 mg kg-1 p.o.) on inflammatory hyperalgesia, inflammatory oedema, and nociceptive thresholds in rats. 2. At the lower dose (25 mg kg-1), paracetamol reduces only central hyperalgesia. 3. At the doses of 50 and 100 mg kg-1, paracetamol reduces also peripheral hyperalgesia; moreover, it enhances nociceptive thresholds to a mechanical stimulus in the non-inflamed paws. 4. Neither paw inflammatory oedema nor tail nociceptive thresholds to a thermal stimulus were modified by paracetamol administration. 5. Our results suggest that paracetamol can reduce hyperalgesia without affecting physiological nociception and inflammation.     

Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone (metamizol) in mice

Dipyrone is a common nonopioid analgesic and antipyretic, which, in many countries, is available over the counter and is more widely used than paracetamol or aspirin. However, the exact mechanisms by which dipyrone acts remain inconclusive. Two novel arachidonoyl-conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase (FAAH), which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide. These arachidonoyl metabolites not only inhibit cyclooxygenase (COX-1/COX-2) but also bind to cannabinoid receptors at low micromolar concentrations. The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested. Accordingly, the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would (a) be blocked by cannabinoid receptor antagonists and (b) occur in FAAH mice. Here, we report that thermal antinociceptive, hypothermic, and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH. These findings indicate that FAAH-dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions.     

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.     

Mechanisms of action of paracetamol and related analgesics

Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower flux through this pathway produces lesser levels of the hydroperoxide, PGG(2), than the pathway involving COX-1. Apart from the lack of anti-inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but, further work, particularly at low concentrations of arachidonic acid is required. We suggest that paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).     

The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors

Paracetamol analgesic mechanism of action is still poorly defined but mainly involves central inhibition of cyclooxygenases. Here we tested the peripheral antinociceptive effects of paracetamol (intraplantar injections) in a rat model of neuropathic pain. Paracetamol dose-dependently decreased mechanical allodynia and lowered nociceptive scores associated with hyperalgesia testing. These effects were inhibited by the administration of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. The participation of the peripheral cannabinoid system in paracetamol analgesia is suggested.     

Beneficial action of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one, a novel long-chain fatty alcohol, on diabetic hypoalgesia and neuropathic hyperalgesia

The effects of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one (tCFA15) on diabetic hypoalgesia and neuropathic hyperalgesia were examined. Treatments of streptozotocin (STZ)-pretreated mice with tCFA15 (8 - 40 mg/kg, i.p.) for 7 days significantly reversed the depressed inflammatory nociceptive licking response in the formalin test. In addition, similar drug treatments and dosing in 7-day postoperative neuropathic pain model rats (prepared by the method of Bennett and Xie) yielded a similarly favorable outcome by significantly reversing decreased nociceptive thresholds in the paw pressure test. These results suggest that tCFA15 may have the potential to normalize sensory nerve abnormalities induced in experimental diabetes and nerve injury.     

Mechanisms of action of paracetamol and related analgesics

Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower flux through this pathway produces lesser levels of the hydroperoxide, PGG₂, than the pathway involving COX-1. Apart from the lack of anti-inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but, further work, particularly at low concentrations of arachidonic acid is required. We suggest that paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).     

Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism

This study investigated the effect of bergamot essential oil (BEO) containing linalool and linalyl acetate as major volatile components in the capsaicin test. The intraplantar injection of capsaicin (1.6 μg) produced a short-lived licking/biting response toward the injected paw. The nociceptive behavioral response evoked by capsaicin was inhibited dose-dependently by intraplantar injection of BEO. Both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal (i.p.) and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly reversed BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting μ-opioid receptor preferring antagonist, resulted in a significant antagonizing effect on antinociception induced by BEO and linalool. Antinociception induced by i.p. or intrathecal morphine was enhanced by the combined injection of BEO or linalool. The enhanced effect of combination of BEO or linalool with morphine was antagonized by pretreatment with naloxone hydrochloride. Our results provide evidence for the involvement of peripheral opioids, in the antinociception induced by BEO and linalool. Combined administration of BEO or linalool acting at the peripheral site, and morphine may be a promising approach in the treatment of clinical pain.     

Inflammatory mediators involved in the nociceptive and oedematogenic responses induced by Tityus serrulatus scorpion venom injected into rat paws

The present study investigated the role of kinins, prostaglandins (PGs) and nitric oxide (NO) in mechanical hypernociception, spontaneous nociception and paw oedema after intraplantar (ipl) injection of Tityus serrulatus venom (Tsv) in male Wistar rats. Tsv was ipl-injected in doses of 0.01-10microg/paw. Pre-treatment (30min prior) with DALBK (100nmol/paw) and icatibant (10nmol/paw), B1 and B2 selective kinin receptor antagonists, L-NAME (50mg/kg, i.p., a non-selective nitric oxide synthase inhibitor) or celecoxib, selective COX-2 inhibitor, was given 1h prior per os (5mg/kg, p.o.), significantly reduced the hypernociceptive response (Von Frey method), the spontaneous nociception (determined by counting the number of flinches) and paw oedema (plethysmometer method) induced by Tsv at doses of 1.0 and 10microg/paw for both nociceptive and oedematogenic responses, respectively. Nevertheless, indomethacin (5mg/kg, i.p., 30min prior) was ineffective in altering all of these events. The results of the present study show that Tsv, injected ipl into the rat paw, causes a dose-dependent paw oedema, mechanical hypernociception and flinches (a characteristic biphasic response) in which kinins and NO are substantially involved. Although celecoxib was effective against the oedema and pain caused by Tsv, COX-2 does not seem to be involved in the inflammatory response caused by Tsv.     

Local inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue

Inflammation was induced in rats by intraplantar administration of carrageenan (500 micrograms in 0.1 ml). Nociceptive thresholds were measured on both inflamed and contralateral hindpaws with the pressure test of Randal and Sellito. Low doses (0.03-10 micrograms/kg) of naloxone hydrochloride (Nx) or of methylnaloxone methylsulfonate (MeNx) were injected 4 h after carrageenan in the inflamed paw: Nx (3 micrograms) and MeNx (1-10 micrograms) diminished inflammatory pain; a slight, nonspecific hyperalgesia was observed in the contralateral paw after Nx, MeNx or NaCl. Neither drug was effective when injected s.c. at the same doses and time; however activities were shown to be influenced by the experimental schedule. Low s.c. doses of Nx antagonized the analgesia produced by s.c. morphine whereas MeNx did not. This work demonstrates the local site of the analgesic action of the doses of Nx and MeNx used here, bringing new evidence in favour of the existence of cutaneous opioid receptors. Opiate antagonists might inhibit inflammatory pain by interacting with a particular population of cutaneous receptors and (or) by being dealkylated locally into agonists.     

Acquisition and expression of conditioned hypoalgesia in morphine-naive and morphine-tolerant rats

The present study used a within-subject design to examine acquisition and expression of conditioned hypoalgesia in 50 male Wistar rats. Morphine-naive rats preexposed to a heat stressor with saline were hypoalgesic when subsequently tested for latencies to tail flick or paw lick. However, morphine-tolerant rats preexposed to the heat stressor with saline failed to display hypoalgesia when tested for latencies to tail flick, but showed hypoalgesia when tested for latencies to paw lick. Taken together, these findings suggest that expression of conditioned hypoalgesic responses in morphine-tolerant rats may depend on the nociceptive test used. Both morphine-naive and morphine-tolerant rats preexposed to the heat stressor with morphine failed to display hypoalgesia on either the tail-flick or the hot-plate test, demonstrating that morphine's ability to block acquisition of conditioned hypoalgesia is independent of the test used to assess nociceptive sensitivity.     

Endogenous opioids are involved in morphine and dipyrone analgesic potentiation in the tail flick test in rats

The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in na?ve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.     

Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non‐opioid analgesics, namely nefopam, a centrally acting non‐opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo‐oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED₅₀ values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED₅₀ values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of nefopam at a non‐analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan‐induced tactile allodynia, the combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non‐analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.