The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans

Abstract

Non-steroidal antiinflammatory drugs (NSAIDs) are known to induce analgesia mainly via inhibition of cyclooxygenase (COX). Although the inhibition of COX in the periphery is commonly accepted as the primary mechanism, experimental and clinical data suggest a potential role for spinal COX-inhibition to produce antinociception and reduce hypersensitivity. We used an experimental model of electrically evoked pain and hyperalgesia in human skin to determine the time course of central analgesic and antihyperalgesic effects of intravenous parecoxib and paracetamol (acetaminophen). Fourteen subjects were enrolled in this randomized, double blind, and placebo controlled cross-over study. In three sessions, separated by 2-week wash-out periods, the subjects received intravenous infusions of 40 mg parecoxib, 1000 mg paracetamol, or placebo. The magnitude of pain and areas of pinprick-hyperalgesia and touch evoked allodynia were repeatedly assessed before, and for 150 min after the infusion. While pain ratings were not affected, parecoxib as well as paracetamol significantly reduced the areas of secondary hyperalgesia to pinprick and touch. In conclusion, our results provide clear experimental evidence for the existence of central antihyperalgesia induced by intravenous infusion of two COX inhibitors, parecoxib and paracetamol. Since the electrical current directly stimulated the axons, peripheral effects of the COX inhibitors on nociceptive nerve endings cannot account for the reduction of hyperalgesia. Thus, besides its well-known effects on inflamed peripheral tissues, inhibition of central COX provides an important mechanism of NSAID-mediated antihyperalgesia in humans.

Assessing efficacy of non‐opioid analgesics in experimental pain models in healthy volunteers: an updated review

“…Here the ongoing pain was unaffected, whereas the hyperalgesia was decreased [43]. The ongoing pain was assessed by subjective ratings and the limited sensitivity of this measuring method is in consensus with findings of Bromm et al [38,44].…”

“…Compared with NSAIDs, paracetamol has a different mechanism of action with less affinity to the peripheral cyclooxygenases and a more pronounced central effect, and this could explain the different findings for, for example, the cold pressor test and freeze lesion [32,42,46,47]. Furthermore, this is supported by findings in the continuous electrical hyperalgesia model, which probably activates central mechanisms that were attenuated by paracetamol [44]. However, NSAIDs also demonstrate effect towards central hyperalgesic mechanisms [15,22].…”

Preventive Analgesia and Novel Strategies for the Prevention of Chronic Post-Surgical Pain

“…The COX-2 isoform appears to be the enzyme responsible for inflammation and pain. COX-2 inhibitors, such asparecoxib, reduce secondary hyperalgesia and appear to reduce central sensitization in humans [38,39]. Celecoxib (the only COX-2 inhibitor approved in the North American marketplace) has demonstrated a reduction in postoperative pain, a reduced need for postoperative opioid analgesia [40], and did not inhibit bone healing following arthroplasty surgery [41].…”

Parecoxib Added to Ropivacaine Prolongs Duration of Axillary Brachial Plexus Blockade and Relieves Postoperative Pain

“…Several studies [16,17] have shown COX-2 in the spinal dorsal horn could modulate spinal nociceptive processes. Furthermore, epidural parecoxib reportedly has no neurotoxicity in rats over 21 days [15].…”

“…Intravenous use of a COX-2 antagonist may inhibit the systemic inflammatory response and prostaglandin synthesis, relieve inflamed peripheral tissues, and consequently provide pain relief [26]. Two studies showed that COX-2 in the spinal dorsal horn could modulate spinal nociceptive processes and is associated with antihyperalgesia in the central nervous system [16,17]. Therefore, we postulated that applying a COX-2 antagonist directly to the peripheral nerve might reduce the COX-2 activation and down-regulate pain intensity.…”