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Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

Joint inflammation is present in a subpopulation of knee osteoarthritis (OA) patients. Proinflammatory cytokines are known to sensitize the peripheral and central pain pathways. This can be mechanistically assessed by pressure pain thresholds and temporal summation of pain (TSP). Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with paracetamol are recommended as OA treatment. The current study hypothesized that evidence of central sensitization would predict poor responses to peripherally directed therapies in knee OA and therefore aimed to investigate the value of mechanistic pain profiling for predicting pain outcome of treatment with NSAIDs plus paracetamol. One hundred thirty-two patients received ibuprofen 1200 mg/daily, paracetamol 3 g/daily, and pantoprazole 20 mg/daily for 3 weeks. Before administration, cuff pain detection, tolerance threshold, and TSP were assessed. Worst pain within the last 24 hours and pain during activity (visual analogue scales) were assessed before and after treatment. Facilitated TSP was found at baseline in the nonresponders to the 3-weeks treatment as compared to responders for both the 30% and 50% pain alleviation criteria (P < 0.02). Linear regression models identified facilitated TSP (P < 0.01) and low clinical pain scores (P < 0.001) as independent factors for prediction of poor pain alleviation by the treatment. In conclusion, this study found that mechanistic pain profiling can predict pain alleviation of NSAIDs and paracetamol. Facilitated TSP and low clinical pain scores before treatment are independent predictors of poor pain alleviation after NSAIDs and paracetamol. This study adds to the growing evidence that a subgroup of knee OA patients with manifested central sensitization may require special management attention.

Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.

Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1 ± 19.1 mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (P = .06 and P = .33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (P = .063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline. In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.