Valdecoxib is an orally administered, highly selective cyclo-oxygenase (COX)-2 inhibitor with anti-inflammatory and analgesic properties. In well designed trials, valdecoxib demonstrated efficacy versus placebo in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenorrhoea and postoperative pain. Initial results in patients with migraine headache were promising.

Effect of valdecoxib pretreatment on pain and secondary hyperalgesia

Induction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers. The specific aim of this study was to investigate the effect of pretreatment with the COX-2 specific inhibitor valdecoxib on the development of the secondary hyperalgesia in humans. The hypothesis to be tested is that selective COX-2 inhibitors significantly attenuate the central component of sensitization, thereby decreasing the area of secondary hyperalgesia induced by our heat/capsaicin pain model. The study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped.[1]

The main goal of the study was to answer the question whether an administration of the COX-2 inhibitor will reduce responses to heat/capsaicin induced hypersensitivity in humans. We showed that the administration of 40 mg of valdecoxib had no effect on skin sensitization in the heat-capsaicin model. Furthermore, valdecoxib had no analgesic effect following thermal/chemical sensitization (i.e., thermal pain threshold, intensity of the supra-threshold heat stimulation), when compared to baseline or placebo. The observed results were obtained during the period of time corresponding to the recently reported maximal plasma and cerebral spinal fluid, concentration after single 40 mg oral dose of valdecoxib. It was also demonstrated that the single oral dose of 40 mg produced maximum plasma concentrations at 2 hrs after administration and lasting virtually undiminished (75% of maximum plasma concentration) until 6 hours post-administration. In addition, the same authors demonstrated that valdecoxib produced maximum concentrations within the cerebrospinal fluid at 2 hours after administration, which lasted unchanged for another 6 hours. These results indicate that the pain measurements employed in our study were performed during the time of maximum concentrations of valdecoxib in both plasma and the central nervous system. The area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation.

The current study is negative, which indicates either that the drug is ineffective or that the test is insensitive. The only way to demonstrate internal sensitivity of the test would have been to introduce a positive control. Not having the positive control included, we performed post-hoc calculations in order to demonstrate the power of the study regarding secondary hyperalgesia. The calculated power of the study exceeded 0.8 with data collected from 20 study volunteers (in paired design) for both measured components of the hyperalgesia response for at least initial half of all measurements (i.e., at HA1 through HA3), based on expected level of significance (P = 0.05), and the sensitivity threshold to detect a 30% reduction in the areas of hyperalgesia. In other words, the probability of type II error (i.e., not being able to demonstrate the presumable difference between placebo and valdecoxib) was less than 20%. It has been shown that an identical QST and heat-capsaicin model (including in many cases identical apparatus, thermode and the study protocol) had sufficient sensitivity in human volunteers. Taken together, we can assume that the combined QST/heat-capsaicin method is sufficiently specific and sensitive for evaluation of analgesia in healthy volunteers. It is, however, possible that the level of sensitivity obtained by using this technique (i.e. 30% reduction in the surface area) is insufficient to detect the minimal analgesic effects of oral valdecoxib on secondary hyperalgesia.

Efficacy and safety of valdecoxib for treatment of osteoarthritis

Our objective was to determine the efficacy and safety of valdecoxib (a cyclo-oxygenase 2 inhibitor) in the treatment of arthritis. Randomised, controlled trials comparing 10 or 20mg valdecoxib with placebo or non-steroidal anti-inflammatory drugs (NSAIDs) in patients with active osteoarthritis or rheumatoid arthritis. The manufacturer provided clinical trial reports. Data were combined through meta-analysis. Main outcomes were patient global rating of arthritis, arthritis pain, Western Ontario and McMaster Universities indices for osteoarthritis, American College of Rheumatology indices for rheumatoid arthritis, discontinuation, endoscopic ulcers, clinically significant upper gastrointestinal or renal events. Nine trials (five in osteoarthritis, four in rheumatoid arthritis) were included with 5726 patients.[2]

Overall, valdecoxib 10 and 20mg were superior to placebo and equivalent in efficacy to maximum daily doses of NSAIDs. Significantly fewer discontinuations because of gastrointestinal adverse events (4% versus 8%), or endoscopic ulcers of 3mm or more (5% versus 13%) occurred with valdecoxib compared with NSAIDs. Clinically significant upper gastrointestinal events occurred in 2/2733 (0.1%) with valdecoxib compared with 8/1846 (0.4%) with NSAIDs. Rates of clinically significant renal events were the same (2-3%) for valdecoxib and NSAIDs. At an appropriate dose valdecoxib was as effective as NSAIDs in osteoarthritis and rheumatoid arthritis. There were fewer gastrointestinal adverse event withdrawals and endoscopically detected ulcers. Convincing evidence of reduced major gastrointestinal adverse events could not be addressed by the trials.

Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity

The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib).[3]

The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans.

References

[1]Burns D, Hill L, Essandoh M, Jarzembowski TM, Schuler HG, Janicki PK. Effect of valdecoxib pretreatment on pain and secondary hyperalgesia: a randomized controlled trial in healthy volunteers [ISRCTN05282752, NCT00260325]. BMC Anesthesiol. 2006 Mar 10;6:3.

[2]Edwards JE, McQuay HJ, Moore AR. Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Pain. 2004 Oct;111(3):286-296.

[3]Gierse JK, Zhang Y, Hood WF, Walker MC, Trigg JS, Maziasz TJ, Koboldt CM, Muhammad JL, Zweifel BS, Masferrer JL, Isakson PC, Seibert K. Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. J Pharmacol Exp Ther. 2005 Mar;312(3):1206-12.