This document has not been circulated to either the industry or Consultants within the Suffolk system.

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1 New Medicine Report Document Status COX II Inhibitors In Acute Analgesia For Suffolk Drug & Therapeutics Committee Date of Last Revision 15 th February 2002 Reviewer s Comments There seems to be a growing evidence base for the use of Cox II inhibitors in analgesia. The majority of papers described below show this. It would seem likely that there will be some variation in patient response and this may determine which one is used in practice. This document has not been circulated to either the industry or Consultants within the Suffolk system. Review The Suffolk Drug & Therapeutics Committee at its last meeting requested a review of the evidence for the control of acute pain in patients using Cox II inhibitor medication (Coxibs). For centuries many substances have been given to humans to combat pain and inflammation. One hundred years ago aspirin was first identified as an active drug entity and since then many analgesics and non-steroidal antiinflammatory drugs (NSAIDs) have been developed. However, these drugs had beneficial effects and harmful side effects both of which were caused by their inhibition of prostaglandin-h-synthase, also known as cyclooxygenase (COX). Further research showed that there were two distinct COX enzyme systems with COX-1 being responsible for the production of prostaglandins required for homeostatic functions and COX-2 being expressed in response to certain stimuli and at the site of inflammation. It is possible that further sub-systems or additional receptor types may be found in the future. It was proposed that the therapeutic action of NSAIDs is dependent on their ability to inhibit prostaglandin production through the COX-2 enzyme system. However some NSAIDs have little COX-2 activity and many are used to treat conditions that are not regarded as inflammatory. In addition attempts to explain the toxicity of existing NSAIDs in terms of their COX-2 selectivity have not been successful since they are in the main COX-1 selective with only diclofenac reaching equipotency with respect to COX-1 and COX-2 activity. It Page 1 of 6

2 should be noted that the specificity and selectivity measurements have been made in vitro. Licensed COX-2 preferential inhibitors. Both meloxicam (Mobic ) and nimesulide (Mesulid ) are known to show COX-2 selectivity. Two further drugs etodalac (Lodine ) and nabumetone (Relifex ) may be COX-2 selective but the evidence is less developed. Licensed COX-2 specific inhibitors. A number of new drug entities have been developed of which rofecoxib (Vioxx ) and celecoxib (Celebrex ) were the first to reach the market. More recently rofecoxib has been given a licence for use in acute pain (Vioxxacute ). New Products Not Yet Licensed Three new products are currently awaiting approval in the UK. Valdecoxib (Bextra ) was given FDA approval in November It is thought that the product may be launched in the UK in The licensed indications in the USA are for the treatment of osteoarthritis, rheumatoid arthritis and the treatment of dysmenorrhoea. Parecoxib (Xapit/Dynastat/Rayzon ) has received a positive opinion from the CPMP in Europe but has not been granted a licence by the FDA. The CPMP approved indication is for the short-term treatment of post-operative pain via IM or IV injection. Parecoxib is metabolised into valdecoxib in the body. Etoricoxib (Arcoxia ) has been filed for approval in the USA for the treatment of osteoarthritis, rheumatoid arthritis, acute and chronic pain and dysmenorrhoea. It is expected that a licence will be obtained at sometime in A Review of Current Papers A number of papers have been reviewed and a brief outline of the findings from each one is given below in approximate reverse date order. Camu F, Beecher T, Recker DP, Verburg KM. Valdecoxib, a COX-2 Specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty Am J Ther 2002 Jan-Feb;9(1):43-51 (Pubmed Abstract) The authors report a multi-centre multiple-dose, double-blind, parallel-group study comparing the opioid sparing effect of valdecoxib twice daily, with the first dose 1 to 3 hours pre-operatively, compared to placebo. Patients receiving 20mg or 40mg valdecoxib twice daily were reported to require, on Page 2 of 6

3 average, 40% less patient controlled morphine than patients in the placebo group. Geba GP, Weaver AL, Polis AB et al. Efficacy of rofecoxib, celecoxib amd acetominophen in ostoearthritis of the knee. A randomized trial. JAMA 2002;287:64-71 (The VACT Study Sponsored Merck) The randomised, parallel-group, double-blind, multi-centred trial compared the pain relief on walking, at night and at rest together with morning stiffness following rofecoxib 12.5mg daily, or 25mg daily, celecoxib 200mg daily or acetominophen 4000mg daily for 6 weeks. The overall conclusion of the study was that rofecoxib 25mg per day provided efficacy advantages over the other treatments for the symptomatic knee OA. Desjardins PJ, Grossman EH, Kuss ME et al. The injectable cyclooxygenase-2-specific inhibitor parecoxib has analgesic efficacy when administered preoperatively. Anesth Analg 2001;93: (Sponsored Pharmacia) The study compared various doses of parecoxib against placebo in 224 patients undergoing extraction of two ipsilateral impacted third molars using a single-dose, randomised, double-blinded, placebo-controlled, parallel group clinical trial. A dose of medication was given by the IV route minutes before extraction and the duration of surgery was limited to minutes. Each patient received lidocaine/epinephrine and also nitrous oxide/oxygen mixture if required. The primary end point was the time to rescue medication. The results are shown in Table 1 Table 1 To show the time to rescue medication Treatment Group Median time to rescue medication (h:min) 95% confidence interval % patients taking rescue medication P value compared to placebo Placebo 02:51 02:16 to 03:16 93 Parecoxib 20mg 06:17 04:04 to 11: Parecoxib 40mg >24:00 11:04 to >24:00 48 <0.001 Parecoxib 80mg 12:00 06:24 to 16:37 59 <0.001 Harris SI, Kuss M, Hubbard RC, Goldstein JL. Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclo-oxygenase-2- specific inhibitor, compared with ketorolac, naproxen and placebo. Clin Ther 2001;23: (Sponsored Pharmacia) The authors report on a randomised double-blind, double-dummy, placebocontrolled, parallel-group study where healthy elderly patients were given either parecoxib IV (10mg bd), or oral naproxen (500mg bd), or placebo, or placebo for 2 days followed by IV ketorolac (15mg qid) for 5 days. Endoscopy Page 3 of 6

4 was performed at initiation of the treatment and again at day 7. Among the first 17 subjects enrolled ulcers were observed in all treatment groups except those receiving parecoxib ( ketorolac 4/4, naproxen 2/4, placebo 2/5). Four subjects in the ketorolac group and 1 in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the high incidence of ulcers the study was stopped and the randomisation blind broken. The range for the ulcer size was 0.3cm to 1.0cm with the two placebo patients having 1.0cm ulcers. The authors conclude that although the sample size is small elderly patients may be at risk of GI ulceration even after shortterm use of NSAIDs (and presumably placebo tablets as well!). Daniels SE, Grossman EH, Kuss ME et al. A double blind, randomised comparison of intramuscular and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model Clin Ther 2001;23: In a similar study to that performed by Desjardins PJ et al 304 patients were given two injections one IV the other IM of either active substance and placebo or both of placebo. The results are shown in Tables 2 and 3. Table 2 To show time to onset of analgesia. Treatment Group Number of patients % of patients experiencing analgesia Median time to onset of analgesia h:min Parecoxib 20mg IM :13 20mg IV :13 40mg IM :13 40mg IV :13 Ketorolac 60mg IM :12 Placebo >24:00 Table 3 To show time to use of rescue medication Treatment Group Number of patients % of patients requiring rescue medication Median time to use of rescue medication h:min Parecoxib 20mg IM :20 20mg IV :03 40mg IM :43 40mg IV :39 Ketorolac 60mg IM :01 Placebo :03 Page 4 of 6

5 Huang JJ, Taguchi A, Hsu H et al. Preoperative oral rofecoxib does not decrease postoperative pain or morphine consumption in patients after radical prostatectomy; a prospective, randomised, double-blinded, placebo-controlled trial J Clin Anesth 2001 Mar;13(2):94-7 (PubMed abstract) The authors found that when rofecoxib is given orally before surgery it does not provide significant analgesia that results in reduction in pain scores or analgesic requirements for patients after radical prostatectomy. Reicin A, Browm J, Jove M et al. Efficacy of single dose and multidose rofecoxib in the treatment of post-orthopedic surgery pain. Am J Orthop 2001 Jan;30(1):40-8 (PubMed Abstract Work Sponsored Merck) The authors report that rofecoxib is more effective than placebo and similar to naproxen for all single dose measures of pain relief. Gimbel JS, Brugger A, Zhao W et al. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults. Clin Ther;23(2): Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy of celecoxib 200mg compared with hydrocodone 10mg/acetaminophen 1000mg or placebo following outpatient orthopaedic surgery. In the single dose phase celecoxib was as effective as hydrocodone/acetaminophen. In the five-day period celecoxib 200mg three times a day was found more effective than hydrocodone/acetaminophen Day R, Morrison B, Luza A et al. A randomised trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med 2000;160: (Sponsored Merck) A randomised double-blind trial of 809 adults with OA compared the efficacy and tolerability of rofecoxib 12.5mg or 25mg daily with ibuprofen 800mg three times a day for a six week period. The results showed that for both the primary and secondary endpoints rofecoxib and ibuprofen provided significantly (p<0.001) greater efficacy than placebo. All treatments were well tolerated. The overall incidence rates of clinically adverse events were not significantly different (p>0.05) among the treatment groups. Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxob or rofecoxib after spinal fusion. Anesth Analg 2000;91: The trial studied 60 patients who were given celecoxib, rofecoxib or placebo 1 hour prior to surgery. The outcome measures were morphine use and pain scores measured at 4 hourly intervals following the surgery. Both rofecoxib Page 5 of 6

6 and celecoxib produced similar analgesic effect at 4 hours post operation. Rofecoxib demonstrated an extended analgesic effect over the 24 hour period compared to celecoxib. However it should be noted that celecoxib is licensed in this country for a twice daily dose and thus one might expect the efficacy to decrease over the study timescale whereas rofecoxib acute is licensed for a once daily dosage schedule and would thus be expected to remain efficacious for a longer time period. Bandolier completed a review of the then new Cox-2 inhibitors in May There seems little doubt that Coxibs work in acute pain models. Table 4 gives the NNT for a number of products derived from a number of RCTs, which measured an outcome of at least 50% pain relief with treatment measured over four to six hours. Table 4 To show the NNT for a number of preparations to give at least 50% acute pain relief from Cox-2 trials Treatment NNT (95% CI) Rofecoxib 50mg 1.9 (1.6 to 2.2) Celecoxib 200mg to 4.4) Ibuprofen 400mg 2.1 (1.7 to 2.6) There is similar evidence for the efficacy of coxibs in chronic pain. The major debate is around their ability not to induce gastrointestinal bleeding. A meta-analysis of perforations, ulcers and bleeds (PUBs) in the phase II and III randomised trials of rofecoxib examined serious gastrointestinal bleeding. The results are shown in Table 5. Table 5 To show perforations, ulcers and bleeds in pre-planned analysis of all rofecoxib randomised trials. Percent per 100 Treatment No of Patients Exposure (pt years) Number with PUBs Mean exposure (Years) Crude Risk (%) patient years over 4 12 Months Months Placebo Rofecoxib NSAID The cumulative incidence of PUBs over 12 months with rofecoxib was about half that with classical NSAIDs, with a relative risk reduction of 0.51 (0.26 to 1.0). A weakness of this analysis is that patients who developed an endoscopic ulcer in the original trials discontinued treatment. Since NSAIDs produced higher rates than rofecoxib or placebo the likelihood is that the results are biased against rofecoxib. It should however be noted that as yet the level of evidence is based on very limited information. Page 6 of 6