2 inhibitors in postoperative pain and chronic pain ... - MedIND

170 J. Anaesth. 2005; 49 (3) : 170 - 179 Indian

INDIAN JOURNAL OF ANAESTHESIA, JUNE 2005 170

REVIEW ARTICLE

CYCLOOXYGENASE - 2 INHIBITORS IN POSTOPERATIVE PAIN AND CHRONIC PAIN MANAGEMENT : CURRENT OPINIONS AND FUTURE PRESPECTIVES Dr. Ashok K. Saxena 1 Dr. Rashmi Ramachandran 2 Dr. Monica Gulati 3 Dr. Mahendra Kumar 4 SUMMARY Adequate management of post operative pain contributes significantly for the overall sucessful outcome of any surgery.Advent of NSAIDs revolutionised the pharmacologhical post operative management, but suffered a transient set back in no time,because of their associated side effects.The isolation of COX-1,COX-2,and COX-3 enzymes resulted in seperation of therapeautic and adverse effects of NSAIDs and the newer COX inhibitors might prove promising in the near future.This review address the post op pain and also the chronic pain management and the related issues with these newer drugs.

Introduction The use of non steroidal anti-inflammatory drugs (NSAIDs) is one of the most common non opioid analgesic approaches currently used for management of postoperative pain and chronic pain. However, inhibition of prostaglandin synthesis by NSAIDs may induce complications including renal injury, gastric ulceration and bleeding. The isolation of COX-1 and COX-2 enzymes has resulted in the development of exiting hypothesis that the therapeutic and adverse effects of NSAIDs could be uncoupled. So the development of COX-2 selective inhibitors has opened a new era of clinical investigations in NSAIDs. Over the last 5 years the clinical use of COX-2 inhibitors (COX-2Is) has exponentially grown and widely surpassed their market expectations due to the low side effect profile. In 1991, Xie and O’Banion, molecular biologists, discovered that the enzyme cyclooxygenase (COX) exists in two isomeric forms (COX-1 and COX-2) (fig. 1). Two different gene codes were found for the isomers. These genes were cloned, sequenced, expressed and characterized.1,2 COX-1 mediates gastric mucosal integrity and renal and platelet functions, while COX-2 is expressed after injury to contribute to inflammation and hyperalgesia (fig 1). They both have the same molecular weight. The 1. 2. 3. 4.

M.D.,D.A., Prof. M.D., Sr. Resident M.D., Sr. Resident M.D.,D.A., Prof. Dept. of Anaesthesiology University of Medical Sciences and G.T.B Hospital, Shahdara, Delhi - 110 095, India Correspond to : Dr. Ashok K. Saxena E-mail : [email protected] (Accepted for publication on 28-03-2005)

Fig. 1

COX-2 active site is somewhat larger than that of COX-1, thus increasing its capacity to accept a wider range of fatty acid molecules and other substrates, as well as making selective inhibition of COX-2 possible.3 Obviously COX-2Is have been developed as bigger NSAID molecules by the addition of a side sulfonyl, sulfone, or sulfonamide group to the main chain. The so called, COX-2Is are 2-3 orders of magnitude more potent against COX-2 than against COX-1 (200 times for celecoxib and 800 times for rofecoxib, depending on the essay model). According to Willoughby, there may exist a third isoform expressed in a late recovery phase (proposed to be COX-3 in charge of producing anti-inflammatory prostaglandins) that being sensitive to selective and nonselective NSAID would preclude the continued use of these drugs during the recovery phase (fig. 2).4 Hence the newly formed “COX-2” in the resolution phase may represent a third COX isoform, “COX-3” (fig. 3). The chief objective of this review article is to review the differences between NSAIDs and COX-2Is and to analyze currently available COX-2I’s clinical applications in postoperative pain management and chronic pain management.

SAXENA, RAMACHANDRAN, GULATI, KUMAR : CYCLOOXYGENASE INHIBITORS & PAIN MANAGEMENT

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capacity in a variety of cell types, including human blood monocytes,8 rat microglia cells, murine macrophages9 and murine keratinocytes.10 COX-2 is also regulated at the post transcriptional level.11 Loss of post transcriptional regulation of COX-2 may lead to COX-2 over expression. This mechanism has been proposed as a crucial factor involved in colon carcinogenesis.12

Fig. 2 : Proposed basis that prompted a new generation of NSAIDs that selectively inhibit COX - 2

Fig. 3 : New evidence suggests that COX-1, COX-2 and perhaps a thirs isoform, COX-3, are expressed during the onset and resolution of acute inflammation.

Binary classification of COX-1 and COX-2 COX-1 protein represents as “housekeeping” protein and COX-2 as “pro-inflammatory” protein. The genes for COX-1 and COX-2 are located on human chromosome 9 and 1 respectively.5 COX-1 lacks a TATA box,5 but COX-2 contains a TATA box and binding sites for several transcriptional factors including nuclear factor-kB (NF-kB), nuclear factor for interleukin-6 (NF-IL6) and cyclic AMP (cAMP) response element binding protein (CREB). The expression of COX-2 is regulated by a broad spectrum of mediators involved in inflammation; lipopolysaccharide proinflammatory cytokines (IL-beta, TNF) and growth factors may induce COX-2, whereas glucocorticoids, IL-4, IL-13 and IL-10, inhibit the expression of this enzyme.6 Also there is emerging evidence to suggest that products of COX-2 pathway may cell dependently exert regulatory feedback actions on the expression of its biosynthesizing enzyme. A recent study using rat model of carragecnan-induced inflammation has shown that indomethacin may block COX-2 expression in the inflamed paw, implying that prostaglandins produced at the sites of inflammation may potentiate COX-2 expression via a positive feedback loop.7 In agreement with this finding, the major COX-2 product prostaglandin E2 has been shown to upregulate COX-2 expression by virtue of its cAMP elevating

Functions of COX-1 and COX-2 COX-1 mediates gastric mucosal integrity and renal and platelet function, while COX-2 is expressed after injury to contribute to inflammation and hyperalgesia (fig. 2). Conventional NSAIDs nonselectively inhibit both COX isoforms. Selective (nonacidic) COX-2 inhibitors The pharmacokinetic characteristics (slow absorption and elimination) of oral celecoxib and rofecoxib make them poor candidates for acute pain. However, following a single I.M. dose of rofecoxib, the Cmax is achieved in 0.5 hr, compared to 2-4 hrs with oral rofecoxib. They are effective for osteoarthritic pain and rheumatoid arthritis.13 These compounds interfere with water and salt excretion by the kidneys, as do standard drugs. In addition, theoretical considerations, experimental data13 and clinical evidence14 suggest that these compounds may increase the risk of cardiovascular events in patients at risk. Celecoxib has limited oral bioavailability, low potency, and relatively fast elimination in most patients (table 1), whereas rofecoxib is more potent, is almost 100% bioavailable and is excreted more slowly. Table - 1 : Pharmacokinetic characteristics of selective COX-2 inhibitors in clinical use. Drug

T max (hrs)

T 50% (hrs)

F oral ( % )

Celecoxib

2-4 P.O.

8.12

20-60

Rofecoxib

2-3 P.O.

17

100

Valdecoxib

2-3 P.O.

8

80

Parecoxib

0.5 I.V. 1.5 I.M.

0.5

-

Etoricoxib

1-1.5 P.O.

22

100

Tmax : Time to maximal plasma concentration; T50% : Terminal elimination halflife; Foral : Oral bioavailability; P.O. : Per orally

Recently it has been noted that Merck Co. has withdrawn (30.09.2004) rofecoxib from the US market in view of high incidence of MI in patients receiving continuous

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rofecoxib for 18 months in a trial for evaluating the efficacy of rofecoxib in cancer patients. More recently, valdecoxib (Bextra) has also been withdrawn because of cardiovascular complications induced by this drug. Equipotent doses of NSAIDs and selective COX-2 inhibitors Various studies suggest that rofecoxib exhibits maximal analgesic efficacy at 50 mg, comparable to ibuprofen at 400 mg but with a longer duration.15 For celecoxib, maximal analgesic efficacy at 200 mg appears comparable to that of aspirin at 650 mg but less than that of ibuprofen at 400 mg or rofecoxib at 50 mg.16 It has been proposed that celecoxib should be dosed at 400 mg. However early dose ranging studies in dental pain model suggest that dose increase of celecoxib above 200 mg up to 400 mg confer no additional analgesic benefit.16 Recent meta-analysis including 18 randomized controlled trials done on 2783 patients clearly showed that there was no significant difference between the oral COX-2Is and NSAIDs drugs except that celecoxib 200 mg was less effective than ibuprofen 400 mg and rofecoxib 50 mg.17 Pharmacokinetic characteristics of selective COX-2 inhibitors Celecoxib It is one of the first COX-2Is to be introduced for clinical use. Rate of absorption after its oral administration is moderate, with peak plasma levels occurring after 2-4 hrs; the extent of absorption is not known. It is extensively bound to plasma protein. Little is excreted unchanged; most is excreted as carboxylic acid and glucuronide metabolites in urine and feces. The elimination half life is approximately 11 hrs. Plasma concentrations are lower in patients with renal insufficiency in whom there is 47% increase in apparent clearance. Plasma concentrations are increased by apparently 40-180% in patients with mild to moderate hepatic impairment. Rofecoxib Chemically it is 4-[4-(methylsulfonyl) phenyl-] 3-phenyl-2(SH)-Furane. The empirical formula for rofecoxib is C17H14O4S1 and the molecular weight is 314.36. The chemical structure is mentioned in fig. 4. Approximately 87% of rofecoxib is bound to plasma proteins in concentrations ranging from 0.05-25 mgml-1. Following a single I.M. dose of 25 mg; the Cmax is achieved in 0.5 hrs as compared to 2-3 hrs with oral dose of 25 mg rofecoxib. Its elimination half life is 17 hrs. Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes and the principal

INDIAN JOURNAL OF ANAESTHESIA, JUNE 2005

metabolites are cis-hydro and trans-dihydro derivatives of rofecoxib.

Fig. 4 : Chemical structure of rofecoxib

Valdecoxib Chemically it is 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and chemical structure is mentioned in fig. 5. The empirical formula for valdecoxib is C16H14N2OS and molecular weight is 314.36. Valdecoxib has a very strong affinity for COX-2 receptors. The first step in COX-2 inhibition is an interaction between the inhibitor at the enzyme surface near the membrane binding region, referred to as the lobby region. The second step is translocation of the inhibitor from the lobby to the COX active site and the third step is a movement of the inhibitor within the active site, resulting in strong valdecoxib and protein residues. Valdecoxib has 90 times greater selectivity for COX-2 as compared to the 1st generation COX-2Is, rofecoxib and celecoxib, and 34,000 times greater selectivity than ketorolac. Valdecoxib can cause anaphylactoid reactions in some individuals. Also rofecoxib and celecoxib are contra-indicated in patients who have experienced asthma, urticaria or allergic-type reactions after taking sulphonamides, aspirin or other NSAIDs.

Fig. 5 : Chemical structure of Parecoxib and its active metabolite, Valdecoxib.


Parecoxib The pharmacological activity of parecoxib is primarily via its principal metabolite valdecoxib, but also by an active metabolite valdecoxib (M1) that is about 10% of the concentration of valdecoxib. Following I.V. administration of 40 mg of parecoxib to healthy adult patients, peak parecoxib plasma concentration was achieved within 2-3 minutes and then declined rapidly. The first perceptible analgesia occurs in 7-13 mins; clinically meaningful analgesia occurs in 23-39 min and peak effect occurs within 2 hrs. Parecoxib is rapidly and extensively converted to valdecoxib. The elimination half-life of the former being about 30-40 minutes and the latter about 8 hrs. Parecoxib is available in a lyophilized formulation in I.V. or I.M. use. Lyophilizatin or freeze drying is a method of removing water from various materials. The duration of action of I.V. parecoxib is 16-20 hrs. Etoricoxib : It is a novel dipyridinyl agent that selectively inhibits COX-2 (fig. 6). Its selectivity is more than 106-fold higher than other NSAIDs, compared to values of 35, 30, 7.6 and 0.4 for rofecoxib, valdecoxib, celecoxib and indomethacin respectively. Etoricoxib has elimination half life of 22 hrs after administration of single dose of 60 to 120 mg. It is administered in a doses of 60, 90 or 120 mg for the management of osteoarthritis and rheumatoid arthritis and as a therapeutic dose. The pharmacokinetics of etoricoxib in patients with moderate to severe renal insufficiency and patients with end stage renal disease on hemodialysis is not significantly different from those in healthy subjects.

Fig. 6 : Chemical structure of etoricoxib.

COX-2 and the gastrointestinal tract In the VIOXX gastrointestinal outcome research (VIGOR) study, treatment with rofecoxib at twice the approved maximal dosage for long term use resulted in significantly lower rates of clinically important upper GIT events.14 In group of patients not taking aspirin, celecoxib

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at a dosage 2-4 times greater than the maximum therapeutic dosage was associated with a significantly lower incidence of symptomatic ulcers and ulcer complications compared with NSAIDs. Although various data point towards a significantly improved risk benefit ratio of COX-2 inhibitors in terms of GIT safety as compared with traditional NSAIDs, it is noteworthy that specific COX-2 inhibitors are associated with dyspepsia, with an incidence lower than that seen with NSAIDs.18 Recent animal studies indicate that COX-2Is retard ulcer healing,19 possibly by interfering with angiogenesis.20 COX-2 and kidney functions The prevailing assumption was that COX-2 is not expressed constitutively (i.e. in basal condition), but only after tissue damage and inflammation. But recent evidence has shown that COX-2 is expressed constitutively in human kidney and central nervous system. COX-2 immunoreactivity has been observed in renal vasculature, medullary interstitial cells and macula densa.21 There is also evidence for a causal relationship between renal COX-2 expression and the renin-angiotensin system.20 Recent studies have shown that specific COX-2Is, similar to other NSAIDs, may cause peripheral edema, hypertension and exacerbation of pre-existing hypertension by inhibiting water and salt excretion by the kidneys.22,23 Moreover, in healthy elderly volunteers, specific COX-2 inhibitors decreased renal prostacyclin production and led to a significant transient decline in urinary sodium excretion.24 In brief it is advisable to use specific COX-2Is with caution in patients with fluid retention, hypertension and heart failure. COX-2 and cardiovascular system A temporal association between celecoxib treatment and ischemic complications recently was reported in four patients with connective tissue diseases who had multiple risk factors for hypercoagulability,25 implying an increased thrombogenic risk for specific COX-2Is. The celecoxib long term arthritis safety study (CLASS) trial found no difference in the incidence of cardiovascular events (CVA, MI, angina) between celecoxib and NSAIDs (ibuprofen and diclofenac).26 On the other hand, in the VIGOR study, patients receiving rofecoxib had a significant four fold increase in the incidence of MI, as compared with patients randomized to naproxen.14 But, actually speaking, 22% of patients included in the CLASS trial took aspirin as a cardioprotective agent, where as the entry criteria for the VIGOR study precluded aspirin consumption. In addition, the VIGOR study was performed on patients with rheumatoid arthritis, a condition associated with an

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enhanced rate of cardiovascular events. By contrast, the CLASS trial included patients with osteo arthritis, a condition that is not associated with an increased risk of cardiovascular complications. Hence, a possible thrombogenecity of specific COX-2Is deserves further well controlled studies. COX-2 and other body functions The enzyme COX-2 is constitutively expressed in several other organs. High concentrations are found in the hippocampus27 and in the eye.28 However, recent studies indicate that COX-2 is also expressed under physiological conditions in the ovaries, uterus, brain, spinal cord, kidney and other organs, suggesting that this isoenzyme may play a more complex physiological role than had been expected. The importance of these findings remains undefined at present. COX-2Is and hyperaemic response of skin to artery occlusion Recently Moppet et al noted that both COX-2Is and non selective NSAIDs, when given to healthy volunteers as a single therapeutic dose, decrease the skin micro vascular tone with reduction in transient hyperaemic response ratio (THRR), but do not impair maximal vasodilatory ability.29 Gilroy et al’s, investigation has been surprising as COX-2Is showed anti-inflammatory properties in the early phase as well as non selective ones did, but after 6 hrs, the selective COX-2Is were without effect while the dual COX were still effective.30 COX-2 inhibition and cancer Experimental evidence suggests that the COX pathway is involved in tumor promotion. Although the precise mechanism or mechanisms by which these drugs affect tumor progression is not completely understood, it is likely that part of their anti-tumor effect is due to inhibition of COX-2 enzyme. COX-2 derived bioactive lipid products promote tumor-associated neovascularization, inhibit cell death, and stimulate cell proliferation and motility.31 In an in-vitro study on prostate and breast cancer cell lines, significant growth inhibition was observed in a dose dependent manner after treatment with rofecoxib.32 A pilot study of celecoxib and infusional 5-fluorouracil in patients with pancreatic ductal adenocarcinoma (PDAC) showed some favorable results.33 The combination of oral celecoxib and 5-FU by protracted I.V. infusion, for a maximum of 9 treatment months, was found to be feasible and well tolerated. It was capable of inducing durable objective responses in patients with far advanced, gemcitabine-


resistant/refractory PDAC. Ongoing human clinical trials are underway to test the efficacy of COX-2 selective inhibitors in a number of human cancers. Efficacy of COX-2Is in TMJ disc displacement In a randomized controlled trial involving 68 patients with TMJ disc displacement (TMJ DD) celecoxib 100 mg BD continuously for 6 weeks was evaluated with naproxen 500 mg BD.34 Significant improvement in mandibular range of motion (ROM) was observed in naproxen group; 12.6 mm as compared to 8.2 mm in celecoxib group and 7.3 mm in placebo group. These improvements in ROM correlated well with the pain relief achieved by the patients. In this study Lauren et al concluded that inhibition of both COX-1 and 2 is needed to achieve a significant improvement in mandibular ROM and to achieve effective analgesia. COX-2Is and evidence based analgesic efficacy Most of the randomized controlled trials designed to study the analgesic efficacy of rofecoxib and celecoxib, have been found to equal that of other NSAIDs in chronic pain35,36,37 which is a matter that definitely suggests their usage as analgesics and anti-inflammatory drugs in patients at risk of GI secondary effects. Also some articles on treating post-surgical dental pain with rofecoxib and celecoxib38,39 suggest a role in the management of acute inflammatory pain. Apart from these studies in dental pain, COX-2 has been evaluated also as an opioid sparing adjuvant in spine fusion surgery suggesting that celecoxib 200 mg may not be equianalgesic to 50 mg rofecoxib.40 Various clinical studies have demonstrated that I.V. parecoxib sodium is effective in several models of post operative pain, both when administered pre operatively41 and intra operatively for relieving post operative pain following gynecologic laparotomy42 and following postorthopedic knee surgery.43 Recently Hubbard et al observed in a multicentric double blind, placebo controlled study that Parecoxib-sodium administered with morphine provided significantly greater pain relief than morphine alone at 6 hrs.44 Safety of selective COX-2Is in the treatment of chronic arthritis Currently the major indication of chronic COX-2Is use is for the treatment of arthritic pain, although early studies suggest promise for the prevention of colorectal cancer and Alzheimer’s disease. COX-2Is are evidently safer than traditional NSAIDs with respect to GIT ulceration and bleeding, but not renal dysfunction and furthermore, COX-2Is may confer increased risk for cardiovascular


events.14 COX-2Is can cause sodium retention and decreased GFR.45 GIT safety data comes largely from two studies, VIGOR trial14 and CLASS study.26 In the VIGOR trial, rofecoxib was shown to cause a significantly lower incidence of upper GIT perforation, ulceration and bleeding as compared to naproxen, but rofecoxib caused a four-fold increase in the incidence of myocardial infarction compared to naproxen. In the CLASS study, there was no difference in GIT toxicity between celecoxib and traditional NSAIDs across patients who were also taking low-dose aspirin. It was suggested that aspirin’s GIT risks eliminated celecoxib’s benefits. It has been suggested that COX-2Is cause an increased risk of thrombotic cardiovascular events as they may unfavorably alter the thromboxane prostacyclin balance by inhibiting the vasoprotective prostacyclin but not the procoagulant thromboxane (thromboxane A2).45,14 The potential for CVS toxicity should be considered when using COX-2Is in patients at risk for coronary artery disease. Further concerns regarding potential CVS effects of COX-2Is are raised by a recent study in hypertensive patients with osteoarthritis demonstrating that rofecoxib, but not the NSAID namebutone, increased nocturnal blood pressure.46 COX-2 selective inhibitors are (slightly) more efficacious than acetaminophen has been demonstrated in osteoarthritis in only one trial.47 General data from double-blind randomised controlled trials (RCTs) involving 14 RCTs that included 11,008 OA or RA patients treated upto 24 weeks, indicated annual ulcer complication incidence of 0.2% for celecoxib versus 1.68% (8 fold higher) for the non selective NSAID study group.48 The potential cost saving advantage of using COX-2Is would lay mainly in the cost saving prevention of GIT complications. In a recent evaluation of use of selective as well as non selective COX-2Is, in patients with osteoarthritis and rheumatoid arthritis over a continuous period of 1 year, Etoricoxib was found to be cost saving as compared with non selective NSAIDs plus proton pump inhibitors or non selective NSAIDs plus misoprostol.49 Perioperative clinical trials of COX-2Is Cochrane and MEDLINE database search till February 2003 for perioperative clinical trials of COX-2Is yielded a total of 27 publications of COX-2I trials, one of which described 6 trials,50 for a total of 32 controlled trials. These included 25 single dose and 7 multidose trials of rofecoxib (19),40,47,50-58 celecoxib (6),59-62 parecoxib (5),41-43,63,64 valdecoxib (3)65-67 and nimesulide (1)68 and meloxicam (1).69 Surgical procedures included oral surgery, gynaecologic surgery, prostatectomy, lumbar discectomy, spinal fusion and joint arthroplasty.

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Analgesic efficacy Of the 19 rofecoxib trials, 17 showed superior efficacy of rofecoxib to placebo, whereas 2 trials showed no difference.51,52 Five of 6 celecoxib trials showed superiority to placebo, and 1 showed no difference. Parecoxib (the parenteral produrg of valdecoxib), valdecoxib, nimesulide and meloxicam were found to be superior to placebo in all reported trials. A recent meta-analysis of 5 rofecoxib trials that investigated 1,118 patients (of whom 211 received placebo and 464 received 50 mg rofecoxib) reported a number needed to treat of 2.3.69 Three trials compared COX-2Is to each other, two of which showed that rofecoxib is more efficacious than celecoxib.39,40 It has also been shown that 50 mg rofecoxib given 1 hr preoperatively was more effective at reducing postoperative pain than the same dose given 15 min postoperatively, suggesting that as with traditional NSAIDs, COX-2Is may have preemptive analgesic effects.40 In a randomized, double blind, controlled trial, patients experiencing moderate or severe pain received single dose valdecoxib 40 mg, rofecoxib 50 mg or placebo within 4 hours after multiple third molar extraction with bone removal.71 Onset of action was significantly faster with valdecoxib (30 min) compared with rofecoxib (45 min). However both provided a similar magnitude of analgesic effect. In another study, 60 patients undergoing total abdominal hysterectomy were randomized to receive either placebo or rofecoxib 50 mg orally 1 hr prior to surgery. It was found that rofecoxib significantly decreased the total and incremental tramadol consumption via the PCA-device in the post-operative period.72 Rofecoxib 50 mg, given before and after surgery, per orally, has also been shown to improve postoperative pain management, as well as speed and quality of recovery after outpatient inguinal herniorrhaphy.73 The effects of rofecoxib were examined on the effort dependent pain, postoperative morphine requirements and pulmonary function in 48 patients recovering from open abdominal surgery. The authors found that patients treated with rofecoxib before the surgery required less I.V. morphine during the first day of recovery. These patients also reported lower pain intensity scores at rest and after vigorous cough. Improvements in pain control correlated with greater preservation of baseline cough effectiveness (vital capacity) at 12 h thus showing that COX-2Is may offer clinical advantages in patients with preexisting pulmonary disease.74 In a recent multicentric, double-blinded, randomized, placebo-controlled study the analgesic and opioid sparing efficacy of a single preoperative dose of I.V. parecoxib 40 mg followed by oral valdecoxib, 40 mg QD in the

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postoperative period, in treating pain associated with elective laparoscopic cholecystectomy was evaluated. Parecoxib was found to be a valuable opioid sparing (in this case fentanyl) adjunct to the standard of care for treating pain after the surgery and subsequent treatment with oral valdecoxib extended this clinical benefit.75 However, in another study comparing the effects of ketorolac and parecoxib on early postoperative pain in patients undergoing laparoscopic sterilization, the pain scores at rest and on deep inspiration were significantly lower in patients given ketorolac compared with those given parecoxib.76 Post-operative analgesic dose response studies In orthopedic surgeries, daily dose of rofecoxib 50 mg but not 25 mg results in significantly less consumption of supplemental analgesic medication.54 In the parecoxib trial, 40 mg IV is more efficacious than 20 mg, but indistinguishable from 80 mg.41 A recent study of valdecoxib revealed dose-dependent analgesia between 10 and 40 mg, but no difference between 40 and 80 mg, suggesting an analgesic ceiling also for valdecoxib.67 In summary, various data suggest that COX-2Is, at least in the case of rofecoxib, parecoxib, and valdecoxib, have a postoperative analgesic dosage ceiling similar to that of traditional NSAIDs. Safety of COX-2Is in the postoperative setting In two trials, a significantly greater incidence of post dental extraction alveolitis (“dry socket”) was observed with 50 mg oral rofecoxib as compared to placebo.50 None of the trials reported any difference in blood loss between the studied COX-2Is and placebo. Single isolated cases of celecoxib induced oliguria,77 and rofecoxib induced aseptic meningitis after brief postoperative use have been recently reported.78 Side-effect profiles from postoperative COX-2Is trials Adverse effects like headache, nausea, vomiting, dizziness and postdental extraction alveolitis have been reported with COX-2Is (rofecoxib, parecoxib and valdecoxib) COX-2Is may cause peripheral oedema and hypertension, by inhibiting water and salt excretion by the kidneys.41,43,56,63,65,66,79 Treatment with valdecoxib and rofecoxib should be initiated with caution in patients with mild to moderate hepatic impairment and fluid retention. Both of them are not recommended in patients with severe hepatic impairment (Child Pugh class C) and advanced renal disease. Contraindications of COX-2Is COX-2Is have not yet been proven to be safe in children less than 12 yrs of age. Hence their use is presently


not recommended in pediatric age group. Similarly their use is not recommended in 3rd trimester of pregnancy and during lactation. Their use is also contra indicated in severe renal and hepatic impairment (Child Pugh score >9). Patients allergic to sulphonamides should not be given valdecoxib and parecoxib as they also have sulphonamide moity in their molecular structure. Etoricoxib is the drug of choice in these patients. Concomitant therapy No interactions have been reported on rofecoxib with aspirin, heparin and I.V. propofol and midazolam and oral anticoagulants. Coadministration of valdecoxib with warfarin causes a significant increase in plasma exposures of R-warfarin and S-warfarin. Co-administration of fluconazole and ketoconazole enhances the total plasma exposure of valdecoxib. NSAIDs may diminish the antihypertensive effect of ACE inhibitors.14 This interaction should be given consideration in patients taking valdecoxib or rofecoxib concomitantly with ACE inhibitors. They should be used with caution in patients with fluid retention, hypertension or heart failure. Because of their lack of antiplatelet effect, valdecoxib or rofecoxib are not a substitute for aspirin for cardiovascular prophylaxis. Potential source of bias in trials of COX-2Is Although subjected to many recognized influences, the patient pain report is the end point of analgesic studies. But to correctly interpret the analgesic efficacy studies and their relevance to the pain, we have to recognize (unfortunately frequent) potential source of bias as: 1.

The compared doses need to be equianalgesic.

2.

Even though we may be applying the correct method of study design for analgesic efficacy (i.e. double blinded RCTs), we must remember that we are observing the analgesic effect of various mechanisms (COX mediated and others?) that may not be common to all NSAIDs.

3.

As we may have seen in the experimental models, the mechanisms may render different responses depending on the observation time, and probably also depending on the type of inflammatory process (differences in experimental models as well as acute versus chronic pain?), meaning that we may have been mixing data as “oranges and apples”, and finally,

4.

A statistical significance does not necessarily mean a significant difference in the pain clinic. If we accept these statements, we should be cautious in generalizing conclusions of analgesia effectiveness from one patient pain syndrome model to others.


Conclusion Various clinical trials support the hypothesis that specific COX-2Is may provide a significantly improved risk-benefit ratio in terms of GIT safety as compared with conventional (acidic) NSAIDs. Hence specific COX-2Is may be preferred over traditional NSAIDs in patients at increased risk of serious upper GIT complications. These patients include individuals more than 60 yrs old, those with a history of peptic ulcer disease and those taking glucocorticoids (with NSAIDs) and anti-coagulants. COX-2 enzyme appears to be short lived and is diversely regulated in different cell and organ systems at different periods of life. The clinical bottom line is that beyond no further gain in the analgesic efficacy with this selectivity, there is yet no justification for an indiscriminate prescription of these newly discovered class of drugs as “general pain killers”. Specifically mentioning, well controlled studies are needed to define the clinical utility of specific COX-2Is in patients at risk of renal disease, hypertension or chronic heart failure. Possible effects of specific COX-2Is on reproductive functions, endothelial functions and wound healing need to be evaluated in forthcoming clinical trials. More recent data does in fact support a role for COX-2 in bone healing and clinical investigation is needed to address this problem. On the other hand, the available COX-2 selective inhibitors do not compare favorably with the old non acidic anti-pyretic analgesics such as acetaminophen and propoxyphenazone. Comparisons with phenazone or its derivatives as well as with acetaminophen in other pain states are lacking. Current evidence published to date does not suggest that COX-2Is provide a major advantage over traditional NSAIDs. We still have to prove that coxibs may be called “super aspirins” in the popular press. Cardiovascular risks of COX-2Is remains controversial, and more recent evidence suggests that rofecoxib and valdecoxib are notorious for causing increasing number of reports of rise in the incidence of MI following prolonged use in cancer trial patients and since then have been withdrawn from the market by the respective pharmaceutical companies. As regards parecoxib and etoricoxib, additional data from larger, multicenter, multidose comparative trials could determine whether individual COX-2Is are more efficacious, cost-effective, and/or safe versus non selective NSAIDs with respect to gastric, renal, coagulation and cardiovascular problems, and may be that until then, cost-benefit considerations will likely guide COX-2Is in the postoperative setting and chronic pain management.

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