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- Frampton, J.E. & Keating, G.M. Drugs (2007) 67: 2433. doi:10.2165/00003495-200767160-00008
Celecoxib (Celebrex®), the first cyclo-oxygenase (COX) 2-selective inhibitor (coxib) to be introduced into clinical practice, has been available for almost a decade. It is approved in one or more countries worldwide for the relief of the signs and symptoms of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (in patients aged ≥2 years) and ankylosing spondylitis (AS), the management of acute pain in adults, the treatment of primary dysmenorrhoea and the reduction in the number of adenomatous colorectal polyps in familial adenomatous polyposis.
Celecoxib remains an effective and useful altenative to nonselective NSAIDs in the treatment of acute or chronic musculoskeletal pain. In the latter setting, it offers the prospect of improved gastrointestinal (GI) tolerability and, in patients not taking aspirin for cardioprophylaxis, a GI safety advantage. Currently available evidence of an increase in cardiovascular (CV) risk with celecoxib is inconsistent; any increase in risk is likely to be small and similar to that with nonselective NSAIDs. As with all NSAIDs, the potential GI, CV and renal risks of celecoxib must be weighed against the potential benefits in each individual; it is a rational choice for patients at low CV risk who require NSAID therapy, especially those at increased risk of NSAID-induced GI toxicity, but also those unresponsive to, or intolerant of, other NSAIDs. If selected, celecoxib, like all NSAIDs, should be used at the lowest effective dose for the shortest possible duration.
Celecoxib is 30 times more potent at inhibiting COX-2 than COX-1; the analgesic and anti-inflammatory effects of therapeutic dosages of the drug are mediated through COX-2 inhibition. Celecoxib has no effect on platelet function in healthy volunteers; it has qualitatively, if not quantitatively, similar effects on the kidney compared with nonselective NSAIDs.
Celecoxib demonstrates approximate dose-proportionality over the therapeutic dosage range (up to 200mg twice daily). Peak plasma concentrations are attained within 3 hours of an oral dose; steady-state plasma concentrations are achieved within 5 days. Celecoxib is extensively metabolised by the hepatic cytochrome P450 2C9 isoenzyme into inactive metabolites, which are excreted in the urine and faeces. The daily dosage should be reduced by 50% in patients with moderate (Child-Pugh class B) hepatic impairment. Celecoxib has demonstrated potentially significant drug interactions with fluconazole and lithium.
In clinical trials of up to 26 weeks’ duration, celecoxib at dosages between 200 and 800 mg/day was at least as effective as paracetamol (acetaminophen) 4 g/day in treating the signs and symptoms of OA, was generally as effective as, or noninferior to, standard dosages of nonselective NSAIDs (e.g. naproxen, diclofenac, ketoprofen and ibuprofen) in the treatment of OA, RA or AS, and was as effective as other COX-2-selective inhibitors (etoricoxib 30 mg/day and lumiracoxib 100–400 mg/day) in the treatment of OA. Unlike glucosamine 1500 mg/day and/or chondroitin sulfate 1200 mg/day, celecoxib 200 mg/day was significantly more effective than placebo in relieving pain associated with OA of the knee.
Celecoxib was generally similar to nonselective NSAIDs in improving overall health-related quality of life (HR-QOL) in patients with OA or RA flare. However, it demonstrated superiority over paracetamol and nonselective NSAIDs in OA studies assessing patient preference and satisfaction, respectively. Acute pain was significantly reduced within 1–2 days of starting treatment (OA flare); significant responses relative to placebo were apparent within 1 week (AS) or 2 weeks (OA or RA flare) of starting treatment. Continuous, but not on-demand, use of NSAIDs (primarily celecoxib) reduced radiographic progression in a 2-year open-label comparison of these treatment strategies in patients with AS.
The analgesic efficacy of celecoxib 400mg in the postoperative dental pain model was superior to that of placebo and generally similar to that of ibuprofen 400mg. Celecoxib 200mg was at least as effective as hydrocodone/paracetamol 10mg/1000mg after uncomplicated orthopaedic surgery. Perioperative or postoperative administration of celecoxib (400mg followed by 200mg as required or 200mg twice daily) to patients undergoing arthroscopic knee surgery, spinal fusion surgery, laparoscopy or anterior cruciate ligament reconstruction surgery resulted in a significant reduction in postoperative opioid use and/or pain scores relative to placebo.
Celecoxib 400 mg/day was superior to placebo and at least as effective as, or noninferior to, standard dosages of nonselective NSAIDs in the treatment of acute, painful musculoskeletal conditions, namely ankle sprain, lower back pain and shoulder strain/pain.
Gastrointestinal Tolerability and Safety
In large-scale GI clinical outcomes studies (SUCCESS-1 and CLASS), the upper GI tolerability of celecoxib ≤800 mg/day was superior to that of nonselective NSAIDs (naproxen, diclofenac and ibuprofen) in terms of the incidence of individual GI symptoms (abdominal pain, dyspepsia and nausea) and the incidence of symptomatic plus complicated ulcers combined. With regard to the incidence of complicated ulcers alone, a therapeutic dosage of celecoxib 200 or 400 mg/day was superior to nonselective NSAIDs at 12 weeks in SUCCESS-1, whereas a supratherapeutic dosage of celecoxib 800 mg/day was not superior to nonselective NSAIDs, either at 6 or 12–15 months in CLASS. The CLASS results may, however, have been subject to confounding factors, including the higher than anticipated level of concomitant low-dose aspirin use and, beyond 6 months, the higher rate of withdrawal of high GI risk patients (i.e. those with symptomatic ulcers) from the combined nonselective NSAID comparator group. Consistent with this, the annualised incidence of complicated ulcers in the subgroup of patients not taking aspirin was significantly reduced with celecoxib at 6 months, but not at 15 months.
In randomised studies in very high GI risk patients with a recent history of ulcer bleeding, the incidence of recurrent bleeding with celecoxib alone was similar to that with a nonselective NSAID plus a proton-pump inhibitor (PPI), but greater than that with celecoxib combined with a PPI.
Cardiovascular Adverse Event Profile
Currently available evidence of an increased CV risk with celecoxib is inconsistent; any increase in risk is likely to be small and similar to that with nonselective NSAIDs. Specifically, celecoxib 400 mg/day was associated with an increase in long-term CV risk in one placebo-controlled study (APC), but not in two other, similar trials (ADAPT, PreSAP). Similarly, whereas celecoxib 400–800 mg/day was associated with an increase in CV risk based on pooled data from APC and PreSAP, celecoxib at dosages ranging from 200 to 800 mg/day was, in general, not associated with an increase in short- or long-term CV risk relative to placebo and/or nonselective NSAIDs in larger meta-analyses of randomised clinical trials. Consistent with the bulk of the randomised data, numerous observational studies (and meta-analyses) suggest that celecoxib, unlike rofecoxib, does not increase the risk of CV events relative to that associated with the use or non-use of nonselective NSAIDs.
The renovascular tolerability of celecoxib at therapeutic and supratherapeutic dosages was at least as good as that of nonselective NSAIDs; clinically significant blood pressure elevation and/or oedema occurred less frequently with celecoxib (at a low therapeutic dosage) than with rofecoxib (at a high therapeutic dosage).