In the clinical development of analgesics, the first step is to demonstrate that they take away pain. This can only be done by testing them in people with established moderate or severe pain, and experience has shown that this must be clinical, rather than experimentally‐induced, pain. To show that the analgesic is working it is necessary to use placebo (McQuay 2005). There are clear ethical considerations in doing this. These ethical considerations are answered by using acute pain situations where the pain is expected to go away, and by providing additional analgesia, also called rescue analgesia, if the pain has not diminished after about an hour. This is fair, because not all participants given an analgesic will have significant pain relief, and about 18% of participants given placebo will have significant pain relief (Moore 2006).

The demonstration that a drug is an analgesic after a single dose in an acute pain situation is important. In itself, such demonstration does not determine the utility of the tested drug in any particular situation. However, because drugs that work well in one pain condition generally work well in others, with a similar relative efficacy, acute pain trials provide useful information relevant to many other pain conditions. Knowing the relative efficacy of different analgesic drugs at various doses can be helpful. An example is the relative efficacy in the third molar extraction pain model (Barden 2004).

Clinical trials measuring the efficacy of analgesics in acute pain have been standardised over many years. Trials have to be randomised and double blind. Typically, in the first few hours or days after an operation, patients develop pain that is moderate to severe in intensity, and will then be given the test analgesic or placebo. Pain is measured using standard pain intensity or pain relief scales immediately before the intervention, over the following four to six hours for shorter acting drugs, and up to 12 or 24 hours for longer acting drugs. Pain relief of half the maximum possible pain relief or better (at least 50% pain relief) is typically regarded as a clinically useful outcome. Patients with inadequate pain relief after 60 to 120 minutes are given rescue medication. For these patients it is usual for no additional pain measurements to be made, and for all subsequent measures to be recorded as initial pain intensity or baseline (zero) pain relief (baseline observation carried forward). This process ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention. In some trials the last observation is carried forward, which gives an inflated response for the test intervention compared to placebo, but the effect has been shown to be negligible over four to six hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first six hours following the intervention, with measurements supervised, although they may then be allowed home to make their own measurements in trials of longer duration.

Acute postoperative pain is a manifestation of inflammation due to tissue injury. The management of postoperative pain and inflammation is a critical component of patient care. Clinicians prescribe non‐steroidal anti‐inflammatory drugs (NSAIDs) to their patients on a routine basis for various types of mild‐to‐moderate pain. NSAIDs are the most commonly prescribed analgesic medications worldwide, and their efficacy for treating acute pain has been well demonstrated (Moore 2003). They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins and thromboxane A2 (FitzGerald 2001). Prostaglandins mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive processes. However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cyclooxygenase‐dependent prostanoid formation (Hawkey 1999).

Cyclooxygenase (COX) activity has been found to be associated with at least two distinct isoenzymes: COX‐1 and COX‐2. COX‐1 was hypothesized to be involved in the maintenance of physiologic functions such as gastric protection and haemostasis; COX‐2 was thought to be involved in pathophysiologic processes such as inflammation, pain and fever. These hypotheses led to the development of the selective COX‐2 inhibitors, such as celecoxib, rofecoxib and etoricoxib. These agents have analgesic efficacy comparable with conventional NSAIDs. In addition, they have no anti‐platelet activity at therapeutic doses, and therefore may be associated with reduced gastrointestinal adverse effects compared with conventional NSAIDs such as ibuprofen. Concerns about cardiovascular safety in long term use have led to the withdrawal of rofecoxib, and in some countries lumiracoxib.

The most common route for postoperative analgesia is oral, but when patients are unable to swallow, for instance perioperatively, parenteral administration (e.g., intramuscular, intravenous, intrathecal) may be preferred. Some NSAIDs can be administered intramuscularly (e.g., diclofenac, ketoprofen and ketorolac) but this route can be painful in itself. Diclofenac and ketorolac can be administered intravenously, but ketorolac is contraindicated for patients receiving heparin and those who might be susceptible to bleeding from gastrointestinal ulcers or who have renal impairment.

Parecoxib is the first COX‐2 that can be administered parenterally. It is a prodrug (the parent drug is inactive) that is rapidly hydrolysed in vivo to its active form, valdecoxib. Clinical trials have indicated that parecoxib is effective in treating postoperative pain resulting from oral surgery, orthopedic surgery and abdominal hysterectomy pain (Barden 2003). Other studies have demonstrated no significant effects on platelet function or upper gastrointestinal mucosa (Graff 2007; Harris 2004; Noveck 2001; Stoltz 2002). As a result, parecoxib sodium has been approved in European countries for the treatment of postoperative pain. In the UK, for example, parecoxib 20 mg or 40 mg powder (and solvent for solution for injection) is licensed for the short‐term treatment of postoperative pain.

In 2002 concerns were raised about the potential for serious adverse effects from parecoxib because of reactions experienced by some patients to valdecoxib, the active metabolite of parecoxib sodium. These effects included anaphylaxis, angioedema, and serious skin reactions such as toxic epidermal necrolysis (EMEA 2002), and led to withdrawal of valdecoxib in 2005. As a result, parecoxib is contraindicated in patients who have a history of sensitivity to sulphonamides (a type of antibiotic used to treat infections) because of the risk of severe adverse effects.

A previously published systematic review (Barden 2003) assessed the evidence for the effectiveness of parecoxib for treating postoperative pain from four randomised controlled trials (620 participants) and concluded that parecoxib is an effective analgesic in the postoperative setting. Since then, new studies have been published, and it is hoped that they will provide additional data for more robust estimates of the benefits and harms of parecoxib.

This review is one of a series of reviews examining the efficacy (and to some extent safety) of single doses of oral analgesics in typical acute pain situations. The studies will have been performed principally for registration purposes, to demonstrate analgesia rather than to show how best to control postoperative pain. Trials will typically be of short in duration, rarely over 12 hours, and the numbers will be small, so that no reliable conclusions can be drawn about safety. The aim of this series of reviews is to present evidence for relative analgesic efficacy through indirect comparisons, with placebo, in very similar trials performed in a standard manner, with very similar outcomes, and over the same duration. Such relative analgesic efficacy does not in itself determine choice of drug for any situation or patient, but guides policy‐making at the local level.

Recent reviews include Lumiracoxib (Roy 2007) and Celecoxib (Derry 2008), and will include updates of existing reviews like Ibuprofen (Collins 2002) and Aspirin (Edwards 2000).