Management of acute pain
There is clearly a need to improve pain management services worldwide. The introduction of comprehensive pain management services that include improved assessment of postoperative pain, increasing education and awareness among healthcare personnel and patients alike, and the implementation of new technology and therapeutic agents will help combat the problem of the undermanagement of pain. The benefits of effective pain management are numerous. Improving patient pain relief, comfort and satisfaction is clearly the primary objective of such services. There are, however, other benefits. Improved pain relief can result in a reduction of side-effects in postoperative patients, thereby reducing the burden on nursing staff in postsurgical wards. Earlier patient mobilisation and discharge from hospital can also be a byproduct of improved pain management and a reduction in postoperative side-effects. Such fiscal benefits, while secondary to improved patient care, are nonetheless important.
Current treatment for acute pain, in particular postoperative pain, is dominated by opioids and conventional non-steroidal anti-inflammatory drugs (NSAIDs). As has been described, both classes of drug are effective analgesics, but are associated with a wide range of side-effects. Thus, there is a need for new drugs that combine good analgesic efficacy and improved safety.
In recent years, COX-2-selective inhibitors, which provide equivalent efficacy to conventional NSAIDs but have significantly improved platelet and gastrointestinal safety profiles, have been introduced [1,2]. COX-2-selective inhibitors have distinct structural differences from conventional NSAIDs that allow them to bind selectively to COX-2 at therapeutic doses. COX-2 is upregulated in the periphery and in the CNS in response to inflammatory stimuli and tissue damage, and is a key mediator of prostaglandin reduction in pain pathways. In contrast, there is no experimental evidence that COX-1 is involved in inflammatory responses, whereas this isoform is involved in platelet homeostasis and the protection of gastric mucosa. Thus, the COX-1-sparing nature of COX-2-selective inhibitors means that they have analgesic and anti-inflammatory effects without causing inhibition of platelet function or gastrointestinal ulceration, perforation or bleeding.
Clinical experience with COX-2-selective inhibitors
Clinical trials involving COX-2-selective inhibitors such as celecoxib and rofecoxib have confirmed the analgesic efficacy and improved platelet and gastrointestinal safety predicted by their selective inhibition of COX-2 [2,3]. These are currently available for the treatment of the signs and symptoms of OA and RA and are effective in treating pain. However, these agents are available only as oral formulations. Oral medication is often contraindicated in surgical patients, and many postoperative patients cannot tolerate oral medication in the first 24-48 h following surgery. Thus, there is a requirement for injectable COX-2-selective inhibitors that can be administered intravenously or intramuscularly.
Parecoxib sodium is an injectable prodrug of the novel COX-2-selective inhibitor valdecoxib. As one might expect of an injectable formulation, parecoxib sodium has a rapid onset of action equivalent to the parenteral conventional NSAID, ketorolac. Furthermore, parecoxib provides pain relief in a variety of surgical models that is similar to ketorolac [4,5]. In addition to its significant efficacy in managing acute postoperative pain, parecoxib sodium also demonstrates improved platelet and GI safety [6-8]. Platelet aggregation responses and bleeding time following treatment with parecoxib are not significantly different from placebo in healthy adults and healthy elderly adults. In contrast, data from the same study demonstrated that treatment with the active comparator ketorolac resulted in almost 100% inhibition of platelet aggregation and significantly prolonged bleeding times compared with both placebo and parecoxib sodium . Similarly, no gastrointestinal ulceration was observed in response to either placebo or parecoxib sodium in healthy elderly adults, whereas ketorolac treatment resulted in development of gastroduodenal ulcers in 23% of subjects after 5 days of treatment [6,7].
The efficacy and significantly improved safety profile of parecoxib sodium compared with conventional NSAIDs has distinct clinical implications when managing pain in surgical patients.
Multimodal therapy is being used more frequently as a means of improving patient analgesia following surgery, while reducing adverse effects, particularly opioid-related side-effects. However, this approach introduces the potential for increasing the range of side-effects that patients experience. Conventional NSAIDs, which are commonly used as part of multimodal treatment strategies to reduce opioid consumption, cause bleeding complications due to inhibition of platelet function and serious gastrointestinal effects . Serious gastrointestinal effects can arise even with short-term use of NSAIDs. It is recommended that ketorolac use, the only injectable NSAID available in the USA, be limited to ≤5 days to avoid such complications . Thus, while the premise of multimodal therapy is good, there is a requirement for non-opioid agents with good analgesic efficacy and an improved safety profile that could be applied to such treatment strategies. COX-2-selective inhibitors such as parecoxib sodium have improved platelet and upper gastrointestinal safety compared with conventional NSAIDs while maintaining a similar efficacy in the management of acute pain [4-6,8]. Therefore, the use of parecoxib sodium could provide anaesthesiologists with an alternative therapeutic option as part of a multimodal treatment strategy to reduce opioid consumption, improve patient pain relief and reduce opioid-related side-effects.
Preoperative administration of parecoxib sodium
COX-2 expression is induced peripherally and centrally in response to tissue damage and inflammation [11,12]. High concentrations of COX-2 and PGE2 have been demonstrated in tissue surrounding the sites of surgical incisions . Currently, administration of conventional NSAIDs such as ketorolac and diclofenac, either pre- or intraoperatively, is precluded because of the risk of bleeding complications, which are already high in a surgical patient population. As COX-2-selective inhibitors such as parecoxib sodium are not associated with such bleeding risks, they potentially could be administered before surgery without such complications. Moreover, the availability of an injectable formulation of a COX-2 inhibitor allows a flexibility of administration. Therefore, it can be administered to patients earlier, before the effects of anaesthesia have worn off or before they would be able to tolerate oral medication. Thus, rather than delaying analgesia due to concerns over safety or formulation and allowing an accumulation of COX-2 and prostaglandin in their peripheral tissues and the CNS, patients could receive uninterrupted analgesia, maintaining a high level of inhibitor in their blood stream before and throughout surgery and during the postoperative recovery period.
1. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol
1999; 26 (Suppl 56):
2. Schnitzer TJ, Truitt K, Fleischmann RM, et al.
The safety profile, tolerability and effective dose range of rofecoxb in the treatment of rheumatoid arthritis. Phase II rofecoxib rheumatoid arthritis study group. Clin Ther
3. Emery P, Zeidler H, Kvien TK, et al.
Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: a randomised double-blind comparison. Lancet
4. Rasmussen GL, Steckner K, Hogue C, et al.
Intravenous parecoxib sodium for acute pain after postorthopedic knee surgery. Am J Orthop
5. Barton SF, Langeland FF, Snabes MC, et al.
Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following orthopedic surgery. Anesthesiology
6. Harris S, Kuss M, Hubbard RC, et al.
Upper gastrointestinal tolerability evaluation of parecoxib sodium, a new parenteral COX-2 specific inhibitor, as compared to ketorolac, naproxen or placebo. Clin Ther
7. Stoltz R, Harris S, Kuss M, et al.
Upper gastrointestinal safety of parecoxib sodium in the elderly. Am J Gastroenterol
8. Noveck RJ, Laurent A, Kuss M, et al.
The COX-2 specific inhibitor, parecoxib sodium, does not impair platelet function in healthy elderly and nonelderly subjects: two randomized, controlled trials. Clin Drug Invest
9. Verburg KM, Maziasz TJ, Weiner E, et al.
COX-2-specific inhibitors: definition of a new therapeutic concept. Am J Ther
10. Syntex Laboratories I. Ketorolac prescribing information. Nutley, USA. Roche.
11. Hay CH, Trevethick MA, Wheeldon A, et al.
The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience
12. Seibert K, Zhang Y, Leahy K, et al.
Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain. Proc Natl Acad Sci USA
13. Roszkowski MT, Swift JQ, Hargreaves KM. Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S
)-flurbiprofen following extraction of impacted third molars. Pain