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Do Cox-2 inhibitors have the potential to improve postoperative pain control?

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Margaret M. Dunham, BA (Hons), MSc, RN.

Lecturer in Nursing and Pain Management, School of Nursing and Midwifery, University of Sheffield, Northern General Hospital, Sheffield

Pain management strategies have traditionally relied on the use of opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen), as well as other adjuvant analgesics. However, the limitations of their use, combined with potential major side-effects, has left many patients without reliable effective treatment.

Pain management strategies have traditionally relied on the use of opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen), as well as other adjuvant analgesics. However, the limitations of their use, combined with potential major side-effects, has left many patients without reliable effective treatment.

Advances in the understanding of pain and its pathophysiology have led to the development of innovative therapeutic options. Cyclo-oxygenase inhibitors (Cox-2) are now well-established in the treatment of chronic arthritic pain, with their therapeutic effects comparable to that of non-steroidal anti-inflammatory drugs, without the degree of gastrointestinal complications commonly attributed to NSAIDs.

Cox-2 inhibitors have been found to be effective in managing acute pain in a range of clinical settings, including orthopaedic surgery, gynaecology and dental surgery. The superior safety profile of Cox-2 inhibitors in conjunction with a comparable efficacy to non-selective NSAIDs supports the inclusion of Cox-2 inhibitors in pain management guidelines and protocols.

NSAIDs
NSAIDs are a large group of drugs with common pharmacological properties: they inhibit cyclo-oxygenase (Cox). This inhibition interferes with the production of prostaglandins, which are responsible for the mediation of inflammation and pain. They come in different formulations and may be found as oral preparations, topical formulations, rectal or parenteral forms. They generally have analgesic, anti-inflammatory and antipyretic effects.

NSAIDs block nociceptor transduction, reduce pain and inflammation, and are opioid sparing (Sinatra, 2002). They are generally classified as either Cox-1 or Cox-2, on the basis of their relative ability to inhibit either.

NSAIDs are effective for short-term symptomatic relief of acute pain problems. Most have similar effectiveness, but harmful side-effects are common. These include gastrointestinal, heart and renal side-effects, which may be dose dependent. The Table (page 34) provides a summary of commonly used NSAIDs.

NSAID morbidity and mortality
NSAIDs may cause gastrointestinal problems, dyspepsia and bleeding. In 1999, the NHS costs of dealing with their side-effects were estimated at £251 million, and half of all antacid prescriptions were for NSAID-related problems (Moore and Phillips, 1999). All NSAIDs cause salt and water retention, which may result in oedema. They inhibit the desired effect of diuretics (to prompt urination and the excretion of fluid to regulate fluid balance). Those aged over 80 are particularly prone to many of the side-effects and contraindications of NSAIDs (van Walraven et al, 2000).

Cox-2s
The new Cox-2 drugs or coxibs (which selectively target the cyclo-oxygenase-2 enzyme) have been derived from NSAIDs but appear to exhibit fewer gastric irritant effects. However, they still have the general side-effects profile of the NSAID - that is, their use carries the risk of cardiac and renal dysfunction (Chang et al, 2001). Both NSAIDs and coxibs can cause chronic heart failure and hypertension. The combination of low-dose aspirin and coxibs can reduce the gastrointestinal benefit of coxibs, and the cardiac-protective dose of aspirin taken by many is severely diminished in the presence of NSAIDs.

One study noted a 40% rise in NSAID use, thought to be due to increased use of Cox-2 inhibitors, which was accompanied by a 10% increase in upper gastrointestinal haemorrhage (Mamdani et al, 2004a). Studies suggest a lower risk of upper gastrointestinal haemorrhage for Cox-2 inhibitors compared with non-selective NSAIDs, but the former may still cause gastrointestinal toxicity. The widespread increase in use of Cox-2 inhibitors might lead to an increase in the overall number of people exposed to anti-inflammatory drugs with uncertain implications on rates of population-wide gastrointestinal problems.

NICE recommendations
National Institute for Clinical Excellence guidance (2001) excludes the routine use of Cox-2 inhibitors for rheumatoid arthritis and osteoarthritis because there are other suitable first-line medications. NICE recommends the use of Cox-2s only in patients at high risk of developing serious gastrointestinal problems.

In one study of 27 patients aged under 65 years, seven (25.93%) were incorrectly prescribed Cox-2 drugs in contravention of NICE guidelines (Dindyal, 2004).

The effects of NSAIDs on bone healing have also been questioned. For example, prostaglandins, which play an important role in bone repair and normal homeostasis, are released as part of the inflammatory response and synthesised from arachidonic acid by Cox-1 and Cox-2 enzymes. However, some animal studies (Gerstenfeld and Einhorn, 2004) indicate that Cox inhibitors may impair fracture healing, raising questions about their safety for short-term use, particularly in patients who have had orthopaedic surgery.

In view of these findings, it is imperative to make a thorough assessment of a patient's history and medical status before prescribing any NSAID or coxib medications.

Cox-2s: the future
Despite the side-effects and drawbacks of using any kind of NSAID, research has produced some valuable insights into the effects and potential benefits of the Cox-2 group of drugs.

Neurogenic pain

Ghilardi et al's (2004) research with animals led them to conclude that Cox-2 inhibitors represent an important advance in pain management. Although the mechanism is not fully understood, these inhibitors exert some anti-hyperalgesic actions.

The research appears to demonstrate that inhibition of spinal Cox-2 reduces the activation of primary afferent neurons, spinal neurons and the mechanical and thermal hyperalgesia that normally occurs after peripheral tissue injury. Ghilardi et al's findings suggest that modification of Cox-2 levels before tissue injury may reduce the peripheral and central sensitisation that occurs after injury, which could be useful in preventing chronic pain following surgery.

Cancer

Studies suggest that one of the chemicals involved in causing the inflammation and pain associated with arthritis may play a role in the development of ovarian cancer (Kalifeh et al, 2004; Li et al, 2004). The research indicates that an overproduction of Cox-2 appears to promote development of ovarian cancer. Overproduction of Cox-2 causes the loss of tissue membrane that helps anchor normal ovarian cells. The loss of this type of tissue increases risk of cancer growth.

The decreased gastrointestinal and antiplatelet effects of Cox-2 inhibitors compared with traditional NSAIDs may lead to the inclusion of these coxibs in pain management regimens for cancer pain. This research may help explain why this class of pain relievers and arthritis drugs, such as aspirin, and NSAIDs, such as ibuprofen, may slow the growth of some cancerous tumours (Hur et al, 2004).

Cox-2s and arthritis
Four randomised, double-blind, controlled trials have compared the Cox-2 inhibitors celecoxib, etoricoxib and rofecoxib with the NSAIDs naproxen and diclofenac (Simon et al, 1999; Emery et al, 1999; Bombardier et al, 2000; Collantes et al, 2002). The two groups of drugs were found to have similar efficacy in nearly all outcomes in patients with rheumatoid arthritis.

Studies have demonstrated that the efficacy of Cox-2 inhibitors is similar to that of non-selective NSAIDs in reducing gastric symptoms.

These findings and those of other researchers concur with NICE guidelines (2001), which recommend the use of Cox-2 inhibitors over other NSAIDs only in patients with rheumatoid arthritis at high risk of serious gastrointestinal effects.

The outcome of a study comparing the effects of NSAIDs with physiotherapy for the treatment of osteoarthritis appears to support the use of an alternative to NSAIDs. A randomised controlled trial involving patients with knee osteoarthritis compared the effects of manipulation with the administration of meloxicam (a Cox-1 and 2 inhibitor) - both treatments were equally effective for the short-term pain management (Tucker et al, 2003).

Cardiac disease

Research carried out in Canada suggests that celecoxib over rofecoxib is the preferred choice for treating patients with heart problems who risk developing congestive heart failure. This effect may be due to rofecoxib's longer half-life and delayed elimination (Mamdani et al, 2004b).

However, NICE recommends against routinely prescribing Cox-2 inhibitors in patients with cardiovascular disease - because of the possibility that they may increase the risk of myocardial infarction.

Pain after surgery

The findings of a large multicentre trial in the USA has supported the effectiveness of Cox-2 drugs in reducing the need for opioids after surgery, suggesting that patients may recover faster and that the drug may be useful postoperatively.

In the study, patients undergoing laparoscopic cholecystectomy were administered parecoxib pre-operatively and valdecoxib postoperatively. The researchers found a considerable reduction in patients' opioid requirements, combined with superior pain relief (Joshi et al, 2004). This concurs with earlier work into the morphine-sparing effects of parecoxib in patients undergoing hip surgery (Malan et al, 2003).

Conclusion
The use of any new pharmaceutical carries an initial high cost to the user, which usually reduces over time; this is no different for Cox-2 drugs. In the context of budgetary constraints and the drive for more effective use of resources it is important to fully assess the cost implications of any changes in treatment strategy. Soaring pharmacy costs have led the NHS to focus on more appropriate management of expenditure, both within a long-term global context and a short-term approach, with its focus on newly marketed products.

The widespread introduction of Cox inhibitors, perceived as a safer alternative to NSAIDs, has been anticipated for some time. How health-care providers react to the launch of this new subclass of drugs is likely to set a pattern for future management of new drugs.

The task of drawing up a policy on the use of Cox-2 inhibitors may pose challenges in view of trusts' budgetary constraints, but should include issues such as evaluating information, comparing the cost of the new drug, identifying appropriate patient selection criteria and, most importantly, educating the health-care professionals administering and evaluating the treatment.

Pain Network Conference
Challenging Traditions, Friday November 12, 2004, Chesterfield Hotel, Chesterfield. Costs: £40 (£80 non-members; £12 membership) Details: Jenny Coen, organiser, email: jenny.coen@ulh.nhs.uk

Latest Policy
NICE guidance on Cox-2 inhibitors

- Cox-2 inhibitors (celecoxib, etodolac, meloxicam and rofecoxib) should be prescribed only after careful consideration of the risks and benefits to the patient

- Cox-2 selective inhibitors should not be used for the routine (regular) management of rheumatoid arthritis or osteoarthritis

- Advice is that they should not currently be used in preference to other standard NSAIDs, except where specifically indicated according to the drug licence for patients with a history of gastrointestinal bleeding or gastroduodenal ulcers, or at high risk of either

- In preference to standard NSAIDs for patients with cardiovascular disease

People at high risk of developing serious gastrointestinal problems include those aged 65 years and over; those using other medicines known to increase risk of gastrointestinal problems; those with other serious co-morbidities; those requiring the long-term use of standard NSAIDs at the maximum dose

Source: NICE, 2001. Available at: www.nice.org.uk/pdf/coxiifullguidance.pdf

Author's contact details
Margaret M. Dunham, Lecturer in Nursing and Pain Management, School of Nursing and Midwifery, University of Sheffield, Samuel Fox House, Northern General Hospital, Sheffield S5 7AU. Email: m.dunham@sheffield.ac.uk

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Collantes, E., Curtis, S.P., Lee, K.W. et al. (2002)A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. BMC Family Practice 3: 1, 10.

Chang, D.J., Fricke, J.R., Bird, S.R. et al. (2001)Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial. Clinical Therapeutics 23: 9, 1446-1455.

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Gerstenfeld, L.C., Einhorn, T.A. (2004)COX inhibitors and their effects on bone healing. Expert Opinion on Drug Safety 3: 2, 131-136.

Ghilardi, J.R., Svensson, C.I., Rogers, S.D. et al. (2004)Constitutive spinal cyclooxygenase-2 participates in the initiation of tissue injury-induced hyperalgesia. Journal of Neuroscience 24: 2727-2732.

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Joshi, G.P., Viscusi, E.R., Gan, T.J. et al. (2004)Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral Cox-2 specific inhibitor. Anesthesia and Analgesia 98: 2, 336-342.

Kalifeh, I., Munkarah, A.R., Lonardo, F. et al. (2004)Expression of Cox-2, CD34, Bel-2 and p53 and survival in patients with primary peritoneal serous carcinoma and primary ovarian serous cancer. International Journal of Gynaecological Pathology 23: 2, 162-169.

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Simon, L.S., Weaver, A.L., Graham, D.Y. et al. (1999)Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. Journal of the American Medical Association 282: 20, 1921-1928.

Sinatra, R. (2002)Role of COX-2 inhibitors in the evolution of acute pain management. Journal of Pain and Symptom Management 24: 1 (suppl), S18-S27.

Tucker, M., Brantingham, J.W., Nyburg, C. (2003)Relative effectiveness of a non-steroidal anti-inflammatory medication (meloxicam) versus manipulation in the treatment of osteoarthritis of the knee. European Journal of Chiropractic 50: 3, 163-183.

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