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Evidence for the use of non-steroidal anti-inflammatory drugs for acute pain in the post anaesthesia care unit.

Introduction

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (IASP 1979). During surgery tissue damage is unavoidable and causes changes in the peripheral and central nervous system, which in turn produce reversible pain hypersensitivity in the inflamed and surrounding tissue (Warfield et al 2004). This sensation of pain then helps to protect the area from further damage until wound healing has occurred. In this way acute pain has a protective role and is usually short lived. Unfortunately for some this is not the case: the hypersensitised pain state can lead to the development of chronic pain. The association between surgery, acute postoperative pain and ongoing chronic pain (unexpected pain beyond three months) is well defined (Poobalan et al 2003, Nikolajsen et al 2004).

Acute postoperative pain is accompanied by an emotional response and an autonomic response and both contribute to a physiological response which may disrupt the healing process. The physiological consequences of acute postoperative pain include: muscle splinting and an inability to cough, effectively leading to retained secretions and impaired respiratory function; tachycardia and hypertension leading to increased myocardial work and oxygen consumption; intestinal motility slows and endocrine effects can result in hyperglycaemia and retention of sodium and water (this has been implicated as a cause of anastomotic failure in the postoperative period). Immobility from acute postoperative pain increases patients' risk of deep vein thrombosis and pulmonary embolism. Inadequate management of acute post-operative pain contributes to discomfort and distress, postoperative morbidity and increased hospital stay (American Society of Anesthesiologists 2004). It is therefore vitally important that acute postoperative pain is managed successfully in the PACU.

One of the aims of the PACU team is the successful management of acute postoperative pain by following analgesic guidelines which are designed to maximise pain relief whilst minimising side effects. This is best achieved using a 'multimodal' approach or 'balanced' analgesia--by using a combination of opioids, NSAIDs, regional local anaesthesia techniques and other adjuvants. The purpose of this article is to consider the evidence for the use of NSAIDs for acute postoperative pain.

[FIGURE 1 OMITTED]

The World Health Organisation (WHO) analgesic ladder (Figure 1) is a graded approach to guide pharmacological therapy for cancer pain relief. It can also be used to guide therapy for the relief of postoperative pain. Step one on the analgesic ladder recommends non-opioid analgesics such as NSAIDs and paracetamol for the relief of mild pain. If pain persists or increases then step two on the ladder recommends 'mild opioids' such as codeine plus non-opioids and adjuvants if required for moderate pain. If pain continues to persist or increase then step three recommends 'strong opioids' such as morphine plus non-opioids and adjuvants if required for severe pain. WHO recommends analgesics be given regularly 'by the clock' as opposed to 'on demand'. NSAIDs are used widely for the management of mild to moderate pain and to decrease opioid requirements (and thus reduce opioid-related side effects) in the perioperative period.

NSAID pharmacology

There are two classes of anti-inflammatory drugs: NSAIDs and cyclo-oxygenase type 2 inhibitor drugs (COX-2s). Paracetamol is sometimes classified as a NSAID because of its analgesic and antipyretic effects, however it is structurally different and its mode of action remains uncertain. NSAIDs are usually administered via the oral or rectal route although some agents can be administered intravenously (diclofenac, ketorolac, tenoxicam). NSAIDs are rapidly absorbed through the small bowel.

Both NSAIDs and COX-2s work by inhibiting the enzyme cyclo-oxygenase (COX) which in turn stops the production of prostaglandins (PGE2 and PGF2[alpha]) and thromboxanes from membrane phospholipids. Decreased PGE2 and PGF2[alpha] are responsible for NSAIDs' anti-inflammatory effect. The antipyretic action of NSAIDs is due to inhibition of centrally produced prostaglandins that stimulate pyrexia. Thromboxane is related to prostaglandins and is released by platelets at sites of injury and causes vasoconstriction and platelet aggregation. Decreased thromboxane synthesis by NSAIDs leads to decreased platelet aggregation and adhesiveness. Changes in the synthesis of prostaglandins are responsible for the side effects of NSAIDs.

The inhibition of COX by NSAIDs is reversible so the enzyme becomes active again once the plasma levels of NSAIDs fall. The exception is aspirin. Aspirin produces irreversible inhibition of COX; the synthesis of prostaglandins becomes dependent on the production of new cyclo-oxygenase enzyme.

The COX enzyme exists as (at least) two isoenzymes--COX-1 and COX-2. COX-1 (constitutive form) is constantly active in most tissues synthesising essential prostaglandins that help control renal blood flow and haemostatic function and form the protective gastric mucosal barrier. COX-2 (inducible form) is produced in response to tissue damage and the prostaglandins produced mediate inflammation and pain. Inhibition of COX-2 produces anti-inflammatory, analgesic and antipyretic effects, while inhibition of COX-1 appears to be responsible for the adverse effects of NSAIDs. Most NSAIDs inhibit both COX-1 and COX-2 enzymes. The COX-2s such as celecoxib and rofecoxib have a dose-dependent selective action against the COX2 isoenzyme and were developed to minimise the adverse effects mediated by COX-1 inhibition. The newer COX-2s have improved biochemical selectivity and include etorocoxib, valdecoxib, parecoxib and lumiracoxib (Figure 2).

Paracetamol is frequently used as a non-opioid analgesic in postoperative pain. The mechanism of action of paracetamol remains unclear: it has no endogenous binding sites and does not significantly inhibit peripheral COX enzymes. Current evidence suggests that it may have a central anti-nociceptive action, involving inhibition of central nervous system COX enzymes, reinforcement of the inhibitory descending serotinergic pathways (Bonnefort et al 2003) and indirect activation of cannabinoid receptors (Bertolini et al 2006). It has also been shown to independently inhibit prostaglandin production at the cellular transcription level (Mancini et al 2003). Paracetamol comes in oral, rectal and most recently parenteral (Perfalgan[R] and propacetamol) formulations. Like NSAIDs paracetamol is absorbed through the small bowel. The oral bioavailability ranges from 63-89% (Rawlins et al 1977) while rectal bioavailability ranges from 24-98% (Ward & Alexander-Williams 1999). Perfalgan[R] is a parenteral preparation of paracetamol which is licensed in the United Kingdom. Propacetamol is another intravenous paracetamol preparation which needs to be reconstituted before use and is not licensed in the United Kingdom.

One of the advantages of parenteral paracetamol in the postoperative period is that it produces more predictable plasma concentrations. A clinical study by Pettersson et al (2004) found that oral paracetamol given post-operatively resulted in huge variations in plasma concentrations compared to parenteral administration. The minimum plasma concentration of paracetamol for analgesia is estimated to be 10mcg/ml (Anderson et al 1999). Peak plasma concentrations are achieved 25 min after intravenous infusion, 45 min after oral administration and 3.5-4.5h after rectal administration. The maximum analgesic activity of paracetamol occurs about 1-2h after the peak plasma level has been reached (Ward et al 1999, Lonnqvist & Morton 2005).

Unlike NSAIDs, paracetamol has few side effects and is relatively safe when used in the recommended doses. The therapeutic range for paracetamol is 10-20mcg/ml and the toxic threshold is 150mcg/ml. The main potential harm is liver toxicity which is caused by the accumulation of a toxic metabolite produced when the liver is depleted of glutathione. This is extremely rare following therapeutic dosing (Prescott 2000).

Evidence for NSAIDs and COX-2s for acute pain

Number needed to treat (NNT) values can be used to assess the efficacy of analgesics for the management of acute pain. The Oxford league table of analgesic efficacy (Table 1) was constructed using data from systematic reviews of randomised, double-blind and single-dose studies in patients with moderate to severe acute pain (Bandolier 2007). The efficacy of each analgesic is expressed as the NNT, that is, the number of patients that need to receive the drug for one patient to achieve at least 50% pain relief compared with placebo over a 4-6 hour treatment period. The most effective drugs have the lowest NNT.

The table shows that NSAIDs, COX-2s and paracetamol are effective analgesics in the treatment of moderate acute pain.

Concurrent administration of two analgesics with different mechanisms of action is more effective than either drug alone. NSAIDs can be co-administered with opioid analgesics with a documented 30-50% morphine sparing effect and improved analgesia (Beaulieu 2007). A meta-analysis by Marret et al (2005) showed that NSAIDs with morphine patient controlled analgesia (PCA) decreased postoperative nausea and vomiting by 30%, sedation by 29% but had no significant effect on pruritis, urinary retention and respiratory depression. They also demonstrated that preoperative NSAIDs were of no analgesic benefit when compared with postoperative administration. Remy et al (2005) showed that paracetamol combined with PCA morphine had a significant morphine sparing effect but did not alter the incidence of morphine-related side effects.

Two systematic reviews have looked at the comparable effect of paracetamol, NSAIDs or their combination in postoperative pain management. Both found a clinically relevant analgesic effect of paracetamol and a superior analgesic effect when an NSAID was administered with paracetamol compared to paracetamol alone. (Hyllested et al 2002, Romsing et al 2002) In addition, Hyllested et al (2002) found that the analgesic efficacy of NSAIDs and paracetamol differed depending on the type of surgery performed. In particular, NSAIDs were superior after dental surgery but after major and orthopaedic surgery no substantial difference was seen. However, both reviews are limited by the small number of studies reviewed (Hyllested et al reviewed 41 double-blind randomised studies and Romsing et al reviewed 24 randomised controlled trials).

Adverse effects of NSAIDs and COX-2s Gastrointestinal

The toxicity of NSAIDs is related to the COX1 inhibition of prostaglandin synthesis. The gastrointestinal mucous layer, bicarbonate secretion, rapid cell turnover and blood supply all contribute to intestinal protection against acid. Prostaglandins are involved in many of these elements; low levels of prostaglandins mean that protection is reduced. Gastrointestinal side effects range from gastrointestinal symptoms such as dyspepsia, nausea and abdominal pain through to serious complications such as bleeding and perforation. Mucosal lesions are seen at endoscopy in 20-40% of patients taking NSAIDs (Stannard & Booth 2004) and every year 0.5-2% of people taking NSAIDs have a serious gastrointestinal event (Grady et al 2000).

Risk factors include:

Patient factors

* age > 65 years (over the age of 75 years the risk is increased by fivefold)

* concomitant serious systemic disease (rheumatoid arthritis, heart disease)

* history of peptic ulcer disease or oesophagitis

* family history of peptic ulcer disease

* alcoholism

* smoking

* Helicobacter pylori infection.

Medication factors

* concurrent corticosteroids

* concurrent anticoagulants

* multiple NSAIDs or long half life NSAIDs e.g. naproxen

* high dose NSAIDs

* prolonged use of NSAIDs

Prescriptions should be for the lowest effective dose for the shortest possible time (as recommended by the Committee on Safety and Medicines (CSM) in the UK). The risk of gastrointestinal side effects can be reduced by giving proton pump inhibitors (e.g. omeprazole) and prostaglandin analogues (e.g. misoprostil). Mucosal protectants such as sucralfate and [H.sub.2] blockers (e.g. ranitidine) appear to be ineffective.

The COX-2s produce significantly less clinical gastrointestinal ulceration (Hawkey & Skelly 2002) and less endoscopically evident gastrointestinal ulcers than NSAIDs (Bombardier 2002). In the CLASS study (Silverstein et al 2000), celecoxib, when used in a dosage 2 to 4 times the maximum therapeutic dosage for a period of 6 months, was associated with a lower incidence of symptomatic ulcers and ulcer complications compared with NSAIDs (ibuprofen and diclofenac) at standard dosages. The incidence of symptomatic ulcers and/or ulcer complications was not significantly different between the two groups in those patients taking concomitant low dose aspirin. Laine (2003) estimated that the number of patients needed to treat with COX-2s in preference to NSAIDs to avoid one gastrointestinal event per year is 40-100. There is ongoing debate regarding the safety profile of COX-2s in patients who have risk factors for ulcer disease. Active gastrointestinal ulcer disease still remains a contraindication to the use of COX-2s.

Renal

The adverse effects of NSAIDs on the kidneys are estimated to occur in about 1-5% of patients. Renally produced prostaglandins participate in the autoregulation of renal blood flow, glomerular filtration, modulation of renin release, sodium and potassium transport and water metabolism. Prostaglandins have an important role in maintaining normal renal blood flow during times of stress when levels of circulating catecholamines are high, as can occur during surgery and anaesthesia or if a patient is hypovolaemic or septic. In these circumstances, NSAIDs can cause acute reversible vasomotor renal failure. Interference with sodium, potassium and water excretion can lead to electrolyte and water retention and interfere with antihypertensive and diuretic therapy. Administration of NSAIDs may also cause acute interstitial nephritis, nephrotic syndrome and chronic use can lead to 'analgesic nephropathy'.

Although the COX-2 isoenzyme was heralded as an inducible enzyme producing prostaglandins only during times of inflammation it appears that there is also a constitutive form expressed in the kidney. Like COX-1, COX-2 metabolites are also important in the maintenance of renal blood flow, the mediation of renin release and the regulation of sodium, potassium and water excretion. Therefore COX-2s produce similar adverse effects on renal function to NSAIDs.

Platelet function

Reduced levels of circulating thromboxane prevent platelet aggregation and vasoconstriction such that bleeding time is prolonged when patients are taking NSAIDs. This may become problematic during the perioperative period and may cause increased blood loss. NSAIDs should be avoided in cases where large blood loss is expected, if patients have known bleeding disorders or if postoperative bleeding would be catastrophic (e.g. neurosurgery, spinal surgery, cardiac surgery).

Platelets do not produce COX-2 therefore COX-2s do not reduce platelet function. Hegi et al (2004) found fewer disturbances of stimulated platelet function and a reduction in surgical blood loss when they compared perioperative rofecoxib to diclofenac. COX-2s may be useful for perioperative analgesia in patients with a bleeding disorder or when surgical blood loss is expected to be high.

Asthma

Inhibition of cyclo-oxygenase leads to an increase in leukotrienes which are known to precipitate bronchospasm. Approximately 20% of asthmatics have sensitivity to NSAIDs and administration can precipitate a severe asthma attack (Peck & Williams 2000). A number of studies have shown that COX-2s do not produce bronchospasm in aspirin sensitive asthmatics (Martin-Garcia et al 2003, Szczeklik & Stevenson 2003).

Bone healing

The process of bone repair is complex and prostaglandins help mediate the balance between bone resorption and formation. As NSAIDs and COX-2s inhibit prostaglandin synthesis it would appear that they could decrease heterotrophic bone healing. However both animal and human studies remain inconclusive. Reuben et al (2005) in their retrospective study concluded that short term perioperative administration of celecoxib, rofecoxib or low dose ketorolac (<110mg per day) showed no deleterious effects on non-union following spinal fusion surgery, while high dose ketorolac (120-240mg per day) increased the incidence of non-union. In a review by Bandolier (2004) they concluded that, apart from ketorolac and possibly indomethacin, there is no sound evidence that NSAIDs or COX-2s make any difference to bone healing after surgery or trauma unless they are continued for months.

Cardiovascular

Over the last few years there have been major concerns over the adverse cardiovascular effects (leading to myocardial infarction and stroke) associated with COX-2s. Concerns were borne out when a 5-fold increase of myocardial infarction (MI) was seen in the Vioxx (rofecoxib) Gastrointestinal Outcome Research (VIGOR) study (Bombardier et al 2000). The APPROVe study (Bresalier et al 2005), comparing rofecoxib to placebo, confirmed a 1.7-fold increased risk of MI and led to the withdrawal of rofecoxib from the market. Two trials by Solomon et al (2006) showed nearly a twofold increased cardiovascular risk with the use of celecoxib 400mg. Ott et al (2003) found a significant increase in cerebrovascular complications and MI after supramaximal dosing with 40mg of parecoxib/valdecoxib twice daily for 14 days following coronary artery bypass grafting.

It has been postulated that, by disturbing the balance between thromboxane and prostacyclin, COX-2s may be prothrombotic. Inhibition of the COX-2 enzyme decreases the synthesis of prostacyclin (PGI2) leaving unopposed thromboxane activity resulting in platelet aggregation and vasoconstriction. Several other NSAIDs have also been shown to increase cardiovascular risk, including diclofenac and indomethacin. Current evidence does not suggest an increased thrombotic risk for short-term, low dose treatment with ibuprofen; however, high-dose ibuprofen (600-800mg, which is not available over the counter) may be associated with a small increased thrombotic risk. The risk for these adverse effects is likely to be greatest in patients with a prior history of cardiovascular disease or with conditions increasing the risk of cardiovascular disease.

The current recommendations regarding COX- 2s and NSAIDs from the CSM (2005) in the UK are:

* Patients with established ischaemic heart disease, moderate heart failure (NYHA class II-IV) or cerebrovascular disease should not be prescribed COX-2s.

* For all patients the balance between cardiovascular risk and gastrointestinal risk should be considered before prescribing a COX-2.

* The lowest possible dose of a COX-2 should be used for the shortest necessary time.

* Gastro-protective agents should be considered for patients switched to NSAIDs.

* Etorocoxib should not be prescribed for patients with uncontrolled hypertension.

* Patients taking etorocoxib should have their blood pressure monitored.

* Traditional NSAIDS may be associated with a small increased risk of thrombotic events such as heart attack or stroke. The lowest effective dose of non-selective NSAID should be prescribed for the shortest possible time.

NSAIDs for the management of post-operative pain in paediatrics

For post-operative pain in children, a multimodal approach using regional anaesthesia combined with paracetamol, NSAIDs and opioids is a widely accepted approach. Paracetamol has fewer side effects than NSAIDs and opioids so is the first line analgesic used for the paediatric population. Paracetamol is approved for use from one month of age and comes in paediatric-friendly formulations such as liquids and chewable tablets. The oral route of administration is recommended with a peak analgesic time of about 60 minutes and duration of action 4 hours (Lonnqvist & Morton 2005). The rectal route is no longer recommended because of the unpredictable plasma concentrations which can result. Paracetamol has repeatedly been shown in placebo-controlled clinical trials to be an effective analgesic in children with mild to moderate pain. It is effective for postoperative pain after minor procedures such as adenotonsillectomies. Compared with adults, children are less susceptible to the acute toxic effects of paracetamol, and toxicity occurs with doses greater than 150mg/kg/24h.

Ibuprofen is the most commonly used NSAID prescribed for children and the approved minimum age for administration is 3 months. The side effects of NSAIDs are the same for the paediatric population as for adults, although NSAID-induced asthma is rarer in children than in adults. Aspirin-sensitivity occurs in about 2% of children with asthma, with about 5% of these patients having cross-sensitivity to other NSAIDs (Lonnqvist & Morton 2005). As with adults, NSAIDs should not be administered to children with dehydration or hypovolaemia, renal or hepatic failure, coagulation disorders, peptic ulcer disease or where there is significant risk of haemorrhage. Controversy still remains regarding whether perioperative NSAIDs contribute to post-tonsillectomy haemorrhage. A meta-analysis by Moinche et al (2003) showed a small increased risk of re-operation for bleeding patients receiving NSAIDs but good pain control and reduced postoperative nausea and vomiting. Several COX-2s have been evaluated in paediatrics. Studies show equal efficacy to other NSAIDs and paracetamol and a morphine sparing effect (Lonnqvist & Morton 2005).

Conclusion

Successful management of acute postoperative pain in the PACU is vitally important. Inadequate management of acute postoperative pain contributes to discomfort and distress, postoperative morbidity, increased hospital stay and is associated with the development of chronic postoperative pain. Use of a multimodal approach incorporating analgesics with varying sites of action is recommended. NSAIDs have proven efficacy as the sole analgesic agent for the management of mild to moderate pain after minor surgical procedures, and in combination with opioid analgesics in the management of moderate to severe pain.

COX-2s are as effective analgesics as NSAIDs but current evidence indicates that they have important adverse cardiovascular effects that include increased risk for myocardial infarction, stroke, heart failure, and hypertension. COX-2s would be an appropriate choice for patients with low cardiovascular risk but with increased probability of gastrointestinal complications and bleeding. Prescriptions of COX-2s and NSAIDs in the post-operative period should always have a stop date included.

Paracetamol is an effective analgesic with a favourable side effect profile. It is a viable alternative to the NSAIDs in patients unable to take NSAIDs or after surgeries where post-operative bleeding is considered a risk. Route of administration and timing of dosing needs to be considered in the perioperative period. Intravenous paracetamol rapidly gives predictable plasma concentrations making it a good choice. Plasma concentrations can then be maintained with oral paracetamol. Rectal administration should be avoided due to unpredictable plasma concentrations, with the possibility of therapeutic concentrations never being reached.

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Claire Frampton

MBChB, FRCA

Specialist Registrar in Anaesthesia, Nuffield Department of Anaesthetics, Oxford Radcliffe Hospitals NHS Trust, Oxford

Jane Quinlan

MBBS, FRCA, FFPMRCA

Consultant in Anaesthesia and Acute Pain Management, Nuffield Department of Anaesthetics, Oxford Radcliffe Hospitals NHS Trust, Oxford, Honorary Senior Clinical Lecturer, University of Oxford

Correspondence address: Claire Frampton, Nuffield Department of Anaesthetics, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU. Email:claireframpton@hotmail.com
Table 1: NNT from Oxford League Table of
Analgesic Efficacy (oral administration unless
otherwise specified).

Analgesic                                 NNT

Etoricoxib 180/240                        1.5
Valdecoxib 20mg                           1.7
Ketorolac 20mg                            1.8
Diclofenac 100mg                          1.9
Piroxicam 40mg                            1.9
Naproxen 440mg                            2.0
Parecoxib i.v 40mg                        2.2
Paracetamol 1000mg + codeine 60mg         2.2
Diclofenac 50mg                           2.3
Ibuprofen 400mg                           2.4
Ibuprofen 200mg                           2.7
Parecoxib 20mg                            3.0
Paracetamol 500mg                         3.5
Paracetamol 1000mg                        3.8
Celecoxib 200mg                           4.5

Figure 2: Synthesis, function and inhibition of COX-1 and COX-2
isoenzymes

Enzyme                 COX-1                  COX-2
Synthesis
                       Constitutive           Inducible

Functions              Gastric protection     Pro-inflammatory
                       Platelet aggregation   prostaglandins
                       Vascular tone
                       Renal blood flow
                       Sodium excretion

                       COX-1                  COX-2
Inhibition by NSAIDs   Indomethacin
                       Aspirin
                       Pirioixcam
                       Ibuprofen
                       Diclofenac
                       Celecoxib
                       Lumiracoxib
                       Etoricoxib
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Title Annotation:CLINICAL FEATURE
Author:Frampton, Claire; Quinlan, Jane
Publication:Journal of Perioperative Practice
Article Type:Report
Geographic Code:4EUUK
Date:Dec 1, 2009
Words:4552
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