Nonsteroidal Anti-Inflammatory Drugs in Perisurgical Pain Management

PRACTICAL THERAPEUTICS Drugs 49 (I): 51-70, 1995 0012-6667/95/0001-0051/$20.00/0

© Ads International Limited. All rights reserved,

Nonsteroidal Anti-Inflammatory Drugs in Perisurgical Pain Management Mechanisms of Action and Rationale for Optimum Use

Jeremy Cashman and Gregory McAnulty Department of Anaesthesia, St George's Hospital, London, England

Contents Summary , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 1, The Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

1 ,1 Tissue Injury and the Arachidonic Acid Cascade ,"" 1 ,2 Inhibition of Prostaglandin Biosynthesis """"'" 1 ,3 Central Antinociceptive Mechanism of Action of NSAIDs ,

2, Dose-Response Effects and Enantiomeric NSAIDs 2,1 Variability in Drug Response , 2,2 Stereoisomerism and NSAIDs , ,

3, Adverse Responses to NSAIDs ",. 3.1 Adverse Gastrointestinal Effects 3.2 Adverse Renal Effects .. , , , , 3.3 Aspirin and Bronchospasm '"

4, Choosing an NSAID for Use in the Peri operative Period . 4.1 Rational Prescribing of NSAIDs ...... . 4.2 Pharmacokinetic-Pharmacodynamic Relationships.

5. Dosage Regimens . . 5.1 Oral and Rectal . , . 5.2 Parenteral . . . . . ,

6. Preoperative Administration 7, Conclusions . . . , . . . . . .

51 52 52 55 57 58 58 59 60 61 62 63 63 63 63 65 65 65 66 66

Summary Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of agents with similar actions but diverse chemical structures. Aspirin (acetylsalicylic acid) and sodium salicylate were the first drugs of this type to be used clinically. However, over the past 3 decades there has been a dramatic increase in the number of NSAIDs available for the treatment of postoperative pain.

Tissue injury, such as occurs with surgical intervention, is associated with the release of numerous inflammatory mediators including prostaglandins. Prostaglandins derived from the arachidonic acid cascade are implicated in the production of inflammatory pain, and in sensitising nociceptors to the actions of other mediators. They are synthesised from arachidonic acid via the endoperoxide biosynthesis pathway, the initial step of which is catalysed by the enzyme cyclooxygenase. Two forms ofthe cyclo-oxygenase enzyme (COX-I and COX-2) have been characterised. COX-l is important in circumstances where prostaglandins

52 Cashman & McAnulty

have a protective effect such as gastric mucus production and renal blood flow maintenance. NSAIDs inhibit the synthesis of prostaglandins at 1 or more points in the endoperoxide pathway. Three mechanisms of inhibition of the biosynthetic enzymes have been proposed: (i) rapid, reversible competitive inhibition; (ii) irreversible, time-dependent inhibition; and (iii) rapid, reversible noncompetitive (free radical trapping) inhibition. In addition, there is evidence that NSAIDs have a central anti nociceptive mechanism of action that augments the peripheral effect. This may involve inhibition of central nervous system prostaglandins or inhibition of excitatory amino acids or bradykinins.

There is considerable variability in the pain relief obtained from NSAIDs. Such variability in drug response may be explained in terms of differences between agents with respect to either pharmacodynamic actions or pharmacokinetic parameters or a combination of both. Stereoisomerism, where preparations exist as racemic mixtures and where only 1 enantiomer is active, may also be important. However, chiral inversion from inactive to active enantiomer may occur and may be rapid or slow.

NSAIDs have numerous adverse effects. Gastrointestinal disturbances including ulceration are the commonest adverse responses to NSAIDs and carry the greatest risk of death. Also significant are renal impairment and an increased risk of postoperative haemorrhage. Asthma and allergic reactions are uncommon.

The choice of NSAID should be made on a rational basis. For short term perioperative use it is advisable to favour drugs with good safety profiles, which are available in a range of formulations. It is important to review therapy regularly, changing to an alternative NSAID if there is poor response to treatment. NSAIDs should not be used in patients with known contraindications to their use. Disparity between clinical effect and plasma concentration of some NSAIDs may be due to a complex, time-dependent concentration-effect relationship. Dosage of NSAIDs should be tailored to individual patient response, based on clinical assessment. Oral mandatory dosage regimens and intravenous (or even intramuscular) infusions may result in steady state therapeutic plasma concentrations of NSAIDs and therefore provide consistent analgesia. Finally, there seems to be little benefit from preoperative administration of NSAIDs, indeed haemorrhagic complications may be more likely.

Sodium salicylate was first used for the treatment of rheumatic fever in 1875. In 1899, aspirin

(acetylsalicylic acid) was introduced as a result of its antipyretic, anti-inflammatory and analgesic effects. Within a comparatively short period of time a number of other drugs with diverse chemical structures, which shared some, if not all, of the effects (as well as the adverse effects) of aspirin, were discovered. As a result of the similarity of thera

peutic action of these drugs they have tended to be

regarded as a single group known as the aspirin

like drugs. More commonly these agents are re-

ferred to as the nonsteroidal anti-inflammatory drugs (NSAIDs).

1. The Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

1.1 Tissue Injury and the Arachidonic Acid Cascade

Tissue damage is associated with release of a host of inflammatory mediators including histamine, serotonin (5-hydroxytryptamine), bradyki-

© Adis International Limited, All rights reserved. Drugs 49 (1) 1995

NSAIDs in Peri surgical Pain Management

nin, platelet activating factor, interleukin-l, prostaglandins, thromboxanes and leukotrienes.[l] The importance of these mediators in the inflammatory response can be ascertained by eliminating activity of each mediator in turn, either by using enzyme inhibitors or by blocking the pharmacological effect of the mediator using specific antagonists.[l] The discovery that NSAIDs selectively inhibit the biosynthesis of prostaglandins led to the theory that prostaglandins are important inflammatory mediators)2,3] Furthermore, the analgesic effect of drugs that inhibit prostaglandin biosynthesis may be explained if prostaglandins are responsible for inflammatory pain.l4]

Von Euler[5] coined the term prostaglandin to describe the extract from semen that contracted uterine smooth muscle. Although prostaglandins are derived from arachidonic acid and other polyunsaturated fatty acids, the 20-carbon polyunsaturated essential fatty acid (arachidonic acid) is the major source in mammalian tissues. Prostaglandins derived from arachidonic acid contain 2 double bonds [e.g. prostaglandin E2 (PGE2), thromboxane and prostacyclinJ. Analogous compounds synthesised from eicosatrienoic (linoleic) and eicosapentaenoic acid contain 1 less or 1 more double bond in the side chains (e.g. PGEl and PGE3, respectively). The various groups of prostaglandins, thromboxanes, hydroxy acids and leukotrienes which retain the 20-carbon unsaturated fatty acid backbone are collectively known as eicosanoids. The 3 fatty acid precursors (eicosatetraenoic acid, eicosatrienoic acid and eicosapentaenoic acid) are derived directly or indirectly from dietary fat and are esterified into cell membranes. Their release, usually as a result of trauma, is the major stimulus for eicosanoid production as prostaglandins cannot be stored and are released as soon as they are synthesised.

A number of enzymes catalyse the conversion of arachidonic acid to prostaglandins, thromboxanes, leukotrienes and hydroxy acids. The production of prostaglandins depends on the release of arachidonic acid from cell membrane phospholipids. Phospholipase activation liberates ara-

© Adis International Limited. All rights reserved.

53

chidonic acid which in turn acts as a substrate for cyclo-oxygenase and hence, because tissue damage is associated with inflammation, prostaglandin production accompanies the inflammatory response. Phospholipase A2 is activated in response to mechanical, chemical and immunological stimulation. The enzyme cyclo-oxygenase, which is a membrane-bound haemo- and glycoprotein with a molecular weight of7lkD, was isolated in 1976J6] Cyclo-oxygenase catalysed peroxidation of arachidonic acid results in a cyclic structure whereas peroxidation catalysed by lipo-oxygenase produces straight chain hydroxy-peroxy acids (HPETEs) which can then be converted to hydroxy acids (HETEs). The cyclo-oxygenase and lipooxygenase pathways represent the major routes for the oxidative metabolism of arachidonic acid (fig. 1).[1]

Prostanoids do not generally activate nociceptors directly, but sensitise them to mechanical stimuli and chemical mediators of nociception such as bradykininJ4,7] However, the evidence clearly indicates that stable prostaglandins of the E series are involved in the hyperalgesia seen in acute inflammation.l81 PGE2 is the predominant eicosanoid in such inflammatory conditions, acting synergistically with other mediators to produce inflammatory pain.l l ,9] PGE2 has no direct pain producing activity,[lO] but it does sensitise receptors on afferent nerve endings to the actions of bradykinin and histamineV]

Many other cyclo-oxygenase products have been detected in inflammatory lesions, but usually they are present at only a fraction of the concentration of PGE2. Prostacyclin is the most important of these in terms of inflammatory signs[l] and may even be present in comparable concentrations to PGE2JlO] Higgs et al.[ll] proposed that prostacyclin was a more potent vasodilator than PGE2 by several orders of magnitude. More recently however, Vane and Botting,D] have suggested that their potency is similar. Nevertheless, prostacyclin is a more potent hyperalgesic agent in both rats and dogsJ4,l2] In both these animal models the hyperalgesia produced by prostacyclin is immediate and

Drugs 49 (1) 1995

54

Vasoconstrictionfvasodilatation Pain Inflammation Bronchial constriction Gastric mucus production

Fig. 1. The endoperoxide biosynthesis pathway.

of short duration. That produced by PGE2 is slow in onset and of long duration.!4,JO)

Higgs et aU8) report that carrageenin-induced hyperalgesia in rat paw preparations is likely to be mediated by release of a short-acting product of cyclo-oxygenase since the response is interrupted by indomethacin. This observation has prompted the suggestion that, because aspirin-like drugs would be ineffective against the prolonged activity of PGE2, the endogenous mediator of hyperalgesia is probably prostacyclin.!8l The lipo-oxygenase


Platelet disaggregation Vasodilatation

Prostaglandins

Pain Inflammation Fever

Cashman & McAnulty

Platelet aggregation VasoconstrICtion

Bronchial constrictionfdilatation Blood flow

pathway results in the production of other arachidonic acid metabolites which may also have algogenic properties. Leukotriene B4 is a potent chemotactic factor for polymorphs, which in turn lowers the firing threshold of pain fibres and thus stimulate nociceptors directly. HETE is also highly chemotactic (fig. 1).

It is now known that the cyclo-oxygenase enzyme is encoded by 2 genes.!l3l Two forms of the cyclo-oxygenase enzyme (COX-l and COX-2) have been characterised.

Drugs 49 (1) 1995

NSAIDs in Perisurgical Pain Management

COX-1 is produced in normal, quiescent conditions and is a constituent of healthy cells. It is important in circumstances where prostaglandins have a protective function, such as gastric mucus production and renal blood flow maintenance. COX-2, the inducible form of the enzyme, is the major isozyme associated with inflammation. COX-2 is induced in endothelial cells, macrophages and synovial fibroblasts by inflammatory agents.

The ratio of inhibition of COX-1 to COX-2 by NSAIDs will determine the likelihood of adverse effects. NSAIDs such as aspirin and indomethacin with a high ratio (indicating a greater degree of inhibition of the protective COX-1 enzyme) will exhibit more adverse effects than an NSAID such as ibuprofen that has alow ratio ofCOX-1 to COX-2 inhibition. The challenge must be to develop drugs selective for the inducible form of the enzyme. It is of interest that dexamethasone, at concentrations that are anti-inflammatory, inhibits COX_2.[13]

1.2 Inhibition of Prostaglandin Biosynthesis

NSAIDs inhibit the synthesis of prostaglandins at 1 or more points in the endoperoxide biosynthesis pathway. This property is a general characteristic of the aspirin-like drugs[l] and is believed to be the basis of their analgesic action since the products of the arachidonic acid cascade promote the pain associated with inflammation.

Up until the early 1970s, many attempts had been made to link the anti-inflammatory actions of substances like aspirin with the ability to inhibit the activity of endogenous substances such as kinins, slow reacting substance of anaphylaxis (SRSA), adenosine triphosphate (ATP), arachidonic acid and prostaglandins. The hypothesis that antiinflammatory substances such as aspirin might act by inhibition of the enzymes which synthesise prostaglandins was tested by Vane in 1971.[3] In cell-free homogenates of guinea-pig lung, dosedependent inhibition of prostaglandin formation by (in order of potency) indomethacin, aspirin and sodium salicylate was demonstrated. Three other


55

drugs, morphine, hydrocortisone and mepyramine, had little effect. Vane proposed that the pain relieving action of aspirin-like drugs could be explained by inhibition of prostaglandin synthesisJ3,14-16]

At about the same time Ferreira and colleagues demonstrated that indomethacin and aspirin (but, interestingly, not sodium salicylate) blocked prostaglandin release from isolated perfused dog spleen, an organ known to release large amounts of prostaglandins (mainly E2 and F2a) in response to sympathetic nervous system stimulation,l3] Hydrocortisone was again without effect. Using the same dog spleen model, Flower[17] demonstrated that, in addition to aspirin and indomethacin, many other drugs of the aspirin type (including phenylbutazone and mefenamic acid) and paracetamol (acetaminophen) blocked prostaglandin biosynthesisJI5,17] Indomethacin is a more potent inhibitor of prostaglandin synthetase than aspirin in the microsomal extract of dog spleen, while mefenamic acid and phenylbutazone are intermediate in potency between aspirin and indomethacinJl5]

In a detailed examination of the mechanism of the anticyclo-oxygenase activity of NSAIDs, Lands proposed that cyclo-oxygenase inhibitors can be classified into at least 3 distinct categories:[18]

• drugs which cause rapid, reversible competitive enzyme inhibition

• drugs which cause irreversible, time-dependent enzyme inactivation

• drugs which cause rapid, reversible noncompetitive (free radical trapping) inhibition (fig. 2). Competitive inhibition occurs when a substrate

analogue, such as a closely related polyunsaturated fatty acid, has a binding constant for the enzyme that is similar to the substrate arachidonic acid, but which does not form a product. Drugs such as mefenamic acid and the propionic acid derivative ibuprofen provide examples of this type of inhibitionJl9] Flufenamic acid and sulindac are considered also to compete with arachidonic acid for binding to cyclo-oxygenaseJI9] A substituted carboxylic acid residue probably mimics the terminal carboxyl of arachidonic acid whilst hydrophobic

Drugs 49 (1) 1995

56

Substrate or substrate analogue

+ I Enzyme I

+ I Inhibitor I ~================

2

Enzymelinhlbitor complex

3

Cashman & McAnulty

Enzyme/substrate

Stable, inactive enzymelinhlbitor complex

Fig. 2. Suggested mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs).[18] Symbols: 1 = drugs which cause rapid, reversible competitive inhibition; 2 = drugs which cause irreversible, time-dependent inactivation; 3 = drugs which cause rapid, reversible noncompetitive (free radical trapping) inhibition.

groups bind to the enzyme; this appears to be necessary for competitive inhibition. The presence of an aryl halogen enhances this activityJ19] Thus, for ibuprofen, binding to cyclo-oxygenase appears to be dependent on hydrophobic features rather than the ionic character of the moleculeJ18]

Aspirin, the best known example of the irreversible, time-dependent class of inhibitors, is a site-specific acetylating agent. It forms a covalent, acetylated derivative of the enzyme by selectively acetylating the hydroxyl group of a single serine (ser 530) residue located 70 amino acids from the C terminus of the enzymeJ20] This causes irreversible inactivation of cyclo-oxygenase. Once the enzyme has been inactivated by this irreversible acetylation, removal of the drug will not result in synthesis of further prostaglandin until new enzyme is formed by protein synthesis in the tissues. Cyclo-oxygenase but not peroxidase activity is inhibited when purified enzyme is acetylated. Thus, at low concentrations aspirin rapidly and selectively acetylates prostaglandin endoperoxidase synthesis. At high concentrations aspirin acetylates nonspecifically a variety of proteins and nucleic acidsJ21]

Other drugs are competitive, irreversible, timedependent inhibitors by virtue of competing with the substrate for enzyme binding rather than inducing acetylation. Kulmacz and Lands[22] have established that indomethacin, meclofenamic acid and

© Adis International Limited, All rights reserved,

flurbiprofen interact in a time-dependent manner with prostaglandin H (PGH) synthetase to inhibit cyclo-oxygenase activity. The effect of these 3 agents is to diminish rather than destroy the catalytic activity of cyclo-oxygenase. Since indomethacin can be recovered intact after inhibiting the enzyme, the process probably does not involve covalent modification but rather a conformational change in the synthetase brought about by stereospecific binding. Binding is initially rapid and reversible, but the synthetase/inhibitor complex gradually decays to produce a stable form with only a fraction of the original activity. The majority of propionic acid derivatives, including naproxen, act as structural analogues of cyclic en do peroxides rather than arachidonic acidJ231

Lands[18] proposed that in inflammatory disorders the continual presence of lipid peroxide induces a free radical chain reaction mechanism which sustains cyclo-oxygenase biosynthesis of more peroxides. Hydroperoxides generated during arachidonic acid metabolism exert a positive feedback mechanism and stimulate cyclo-oxygenase activityJ24] This peroxide tone can be blocked by the addition of free radical scavengers or antioxidant agents, which act as reversible noncompetitive inhibitors. Even when large amounts of cyclooxygenase are present together with substrate, little prostaglandin biosynthesis will occur in the presence of a free-radical scavenger. Paracetamol may

Drugs 49 (1) 1995


block prostaglandin synthesis by this mechanism)25]

There are important differences between reversible inhibitors and irreversible, time-dependent inhibitors. In general, a reversible inhibitor influences cyclo-oxygenase only to the extent that the binding site is occupied by the agent. Dilution of the agent or competitive reversal of its binding by increased substrate allows formation of prostaglandins to proceed. A time-dependent inhibitor appears to depend on the combined presence of a halogen with a free carboxylic acid groupJl9] At low concentrations they may not occupy more than 10% of enzyme sites at a given moment, but will lead to complete loss of activation with time.

1.3 Central Antinociceptive Mechanism of Action of NSAIDs

It is generally believed that the effects of NSAIDs are mediated through a peripheral mechanism related to inhibition of prostaglandin synthesis. However, as early as 1899 Dreser suggested that aspirin might act on the central nervous system)26] There is increasing evidence that NSAIDs have a central mechanism of action which augments the peripheral mechanism. Some of these drugs have an analgesic action that is disproportionate to their anti-inflammatory action)27] Inhibition of prostaglandin release in the central nervous system may be responsible for the antipyretic effect of NSAIDSJI6,28] It is also possible that a central action may involve inhibition of neural activity induced by excitatory amino acids or bradykinins)29]

The behavioural responses of rats to subcutaneous injection of formalin, acetic acid, phenol and carrageenin,[28] as well as evoked activity in response to electrical stimulation of nociceptive afferent nerves,[30,31] have been used to test the hypothesis that NSAIDs may have a central mechanism of action. Ferreira et al)32] compared the peripheral and central effects of aspirin, indomethacin, paracetamol and phenacetin on the hyperalgesia induce by carrageenin injected into rat paws. Administration of these drugs into the cerebral


57

ventricles was associated with an enhanced analgesic effect. Combined administration of these drugs into paws and intraventricularly resulted in a synergistic rather than merely additive effect. Administration of the prostaglandin antagonist into the cerebral ventricles also inhibited hyperalgesia evoked by carrageenin.

Hunskaar[33] suggested that the behavioural response to intra-peritoneal injection offormalin and acetic acid shows 2 phases; the first due to direct stimulation of nociceptors and the second involving pain secondary to inflammation. The short latency of the immediate response, he suggests, represents a central mechanism of action. Acetyl salicylic acid reduced the direct response to acute noxious stimulation. Clear antinociceptive effects of aspirin were noted within 30 seconds of noxious stimulation, at a time when no established inflammation would be present and aspirin and morphine showed almost identical time-effect relationships.

Carlsson et al)30] recorded activity from ascending axons of the spinal cord and single neurones in the dorsomedial part of the ventral nucleus (VDM) of rat thalamus elicited by supramaximal electrical stimulation of nociceptive afferent nerves in the sural nerve. They found that intravenous aspirin, paracetamol, the pyrazolone derivatives metamizol and aminophenazone and morphine, dose-dependently depressed evoked activity in VDM neurones. Naloxone abolished the depressant effects of morphine but failed to reduce those of the nonopioids. Unlike morphine, the nonopioid analgesics, even at relatively high doses, did not completely block evoked activity in VDM neurones. It was suggested that so-called peripherally acting analgesic agents produce a central supraspinal analgesic effect which is weaker than morphine.

Jurna and Brune[31] investigated indomethacin, ibuprofen and diclofenac using the same rat model as Carlson et al. [30] and found that the 3 drugs produced a dose-dependent depression of evoked activity suggesting that a central action contributes to their analgesic effect. They observed that indo-

Drugs 49 (1) 1995

58

methacin was more potent than diclofenac, which was more potent than ibuprofen.

McCormack and Brune[34] have reviewed a number of reports that support the existence of a central mechanism of action of NSAIDs in humans. They quote studies which indicate that NSAIDs inhibit brain prostaglandin synthesis. However, the clinical relevance remains unclear since the pain-related role of prostaglandins in the central nervous system is not well established. In human volunteers the late pain response of the electroencephalogram (EEG) evoked by electrical stimulation of tooth pulp is decreased by diclofenac)35] Electrophysiological evidence for a supraspinal analgesic effect of keto prof en has been strongly suggested in a double-blind crossover study in paraplegic patients)27] Intrathecal administration of lysine acetylsalicylate relieved intractable pain from a variety of aetiologies)36]

Various mechanisms may be suggested to account for the central action of NSAIDs. Interference with the formation of prostaglandins or with transmitters or modulators in the nociceptive system may occur. Alternatively, the central action may be mediated in part by endogenous opioid peptides or they may block the release of serotonin by central secretion of bradykinin)3!]

2. Dose-Response Effects and Enantiomeric NSAIDs

2.1 Variability in Drug Response

Over the last 3 decades there has been a dramatic increase in the number of new NSAIDs available. Unfortunately, this increase has not been matched by a significant improvement in therapeutic index)37] Furthermore, there is considerable interpatient variability in pain relief obtained from NSAIDs.[37-39] As a result, ithas proved extremely difficult to construct any meaningful rank order of efficacy from the published data)37,40] Scott et al. [40] studied the variability in response of patients to aspirin, benory late, diclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen and sulindac. They found that variation


Cashman & McAnulty

between patients in response to the drugs was large whereas there was no discernible difference between the drugs overall.

Early evidence in support of individual variability in response to NSAIDs was from a study[41] of the response of patients with rheumatoid arthritis to 4 different NSAIDs (fenoprofen, ibuprofen, ketoprofen and naproxen). There was striking variation in the individual patient responses despite only minor differences in the mean outcome measures. Adverse effects were less common with ibuprofen and naproxen, but naproxen was recommended as the first choice by these authors because it was slightly more effective.

In another comparative study of aspirin, fenoprofen, ibuprofen, naproxen and tolmetin, Gall et al)42] also noted marked individual differences in response. There may be 2 possible, not necessarily mutually exclusive, causes for the interindividual variability in response to NSAIDs. These include pharmacodynamic actions and pharmacokinetic parameters. [37]

Capell et al)43] were unable to demonstrate a significant difference in serum concentration of unchanged flurbiprofen between responders and nonresponders. Several other studies have investigated the pharmacokinetics ofNSAIDs in responding and nonresponding groups of patients. Baber et al)44] and Orme et al.l45] found no difference between responders and nonresponders in the pharmacokinetics of indomethacin and flurbiprofen. In a dose-response study with ibuprofen, Grennan et al)46] reported considerable variation in plasma concentration and no significant correlation with clinical response. In contrast, Preston et al)47] studied patients' response to flurbiprofen on 2 separate occasions and found that, whilst the response to flurbiprofen correlated with the degree of pain at commencement of the 2 study periods, there was no evidence to support the concept of responders and nonresponders. The basis of the lack of doseresponse and concentration-response relationships in nonresponders may be pharmacokinetic.

Day and Brooks[37] have suggested that measurement of the active component of the drug will

Drugs 49 (1) 1995


be most likely to provide a correlation. This is likely to be most easily demonstrated with the propionic acid derivatives which exist as active and inactive stereoisomers.

2.2 Stereoisomerism and NSAIDs

Stereoisomers possess a centre of asymmetry and exist as either right-handed [R or (-)] or lefthanded [S or (+)] forms which are nonsuperimposable mirror images (enantiomers). Many synthetic chiral drugs, including a number of NSAIDs, are administered as racemic mixtures of Rand S isomers. There are often important differences in the activity of the isomers and the absorption, distribution, metabolism and excretion of such chiral mixtures may be stereospecific. In the case of propionic acid derivatives chiral inversion from one isomer to the other may occur in vivo. Anti-inflammatory analogues of propionic acid exhibit optical isomerism; only the S-enantiomers inhibit prostaglandin synthesis.[48]

The propionic acid derivatives are not the only NSAIDs to exhibit isomerism. Enantiomers of ketorolac have also been identified.l49] However, naproxen is the only member of its class that is presented as the active S-enantiomer, whereas racemic mixtures (inactive R- and active Senantiomers) of other propionic acid derivatives such as benoxaprofen, flurbiprofen, ibuprofen and ketoprofen are used in clinical practice.l50,51]

A unique unidirectional stereospecific inversion of the inactive R-enantiomer to the active Senantiomer occurs to a variable degree in vivo.l48,52] The extent of this inversion varies depending on the drug and the individual person.[50,53] The R-enantiomer of fenoprofen is converted almost totally to the -enantiomer, whereas very little R-ketoprofen or R-flurbiprofen is converted to the S form. [5 1,54] In a study of the kinetics of chiral inversion in dogs Ahn et al.l55] have shown that 70 to 75% of an administered dose of ibuprofen undergoes R to S inversion. Furthermore feedback inhibition occurs, in which R to S inversion may be inhibited by the S-enantiomer.


59

In rats, the bioavailability of the active Senantiomer of pirprofen is greater than the inactive R-enantiomer.l56] No chiral inversion of pirprofen occurs and, because the S-enantiomer is less protein bound, this suggests that first pass metabolism is also stereoselective. In humans, according to Lee et al.l48] an average of 63% of an administered dose of R-ibuprofen is inverted to the S-enantiomer.

The terminal half-lives of the 2 enantiomers of ibuprofen are similar in humans, but plasma concentrations of the S-enantiomer exceed those of the R-enantiomer because of chiral inversion. The pharmacokinetics of each isomer are linear. However, there is large interindividual variability in the ratio of R to S, which probably accounts for the lack of correlation between racemic ibuprofen concentration and therapeutic efficacy.l57]

The inversion reaction probably occurs for all arylpropionic acid analogues. Even naproxen, which is commercially available as the S-enantiomer undergoes chiral inversion.[52] Experiments with rat liver homogenates have shown that R-ibuprofen and Rfenoprofen but not S-ibuprofen or R- and Sflurbiprofen undergo chiral inversion, findings which are consistent with human experienceJ54,58] The prerequisite for stereospecific inversion appears to be the highly stereoselective esterification of the R-enantiomer via its coenzyme-A, thioester. Once the R-ester is formed, racemisation and hydrolysis occurs.l48,50,54,58] In the case of rapid inversion, inactive R-enantiomer acts as a prodrug for the active S-antipode. In the case of slow inversion, R is an unnecessary impurity.[52]

With the exception of naproxen and fenclofenac, no correlation has been established between dose, plasma concentration and effect for any NSAID of the 2-arylpropionic acid class.l45,46] Grennan et al.[46] found very poor correlation between plasma concentration and clinical response to ibuprofen. A plateau effect was observed in rheumatoid arthritis patients, with ibuprofen 1600 mg/day seeming to be the optimal dose. Lee et al.[48] have stated that the pharmacokinetics of ibuprofen cannot be defined satisfactorily in terms of total ibuprofen concentrations. Hutt and Cald-

Drugs 49 (1) 1995

60

Table I. Adverse effects of nonsteroidal anti·inflammatory drugs (NSAIDs)

Common Gastrointestinal disturbances

Gastric irritation

Increased bleeding time

Renal impairment

Uncommon

Asthma

Allergy

well [52] agree and state that it is essential to assay active isomer, since assay of the racemate is oflimited value. It is possible that measurement of the concentration of the active enantiomer rather than racemic drug in plasma will enable a correlation between plasma concentration and efficacy to be established for NSAIDs of the 2-ary lpropionic acid classJ53]

There may be benefits to using the S-enantiomer as opposed to racemic mixtures since toxicity of NSAIDs is related to the active formJ52] Chiral inversion might be expected to enhance toxicity. Hutt and Caldwell[52] suggest that use of the S-enantiomer permits the use of a reduced dose and hence reduces variability of response. Stock et al.l59] found no difference between 2 groups of patients treated with either racemic ibuprofen 600mg 3 times daily or S-ibuprofen 400mg 3 times daily with respect to efficacy or adverse effects. They concluded that S-ibuprofen was advantageous because it reduced the metabolic load to the body. However, not everyone agrees. Geisslinger et al.l60] found that the interindividual variation in the pharmacokinetics of S-ibuprofen following racemate administration was similar to that following administration of the single isomer, suggesting that chiral inversion was not a major factor contributing to variability in drug disposition. Geisslinger et al.l60] felt that the administration of a single isomer offered no advantage.

3. Adverse Responses to NSAIDs

NSAIDs can damage gastrointestinal mucosa, impair renal function and may be associated with


Cashman & McAnulty

an increased risk of postoperative haemorrhage. They can also provoke acute asthma in susceptible patients (table I). However, gastrointestinal adverse effects, such as dyspepsia with a tendency to gastric erosions and ulceration, are the main adverse effects of NSAIDs. Lesions of the gastrointestinal tract are not predictable, and all NSAIDs are incriminated to some extent. The association between peri operative NSAID treatment, upper gastrointestinal, renal, haematological and allergic adverse effects have been extensively reviewed previously in Drugs.l61 ,62]

The UK Committee on Safety of Medicines and the Medicines Control Agency reviewed the evidence on the relative safety of7 of the most widely used oral non-aspirin NSAIDs. Results from 10 epidemiological studies were combined with results from adverse drug reaction reporting in the UK over the last 5 years. The combined information indicates that azapropazone is associated with the highest risk and ibuprofen with the lowest risk of serious upper gastrointestinal toxicity. Diclofenac, indomethacin, ketoprofen, naproxen and piroxi-

Table II. Comparison of acute toxicity (expressed as LD50) and gastrointestinal toxicity (expressed as ED50) of various nonsteroidal anti-inflammatory drugs (NSAIDs)164]

Compound Mean LD50 Mean ED50 (mg/kg) (mg/kg)

Propionic acids Ibuprofen 969 15

Indoprofen 7.5

Flurbiprofen 1.0

Ketoprofen 160 3.5

Naproxen 543 3.2

Acetic acids

Diclofenac 240 6.5

Indomethacin 19

Fenamates

Mefenamic acid 790

Pyrazolones

Phenylbutazone 700

Oxicams

Piroxicam 255 2.9

Abbreviations: ED50 = dose that produces gastriC ulceration in 50% of animals; LD50 = dose that is lethal to 50% of animals.

Drugs 49 Cl) 1995

NSAIDs in Peri surgical Pain Management 61

Table III. Ranking of nonsteroidal anti-inflammatory drugs (NSAIDs) according to total deaths and complications in which they have been implicated651

NSAID Total serious reactions (deaths)

Azapropazone 87.9 (9.9)

Piroxicam 68.1 (6.2)

Fenoprofen 43.7 (6.6)

Naproxen 41.1 (5.6)

Diclofenac 39.4 (3.1)

Flurbiprofen 35.8 (3.3)

Indomethacin na (3.3)

Ketoprofen 38.6 (1.6)

Ibuprofen 13.2 (0.7)

Abbreviation: na denotes data not available.

cam are associated with intermediate risk, although the latter may be associated with a higher risk than other NSAIDs in this group. Non-gastrointestinal adverse reactions to NSAIDs (i.e. renal, hepatic, allergic and haematological) were less common. Spontaneous reporting in the UK over the last 14 years indicates that azapropazone followed by diclofenac are most likely to cause these adverse reactions, while ibuprofen, indomethacin and ketoprofen are least likely.[63]

3.1 Adverse Gastrointestinal Effects

The acute toxicity of NSAIDs in rats is reviewed in table II. Gastrointestinal adverse effects are the commonest adverse reaction to NSAIDs and constitute the greatest risk of death (table III). The dosage and duration of NSAID treatment, as well as a history of peptic ulceration, are the most important determinants of the likelihood of gastric mucosal damage)65] Furthermore, the degree of enzyme inhibition of many NSAIDs correlates with their capacity to erode gastric mucosa)66] The effects on the gastric mucosa result from both a systemic and a direct local irritant action of NSAIDs.[67,68] The use of rectal and parenteral routes of administration, and preparations designed for intestinal rather than gastric release may reduce the extent of any local effect)67] Although gastric adverse effects ofNSAIDs correlate closely with the levels of circulating metabolites, rectal


Gastrointestinal reactions Others

67.0 20.9

58.7 9.4

32.3 11.4

32.8 8.4

20.9 18.5

27.4 8.4

na na

33.2 5.3

6.6 6.6

administration of NSAIDs can reduce gastric intolerance by 20 to 30%.

Concern about the risk of serious NSAIDinduced gastrointestinal toxicity has led to the empirical use of various prophylactic therapies. Synthetic prostaglandins may be useful in the treatment and prevention of NSAID-induced gastropathy.[69] Misoprostol, a synthetic PGEI analogue, inhibits gastric acid secretion by binding to an E-type prostaglandin receptor on the surface of gastric parietal cells)70] There is endoscopic evidence that misoprostol can prevent NSAID-induced gastric and duodenal ulcers associated with long term treatment, whereas histamine H2 receptor antagonists only protect against duodenal ulcers.[69,71,72]

In a controlled trial comparing omeprazole with ranitidine in the treatment of patients with gastric ulcer, Walan et al)73] included a subgroup who continued to receive NSAIDs during anti-ulcer therapy. Although the numbers in each subgroup were small, results with omeprazole were better than those with ranitidine. In addition, continued use of NSAIDs did not impair ulcer healing with omeprazole)73] At present, there are no data to justify the use of sucralfate in NSAID-related gastric ulceration)68]

Although gastrointestinal haemorrhage is generally rare after short term administration, the risk of bleeding in surgical patients following brief short term exposure to NSAIDs is unclear. Dyspep-

Drugs 49 (1) 1995

62

sia and ulceration may occur following administration of rectal and parenteral, as well as oral, formulations. Short term NSAID treatment in volunteers has been shown to result in endoscopically detectable gastroduodenal mucosallesions.[74] However,

serious complications such as bleeding and per

foration were not observed. Lanza et al.l74] found that short term administration of ibuprofen and naproxen in low doses did not induce lesions, but indomethacin and aspirin did.

There have been numerous studies of the risk of gastroduodenal complications during long term treatment with NSAIDs. Meta-analysis of the published data indicates that the odds ratio for overall risk of serious gastroduodenal complications associated with long term NSAID treatment is increased 3-fold compared with untreated patients.l61 ] However, there does not appear to be any increase in the incidence of serious complications during the first week of treatment.

Kehlet and Dahl[61] have analysed the results of 15 studies (927 patients in all) in which perioperative NSAIDs were used for 2 to 7 days for analgesia. Patients who underwent moderate or major surgery and did not receive NSAIDs (603 patients) acted as controls. Of the 1530 patients included in the analysis there was only 1 reported case of haematemesis. This occurred in a patient who had received perioperative rectal indomethacin, but the haematemesis was transient and required no treatment.[7S] None of the control patients had a serious gastrointestinal event. Kehlet and Dahl suggest that NSAID treatment of less than 1 week may lead to superficial gastrointestinal mucosal damage in volunteers, but that there does not appear to be any evidence of an increased risk of severe gastrointestinal complications during perioperative NSAID treatment of similar duration.

Ingham and Portenoy[76] have reviewed the results of long term administration and found that there is a higher risk associated with the use of piroxicam than aspirin, ibuprofen, indomethacin or naproxen. The risk associated with piroxicam is up to 18 times that of ibuprofen, which is associated with less risk than aspirin.


Cashman & McAnulty

Two large studies have recently reported on the odds ratio for the risk of gastrointestinal haemorrhage associated with 7 commonly prescribed NSAIDs.l77,78] Although NSAIDs are associated with an excess risk of bleeding, ibuprofen tends to carry the lowest risk.

3.2 Adverse Renal Effects

Prostaglandins have the capacity to influence all elements of renal function, but under normal conditions prostaglandin synthesis plays only a minor role in the maintenance of renal function. In animal studies, NSAID-induced reduction of renal prostaglandin levels was of little physiological consequenceV9] Renal effects of NSAIDs are dose and duration dependent and tend to recover on cessation of treatment. The majority of clinical studies have not shown any significant effects of NSAIDs on haemodynamics in normal human kidneys.lsO] However, prostaglandin control of renal function becomes significant when there are disturbances in fluid or electrolyte balance with a compensatory increase in vasodilatory prostaglandins to support renal blood flow.

Administration of NSAIDs reduces glomerular filtration rate, can cause renal ischaemia and may lead to acute renal failure.l sO,Sl] NSAIDs, such as indomethacin, have been shown to decrease glomerular filtration rate and effective renal plasma flow when there is disturbed renal function.[l4] In patients with mild chronic renal failure, even a brief course of ibuprofen may precipitate acute renal failure.l S2] Acute renal failure following administration of ketorolac in patients with known risk factors has been reported.lS3]

The stress of anaesthesia and surgery in patients without compromised renal blood flow may increase the risk of renal ischaemia following administration of NSAIDs. Transient postoperative renal impairment after intravenous infusion of diclofenac has been reported following thoracotomy.lS4] Smith et al.lS5] reported, in 2 patients who had previously taken NSAIDs without adverse effect, development of renal failure when they received ketorolac in association with surgery. This con-

Drugs 49 (1) 1995


trasts with the findings of Aitken et aU86] who suggest that ketorolac does not cause the same degree of renal impairment as other NSAIDs. One case of reversible nephrotic syndrome with interstitial nephritis has been reported in a 74-year-old woman who had received topical piroxicamJ81] It is of note that topical application of piroxicam over 14 days in volunteers resulted in blood concentrations 5% of that achieved by the oral routeJ87] Elderly patients may achieve higher concentrations because of reduced plasma clearance, thin skin and frequent application of the drug over large areasJ81]

3.3 Aspirin and Bronchospasm

Aspirin and other NSAIDs may precipitate acute bronchospasm in asthmatic patientsJ16,88] The prevalence of sensitivity to NSAIDs in adults with asthma is of the order of 5 to 10% and is common in those with atopic allergy. The mechanism of the reaction is unclear. Once thought to be allergic in nature,[16] aspirin-related bronchospasm is now considered to have a pharmacological basisJ88] Repeated administration of aspirin induces tolerance and may even be associated with development of a bronchodilator response.l89]

4. Choosing an NSAID for Use in the Peri operative Period

4.1 Rational Prescribing of NSAIDs

Rational prescribing of NSAIDs in the perioperative period is particularly important. The basic tenets for prescribing the drugs for long term use outlined by Orme[90] and by Ingham and Portenoy[76] can be adapted for short term postoperative use.

4. 1. 1 Drug Selection • Choose from a limited selection of NSAIDs

spanning the different chemical groups. • Prefer established drugs with long clinical

experience and good safety profile (e.g. ibuprofen).


63

• Record concurrent drug therapy and be aware of possible pharmacokinetic and pharmacodynamic interactions.

• Avoid NSAIDs in patients with known contraindications to their use.

• Use only one NSAID at a time, and ensure adequate dosage.

4.1.2 Route of Administration

• Be aware of available preparations. Many of the newer NSAIDs have the potential advantage of being available in a range of formulations including oral, rectal, parenteral and topical.

• Use the least invasive route possible.

4.1.3 Dosage

• Adapt dosages to suit patients' requirements, particularly with respect to duration of action.

• Increase dose until adequate analgesia occurs or maximum recommended dose is reached.

• Review therapy frequently and change to an alternative NSAID, possibly from another class, if there is poor response to treatment.

4.1.4 Toxicity • Observe for potential toxicity (gastrointestinal,

renal, haematological, etc.). • Increase frequency of monitoring for at-risk pa

tients (the elderly and those with concurrent disease).

• Consider prophylaxis against adverse gastrointestinal events in these patients.

4.2 Pharmacokinetic-Pharmacodynamic Relationships

In general, the dosage of a drug should be tailored to the individual patient's response, based on clinical assessment. However, the concentration of almost any drug may fluctuate markedly during each dose interval as a result of continuing absorption, distribution and elimination of the drug. An understanding of the pharmacokinetics of drugs is therefore necessary in order to achieve steady-state plasma concentrations.

For single doses of aspirin, analgesic effect has been shown to increase with increasing doses up to

Drugs 49 (l) 1995

64

1200mg.l91 ,92]It may be more appropriate to consider this dose-response relationship as a relationship between drug concentration and response,[93] However, in the case of aspirin and other NSAIDs there is a delay in the time to maximum pharmacological effect relative to the time to peak plasma concentration of the drug. It has been shown using radio-labelled ketorolac that the time to peak plasma concentration after intravenous administration is achieved in less than 5 minutes and more slowly after intramuscular (45 minutes) and oral (30 minutes) administration.l94] However, the time to peak plasma concentration correlates poorly with onset of analgesia which does not reach a peak until 30 minutes after intravenous administration.[94] The time to peak plasma concentration after oral administration in humans has been det~rmined for a number of NSAIDs (table IV).

Levy[93] argues that there is a concentrationeffect relationship for aspirin which is complex and time dependent. He suggests a number of reasons for the observed disparity between clinical effect and plasma concentration:

• the site of action of the drug may have the pharmacokinetic characteristics of a compartment distinct from the central compartment;

• the drug may act indirectly; or • the effects may be mediated by an active meta

bolite. It is possible that aspirin is an example of this

last mechanism since there is still discussion as to whether aspirin is the active compound or merely a pro-drug for salicylate.

In a review of the temporal pattern of pain relief produced by analgesic drugs, Levy[96] concluded that the rate of decline in pharmacological effect was unrelated to the specific analgesic agent. He proposed that the larger the dose (and hence presumably the higher the peak concentration of the drug in the biophase), the greater the analgesic effect would be. Moreover, the greater the maximum analgesic effect, the longer the duration of effect and the greater the total area under the plasma concentration versus time curve. Levy argued that the logical extension of this reasoning is that sustained

© Adis International Lirnited, All rights reserved,

Cashman & McAnulty

Table IV. Pharmacokinetics of various nonsteroidal anti-inflammatory drugs (NSAIDs)[95J

Compound Time to peak plasma Half-life concentration (h) (h)

Flurbiprofen 1.5-3,0 3-6

Ibuprofen 0,5-1,5 2-5

Indomethacin 1.0-2,0 4-8

Ketoprofen 0,3 2-4

Naproxen 1,0-2,0 10-20

Phenylbutazone 2,0 40-80

Piroxicam 2,0 40-80

release preparations are unlikely to provide prolonged analgesia. Rapidly absorbed preparations should produce not only more immediate but also more pronounced analgesia. However, Cass and Frederikl97] found identical durations of analgesia produced by both regular and sustained release aspirin.

Although the pharmacokinetics of repeat doses may have been elucidated for many analgesics, little is known about the pharmacodynamics. Following oral administration of aspirin, salicylate concentrations are up to 50 times higher than aspirin levels and, unlike aspirin, are detectable for several hours.l9] Peak plasma concentrations of salicylate increase after each dose until a steady-state is reached. By contrast, aspirin concentrations decline rapidly to zero during each dose interval because of the very short biological half-life of the drug. Thus, salicylic acid but not aspirin accumulates in the plasma with repeat drug administration. If the analgesic effect of aspirin were due to salicylic acid, a gradually increasing analgesic effect during repeated aspirin administration would result, whereas there would be no such increase in analgesia if the effect were produced primarily by aspirin itself.

Most observations of repeated administration of aspirin are consistent with the view that the analgesic effect is produced mainly by the drug itself rather than its hydrolysis product, salicylic acid. However, salicylic acid seems to be primarily responsible for the anti-inflammatory and toxic effects of aspirin. Salicylate exhibits capacity-limited

Drugs 49 (l) 1995


elimination; hence plasma salicylate concentrations decline relatively more slowly with an increasing daily dose.

5. Dosage Regimens

5.1 Oral and Rectal

Drugs given at fixed dose intervals, rather than in response to patient demand, may be associated with better analgesia. Regular oral ketorolac 5mg and lOmg 4 times daily has been shown to be as effective as regular oral diflunisal 500mg twice daily for the treatment of postmeniscectomy pain. [98] Lovett et al. [99] demonstrated that despite similar pain scores, postoperative papaveretum requirements were reduced 25 to 30% by concurrent regular mandatory doses with intramuscular diclofenac 75mg pre- and postoperatively on the day of surgery, followed thereafter by oral diclofenac 50mg 3 times daily for the next 3 days. This reduction in opioid demand was comparable to that obtained by Owen et al. [1 00] using oral ibuprofen pre- and postoperatively in patients undergoing gynaecological surgery and similar to that demonstrated in a study in abdominal surgery using 2 postoperative doses of dic1ofenacJIOI] However, this degree of morphine-sparing is less impressive than the 50% reduction reported by Derbyshire and Richardsonll02] with only a single (50mg oral) pre- and (lOOmg rectal) postoperative dose of dic1ofenac.

Rectal administration of indomethacin in a relatively high dose (lOOmg 8-hourly) commenced either preoperatively[I03] or postoperatively[75] reduced opioid requirements and improved pain relief after major abdominal surgery. Rectal indomethacin (200mg postoperatively followed by 100mg twice daily) reduced pain scores and opioid requirements compared with placebo following thoracic surgery)104] Preoperative administration of intravenous indomethacin followed by suppositories 3 times daily postoperatively reduced opioid requirement by 29% compared with placebo after gynaecological surgery) 105] In I of these studies there was a significantly higher incidence


65

of haemorrhagic complications with the NSAID than with placebo, but gastrointestinal adverse effects were similar between groups.[75]

5.2 Parenteral

5.2. 1 Intramuscular Parenteral administration of NSAIDs results in

the rapid attainment of a therapeutic plasma concentrations. Postoperative intramuscular diclofenac has been shown to be effective in relieving pain following orthopaedic, gynaecological and major abdominal surgery)106-108] Lindgren and Djupso[106] demonstrated that intramuscular diclofenac 75mg was superior to pethidine (meperidine) 50mg and placebo in relieving postoperative orthopaedic pain. As a result of their findings Lindgren and Djupso suggested that NSAIDs, administered routinely, should be preferred to opioids in the early postoperative period.

Bossi et al.[107] showed that in the management of post cholecystectomy pain, the analgesic effect of a single injection of intramuscular diclofenac 75mg was almost identical to that of intramuscular pentazocine 50mg with regard to potency, onset time and duration of effect. Carlos[108] found that, after abdominal surgery, intramuscular dic10fenac 75mg provided equivalent but longer lasting analgesia to intramuscular pethidine 1 mg/kg and intramuscular nalbuphine 0.14 mg/kg.

Burns et al. [1 09] showed that a continuous intramuscular infusion of ketorolac is superior to intermittent intramuscular injections. Continuous intramuscular infusions of ketorolac were superior to intermittent intramuscular injections and resulted in significant morphine sparing effect[ 109, 110]

5.2.2 Intravenous Intravenous infusions are preferable to bolus

doses because the duration of analgesia following a single intravenous bolus is short. The administration of an analgesic as an infusion results in more stable blood concentrations and may be expected to provide superior analgesia. Harris and Riegelman[1ll] have suggested that a constant rate infusion of aspirin is necessary to achieve a steadystate where the tissues come into distribution

Drugs 49 (1) 1995

66

equilibrium with the plasma. Combining a loading dose with a zero-order (fixed rate) infusion is one way of accelerating the attainment of steady-state drug concentrations.

Loo and Riegelman[l12] and Rowland and Riegelman[113] used healthy volunteers to investigate absorption, distribution, metabolism and excretion kinetics of intravenous aspirin. The methylglucamine salt was administered both as a rapid intravenous injection and as an intravenous infusion. In both studies aspirin was given intravenously at known logarithmic infusion rates (in which the rate of infusion was reduced at fixed intervals with the duration of the intervals determining the half-life) and linear infusion rates, so as to mimic first- and zero-order absorption conditions. These studies showed that the kinetics of aspirin could be described using a 2-compartment model, and that it should be possible to predict plasma levels using a mathematical model. Other investigators[114-116] have investigated the effectiveness of continuous intravenous infusions of aspirin. It was found that intravenous aspirin provided pain relief equivalent to that of pethidine and morphine in a variety of surgical conditions.

Postoperative intravenous indomethacin 25mg followed by a continuous intravenous infusion was more effective in reducing pain scores and increasing pain free periods than oxycodone administered according to a similar regimen. [117] Dic10fenac has been successfully administered by slow intravenous injection[llS,119] and as an intravenous infusion,D20] without apparent adverse effect. Campbell et al.[lIS] administered diclofenac 75mg, diluted to 18ml, by slow intravenous injection after dental surgery to good effect.

Hovorka et al,l119] found that intravenous diclofenac 100mg successfully reduced the need for postoperative analgesia in diagnostic laparoscopy but not in interventional laparoscopy. Laitinen et al.[l20] found that on completion of surgery an infusion of diclofenac (75mg in 100mi isotonic saline over 30 minutes) provided equivalent analgesia to an intravenous infusion of oxycodone and was superior to an intravenous infusion of in-


Cashman & McAnulty

domethacin after orthopaedic surgery. A 2-day intravenous infusion of diclofenac provided effective analgesia after thoracotomy and was associated with a significant reduction in morphine consumption compared with a control group,lS4]

Although many NSAIDs are presented in a variety of formulations, no study has specifically compared the analgesic efficacy of alternative routes of administration of the same drug. On theoretical grounds, continuous intravenous infusions of NSAIDs should provide analgesia that is superior to that of intermittent bolus injections. Several studies have shown that intravenous infusions result in effective pain relief,lS4,1l7-120] In addition, the results of Burns et al,l109] and Gillies et al.[lIO] indicate that constant plasma drug levels are achieved using intramuscular infusions, and are associated with effective analgesia.

6. Preoperative Administration

There seems to be little benefit from administration of an NSAID before major surgery. Murphy and Medley[121] compared pain relief provided by indomethacin given pre- or postoperatively to patients undergoing thoracotomy and found no difference between the 2 groups. Even when NSAIDs were given preoperatively as part of a multimodal pre-emptive analgesic regimen to thoracotomy patients, no significant improvement was found in overall postoperative pain scores,l122] Furthermore, although the preoperative administration of NSAIDs may appear logical, there is a risk of increased bleeding particularly in patients in whom extensive surgical resection is anticipated.[75]

7. Conclusions

There are a number of general conclusions which can be drawn with regard to prescription of NSAIDs for postoperative pain relief. These relate to timing of dose, the regimen and the route of administration.

Levy's work with aspirin[96] suggests a complex relationship between plasma levels and analgesic effect. However, later studies of steady-state infusions with ketorolac indicate that superior pain re-

Drugs 49 (1) 1995


lief is associated with maintenance of constant rather than fluctuating plasma NSAID concentrations.l 109,1l0] Thus, analgesia is likely to be most effective when infusions (either intravenous or intramuscular) or mandatory oral dosage regimens are used.

In comparison with the oral route, the parenteral, rectal and topical routes of administration of NSAIDs are associated with a reduced incidence of adverse effects including gastric effects. Gastric adverse effects correlate closely with the concentrations of circulating metabolites. Nevertheless, rectal administration ofNSAIDs can reduce gastric intolerance by 20 to 30%. Furthermore, sustained release suppository formulations of NSAIDs can be effective alternatives to parenteral administration. The choice of which formulation of analgesic to use for postoperative pain relief is dictated by a number of factors. In general, the oral route cannot be used in the immediate postoperative period although some drugs, notably the oxicams, are absorbed across gastric mucosa independent of the factors that alter gastric emptying.

Future improvements in the therapeutic index of NSAIDs may derive from the development of drugs which more selectively inhibit the inducible form of CYclo-OXygenase (COX-2). Drugs available now, such as ibuprofen, which inhibit COX-2 relatively more than COX-I, can be expected to have a better safety profile than drugs which inhibit COX-I preferentially.

References I. Vane JR, Botting RM. The mode of action of anti-inflammatory

drugs. Postgrad Med J 1990; 66 Suppl. 4: S2-S 17 2. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin

abolish prostaglandin release from spleen. Nature 1971; 231: 237-9

3. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Bioi) 1971; 231: 232-5

4. Ferreira SH. Peripheral analgesia: mechanism of the analgesic action of aspirin like drugs and opiate-antagonists. Br J Clin Pharmacol 1980; 10: 237-245S

5. Von Euler US. On the specific vasodilating and plain muscle stimulating substance from accessory genital glands in man and certain animals (prostaglandin and vesiglandin). J Physio11937; 88: 213-34

6. Hemler M, Lands WEM, Smith WL. Purification of the cyclooxygenase that forms prostaglandins. Demonstration of two


67

forms of iron in the holoenzyme. J Bioi Chern 1976; 251: 2629-36

7. Ferreira SH. Prostaglandins, aspirin-like drugs and analgesia. Nature 1972; 240: 200-3

8. Higgs GA, Higgs EA, Salmon JA. Prostacyciin in inflammation. In: Vane JAR, Bergstrom S, editors. Prostacyclin. New York: Raven Press, 1979: 187-92

9. Higgs GA, Salmon JA, Henderson B, et al. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Natl Acad Sci USA 1987; 84: 1417-20

10. Higgs GA. Arachidonic acid metabolism, pain and hyperalgesia: the mode of action of non-steroid mild analgesics. Br J Pharmacol 1980; 10: 233-235S

II. Higgs GA, Moncada S, Vane JR. Prostacyclin as a potent dilator of arterioles in the hamster cheek pouch. J Physiol (Lond) 1978; 275: 30-1

12. Higgs EA, Moncada S, Vane JR. Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGFla in the rat paw. Prostaglandins 1978; 16: 153-62

13. Dray A, Bevan S. Inflammation and hyperalgesia: the team effort. Trends Pharm Sci 1993; 14: 287-90

14. Vane JR, Flower RJ, Botting RM. The mechanism of action of aspirin. In: Vane JR, Botting RM, editors. Aspirin and other salicylates. London: Chapman & Hall Medical, 1992

IS. Flower R, Gryglewski R, Herbaczynska-Cedro K, et al. Effects of anti-inflammatory drugs on prostaglandin biosynthesis. Nature (New Bioi) 1972; 238: 104-6

16. Vane JR. The mode of action of aspirin and similar compounds. J Allergy Clin Immunol1976; 58: 691-712

17. Flower RJ. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 1974; 26: 33-67

18. Lands WEM. Actions of anti-inflammatory drugs. Trends Pharmacol Sci 1981; 2: 78-80

19. Rome LH, Lands WEM. Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Nat Acad Sci USA 1975; 72: 4863-4865

20. Roth GJ, Majerus pw. The mechanism of the effect of aspirin on human platelets - I: acetylation of a particulate fraction protein. J Clin Invest 1975; 56: 624-32

21. Roth GJ, Stanford N, Majerus pw. Acetylation of prostaglandin synthase by aspirin. Proc Nat! Acad Sci USA 1975; 72: 3073-6

22. Kulmacz RJ, Lands WEM. Stoichometry and kinetics of the interaction of prostaglandin H synthase with anti-inflammatory agents. J Bioi Chern 1985; 260: 12572-8

23. Appleton RA, Brown K. Conformational requirements at the prostaglandin cyclo-oxygenase receptor site: a template for designing non-steroidal anti-inflammatory drugs. Prostaglandins 1979; 18: 29-34

24. Hemler ME, Lands WEM. Evidence for peroxide-initiated free radical mechanism of prostaglandin biosynthesis. J Bioi Chern 1980; 255: 6253-61

25. Lands WEM, Cook HW, Rome LH. Prostaglandin biosynthesis: consequences of oxygenase mechanisms on in vitro assays of drug effectiveness. Adv Prostaglandin Thromboxane Leukot Res 1976; 1: 7-17

26. Dreser H. Pharmacologisches uber Aspirin (Acetylsalicyl-saure). Pfluger's Arch Gesamte Physiol Menschen Tiere 1899; 76: 306-18

27. Wiler JC, De Brouckner T, Bussel B, et al. Central analgesic effect of ketoprofen in humans - electrophysiological evidence for a supraspinal mechanism in a double-blind and cross-over study. Pain 1989; 38: 1-7

Drugs49(lJ 1995

68

28. Ferreira SH, Nakamura M, de Abreu Castro MS. The hyperalgesic effects of prostacyclin and prostaglandin E2. Prostaglandins 1978; 16: 31-7

29. Malmbergh AB,Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance receptor blocked by spinal cyclo-oxygenase inhibition. Science 1992; 257: 1276-9

30. Carlsson K-H, Mangel W, Jurna I. Depression by morphine and the non-opioid analgesic agents, metamizol (dipyrone), lysine acetylsalicylate, and paracetamol, of activity in rat thalamus neurones by electrical stimulation of nociceptive afferents. Pain 1988; 32: 313-26

31. Jurna I, Brune K. Central effect of the non-steroid anti-inflammatory agents, indometacin, ibuprofen, and diclofenac, determined in C fibre-evoked activity in single neurones of the rat thalamus. Pain 1990; 41: 71-80

32. Ferreira SH, Lorenzetti BB, Correa FEM. Central and peripheral antialgesic action of aspirin-like drugs. Eur J Pharmacol 1978; 53: 39-48

33. Hunskaar S. Similar effects of acetylsalicylic acid and morphine on immediate responses to acute noxious stimulation. Pharmacol Toxicol1987; 60: 167-70

34. McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of the non-steroidal antiinflammatory drugs. Drugs 1991; 41: 533-47

35. Attal N, Kayser V, Eschalier A, et al. Behavioural and electrophysiological evidence for an analgesic effect of a non-steroidal anti-inflammatory agent, diclofenac. Pain 1988; 35: 341-8

36. Devoghel J-e. Small intrathecal doses oflysine-acetylsalicylate relieve intractable pain in man. J Int Med Res 1983; II: 90-1

37. Day RO, Brooks PM. Variations in response to non-steroidal antiinflammatory drugs. Br J Clin Pharmacol 1987; 23: 655-8

38. Bellamy N. Variance in NSAID studies: contribution of patient variance. Agents Actions Supp11985; 17: 21-8

39. Day RO. Variability in response to NSAID. Agents Actions Suppl 1985; 17: 15-9

40. Scott DL, Roden S, Marshall T, et al. Variations in response to non-steroidal anti-inflammatory drugs. Br J Clin Pharmacol 1982; 14: 691-4

41. Huskisson EC, Woolf DL, Balme HW, Scott J, Franklyn S. Four new anti-inflammatory drugs: responses and variations. BMJ 1976; 48: 1048-9

42. Gall EP, Caperton JF, McComb JE, et al. Clinical comparison of ibuprofen, fenoprofen calcium, naproxen and tolmetin sodium in rheumatoid arthritis. J Rheumatol 1982; 9: 402-7

43. Capell HA, Konetschnik B, Glass Re. Anti-inflammatory analgesic drug responders and non-responders: a clinico-pharmacological study offlurbiprofen. Br J Clin PharmacoI1977; 15: 311-6

44. Baber N, Halliday LDC, Van Den Heuvel WJA, et al. Indomethacin in rheumatoid arthritis: clinical effects, pharmacokinetics, and platelet studies in responders and non-responders. Ann Rheum 1979; 13: 128-37

45. Orme ML'E, Baber N, Keenan L, et al. Pharmacokinetics and biochemical effects in responders and non-responders to nonsteroidal anti-inflammatory drugs. Scand J Rheumatol 1981; (Suppl. 39): 19-27

46. Grennan DM, Aarons L, Siddiqui M, et al. Dose-response study with ibuprofen in rheumatoid arthritis: clinical and pharmacokinetic findings. Br J Clin Pharmacol 1983; 18: 311-6

47. Preston SJ, Arnold MH, Beller EM, etal. Variability in response to non-steroidal anti-inflammatory analgesics: evidence from controlled clinical therapeutic trial of flurbiprofen in rheumatoid arthritis. Br J Clin Pharmacol 1988; 26: 759-64


Cashman & McAnulty

48. Lee EJD, Williams K, Day R, et al. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19: 669-74

49. Hayball PJ, Tamblyn JG, Holden Y, et al. Stereoselective analysis ofketorolac in human plasma by high-performance liquid chromotography. Chirality 1993; 5: 31-5

50. Williams K, Day R, Knihinicki R, et al. The stereoselective uptake of ibuprofen enantiomers into adipose tissue. Biochem Pharmacol 1986; 35: 3403-5

51. Oates JA, Wood AJJ. Nonsteroidal antiinflammatory drugs -differences and similarities. N Eng J Med 1991; 24: 1716-25

52. Hutt AJ, Caldwell J. The metabolic chiral inversion of 2-aryl propionic acids - a novel route with pharmacological consequences. J Pharm Pharmacol 1983; 35: 693-704

53. Day RO, Williams KM, Graham GG, et al. Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 1988; 43: 480-7

54. Knihinicki RD, Williams KM, Day RO. Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs - I: in vitro studies of ibuprofen and flurbiprofen. Biochem Pharmacol 1989; 38: 4389-95

55. Ahn AHY, Amidon GL, Smith DE. Stereoselective systemic disposition of ibuprofen enantiomers in the dog. Pharm Res 1991; 8: 1186-90

56. Brocks DR, Liang WT, Jamali F. Influence of the route of administration on the pharmacokinetics of pirprofen enantiomers in the rat. Chirality 1993; 5: 61-4

57. Olliary J, Tod M, Nicolas P, et al. Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man. Biopharm Drug Dispos 1992; 13: 337-44

58. Knihinicki RD, Day RO, Williams KM. Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs - II: racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters. Biochem Pharmacol 1991; 42: 1905-11

59. Stock KP, Geisslinger G, Loew D, et al. S-ibuprofen versus ibuprofen-racemate: a randomized double-blind study in patients with rheumatoid arthritis. Rheumatol Int 1991; 11: 199-202

60. Geisslinger G, Stock KP, Loew D, et a1. Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1993; 35: 603-7

61. Kehlet H, Dahl JB. Are perioperative nonsteroidal anti-inflammatory drugs ulcerogenic in the short term? Drugs 1992; 44 Supp1. 5: 38-41

62. Kenny GNe. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992; 44 Suppl. 5: 31-7

63. Committee on Safety of Medicines and the Medicines Control Agency. Relative Safety of oral non-aspirin NSAIDs. Current Problems Pharmacovig 1994; 20 Aug: 9-11

64. Jahn U. Survey of toxicological investigations of azapropozone. In: Rainsford KD, editor. Azapropazone. Dordrecht: Kluwer Academic Publishers, 1989: 21-9

65. Which NSAID? [editorial]. Drug Ther Bull 1978; 25: 81-4 66. Carson JL, Strom BL, Soper KA, et al. The association of non

steroidal antiinflammatory drugs with upper gastrointestinal tract bleeding. Arch Intern Med 1987; 147: 85-8

67. Aspirin and the stomach [editorial]. BMJ 1981; 282: 91-2 68. Soll AH, Weinstein WM, Kursta J, et a1. Nonsteroidal anti-in

flammatory drugs and peptic ulcer disease. Ann Intern Med 1991; 114: 307-19

69. Fenn GC, Robinson Ge. Misoprostol - a logical therapeutic approach to gastroduodenal mucosal injury induced by non-

Drugs 49 (1) 1995


steroidal anti-inflammatory drugs? J Clin Pharm Ther 1991; 16: 385-409

70. Tsai BS, Kessler LK, Schoenhard G, et al. Demonstration of specific E-type prostaglandin receptors using enriched preparations of canine parietal cells and [3H] misoprostol free acid. AmJ Med 1987; 83 Suppl. IA: 9-14

71. Roth S, Agrawal N, Mahowald M, et al. Misoprostal heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989; 149: 775-9

72. Agrawal NM, Saggioro A. Treatment and prevention ofNSAID induced gastroduodenal mucosal damage. J Rheumatol 1991; 18 (Suppl.): 15-8

73. Walan A, Bader J-P, Classen M, et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N Engl J Med 1989; 320: 69-75

74. Lanza FL, Royer Jr GL, Nelson RS, et al. The effects of ibuprofen, indomethacin, aspirin, naproxen and placebo on the gastric mucosa of normal volunteers. Digest Dis Sci 1979; 24: 823-8

75. Reasbeck PG, Rice ML, Reasbeck Jc. Double-blind controlled trial of indomethacin as an adjunct to narcotic analgesia after major abdominal surgery. Lancet 1982; i: 115-8

76. Ingham JM, Portenoy RK. Drugs in the treatment of pain: NSAIDS and opioids. CUff Opin Anaesthesiol 1993; 6: 838-44

77. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769-72

78. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 1075-8

79. Gray DA, Langrieger N, Reschmaier J, et al. The effect of acetylsalicylic acid on renal function in the Pekin duck. Br J Pharmacol 1984; 82: 329-38

80. Harris K. The role of prostaglandins in the control of renal function [editorial]. Br J Anaesth 1992; 69: 233-5

81. 0' Callaghan CA, Andrews PA, Ogg CS. Renal disease and use of topical non-steroidal anti-inflammatory drugs. BMJ 1994; 308: 110-1

82. Whelton A, Stout RL, Spilman PS, et al. Renal effects of ibuprofen, piroxicam and sulindac in patients with asymptomatic renal failure. Ann Intern Med 1990; 112: 568-76

83. Pearce CJ, Gonzales FM, Wallin JD. Renal failure and hyperkalaemia associated with ketorolac tromethamine. Arch Intern Med 1993; 153: 1000-2

84. Perttunen K, Kalso E, Heinonen J, et al. LV. diclofenac in postthoracotomy pain. Br J Anaesth 1992; 68: 474-80

85. Smith K, Halliwell RMT, Lawrence S, et al. Acute renal failure associated with intramuscular ketorolac. Anaesth Intens Care 1993; 21: 700-3

86. Aitken HA, Burns JW, McArdle CS, et al. Effects of ketorolac trometamol on renal function. Br J Anaesth 1992; 68: 481-5

87. Doogan DP. Topical non-steroidal anti-inflammatory drugs. Lancet 1989; ii: 1270-1

88. Power L Aspirin-induced asthma. Br J Anaesth 1993; 71: 619-21

89. Asad SI, Kemeny OM, Youlten L, et al. Effect of aspirin in 'aspirin sensitive' patients. BMJ 1984; 288: 745-8

90. Orme M. Profile of non-steroidal anti-inflammatory drugs. Prescribers J 1990; 30: 95-100

91. Parkhouse J, Rees-Lewis M, Skolinik M, et al. The clinical dose response to aspirin. Br J Anaesth 1968; 40: 433-41

92. Seymour RA, Rawlins MD. Efficacy and pharmacokinetics of aspirin in post-operative dental pain. Br J Clin Pharmacol 1982; 13: 807-10


69

93. Levy G. Clinical pharmacokinetics of salicylates: a reassessment. Br J Clin Pharmacol 1980; 10: 285-290S

94. Greenwald RA. Ketorolac: an innovative non-steroidal analgesic. Drugs Today 1992; 28: 41-6

95. McCormack K. Mathematical model for assessing risk of gastrointestinal reactions to NSAIDs. In: Rainsford KD, editor. Azopropizone. Dordrecht: Kluwer Academic Publishers, 1989: 81-93

96. Levy G. Kinetics of pharmacologic effects. Clin Pharmacol Ther 1967; 7: 362-72

97. Cass LJ, Frederik WS. A clinical evaluation of a sustained-release aspirin. Curr Ther Res 1965; 7: 683-92

98. Honig WJ, Van Ochten J. A multiple-dose comparison of ketorolac tromethamine with diflunisal and placebo in postmeniscectomy pain. J Clin Pharmacol 1986; 26: 700-5

99. Lovett PE, Stanton SL, Hennessey 0, et al. Pain relief after major gynaecological surgery. Br J Nurs 1994; 3: 159-62

100. Owen H, Glavin RJ, Shaw NA. Ibuprofen in the management of postoperative pain. Br J Anaesth 1986; 58: 1371-5

101. Hodsman NBA, Burns J, Blyth A, et al. The morphine sparing effects of diclofenac sodium following abdominal surgery. Anaesthesia 1987; 42: 1005-8

102. Derbyshire DR, Richardson J. Voltarol (diclofenac) as a peri operative analgesic supplement. Br J Anaesth 1987; 59: 1327-8

103. Thind P, Sigsgaard T. The analgesic effect of indomethacin in the early postoperative following abdominal surgery. Acta Chirug Scand 1988; 154: 9-12

104. Pavy T, Medley C, Murphy OF. Effect of indomethacin on pain relief after thoracotomy. Br J Anaesth 1990; 65: 624-7

105. Engel C, Lund B, Kristensen AA, et al. Indomethacin as an analgesic after hysterectomy. Acta Anaesthesiol Scand 1989; 33: 498-501

106. Lindgren U, Djupso H. Diclofenac for pain after hip surgery. Acta Orthop Scand 1985; 55: 28-31

107. Bossi L, Galante G, Conoscente F, et al. Tratamento del dol ore postoperatorio. Confronto in doppio cieco fra diclofenac e pentazocin. Minerva Anest 1984; 50: 373-8

108. Carlos DE. A comparative study of the efficacy of diclofenac sodium, meperidine HCI and nalbuphine HCI in postoperative analgesia. In: Birdwood GFB, Gantmacher JV, editors. Further experience with voltaren. Bern: Hans Huber, 1984: 73-8

109. Burns JW, Aitken HA, Bullingham RES, et al. Double-blind comparison of the morphine sparing effect of continuous and intermittent i.m. administration of ketorolac. Br J Anaesth 1991; 67: 235-8

110. Gillies GW, Kenny GN, Bullingham RE, et al. The morphine sparing effect of ketorolac tromethamine: a study of a new non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 42: 727-31

Ill. Harris PA, Riegelman. Influence of the route of administration on the area under the plasma concentration-time curve. J Pharm Sci 1969; 58: 71-5

112. Loo JCK, Riegelman S. New method for calculating the intrinsic absorption rate of drugs. J Pharm Sci 1968; 57: 918-28

113. Rowland M, Riegelman S. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. J Pharmaceut Sci 1968; 57: 1313-9

114. Miralles FS, Carceles MD, Nicol JA, et al. Administration of lysine acetylsalicylate and pethidine in acute postoperative pain. Rev Esp Anestiol Reanim 1992; 39: 149-54

115. Cashman IN, Jones RM, Foster JMG, et al. Comparison of infusions of morphine and lysine acetyl salicylate for the relief of pain after surgery. Br J Anaesth 1984; 57: 255-8

Drugs 49 (1) 1995

70

116. Jones RM, Cashman IN, Foster JMG, et al. Comparisons of infusions of morphine and lysine acetyl salicylate for the relief of pain following thoracic surgery. Br J Anaesth 1984; 57: 259-63

117. Mattila MK, Ahlstrom-Bengs E, Pekkola P. Intravenous indomethacin in prevention of post-operative pain. BMJ 1993; 287: 1026

118. Campbell WI, Kendrick R, Patterson C. Intravenous diclofenac sodium. Anaesthesia 1990; 45: 763-6

119. Hovorka J, Kallela H, Kortilla K. Effect of intravenous diclofenac on pain and recovery profile after day-case laparoscopy. Eur J Anaesthiol 1993; 10: 105-8

120. Laitinan J, Nuutinen L, Kiiskial E-L, et al. Comparison of intravenous diclofenac, indomethecin and oxycodone as post-

Errata

Cashman & McAnulty

operative analgesics in patients undergoing knee surgery. Eur J Anaesthiol 1992; 9: 29-34

121. Murphy DF, Medley C. Preoperative indomethacin for pain relief after thoracotomy: comparison with postoperative indomethacin. Br J Anaesth 1993; 70: 298-300

122. Kavanagh BP, Katz J, Sandler AN, et al. Multimodal analgesia before thoracic surgery does not reduce postoperative pain. Br J Anaesth 1994; 73: 184-9

Correspondence and reprints: Dr Jeremy Cashman, Consultant Anaesthetist, Department of Anaesthesia, St George's Hospital, Blackshaw Road, London SW17 OQT, England.

Vol. 47, No.5, p. 827: In the summary of Dosage and Administration, the second sentence should read, 'In adults with normal renal function, a loading dose of 400mg (approximately 6 mg/kg) every 12 hours for the first 3 doses, followed by 400mg once daily, is recommended.' [Brogden RN, Peters DH. Teicoplanin: a reappraisal of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994 May; 47 (5): 823-54J

Vol. 48, No.3, p. 389: The first sentence in the Clinical Tolerability summary should read, 'PLS administration has been well tolerated in multicentre clinical trials (including approximately 3200 patients), in which it did .. .'. p. 397: The first sentence in section 4 Clinical Tolerability should read, 'PLS has been well tolerated in large multicentre clinical trials to date (including a total of approximately 3200 infants), in which it did ... '. p. 397: In section 3.2 Prophylactic Use, the sentence beginning on line 7 of the second column should read, 'The findings of a recent meta-analysis of 3 clinical studies, including the trial discussed abov/49J and evaluating a total of 671 neonates, indicate, however, that PLS prophylaxis does significantly improve clinical outcome versus rescue treatmentY°J,

[Wiseman LR, Bryson HM. Porcine-derived lung surfactant: a review of the therapeutic efficacy and clinical tolerability of a natural surfactant preparation (Curosur!) in neonatal respiratory distress syndrome. Drugs 1994 Sept; 48 (3): 386-403J

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

Documents

Nonsteroidal Anti-Inflammatory Drugs in Perisurgical Pain Management