4

Paracetamol and propacetamol for post- operative pain: contrasts to traditional NSAIDs

C. A L B R E C H T W I E B A L C K H U G O VAN A K E N

Acute post-operative pain used to be a routine and relatively simple problem to solve and the most commonly used agents for its control were parenterally administered opioid analgesics. These drugs are potent and extremely effective analgesics, and yet, the inadequate management of post-operative pain is a ubiquitous problem that has continued for decades despite advances in pharmaceutical agents and delivery systems, and new insights into pain physiology (Papper et al, 1952; Keats, 1956; Marks and Sachar, 1973; Cohen, 1980; Donovan et al, 1987; Dauber et al, 1993).

Nevertheless, the advantages of adequate pain relief are numerous: dimin- ished morbidity and mortality have been repeatedly invoked (Cousins, 1989; Moore, 1990; Ballantyne et al, 1993). The comfort of the patient is also increased, and well-being seems to be one of the most important concerns of our modem society. In addition, it gives the anaesthesiologist an unusual degree of prestige and respect from patients and colleagues (Moore, 1990).

Pain should be regarded as only the visible part of an iceberg. Metabolic changes and inflammatory reactions are the other consequences of surgical procedures. Adequate pain relief should be an essential part of a broad acute rehabilitation strategy. Problems that are encountered in realising such a management of post-operative pain are related to the efficacy and safety of drugs and appropriate application of methods. This includes the diagnosis of pain and the assessment of its intensity which depends on the surgical procedure and on the personality of the patient.

What is the role of paracetamol, propacetamol and non-steroidal anti- inflammatory drugs (NSAIDs) in the management of post-operative pain? What are the differences between these agents?

PARACETAMOL/PROPACETAMOL AND NSAIDs P H A R M A C O L O G Y

Paracetamol (acetaminophen), the oldest known synthetic analgesic- antipyretic drug introduced in 1893 (Von Meyring), is one of the most

Batlh~re's Chnical Anaesthestology- 469 Vol. 9, No 3, September 1995 Copyright © 1995, by Bailli~re TmdaU ISBN 0-7020-2070-2 All nghts of reproduction m any form reserved

470 C. A. W I E B A L C K A N D H. V A N A K E N

frequently used around the world. It is almost insoluble and for that reason can not be used parenterally. In certain circumstances, for example after an acute trauma or operation, intravenous administration is preferable because of potential dysfunction of the gastro-intestinal tract and reduced time of onset. Propacetamol is a water-soluble precursor of paracetamol with the same properties. Plasma esterases act on propacetamol and release para- cetamol rapidly and completely (Depr6 et al, 1992). One gram of propa- cetamol is the equivalent of 500mg paracetamol. Depr6 et al (1992) compared the pharmacokinetics of 500 mg paracetamol given orally with 1 g propacetamol given intravenously in a double-blind, placebo- controlled, randomized, two-period cross-over study, Between 1 and 2 hours after administration, mean plasma concentrations of paracetamol became practically identical. These authors also demonstrated that no sig- nificant accumulation of paracetamol occurred even after five dosages of 2 g propacetamol/24 hours. Half-life was 3.6 hours and distribution volume was 93 + 26 litres.

NSAIDs are widely used for their analgesic, anti-inflammatory and for some agents antipyretic effects. As some of these drugs are non-prescrip- tion or over-the-counter drugs, it is estimated that up to 2% of the North American population use NSAIDs on a daily basis (Knodel et al, 1992).

NSAIDs consist of several chemical classes, which are shown in Table 1. The NSAIDs differ from each other both based on their pharmacokinetics and, at least to some extent, their pharmacodynamic profile. The mean plasma elimination half-life ranges from 1 to 60 hours, but it may be that other factors like differences in stereo selectivity, protein binding and kinet- ics in connective tissue are equally important for the clinical efficacy (Lapicque et al, 1993; Simkin et al, 1993). Nevertheless, NSAIDs have much in common: good oral resorption, high protein binding (> 90%) and a relatively small distribution volume, 0.1-0.2 l/kg.

MECHANISMS OF ACTION

A noxious stimulus to tissue initiates a cascade consisting of nociception, inflammation, and hyperalgesia (Woolf, 1989; Dab1 and Kehlet, 1991, 1993). Sympathetic postganglionic neurons produce and release prostaglandins, and primary afferent neuron endings release substance P and related nociceptive peptides. The resultant process is a prostaglandin- mediated inflammation with vasodilation and increased vascular per- meability. Sensitization of nociception increases, indicating that the functional state of the nervous system alters, the pain threshold decreases and hyperalgesia results (Woolf, 1989). Primary hyperalgesia describes the changes in pain threshold within the area of injury, while secondary hyper- algesia refers to changes in the surrounding uninjured tissue as a result of altered central processing of the nociceptive input from the periphery (Dahl and Kehlet, 1991).

Secondary hyperalgesia is explained by expansion of the receptive fields in the central nervous system. The normal pattern of afferent processing

PARACETAMOL AND PROPACETAMOL 471

Table 1. NSAIDs and paracetamol: chemacal classes, dosages and avmlable preparations

Approximate Single adult duration of action Preparataon

Chemical class Available agent dose (mg) (hours) available

Acetic acids Indomethacin 50-100 12 oral rectal 50 12 1.m, 1.v.

Carboxylic acids Aspmn (ASA) 500-1000 6-8 oral Lysm acetylsallcylate 500-1000 6-8 a v Sallcylamide 500-1000 6-8 i m

Enolic acids Oxyphenbutazone 100-200 8-12 oral, rectal Phenylbutazone 200 12-24 oral, rectal PlrOxlcam 10-20 24 oral, rectal

20--40 24 i m Tenoxlcam 20 24 oral, rectal

20 12 i m , i v Fenamle acids Flafenme 200 6 oral, rectal

Mefenamlc acid 250-500 6-8 oral Niflumlc acid 250 8-12 oral

700 12 rectal Para-amlnophenol Paracetamol 300-1000 4-6 oral, rectal

Propacetamol 1000-2000 4-6 I v Phenylacetic acids Aclofenac 500-600 8-12 oral, rectal

650 24 i m D~clofenac 100-150 8-12 oral, rectal

75 12 l m , l v Fenclofenac 600 12 oral Ketorolac 30 4-6 1.m, ~ v

Propionlc acids Flurbiprofen 50-100 6-8 oral, rectal Ibuprofen 400-600 6-8 oral, rectal Ketoprofen 100-200 8-12 oral, rectal

100 8-12 i m , i.v Naproxen 250-500 12 oral, rectal

alters in terms of a decrease in the threshold of the dorsal horn neurons. This change is thought to be mediated centrally by activation of N-methyl- D-aspartate (NMDA) receptors in the dorsal horn of the spinal cord (Davies and Lodge, 1987; Coderre and Melzack, 1992). Consequently, a 'wind-up' phenomenon occurs which results in the formation of a positive feed- forward circuit in which afferent sensory input, central sensitization, and sympathetic outflow all contribute to the modulation of the pain response. As a result, a hypersensitivity state may develop that can outlast the dura- tion of the initial injury (Woolf, 1989).

For many years, the effects of the NSAIDs have been attributed only to their action on the peripheral synthesis of prostaglandins. Most NSAIDs are reversible inhibitors of cyclooxygenase (acetylsalicylic acid is an irre- versible inhibitor). Analgesic effects of NSAIDs were interpreted as the inhibition of prostaglandin synthesis, decreasing the inflammatory response to surgical trauma and, hence, reduced peripheral nociception and pain per- ception (McCormack and Brune, 1991).

However, there are some arguments against an exclusively peripheral action of NSAIDs. They are analgesically effective in dosages too small by

472 C . A . WIEBALCK AND H. VAN AKEN

far to block prostaglandin synthesis. Moreover, paracetamol has analgesic properties without affecting peripheral prostaglandin synthesis (Jurna, 1991). Animal studies suggest an effect on the central nervous system caused by both paracetamol and NSAIDs. Firstly, paracetamol and NSAIDs produce a dose-dependent depression of the rat thalamic response to periph- eral nociceptor input (Carlsson et al, 1988; Juma and Brune, 1990). This effect could not be reversed by naloxone. Secondly, paracetamol and NSAIDs appear to prevent the rise of prostaglandins found in the cere- brospinal fluid following activation of NMDA receptors (Sorkin, 1993; Bj6rkman et al, 1994; Bj6rkman, 1995). Furthermore, intrathecal admini- stration of ketorolac produces a dose-dependent inhibition of both the first and second phase of the rat formalin test (Malmberg and Yaksh, 1992, 1993). The first phase is thought to represent immediate pain, and the second relates to delayed hyperalgesia (Malmberg and Yaksh, 1993). Therefore, it has been suggested that paracetamol and NSAIDs can reduce both acute pain and the subsequent hyperalgesic response by central mechanisms.

Finally, it has been suggested that ketorolac potentiates the anti-nocicep- tire action of opioid analgesics. Using a visceral pain model (colonic dis- tension in rats), ketorolac alone had no significant analgesic action, whereas morphine had a potent effect (Mares et al, 1994). Moreover, ketorolac potentiated the anti-nociceptive effect of morphine and this action was completely reversed by naloxone, suggesting that ketorolac may exert an effect at the opioid receptor.

Experimental studies suggest that indomethacin and some other NSAIDs interact with the adenylate cyclase system by inhibition of phosphodi- esterase, thereby increasing the intracellular concentration of cyclic adeno- sine monophosphate (AMP) and reducing the release of enzymes known to play a role in the inflammatory response (Benoist, 1988; Dahl and Kehlet, 1991).

Paracetamol has no significant influence on the peripheral synthesis of prostaglandins. In vitro, however, it blocks the brain prostaglandin syn- thetase, but not that of peripheral tissue. McCormack (1994) recently pub- lished an extensive review on non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Paracetamol is antipyretic, anti-inflamma- tory (Lekken et al, 1977; Skjelbred et al, 1977; Abbadie and Besson, 1994) and it stimulates the degradation of endoperoxides. This suggests that endoperoxides, and in particular prostaglandin endoperoxide PGG2, play a major role in the pain generating impulses (Benoist, 1988; Moreau et al, 1990).

ANALGESIC EFFICACY

Paracetamol and NSAIDs have a considerable analgesic effect for post- operative pain relief after minor procedures such as dental surgery (Garrec et al, 1991; Hans et al, 1993). Compared with opioids, they have fewer side effects, especially regarding drowsiness and respiratory depression, making NSAIDs more appropriate for ambulatory surgery.

P A R A C E T A M O L AND P R O P A C E T A M O L 473

For certain types of surgery NSAIDs can provide excellent analgesia. For laparoscopy, 800 mg ibuprofen provided better pain relief than 75 gg fentanyl and caused less vomiting (Rosenblum et al, 1990). Furthermore, clinical experience reveals that paracetamol and NSAIDs seem to be par- ticularly efficient in relieving pain related to orthopaedic surgery (Dekens et al, 1988). Hence, the aetiology of pain seems to be an important factor for the effectivity of pain relief by a given drug.

Paracetamol and NSAIDs may be administered in patients undergoing major surgery, but there is no reason to believe that these drugs given alone, provide adequate or even better analgesia than opioids (Baude et al, 1991). Opioids may be combined with paracetamol and NSAIDs as the different working mechanisms result in additive analgesia. This is how paracetamol and NSAIDs may contribute to pain relief after major surgery (Dahl and Kehlet, 1991) in spite of their limited analgesic potency.

The combination of paracetamol and NSAIDs with opioids has been shown to be effective (Rod et al, 1989; Moote, 1992; Wong et al, 1993; Beaulieu, 1994). Several studies found about a 30% sparing effect on opi- old consumption together with a reduction of opioid side effects such as less respiratory depression (Dekens et al, 1988; Moffat et al, 1990; Watcha et al, 1992; Grass et al, 1993; Vandermeulen et al, submitted for publica- tion).

In spite of the widespread use of paracetamol and NSAIDs, there are only a few controlled studies comparing the post-operative analgesic effi- cacy of paracetamol with another NSAID (Table 2). These studies suggest that pain relief after paracetamol is less than or equal to NSAIDs and of

Table 2. Summary of double-blind, controlled climcal trials comparing the post-operative analgesic effectivity of paraeetamol and a NSAID

No. of NSAID Alternative Analgesic Reference Surgery patients treatment treatment effect Remedlcation

Flltzer (1980) Mixed Naproxen (N) Paracetamol (P) N > P N < P McGaw et al Dental 150 Ibuprofen (I) Paracetamol (P) I > P

(1987) 200 mg p.o. 240/360 mg p.o Ogunbode Obstetrics Plroxlcam Paracetamol (P) P1 = P

(1987) (P1) Vargas Busquets Plastic Naproxen (N) Paracetamol (P) N = P

et al (1988) Skovlund et al Obstetrics 56 Naproxen (N) Paracetamol (P) N = P

(1991) 2 x 500 mg 4 x 500 mg Dolcl et al Dental 32 Plroxlcam Paracetamol (P) P1 > P > PI < P

(1993) (P0 20 mg 0 5 g Placebo Mornson and Ophthalmology 60 Ketorolac (K) Paracetamol (P) K > P = I

Repka 60 mg x v. 0 65 g p.o or (1994) Ibuprofen (I)

600 mg p o. Umbram et al Dental 71 Ketorolac (K) Propacetamol (P) K > P > K < P <

(1994) 30 mg x v 2 g i v Placebo Placebo Hynes and Total hip 138 Dlclofenac Propacetamol (P) D = P > D = P <

McCaroll arthroplasty (D) 2 g 1 v. Placebo Placebo (submitted 75 mg Lm. for publication)

474 C. A. W I E B A L C K A N D H. V A N A K E N

shorter duration than the commonly used NSAIDs naproxene, piroxicam, diclofenac and ketorolac. However, interpretation of these results is diffi- cult because of different methods of assessment and major differences in surgical procedures between the patients studied.

DRUG ADMINISTRATION

The timing of drug administration may play an important role. A pre-oper- atively given analgesic may prevent nociceptor sensitization and reduce post-operative pain by modifying the response of the central nervous sys- tem (CNS) and by reducing the inflammatory reaction normally observed after surgical trauma (Moreau et al, 1990; Campbell and Kendrick, 1991). Pre-operative versus post-operative treatment with NSAIDs has been examined, unfortunately only in a few studies. One controlled study sug- gested improved analgesia when flurbiprofen was given before rather than after surgery (Dupuis et al, 1988) whereas oedema and inflammation have been reduced with pre-operative administration of NSAIDs compared with placebo after plastic and rheumatic surgery (Dahl and Kehlet, 1991). The resuks, however, are controversial and interpretation is difficult.

The route of drug administration should also be considered. Most NSAIDs are given orally, intramuscularly or rectally. Only recently, some products have become available in a form for intravenous injection (tenoxi- cam, ketorolac, indomethacin, diclofenac, ketoprofen, propacetamol). These drugs appear to be significantly more effective with a more rapid onset of action (Buckley and Brogden, 1990; Campbell and Kendrick, 1991; Laitinen and Nuutinen, 1992). This may be related to higher plasma levels at the beginning with a more rapid and larger penetration of the blood-brain barrier with a more pronounced CNS effect.

SIDE EFFECTS AND COMPLICATIONS OF NSAIDs

Side effects of NSAIDs may be due to inhibition of prostaglandin synthe- sis (bleeding, gastric-duodenal adverse events, renal adverse events) or to allergic, toxic or idiosyncratic reactions. They are infrequent (O'Brian, 1986), but nevertheless, they can cause severe complications in the post- operative period. Dyspepsia, peptic ulceration, nausea, renal adverse events, skin reactions, hepatic syndromes, neurological problems (e.g. headache and dizziness) and bleeding disorders (Brooks and Day, 1991) have been reported. Advanced age has emerged as one of the most striking risk factors for all of these adverse effects (Sager and Benett, 1992).

Most of the described side effects were found during long-term use of NSAIDs. Moreover, several studies suggest that the most dangerous period concerning side effects is within the first few months of taking an NSAID (Hawkey, 1990) but the data do not allow separation of risk between the first 3-5 days and the following weeks. Hence, a few studies with short-term administration of NSAIDs have been performed to evalu-

PARACETAMOL AND PROPACETAMOL 475

ate the adverse effects on gastro-intestinal tract, coagulation system and kidneys.

Nausea, vomiting and dyspepsia were not found more often after admin- istration of indomethacin, oxycodon and diclofenac (Laitinen et al, 1992). There was no difference in the incidence of nausea between diclofenac- and fentanyl-treated patients undergoing hip surgery (Laitinen and Nuutinen, 1992) whereas Cahadell-Carafi et al (1991) described these side effects as a common feature of ketorolac treatment. While Parker et al (1994) found a similar incidence of nausea and vomiting after ketorolac and opioid anal- gesics, Ready et al (1994) showed a reduced incidence. Moreover, gastric irritation was described after short-term use of diclofenac (Muller et al, 1989) and ketorolac when the daily dose exceeded 120 mg (Lanza et al, 1987). To summarize, the influence of NSAIDs on nausea and vomiting is not easily described. Possibly different side effects of the various NSAIDs and the incomparability of studies may explain contradictory results. Nevertheless, no study (to the knowledge of the authors) demonstrates a higher incidence of nausea and vomiting after NSAIDs than after opioids.

Bleeding time was slightly prolonged but still within the normal range in most studies after a single dosage of indomethacin, diclofenac and ketoro- lac (Nuutinen et al, 1993). The situation, however, was different after administration of warfarin or low-dose acetylsalicylic acid for prophylaxis against thrombosis after total hip replacement. Patients taking NSAIDs until the time of operation had more post-operative bleeding complications, including gastro-intestinal tract bleeding, compared with those not taking NSAIDs (Connelly and Panush, 1991).

Renal function may be affected after short-term use of NSAIDs but this impairment with decline of renal blood flow and glomerular filtration rate is reversible after stopping NSAIDs administration. Controlled studies indi- cated a temporary reduction of urine output (diclofenac) and, for ketorolac, a potassium retention (Nuutinen et al, 1993). Hence, attention should be paid in particular to patients with pre-existing risk factors for abnormal renal function (Table 3).

One side effect of minor importance compared to those previously men- tioned is the recently described disturbance of the normal sleeping patterns (Murphy et al, 1994). The authors demonstrated, that patients after admin- istration of acetylsalicylic acid and indomethacin were less refreshed and recuperated in the morning than those after paracetamol and placebo, due to delayed sleep and significantly more disruptions of sleep during the night.

Referring to NSAID treatment in pregnant patients, there is no evidence for teratogenicity of any NSAIDs in humans. However, due to inhibition of prostaglandin synthesis, a shared property of all NSAIDs, adverse effects such as constriction of the ductus arteriosus in utero, persistent pulmonary hypertension in the neonate, intracranial haemorrhage, prolongation of pregnancy and labour, and increased maternal blood loss associated with delivery, are possible (~stensen, 1994).

Other side effects of NSAIDs may be related to drug interactions. The relative frequency of drugs that may have adverse interactions with

476 C. A. WIEBALCK AND H. VAN AKEN

Table 3. Risk factors for possible NSAIDs-lnduced adverse events.

Risk factor Possible adverse event

Allergic con&tions Allergic reactmns Asthma Cross intolerance with aspmn

Alcohohsm Bleeding Bleeding &sorders Drug interactions with anticoagulants Elderly patients Gastroduodenopathy Nasal polyps

Alcoholism Drug interactmn with cort~colds,

anUcoagulants Elderly patients Gastroduodenopathy

Atherosclerosis Congestive heart failure Drug interactions with diuretics,

[5-blockers and nephrotoxlc drugs Elderly patients Hypotonia Hypovolaewaa Liver cirrhosis Renal failure Sepsis

Atherosclerosls Drug interactions w~th diuretics,

[5-blockers Elderly patients Hypovolaemia

Lxthium, Methotrexate, Cyclosporine, oral hyperglycemic agents (Brouwers and De Smet, 1994)

Gastric adverse events

Renal adverse events

Disturbed control of blood pressure

Drug interactions with potentially severe side effects

NSAIDs is partially due to both properties of NSAIDs, the high percentage bound to protein, and the small distribution volume. From a theoretical point of view the toxicity of NSAIDs may be increased by coadministration of interacting drugs, or by increasing the toxicity of coadministered drugs (Table 3). The most important drugs are those affecting the coagulation sys- tem, the renal function, some chemotherapeutica and antidiabetica. Drug interactions in elderly people are not infrequent, they occurred two times more often in NSAID users than in the control group of non-NSAID users (Hogan et al, 1994). Reduction of the incidence may be possible because Buchan and Bird (1991) identified drug interactions in half of the patients being treated with NSAIDs for symptoms of arthritis, although only a minority of these patients had clinical manifestations.

In summary, the well known side effects during prolonged use of NSAIDs may limit their potential use in the peri-operative period. However, data from prospective controlled studies do not suggest that

PARACETAMOL AND PROPACETAMOL 477

short-term NSAID treatment (< 1 week) may have clinically significant adverse effects (Dahl and Kehlet, 1991). Thus the fear of side effects should not limit use of NSAIDs in the healthy surgical patient but caution and restrictive use are required in patients potentially at risk (Table 3).

SIDE EFFECTS AND COMPLICATIONS OF PARACETAMOL

There are very few drugs that have such a low intensity and frequency of side effects and complications as paracetamol. Some case studies have reported allergic reactions [cross allergy to acetylsalicylic acid (Ispano et al, 1993)], also, during rapid injection, propacetamol may lead to a tempo- rary decrease of blood pressure and a slight irritation at the site of injection. Several drug interactions are theoretically possible, but they are clinically irrelevant (Lechat and Kisch, 1989). Dosages should be reduced in patients with severe renal insufficiency (creatinine clearance < 10 ml/min) and with severe deficiency of liver cell glutathione which may occur in patients with profound hepatocellular insufficiency, administration of antiepileptica and premature babies. In summary, paracetamol may be administered in almost all patients irrespective of age, underlying disease or pregnancy.

CLINICAL USE OF NSAIDs

The goal of post-operative pain relief is to allow the patient the quickest and most convenient restoration of his normal functions, e.g. breathing, coughing and mobility. This can be supported by the inhibition of trauma- induced nociceptive impulses in order to blunt autonomic and somatic reflex responses to pain (Kehlet, 1994).

Post-operative pain therapy should be structured. It should be based on the general principles of pre-emptive analgesia and the multimodal approach (Kehlet and Dalai, 1993). The value of pre-emptive analgesia is limited at present (Dahl and Kehlet, 1993), but this principle may have some implications in the future. The multimodal approach includes the principle of balanced analgesia. The basic idea is to combine different anal- gesic drugs and techniques to achieve an additive or synergistic analgesic effect. So, the doses of the single drugs can be reduced and side effects are limited. Another element is the assessment of pain and the choice of the appropriate treatment.

The first step of the 'analgesic treatment ladder' is represented by para- cetamol and NSAIDs which are the first line drugs for control of mild to moderate pain. This has been recommended by many authors and the World Health Organization (Rummans, 1994) as these analgesics have less side effects than opioids. Patients treated with NSAIDs are less drowsy than opioid-treated patients, although the incidence of nausea and vomit- ing is similar with both treatments. No respiratory effects have been observed after paracetamol/NSAIDs, in contrast, a decrease in respiratory rate and an increase in arterial partial pressure of carbon dioxide may

478 C. A. W I E B A L C K A N D H. V A N A K E N

occur in opioid-treated patients. For minor surgery, paracetamol and NSAIDs will minimize the need for opioid analgesics in the post-operative period.

The second step of the 'analgesic treatment ladder' for the control of more severe pain includes the combination of these drugs with opioids. As already mentioned, paracetamol/NSAIDs have fewer side-effects than opi- oids and by combination of both groups a low dose of opioids can be administered (opioid sparing). It should be remembered that opioid sparing produces reductions in nausea and vomiting, respiratory depression and sedation.

A third step of the 'analgesic treatment ladder' might be necessary for patients with severe pain. This step includes the use of local anaesthetics and other adjuvant medications that can improve the pain treatment (cloni- dine, corticoids, antispasmodics, neuroleptica, anticonvulsants, muscle relaxants, antidepressants, etc). A conception for the realization of such a post-operative pain management has been proposed by Wiebalck et al (sub- mitted for publication).

DIFFERENCES IN USE AND INDICATIONS FOR PARACETAMOL AND NSAIDs

Paracetamol and NSAIDs, both and even together are indicated for the treatment of mild to moderate pain and for more severe pain, in combina- tion with opioids, local anaesthetics and other adjuvant medications. The most problematic side effects of NSAIDs are related to the inhibition of the peripheral cyclooxygenase-system: bleeding, gastro-duodenal and renal adverse events. The analgesic potential of paracetamol may be less pro- nounced and of shorter duration, but there are almost no side effects.

As one of the highest commandments 'Nihil nocere.t' requires, NSAIDs should be avoided if certain risk factors for NSAIDs-induced side effects are present such as advanced age, gastroduodenopathy, bleeding diathesis, renal insufficiency and other factors listed in Table 3. Today, it is recom- mended that paracetamol alone represents the non-opioid background anal- gesia.

In the future, a more rational choice of the optimal drug may be possible as there are some differences among non-steroidal anti-inflammatory drugs (Furst, 1994). Research on efficacy, tolerance, incidence of adverse effects, optimal route of administration and dosage schedules will provide more information. Then, the choice of a specifically indicated NSAID can be based on (patient-related) efficacy, patients' concomitant medications and diseases, and consideration of cost.

SUMMARY

Although less efficacious than opioid compounds, parenterally adminis- tered NSAID and paracetamol are effective analgesics that have a clear role

PARACETAMOL AND PROPACETAMOL 479

in the management of post-operative pain. They should be considered as part of a balanced approach to analgesia using a combination of different drugs and techniques.

Pain therapy should be structured. Assessment of pain allows the finding of appropriate measures of treatment. The first step of the 'analgesic treat- ment ladder' is represented by paracetamol/NSAIDs (mild analgesics) which are the first line drugs for control of mild to moderate pain. The second step of the 'analgesic treatment ladder' for the control of more severe pain includes the combination of these drugs with opioids. Paracetamol/NSAIDs have fewer side effects than opioids and by combi- nation of both groups a lower dose of opioids can be administered (opioid sparing). A third step of the 'analgesic treatment ladder' might be necessary for patients with severe pain. This step includes the use of local anaesthetics and other adjuvant medications that can improve the pain treatment (Kehlet and Dahl, 1993).

Paracetamol and NSAIDs, are indicated for the treatment of mild to moderate pain and for more severe pain, in combination with opioids, local anaesthetics and other adjuvant medications.

If a patient presents risk factors for NSAIDs-induced adverse events, today it is recommended to achieve the regular background analgesia with paracetamol alone. In the future, a more selective use of NSAIDs will pro- vide more advantages. For this reason, more research is required to distin- guish the differences between the various NSAIDs concerning efficacy, tolerability, incidence of adverse effects, optimal route of administration and dosage schedules.

Today, the optimal regimen for the peri-operative management of pain would appear to involve primarily paracetamol, the selective use of NSAIDs in low-risk patients in combination with opioid analgesics and local anaesthetics whenever necessary.

REFERENCES

Abba&e C & Besson J-M (1994) Chronic treatment with aspirin and acetammophen reduce both the development of polyarthntis and post Fos-hke immunoreactivity in rat lumbar spinal cord Pam 59:45-54

Ballantyne JC, Cart DB, Chalrners TC et al (1993) PostoperaUve patient-controlled analgesia Meta- analyses of mmal randomized control trials Journal of Climcal Anesthesia 5: 182-193.

Baude C, Long D, Chabrol B e t al (1991) Postoperative analgesia for nephrectomy Cahters d'Anesthgsiologw 39: 533-536.

Beanheu P (1994) Intravenous admimstratlon of paracetamol (Propacetamol) for postoperative anal- gesia Anaesthesta 49:739-740

Benoxst JM (1988) Mamement des analgtslques antlpyrttiques In Boreau Fr (ed.) Prattque du Traltement de la Douleur, pp 125-143. Paris- Dora Editeurs.

Bjorkman R (1995) Central antinoclceptive effects of non-steroidal anla-inflammatory drugs and paracetamol. Acta Anaesthestologwa Scandmavtca 39 (supplement 103): 1M-4

Bjtrkman R, Hallman K, Hedner Je t al (1994) Acetammophen blocks spinal hyperalgesla induced by NMDA and substance P Pare 57: 259-264.

Brooks PM & Day RO (1991) Nonsteroldal anU-mflammatory drugs~&fferences and slrrulantles New England Journal of Medicine 324:1716--1725

480 C.A. WIEBALCK AND H. VAN AKEN

Brouwers JRBJ & De Smet AGM (1994) Pharmacokinetlc-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs Chntcal Pharmacoktnetws 27: 462-485.

Buchan IE & Bird HA (1991) Drug interactions in arthritic patients. Annals of the Rheumatic Diseases 50:680-681

Buckley MM-T & Brogden RN (1990) Ketorolac A review of its pharmacodynamic and pharmaco- kinetic properties, and therapeutic potential. Drugs 39: 86--109.

Cahadell-Carafi J, Moreno-Londono A & Conzales-Caudevllla B (1991) Ketorolac, a new non-oplmd analgesic: a single blind trial versus buprenorphine in pain after orthopaedic surgery Current Medtcal Research and Opmton 12:343-349

Campbell WI & Kendrick R (1991) Intravenous &clofenac sodium. Does its administration before operation suppress postoperative pain? Anaesthesia 4: 763-766.

Carlsson KH, Mouzel W & Jurna I (1988) Depression by morphine and the non-oploid analgesic agents, metamizol (&pyrone), lyslne acetylsahcylate, and paracetamol of activity in rat thalamus neurons evoked by electrical stimulation of nociceptive afferents Pam 32: 313-326.

Coderre TJ & Melzack R (1992) The contribution of excitatory ammoacids to central sensitization and perslstant nociceptIon after formalin induced tissue injury Journal of Neurosctence 12: 3665-3670.

Cohen FL (1980) Postsurgical pain relief Patients' status and nurses' medication choices. Pain 9: 265-274.

Connelly CS & Panush RS (1991) Should non-steroidal anti-inflammatory drugs be stopped before elective surgery? Archives of Internal Medtcine 151: 1963-1966.

Cousins MJ (1989) Acute pain and the injury response: immediate and prolonged effects Regwnal Anesthesta 14:162-179

Dahl J & Kehlet H (1991) Non-steroidal anti-inflammatory drugs, rationale for use in severe postop- erative pain. British Journal of Anaesthesia 66: 703-712.

Dahl J & Kehlet H (1993) The value of preemptive analgesia in the treatment of postoperative pain. Brlttsh Journal of Anaesthesta 70: 434-439.

Dauber A, Ure BM, Neugebauer E et al (1993) Zur Inzidenz postoperativer Schmerzen auf chlrurgis- chen Normalstatlonen. Anaestheszst 42:448-454

Davies SN & Lodge D (1987) Evidence for involvement of N-methyl-D-aspartate receptors in 'wind up' of class 2 neurones in the dorsal horn of the ~at Bram Research 424: 402--406.

Dekens J, Lepomte F, Besserve P et al (1988) Analg6sie postop6ratotre en chn-urgle ost6oarticulaire par le k6toprof'ene en perfuslon Cahters d'Anesth3slologze 36:25-27

Depr6 M, Van Hecken A, Verbesselt R et al (1992) Tolerance and phannacokinetics of propacetamol, a paracetamol formulation for intravenous use. Fundamentals of Clinical Pharmacology 6: 259-262.

Dolcl G, Ripari M, Pacificl Le t al (1993) Analgesic efficacy and the tolerance for plroxlcam-beta- cyclodextrin compared to plroxlcam, paracetamol and placebo m the treatment of postextractlon dental pare Mmerva-Stomatologlca 42: 235-241.

Donovan M, Dillon P & McGmre L (1987) Incidence and characteristics of pain in a sample of med- xcal-surglcal mpatlents. Pain 30: 69-78.

Dupms R, Lemay H, Bushnelle MC et al (1988) Preoperatwe flarbiprofen in oral surgery a method of choice m controlhng postoperative pain. Pharmacotherapeutwa 8:193-200

Ffltzer HS (1980) Double-bhnd randomized comparison of naproxen sodium, acetaminophen and pentazocine m postoperative pare. Current Therapeutic Research, Clinical and Experimental 27: 293-302

Furst DE (1994) Are there differences among non-steroidal anti-inflammatory drugs? Arthrttls and Rheumattsm 37:1-9

Garret F, Chupm AM & Souron R (1991) Analgesle postop6ratoire par le propacetamol. Cahters d'Anesthgsiologte 39:333-335

Grass JA, Sakima NT, Valley Met al (1993) Assessment of ketorolac as an adjuvant to fentanyl patient- controlled epldurai analgesia after radical retropubic prostatectomy. Anesthestology 78:642-648

Hans P, Brichant JF, B onhomme Vet al (1993) Analgesic efficiency of propacetamol hydrochlonde after lumbar &sc surgery Acta Anaestheslologica Belgica 44: 129-133.

Hawkey CJ (1990) Non-steroidal anta-inflammatory drugs and peptic ulcers. British Medical Journal 300:278-284

Hogan DB, Campbell NR, Crutcher R et al (1994) Prescription of nonsteroldal anti-inflammatory drugs for elderly people in Alberta. Canadzan Medical Assoctatton Journal 151: 315-322.

Ispano M, Fontana A, Scibiha Jet al (1993) Oral challenge with alternative nonsteroldal anti-inflam-

PARACETAMOL AND PROPACETAMOL 481

matory drugs and paracetamol m patients intolerant to these agents. Drugs 46 (supplement 1P): 253-256.

Juma I (1991) Central analgesic effects of non-steroidal anti-rheumatic agents, Zettschrift fur Rheumatologte 50 (supplement 1): 7-13

Jurna I & Brune K (1990) Central effect of the nonsteroldal ants-inflammatory agents lndomethacln, ibuprofen and diclofenac, determined in C fiber-evoked activity m single neurons of the rat thal- amus Pare 41:71-80

Keats AS (1956) Postoperative pain research and treatment Journal ofChromc Dtseases 4:72-83 Kehlet H (1994) Postoperative pare relief--what is the issuer Brttish Journal of Anaesthesta 72:

375-378. Kehlet H & Dahl JB (1993) The value of 'multimodal' or 'balanced analgesia' in postoperative pain

treatment Anesthesta and Analgesta 77:1048-1056 Knodel LC, Rousch MK & Barton TL (1992) Nonsteroldai anti-inflammatory drugs Chnical

Pedtatric Medtcal Surery 9:301-325 Laitinen & Nuutlnen L (1992) Intravenous &clofenac coupled with PCA fentanyl for pain relief after

total hip replacement Anesthestology 76:194-198 Lmtmen J, Nuutmen LS, Kliskil~t EL et al (1992) Comparison of intravenous diclofenac,

lUdomethacin and oxycodon as postoperative analgesics in pataents undergoing knee-surgery European Journal of Anaesthestology 9:29-34

Lanza FL, Karlln DA & Yee JP (1987) A double bhnd, placebo-controlled endoscopic study corn- panng the mucosal injury seen with an orally and parenteralty administered new nonsteroldal analgesic' ketorolac thromethamine at therapeutic and supratherapeutlc doses American Journal of Gastroenterology 82:939

Lapicque F, Muller N, Payan E et al (1993) Protein-binding and stereoselectivity of nonsteroldal anti- inflammatory drugs. Chnwal Pharmacokmetws 25:115-125

Lechat P & Kisch R (1989) Le parac6tamol. Actualisatlon des connalssances en 1989. Thdrapte 44: 337-354

Lckken P, Skoglund LA & Skjelbred P (1977) Anti-Inflammatory efficacy of treatments with aspirin and acetammophen Pare 60: 231-232.

Malmberg AB & Yaksh TL (1992) Antmociceptor actions of spinal non-steroidal anti-inflammatory agents on the formalin test m the rat. Journal of Pharmacology and Experimental Therapeutics 263: 136-146.

Maimberg AB & Yaksh TL (1993) Pharmacology of the spinal action ot ketorolac, morphine, US0488H, and L-PIA on the formalin test and an lsobolographlc analysis of the NSAID interac- tion Anesthestology 79:270-281

Marks RM & Sachar EJ (1973) Undertreatment of medical inpatients with narcotic analgesics Annals of Internal Medwme 78:173-181

Maces TJ, Pechman PS, Meller ST et al (1994) Ketorolac potentiates morphine antinociception dur- ing visceral nocicepaon m the rat. Anesthestology 80:1094-1101

McCormack K (1994) Nonsteroidal antiinflammatory drugs and spinal nocicepave processing Pare 59:9-43

McCormack K & Brune K (1991) Dissociation between the antlnoclceptlve and antllnflammatory effects of the non-steroidal antiinflammatory drugs. Drugs 41:533-547

McGaw T, Raboru W & Grace M (1987) Analgesics in pediatric dental surgery relative efficacy of aluminium ibuprofen suspension and acetammophen ehxlr. Journal of Denttstryfor Children 54: 106-109.

Moffat AC, Kenny GNC & Prentice JW (1990) Postoperative nefopam and dlclofenac evaluation of their morphine-sparing effect after upper abdominal surgery. Anaesthesia 45: 302-305.

Moore DC (1990) The role of the anesthesiologist in managing postoperative pain Regtonal Anesthesia 15: 223-231.

Moote C (1992) Efficacy of non-steroidal anti-inflammatory drugs in the management of postopera- tive pain Drugs 44 (supplement 5): 14-30

Moreau X, Cottmeau C, Cocaud J et al (1990) Analg6sie pedoperatolre en chirurgle vemeuse p6nph6dque Cahters d'Anesth~siologie 38: 403-407.

Morrison NA & Repka NX (1994) Ketorolac versus acetammophen or lbuprofen in controlling post- operaUve pain in patients with strabismus. Ophthalmology 101:915-918

Muller P, Dammann HG, Leucht U & Simon B (1989) Comparison of the gastrodnodenal tolerance of tenoxicam and diclofenac Na a double-blind, endoscopically controlled study in healthy volunteers. European Journal of Chmcal Pharmacology 36:419-421.

482 C.A. WIEBALCK AND H. VAN AKEN

Murphy PJ, Ba&a P, Myers BL et al (1994) Nonstermdal anti-inflammatory drugs affect normal sleep patterns in humans Phystology and Behavtor 55:1063-1066

Nuutinen LS, Lmtmen JO & Salomaki TE (1993) A risk-benefit appraisal of inJectable NSAIDs m the management of postoperaUve pain. Drug Safety, 9:380-393

O'Brian W (1986) Adverse reactions to nonsteroldal antHnflammatory drugs Dlclofenac compared with other nonsteroldal anta-mflammatory drugs. American Journal of Medtcme 80 (supplement 4B): 70-80

Ogunbode O (1987) A comparative trial of plroxlcam and paracetmnol after eplslotomy wound repair Current Therapeutic Research, Climcal and Expertmenta141: 89-94

Ostensen M (1994) Optimlsatlon of antirheumatlc drug treatment in pregnancy. Chmcal Pharmacokmetws 27:486-503

Papper EM, Bro&e BB & Rovenstme EA (1952) Postoperative pain' Its use in comparatwe evalua- tion of analgesics Surgery 32:107-109

Parker RK, Holtman B, Smith I & White PF (1994) Use of ketorolac after lower abdominal surgery Anesthestology 80: 6-12.

Ready KB, Brown CR, Stahlgren LH et al (1994) Evaluation of intravenous ketorolac administered by bolus or infusion for treatment of postoperative pmn Anesthestology 80:1277-1286

Rod B, Monrlgal JP, Lepoittevin Let al (1989) Traitement de la douleur postoperatoare chez l'enfant en salle de reveille Utillsatlon de la morphine et du propacetamol par voie intraveneuse Cahters d'Anesth~szologte 37:525-530

Rosenblum M, Weller RS, Conrad Pet al (1990) Ibuprofen provides better analgesm than fentanyl following laparascopic surgery Anesthestology 73:A778

Rummans TA (1994) Nonopmld agents for treatment of acute and subacute pmn Mayo Chmc Proceedings 69:481-490

Sager DS & Benett RM (1992) Indivlduallsmg the risk/benefit ratao of NSAIDs m older patients Gerlatrtcs 47:24-31

Slmkin PA, Mary PW & Foster DM (1993) Articular pharmacokmeUcs of protein bound antlrheumatlc agents. Chmcal Pharmacokmetics 25:342-350

Skjelbred P, Album P & LOkken P (1977) Acetylsabcylic acid vs paracetamol: effects on postopera- tlve course European Journal of Clmtcal Pharmacology 12:257-264

Skovlund E, Fylhngen G, Landre H et al (1991) Comparison of postpartem pare treatments using a sequential trial design" naproxen versus paracetamol European Journal of Chntcal Pharmacology 40: 539-542.

Sorkin LS (1993) IT ketorolac blocks NMDA-evoked spinal release of prostaglandm E2 (PGE2) and thromboxane B2 (TXB2) Anesthesiology 79: A909.

Umbrmn V, Moerman I & Camu F (1994) Postoperative analgestafor dental surgery: a double bhnd compartson Abstract for Congress 6-11 November 1994 in Bangkok, Thailand

Vargas Busquets MA, Keoshlan LA, Kellemer R et al (1988) Naproxen sodium versus aceta- mmophen-codeine for pmn following plastic surgery Current Therapeuttc Research, Clmtcal and Expertmenta143: 311-316

Von Meynng J (1893) Beltrage zur Kenntnis der AntipyreUka Therapeuttsche Monatsschrtft 7:577 Watcha MF, Jones MB, Lagueruela RG et al (1992) Comparison of ketorolac and morphine as adju-

vants during paediatnc surgery Anesthestology 76: 368-372. Wong HI, Carpenter RL, Popazc DJ et ai (1993) A randomized double-blind evaluation of ketorolac

trlmethamine for postoperative analgesia in ambulatory surgery patients Anesthestology 78" 6-14.

Woolf CJ (1989) Recent advances m the pathophysiology of acute pain. Brmsh Journal of Anaesthesta 63:139-146.