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4 Paracetamol and propacetamol for postoperative pain: contrasts to traditional NSAIDs

C. A L B R E C H T W I E B A L C K HUGO VAN AKEN 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: diminished 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 antiinflammatory drugs (NSAIDs) in the management of post-operative pain? What are the differences between these agents?
PARACETAMOL/PROPACETAMOL AND NSAIDs PHARMACOLOGY

Paracetamol (acetaminophen), the oldest known synthetic analgesicantipyretic drug introduced in 1893 (Von Meyring), is one of the most Batlh~re's Chnical Anaesthestology469
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Dab1 and Kehlet. The mean plasma elimination half-life ranges from 1 to 60 hours. In certain circumstances. 1993).1-0. indicating that the functional state of the nervous system alters. Sensitization of nociception increases. Propacetamol is a water-soluble precursor of paracetamol with the same properties. 1992). high protein binding (> 90%) and a relatively small distribution volume. Primary hyperalgesia describes the changes in pain threshold within the area of injury. which are shown in Table 1. mean plasma concentrations of paracetamol became practically identical. Between 1 and 2 hours after administration. but it may be that other factors like differences in stereo selectivity. 1991). The NSAIDs differ from each other both based on their pharmacokinetics and.470 C. 1989). 1993. The normal pattern of afferent processing . 1992). two-period cross-over study.6 hours and distribution volume was 93 + 26 litres. their pharmacodynamic profile.2 l/kg. randomized. Sympathetic postganglionic neurons produce and release prostaglandins. it is estimated that up to 2% of the North American population use NSAIDs on a daily basis (Knodel et al. Plasma esterases act on propacetamol and release paracetamol rapidly and completely (Depr6 et al. 1989. intravenous administration is preferable because of potential dysfunction of the gastro-intestinal tract and reduced time of onset. 1991. W I E B A L C K A N D H . The resultant process is a prostaglandinmediated inflammation with vasodilation and increased vascular permeability. It is almost insoluble and for that reason can not be used parenterally. placebocontrolled. These authors also demonstrated that no significant accumulation of paracetamol occurred even after five dosages of 2 g propacetamol/24 hours. Nevertheless. 0. protein binding and kinetics in connective tissue are equally important for the clinical efficacy (Lapicque et al. for example after an acute trauma or operation. 1993). NSAIDs consist of several chemical classes. NSAIDs have much in common: good oral resorption. anti-inflammatory and for some agents antipyretic effects. and hyperalgesia (Woolf. As some of these drugs are non-prescription or over-the-counter drugs. Depr6 et al (1992) compared the pharmacokinetics of 500 mg paracetamol given orally with 1 g propacetamol given intravenously in a double-blind. at least to some extent. Simkin et al. Half-life was 3. MECHANISMS OF ACTION A noxious stimulus to tissue initiates a cascade consisting of nociception. Secondary hyperalgesia is explained by expansion of the receptive fields in the central nervous system. One gram of propacetamol is the equivalent of 500mg paracetamol. while secondary hyperalgesia 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. NSAIDs are widely used for their analgesic. V A N A K E N frequently used around the world. A . and primary afferent neuron endings release substance P and related nociceptive peptides. inflammation. the pain threshold decreases and hyperalgesia results (Woolf.

Coderre and Melzack.lv oral 1. i. rectal Fenamle acids Flafenme Mefenamlc acid Niflumlc acid Para-amlnophenol Paracetamol Propacetamol Aclofenac D~clofenac Phenylacetic acids Propionlc acids Fenclofenac Ketorolac Flurbiprofen Ibuprofen Ketoprofen Naproxen alters in terms of a decrease in the threshold of the dorsal horn neurons. reduced peripheral nociception and pain perception (McCormack and Brune. hence.v. rectal Indomethacin Aspmn (ASA) Lysm acetylsallcylate Sallcylamide Oxyphenbutazone Phenylbutazone PlrOxlcam Tenoxlcam Enolic acids im.m. rectal im oral. rectal oral. Analgesic effects of NSAIDs were interpreted as the inhibition of prostaglandin synthesis. For many years. rectal im oral. the effects of the NSAIDs have been attributed only to their action on the peripheral synthesis of prostaglandins. 1. 1992). rectal oral. decreasing the inflammatory response to surgical trauma and.P A R A C E T A M O L AND PROPACETAMOL Table 1. However. NSAIDs and paracetamol: chemacal classes.m. This change is thought to be mediated centrally by activation of N-methylD-aspartate (NMDA) receptors in the dorsal horn of the spinal cord (Davies and Lodge. ~ v oral. They are analgesically effective in dosages too small by . rectal Iv oral. rectal i m . As a result. rectal oral. and sympathetic outflow all contribute to the modulation of the pain response. oral av im oral. rectal lm. dosages and avmlable preparations Single adult Chemical class Acetic acids Carboxylic acids Available agent 471 dose (mg) 50-100 50 500-1000 500-1000 500-1000 100-200 200 10-20 20--40 20 20 200 250-500 250 700 300-1000 1000-2000 500-600 650 100-150 75 600 30 50-100 400-600 100-200 100 250-500 Approximate durationof action (hours) 12 12 6-8 6-8 6-8 8-12 12-24 24 24 24 12 6 6-8 8-12 12 4-6 4-6 8-12 24 8-12 12 12 4-6 6-8 6-8 8-12 8-12 12 Preparataon available oral rectal 1. central sensitization. 1987. rectal oral oral rectal oral. 1989).v oral. there are some arguments against an exclusively peripheral action of NSAIDs. Most NSAIDs are reversible inhibitors of cyclooxygenase (acetylsalicylic acid is an irreversible inhibitor). rectal oral. a 'wind-up' phenomenon occurs which results in the formation of a positive feedforward circuit in which afferent sensory input. 1991). a hypersensitivity state may develop that can outlast the duration of the initial injury (Woolf. Consequently.iv oral.

and the second relates to delayed hyperalgesia (Malmberg and Yaksh. Skjelbred et al. making NSAIDs more appropriate for ambulatory surgery. intrathecal administration of ketorolac produces a dose-dependent inhibition of both the first and second phase of the rat formalin test (Malmberg and Yaksh. . Juma and Brune. Compared with opioids. 1988. 1994) and it stimulates the degradation of endoperoxides. Moreau et al. however. A . it has been suggested that ketorolac potentiates the anti-nociceptire action of opioid analgesics. 1991). Moreover. Paracetamol has no significant influence on the peripheral synthesis of prostaglandins. Secondly. VAN AKEN far to block prostaglandin synthesis. Finally. 1993). The first phase is thought to represent immediate pain. Hans et al. 1993). they have fewer side effects. paracetamol has analgesic properties without affecting peripheral prostaglandin synthesis (Jurna. 1977. 1994). thereby increasing the intracellular concentration of cyclic adenosine monophosphate (AMP) and reducing the release of enzymes known to play a role in the inflammatory response (Benoist. Firstly. Using a visceral pain model (colonic distension in rats). Animal studies suggest an effect on the central nervous system caused by both paracetamol and NSAIDs. and in particular prostaglandin endoperoxide PGG2. suggesting that ketorolac may exert an effect at the opioid receptor. 1991. 1994. Bj6rkman. especially regarding drowsiness and respiratory depression. 1991). play a major role in the pain generating impulses (Benoist. 1988. Moreover. WIEBALCK AND H. 1977. 1992. This suggests that endoperoxides. 1993). This effect could not be reversed by naloxone. Therefore. Bj6rkman et al. it has been suggested that paracetamol and NSAIDs can reduce both acute pain and the subsequent hyperalgesic response by central mechanisms. Furthermore. ANALGESIC EFFICACY Paracetamol and NSAIDs have a considerable analgesic effect for postoperative pain relief after minor procedures such as dental surgery (Garrec et al. Dahl and Kehlet. whereas morphine had a potent effect (Mares et al. ketorolac potentiated the anti-nociceptive effect of morphine and this action was completely reversed by naloxone.472 C . paracetamol and NSAIDs appear to prevent the rise of prostaglandins found in the cerebrospinal fluid following activation of NMDA receptors (Sorkin. it blocks the brain prostaglandin synthetase. ketorolac alone had no significant analgesic action. McCormack (1994) recently published an extensive review on non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Paracetamol is antipyretic. 1988. 1990). 1990). Abbadie and Besson. but not that of peripheral tissue. In vitro. anti-inflammatory (Lekken et al. 1993. paracetamol and NSAIDs produce a dose-dependent depression of the rat thalamic response to peripheral nociceptor input (Carlsson et al. Experimental studies suggest that indomethacin and some other NSAIDs interact with the adenylate cyclase system by inhibition of phosphodiesterase. 1995).

Moote. 1988). Placebo Placebo . Paracetamol and NSAIDs may be administered in patients undergoing major surgery. of NSAID Naproxen (N) Reference Flltzer (1980) McGaw et al (1987) Surgery Mixed patients treatment 150 Ibuprofen (I) 200 mg p. 1994). In spite of the widespread use of paracetamol and NSAIDs. Wong et al. Furthermore. 1992. controlled climcal trials comparing the post-operative analgesic effectivity of paraeetamol and a N S A I D No. Analgesic effect N>P I>P P1 = P N=P N=P P1 > P > Remedlcation N<P Dental Obstetrics Ogunbode (1987) Plroxlcam (P1) Vargas Busquets Plastic et al (1988) Skovlund et al Obstetrics (1991) Naproxen (N) 56 32 Naproxen (N) 2 x 500 mg Plroxlcam (P0 20 mg Dolcl et al (1993) Dental Ophthalmology PI < P Placebo K>P=I Mornson and Repka (1994) Umbram et al (1994) 60 Ketorolac (K) 60 mg x v. 1990). 1992. 800 mg ibuprofen provided better pain relief than 75 gg fentanyl and caused less vomiting (Rosenblum et al. Beaulieu. Opioids may be combined with paracetamol and NSAIDs as the different working mechanisms result in additive analgesia. Watcha et al. Moffat et al. there are only a few controlled studies comparing the post-operative analgesic efficacy of paracetamol with another NSAID (Table 2).o. submitted for publication). provide adequate or even better analgesia than opioids (Baude et al. S u m m a r y of double-blind. For laparoscopy. Propacetamol (P) 2giv Propacetamol (P) 2 g 1 v. This is how paracetamol and NSAIDs may contribute to pain relief after major surgery (Dahl and Kehlet. 1990. 1989. the aetiology of pain seems to be an important factor for the effectivity of pain relief by a given drug. 1991). 1993.o or Ibuprofen (I) 600 mg p o. Grass et al. Alternative treatment Paracetamol (P) Paracetamol (P) 240/360 mg p. The combination of paracetamol and NSAIDs with opioids has been shown to be effective (Rod et al. Hence.o Paracetamol (P) Paracetamol (P) Paracetamol (P) 4 x 500 mg Paracetamol (P) 05g Paracetamol (P) 0 65 g p. Several studies found about a 30% sparing effect on opiold consumption together with a reduction of opioid side effects such as less respiratory depression (Dekens et al. Dental 71 138 Ketorolac (K) 30 mg x v K>P> K<P< Placebo D=P> Placebo D=P< Hynes and Total hip McCaroll arthroplasty (submitted for publication) Dlclofenac (D) 75 mg Lm. 1988. These studies suggest that pain relief after paracetamol is less than or equal to NSAIDs and of Table 2. but there is no reason to believe that these drugs given alone. clinical experience reveals that paracetamol and NSAIDs seem to be particularly efficient in relieving pain related to orthopaedic surgery (Dekens et al. 1993. 1991) in spite of their limited analgesic potency.PARACETAMOL AND PROPACETAMOL 473 For certain types of surgery NSAIDs can provide excellent analgesia. Vandermeulen et al.

474 C. hepatic syndromes. neurological problems (e. Advanced age has emerged as one of the most striking risk factors for all of these adverse effects (Sager and Benett. a few studies with short-term administration of NSAIDs have been performed to evalu- . Most NSAIDs are given orally. V A N A K E N shorter duration than the commonly used NSAIDs naproxene. 1986). A. These drugs appear to be significantly more effective with a more rapid onset of action (Buckley and Brogden. 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. The route of drug administration should also be considered. piroxicam. However. interpretation of these results is difficult 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. 1991). intramuscularly or rectally. nausea. some products have become available in a form for intravenous injection (tenoxicam. several studies suggest that the most dangerous period concerning side effects is within the first few months of taking an NSAID (Hawkey. 1992). peptic ulceration.g. SIDE EFFECTS AND COMPLICATIONS OF NSAIDs Side effects of NSAIDs may be due to inhibition of prostaglandin synthesis (bleeding. ketorolac. toxic or idiosyncratic reactions. are controversial and interpretation is difficult. however. Pre-operative versus post-operative treatment with NSAIDs has been examined. 1990) but the data do not allow separation of risk between the first 3-5 days and the following weeks. Laitinen and Nuutinen. Campbell and Kendrick. headache and dizziness) and bleeding disorders (Brooks and Day. but nevertheless. indomethacin. One controlled study suggested improved analgesia when flurbiprofen was given before rather than after surgery (Dupuis et al. they can cause severe complications in the postoperative period. Dyspepsia. 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. skin reactions. unfortunately only in a few studies. 1990. W I E B A L C K A N D H . 1992). gastric-duodenal adverse events. A pre-operatively given analgesic may prevent nociceptor sensitization and reduce post-operative pain by modifying the response of the central nervous system (CNS) and by reducing the inflammatory reaction normally observed after surgical trauma (Moreau et al. Moreover. The resuks. renal adverse events. 1991) have been reported. diclofenac. renal adverse events) or to allergic. Campbell and Kendrick. Most of the described side effects were found during long-term use of NSAIDs. 1990. propacetamol). They are infrequent (O'Brian. diclofenac and ketorolac. Only recently. Hence. ketoprofen. 1991). 1991.

The relative frequency of drugs that may have adverse interactions with . that patients after administration of acetylsalicylic acid and indomethacin were less refreshed and recuperated in the morning than those after paracetamol and placebo. Nevertheless. prolongation of pregnancy and labour. vomiting and dyspepsia were not found more often after administration of indomethacin. gastric irritation was described after short-term use of diclofenac (Muller et al. due to delayed sleep and significantly more disruptions of sleep during the night. 1992) whereas Cahadell-Carafi et al (1991) described these side effects as a common feature of ketorolac treatment. Nausea. Hence.and fentanyl-treated patients undergoing hip surgery (Laitinen and Nuutinen. One side effect of minor importance compared to those previously mentioned is the recently described disturbance of the normal sleeping patterns (Murphy et al. however. There was no difference in the incidence of nausea between diclofenac. the influence of NSAIDs on nausea and vomiting is not easily described. there is no evidence for teratogenicity of any NSAIDs in humans. Bleeding time was slightly prolonged but still within the normal range in most studies after a single dosage of indomethacin. 1992). a potassium retention (Nuutinen et al. Referring to NSAID treatment in pregnant patients. 1987). 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. a shared property of all NSAIDs. The situation. While Parker et al (1994) found a similar incidence of nausea and vomiting after ketorolac and opioid analgesics. attention should be paid in particular to patients with pre-existing risk factors for abnormal renal function (Table 3). for ketorolac. To summarize. are possible (~stensen. Other side effects of NSAIDs may be related to drug interactions. 1991). intracranial haemorrhage. 1993). and increased maternal blood loss associated with delivery. was different after administration of warfarin or low-dose acetylsalicylic acid for prophylaxis against thrombosis after total hip replacement. 1989) and ketorolac when the daily dose exceeded 120 mg (Lanza et al. no study (to the knowledge of the authors) demonstrates a higher incidence of nausea and vomiting after NSAIDs than after opioids. 1994). due to inhibition of prostaglandin synthesis. adverse effects such as constriction of the ductus arteriosus in utero. Moreover. Possibly different side effects of the various NSAIDs and the incomparability of studies may explain contradictory results. However. oxycodon and diclofenac (Laitinen et al. compared with those not taking NSAIDs (Connelly and Panush. Ready et al (1994) showed a reduced incidence. Controlled studies indicated a temporary reduction of urine output (diclofenac) and. coagulation system and kidneys. 1994). including gastro-intestinal tract bleeding. The authors demonstrated. Patients taking NSAIDs until the time of operation had more post-operative bleeding complications. 1993). diclofenac and ketorolac (Nuutinen et al.PARACETAMOL AND PROPACETAMOL 475 ate the adverse effects on gastro-intestinal tract. persistent pulmonary hypertension in the neonate.

Risk factors for possible NSAIDs-lnduced adverse events.476 C. 1994). data from prospective controlled studies do not suggest that . 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. VAN AKEN Table 3. However. WIEBALCK AND H. 1994) Drug interactions with potentially severe side effects NSAIDs is partially due to both properties of NSAIDs. anUcoagulants Elderly patients Gastroduodenopathy Atherosclerosis Congestive heart failure Drug interactions with diuretics. or by increasing the toxicity of coadministered drugs (Table 3). they occurred two times more often in NSAID users than in the control group of non-NSAID users (Hogan et al. Methotrexate. From a theoretical point of view the toxicity of NSAIDs may be increased by coadministration of interacting drugs. although only a minority of these patients had clinical manifestations. In summary. Risk factor Allergic con&tions Asthma Cross intolerance with aspmn Alcohohsm Bleeding &sorders Drug interactions with anticoagulants Elderly patients Gastroduodenopathy Nasal polyps Alcoholism Drug interactmn with cort~colds. the renal function. the well known side effects during prolonged use of NSAIDs may limit their potential use in the peri-operative period. the high percentage bound to protein. [5-blockers Elderly patients Hypovolaemia Possible adverse event Allergic reactmns Bleeding Gastric adverse events Renal adverse events Disturbed control of blood pressure Lxthium. [5-blockers and nephrotoxlc drugs Elderly patients Hypotonia Hypovolaewaa Liver cirrhosis Renal failure Sepsis Atherosclerosls Drug interactions w~th diuretics. and the small distribution volume. some chemotherapeutica and antidiabetica. oral hyperglycemic agents (Brouwers and De Smet. The most important drugs are those affecting the coagulation system. A. Drug interactions in elderly people are not infrequent. Cyclosporine.

Post-operative pain therapy should be structured. 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. 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).PARACETAMOL AND PROPACETAMOL 477 short-term NSAID treatment (< 1 week) may have clinically significant adverse effects (Dahl and Kehlet. The first step of the 'analgesic treatment ladder' is represented by paracetamol and NSAIDs which are the first line drugs for control of mild to moderate pain. during rapid injection. 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. 1993)]. paracetamol may be administered in almost all patients irrespective of age. This has been recommended by many authors and the World Health Organization (Rummans. This can be supported by the inhibition of traumainduced nociceptive impulses in order to blunt autonomic and somatic reflex responses to pain (Kehlet. coughing and mobility. but this principle may have some implications in the future. 1989). the doses of the single drugs can be reduced and side effects are limited. The value of pre-emptive analgesia is limited at present (Dahl and Kehlet. administration of antiepileptica and premature babies. The basic idea is to combine different analgesic drugs and techniques to achieve an additive or synergistic analgesic effect. Several drug interactions are theoretically possible. In summary. Patients treated with NSAIDs are less drowsy than opioid-treated patients. The multimodal approach includes the principle of balanced analgesia. also. So. breathing. a decrease in respiratory rate and an increase in arterial partial pressure of carbon dioxide may . 1993). 1991). although the incidence of nausea and vomiting is similar with both treatments. 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. in contrast. e.g. It should be based on the general principles of pre-emptive analgesia and the multimodal approach (Kehlet and Dalai. underlying disease or pregnancy. 1994) as these analgesics have less side effects than opioids. Another element is the assessment of pain and the choice of the appropriate treatment. but they are clinically irrelevant (Lechat and Kisch. No respiratory effects have been observed after paracetamol/NSAIDs. 1994). propacetamol may lead to a temporary decrease of blood pressure and a slight irritation at the site of injection. 1993). Some case studies have reported allergic reactions [cross allergy to acetylsalicylic acid (Ispano et al.

A conception for the realization of such a post-operative pain management has been proposed by Wiebalck et al (submitted for publication). antidepressants. NSAIDs should be avoided if certain risk factors for NSAIDs-induced side effects are present such as advanced age. A. a more rational choice of the optimal drug may be possible as there are some differences among non-steroidal anti-inflammatory drugs (Furst. and consideration of cost. renal insufficiency and other factors listed in Table 3. DIFFERENCES IN USE AND INDICATIONS FOR PARACETAMOL AND NSAIDs Paracetamol and NSAIDs. local anaesthetics and other adjuvant medications. anticonvulsants. Research on efficacy. bleeding diathesis. respiratory depression and sedation. Today. paracetamol and NSAIDs will minimize the need for opioid analgesics in the post-operative period. gastroduodenopathy. The analgesic potential of paracetamol may be less pronounced and of shorter duration. W I E B A L C K A N D H . patients' concomitant medications and diseases. 1994). muscle relaxants. corticoids. but there are almost no side effects. For minor surgery. tolerance. the choice of a specifically indicated NSAID can be based on (patient-related) efficacy. paracetamol/NSAIDs have fewer side-effects than opioids and by combination of both groups a low dose of opioids can be administered (opioid sparing). gastro-duodenal and renal adverse events. As one of the highest commandments 'Nihil nocere. A third step of the 'analgesic treatment ladder' might be necessary for patients with severe pain. It should be remembered that opioid sparing produces reductions in nausea and vomiting. Then. etc). As already mentioned. optimal route of administration and dosage schedules will provide more information. The most problematic side effects of NSAIDs are related to the inhibition of the peripheral cyclooxygenase-system: bleeding. SUMMARY Although less efficacious than opioid compounds. it is recommended that paracetamol alone represents the non-opioid background analgesia. incidence of adverse effects. neuroleptica. In the future. parenterally administered NSAID and paracetamol are effective analgesics that have a clear role .478 C.t' requires. both and even together are indicated for the treatment of mild to moderate pain and for more severe pain. antispasmodics. in combination with opioids. The second step of the 'analgesic treatment ladder' for the control of more severe pain includes the combination of these drugs with opioids. This step includes the use of local anaesthetics and other adjuvant medications that can improve the pain treatment (clonidine. V A N A K E N occur in opioid-treated patients.

Hedner J e t al (1994) Acetammophen blocks spinal hyperalgesla induced by NMDA and substance P Pare 57: 259-264. They should be considered as part of a balanced approach to analgesia using a combination of different drugs and techniques. today it is recommended to achieve the regular background analgesia with paracetamol alone. Paracetamol and NSAIDs. the optimal regimen for the peri-operative management of pain would appear to involve primarily paracetamol. Baude C. local anaesthetics and other adjuvant medications. For this reason. 1993).) Prattque du Traltement de la Douleur. The first step of the 'analgesic treatment ladder' is represented by paracetamol/NSAIDs (mild analgesics) which are the first line drugs for control of mild to moderate pain.Dora Editeurs. tolerability. Acta Anaesthestologwa Scandmavtca 39 (supplement 103): 1M-4 Bjtrkman R. the selective use of NSAIDs in low-risk patients in combination with opioid analgesics and local anaesthetics whenever necessary. incidence of adverse effects. 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. If a patient presents risk factors for NSAIDs-induced adverse events. Hallman K. more research is required to distinguish the differences between the various NSAIDs concerning efficacy. a more selective use of NSAIDs will provide more advantages. This step includes the use of local anaesthetics and other adjuvant medications that can improve the pain treatment (Kehlet and Dahl. are indicated for the treatment of mild to moderate pain and for more severe pain. A third step of the 'analgesic treatment ladder' might be necessary for patients with severe pain.PARACETAMOL AND PROPACETAMOL 479 in the management of post-operative pain. Paris. The second step of the 'analgesic treatment ladder' for the control of more severe pain includes the combination of these drugs with opioids. Chalrners TC et al (1993) PostoperaUve patient-controlled analgesia Metaanalyses of mmal randomized control trials Journal of Climcal Anesthesia 5: 182-193. Brooks PM & Day RO (1991) Nonsteroldal anU-mflammatory drugs~&fferences and slrrulantles New England Journal of Medicine 324:1716--1725 . pp 125-143. Paracetamol/NSAIDs have fewer side effects than opioids and by combination of both groups a lower dose of opioids can be administered (opioid sparing). Today. Bjorkman R (1995) Central antinoclceptive effects of non-steroidal anla-inflammatory drugs and paracetamol. optimal route of administration and dosage schedules. in combination with opioids. Chabrol B e t al (1991) Postoperative analgesia for nephrectomy Cahters d'Anesthgsiologw 39: 533-536. Cart DB. Assessment of pain allows the finding of appropriate measures of treatment. Beanheu P (1994) Intravenous admimstratlon of paracetamol (Propacetamol) for postoperative analgesia Anaesthesta 49:739-740 Benoxst JM (1988) Mamement des analgtslques antlpyrttiques In Boreau Fr (ed. In the future. Long D. Pain therapy should be structured.

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