Summary
Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs.
The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibupro-fen), metabolic Isactivation’ of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied.
The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that NSAIDs prolong bleeding times in patients, values generally remain below the upper limits of those in generally healthy patients. Healing of gastrointestinal anastomoses may be compromised by NSAID administration but cor-neal healing and bone remodelling are not. There is a need for further research into the potential for renal side effects with NSAIDs in the perioperative setting, where the effects of anaesthesia and surgery may increase the risk of side effects, particularly in elderly patients. The main benefits of NSAIDs derive from opioid sparing (e.g. reduction in perioperative nausea and vomiting and improvement in ventilation), although some studies allude to an enhanced quality of analgesia from the combination compared with either NSAID or opioid alone. The question of pre- vs postinjury treatment with NSAIDs remains unresolved.
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Brown CR, Mazzulla JP, Mok MS, Nussdorf T, Rubin PD, et al. Comparison of repeat doses of intramuscular ketorolac tro-methamine and morphine sulfate for analgesia after major surgery. Pharmacotherapy 10: 59–70, 1990
Buchanan JM, Baldasera J, Poole PH, Halshaw J, Dallard JK. Postoperative pain relief; a new approach: narcotics compared with non-steroidal anti-inflammatory drugs. Annals of the Royal College of Surgeons of England 70: 332–335, 1988
Campbell WI. Analgesic side effects and minor surgery: which analgesic for minor and day-case surgery? British Journal of Anaesthesia 64: 617–20, 1990
Catania A, Arnold J, Macaluso A, Hiltz ME, Lipton JM. Inhibition of acute inflammation in the periphery by central action of salicylates. Proceedings of the National Academy of Sciences of the United States of America 88: 8544–8547, 1991
Clarke RSJ. Non-steroidal anti-inflammatory analgesics. Current Opinion in Anaesthesiology 3: 607–611, 1990
Conrad KA, Fagen TC, Mackie MJ, Mayshar PV. Effects of ketorolac tromethamine on haemostasis in volunteers. Clinical Pharmacology and Therapeutics 43: 542–546, 1988
Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 10 non steroidal analgesics to humans. Scandinavian Journal of Haematolology 33: 155–159, 1984
Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. British Journal of Anaesthesia 66: 703–712, 1991
Dahl, JB, Rosenberg J, Dirkes WE, Mogensen T, Kehlet H. Prevention of postoperative pain by balanced analgesia. British Journal of Anaesthesia 64: 518–520, 1990
Day RO, Graham GG, Williams KM, Brooks PM. Variability in response in NSAIDs, fact or fiction? Drugs 36: 643–651, 1988
Day RO, Graham GG, Williams KM, Champion GD, De Jager J. Clinical pharmacology of non-steroidal anti-inflammatory drugs. Pharmacology and Therapeutics 33: 383–433, 1987
de Sousa JB, Soares EG, Aprilli F. Effects of diclofenac sodium on intestinal anastomotic healing. Experimental study on the small intestine of rabbits. Diseases of the Colon and Rectum 34: 613–7, 1991
Edwards ND, Barclay K, Catling SJ, Martin DG, Morgan RH. Day case laparoscopy: a survey of postoperative pain and an assessent of the value of diclofenac. Anaesthesia 46: 1077–1080, 1991
Engel C, Lund B, Kristensen SS, Axel C, Nielsen JB. Indometh-acin as an analgesic after hysterectomy. Acta Anaesthesiologica Scandinavica 33: 498–501, 1989
Evans AM. Enantioselective pharmacodynamics and pharmaco-kinetics of chiral non-steroidal anti-inflammatory drugs. European Journal of Clinical Pharmacology 42: 237–256, 1992
Forbes JA. Oral Surgery. In Max M et al. (Eds). Advances in pain research and therapy, Vol. 18, pp. 347–374, Raven Press, New York, 1991
Forrest JAH, Clements JA, Prescott LF. Clinical pharmacokin-etics of paracetamol. Clinical Pharmacokinetics 7: 93–107, 1982
Geisslinger G, Schuster O, Stock KP, Loew D, Bach GL, et al. Pharmacokinetics of S(+) and R(-)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis. European Journal of Clinical Pharmacology 38: 493–497, 1990
Graham GG. Pharmacokinetics and metabolism of non-steroidal anti-inflammatory drugs. Medical Journal of Australia 147: 587–602, 1987
Hargreaves KH, Dionne RA. Evaluating endogenous mediators of pain and analgesia in clinical studies. In Max M (Ed.) Advances in pain research and analgesia. The design of clinical trials, Vol. 18, pp. 579–597, Raven Press, New York, 1991
Harmer M. Postoperative pain relief- time to take our head out of the sand? Anaesthesia 46: 167–168, 1991
Hersh PS, Rice BA, Baer JC, Wells PA, Lynch SE, et al. Topical nonsteroidal agents and corneal wound healing. Archives of Ophthalmology 108: 577–583, 1990
Hiller A, Pitkanen M, Tuominen M, Rosenberg PH. Intravenous indomethacin prevents venipuncture inflammatory sequelae. Acta Anaesthesiologica Scandinavica 32: 27–29, 1988
Huo, MH, Troiano NW, Pelker RR, Gundberg CM, Friedlaender GE. The influence of ibuprofen on fracture repair: biome-chanical, biochemical, histologie, and histomorphometric parameters in rats. Journal of Orthopaedic Research 9: 383–390, 1991
Jackson DL, Moore PA, Hargreaves KM. Preoperative nonsteroidal anti-inflammatory medication for the prevention of postoperative dental pain. Journal of the American Dental Association 119: 641–647, 1989
Jung D, Mroszczak E, Bynum L. Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration. European Journal of Clinical Pharmacology 35: 423–425, 1988
Keller J, Kjaersgaard-Andersen P, Bayer-Kristensen I, Meisen F. Indomethacin and bone trauma. Effects on remodeling of rabbit bone. Acta Orthopaedica Scandinavica 61: 66–69, 1990
Kenny GNC, McArdle CS, Aitken HH. Parenteral ketorolac: opiate-sparing effect and lack of cardiorespiratory depression in the perioperative patient. Pharmacotherapy 10(Suppl. 6): 127–131, 1990
Kenny G, Sommerville K. The perioperative use of non-steroidal anti-inflammatory drugs. Current Opinion in Anaesthesiology 4: 568–573, 1991
Kim DH, Van Arman CG, Armstrong D. The chemistry of the non-steroidal antipyretic agents: structure activity relationships. In Milton AS (Ed.) Pyretics and antipyretics. Handbook of experimental pharmacology, Vol. 60, pp. 317–375, Springer-Verlag, New York, 1982
Laitinen J, Nuutinen L. Intravenous diclofenac coupled with PCA fentanyl for pain relief after total hip replacement. Anesthe-siology 76: 194–198, 1992
Laitinen J, Nuutinen L, Kiiskila EL, Freudenthal Y, Ranta P, et al. Comparison of intravenous diclofenac, indomethacin and oxycodone as post-operative analgesics in patients undergoing knee surgery. European Journal of Anaesthesiology 9: 29–34, 1992
Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain relief. In Max M, et al. (Eds) The design of analgesic clinical trials. Advances in pain research and therapy, Vol. 18, pp. 481–506, Raven Press, New York, 1991
Lim JH, Cochetto DM, Duggan DE. Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drug. Clinical Pharmacokinetics 12: 402–432, 1987
Lysak SZ, Eisenach JC, Dobson CE II. Patient-controlled epidural analgesia during labor: a comparison of three solutions with a continuous infusion control. Anaesthesiology 72: 44–49, 1990
Macdonald FC, Gough KJ, Nicoll RA, Dow RJ. Psychomotor effects of ketorolac in comparison with buprenorphine and diclofenac. British Journal of Clinical Pharmacology 27: 453–459, 1989
Mastboom WJ, Hendriks T, van Eiteren P, de Boer HH. The influence of NSAIDS on experimental intestinal anastomoses. Diseases of the Colon and Rectum 34: 236–243, 1991
Mattie H. Non-opiate analgesics and prostaglandins. In Feldman SA et al. (Eds) Drugs in anaesthesia: mechanisms of action, pp. 309–320, Edward Arnold, London, 1987
Mbugua SW, Skoglund LA, Lokken P. Effects of phenylbutazone and indomethacin on the post-operative course following experimental orthopaedic surgery in dogs. Acta Veterinaria Scan-dinavica 30: 27–35, 1989
McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. Drugs 41: 533–547, 1991
McGlew IC, Angliss DB, Gee GJ, Rutherford A, Wood AT. A comparison of rectal indomethacin with placebo for pain relief following spinal surgery. Anaesthesia and Intensive Care 19: 40–45, 1991
Murray MD, Brater DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Annals of Internal Medicine 112: 559–560, 1990
Okuyama S, Aihara H. The mode of action of analgesic drugs in adjuvant arthritic rats as an experimental model of chronic inflammatory pain: possible central analgesic action of acidic nonsteroidal antiinflammatory drugs. Japanese Journal of Pharmacology 35: 95–103, 1984
Owen H, Glavin RJ, Shaw NA. Ibuprofen in the management of postoperative pain. British Journal of Anaesthesia 58: 1371–1375, 1986
Owen H, McMillan V, Rogowski D. Postoperative pain therapy: a survey of patients’ expectation and their experiences 41: 307–307, 1990
Piletta P, Porchet HC, Dayer P. Central analgesic effect of acetaminophen but not of aspirin. Clinical Pharmacology and Therapeutics 49: 350–354, 1991
Power I, Chambers WA, Greer IA, Ramage D, Simon E. Platelet function after intramuscular diclofenac. Anaesthesia 45: 916–919, 1990a
Power I, Noble DW, Douglas E, Spence AA. Comparison of I.M. ketorolac trometamol and morphine sulphate for pain relief after cholecystectomy. British Journal of Anaesthesia 65: 448–455, 1990b
Randall LO. Non-narcotic analgesics. In Root WS, Hofmann FG (Eds) Physiological pharmacology. The nervous system, Vol. 1 (part A), pp. 313–416, Academic Press, New York, 1963
Resman-Targoff BH. Ketorolac: a parenteral nonsteroidal antiinflammatory drug. Annals of Pharmacotherapy 24: 1098–1104, 1990
Rice ASC, Lloyd J, Miller CG, Bullingham RE, O’Sullivan GM. A double-blind study of the speed of onset of analgesia following intramuscular administration of ketorolac trometham-ine in comparison to intramuscular morphine and placebo. Anaesthesia 46: 541–544, 1991
Rosenblum M, Weller RS, Conrad PL, Falvey EA, Gross JB. Ibuprofen provides longer lasting analgesia than fentanyl after la-paroscopic surgery. Anesthesia and Analgesia 73: 255–259, 1991
Rudy AC, Knight PM, Brater DG, Hall SD. Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen. Journal of Pharmacology and Experimental Therapeutics 259: 1133–1139, 1991
Runciman WB, Mather LE. Effects of anaesthesia on drug disposition. In Feldman et al. (Eds) Mechanisms of action of drugs in anaesthetic practice, pp. 87–122, Edward Arnold, London, 1987
Schulze S, Roikjaer O, Hasselstrom L, Jensen NH, Kehlet H. Epi-dural bupivacaine and morphine plus systemic indomethacin eliminates pain but not systemic response and convalescence after cholecystectomy. Surgery 103: 321–327, 1988
Segstro R, Morley-Forster PK, Lu G. Indomethacin as a postoperative analgesic for total hip arthroplasty. Canadian Journal of Anaesthesia 38: 578–581, 1991
Semple P. Postoperative pain control. A survey of current practice. Anaesthesia 46: 1074–1076, 1991
Smallman JMB, Powell, H, Ewart MC, Morgan M. Ketorolac for postoperative analgesia in elderly patients. Anaesthesia 47: 149–152, 1992
Sommer P, Kromann-Andersen B, Lendorf A, Lyngdorf P, Möller P. Analgesic effect and tolerance of voltaren and ketogan in acute renal or ureteric colic. British Journal of Urology 63: 4–6, 1989
Spindler JS, Mehlisch D, Brown CR. Intramuscular ketorolac and morphine in the treatment of moderate to severe pain after major surgery. Pharmacotherapy 10(Suppl. 6): 51–58, 1990
Spowart K, Greer IA, McLaren M, Lloyd J, Bullingham RES, et al. Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thrombosis and Haemo-stasis 60: 382–386, 1988
Stadler P, Armstrong D, Margalith D, Saraga E, Stolte M, et al. Diclofenac delays healing of gastroduodenal mucosal lesions. Double-blind, placebo-controlled endoscopie study in healthy volunteers. Digestive Diseases and Sciences 36: 594–600, 1991
Stanski DR, Cherry C, Bradley R, Sarnquist FH, Yee JP. Efficacy and safety of single doses of intramuscular ketorolac trome-thamine compared with meperidine for postoperative pain. Pharmacotherapy 10(Suppl. 6): 40–44, 1990
Stillman MT, Schlesinger PA. Nonsteroidal anti-inflammatory drug nephrotoxicity. Should we be concerned? Archives of Internal Medicine 150: 268–270, 1990
Tigerstedt I, Tammisto T, Neuvonen PJ. The efficacy of intravenous indomethacin in prevention of postoperative pain. Acta Anaesthesiologica Scandinavica 35: 535–540, 1991
Times (London). Antiquated medical attitudes blamed for patients’ pain, September 26, 1990
Troullos ES, Hargreaves KM, Butler DP, Dionne RA. TI: comparison of nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen, with methylprednisolone and placebo for acute pain, swelling, and trismus. Journal of Oral and Maxillofacial Surgery 48: 945–952, 1990
Utting JE, Smith JM. Postoperative analgesia. Anaesthesia 34: 320–332, 1979
Verbeeck RK, Blackburn JL, Loewen GR. Clinical pharmacoki-netics of non-steroidal anti-inflammatory drugs. Clinical Phar-macokinetics 8: 297–331, 1983
Waterbury L, Kunysz EA, Beuerman R. Effects of steroidal and non-steroidal anti-inflammatory agents on corneal wound healing. Journal of Ocular Pharmacology 3: 43–54, 1987
Watt JA, Dickinson RG. The effect of ethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats. Xenobiotica 20: 289–301, 1990
Weissman G. Aspirin. Scientific American 264: 84–90, 1991
Williams K. Enantiomers in arthritic disorders. Pharmacology and Therapeutics 46: 273–295, 1990
Woodhouse KW, Wynne H. The pharmacokinetics of non-steroidal anti-inflammatory drugs in the elderly. Clinical Pharmacokinetics 12: 111–122, 1987
Wood-Smith FG, Stewart HC, Vickers M. Drugs in anaesthetic practice, 3rd ed., p. 98, Butterworths, London, 1968
Wuolijoki E, Oikarinen VJ, Ylipaavalniemi P, Hampf G, Tolvanen M. Effective postoperative pain control by preoperative injection of diclofenac. European Journal of Clinical Pharmacology 32: 249–252, 1987
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Mather, L.E. Do the Pharmacodynamics of the Nonsteroidal Anti-Inflammatory Drugs Suggest a Role in the Management of Postoperative Pain?. Drugs 44 (Suppl 5), 1–13 (1992). https://doi.org/10.2165/00003495-199200445-00003
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DOI: https://doi.org/10.2165/00003495-199200445-00003