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50 mg IM (n = 62) 75 mg IM (n=62)

Rational prescription of NSAIDs in the perioperative period is important toobtain the best analgesic effect ofeach drug. Adequate prescription begins with the selection of the correct drug. Over the last 3 decades there has been a dramatic increase in the number of new NSAIDs available and although they are classified in the same group of drugs, the relative potency ofthe three main therapeutic effectsofNSAIDs (anti-in - flammatory , analgesic, antithermic) vary considerably among individual agents. Additionally , they may have direct central activity and the balance between peripheral and central analgesic effects may differ among agents.

Diclofenac is anon-selective inhibitor of cyclooxigenase. It is superior to other NSAIDs to control postoperative pain because itnot only has agreater analgesic potency inrelation to its anti-inflammatory effects but it is also less toxic to the gastrointestinal tract than drugs such as ketoprofen, piroxicam and indomethacin 6. It is also safe for the breastfeeding women, as the amount of diclofenac found in the milk is small and offers no risk for the nursing infant 7. Diclofenac may be administered by the oral, rectal and parenteral route. Ideally, the least invasive route should always be chosen. However, different regimens of administra - tion may determine different analgesic effects. Although the oral route is the least invasive, it was not evaluated in this study,asitisoflimited value inthe early postoperative period, particularly in patients submitted to abdominal surgery. Nausea and vomiting can make absorption of the drug erratic and so reduce its analgesic efficacy. Intravenous infusions result in more stable blood concentrations and enable high tissue levels to be achieved within a few minutes. However, unless diluted properly beforehand, pain during injection of the drug and thrombophlebitis may commonly occur. So, we decided to compare the analgesic efficacy of the rectal and intramus - cular routes. The intramuscular route is probably the most commonly used for postoperative analgesia and it is associated fast therapeutic plasma concentrations. Rectal administration is a good alternative route, especially when oral administration is not possible, as it does not rely on gastric absorption and emptying. However, previous discussion with patientsisnecessary ,asmany will not agree with the route of administration. In this study, the evaluation of the analgesic efficacy of different regimens of administration of diclofenac showed that the intramuscular route was superior to the rectal route to control postoperative pain. The need for rescue analgesics, analgesic consumption and mean postoperative pain scores were higher in the group that received diclofenac rectally. These results are in agreement with the ones obtained by Campbell et al. 8 and Jakobson et al. 9 that showed that the parenteral administration of diclofenac was associated with better postoperative analgesia than the oral route, and differ from the ones obtained by Hyrkas et al 10 and Moore et al. 1, who found equivalent postoperative analgesia when they compared the oral vs intramuscular and the rectal vs intramuscular administration of diclofenac respectively . However, it is important to notice that in the last two studies, diclofenac doses administered were higher in the oral and rectal groupsand lower in the intramuscular groups. It is possible that this apparent controversy may be related to the pharmacokinetics of the drug. In therapeutic doses of 25-150 mg, the bioavailability of diclofenac increases linearly following its administration by the oral, rectal and intramuscular routes. However, drugs used by the oral and rectal routes undergo the first-p ass metabolism effect, which reduces itsbioavailabilty in 50% 12.I ti s possible that in the studies done by Hyrkas et al. 10 and Moore et al. 1, the larger doses given in the oral and rectal groups may have compensated for a reduced amount of diclofenac

670 Revista Brasileira de Anestesiologia Vol. 52, Nº 6, Novembro - Dezembro, 2002 that would reach the systemic circulation due to the first-p ass effect. When different doses of diclofenac were administered by the same route, no differences in the analgesic efficacy were observed between groups that received 50 and 75 mg of diclofenac intramuscularly . This fact suggest s that the bioavailabilty of diclofenac may be directly correlated with its analgesic efficacy and that there is a ceiling effect, above which increases in the bioavailabilty of the drug are not associated with improvement s in the quality of postoperative analgesia. These dataare in agreement with the ones obtained by O’Hara 13 who also demonstrated a ceiling effect for ketorolac, when the administration of doses higher than 30 mg were not associated with an improvement in the quality of postoperative analgesia. Adequate comparison of the analgesic efficacy of different regimens of diclofenac administration requires an appropri - ate model of postoperative pain. Surgeries associated with low postoperative pain scores may not serve to distinguish analgesic efficacy following the administration of a specific drug by different routes and in different doses. Under these circumst ances, equivalency among groups may be due to a lack in the internal sensitivity of the pain model. An index of internal sensitivity may be obtained by including a placebo group, in which no treatment is used or administering two different doses of the same drug, preferably by the same route in order to obtain a dose-response curve. As the purpose of this study was to comp are the analgesic efficacy of diclofenac, when administered by different routes and doses, a control group was not included. Spinal morphine was intentionally administered in association with hyperbaric bupivacaine, as diclofenac alone was not sufficient to control postoperative pain following cesarean section. On the other hand, with the addition of spinal morphine, one may question the validity of administering diclofenac to control post-cesarean pain, as analgesia might be solely attributed to the action of that opioid. However, Cardoso etal. 3demonstrated that inpatientssubmitted tocesarean section under spinal anesthesia with up to 100 µg of morphine, the need for rescue analgesics occurred in up to 75% of the patients. In approximately 25% of patients, spinal morphine alone was sufficient to control postoperative pain. However, in clinical practice, it is not possible to predict such patients and the association of opioid and NSAIDs is clinically justifiable. In the recovery room, pain was evaluated using the visual analogue scale, which is a sensitive, reliable and simple method to quantify postoperative pain 14. Although patient-controlled analgesia devices, which should be the ideal method of study, were not used, postoperative pain was assessed every 30 minutes, and rescue analgesics were ready to be administered whenever patients reported pain higher than 3cm(VAS). Meperidine was chosen as the rescue analgesic, as it is commonly administered in the perioperative period of obstetric patients. Analgesic consumption in the postoperative period was not evaluated alone. The quality of postoperative analgesia also included mean pain scores and the need for rescue analgesics. Although the preemptive effect of NSAIDs is always questioned, it is clear that the preoperative administration of NSAIDs is of interest, since NSAIDs exert their effects on the pain pathways by inhibiting the action of the cyclooxigenase, thus preventing the production of prost aglandins. Depending on the dose, route and rate of administration, different time intervals are required before the drugs reach their site of action, inhibit the enzyme and exert a clinical effect. NSAIDs have nodirect effect onthe activity ofprostaglandins that have already been synthesized. In this study, diclofenac was not administered preoperatively ,aswewere treating obstetric patients. According to Willis et al. 12 peak plasma concentrations of the drug are reached in around 30 minutes, exposing the neonate to itspossible side effectssuch as gastric hemorrhage, hyperbilirubinemia, transient renal dysfunc - tion, pulmonary hypertension and fetal ductus arteriosus closure. We choose to administer diclofenac 90 minutes after spinal anesthesia, when surgery was completed in all patients and pain was not yet present. The study ended at 360 minutes after diclofenac administra - tion as it corresponds with the period that patient sstayinthe recovery room and under direct supervision of the anesthe - siologist s. In conclusion, the resultsofthis study demonstrate that while combined with small doses of spinal morphine, the intramuscularly administration of diclofenac offers better postoperative analgesia than the rectalroute. Additionally ,itseems that there is a ceiling effect for this drug, used for immediate postoperative pain management; no advantages are observed with doses larger than 50 mg intramuscularly .

01. Luthman J, Kay NH, White JB - The morphine sparing effect of diclofenac sodium following cesarean section under spinal anesthesia. Int J Obstet Anesth, 1994;3:82-86. 02. Dennis AR, Leeson-Payne CG, Hobbs GJ - Analgesia after cesarean section. The use of diclofenac as an adjunct to spinal morphine. Anaesthesia, 1995;50:297-299 03. Cardoso MMSC, Carvalho, JCA, Amaro AR et al -Small doses of spinal morphine combined with systemic diclofenac for postoperative analgesia after cesarean delivery . Anesth Analg, 1998;86:538-541. 04. McCormack K - The spinal actions of nonsteroidal anti-inflam - matory drugs and the dissociation between their anti-inflamma - tory and analgesic effects. Drugs, 1994;47:28-45. 05. Bjorkman R - Central antinociceptive effects of nonsteroidal anti-inflammatory drugs and paracetamol. Acta Anaesthesiol Scand, 1995;39:1-4. 06. Peloso PM - Strategies and practice for use of nonsteroidal anti-inflammatory drugs Scand J Rheumatol, 1996;105:29-48. 07. Ostensen M, Husby G - Antirheumatic drug treatment during pregnancy and lactation. Scand J Rheumatol, 1985;14:1-7. 08. Campbell WI, Kendrick R, Patterson C - Intravenous diclofenac sodium. Does its administration before operation suppress postoperative pain? Anaesthesia, 1990;45:763-766.

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09. Jakobson J, Rane K, Davidson S - Intramuscular NSAID reduces postoperative pain after minor outpatient anesthesia. Eur J Anaesth, 1996;13:67-71. 10. Hyrkas T, Ylipaavalniemi P, Oikarinen VJ et al - Postoperative pain prevention by a single-dose formulation of diclofenac producing a steady plasma concentration. J Oral Maxillofac Surg, 1992;50:124-127 1. Moore AP, Thorpe JA, Mulley BA et al - Which diclofenac form is best? Post-thoracotomy pain: intramuscular vs rectal administration of diclofenac. Hosp Pharm Pract, 1993;431-432. 12. Willis JV, Kendall MJ, Flinn RM et al - The pharmacokinetics of diclofenac sodium following intravenous and oral administra - tion. Eur J Clin Pharmacol, 1979;16:405-410. 13. O’Hara DA, Fragen RJ, Kinzer M et al - Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther, 1987;41:556-561. 14. Scott J, Huskisson EC - Graphic representation of pain. Pain, 1976;2:175-184.

RESUMEN Cardoso MMSC, Carvalho JCA, Tahamtani SMM - Diclofenaco por Vía Muscular o Rectal Asociado con Bajas Dosis de Morfina Subaracnóidea para Analgesia Pós-Operatoria en Cesáreas

Justificativa y Objetivos - El diclofenaco ha sido utilizado en combinación con opioides por vía subaracnóidea en el control del dolor pós-operatorio; mientras que, la mejor forma de su administración no es conocida. Este estudio evaluó la calidad de la analgesia pós-operatoria de diferentes esquemas de administración de diclofenaco, en pacientes sometidas a cesárea bajo raquianestesia con bupivacaína y morfina.

Método - Después del final de la cirugía, las pacientes fueron distribuidas aleatoriamente en tres grupos que recibieron diclofenaco como se sigue: G50VR (n=62), 50 mg por vía rectal; G50IM (n=62), 50 mg por vía muscular y G75IM (n=62), 75 mg por vía muscular . El dolor fue evaluado con una escala analógica visual de 0-10 cm (EAV) a cada 30 minutos en las primeras seis horas y meperidina, vía venosa, fue administrada como medicación de rescate siempre que la EAV fuera igual o mayor que 3 cm.

Conclusiones - Cuando combinada con bajas dosis de morfina subaracnóidea, la administración de diclofenaco por vía muscular promueve mejor analgesia pós-operatoria que por vía rectal. Después de eso, parece haber un efecto techo para esta droga, ya que no se observan ventajas con dosis superiores a 50 mg por vía muscular .

672 Revista Brasileira de Anestesiologia Vol. 52, Nº 6, Novembro - Dezembro, 2002

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