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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Persistently High Plasma Morphine-6-Glucuronide Levels Despite Decreased Hourly Patient-Controlled Analgesia Morphine Use After Single-Dose Diclofenac: Potential for Opioid-Related Toxicity

University Department of Anaesthesia, Queen's Medical Centre, Nottingham, United Kingdom

Address correspondence to Dr. K. Elaine Tighe, Department of Anaesthetics, Leicester, Royal Infirmary, Infirmary Rd., Leicester, United Kingdom LE1 5WW.

We studied the time course of clinical and pharmacokinetic effects after the rectal administration of diclofenac 100 mg in seven patients using patient-controlled morphine (PCA) on the first postoperative day after major spinal surgery. Plots of plasma diclofenac concentrations and pain intensity difference (PID) demonstrated counterclockwise hysteresis consistent with distribution to a central effect compartment such as the central nervous system. Mean ± SEM (range) maximum PID and its timing were 62% ± 10% (32%–98%) and 309 ± 20 (210–360) min after the administration of diclofenac, respectively. Minimal respiratory rates were significantly slower after the administration of diclofenac (P < 0.001), occurring at 197 ± 51.9 (60–360) min; arterial desaturations occurred in two patients without oxygen therapy. Plasma morphine and morphine-6-glucuronide (M6G) concentrations interpolated to the average time of minimal respiratory rate indicated decreases of 23% ± 13% (0%–79%) and 1% ± 9% (0%–32%) from their respective starting values. Plasma M6G concentrations were significantly different from baseline only 420 and 480 min after the administration of diclofenac. The potential opioid-sparing effects of a nonsteroidal antiinflammatory drug added during PCA morphine use may not be manifest for several hours. During this lag, plasma concentrations of M6G may reach and remain at levels high enough to increase the risk of respiratory depression and other opioid side effects for hours.

Implications: Plasma concentrations of morphine, morphine-6-glucuronide, and diclofenac were measured postoperatively after a single dose of rectal diclofenac 100 mg was added to morphine patient-controlled analgesia. Peak analgesia occurred 309 min and respiratory depression 197 min after diclofenac administration. Morphine consumption had decreased by 20%, but concentrations of the active metabolite morphine-6-glucuronide were unchanged. Vigilance is recommended in patients receiving patient-controlled analgesia opioids and nonsteroidal antiinflammatory drugs.

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				S. Ohno, K. Kawana, and S. Nakajin Contribution of UDP-Glucuronosyltransferase 1A1 and 1A8 to Morphine-6-Glucuronidation and Its Kinetic Properties Drug Metab. Dispos., April 1, 2008; 36(4): 688 - 694. [Abstract] [Full Text] [PDF]

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				M. Hyllested, S. Jones, J. L. Pedersen, and H. Kehlet Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review Br. J. Anaesth., February 1, 2002; 88(2): 199 - 214. [Abstract] [Full Text] [PDF]

				C. King, W. Tang, J. Ngui, T. Tephly, and M. Braun Characterization of Rat and Human UDP-Glucuronosyltransferases Responsible for the in Vitro Glucuronidation of Diclofenac Toxicol. Sci., May 1, 2001; 61(1): 49 - 53. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999