Persistently high plasma morphine-6-glucuronide levels despite decreased hourly patient-controlled analgesia morphine use after single-dose diclofenac: potential for opioid-related toxicity.
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.


CONCLUSIONS
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.
D000285:Administration, Rectal; D000328:Adult; D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004008:Diclofenac / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008875:Middle Aged; D009020:Morphine / Q000009:adverse effects* / Q000097:blood; D009022:Morphine Derivatives / Q000097:blood*; D010149:Postoperative Pain / Q000188:drug therapy*; D012119:Respiration / Q000187:drug effects