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Postoperative Opioid Sparing to Hasten Recovery: What Are the Issues?

Kehlet, Henrik M.D., Ph.D.

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OPIOIDS continue to have a major role in pain management despite that they may contribute to increased in-hospital morbidity and costs.1,2 In this context, postoperative patients may be at significant risk for opioid-related adverse effects (postoperative nausea and vomiting [PONV], sedation, sleep disturbances, urinary retention, and respiratory depression).3 The recently defined new standard for pain management by Joint Commission for Accreditation of Health Care Organizations with increased efforts to reduce patients’ pain scores may further increase the risk of adverse effects when sufficient analgesia is achieved by opioids.4
The concept of multimodal, balanced analgesia introduced more than a decade ago5 suggested that both improved analgesia and reduction of (opioid-related) adverse effects could be achieved by combining different analgesics. Subsequently, it has been established that many analgesic techniques, such as nonsteroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) inhibitors,6,7 acetaminophen,8 ketamine,9 gabapentin and pregabalin,10 and regional anesthetic techniques11 provide 20–50% opioid sparing in the postoperative setting. However, it remains to be answered whether such opioid sparing would reduce “opioid-related” adverse effects, thereby hastening recovery and reducing morbidity. Results from the many previous investigations have not been consistent, probably because of underpowered studies, different dosage and drug regimens, different types of surgery, and inconsistent reporting and assessment of all opioid-related adverse effects. The topic is further complicated by the many concurrent factors that may contribute to “opioid-related” adverse effects such as pain per se, which may increase the risk of PONV,12 and that high pain scores increase the opioid requirements.13 In this context, the type of surgery may be associated with different pain patterns and consequently modify the effectiveness of analgesics14 and thereby the “opioid-related” adverse effects. In addition, it is well established that opioid-like effects such as pulmonary dysfunction may be more prominent with surgeries close to the diaphragm and the risk of urinary retention more prominent after pelvic, inguinal, and anorectal operations. Because PONV has been the most often addressed “opioid-related” adverse effect, predisposing factors to PONV per se, such as sex, location of the surgical injury, smoking habits, and previous postoperative PONV experiences, may also potentially influence the effects of opioid-sparing techniques,15 although rarely assessed in previous studies.
These precautions being said, it is most welcome that Marret et al.16 in this issue of Anesthesiology have performed a meta-analysis of randomized controlled trials examining the effect of NSAID and COX-2 inhibitor treatment on PONV and other opioid-related adverse effects. The results show that the well-known opioid sparing (approximately 30%) by these drugs significantly reduced PONV and sedation by approximately 30%, whereas effects on urinary retention and respiratory problems were inconclusive. At first glance, this is important (but probably not unexpected) news for clinicians treating postoperative pain. The results of the analysis by Marret et al.16 are further supported by recent studies with improved design to assess the clinical consequences of opioid sparing. Thus, a large, multicenter trial in a well-defined surgical operation (laparoscopic cholecystectomy) showed improved pain relief and the usual approximately 30% opioid-sparing by COX-2 inhibitor treatment.17 In this study published in different versions,17–19 the opioid-related adverse effects were assessed in detail on an opioid-related symptoms-distress scale and as clinically meaningful events. Postoperative recovery was improved with less opioid-related side effects compared with placebo treatment.17–19 Interestingly, morphine sparing of 3 mg was related to reduction to one clinically meaningful event. Similarly, in their regression analysis, Marret et al.16 were able to demonstrate a reduction in PONV of approximately 0.5% for each milligram of morphine spared by NSAID/COX-2 inhibitor treatment. Other recent studies with a more detailed assessment of opioid-related adverse effects have also shown less PONV and sleep disturbance together with approximately 30% opioid sparing with a COX-2 inhibitor after knee replacement20 and faster and improved recovery after ambulatory inguinal herniorrhaphy.21 Also, opioid sparing and improved pain relief by dexamethasone before laparoscopic cholecystectomy reduced PONV and fatigue and hastened resumption of normal activity.22
Although these data are of obvious benefit for our patients and to support opioid-sparing analgesic therapies, several questions remain to be addressed regarding the general applicability of the results. First, because PONV has been the main outcome parameter, more detailed studies are required to define whether the achieved effect is due to the reduced pain per se or strictly to the reduction in opioid use. Also, more procedure-specific data are needed because the type of surgical injury may influence PONV and respiratory and urinary bladder dysfunction per se. In addition, the pain-relieving effect by different analgesics is not equipotent in all procedures, as recently demonstrated in a reanalysis of acetaminophen data where the number-needed-to-treat values are significantly higher in major compared with minor surgery.14,23 Furthermore, because postinjury pain may show large interindividual variability,24,25 procedure-specific studies should assess the opioid-sparing outcome effects in different types of patients and operations. Finally, the benefits of opioid-sparing must be weighed against the adverse effects associated with the drugs to provide opioid sparing, examples being a bleeding risk with NSAIDs26 and cardiovascular complications in certain high-risk patients with COX-2 inhibitors.27
In the analysis by Marret et al.,16 the data were not analyzed in relation to pain scores, but the authors analyzed the opioid-sparing effects in relation to orthopedic versus abdominal surgery and found no differences. However, in these two surgical specialties, different types of orthopedic procedures were included, ranging from disc surgery to major joint replacement, as well as the abdominal procedures included major abdominal surgery, gynecologic surgery, and laparoscopic urologic procedures, which may have different risks for “opioid-related” adverse effects per se. Also, their analysis demonstrated inconsistencies in the reporting of “opioid-related” adverse effects in the available studies, which may pose a risk of publication bias thereby hindering definite interpretation.
Although the sophisticated analysis of existing data such as the study by Marret et al.16 and the more detailed procedure-specific analyses in laparoscopic cholecystectomy,17–19,22 knee replacement,20 and inguinal herniorrhaphy21 are of major clinical relevance at this time, the question is, where we go from here? First, future, well-designed studies are required, with detailed and complete assessment of all potential opioid-related side effects and being procedure specific to allow final conclusions. Also, such studies should report their results in milligrams of morphine spared because a percentage sparing may not be clinical relevant, as has been shown in a large negative multisurgery outcome study, where 30% opioid sparing was achieved by acetaminophen, but the amount of morphine spared was only 6 mg.28 However, most importantly, because single-agent opioid sparing of 20–50% has been demonstrated by NSAIDs,6 COX-2 inhibitor,7 acetaminophen,8 ketamine,9 gabapentin and pregabalin,10 and regional anesthetic techniques,11 achievement of more efficient analgesia and opioid sparing should be possible by multicombination analgesic therapy. Unfortunately, limited data are available so far, but recent data suggest additional opioid sparing and reduction of opioid-related adverse effects after hysterectomy with combined treatment with a COX-2 inhibitor and gabapentin compared with either therapy alone.29 The future is now for such clinically important studies.
Henrik Kehlet, M.D., Ph.D.
Section of Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark. henrik.kehlet@rh.dk
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References

1. Philip BK, Reese PR, Burch SP: The economic impact of opioids on postoperative pain management. J Clin Anesth 2002; 14:354–64

2. Oderda GM, Evans S, Lloyd J, Lipman A, Chen C, Ashburn M, Burke J, Samore M: Cost of opioid-related adverse drug events in surgical patients. J Pain Sympt Manage 2003; 25:276–83

3. Taylor S, Voytovich AE, Kozol RA: Has the pendulum swung too far in postoperative pain control? Am J Surg 2003; 186:472–5

4. Wheeler M, Oderda GM, Ashburn MA, Lipman AG: Adverse events associated with postoperative opioid analgesia: A systematic review. Clin J Pain 2002; 3:159–80

5. Kehlet D, Dahl JB: The value of “multi-modal”or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993; 77:1048–56

6. Power I, Barrett S: Analgesic agents for the postoperative period. Non-opioids. Surg Clin N Am 1999; 79:275–95

7. Rømsing J, Møiniche S: A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain. Acta Anaesthesiol Scand 2004; 48:525–46

8. Rømsing J, Møiniche S, Dahl JB: Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth 2002; 88:215–26

9. Elia N, Tramér MR: Ketamine and postoperative pain: A quantitative systematic review of randomised trials. Pain 2005; 113:61–70

10. Dahl JB, Mathiesen O, Møiniche S: Protective premedication: An option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004; 48:1130–6

11. Borgeat A, Ekatodramis G, Schenker CA: Postoperative nausea and vomiting in regional anesthesia. Anesthesiology 2003; 98:530–47

12. Andersen R, Krohg K: Pain as a major cause of postoperative nausea. Can Anaesth Soc J 1976; 23:366–9

13. Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B: Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology 2003; 98:1415–21

14. Kehlet H: Procedure specific postoperative pain management. Anesthesiol Clin North Am 2004; 23:203–10

15. Gan TJ, Meyer T, Apfel CC, Chung F, Davis PJ, Eubanks S, Kovac A, Philip BK, Sessler DI, Temo J, Tramér MR, Watcha M: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003; 97:62–71

16. Marret E, Kurdi O, Zufferey P, Bonnet F: Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: Meta-analysis of randomized controlled trials. Anesthesiology 2005; 102:1249–60

17. Gan TJ, Joshi GP, Zhao SZ, Hanna DB, Cheung RY, Chen C: Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects. Acta Anaesthesiol Scand 2004; 48:1194–207

18. Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C: Reliability and validity of the perioperative opioid-related symptom distress scale. Anesth Analg 2004; 99:699–709

19. Zhao SZ, Chung F, Hanna DB, Raymundo AL, Cheung RY, Chen C: Dose-response relationship between opioid use and adverse effect after ambulatory surgery. J Pain Sympt Manage 2004; 28:35–46

20. Buvanendran A, Kroin JS, Tuman KJ, Lubenow TR, Elmofty D, Moric M, Rosenberg AG: Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor of pain management and recovery of function after knee replacement. JAMA 2003; 290:2411–8

21. Ma H, Tang J, White PF, Zaentz A, Wender RH, Sloninsky A, Naruse R, Kariger R, Quon R, Wood D, Carroll BJ: Perioperative rofecoxib improves early recovery after outpatient herniorrhaphy. Anesth Analg 2004; 98:970–5

22. Bisgaard T, Klarskov B, Kehlet H, Rosenberg J: Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy. Ann Surg 2003; 238:651–60

23. Gray A, Kehlet H, Bonnet F, Rawal N: Predicting postoperative analgesia outcomes: NNT league tables or procedure-specific evidence? Br J Anaesth 2005 (in press)

24. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ: Post-cesarean pain prediction by preoperative experimental pain assessment. Anesthesiology 2003; 99:1422–6

25. Werner MU, Duun P, Kehlet H: Prediction of postoperative pain by preoperative nociceptive responses to heat stimulation. Anesthesiology 2004; 100:115–9

26. Marret E, Flahault A, Samama CM, Bonnet F: Effects of postoperative, nonsteroidal, anti-inflammatory drugs on bleeding risk after tonsillectomy. Anesthesiology 2003; 98:1497–502

27. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT: Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Sureg 2003; 6:1481–92

28. Aubrun F, Kalfon F, Mottet P, Bellanger A, Langeron O, Coriat P, Riou B: Adjunctive analgesia with intravenous propacetamol does not reduce morphine-related adverse effects. Br J Anaesth 2003; 90:314–9

29. Gilron I, Orr E, Dongsheng T, O’Neill JP, Zamora JE, Bell AC: A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Pain 2005; 13:191–200

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