OPIOIDS continue to have a major role in pain management despite that they may contribute to increased in-hospital morbidity and costs.1,2In 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).3The 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 ago5suggested 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,6,7acetaminophen,8ketamine,9gabapentin and pregabalin,10and regional anesthetic techniques11provide 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,12and that high pain scores increase the opioid requirements.13In this context, the type of surgery may be associated with different pain patterns and consequently modify the effectiveness of analgesics14and 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,15although rarely assessed in previous studies.

These precautions being said, it is most welcome that Marret et al.  16in 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.  16are 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.17In this study published in different versions,17–19the 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.17–19Interestingly, morphine sparing of 3 mg was related to reduction to one clinically meaningful event. Similarly, in their regression analysis, Marret et al.  16were 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 replacement20and faster and improved recovery after ambulatory inguinal herniorrhaphy.21Also, 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.14,23Furthermore, because postinjury pain may show large interindividual variability,24,25procedure-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 NSAIDs26and cardiovascular complications in certain high-risk patients with COX-2 inhibitors.27 

In the analysis by Marret et al. ,16the 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.  16and the more detailed procedure-specific analyses in laparoscopic cholecystectomy,17–19,22knee replacement,20and inguinal herniorrhaphy21are 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.28However, most importantly, because single-agent opioid sparing of 20–50% has been demonstrated by NSAIDs,6COX-2 inhibitor,7acetaminophen,8ketamine,9gabapentin and pregabalin,10and regional anesthetic techniques,11achievement 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.29The future is now for such clinically important studies.

Section of Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark. henrik.kehlet@rh.dk

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