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From the *Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas; and Section for Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark.
Address correspondence and reprint requests to Dr. Paul F. White, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu.
The most recent systematic review of the pain literature by Liu and Wu (1) examined the effect of the postoperative analgesic technique on the incidence of complications after surgery. The authors reanalyzed 18 meta-analyses and 10 systematic reviews (in addition to 8 randomized clinical trials and 2 observational studies), and concluded that "there is insufficient evidence to confirm or deny the ability of postoperative analgesia techniques to affect postoperative mortality or morbidity."
Unfortunately, many anesthesiologists and surgeons may erroneously conclude from this analysis that optimizing pain management does not really make any difference with respect to patient outcome after surgery. Therefore, this review raises several important questions for the anesthesia community. For example, what is the value of a systematic review of a complex multifactorial problem involving the interplay between postoperative pain and its effects on patient outcomes? In comparing their findings to published reviews on this topic (2–5), it would appear that the current analysis contains little, if any, new information. Given that their findings largely represent a "reanalysis" of previous analyses from the pain literature, the authors’ conclusion is not unexpected. However, another potential explanation for the negative findings regarding the potential beneficial effects of IV patient-controlled analgesia and epidural analgesia on major postoperative complications relates to the possibility of a type-2 statistical error due to an "insufficient number of comparable subjects," given the low incidence of serious complications in the postoperative period.
The second, and even more important, question relates to the value of continuing to "meta-analyze" old studies involving a single type of intervention in nonhomogenous surgical populations (6). These studies have repeatedly found limited effects of a single intervention on adverse postoperative outcomes unless every aspect of perioperative care is tightly controlled. For example, the well-documented reduction in postoperative ileus when a continuous thoracic epidural with local anesthetics is administered for pain control after major intraabdominal surgery does not lead to improved patient outcomes (e.g., decreased major complications) or reduced hospital stay unless the patient is encouraged to rapidly resume oral intake and begins to ambulate in the early postoperative period (6).
Liu and Wu (1) suggested that, despite the vast peer-reviewed literature documenting the benefits of a wide variety of analgesic drugs and drug combinations in the perioperative period, we need to perform more "large scale outcome studies" to establish the benefits of analgesic therapies. We would suggest that the negative findings from the current reanalysis of the pain literature were related in part to the fact that the authors only included large-scale randomized studies (7,8) while ignoring smaller, well-controlled clinical trials containing group sizes of <100 patients. In the large Veterans Administration hospital study (7), epidural opioids were used for ill-defined time intervals after different types of operations, rather than as part of a carefully controlled fast-track perioperative care regimen (9). Furthermore, it is well known that epidural opioids without local anesthetics have minimal effects on the undesirable pathophysiologic responses and major organ system dysfunction which can occur after surgery. Finally, epidural analgesia is not always epidural analgesia and must be defined and optimized according to level of insertion and sufficient use of local anesthetic (10–12). In another large scale, the so-called MASTER anesthesia trial (8), neither the site nor even the specific drugs administered for epidural analgesia were described. More importantly, the surgical procedures which were studied varied from abdominal hysterectomy to esophagectomy!
Other factors (e.g., fluid management) can also have a major impact on postoperative complications and, therefore, must be controlled in analgesic studies (especially when a central neuroaxial block is involved) (13). For example, in patients undergoing aortic aneurysm surgery, use of epidural analgesia in combination with early nutritional intake and mobilization eliminated pulmonary morbidity and reduced the length of the hospital stay to about 3 days when fluid administration was tightly controlled (14). On the other hand, in outpatients undergoing ambulatory surgery, aggressive hydration to avoid functional hypovolemia will improve the recovery profile by reducing side effects and minimizing organ dysfunction (15,16).
The authors’ statement suggesting that the problem in finding a beneficial effect of postoperative analgesic techniques on complications after surgery is related to the "morass of underpowered randomized clinical trials" could also be seriously questioned. The vast majority of carefully controlled, randomized, prospective clinical trials demonstrating benefits of specific analgesics and novel administration techniques have group sizes which range from 25 to 100 patients. Therefore, it is hardly surprising that a systematic review which eliminated all studies with group sizes of <100 patients would have a negative result. An important lesson regarding this issue can be learned from examining the peer-reviewed literature on the comparative effects of antiemetic drugs in the prevention of postoperative nausea and vomiting (PONV).
In a relatively small, single-site, placebo-controlled study involving ondansetron and droperidol, the two antiemetics were found to have similar efficacy and side effect profiles (versus placebo) when administered for the prevention of PONV (17). The manufacturer of the 5-HT3 antagonist assumed that the failure to find any significant differences between the two antiemetics was simply due to the fact that the earlier study was inadequately powered because of the allegedly small group sizes (n = 40) (17). Subsequently, a large multicenter study was performed with group sizes of more than 500 patients each, and the findings were identical to the original comparative study (18,19). In a subsequent large multi-center comparative study by Apfel et al. (20) involving more than 4000 patients, the original findings of Tang et al. (17) were once again confirmed. When studying multifactorial problems like PONV and postoperative pain, clinical trials conducted at a single site, where potentially confounding factors are tightly controlled, may actually prove to be more valuable than less rigorously controlled multicenter studies having huge group sizes.
Another important question relates to what, if any, additional information a large meta-analysis provides that a well-conducted, adequately powered, prospective, randomized, double-blind study conducted at a single site apparently lacks (21)? A critical reading of the peer-reviewed literature would suggest that the answer to this question is not obvious. In fact, small-scale, single-institution studies which are well designed and carefully conducted can be hypothesis-generating and provide important information about how to optimally design larger confirmatory trials which target important outcome variables that occur with a low frequency (e.g., serious postoperative complications). If the primary goal of anesthesiologists in trying to optimize pain management was only to prevent major complications such as myocardial infarction, pulmonary emboli, and strokes, we could probably simply ignore the problem and go home!
For most anesthesia practitioners, the primary goal in trying to improve pain management is to enhance patient comfort and facilitate the recovery process after surgery (9), as well as to minimize postoperative complications. Therefore, it is critically important to incorporate the principle of optimizing perioperative medical care by using a fast-track recovery paradigm in future studies examining the impact of pain management on patient outcomes (6,9). Well-controlled and appropriately powered clinical studies which examine the impact of improved analgesic techniques on patient comfort, quality of recovery, and resumption of normal activities of daily living (i.e., fast-track recovery) are probably of greater relevance than the mega-studies proposed by Liu and Wu, which largely focus on end points that are relatively rare and which include multiple pathogenic mechanisms that are very difficult to tightly control.
Hopefully, these investigators will begin to perform well-designed prospective, randomized outcome studies with clinically meaningful end points when effective analgesic techniques are integrated in perioperative care and rehabilitation, as was suggested more than a decade ago (22). It is time to "roll up our sleeves and get back to work" doing high-quality clinical research rather than simply reanalyzing previously published studies.
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Endowment funds from the Margaret Milam McDermott Distinguished Chair of Anesthesiology provides salary support for Dr. White, and the White Mountain Institute, a private nonprofit foundation, also provides support for Dr. White’s academic activities.
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  P. F. White, H. Kehlet, and S. Liu Perioperative Analgesia: What Do We Still Know? Anesth. Analg., May 1, 2009; 108(5): 1364 - 1367. [Full Text] [PDF]
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A. Turan, P. F. White, O. Koyuncu, B. Karamanliodlu, G. Kaya, and C. C. Apfel Transdermal Nicotine Patch Failed to Improve Postoperative Pain Management Anesth. Analg., September 1, 2008; 107(3): 1011 - 1017. [Abstract] [Full Text] [PDF]
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 Y. Sun, T. J. Gan, J. W. Dubose, and A. S. Habib Acupuncture and related techniques for postoperative pain: a systematic review of randomized controlled trials Br. J. Anaesth., August 1, 2008; 101(2): 151 - 160. [Abstract] [Full Text] [PDF]
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P. F. White Red-Hot Chili Peppers: A Spicy New Approach to Preventing Postoperative Pain Anesth. Analg., July 1, 2008; 107(1): 6 - 8. [Full Text] [PDF]
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P. F. White and H. Kehlet Improving Pain Management: Are We Jumping from the Frying Pan into the Fire? Anesth. Analg., July 1, 2007; 105(1): 10 - 12. [Full Text] [PDF]
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