“So where do we go from here … given the financial, clinical, and psychosocial consequences of persistent postsurgical pain[?]”
The prevention of persistent postsurgical pain represents the intersection between anesthesiology, surgical, and pain medicine research. It affects primary care providers who are on the front line in the treatment of chronic pain and make many of the medical decisions regarding pain management. Some may justifiably argue that this topic also contains widespread societal implications, with a recent study demonstrating that a significant proportion of opioid-naïve surgical patients will become chronic users, even after minor operations.1 Therefore, for some researchers, identifying medications or developing an effective treatment strategy to prevent persistent postsurgical pain constitutes the summit of their professional mission.
This issue of Anesthesiology contains a narrative review by Richebe et al.2 on the pathophysiology and prevention of persistent postsurgical pain. In the first part of the article, the authors discuss the epidemiology of persistent postsurgical pain, which they point out is contingent on the type of surgery; pre-, peri-, and postoperative risk factors; and how the condition is defined. Among the various preoperative factors, some may be modifiable (e.g., poorly controlled psychopathology, severe baseline pain), whereas others are unalterable and in some cases unknowable at present without invasive and possibly financially prohibitive testing (e.g., genetics, immune factors).3 In the second part, they perform an in-depth discussion of mechanisms, which include peripheral, central, and iatrogenic etiologies, including factors that can be magnified or attenuated by anesthesiologists, such as opioid-induced hyperalgesia.4 In the last part, the authors outline the effects of various preventative measures to reduce persistent postsurgical pain and outline future directions. Treatments that the authors identified to be effective in reducing the development of persistent postsurgical pain include regional anesthesia and possibly intravenous lidocaine, but these conclusions are based on very limited evidence. For gabapentinoids, which are first-line adjuvants for neuropathic pain, despite the early exuberance based on mostly industry-sponsored studies, the authors found equivocal evidence for intermediate- and long-term benefit. Considering their side effects, which in this setting can include postoperative sedation and delayed hospital discharge,5 this narrative should serve as a cautionary tale. Regarding ketamine, the medication with perhaps the most research—and controversy—behind it (there is currently a national shortage of ketamine in the United States, which in part is due to overuse), the results of meta-analyses are mixed,6,7 which reinforces the need for context and objective synthesis of data when critically evaluating literature. The conclusions of the authors on these interventions are mostly in-line with systematic reviews on the topic, which as noted above for ketamine sometimes yield mixed results.
The article by Richebe et al.2 is in the style of a narrative review. Such reviews describe and discuss a topic from a theoretical and contextual point of view; often integrate a broad diversity of preclinical, experimental, and clinical research findings; and present etiologies and mechanisms. This contrasts with systematic reviews and meta-analyses, which often more narrowly evaluate specific treatments, with greater critical analysis and standardization. In narrative reviews, critical evaluation of cited studies, including methodology (e.g., bias, heterogeneity, inclusion and exclusion criteria), technical parameters, and compilation of data, is at the discretion of the authors. Such reviews may therefore be influenced by authors’ opinions, experience, priorities, and bias, which can affect selection criteria, interpretation of data, and reporting. Although the review by Richebe et al.2 appears relatively free of bias and the authors’ backgrounds and insights help to prioritize findings, a reproducible search strategy with selection criteria, critical evaluation of the benefits, flaws and limitations of important studies, meta-analyses when relevant, and a discussion of the effect industry sponsorship has on the results (e.g., for gabapentinoids) would have been helpful.
So where do we go from here? Given the financial, clinical, and psychosocial consequences of persistent postsurgical pain, we must continue to investigate this topic, although there are some points we should consider now. First, how reliable and reproducible are the results, especially in positive trials? If rigorously designed studies whose goals are to obtain Food and Drug Administration approval have determined that studies evaluating pregabalin, a first-line agent and one of the few medications shown to possess possible short-term preventative analgesic properties before surgery, require between 150 and 350 patients to detect a modest 15 to 25% difference between the treatment and control groups,8 how many patients should theoretically be required to detect a categorical difference (categorical outcomes generally require more participants to detect a significant difference) in a study designed with less stringent selection criteria (e.g., preventative studies often fail to exclude patients with psychopathology, those on opioids and other analgesics, and people who have long-standing symptoms), in which the index condition—persistent postsurgical pain—occurs in only a fraction of patients? The number of patients needed to enroll in this type of a study is thus likely to be considerably higher (800 to more than 1,200 patients) than those recruited in previous studies evaluating preventative analgesia. Second, the number-needed-to-treat for most first-line medications ranges between 6 and 8 for neuropathic pain,9 which is why many patients end up on multiple medications. For chronic pain, well designed studies have found greater benefit when more than one medication is used than for stand-alone therapy, and most pain clinicians typically utilize rational polypharmacy.10 However, few studies evaluating preventative analgesia have utilized multiple concurrent therapies. Studies evaluating different combinations of medications can be incredibly complex and expensive, and because this strategy would probably not be a cost-effective way for industry to allocate research money, funding could be an issue. This could be addressed using adaptive study designs, streamlining existing resources, and employing large-scale registries. Third, although animal models exist for persistent postsurgical pain,11 they do not take into account the multifarious mechanisms that may be involved, including psychologic factors for high-risk surgical procedures done for cancer (e.g., mastectomy, thoracotomy), which magnifies the preexisting challenges for translation. Means by which this might be rectified could include the development of more refined models based on the anticipated trauma and randomizing more animals into a greater number of treatment arms. Fourth, given the costs—both financial and personal—of a shotgun approach to preventative analgesia, it is essential to determine which patients and operative procedures are likely to benefit from treatment (i.e., precision medicine to identify responder phenotypes), as was recently identified as a top pain research priority by the National Institutes of Health.12 For example, a comprehensive preanesthetic evaluation and implementation of a multimodal preventative analgesic strategy might be reasonable for an anxious and depressed patient on chronic opioid therapy for cancer who is scheduled for an elective thoracotomy but would not be not cost-effective in a relatively healthy person undergoing a short, routine cosmetic surgical procedure. Quantitative sensory testing, psychologic screening, large-scale, multicenter trials, database reviews, and prospective registries among others, may all provide useful information, alone or in combination, in determining which patients should be targeted for preventative treatments. Last, efforts should be undertaken to evaluate treatments not addressed in this review, including but not limited to presurgical psychologic interventions, integrative therapies, and preoperative opioid tapering, all of which are supported by mechanistic underpinnings but have not been critically evaluated.
The author is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.