Pharmacotherapy for the prevention of chronic pain after surgery in adults
Chronic pain can often occur after surgery, substantially impairing patients’ health and quality of life. It is caused by complex mechanisms that are not yet well understood. The predictable nature of most surgical procedures has allowed for the conduct of randomized controlled trials of pharmacological interventions aimed at preventing chronic postsurgical pain.
The primary objective was to evaluate the efficacy of systemic drugs for the prevention of chronic pain after surgery by examining the proportion of patients reporting pain three months or more after surgery. The secondary objective was to evaluate the safety of drugs administered for the prevention of chronic pain after surgery.
We identified randomized controlled trials (RCTs) of various systemically administered drugs for the prevention of chronic pain after surgery from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 17 July 2013.
Included studies were double‐blind, placebo‐controlled, randomized trials involving adults and evaluating one or more drugs administered systemically before, during or after surgery, or both, which measured pain three months or more after surgery.
Data collection and analysis
Data collected from each study included the study drug name, dose, route, timing and duration of dosing; surgical procedure; proportion of patients reporting any pain three months or more after surgery, reporting at least 4/10 or moderate to severe pain three months or more after surgery; and proportion of participants dropping out of the study due to treatment‐emergent adverse effects.
We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non‐steroidal anti‐inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N‐methyl‐D‐aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta‐analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect.
Additional evidence from better, well designed, large‐scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non‐steroidal anti‐inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.
Luis Enrique Chaparro, Shane A Smith, R Andrew Moore, Philip J Wiffen, Ian Gilron
Plain language summary
Systemic drugs for the prevention of chronic pain after surgery
Pain associated with surgery generally resolves within one to two weeks, however in some situations surgical patients are left with longstanding pain for months or even years after the surgical procedure. Researchers have studied the ability of various drug treatments to prevent the development of chronic pain after surgery and this systematic review evaluated published studies in this field. Available studies suggest a modest effect of ketamine, compared to placebo, for prevention of chronic pain after surgery, however small study size could lead to an overestimation of this effect. Studies of other drugs such as gabapentin and pregabalin did not suggest the same preventative effect. Additional large studies using improved research methods are necessary to more clearly identify treatments that are beneficial for preventing chronic postsurgical pain.
Luis Enrique Chaparro, Shane A Smith, R Andrew Moore, Philip J Wiffen, Ian Gilron
Implications for practice
Comments below about the clinical implications of drug intervention studies included in this review refer only to the reported long‐term pain prevention effects, that is just because evidence does not support efficacy for chronic postoperative pain prevention for a particular drug does not mean that it is not beneficial for the treatment of early postoperative pain.
Although our meta‐analyses of ketamine seem to suggest population efficacy for reducing the prevalence of chronic postsurgical pain, results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to overestimation of treatment effect. Therefore, additional large‐scale trials are necessary to better determine which patient subgroups are likely to benefit from routine perioperative ketamine administration as well as to determine the optimal dosing regimen for chronic pain prevention.
Finally, available evidence does not support the efficacy of gabapentin, pregabalin, or other studied drugs for the prevention of chronic postoperative pain. Therefore, administration of these drugs specifically for the purpose of preventing chronic pain cannot be recommended.
Implications for research
Results of this review underscore the need for continued investigation into the etiology and pathogenesis of chronic postsurgical pain in order to better understand the inciting mechanisms (for example injury of nerves versus other tissues and other perioperative alterations in ascending and descending pain modulation) and novel pharmacological targets of prevention (Katz 2009; Kehlet 2006; Rappaport 2010).
Given the necessary resources to conduct well designed and conclusive pain prevention trials, the impact of future research would be maximized by focusing largely on surgical procedures associated with the highest prevalence of chronic postsurgical pain (for example amputation, thoracotomy, coronary artery bypass surgery and breast surgery).
The relevance of future chronic postsurgical pain prevention trials certainly relies on the use of clinically relevant outcome measures. In particular, pain outcomes should be assessed at multiple time points, for example from three months after surgery and forward to also include six, nine, 12 months and beyond as trial logistics allow. It would be optimal to include pain outcome measures that could be standardized (for example pain intensity on a 0 to 10 numerical rating scale or 0 to 100 visual analog scale) and, further, to define outcomes that can be dichotomized (for example 'any non‐zero pain' and 'moderate‐to‐severe pain'). Other useful secondary outcomes at long‐term follow‐up time points include the use of or need for analgesics or other pain treatments as well as other functional (for example Brief Pain Inventory) and quality of life (for example SF‐36) measures.
Determination of appropriate sample sizes for future prevention studies requires careful consideration and should be closely related to anticipated baseline rates of chronic postsurgical pain in the surgical population of interest (Kehlet 2010). Thus, studies of surgical procedures associated with a lower prevalence of chronic postsurgical pain will need larger sample sizes in order to demonstrate statistically significant differences in outcome between control and intervention groups. Also, consideration must be given to clinically important differences in light of the safety and tolerability, cost and ease of use of the study intervention (Dworkin 2010). Avoidance of attrition bias requires attention and all attempts must be made to avoid loss to follow‐up among study participants. Finally, stratification of study populations between those with and those without preoperative pain is crucial for proper interpretation of prevention trials and may affect statistical power and sample size determinations.
As suggested by this review, numerous pharmacological agents have been studied for the prevention of chronic postoperative pain. Most of these medications are known to be effective for the treatment of early postoperative pain but their efficacy in chronic pain prevention remains in question. The somewhat disappointing results from single‐agent studies included in this review support recent suggestions by Dahl and Kehlet (Dahl 2011) that future, likely more complex studies should evaluate the potential for multimodal prevention strategies to more effectively prevent chronic postsurgical pain. This could include the combination of two or more drugs with different mechanisms of action (including at least one known to suppress central sensitization), the combination of regional analgesic techniques with the aforementioned pharmacological approaches, and possibly even the combination of nerve‐sparing surgical techniques with the above analgesic strategies (Dahl 2011).