HHS Public Access Author manuscript Author Manuscript J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Published in final edited form as: J Reconstr Microsurg. 2013 May ; 29(4): 213–222. doi:10.1055/s-0032-1329921. Perioperative Interventions to Reduce Chronic Postsurgical Pain Ian Carroll, MD, MS1, Jennifer Hah, MD1, Sean Mackey, MD, PhD1, Einar Ottestad, MD1, Jiang Ti Kong, MD1, Sam Lahidji, MD1, Vivianne Tawfik, MD, PhD1, Jarred Younger, PhD1, and Catherine Curtin, MD2 1 Department of Anesthesiology, Division of Pain Management, Stanford School of Medicine, Palo Alto, California Author Manuscript 2 Department of Plastic Surgery, Stanford School of Medicine, Palo Alto, California Abstract Author Manuscript Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors–so called “preventative analgesia.” In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan. Keywords pain; neuropathic pain; preventative analgesia Author Manuscript Chronic postoperative surgical pain presents a continuing clinical problem. Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain.1 Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The fact that perioperative medical management can reduce chronic pain is of keen interest to surgeons, as every incision damages nerves and risks the development of chronic pain. Mitigating postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have increased risk for developing chronic Address for correspondence Ian Carroll MD, MS (EPI), Department of Anesthesiology, Stanford University, 780 Welch Road, Suite 208, Palo Alto, CA 94304 (irc39@pain.stanford.edu).. Carroll et al. Page 2 Author Manuscript postsurgical pain.2–4 The surgeon, working with the anesthesiologist, has the ability to modify the early and chronic postoperative pain experience by implementing an evidencebased program that employs the concept of “preventative analgesia.” Chronic pain following nerve injury has been extensively studied using animal models. These studies have found that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors–so called “preventative analgesia.” In animal models, perineural local anesthetic,5 systemic intravenous local anesthetic,6 perineural clonidine,7 systemic gabapentin,8 systemic tricyclic antidepressants,9 and minocycline10,11 have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Author Manuscript The core issues for surgeons to understand regarding the occurrence of new chronic postsurgical pain are: Author Manuscript 1. Chronic postsurgical pain is most often not a failure of surgical technique but a function of good biology gone bad. 2. Despite the truth of the first point, the surgeon has several efficacious interventions to reduce chronic postsurgical pain. 3. Perioperatively there is a critical window of time to intervene to reduce chronic postsurgical pain. 4. Preventing postsurgical chronic pain is the responsibility of the surgeon. It is the surgeon who sees the patient before surgery and who has the opportunity to initiate preoperative medications to reduce chronic postsurgical pain, and it is the surgeon who will initially manage the patient’s medications postoperatively. 5. One common thread has emerged in studies examining chronic postsurgical pain; severe pain immediately postop increases the risk of chronic pain. This may be mediated by the long-term sensitization of pain-carrying neurons by brief periods of high-intensity pain. The remainder of this paper will provide information on their effectiveness at reducing postsurgical chronic pain in humans (▶Table 1). Gabapentinoids Author Manuscript Gabapentinoids (gabapentin and pregabalin) are anticonvulsant medications that may reduce acute and chronic pain after surgery.2 Both drugs bind to a subunit of voltagegated calcium channels thought to participate in evoked neurotransmitter release in pain-carrying neurons. In addition, these drugs may also increase spinal descending inhibitory noradrenergic signals that decrease pain transmission in the dorsal spinal cord. There have been many clinical trials of perioperative gabapentin to reduce pain after surgery. Gabapentinoids reduce opioid consumption and postoperative pain scores by as much as 50%.12–15 Long-term benefits of the perioperative gabapentinoids are less established, but there are sufficient data to warrant J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 3 Author Manuscript their use in populations at high risk for chronic postoperative pain, including patients in whom nerves are deliberately being cut, manipulated, or repaired. Perioperative Gabapentin: Effect on Chronic Pain Author Manuscript The studies assessing the effect of perioperative gabapentin on persistent postsurgical pain have been limited by small sample size, limited follow-up, and widely varying regimens. As of February 2012, the authors identified 12 distinct clinical trials examining the effect of perioperative gabapentin on pain at least 1 month after surgery (▶Table 2). Eight of these trials demonstrated at least somewhat positive results. The best results were in studies with higher doses of preoperative gabapentin (1,200 to 1,800 mg), which demonstrated a reduced incidence of persistent pain and generally lower pain scores in those with pain.16–19 Two studies administered lower doses of gabapentin (300 to 400 mg) preoperatively and noted a reduced incidence of burning pain 3 to 6 months after surgery without reducing overall pain scores.16,17 The four trials that failed to identify any positive benefit in long-term pain with gabapentin were all underpowered.18–21 In sum, the existing studies suggest that higher preoperative and additional postoperative doses may be more likely to reduce the development of chronic postsurgical pain. Larger studies with improved patient retention are needed to define the optimal dosing and duration of perioperative gabapentin treatment. Perioperative Pregabalin: Effect on Chronic Pain Author Manuscript Pregabalin is a newer gabapentinoid. As of February 2012, only three studies assessed longterm effects of pregabalin on postsurgical pain.22–24 Of these, two studies identified a significant benefit to using pregabalin,25,26 and one failed to find any effect.27 The studies that found long-term benefit to pregabalin administered 300 mg of preoperative pregabalin and gave at least two postoperative doses. The best-powered study was conducted by Buvanendran et al, who randomized 240 people to receive either placebo or pregabalin 300 mg preoperatively and 150 mg twice a day for the first 10 days after total knee replacement, then tapering to 50 mg twice a day before stopping on postop day 14. Range of motion was improved in the pregabalin group at 30 days after surgery, and the incidence of chronic postsurgical neuropathic pain was reduced in the pregabalin group (0%) compared with the placebo group (8.7% and 5.2% at 3 months and 6 months respectively; p ¼ 0.001 and p ¼ 0.014).25 Optimal Dosing Strategies for Perioperative Gabapentinoids Issues of Timing Author Manuscript It is unclear whether or not gabapentinoids are more effective when administered preoperatively versus postoperatively. Some studies28–30 have found no or little difference between the dosing strategies in reducing postoperative pain. In one exception, it was found that individuals administered gabapentin postoperatively used significantly less patientcontrolled analgesia (PCA) morphine than those given preoperative gabapentin. However, most studies using preoperative gabapentinoids administered the drugs between 1 and 2 hours prior to surgery (likely based on peak plasma level data). However, because cerebrospinal fluid (CSF) peak levels may occur much later,31 future studies may need to employ an earlier dosing to observe the full benefits of preoperative administration. J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 4 Issues of Medication Quantity Author Manuscript Author Manuscript Several studies have examined the optimal dosage of preoperative gabapentinoids for preventing early postoperative pain and reducing opioid use.29,32,33 These studies generally indicate that higher dosages of gabapentin (900 mg or more) are more effective than lower dosages (600 mg or less). Larger dosages of pregabalin (300 mg or larger) have also been found to be more effective than lower dosages.22,23 Based on the available literature, we recommend the following for patients at risk of severe postoperative acute pain or chronic pain: (1) giving gabapentin 1,200 mg or pregabalin 300 mg at least 2 hours prior to surgery and (2) continuing postoperatively for 14 days with pregabalin 150 mg twice a day or gabapentin 400 to 600 mg three times a day. Postoperative gabapentinoids should be decreased or stopped for postoperative sedation, dizziness, or confusion. Further definition of uncommon side effects, and the optimal preoperative dose, postoperative dose, and timing of doses is needed before perioperative gabapentinoids can be recommended as the standard of care for all patients. Perioperative Ketamine Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, which has been used as a general anesthetic and short-acting analgesic.24,28,29 The NMDA receptor plays a key role in activating and sensitizing pain-carrying neurons in the dorsal horn of the spinal cord. NMDA receptor–dependent changes may participate in making pain-carrying neurons permanently hyperexcitable, contributing to chronic pain. When given at the time of injury, ketamine may decrease pain by blocking the NMDA pathway.24,28,29 Author Manuscript The question of the long-term benefits of perioperative ketamine on long-term pain is unclear.18,34–43 A study of rectal carcinoma resections found that higher-dose perioperative intravenous ketamine reduced the incidence of persistent pain at 2 weeks, 1 month, and 6 months following surgery.30 Perioperative ketamine improved rehabilitation after total hip surgery 1 month after surgery and decreased the prevalence of postoperative chronic pain 6 months after surgery. Another study showed perioperative ketamine in chronic opioid– consuming patients reduced average pain intensity 6 weeks after surgery.44 This study suggests that intraoperative ketamine may reduce chronic pain in chronic opioid users, who can present a challenge for postoperative pain control. There is some evidence that dosing of ketamine is important. A large study of microdosing of ketamine in the PCA did not effect either acute or chronic pain.32 Whereas other studies with higher doses of ketamine added to morphine PCA found improved pain control with fewer opioid-related side effects.33,45 Author Manuscript In summary, low-dose perioperative ketamine results in improved immediate postoperative analgesia and opioid-sparing effects. Furthermore, this intervention is one of the few evidence-based ways for improving pain control in chronic opioid–consuming patients. The available data suggest that subanesthetic intravenous (IV) ketamine given intraoperatively may reduce the incidence of chronic post-surgical pain. A note of caution is indicated from a recent study of 100-hour ketamine infusions for pain relief in complex regional pain syndrome (CRPS), which was discontinued prematurely due to the development of possible J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 5 Author Manuscript drug-induced liver injury in two patients and liver injury of unclear etiology in a third patient.46 Perioperative Antidepressants Author Manuscript The dorsolateral funiculus of the spinal cord carries descending noradrenergic inhibitory signals from the brain to pain synapses in the dorsal horn of the spinal cord. The brain therefore is constantly modulating the amount of pain an organism can feel. These descending signals are thought to be responsible for the reports from many trauma victims that their wounds are often not felt to be painful during the initial life-threatening phase of injury but are only felt as painful at later time points (e.g., President Reagan reported believing he had not been shot and felt no pain immediately following his attempted assassination). Tricyclic antidepressants, venlafaxine (Effexor, Wyeth Pharmaceuticals Inc.), and duloxetine (Cymbalta, Eli Lilly, Indianapolis, IN) increase synaptic availability of norepinephrine and, to varying degrees, of serotonin by inhibiting reuptake of these neurotransmitters. These drugs thereby augment descending noradrenergic inhibitory signals from the brain that reduce pain transmission in the spinal cord. Tricyclic Antidepressants Author Manuscript Among antidepressants, tricyclic antidepressants have been most examined in the perioperative environment but have been examined only with regard to their effect on acute pain and opioid use—not their effect on chronic pain. This limitation is important, because animal studies suggest that perioperative amitriptyline has a long-term protective effect on pain following nerve injury.9 Human data have been mixed. Antidepressants that more potently inhibit serotonin reuptake (amitriptyline and fluoxetine) have resulted in more pain or diminished response to opioids early after surgery.47,48 In contrast, perioperative desipramine (a more potent reuptake inhibitor of norepinephrine) appears to significantly improve the efficacy of opioid analgesia.34,35,49 In summary, the effect of tricyclic antidepressants on chronic postoperative pain has not been examined in humans. In the immediate postoperative time frame, perioperative desipramine seems to enhance analgesia, but perioperative fluoxetine and amitriptyline appear to augment pain on postoperative day one and two. Therefore, perioperative tricyclic antidepressants cannot be recommended at this time. Venlafaxine and Duloxetine Author Manuscript In one study, 150 patients scheduled for either partial or radical mastectomy with axillary dissection were randomized to receive either venlafaxine 37.5 mg, gabapentin 300 mg, or placebo for 10 days starting the night before surgery. At 6 months, venlafaxine reduced pain scores with movement by nearly 50% compared with both placebo and gabapentin (p < 0.0001). Opioid analgesic use was also significantly decreased by venlafaxine compared with both placebo and gabapentin. Although the dose of gabapentin used in this study (300 mg/day) was quite low compared with other studies of perioperative gabapentin use, the dose of venlafaxine used was also quite low.16 We were only able to identify one study of perioperative duloxetine examining whether it prevents chronic pain following surgery as of February 2012.36 In this small, underpowered study, at 3 and 6 months following surgery there were nonsignificant trends toward diminished pain and diminished abnormal J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 6 Author Manuscript sensations among the patients who received duloxetine. Further studies of antidepressants with significant norepinephrine reuptake inhibition should be done, including comparison of venlafaxine and duloxetine. Until then, based on the currently available evidence, venlafaxine 37.5 mg should be considered to be started the day before surgery and continued for 10 to 14 days in patients at high risk of developing chronic postsurgical pain. Epidural and Intrathecal Local Anesthetics Several studies have highlighted a role for epidural or spinal local anesthetics in improving acute postoperative pain control, but the long-term effect of these interventions on the development of chronic postsurgical pain remains controversial. Author Manuscript There have been attempts to study the role of regional anesthesia in blocking the progression of acute to chronic pain. Kairaluoma et al37 compared preoperative placement of a paravertebral block with 0.5% bupivacaine versus a sham block in patients undergoing breast surgery and found the block group experienced improved pain acutely and on followup at 1, 6, and 12 months.38 The prevalence of postthoracotomy pain is reported to be as high as 80% at 3 months.39 In a trial of 70 patients undergoing thoracic surgery, initiation of a continuous epidural block with mepivacaine prior to surgical incision was associated with decreased pain at 3 and 6 months when compared with epidural analgesia performed after the completion of surgery.40 Other studies have supported the findings that preoperative block reduced chronic pain.50,51 Taken together, these studies highlight the potential role of epidural analgesia to both reduce severe postoperative pain and perhaps more importantly prevent the subsequent development of chronic pain. Author Manuscript Vitamin C Author Manuscript Vitamin C is a free radical scavenger that has decreased tumor necrosis factor alpha (TNF α) and interleukin-6 (IL-6) in experimental models of inflammation. Zollinger et al first reported that 500 mg of vitamin C for 50 days was superior to placebo in preventing the occurrence of complex regional pain syndrome following wrist fracture.41 They subsequently found that 500 mg per day and 1,500 mg per day dosing were superior to lower doses42,43 Besse et al52 reported the results of a quasi-experimental study of perioperative vitamin C in cohorts of patients undergoing foot and ankle surgery. Before the use of vitamin C, 9.6% of cases developed CRPS compared with 1.7% of patients developing CRPS following the institution of perioperative vitamin C. In summary, only three studies have examined the potential impact of vitamin C on the development of complex regional pain syndrome. However two of these were placebo-controlled, blinded, and randomized trials of high methodological quality. In all three studies vitamin C reduced the risk of developing chronic pain and CRPS. There appeared to be a dose-response relationship, with 500 mg of vitamin C per day appearing to be sufficient. Although this work clearly has to be repeated by other authors and in other settings, and particularly with controlled trials in the perioperative setting, the potential benefit when weighed against the known safety of vitamin C at this dose argues for including vitamin C in a perioperative treatment plan. J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 7 Clonidine Author Manuscript Clonidine is an α-2 adrenergic receptor agonist that has several pathways by which it may reduce pain.53–60 It has both central and peripheral actions, which leads to analgesia following diverse routes of administration.61–64 Spinal (intrathecal and epidural) clonidine appears to be more effective with fewer hypotensive side effects than intravenous clonidine. When given in combination with either local anesthetic or opioid, spinal clonidine reduces early pain and postoperative opioid requirements, and it also prolongs the time needed until first rescue analgesic.62,63,65 Author Manuscript Several studies have examined the effect of perioperative clonidine on long-term pain. In a small, nonrandomized, nonblinded study of patients undergoing lower limb amputation, stump pain and phantom pain were dramatically reduced at both 6 months and 1 year in the group receiving epidural bupivacaine, clonidine, and diamorphine,50 Lavand’-homme et al studied patients undergoing colon resection. Continuous infusion of analgesics belonging to the same class (including clonidine) was administered by either intravenous or epidural route before incision until 72 hours after surgery. They found that patients who received epidural analgesia including clonidine versus intravenous administration of clonidine at any time point (during or after surgery) demonstrated markedly less need for supplemental analgesics; reduced skin surface area that was hyperalgesic, and reduced pain at both 6 months and 1 year following surgery.51 These results suggest that (1) multimodal epidural analgesia including epidural clonidine reduces postoperative pain, hyperalgesia, and residual pain, and (2) multimodal epidural analgesia is more effective when started intraoperatively rather than postoperatively. Author Manuscript Another study randomized 60 patients undergoing a right colon resection to receive 300 μg of clonidine, 10 mg of bupivacaine, or saline intrathecally prior to surgery.66 Intrathecal clonidine significantly reduced PCA morphine use compared with both intrathecal bupivacaine and saline, and no patients in the intrathecal clonidine group experienced residual pain 6 months following surgery compared with six patients in the group that had received intrathecal saline (p < 0.05). It should be noted that intrathecal clonidine (300 μg) has been associated in other studies with a higher rate of postoperative sedation, and adverse hemodynamic changes. Using bispectral index monitoring to ensure the correct depth of anesthetic may help anesthesiologists prevent intraoperative and postoperative hypotension in those patients who had received clonidine. Author Manuscript In summary, three small prospective studies indicate that clonidine perioperatively may help prevent chronic pain following surgery. Spinal administration of clonidine appears to be more effective than systemic administration of clonidine and appears to be more effective when accomplished prior to incision rather than postoperatively. J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 8 Author Manuscript Perioperative Interventions with Evidence for Reducing Acute Pain, but of Unknown Efficacy in Reducing the Progression from Acute to Chronic Pain NSAIDs Author Manuscript Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory and analgesic properties that inhibit spinal and peripheral cyclooxygenase (COX-1 and COX-2) enzymes needed for the production of prostaglandins.67 NSAIDs are useful adjuncts in multimodal analgesia and a Cochrane review demonstrates efficacy among NSAIDs when given even as a single-dose for reducing acute postsurgical pain.68,69 Moreover, meta-analyses demonstrate that NSAIDs not only reduce postoperative pain scores but also reduce opioid consumption and show that when they are given in conjunction with opioids, they reduce postop pain, nausea, vomiting, and sedation.70–73 COX-2 inhibitors appear to be equally effective as nonselective NSAIDs.74 Meta-analyses of COX-2 inhibitors demonstrate more effective acute postoperative analgesia than placebo with no increase in adverse events.75–77 Preventative effects of NSAIDS on the progression of acute to chronic pain have not been well studied. In a randomized controlled trial of patients undergoing total knee replacement, celecoxib demonstrated 30% lower pain scores during the first 4 weeks after surgery and lower morphine consumption after surgery, but no effect was seen on pain or subjective outcome at 1-year follow-up.78 A well done highly powered study randomized 902 patients who had undergone hip replacement to receive placebo or 400 mg of ibuprofen three times a day starting within 24 hours of completing surgery and continuing for 14 days. No significant differences in chronic pain were observed 6 and 12 months after surgery.79 Perioperative nonsteroidal NSAID has also failed to demonstrate a reduction in the incidence of postmastectomy pain syndrome in one small trial of 30 patients at 12 months.80 Author Manuscript In summary, there are good data that both nonselective NSAIDs and COX-2 inhibitors reduce pain in the immediate postoperative period. However, the available data indicate that any protective effect of postoperative ibuprofen for preventing chronic pain is clinically insignificant if it exists at all. Acetaminophen Author Manuscript Acetaminophen is a commonly used nonopioid analgesic. Its mechanism of action remains unclear, though it may inhibit central cyclooxygenase transcription.67,81 Oral acetaminophen provides effective analgesia for acute postoperative pain and reduces opioid requirements.72,82,83 For acute pain, combining acetaminophen with NSAIDs is considered more effective than acetaminophen alone.84 However, evidence for prevention of postsurgical chronic pain is lacking. Glucocorticoids Glucocorticoids are routinely administered perioperatively for their antiemetic effects,85 but they also have important analgesic effects. They reduce proinflammatory cytokines and increase anti-inflammatory cytokines. This may reduce the development and maintenance of central sensitization and neuropathic pain associated with nerve injury.86 J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 9 Author Manuscript Increasing evidence suggests glucocorticoid administration may augment acute pain relief following minor and ambulatory surgical procedures.87–89 Of particular interest is the suggestion that dexamethasone may also have an additive effect when used in combination with a gabapentinoid.90 Examination of the effects of perioperative single-dose dexamethasone on acute postoperative pain and opioid consumption were recently reviewed. Analgesic benefit was observed in even low-dose dexamethasone. This group concluded that dexamethasone, at doses > 0.1 mg/kg, is an effective adjunct in acute postoperative pain relief,91 and it does not increase complications such as wound infection. Author Manuscript In summary, glucocorticoids appear to have a significant role in reducing acute pain and opioid use immediately following surgery. However, at this point, data are lacking to support the use of perioperative glucocorticoids to prevent the progression from acute to chronic pain. Systemic Lidocaine Lidocaine is a sodium channel blocker and local anesthetic.92 Intravenous lidocaine given intraoperatively reduces immediate postoperative pain. A recent meta-analysis of 29 randomized controlled trials of IV lidocaine infusions during general anesthesia showed significantly reduced pain at rest and at 6 and 12 hours after surgery. Also, IV lidocaine reduced postoperative opioids, time to first flatus/feces, nausea/vomiting, and hospital length of stay. Although incidence of cardiac and neurologic events was comparable, 8 of 12 studies reported toxic plasma levels of lidocaine.93 Author Manuscript Abdominal surgery was strongly associated with benefit from IV lidocaine.94 A study of elective surgery for colon resection patients randomized thoracic lidocaine epidural analgesia and IV saline, or an equivalent amount of lidocaine intravenously and epidural saline, or IV and epidural saline. Thoracic epidural analgesia with lidocaine resulted in the most pain relief but the IV lidocaine was more effective than placebo.95 thus IV lidocaine is a good alternative in patients unable or unwilling to receive an epidural catheter. In summary, perioperative IV lidocaine appears effective in certain patient populations to reduce immediate postoperative pain and opioid requirements. Specifically, patients undergoing major abdominal procedures appear to receive the greatest benefit. Epidural lidocaine appears to be superior to intravenous lidocaine, but both are better than placebo. However, there do not appear to be any studies testing whether intravenous lidocaine reduces the likelihood of chronic postsurgical pain. Author Manuscript Topical Interventions EMLA cream has shown some promise as an adjunct treatment for perioperative pain. In one trial of preoperative EMLA cream to prevent postoperative pain following breast surgery, EMLA cream did not reduce acute pain during the first 24 hours following surgery. However analgesic consumption during the second through fifth days following surgery was less in the EMLA cream group. Three months after surgery, EMLA reduced the incidence of chronic pain by 50% (p < 0.002).96 J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 10 Author Manuscript Wound infiltration with anesthetic also has also been reported to reduce chronic postsurgical pain. A trial of craniotomy patients randomized to wound infiltration with 0.75% ropivacaine or to not have wound infiltration found that the ropivacaine group had reduced pain acutely, and dramatically reduced the prevalence of persistent pain 2 months postprocedure.97 A similar small study of the application of bupivacaine to iliac crest donor site indicated that local anesthetic infiltration in addition to morphine at the graph site reduced long-term pain 12 weeks following surgery.98 This data suggests that wound infiltration with anesthetic may reduce chronic postoperative pain and is concordant with rat studies suggesting local anesthetic application to acute injured nerves has long term benefits.5 Conclusions Author Manuscript Author Manuscript Many animal and human studies now suggest that preventing chronic postsurgical pain is within our grasp. A fundamental problem in the human clinical trials defining effective interventions to prevent chronic postsurgical pain is that only a minority of patients from even the most painful surgeries progress to develop chronic pain. As a result, to be adequately powered to reliably show a statistically significant difference in the rates of chronic postsurgical pain (or conversely to be convincing that a given intervention does not work) clinical trials in this area need to go from having tens of patients per trial arm to having hundreds (or thousands) of patients per trial arm. It is truly time to see the advent of multicenter clinical trials sponsored by the National Institutes of Health to address this major public health concern. These trials should aim to address proof of concept first, and then go on to define optimal doses, durations of treatment, and optimal timing of initiating individual treatments. Future work can then begin to address optimal combinations of treatments, and develop a framework for personalizing these combinations to a given patient and a given surgery. References Author Manuscript 1. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006; 367:1618–1625. [PubMed: 16698416] 2. Wallace MS, Wallace AM, Lee J, Dobke MK. Pain after breast surgery: a survey of 282 women. Pain. 1996; 66:195–205. [PubMed: 8880841] 3. Stokvis A, van der Avoort DJ, van Neck JW, Hovius SE, Coert JH. Surgical management of neuroma pain: a prospective follow-up study. Pain. 2010; 151:862–869. [PubMed: 20974520] 4. Stokvis A, Coert JH, van Neck JW. Insufficient pain relief after surgical neuroma treatment: Prognostic factors and central sensitisation. J Plast Reconstr Aesthet Surg. 2010; 63:1538–1543. [PubMed: 19559663] 5. Xie W, Strong JA, Meij JT, Zhang JM, Yu L. Neuropathic pain: early spontaneous afferent activity is the trigger. Pain. 2005; 116:243–256. [PubMed: 15964687] 6. Araujo MC, Sinnott CJ, Strichartz GR. Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions. Pain. 2003; 103:21–29. [PubMed: 12749955] 7. Lavand’homme PM, Eisenach JC. Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain. 2003; 105:247–254. [PubMed: 14499442] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 11 Author Manuscript Author Manuscript Author Manuscript Author Manuscript 8. Hahm TS, Ahn HJ, Bae CD, et al. Protective effects of gabapentin on allodynia and alpha 2 delta 1subunit of voltage-dependent calcium channel in spinal nerve-ligated rats. J Korean Med Sci. 2009; 24:146–151. [PubMed: 19270828] 9. Arsenault A, Sawynok J. Perisurgical amitriptyline produces a preventive effect on afferent hypersensitivity following spared nerve injury. Pain. 2009; 146:308–314. [PubMed: 19748184] 10. Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005; 115:71–83. [PubMed: 15836971] 11. Lin CS, Tsaur ML, Chen CC, et al. Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pain in rats. Reg Anesth Pain Med. 2007; 32:209– 216. [PubMed: 17543815] 12. Dauri M, Faria S, Gatti A, Celidonio L, Carpenedo R, Sabato AF. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009; 10:716–733. [PubMed: 19702520] 13. Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg. 2007; 104:1545–1556. table of contents. [PubMed: 17513656] 14. Mathiesen O, Møiniche S, Dahl JB. Gabapentin and postoperative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007; 7:6. [PubMed: 17617920] 15. Gilron I. Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: current evidence and future directions. Curr Opin Anaesthesiol. 2007; 20:456–472. [PubMed: 17873599] 16. Amr YM, Yousef AA. Evaluation of efficacy of the perioperative administration of Venlafaxine or gabapentin on acute and chronic postmastectomy pain. Clin J Pain. 2010; 26:381–385. [PubMed: 20473044] 17. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg. 2002; 95:985–991. table of contents. [PubMed: 12351281] 18. Ucak A, Onan B, Sen H, Selcuk I, Turan A, Yilmaz AT. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011; 25:824–829. [PubMed: 21232979] 19. Clarke H, Pereira S, Kennedy D, et al. Adding gabapentin to a multimodal regimen does not reduce acute pain, opioid consumption or chronic pain after total hip arthroplasty. Acta Anaesthesiol Scand. 2009; 53:1073–1083. [PubMed: 19572933] 20. Moore A, Costello J, Wieczorek P, Shah V, Taddio A, Carvalho JC. Gabapentin improves postcesarean delivery pain management: a randomized, placebo-controlled trial. Anesth Analg. 2011; 112:167–173. [PubMed: 21081764] 21. Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J, Jensen TS. A randomized study of the effects of gabapentin on postamputation pain. Anesthesiology. 2006; 105:1008–1015. [PubMed: 17065896] 22. Kim JC, Choi YS, Kim KN, Shim JK, Lee JY, Kwak YL. Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery. Spine. 2011; 36:428–433. [PubMed: 21372654] 23. Jokela R, Ahonen J, Tallgren M, Haanpää M, Korttila K. Premedication with pregabalin 75 or 150. mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery. Br J Anaesth. 2008; 100:834–840. [PubMed: 18448418] 24. Barash, PG. Clinical Anesthesia. 6th. Wolters Kluwer/Lippincott Williams & Wilkins; Philadelphia: 2009. 25. Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg. 2010; 110:199–207. [PubMed: 19910619] 26. Burke SM, Shorten GD. Perioperative pregabalin improves pain and functional outcomes 3 months after lumbar discectomy. Anesth Analg. 2010; 110:1180–1185. [PubMed: 20103545] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 12 Author Manuscript Author Manuscript Author Manuscript Author Manuscript 27. Kim SY, Jeong JJ, Chung WY, Kim HJ, Nam KH, Shim YH. Perioperative administration of pregabalin for pain after robot-assisted endoscopic thyroidectomy: a randomized clinical trial. Surg Endosc. 2010; 24:2776–2781. [PubMed: 20376496] 28. Benzon, HT. Essentials of Pain Medicine. 3rd. Elsevier/Saunders; Philadelphia, PA: 2011. 29. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999; 82:111–125. [PubMed: 10467917] 30. De Kock M, Lavand’homme P, Waterloos H. ’Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain. 2001; 92:373–380. [PubMed: 11376910] 31. Buvanendran A, Kroin JS, Kari M, Tuman KJ. Can a single dose of 300. mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? Reg Anesth Pain Med. 2010; 35:535– 538. [PubMed: 20975469] 32. Sveticic G, Farzanegan F, Zmoos P, Zmoos S, Eichenberger U, Curatolo M. Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patientcontrolled analgesia? Anesth Analg. 2008; 106:287–293. table of contents. [PubMed: 18165592] 33. Nesher N, Ekstein MP, Paz Y, Marouani N, Chazan S, Weinbroum AA. Morphine with adjuvant ketamine vs higher dose of morphine alone for immediate postthoracotomy analgesia. Chest. 2009; 136:245–252. [PubMed: 18753471] 34. Max MB, Zeigler D, Shoaf SE, et al. Effects of a single oral dose of desipramine on postoperative morphine analgesia. J Pain Symptom Manage. 1992; 7:454–462. [PubMed: 1287107] 35. Levine JD, Gordon NC, Smith R, McBryde R. Desipramine enhances opiate postoperative analgesia. Pain. 1986; 27:45–49. [PubMed: 3785963] 36. Ho KY, Tay W, Yeo MC, et al. Duloxetine reduces morphine requirements after knee replacement surgery. Br J Anaesth. 2010; 105:371–376. [PubMed: 20573635] 37. Kairaluoma PM, Bachmann MS, Rosenberg PH, Pere PJ. Preincisional paravertebral block reduces the prevalence of chronic pain after breast surgery. Anesth Analg. 2006; 103:703–708. [PubMed: 16931684] 38. Kairaluoma PM, Bachmann MS, Korpinen AK, Rosenberg PH, Pere PJ. Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy. Anesth Analg. 2004; 99:1837–1843. [PubMed: 15562083] 39. Perttunen K, Tasmuth T, Kalso E. Chronic pain after thoracic surgery: a follow-up study. Acta Anaesthesiol Scand. 1999; 43:563–567. [PubMed: 10342006] 40. Obata H, Saito S, Fujita N, Fuse Y, Ishizaki K, Goto F. Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anaesth. 1999; 46:1127–1132. [PubMed: 10608205] 41. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999; 354:2025–2028. [PubMed: 10636366] 42. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multileft doseresponse study. J Bone Joint Surg Am. 2007; 89:1424–1431. [PubMed: 17606778] 43. Zollinger PE, Kreis RW, van der Meulen HG, van der Elst M, Breederveld RS, Tuinebreijer WE. No higher risk of CRPS after external fixation of distal radial fractures - subgroup analysis under randomised vitamin C prophylaxis. Open Orthop J. 2010; 4:71–75. [PubMed: 20309405] 44. Sano M, Inaba S, Yamamoto T, Nishino T. [Intra-operative ketamine administration reduced the level of post-thoracotomy pain]. Masui. 2005; 54:19–24. [PubMed: 15717462] 45. Nesher N, Serovian I, Marouani N, Chazan S, Weinbroum AA. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects. Pharmacol Res. 2008; 58:38–44. [PubMed: 18602474] 46. Noppers IM, Niesters M, Aarts LP, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain. 2011; 152:2173–2178. [PubMed: 21546160] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 13 Author Manuscript Author Manuscript Author Manuscript Author Manuscript 47. Gordon NC, Heller PH, Gear RW, Levine JD. Interactions between fluoxetine and opiate analgesia for postoperative dental pain. Pain. 1994; 58:85–88. [PubMed: 7970842] 48. Kerrick JM, Fine PG, Lipman AG, Love G. Low-dose amitriptyline as an adjunct to opioids for postoperative orthopedic pain: a placebo-controlled trial. Pain. 1993; 52:325–330. [PubMed: 8460050] 49. Gordon NC, Heller PH, Gear RW, Levine JD. Temporal factors in the enhancement of morphine analgesia by desipramine. Pain. 1993; 53:273–276. [PubMed: 8351157] 50. Jahangiri M, Jayatunga AP, Bradley JW, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl. 1994; 76:324–326. [PubMed: 7979074] 51. Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005; 103:813–820. [PubMed: 16192774] 52. Besse JL, Gadeyne S, Galand-Desmé S, Lerat JL, Moyen B. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009; 15:179– 182. [PubMed: 19840748] 53. Bylund DB. Subtypes of alpha 2-adrenoceptors: pharmacological and molecular biological evidence converge. Trends Pharmacol Sci. 1988; 9:356–361. [PubMed: 2855960] 54. Kroin JS, Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats Is mediated via the hyperpolarization-activated cation current, not by alpha-adrenoreceptors. Anesthesiology. 2004; 101:488–494. [PubMed: 15277933] 55. Ono H, Mishima A, Ono S, Fukuda H, Vasko MR. Inhibitory effects of clonidine and tizanidine on release of substance P from slices of rat spinal cord and antagonism by alpha-adrenergic receptor antagonists. Neuropharmacology. 1991; 30:585–589. [PubMed: 1717870] 56. Unnerstall JR, Kopajtic TA, Kuhar MJ. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res. 1984; 319:69–101. [PubMed: 6324960] 57. Eisenach JC, Hood DD, Tuttle R, Shafer S, Smith T, Tong C. Computer-controlled epidural infusion to targeted cerebrospinal fluid concentrations in humans. Clonidine. Anesthesiology. 1995; 83:33–47. [PubMed: 7605017] 58. Birder LA, Perl ER. Expression of alpha2-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation. J Physiol. 1999; 515:533–542. Pt 2. [PubMed: 10050019] 59. Gold MS, Dastmalchi S, Levine JD. Alpha 2-adrenergic receptor subtypes in rat dorsal root and superior cervical ganglion neurons. Pain. 1997; 69:179–190. [PubMed: 9060029] 60. Lavand’homme PM, Ma W, De Kock M, Eisenach JC. Perineural alpha(2A)-adrenoceptor activation inhibits spinal cord neuroplasticity and tactile allodynia after nerve injury. Anesthesiology. 2002; 97:972–980. [PubMed: 12357167] 61. Buvanendran A, Kroin JS. Useful adjuvants for postoperative pain management. Best Pract Res Clin Anaesthesiol. 2007; 21:31–49. [PubMed: 17489218] 62. Chan AK, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother. 2010; 11:2849–2868. [PubMed: 20707597] 63. Eisenach JC, De Kock M, Klimscha W. alpha-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984–1995). Anesthesiology. 1996; 85:655–674. [PubMed: 8853097] 64. Schug SA, Saunders D, Kurowski I, Paech MJ. Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia. CNS Drugs. 2006; 20:917–933. [PubMed: 17044729] 65. Elia N, Culebras X, Mazza C, Schiffer E, Tramèr MR. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med. 2008; 33:159–167. [PubMed: 18299097] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 14 Author Manuscript Author Manuscript Author Manuscript Author Manuscript 66. De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery. Anesth Analg. 2005; 101:566–572. table of contents. [PubMed: 16037177] 67. Botting RM. Inhibitors of cyclooxygenases: mechanisms, selectivity and uses. J Physiol Pharmacol. 2006; 57(Suppl 5):113–124. [PubMed: 17218763] 68. Derry C, Derry S, Moore RA, McQuay HJ. Single dose oral ibuprofen for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD001548. [PubMed: 19588326] 69. Derry C, Derry S, Moore RA, McQuay HJ. Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD004234. [PubMed: 19160232] 70. Marret E, Elia N, Dahl JB, et al. Susceptibility to fraud in systematic reviews: lessons from the Reuben case. Anesthesiology. 2009; 111:1279–1289. [PubMed: 19934873] 71. 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; 102:1249–1260. [PubMed: 15915040] 72. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005; 103:1296–1304. [PubMed: 16306743] 73. Joshi GP, Rawal N, Kehlet H, et al. PROSPECT collaboration. Evidence-based management of postoperative pain in adults undergoing open inguinal hernia surgery. Br J Surg. 2012; 99:168– 185. [PubMed: 21928388] 74. 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; 48:525–546. [PubMed: 15101847] 75. Bulley S, Derry S, Moore RA, McQuay HJ. Single dose oral rofecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD004604. [PubMed: 19821329] 76. Clarke R, Derry S, Moore RA, McQuay HJ. Single dose oral etoricoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD004309. [PubMed: 19370600] 77. Lloyd R, Derry S, Moore RA, McQuay HJ. Intravenous or intramuscular parecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD004771. [PubMed: 19370610] 78. Meunier A, Lisander B, Good L. Effects of celecoxib on blood loss, pain, and recovery of function after total knee replacement: a randomized placebo-controlled trial. Acta Orthop. 2007; 78:661– 667. [PubMed: 17966026] 79. Fransen M, Anderson C, Douglas J, et al. HIPAID Collaborative Group. Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): randomised controlled trial. BMJ. 2006; 333:519. [PubMed: 16885182] 80. Lakdja F, Dixmérias F, Bussières E, Fonrouge JM, Lobéra A. [Preventive analgesic effect of intraoperative administration of ibuprofen-arginine on postmastectomy pain syndrome]. Bull Cancer. 1997; 84:259–263. [PubMed: 9207871] 81. Mancini F, Landolfi C, Muzio M, et al. Acetaminophen down-regulates interleukin-1beta-induced nuclear factor-kappaB nuclear translocation in a human astrocytic cell line. Neurosci Lett. 2003; 353:79–82. [PubMed: 14664905] 82. Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev. 2008:CD004602. [PubMed: 18843665] 83. Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth. 2002; 88:215–226. [PubMed: 11878655] 84. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg. 2010; 110:1170–1179. [PubMed: 20142348] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 15 Author Manuscript Author Manuscript Author Manuscript Author Manuscript 85. Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2007; 105:1615–1628. table of contents. [PubMed: 18042859] 86. Romundstad L, Stubhaug A. Glucocorticoids for acute and persistent postoperative neuropathic pain: what is the evidence? Anesthesiology. 2007; 107:371–373. [PubMed: 17721239] 87. Holte K, Kehlet H. Perioperative single-dose glucocorticoid administration: pathophysiologic effects and clinical implications. J Am Coll Surg. 2002; 195:694–712. [PubMed: 12437261] 88. Hval K, Thagaard KS, Schlichting E, Raeder J. The prolonged postoperative analgesic effect when dexamethasone is added to a nonsteroidal antiinflammatory drug (rofecoxib) before breast surgery. Anesth Analg. 2007; 105:481–486. [PubMed: 17646509] 89. Thagaard KS, Jensen HH, Raeder J. Analgesic and antiemetic effect of ketorolac vs. betamethasone or dexamethasone after ambulatory surgery. Acta Anaesthesiol Scand. 2007; 51:271–277. [PubMed: 17257175] 90. Mathiesen O, Jacobsen LS, Holm HE, et al. Pregabalin and dexamethasone for postoperative pain control: a randomized controlled study in hip arthroplasty. Br J Anaesth. 2008; 101:535–541. [PubMed: 18653493] 91. De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2011; 115:575–588. [PubMed: 21799397] 92. Carroll I. Intravenous lidocaine for neuropathic pain: diagnostic utility and therapeutic efficacy. Curr Pain Headache Rep. 2007; 11:20–24. [PubMed: 17214917] 93. Vigneault L, Turgeon AF, Côté D, et al. Perioperative intravenous lidocaine infusion for postoperative pain control: a meta-analysis of randomized controlled trials. Can J Anaesth. 2011; 58:22–37. [PubMed: 21061107] 94. McCarthy GC, Megalla SA, Habib AS. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials. Drugs. 2010; 70:1149–1163. [PubMed: 20518581] 95. Kuo CP, Jao SW, Chen KM, et al. Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel function in patients undergoing colonic surgery. Br J Anaesth. 2006; 97:640–646. [PubMed: 16952918] 96. Fassoulaki A, Sarantopoulos C, Melemeni A, Hogan Q. EMLA reduces acute and chronic pain after breast surgery for cancer. Reg Anesth Pain Med. 2000; 25:350–355. [PubMed: 10925929] 97. Batoz H, Verdonck O, Pellerin C, Roux G, Maurette P. The analgesic properties of scalp infiltrations with ropivacaine after intracranial tumoral resection. Anesth Analg. 2009; 109:240– 244. [PubMed: 19535716] 98. Gündeş H, Kiliçkan L, Gürkan Y, Sarlak A, Toker K. Short- and long-term effects of regional application of morphine and bupivacaine on the iliac crest donor site. Acta Orthop Belg. 2000; 66:341–344. [PubMed: 11103484] 99. Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006; 23:136– 141. [PubMed: 16426468] 100. Sen H, Sizlan A, Yanarateş O, et al. The effects of gabapentin on acute and chronic pain after inguinal herniorrhaphy. Eur J Anaesthesiol. 2009; 26:772–776. [PubMed: 19424073] 101. Sen H, Sizlan A, Yanarates O, et al. A comparison of gabapentin and ketamine in acute and chronic pain after hysterectomy. Anesth Analg. 2009; 109:1645–1650. [PubMed: 19843803] 102. Brogly N, Wattier JM, Andrieu G, et al. Gabapentin attenuates late but not early postoperative pain after thyroidectomy with superficial cervical plexus block. Anesth Analg. 2008; 107:1720– 1725. [PubMed: 18931238] 103. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 2005; 101:1427–1432. [PubMed: 16244006] 104. Fassoulaki A, Melemeni A, Stamatakis E, Petropoulos G, Sarantopoulos C. A combination of gabapentin and local anaesthetics attenuates acute and late pain after abdominal hysterectomy. Eur J Anaesthesiol. 2007; 24:521–528. [PubMed: 17207299] J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 16 Table 1 Author Manuscript Summary of recommendations for reducing the risk of chronic postsurgical pain 1) Give a gabapentinoid Gabapentin (Pfizer, Vega Baja, PR; Neurontin) 1,200 mg 2 hours pre-incision; 400–600 mg three times a day for 14 days postoperatively. Or Pregabalin (Lyrica; Pfizer; capsules, Vega Baja, PR; oral solution; Kalamazoo, MI) 300 mg 2 hours pre-incision; 150 mg twice a day for 14 days following surgery. If not given before surgery, begin immediately postoperatively or after incision via a nasogastric tube intraoperatively. Lower doses appear to be helpful, but less than the doses recommended here. 2) Ketamine Pre-incision intravenous bolus 0.5 mg/kg followed by intravenous infusion 0.25 mg/kg /hour. This intervention should not be done for patients with known liver disease or with significant risk factors for liver disease (e.g., alcoholism). 3) Make it numb Author Manuscript Initiate regional anesthesia with a regional block or an epidural before incision. Or Infiltrate ropivacaine 0.75% 20 mL in the wound (n.b., if given in conjunction with a regional block using conventional dosages or accidentally injected intravenously, this ropivacaine dose is sufficient to induce severe local anesthetic toxicity). Or Apply 20 g of EMLA (eutectic mixture of local anesthetics) cream around the site of the wound preoperatively 5 minutes before surgery and daily for the first 4 days following surgery. 4) Give venlafaxine (Effexor XR, Wyeth Pharmaceuticals Inc., Philadelphia, PA) 37.5 mg of extended-release venlafaxine starting the day before surgery and continuing for 10 to 14 days following surgery (n.b., this may not be appropriate in patients already taking other antidepressants). 5) Vitamin C 500 to 1,000 mg for 50 days following surgery, based on known safety and efficacy in preventing complex regional pain syndrome following wrist fracture and foot and ankle surgery. Author Manuscript Author Manuscript J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02. Carroll et al. Page 17 Table 2 Author Manuscript The effectiveness of perioperative gabapentin for chronic pain Positive Studies Author Manuscript Author Manuscript Author Manuscript Surgery type Patients Most remote follow-up Positive findings Negative findings Abdominal hysterectomy99 25 1 month Gabapentin reduced incidence of pain 1 month after surgery. Did not identify a statistically significant decrease in immediate postoperative pain Inguinal herniorrhaphy100 30 6 months Gabapentin reduced pain scores at 1, 3, and 6 months after surgery. The number of patients with daily activity adversely affected by pain was lower in the gabapentin group at 1 month. The number of patients whose daily activities were adversely affected by pain was similar between groups at 3 months and 6 months Abdominal hysterectomy101 20 6 months Gabapentin reduced pain scores, pain impact, and incidence of pain at 1, 3, and 6 months. Pain impact on activities of daily living was not significantly different at 6 months Thyroidectomy102 23 6 months Gabapentin reduced total pain score and the incidence of more intense pain at 6 months. Nonsignificant trend toward decreased burning sensation and numbness in the gabapentin group. Mastectomy16 50 6 months At 6 months gabapentin reduced the incidence of burning pain. Gabapentin did not reduce global pain severity and opioid use at 6 months. Breast cancer surgery17** 22 3 months Gabapentin and mexiletine each reduced the incidence of burning pain at 3 months. Gabapentin did not reduce the incidence of chronic pain, or patients requiring analgesics at 3 months. Breast cancer surgery103** 20 6 months Gabapentin reduced the incidence of chronic pain and analgesic use at 3 months. Gabapentin did not reduce the incidence of chronic pain, and analgesic use at 6 months. Abdominal hysterectomy104 27 1 month Gabapentin reduced the incidence of pain at 1 month. Gabapentin did not reduce the incidence of analgesic use at 1 month. Surgery type Patients* Most remote follow-up Positive findings Negative findings Coronary artery bypass graft surgery18 20 3 months Gabapentin reduced pain intensity immediately after surgery Gabapentin did not reduce pain intensity at 1 month and 3 months. Total hip arthroplasty19 28 6 months None Gabapentin did not reduce pain at any time point (one third of patients lost to remote follow-up). Cesarean delivery20 16 3 months Gabapentin improved acute but not chronic pain. Gabapentin failed to reduce persistent pain, or median pain scores at 3 months. Lower limb amputation21 15 6 months None Gabapentin failed to reduce the incidence and intensity of pain at 6 months. Negative Studies * Indicates the number of gabapentin patients per group available for most remote follow-up. ** Modified radical mastectomy or lumpectomy with axillary lymph node dissection. J Reconstr Microsurg. Author manuscript; available in PMC 2016 May 02.