Chronic Pain After Surgery: What Can We Do to Prevent It?

Scott S. Reuben, MD

Corresponding author Scott S. Reuben, MD Department of Anesthesiology, Baystate Medical Center, 759 Chestnut Street, Springeld, MA 01199, USA. E-mail: scott.reuben@bhs.org
Current Pain and Headache Reports 2007, 11:5 13 Current Medicine Group LLC ISSN 1531-3433 Copyright 2007 by Current Medicine Group LLC

The development of chronic pain after surgery is not an uncommon event. Despite increased attention devoted to this topic in the recent medical literature, little is known about the underlying mechanisms, natural history, and response to therapy of each syndrome. Central nervous system plasticity that occurs in response to tissue injury may contribute to the development of persistent postsurgical pain. As evidence continues to accumulate concerning the role of central sensitization in the prolongation of postoperative pain, many researchers have focused on methods to prevent central neuroplastic changes from occurring through the use of preemptive or preventative analgesic techniques. Effective preventative analgesic techniques may be useful in reducing not only acute pain but also chronic postsurgical pain and disability. This review examines the efcacy of using a variety of analgesic techniques aimed at preventing or reducing chronic pain after surgery. Specic chronic postsurgical pain syndromes evaluated include complex regional pain syndrome, phantom limb pain, chronic donor site pain, post-thoracotomy pain syndrome, and postmastectomy pain syndrome.

Introduction
One of the potential complications after surgery is the development of chronic pain. The incidence of postsurgical pain that persists well beyond what might be expected (ie, > 36 months) can be alarmingly high. The exact incidence of persistent postoperative pain remains controversial but has been reported after numerous surgical procedures, including limb amputation, thoracotomy, mastectomy, cholecystectomy, and inguinal hernia surgery [1,2]. Clearly there is signi cant variability in the incidence of chronic pain for each of these procedures, and speci c risk factors for its development have been

identi ed. These include, among others, preoperative pain of greater than 1 months duration, intensity of acute postoperative pain, psychological vulnerability and anxiety, and a surgical approach with risk of nerve damage [1]. Despite the identi cation of chronic postsurgical pain syndromes, little is known about the underlying mechanisms, natural history, and response to therapy of each syndrome [3]. It is now recognized that nociceptor function is dynamic and may be altered after tissue injury, which may contribute to persistent pain [4,5]. Repetitive stimulation of small diameter primary afferent bers generates a progressive increase in action potential discharge and increased excitability of both peripheral and central nervous system (CNS) neurons, an event termed central sensitization or windup [4]. This is the mechanism by which pain may be prolonged beyond the duration normally expected with an acute insult. Prolonged central sensitization has the capacity to lead to permanent alterations in the CNS, including the death of inhibitory neurons, replacement with new afferent excitatory neurons, and the establishment of aberrant excitatory synaptic connections [5]. These alterations result in a prolonged state of sensitization resulting in intractable postsurgical pain that is unresponsive to many analgesics [6]. As evidence continues to accumulate concerning the role of sensitization in the prolongation of postoperative pain, many researchers have focused on methods by which to not simply treat the symptoms as they occur, but prevent windup from occurring through the use of preemptive analgesic techniques. The evidence in support of preemptive analgesia has been equivocal, with one recent systematic review of the literature demonstrating no bene cial effect [7], whereas a more recent review [8] demonstrated an overall bene t of this concept. However, the concept of preemptive analgesia has evolved beyond the importance of only reducing the nociceptive afferent input brought about by the surgical incision. The term preventative analgesia [9] was introduced to emphasize the fact that central neuroplasticity is induced by pre-, intra-, and postoperative nociceptive inputs. Thus, the goal of preventative analgesia is to reduce central sensitization that arises from noxious inputs arising throughout the entire perioperative period and not just from those occurring during the surgical incision. Effective preventative analgesic

6 Anesthetic Techniques in Pain Management

techniques may be useful in reducing not only acute pain but also chronic postsurgical pain and disability. This review examines the ef cacy of using a variety of preemptive or preventative analgesic techniques aimed at reducing ve chronic pain syndromes after surgery: complex regional pain syndrome (CRPS), phantom limb pain, chronic donor site pain, post-thoracotomy pain syndrome, and postmastectomy pain syndrome (PMPS).

CRPS
CRPS (formerly knows as re ex sympathetic dystrophy or causalgia) is a disorder characterized by the presence, after a noxious event, of regional pain and sensory changes such as temperature alterations, abnormal skin color, abnormal sudomotor activity, and/or edema [10]. Its onset is associated with a history of trauma (that is often innocuous) or immobilization, and there is typically no correlation between the severity of the initial injury and the ensuing painful syndrome [11]. The incidence of CRPS occurring after surgery is variable and may be underreported [12]. Approximately 20% of CRPS patients who present to chronic pain clinics have a history of prior surgical, often orthopedic, procedures in the affected area [12,13,14]. The use of regional nerve blocks that provide for a perioperative sympathectomy may be advantageous for CRPS patients requiring surgery. It has been our practice to administer a stellate ganglion block to patients with CRPS undergoing upper extremity surgical procedures in the presence of local or general anesthesia. In a retrospective study of 100 CRPS patients undergoing surgery on the affected upper extremity, we observed a reduction in the recurrence of CRPS when performing a perioperative stellate ganglion block [15]. The recurrence rate of CRPS during the 12-month period after surgery was signi cantly lower in patients receiving a perioperative stellate ganglion block (n = 5; 10%), compared with those receiving no intervention (n = 36; 72%). In addition to stellate ganglion blocks, patients undergoing upper extremity surgical procedures may bene t from the perioperative sympathectomy provided by either brachial plexus block or intravenous regional anesthesia (IVRA) with clonidine. Clonidine possesses peripheral analgesic properties in patients with sympathetically maintained pain, possibly because it reduces the release of norepinephrine from prejunctional -adrenoceptors in the periphery [16]. We have pre2 viously shown that IVRA with lidocaine and the -adrenergic agonist clonidine (1 g/kg) is an effective 2 technique for managing both acute postoperative pain [17] and symptoms of CRPS [18]. A prospective study of four anesthetic techniques (general anesthesia, IVRA with lidocaine, IVRA with lidocaine and clonidine, and axillary block) for 300 consecutive patients undergoing fasciectomy for Dupuytrens contracture con rmed

a bene cial effect of the latter two regional techniques [19]. Signi cantly (P < 0.01) more patients developed postoperative CRPS in the general anesthesia group (n = 25; 24%) and IVRA lidocaine group (n = 12; 25%), compared to either the axillary block group (n = 5; 5%) or the IVRA lidocaine and clonidine group (n = 3; 6%). In addition to perioperative regional blocks, the use of pharmacologic agents, including calcitonin, mannitol, vitamin C, corticosteroids, carnitine, and ketanserin, has been advocated for the prevention of postoperative CRPS [12]. Interestingly, only vitamin C, a natural antioxidant that scavenges free radicals, has been shown to be bene cial in prospective, placebo-controlled studies [20,21]. Zollinger et al. [20] evaluated the ef cacy of administering either 500 mg vitamin C or placebo daily for 50 days to 123 adults with 127 wrist fractures. There was a signi cant reduction in the incidence of CRPS in the vitamin C group (7%) compared to the placebo group (22%) at 1-year follow-up (95% CI for differences 2% to 26%). This simple, safe, and inexpensive technique may have signi cant implications in the development of protocols for the prevention and management of CRPS. In addition, the role of preventative multimodal analgesic techniques in conjunction with physical therapy and rehabilitation after surgery appears to be promising for reducing the incidence of postsurgical CRPS. A recent retrospective study of 1200 patients undergoing anterior cruciate ligament surgery examined the ef cacy of administering a preventative multimodal analgesic technique (n = 500), versus a standard postoperative pain protocol (n = 700) [22]. Patients in the preemptive multimodal group received acetaminophen, 1000 mg, every 6 hours and rofecoxib, 50 mg, daily starting 48 hours before surgery. In addition, 30 minutes before surgery, a femoral nerve block and an intra-articular injection of bupivacaine/clonidine/morphine were performed. Postoperative analgesia included acetaminophen, rofecoxib, controlledrelease oxycodone, and a cryotherapy cuff. In contrast, patients in the standard postoperative analgesic group received no preemptive analgesics before surgery and were administered ibuprofen and acetaminophen, with oxycodone on an as-needed basis postoperatively. All patients were subsequently enrolled in a 6-month accelerated rehabilitation protocol. This study revealed signi cantly lower pain scores and greater number of patients able to complete this prescribed 6-month rehabilitation protocol among those receiving multimodal treatment [22]. In addition, a signi cantly (P < 0.001) higher incidence of complications was observed at 1-year follow-up in the standard treatment group, compared to the preemptive multimodal group [22].

Phantom Limb Pain

Patients who suffer the loss of a limb, either traumatically or surgically, almost always report some degree of

Chronic Pain After Surgery: What Can We Do to Prevent It? Reuben 7

perceived sensation in the lost limb. A distinction should be made between phantom limb pain (painful sensations referred to the absent limb), phantom limb sensation (any sensation in the absent limb, except pain), and stump pain (pain localized in the stump), although each of these may coexist in an individual patient at different times [23]. Recent literature suggests that the incidence of phantom pain is probably between 50% to 80% [2426]. Several risk factors have been identi ed for the development of phantom limb pain, including the degree of preoperative pain, the magnitude of intraoperative noxious input, the intensity of postoperative pain, and psychological factors [27,28]. The mechanisms of phantom pain are not completely clear. As is the case with other types of neuropathic pain, there are likely both peripheral and central factors at play. Increased spontaneous activity of both afferent peripheral nerves and dorsal root ganglion cells has been observed experimentally after the transection of a nerve [5]. Additionally, it is now known that the CNS, including the spinal cord, brainstem, thalamus, and cerebral cortex, undergoes signi cant functional reorganization after amputation [29]. Several investigations have focused on using preventative regional analgesic techniques to reduce perioperative pain and long-term phantom pain after lower extremity amputation surgery [30]. Bach et al. [31] initially examined the effect of epidural morphine, epidural bupivacaine, or both in combination for 3 days before amputation (n = 11) or conventional analgesia (n = 14). All patients received epidural or spinal anesthesia for amputation and received conventional analgesics postoperatively. The incidence of phantom pain was reduced 6 months after amputation but not after 1 week or after 12 months in the epidural treatment group, compared with the control group. Jahangiri et al. [32] con rmed the bene cial effects of perioperative epidural administration on preventing phantom pain after amputation surgery. These investigators examined the effect of an epidural infusion of bupivacaine, diamorphine, and clonidine (n = 13) preoperatively and maintained for at least 3 days postoperatively. For comparison, the control group (n = 11) received on-demand opioid analgesia. These authors observed a signi cant reduction in the incidence of phantom pain at 1 year after surgery. However, the largest prospective study (n = 60) to examine the effect of epidural analgesia on phantom pain failed to document any bene t at 7 days, 3 months, 6 months, and 12 months, postoperatively [33]. Similarly, clinical investigations evaluating the ef cacy of continuous postoperative regional analgesia by nerve sheath block for amputation surgery have been equivocal, with some studies revealing bene cial effects [34,35], whereas others have demonstrated no long-term bene t [36,37]. A later study investigated whether postamputation stump and phantom pain could be reduced by preoperative epidural block with bupivacaine and diamorphine, compared with

intraoperative placement of a perineural catheter infusing bupivacaine [38]. These investigators observed that both regional techniques were equally effective in preventing phantom pain, but the epidural analgesic technique was more effective in relieving stump pain in the immediate postoperative period. However, many of the regional analgesic studies evaluating the effect on reducing long-term phantom pain have signi cant design aws, including that they were not prospective, randomized, or blinded, used either no control group or historical controls, investigated a heterogeneous study group, or lacked suf cient power. The authors of a recent systematic review of the literature concluded that because of the poor quality and contradictory results, the randomized and controlled trials do not provide evidence to support any particular treatment of phantom limb pain in the acute perioperative period or later [30].

Chronic Donor Site Pain

The occurrence of chronic pain after spinal fusion surgery is not an uncommon complication. Autogenous bone grafts from the ilium are frequently harvested for the purposes of bone fusion in patients undergoing spinal stabilization surgery. Often, the pain from the donor site is more severe than that from the laminectomy incision [3942]. Although this pain usually resolves over a period of several weeks, it may persist and represent a signi cant source of postoperative morbidity [3942]. The precise mechanism of donor site pain remains obscure. It has been postulated to be muscular or periosteal in nature, secondary to stripping of the abductors from the ilium [39]. In addition, the pain may be neuropathic in origin, secondary to injury to small sensory nerves at the donor site. Three recent studies have demonstrated a signi cant reduction in the incidence of chronic donor site pain with the preemptive administration of analgesics [43,44,45]. Gndes et al. [45] infused 20 mL saline, 50 mg bupivacaine, or 50 mg bupivacaine with morphine, 5 mg, via a 17-gauge catheter placed at the iliac crest donor site in 45 patients undergoing spinal fusion surgery. These investigators reported the absence of chronic donor site pain at the 12-week follow-up in the bupivacaine and morphine group, compared with ve of 15 patients (33%) in the saline group and two of 15 patients (13%) in the bupivacaine group. Reuben et al. [43] subsequently evaluated the analgesic effect of low-dose morphine alone administered to the site of bone graft harvesting in patients undergoing spinal fusion surgery. Sixty patients were randomized to receive either saline in ltration into the harvest site (n = 20), intramuscular morphine, 5 mg (n = 20), or morphine, 5 mg, in ltrated into the harvest site (n = 20). This study revealed that morphine in ltrated into the bone graft harvest site resulted in a signi cant reduction in pain scores and opioid use for the rst 24 hours after

8 Anesthetic Techniques in Pain Management

surgery. Furthermore, the association of chronic donor site pain was signi cantly lower in the local morphine group (5%), compared with the intramuscular morphine (37%) or saline in ltration (33%) groups. Reuben et al. [44] also examined the analgesic effects of preemptive cyclooxygenase-2 (COX-2) administration on chronic donor site pain after spinal fusion surgery. It has been shown that COX-2 plays an integral role in the processes of peripheral and central sensitization [46], and it is possible that early and sustained treatment with COX-2 inhibitors may thwart the progression of acute to chronic pain [47]. Eighty patients scheduled to undergo instrumented posterior spinal fusion were randomized to receive either celecoxib, 400 mg, 1 hour before surgery and then 200 mg every 12 hours postoperatively for the rst 5 days, or matching placebo at similar time intervals. Patients administered celecoxib reported lower pain scores and had less opioid use during the rst 5 postoperative days. Chronic donor site pain was signi cantly higher in the placebo group (12/40, 30%), compared to the celecoxib group (4/40, 10%) at 1 year after surgery [44]. The development of neuropathic pain after spinal fusion surgery may in part be mediated by central COX-2 expression resulting in central neuronal plasticity. Spinal COX-2 has been implicated in the development of allodynia after nerve injury in rats [48], and peripheral prostaglandins have been implicated in the pathogenesis of neuropathic pain [49]. However, after the development of neurogenic in ammation, the responses to mechanical stimuli are not affected by spinal COX-2 inhibition [48]. Thus, spinal prostaglandin synthesis may be important for the induction and initial expression, but not for the maintenance of spinal cord hyperexcitability [50]. This may explain the lack of analgesic ef cacy of NSAIDs for treatment of chronic donor site pain observed in the study by Reuben et al. [44]. These three studies [43,44,45] highlight the importance of using preemptive analgesics for pain management after spinal fusion surgery. Further studies are needed to assess the appropriate dosages, timing, and duration of various preventative analgesic techniques on reducing chronic donor site pain.

Post-thoracotomy Pain Syndrome

Pain after thoracic surgery has been reported to be among the most intense clinical experiences known [51]. Unrelieved acute pain after thoracic surgery can not only contribute to postoperative pulmonary dysfunction [52] but may also contribute to the development of postthoracotomy pain syndrome [1,2]. Post-thoracotomy pain syndrome is de ned as pain that recurs or persists along a thoracotomy incision for at least 2 months after the surgical procedure [53]. The true incidence of post-thoracotomy pain syndrome is difcult to determine, with a reported range from 5% to

80% [54]. It has been estimated that 50% of all patients still alive 1 to 2 years after thoracotomy will suffer with persistent chest wall pain [55]. Furthermore, as many as 30% of patients might still experience pain 4 to 5 years after surgery [55]. The exact mechanism for the pathogenesis of postthoracotomy pain syndrome is still not clear. Similar to chronic donor site pain, it has been suggested that both peripheral and central neuropathic and myofascial nociceptive pathways contribute to the development of post-thoracotomy pain syndrome. A variety of preemptive or preventative analgesic techniques have been used in an attempt to reduce sustained nociceptive input into the CNS and concomitant acute and chronic pain after thoracic surgery. In a retrospective review of 1000 thoracic surgery patients, Richardson et al. [56] assessed the ef cacy of acute postoperative pain on the incidence of post-thoracotomy pain syndrome at 2 months after surgery. The use of systemic opioids alone was associated with a 23.4% incidence of post-thoracotomy pain syndrome [56]. However, the use of continuous paravertebral infusion of bupivacaine in conjunction with systemic opioids decreased the incidence to 14.8% (110). Furthermore, the addition of an NSAID to this analgesic regimen reduced the incidence of post-thoracotomy pain syndrome to 9.9% [56]. These ndings highlight the importance of using a multimodal analgesic regimen for the prevention of acute and chronic postsurgical pain. In addition, even when a perioperative local anesthetic block is used, nociceptive afferent pathways to the CNS can still be activated, leading to central sensitization [56]. There appear to be two forms of nociceptive input from peripheral in amed tissue to the CNS [46]. The rst is mediated by neural activity innervating the area of injury, which may be reduced with local anesthetic neural blockade and/or peripherally acting COX-2 inhibitors. The second pathway is humorally mediated, in which interleukins reach the CNS via systemic pathways, leading to upregulation of COX-2 in the CNS. This latter pathway is not affected by regional anesthesia and only blocked by centrally acting COX-2 inhibitors [46]. McCrory et al. [57] con rmed the analgesic bene t of adding a centrally acting COX-2 inhibitor with neuraxial analgesia for post-thoracotomy pain. This randomized, prospective, double-blind study evaluated the analgesic ef cacy of ibuprofen (peripherally acting NSAID), nimesulide (centrally acting NSAID), or placebo in conjunction with neuraxial analgesics. This study revealed a signi cant reduction in postoperative pain and opioid use with the centrally acting NSAID, nimesulide, compared with either ibuprofen or placebo. This pain reduction correlated with a signi cant reduction in cerebrospinal uid prostaglandin E2 observed in the nimesulide group, which was not seen with either placebo or ibuprofen. In a retrospective study of 159 patients undergoing posterolateral thoracotomy, Hu et al. [58] examined the

Chronic Pain After Surgery: What Can We Do to Prevent It? Reuben 9

effects of thoracic epidural analgesia on the incidence of post-thoracotomy pain syndrome. One hundred and nineteen patients received thoracic epidural anesthesia in conjunction with general anesthesia, and 40 patients received only general anesthesia. Thoracic epidural analgesia was initiated before surgical incision and maintained intraoperatively with an infusion of bupivacaine 0.5%. After surgery, these patients were administered epidural morphine every 12 hours for the rst 3 days. These authors reported a similar incidence in post-thoracotomy pain syndrome in the epidural analgesia group (42%), compared to the general anesthesia group (39%). In contrast to these ndings, Obata et al. [59], in a prospective, randomized, double-blind study, revealed a signi cant analgesic bene t when epidural analgesia was initiated before thoracic surgery. These investigators compared the analgesic effects of a continuous thoracic epidural infusion of mepivacaine initiated 20 minutes before surgery or at the completion of surgery and continued for the rst 3 postoperative days. This study revealed a signi cant reduction in both acute and chronic post-thoracotomy pain at 6 months after surgery in the preincisional epidural analgesia group, compared with the postincisional group. The bene cial effects of epidural analgesia after thoracic surgery were con rmed in a more recent prospective, randomized, double-blind study performed by Senturk et al. [60]. These investigators compared the analgesic effects of three different analgesic techniques on acute postoperative pain and the incidence of post-thoracotomy pain syndrome 6 months after surgery: 1) thoracic epidural analgesia initiated before surgical incision; 2) thoracic epidural analgesia initiated after surgical incision; and 3) intravenous patientcontrolled analgesia (PCA). Patients in the prethoracic epidural group reported signi cantly less pain compared with the post-thoracic epidural or the PCA groups for the rst 48 hours after surgery. The incidence of postthoracotomy pain syndrome was also signi cantly lower in the prethoracic epidural group (45%), compared with either the post-thoracic epidural (63%) or the PCA (78%) groups. Although both Obata et al. [59] and Senturk et al. [60] demonstrated a bene cial effect with the preemptive administration of epidural analgesia for thoracic surgery, Ochroch et al. [61] were unable to report similar ndings. In a prospective, randomized, double-blind study of 157 patients, these investigators examined the analgesic ef cacy of thoracic epidural analgesia initiated before surgical incision or at the time of rib approximation. Overall, there were no differences in pain scores or activity level during hospitalization or after discharge between the two groups. Furthermore, the number of patients reporting pain 1 year after surgery was similar in between the two groups. From these studies, it can be concluded that the method of perioperative pain management has a variable effect on the incidence of post-thoracotomy pain syndrome. The reason for this variability may be explained by the multiple sources of nociceptive afferent pathways

involved in the perception of pain after thoracic surgery [62]. These pain sources may be conveyed to the CNS via somatic nerves (intercostal nerves), phrenic nerve, cranial nerve (vagus nerve), the sympathetic nervous system, the parasympathetic system, and the brachial plexus [54]. Therefore, the use of regional blockade by itself is insufcient in providing complete pain relief and preventing central sensitization of the nervous system after thoracic surgery. A multimodal analgesic regimen, in which regional blocks are combined with NSAIDs and other analgesics, as described by Richardson et al. [56], may provide for a reduction in both acute and chronic pain after thoracic surgery. Future prospective, randomized studies are needed to evaluate the ef cacy of using preventative multimodal analgesic techniques on the incidence of post-thoracotomy pain syndrome.

PMPS
PMPS is a neuropathic pain syndrome that is poorly documented, poorly understood, and understudied. This syndrome consists of persistent pain in the anterior chest, and axilla, medial, and posterior parts of the arm after breast surgery. The exact mechanism producing PMPS is unclear, but is thought to be due to surgical injury to the intercostobrachial nerve [63]. The reported incidence of PMPS after surgery for breast cancer varies considerably, with reports from as low as 4% to 6% [64] to as high as 100% [65]. This pain can be suf ciently severe enough to interfere with sleep and performance of daily activities [66,67]. In addition, if poorly treated, patients may develop an immobilized arm, which can lead to severe lymphedema, frozen shoulder syndrome, and CRPS [68]. A variety of perioperative analgesics have been administered for mastectomy surgery in an attempt to preempt the process of central sensitization and thus the incidence of pain. Previous studies have evaluated the analgesic ef cacy of administering either ibuprofen, mexiletine, gabapentin, venlafaxine, eutectic mixture of local anesthetics (EMLA), local anesthetic in ltration, and brachial plexus block on the incidence of acute and/or chronic pain after breast cancer surgery [6973]. Fassoulaki et al. [73] were the rst investigators to examine the ef cacy of using preemptive analgesia in an attempt to prevent the occurrence of PMPS. This study prospectively evaluated 30 patients scheduled for partial or total mastectomy with axillary dissection who received either ibuprofen, 400 mg, (n = 15) or placebo (n = 15) 90 minutes before surgery, 2 hours after surgery, and then every 8 hours in the rst 32 postoperative hours. This study revealed no signi cant reduction in either the incidence of acute pain for the rst 42 postoperative hours or the incidence of PMPS at 6 months postoperatively. This study can be criticized for using a subtherapeutic dose of ibuprofen [74] and administering this NSAID for a rather brief period of time after the surgical procedure. Furthermore, centrally acting

10 Anesthetic Techniques in Pain Management

NSAIDs may be more effective analgesics in preventing central sensitization after peripheral trauma [75]. Because ibuprofen has little effect on the upregulation of COX-2 in the CNS and resultant central prostaglandin E2 synthesis [57], it may not effectively prevent the development of central neuroplasticity and the subsequent development of chronic pain. In an attempt to attenuate the ectopic neural activity that is thought to be associated with the pathogenesis of PMPS, Fassoulaki et al. [71] investigated the effect of regional brachial plexus block, oral mexiletine, and the combination of both on acute and chronic pain after breast cancer surgery. Patients were administered mexiletine, 200 mg, twice a day for the rst 6 postoperative days starting the night before surgery. This study demonstrated that analgesic requirements were reduced in the immediate postoperative 24 hours by regional block, whereas the addition of mexiletine reduced the total oral analgesic requirements during the rst 5 postoperative days. However, there was no signi cant reduction in the incidence of PMPS, with the only long-term change noted being a reduction in hypoesthesia observed in patients who received both treatments. In an attempt to further improve on its analgesic ef cacy, Fassoulaki et al. [72] evaluated an increased mexiletine dosage (600 mg/day) administered for a prolonged duration (10 days) after breast cancer surgery. This study also compared the ef cacy of this dosing regimen of mexiletine to that of gabapentin, 1200 mg/day. Gabapentin possesses antihyperalgesic and antiallodynic effects in the setting of peripheral tissue injury [76]. In addition, gabapentin has been shown to enhance the analgesic effects of morphine in healthy volunteers [77], and a single 1200-mg dose of gabapentin before mastectomy surgery reduced both acute pain and morphine use [78]. However, Fassoulaki et al. [72] were unable to demonstrate a reduction in the incidence of chronic pain after mastectomy surgery with the perioperative administration of gabapentin, 1200 mg/day, for 10 postoperative days. Recently, the perioperative administration of EMLA has been evaluated for postmastectomy surgical pain [70]. This study evaluated the application of 5 g of EMLA or placebo on the sternal area 5 minutes before surgery, and 15 g on the supraclavicular area and axilla at the end of the operation. In addition, treatment with EMLA cream, 20 g, or placebo was applied daily for the rst 4 days after surgery. This study revealed a signi cant reduction in postoperative analgesic requirements and the incidence and intensity of chronic pain with the application of EMLA. In an attempt to improve on the analgesic ef cacy observed in this study [70], Fassoulaki et al. [73] evaluated the effect of using multiple analgesics, including gabapentin, local anesthetic in ltration, and EMLA cream, on acute and chronic pain after breast cancer surgery. In this study, 50 patients were randomized to receive gabapentin, 400 mg, every 6 hours starting the evening before surgery and continued for the rst 8 postoperative days; EMLA cream,

20 g, applied on the day of surgery and continued until the third postoperative day; and irrigation of the axillary brachial plexus and third, fourth, and fth intercostal nerves with 19 mL of ropivacaine 0.75%. In the control group, matching placebo capsules, placebo cream, and normal saline irrigation were used in a double-blind fashion. This study demonstrated a signi cant reduction in acute and chronic pain after surgery with this multimodal analgesic therapy. Patients in the treatment group reported lower pain scores and consumed fewer analgesics in the postoperative period. Three months after surgery, signi cantly more patients in the treatment group (18/22; 82%) versus the control group (12/21; 57%) developed chronic pain (P = 0.028). Although at 6 months after surgery 10 of 22 (45%) and six of 30 (30%) patients developed chronic pain in the treatment versus control groups, respectively, this did not reach statistical signi cance (P = 0.424). Venlafaxine, a serotonin and norepinephrine reuptake inhibitor that is devoid of antihistaminergic, anticholinergic, or -adrenergic effects [79], was shown to be effective in the management of PMPS [80]. Furthermore, the preemptive administration of venlafaxine was shown to be ef cacious in mitigating hyperalgesia in the rat model of neuropathic pain [81]. Reuben et al. [82] examined the ef cacy of administering perioperative venlafaxine for acute and chronic pain after breast cancer surgery. In this study, venlafaxine, 75 mg, or placebo was administered for 2 weeks starting the night before surgery to 100 patients scheduled for either partial or radical mastectomy with axillary dissection. There were no differences between the two groups in postoperative pain scores or opioid use during the rst week after surgery. At 6 months postoperatively, there was a signi cant decrease in the incidence of chronic pain, including chest wall pain (55% vs 19%; P = 0.0002), arm pain (45% vs 17%; P = 0.003), and axilla pain (51% vs 19%; P = 0.0009), between the control group and the venlafaxine group, respectively. Unlike the previous studies that demonstrated a reduction in chronic pain after breast surgery [70,73], this was the rst study to demonstrate a reduction in chronic pain without a concomitant reduction in acute pain. This is surprising, because one of the predictive risk factors for the development of PMPS is unrelieved acute pain [1].

Conclusions
The development of chronic pain after surgery continues to be a major source of morbidity in a variety of surgical procedures. Despite its prevalence, our understanding of chronic postoperative pain and the potential means of risk reduction is somewhat de cient. We need to classify these chronic pain syndromes according to symptoms and mechanisms, and greater emphasis needs to be placed on preventing their development. Preventative analgesic techniques may play a role in reducing the incidence of certain chronic postsurgical pain syndromes. It has been suggested

Chronic Pain After Surgery: What Can We Do to Prevent It? Reuben

8.

11

that effective treatment of acute pain, particularly when accompanied by a neuropathic element, may prevent the development of chronic postsurgical pain syndromes [83]. The reduction in chronic pain may be attributed to a preventative analgesic effect in which a reduction in spinal cord neuroplasticity derives from prompt reduction in the perioperative noxious afferent input associated with surgery. Regardless of whether the timing of an analgesic intervention in the perioperative period ends up being a critical part of the puzzle, the value of aggressive and comprehensive pain control for surgical patients should not be underestimated. In order to effectively prevent the development of central neuroplasticity, we need to administer analgesics during the pre-, intra-, and postoperative periods. Furthermore, we have learned from post-thoracotomy pain studies that regional blockade by itself may be insuf cient in providing complete pain relief and preventing central sensitization. A multimodal analgesic regimen using regional blockade, NSAIDs, and other peripherally and centrally acting analgesics administered throughout the perioperative period may be the most ef cacious strategy. In other words, the provision of intensive and prolonged, multimodal analgesic interventions [7] may serve to insulate the susceptible neural pathways from a continuous barrage of nociceptive input over the long term, resulting in improved comfort to our patients and possibly a reduction in chronic pain. Future large-scale, randomized, controlled trials are necessary to support the use of preventative multimodal analgesic techniques in reducing chronic postsurgical pain syndromes.

References and Recommended Reading

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