Pain Management

Preemptive analgesia as a concept began over 90 years ago, when Crile and Lower proposed that blocking noxious signals prior to a surgical incision may lead to some degree of central nervous system (CNS) protection against postoperative pain, though at that time the mechanism remained unclear.¹ Crile believed that a combination of loco-regional blocks and general anesthesia (GA) favorably influenced the postoperative recovery compared to GA alone, especially when the blocks were performed in advance of the painful stimulus. Crile concluded that “patients given inhalational anesthesia still need to be protected by regional anesthesia otherwise they might incur persistent central nervous system changes and enhanced postoperative pain”.² The notion that the central nervous system “modulates” afferent pain signals before being perceived by the individual was furthered in 1965 when Melzack and Wall proposed their gate theory.³ This landmark paper suggested that incoming pain signals are subject to inhibition by either competing non-painful afferent input at the same spinal level or from supraspinal descending pathways. For example, rubbing one’s foot after stubbing your toe lessens the perception of pain due to the “closure” of a theoretical gate in the substantia gelatinosa that allows for only one type of afferent impulse to be transmitted to the CNS. However, this theory did not incorporate long-term changes in the CNS following nociceptive input and to other external factors that impinge upon the individual. It is now recognized that nociceptor function is dynamic and may be altered following tissue injury. Repetitive stimulation of small diameter primary afferent fibers generates a progressive increase in action potential discharge and increased excitability of both peripheral and CNS neurons, an event termed sensitization or “windup”. This is the mechanism by which pain may be prolonged beyond the duration normally expected with an acute insult. Further, this increased excitability in the CNS has the capacity to permanently alter spinal cord function leading to the development of chronic pain following an acute injury. Preemptive analgesia has been proposed as a method of decreasing postoperative pain by the prevention or attenuation of this windup phenomenon.

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The perception of pain is not a hard-wired mechanism, wherein stimuli are always transmitted and processed in an identical manner each time. In fact the central nervous system exhibits a great deal of plasticity. The processing of pain signals is now recognized to be a complex physiological cascade that involves dozens of different neurotransmitters and chemical substrates at several different anatomical locations. Operative procedures produce an initial afferent barrage of pain signals and generate a secondary inflammatory response, both of which contribute substantially to postoperative pain. The signals have the capacity to initiate prolonged changes in both the peripheral and central nervous system that will lead to the amplification and prolongation of postoperative pain. Peripheral sensitization, a reduction in the threshold of nociceptor afferent peripheral terminals, is a result of inflammation at the site of surgical trauma.⁴ Central sensitization, an activity-dependent increase in the excitability of spinal neurons, is a result of persistent exposure to nociceptive afferent input from the peripheral neurons.⁵ Taken together, these two processes contribute to the postoperative hypersensitivity state (“spinal windup”) that is responsible for a decrease in the pain threshold, both at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia).

The perception of acute pain begins with the transduction of a mechanical, thermal, or chemical stimulus by peripheral nociceptors. These free nerve endings are not simply passive conductors of information, but are subject to modulation at the site of activation. Tissue injury (e.g. surgical incision) results in several local responses that impact on pain signal transduction and transmission. First, an inflammatory response is provoked by the release of contents from damaged cells. At the same time, nociceptor activation directly leads to the discharge of neuropeptides such as neurokinin A, calcitonin gene-related peptide (CGRP) and substance P from peripheral terminals of the primary nerve fibers.⁶ These two processes contribute to the presence of a “sensitizing soup” of inflammatory mediators that include bradykinin, serotonin, histamine, nitric oxide and several others (table 1).⁷ It is now known that these mediators act directly on the nociceptors themselves, causing an increase in spontaneous activity, a lowered threshold for activation, and increased and prolonged firing to a suprathreshold stimulus by the primary afferent neurons.⁸ As a result of this peripheral sensitization, low-intensity stimuli that would normally not cause a painful response prior to sensitization now become perceived as pain, an effect termed allodynia (Figure 1).

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Table 1: Local Anesthetic Wound Infiltration

Figure 1: Pain Sensitization

Following transduction, nociceptive signals are carried by myelinated A-delta fibers and unmyelinated C fibers to the dorsal horn of the spinal cord, where they synapse with second-order neurons.  The two different types of fibers typically exhibit specialization, with A-delta fibers responsible for the discrete, sharp response called “first pain”, which is perceived almost immediately and is brief in duration.  C fibers are slower to conduct, and trigger a poorly-localized, burning or aching type of pain (“second pain”) that tends to last beyond the termination of the acute stimulus, and is associated with a growing region of hypersensitivity around the point where the noxious stimulus was applied.

These primary fibers terminate primarily in lamina I, II and V⁹ of the dorsal horn, where they synapse with second order spinal neurons.  There are two forms of second order neurons that are important to the understanding of central sensitization.  The first are called nociceptive-specific neurons, and, as the name suggests, respond only to painful signals from A-delta and C fibers caused by a high-intensity stimulus.  In contrast, wide dynamic range (WDR) neurons accept convergent input from a variety of nociceptive and non-nociceptive sources (e.g. non-painful touch).  Normally, low-intensity non-painful stimuli carried by A-beta fibers to WDR neurons are interpreted (correctly) as inoffensive.  However, under the constant barrage of nociceptive input that is associated with actual tissue damage, WDR neurons become sensitized and hyperresponsive.  When this occurs, they may begin to discharge at a high rate following a normally innocuous stimulus, leading to allodynia and hyperalgesia.

In this manner, prolonged central sensitization has the capacity to lead to permanent alterations in the central nervous system that contribute to chronic pain long after the acute stimulus has been withdrawn. Sustained input from peripheral neurons can result in the death of inhibitory neurons, replacement with new afferent excitatory neurons, and the establishment of aberrant excitatory synaptic connections.¹⁰ These alterations result in a prolonged state of sensitization resulting in intractable post-surgical pain that is unresponsive to many analgesics.¹¹ The incidence of post-surgical pain that persists well beyond what might be expected (i.e. greater than 6-12 months) can be alarmingly high.  A review of the current literature reveals estimates such as 6-12% after craniotomy,^12,13 50-80% after leg amputation,^14-16 50% after thoracotomy,^17,18 11-57% after breast surgery,^19,20 3-56% after laparoscopic cholecystectomy,^21-23 and 12% following inguinal herniorrhaphy.²⁴  Clearly there is significant variability in the incidence of chronic pain for each of these procedures, and specific risk factors for its development have been identified.  These include, among others, preoperative pain of greater than one month’s duration, intensity of acute postoperative pain, psychologic vulnerability and anxiety, and a surgical approach with risk of nerve damage, such as posterolateral thoracotomy.²⁵  Interestingly, there is evidence that individual differences in the degree of endogenous modulation may predict one’s likelihood of sustaining a prolonged painful state.²⁶  In other words, certain individuals may have heightened baseline pain sensitivity and reduced cortical-inhibitory modulation, rendering them more likely to develop chronic pain after surgery than individuals with ‘normal’ pain processing. 

Despite the identification of chronic post-surgical pain syndromes, little is known about the underlying mechanisms, natural history, and response to therapy of each syndrome.²⁷  However, 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.  This has led to the concept of preemptive analgesia.

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In 1988, Wall suggested that “we should consider the possibility that pre-emptive pre-operative analgesia has prolonged effects which long outlast the presence of drugs”.²⁸  Some of the earliest experimental evidence supporting this theory noted that a painful stimulus in rats resulted in a distinct biphasic excitatory response in dorsal horn neurons – an immediate acute peak (at 0-10 minutes) and a subsequent, prolonged tonic phase lasting 20-65 minutes.²⁹  The study concluded that intrathecal opiates administered prior to the first-phase response but reversed with naloxone before the expected onset of the second-phase response were capable of preventing this latter stage.  On the other hand, if the opiates were administered after the painful stimulus, the inhibitory effect on the second-phase pain response in the dorsal horn was greatly diminished.  This experimental model was also used to investigate the role of local anesthetics in the dorsal horn response to pain.  Coderre et al. showed that local anesthetics applied either at the site of injury or intrathecally prior (but not subsequent) to a subcutaneous formalin injection abolished the expression of the second tonic phase of the pain response in dorsal horn neurons.³⁰

These early works lent support to the idea that sensitization may be preventable by pharmacologically inhibiting the action of these substances prior to the onset of the nociceptive onslaught.  Since then, clinical studies have sought to test the hypothesis that preemptive analgesia provides for greater postoperative pain control than ‘traditional’ intra- and postoperative analgesic regimens.  A wide variety of drugs have been employed, such as non-steroidal anti-inflammatory agents (NSAIDs), opioids, alpha-2 agonists, and NMDA antagonists such as ketamine and dextromethorphan.³¹  In addition, clinical investigators have attempted to target the sensitization process at one or more anatomical sites along the pathway including the site of injury, peripheral nerve axon, dorsal horn of the spinal cord, and cerebral cortex (Figures 2 and 3).

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Despite elegant demonstrations of its effect in some animal models, there exists some degree of controversy regarding the validity of preemptive analgesia in the clinical setting.  Many studies have obtained equivocal results or have failed to clearly demonstrate that preemptive analgesia is efficacious.  The reason for this may be related to the difference between the intensity and duration of the painful stimulus in early animal protocols compared with that experienced following a large surgical incision.  In addition, some negative studies have been criticized for their methodology, especially in cases where the duration of the surgical pain far exceeds the experimental analgesic intervention.  Studies that include pain as an outcome measure are often difficult to interpret given the subjective nature of the symptom and the tendency for confounding factors (e.g. psychological elements) to play a role.

Since timing is thought to be the key issue, investigations into preemptive analgesia are best performed when a comparison is made between an intervention performed prior to incision with the same intervention performed after surgery has begun (e.g. brachial plexus block before surgery or postoperatively).  If preemptive analgesia is efficacious, then those patients who had their block placed preoperatively should have less pain than those who had their block placed after the incision but before the end of the procedure.  Unfortunately, many studies of preemptive analgesia choose a methodology whereby a pre-incisional strategy is employed and compared with placebo (e.g. local infiltration into the wound site before incision versus no infiltration).  This study design does little to address the question of whether ‘pre- versus post-’ makes a difference. Further, the focus on demonstrating that pretreatment is more effective than the same treatment administered after incision or surgery has sidetracked progress since inclusion of a control group (e.g., placebo administered before and after incision) has been ignored.³²  Two group studies that fail to demonstrate a superiority of the preincisional over the postincisional analgesic treatment intervention are inherently flawed because it is not known whether the absence of an effect reflects the relative efficacy of the postoperative blockade or the inefficacy of preoperative blockade in reducing central sensitization.³³

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In the last two decades, hundreds of studies of varied quality have been published relating to the efficacy and utility of preemptive analgesia strategies.  The consensus is far from clear, with different reviewers reaching fundamentally dissimilar conclusions depending on the particular intervention used, the choice of control, the outcome measures, and so on.  Two relatively recent meta-analyses attempted to clarify the picture by summarizing and analyzing data from high-quality, double-blinded, randomized controlled trials.  Moiniche et al. included 80 randomized controlled trials (RCTs) representing 3761 patients published from 1983 to 2000.³⁴  Ong et al. analyzed 66 RCTs and 3261 patients that were published between 1987 and 2003.³⁵  Both sought to include only those papers in which an intervention was compared before and after surgical incision by the same route, and no placebo or dummy treatment was used.  Also, the outcome measures that were extracted from the studies were standardized where possible.  These were 1) pain intensity scores (e.g. VAS), 2) time to first analgesic request or rescue dose, and 3) total supplemental analgesic dose.

These two meta-analyses represent the vast bulk of well-conducted clinical trials investigating preemptive analgesia in the current literature.  The outcome measures chosen by the authors are traditional markers of analgesic efficacy in pain studies.  In particular, pain intensity scores and total analgesic dose have been held up as the most reliable measures of a preemptive effect.^36,37  Given the broad range of analgesic strategies available (e.g. local infiltration, neuraxial blocks, NSAIDs, etc.), it is useful to review the existing evidence for each approach independently, using the combined results of these two meta-analyses, and, where possible, any additional published evidence.

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Infiltrating local anesthetics into the skin and subcutaneous tissue prior to making an incision may be the simplest approach to preemptive analgesia.  It is easy to perform by both surgeon and/or anesthesiologist, and with the appearance of a skin wheal, it provides a clear end-point to the intervention.  It is also a very safe procedure with few side effects, and low risk for toxicity.  In the Moiniche et al. study, 14 trials (736 patients) compared pre- versus post-incisional wound infiltration for a variety of abdominal, thoracic, orthopedic and head and neck procedures.  Overall, no difference was found between study groups for all three outcome measures (table 1).  On the other hand, Ong et al. looked at 15 RCTs (671 patients) addressing local infiltration and concluded that local anesthetic infiltration was clinically effective in reducing the total analgesic use as well as prolonging the time to rescue analgesia, but did not achieve statistical significance with respect to reducing pain intensity when compared with traditional methods.

Table 1: Local Anesthetic Wound Infiltration

Other recent randomized trials comparing pre- and post-incisional local anesthetic infiltration also suggest no significant difference in pain outcomes. These include studies of infiltration of laparoscopic ports,^38,39 intra-articular sites40, laparotomy wounds,⁴¹ and tonsillectomy wounds.⁴² Pre-incisional local wound infiltration appears to have little effect on postoperative pain scores compared with infiltration carried out at the conclusion of surgery. The data seem to suggest a potential benefit with respect to the amount of postoperative analgesic use, and time to rescue dose, but this is controversial. It remains unclear from these data whether local anesthetic infiltration into the wound provides long-term prevention of chronic incisional pain. Most of the studies terminated their assessment of effect at 24-48 hours, well before the abatement of the acute postoperative pain. Since it is usually not a particularly challenging task to provide rescue analgesia in the immediate postoperative period, the utility of local infiltration prior to incision may be diminished.⁴³ However, the downside to the intervention is negligible, and there was no suggestion of a negative treatment effect. Also, there is evidence that local anesthetics possess antimicrobial properties when injected into a surgical wound,⁴⁴ and are unlikely to negatively influence wound healing.⁴⁵

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Peripheral nerve blocks (PNBs) are an attractive method of providing postoperative analgesia that, compared to general anesthesia alone, cut down on time to hospital discharge, reduce postoperative pain, and improve overall patient satisfaction.^46,47 Few clinicians would argue that a well-performed block provides for excellent pain control, but whether such blocks are best performed prior to incision or at the conclusion of surgery is still debated. A common belief is that it requires less analgesic to control pain before it starts than after the noxious input has begun, but there are few of studies that directly address this issue.

Suresh et al. investigated the effect of a pre-incisional great auricular block with 0.25% bupivacaine on postoperative pain in children undergoing tympanomastoid surgery compared with post-incisional block alone.⁴⁸ There was no difference in postoperative analgesic requirements, time to first rescue dose, or vomiting. Another study of preemptive PNBs in the pediatric population was performed by Altintas et al., in which children undergoing hand surgery were randomized to receive an axillary block with 0.25% bupivacaine.⁴⁹ One group received the block after induction but before incision, while the other received the block at the end of the procedure but while still under general anesthesia. The authors found essentially no difference between groups, except for significantly less isoflurane used in the preincisional group. This methodology brings to the forefront the observation that it is generally deemed acceptable to carry out regional anesthetic techniques in anesthetized children, but not adults, although this attitude may be changing with the adoption of more objective measures of injection pressures when performing nerve blocks.⁵⁰

Doyle and Bowler looked at the effect of preemptive intercostal blocks on post-thoracotomy pain compared with blocks performed at the conclusion of surgery.⁵¹ Patients were followed for a minimum of twelve months. Pain scores when taking a vital capacity breath during the first 48 hours were somewhat decreased in the ‘pre’ group, but no other measure showed a significant difference, including VAS scores, extent and duration of intercostal nerve block, analgesic consumption and the incidence of complications.

Huffnagle et al. investigated the efficacy of bilateral ilioinguinal and iliohypogastric nerve blocks when performed in conjunction with spinal anesthesia for cesarean delivery.⁵² Patients were randomized to have the block performed before incision, after incision, or not at all. While the results showed that postoperative patient satisfaction and morphine use did not differ amongst groups, the data may be hard to interpret given a 50% block failure rate in the ‘pre’ group.
Several studies examining the effect of intraneural⁵³ or perineural^54,55 catheters placed at the time of amputation showed little effect on long-term phantom pain, although the methodology was not appropriate for investigating preemptive analgesia.

In general, it appears to matter little whether a PNB used for postoperative pain is placed before or after incision. This again probably has to do with the duration of blockade following a painful surgical wound For example, a patient having undergone rotator cuff repair with a single-shot brachial plexus block is likely to have significant pain on postoperative day one. The widespread use of indwelling perineural catheters may change the balance of evidence in favor of preemptive placement, but this remains to be elucidated with clinical studies. Practical matters may play a more important role in the pre- or post- decision, such as the availability of skilled staff to conduct the block in the recovery room or the wish to avoid a painful window period between the termination of general or neuraxial anesthesia, and the onset of a block placed postoperatively.

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Epidural (and to a lesser extent caudal) analgesia is often carried through into the postoperative period by means of a catheter, which provides the potential advantage of an unbroken period of pain control from the operating room through until the catheter is removed, usually 24-72 hours later.⁵⁶  Combinations of local anesthetic, opioids, and other medications can be titrated to patient comfort and allow for an acceptable degree of motor function while still imparting a sensory block.  Because a catheter can be placed in the epidural space preoperatively and utilized ad lib, epidural analgesia is a technique well suited to the study of any potential preemptive effect.

Moiniche et al. analyzed ten studies of single-dose epidural analgesic regimens, for procedures such as thoracotomy, laparotomy, hysterectomy, and lumbar laminectomy.³⁴  The results were inconsistent with a clear treatment effect.  Likewise, of eight trials investigated for continuous epidural regimens, only three displayed significantly reduced VAS scores, whereas no differences were found in the other trials.  Five studies comparing pre- and postincisional caudal blocks in children also revealed no clear difference between study groups with respect to any of the outcome measures.

The Ong et al. meta-analysis identified 13 studies (653 patients) comparing preincisional versus postincisional epidural analgesia35.  Of these, 7 favored pretreatment based on VAS scores, while the remaining 6 were found to be not significant.  However, differences were found for total amount of supplemental analgesia – 10 versus 3 studies came out in favor of preincisional epidural analgesia.

Both Beilin et al.⁵⁷ and Neustein et al.⁵⁸ studied the effect of preemptive epidural bupivacaine/fentanyl analgesia on pain outcomes following hysterectomy and thoracic surgery, respectively.  The former trial reported significantly less severe postoperative pain in the preemptive group, as well as less elevated levels of both proinflammatory and anti-inflammatory cytokines.  In contrast, the study of analgesia following thoracic surgery revealed no treatment effect for the preincisional epidural blockade except for reduced isoflurane requirements.
Epidural anesthesia begun 18-72 hours prior to amputation appears to provide no significant advantage in preventing phantom pain than standard opioid therapy, placebo, or local anesthetic via surgically-placed perineural catheter.^59-62

Even though a centrally acting neural blockade such as epidural anesthesia should effectively block afferent pain impulses from being transmitted to the CNS, there is no substantial evidence that initiating the block prior to incision confers any considerable analgesic benefit once the epidural has been stopped.  It appears that there may be a case to be made for epidural analgesia in reducing the amount of analgesics required, at least while the epidural is operating.  In addition, there is evidence that neuraxial anesthesia provides other salutary effects such as improved gastric motility,⁶³ a blunted stress response to surgery,⁶⁴ and reduced thromboembolic complications.⁶⁵ Epidural and caudal analgesia may be clinically useful in prolonging the time to first analgesic request, but does not predictably reduce pain scores after surgery.

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Surgical trauma results in the induction of cyclooxygenase (COX), leading to the release of prostaglandins, which sensitize peripheral nociceptors and produce localized hyperalgesia (primary hyperalgesia) which can contribute to central sensitization in the postoperative period.  Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) are thought to exert their analgesic effects by inhibiting the production of prostanoids from arachidonic acid, thus decreasing peripheral sensitization and the activation of peripheral nociceptor66. Recently, considerable information has emerged in recent years regarding the involvement of prostaglandins and cyclooxygenases in the spinal cord67.

Recent evidence has suggested that COX-2 in the CNS may play a novel role in targeting nociceptive pathways68,69. This has been evidenced by a rapid upregulation of COX-2 expression in the CNS following peripheral trauma leading to central sensitization and pain hypersensitivity. The role of spinal COX in nociception has been implicated in several studies. First, intrathecal prostaglandin E2 (PGE2) causes hyperalgesia in rats70,71. It has been suggested that this inflammation-induced central sensitization is the result of an interaction of spinal prostaglandins and NMDA receptors70. Secondly, the intraspinal administration of COX-2 inhibitors significantly decreases centrally generated inflammatory pain hypersensitivity69. These results suggest that if COX-2 both inside and outside the brain is inhibited, then better pain relief is achieved72.

NSAIDs have demonstrated to be effective analgesics when administered at the conclusion of surgery73.  In an attempt to further reduce pain hypersensitivity, clinical trials have examined the effect of administering NSAIDs prior to surgical incision. The preemptive analgesic effects of NSAIDs has been previously studied after a wide variety of surgical procedures demonstrating equivocal results7,34,35,74. Unfortunately, many methodological problems have been encountered in these studies33.  Reuben et al. were the first investigators to examine the analgesic effects of administering the same dose of NSAID either before or after arthroscopic knee surgery75. The results of this study demonstrated that preoperative NSAID administration produced a significantly longer duration of postoperative analgesia, less 24 hour opioid use, and lower incidental pain scores compared with administering the same drug in the postoperative period.

A review of 18 randomized, single- or double-blinded studies that used a NSAID as the target intervention revealed that only six studies (33%) demonstrated a preemptive analgesic effect74.  Furthermore, the beneficial effects of preemptive NSAIDs observed in most studies were minimal. The review by Moniche et al. included twenty clinical trials comparing preincisional with postincisional NSAID using a parallel or crossover design34.  The authors concluded that some aspects of postoperative pain were improved by preemptive treatment in 4 of the 20 trials.  Overall, the data demonstrated preemptive NSAIDs to be of no analgesic benefit when compared with postincisional administration of these drugs.  In contrast, Ong et al. reviewed data from 16 randomized controlled trials with preemptive NSAIDs, concluding that these drugs improved analgesic consumption and time to first analgesic request, but not postoperative pain scores35.

Although preemptive NSAIDs by themselves may be ineffective in eliminating pain following surgery, when utilized in combination with other analgesic drugs they may be effective in reducing the incidence of both acute and chronic pain76,77.

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While much of the focus of preemptive analgesia research has been on neural blockade – either through local infiltration, peripheral nerve blocks, or neuraxial anesthesia – there is great interest in expanding the understanding of other medications in preventing sensitization or windup following surgery.  In addition to traditional agents such as opioids and NSAIDs, interest has been generated in the use of newer therapies such as N-methyl-D-aspartate (NMDA) receptor antagonists78,79 and gabapentin80,81.  Overall, the effect of preemptive opioids and NMDA receptor antagonists is unclear, with most studies in the two large meta-analyses showing no significant difference between groups.  On the other hand, preemptive NSAIDs have been largely shown to reduce both analgesic consumption and the time to rescue analgesic following surgery35,75

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Despite its prevalence, our understanding of chronic postoperative pain and the potential means of risk reduction are somewhat deficient. We need to classify these chronic pain syndromes according to symptoms and mechanisms and greater emphasis needs to be placed on preventing its development.  Preemptive analgesic techniques may play a role in reducing the incidence of certain chronic post-surgical pain syndromes82 and future large-scale randomized controlled trials are necessary to support these initial findings.  Four chronic pain syndromes that are important clinically to the anesthesiologist are complex regional pain syndrome, phantom limb pain, chronic donor site pain, and postthoracotomy pain syndrome.

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is a disorder characterized by the presence, following a noxious event, of regional pain and sensory changes such as temperature alterations, abnormal skin color, abnormal sudomotor activity, and/or edema83. 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 syndrome84. The Consensus Conference of the International Association for the Study of Pain (IASP) has identified two forms of CRPS: CRPS type I (formerly known as reflex sympathetic dystrophy) and CRPS type II (formerly known as causalgia)85. The characteristics of each are summarized in Table 2.

Table 2: CRPS type I and II characteristics

CRPS type I 1. Type I is a syndrome that develops after an initiating noxious event. 2. Spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event. 3. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event. 4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.

CRPS type II 1. Type lI is a syndrome that develops after a nerve injury. Spontaneous pain or allodynia/hyperalgesia occurs and is not necessarily limited to the territory of the injured nerve. 2. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event. 3. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.

Because there has been some debate regarding nomenclature and diagnostic standards, the IASP has also recently suggested a formal set of criteria for the diagnosis of CRPS86,87. Accordingly, patients should have:

1. at least one symptom in each of the following categories:
   1. sensory (hyperesthesia)
   2. vasomotor (temperature abnormalities or skin color abnormalities)
   3. sudomotor/fluid balance (edema or sweating abnormalities)
   4. motor (decreased range of movement, weakness, tremor or neglect)
2. and at least one sign within two or more of the following categories:
   1. sensory (allodynia or hyperalgesia)
   2. vasomotor (objective temperature abnormalities or skin color abnormalities)
   3. sudomotor/fluid balance (objective edema or sweating abnormalities)
   4. motor (objective decreased range of motion, weakness, tremor or neglect)

CRPS is often, but not always, associated with a state of sympathetically maintained pain (SMP)88. This type of pain is sustained by sympathetic efferent innervation or by circulating catecholamines, and is relieved by specific sympatholytic procedures such as nerve blocks. Sympathetically independent pain (SIP), in contrast, does not respond to sympatholytic blocks. Patients with CRPS may have varying elements of SMP or sympathetically independent pain throughout the course of the disease89.

CRPS is a potentially debilitating syndrome that leaves many patients without use of the affected limb. Once diagnosed, treatment should begin immediately. A multi-focal approach is often recommended, including a combination of physiotherapy, antidepressant and anticonvulsant medications, steroids, sympathetic blocks, and, in some cases, spinal cord stimulation89.

The incidence of CRPS occurring after surgery is variable, and may be underreported90. Approximately 20% of CRPS patients who present to chronic pain clinics have a history of prior surgical procedures in the affected area91,92. There are accounts of CRPS after such procedures as breast surgery93,94, radial artery harvesting for cardiac surgery95, skin nevus excision96, and lumbar spine surgery97. However, perhaps not surprisingly, most reports of postoperative CRPS occur in the orthopedic population, especially after operations on the extremities. Estimates for various procedures include 2.3% following knee arthroscopy98, 2.1-5% following carpal tunnel release99-101, and 0.8-13% following total knee arthroplasty. 102-105There is a wide range of reported incidences of this disorder after surgery, and this may be due to differences in methodology, particularly with respect to the interval at which the patients are assessed106. For example, patients assessed three months postoperatively are likely to have a different clinical presentation than those assessed one year out. Also, many of the reports originated before the definition of the syndrome was modified in the mid-1990s, so the external validity may be compromised for earlier investigations. Patients with CRPS who undergo surgery on the affected limb are thought to be at increased risk for recurrence or worsening of symptoms107,108.

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Phantom limb pain

People who suffer the loss of a limb, either traumatically or surgically, almost always report some degree of perceived sensation in the lost limb.  This phenomenon, first described over 400 years ago, was dubbed ‘phantom limb’ in 1871 by S.W. Mitchell109.  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 times110.

Early studies reported that the incidence of phantom pain in amputees was below 5%111.  Recent literature, however, suggests that the incidence is much higher, and is probably between 50-80%112-114.  The discrepancy may be explained by differences in methodologies.  Early studies tended to base prevalence on the patient’s request for pain relief, which may have underestimated the problem in patients who were reluctant to report pain to medical staff.  Several risk factors have been identified 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 factors115,116.

Typically, phantom pain occurs early in the post-amputation course with up to 70% of patients experiencing pain in the first several days after the injury117,118.  While phantom pain can be constant in some cases, it is predominantly intermittent in nature112.  Some patients report a background low-intensity pain coupled with intermittent episodes of excruciating, debilitating pain119 .  It is often characterized as knife-life or stabbing, but sufferers frequently describe other varied sensations such as shooting, squeezing, burning, aching, and throbbing119,120.  Pain can be perceived anywhere along the absent limb, but is typically reported in distal areas (i.e. hands and feet) as opposed to more proximal locations121.  In prospective studies of the duration of phantom pain, patients tend to report an overall decrease in pain intensity and frequency of attacks over time, with some patients experiencing a complete remission.  Unfortunately, this is the exception, and up to 60% of amputees are left with some degree of phantom pain 12 to 24 months after loss of the affected limb112,116,118.

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 following the transection of a nerve.  In addition, the sympathetic nervous system may have a role in sensitizing and maintaining the abnormal afferent output from damaged nerve fibers after amputation.  It is now known that the central nervous system, including spinal cord, brainstem, thalamus and cerebral cortex, undergoes significant functional reorganization following amputation.  Studies using functional brain imaging have shown that areas of the somatosensory cortex corresponding to the amputated structure become responsive to neighboring cell assemblies as early as 10 days after the injury122.  For example, a common finding in upper extremity amputees is a shift of the cortical representation of the mouth into the (deafferented) hand area123.  The degree to which this reorganization occurs has been correlated with the magnitude of phantom limb pain, underscoring the role that CNS plasticity has in the generation and maintenance of neuropathic pain124.

The treatment of phantom limb pain remains challenging, despite the multitude of proposed treatments.  A review of therapies for phantom pain published in 1980 reported over 40 different methods, but concluded that few provided consistent relief125.  The majority of interventions are medical, and consist of the same drugs used for the management of other neuropathic pain conditions, such as tricyclic antidepressants and anticonvulsants110.  Other modalities include non-medical options such as TENS, massage, and acupuncture.  Surgical therapies such as neurectomy, rhizotomy, and cordotomy are probably the least effective and may be best reserved for the most intractable cases.

            Several investigations have focused on utilizing preventative regional analgesic techniques to reduce perioperative pain and long-term phantom pain following lower extremity amputation surgery126. Bach et al.59 initially examined the effect of epidural morphine, epidural bupivacaine, or both in combination for three 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.60 confirmed the beneficial effects of perioperative epidural administration on preventing phantom pain following 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 significant reduction in the incidence of phantom pain at 1 year following surgery. However, the largest prospective study (n=60) to examine the effect of epidural analgesia on phantom pain failed to document any benefit at 7 days, 3 months, 6 months, and 12 months postoperatively. Similarly, clinical investigations evaluating the efficacy of continuous postoperative regional analgesia by nerve sheath block for amputation surgery have been equivocal with some studies revealing beneficial effects54,127 while others have demonstrated no long-term benefit53,55. It is interesting that perineural analgesia provided for a reduction in phantom pain in these two studies54,127 since this technique is ineffective in blocking nociceptive inputs from the pre- or intraoperative periods. 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 bupivacaine62. 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.

Unfortunately, many of the regional analgesic studies evaluating the effect on reducing long-term phantom pain have significant design flaws including: not prospective, randomized, or blinded, utilized either no control group or historical controls, investigated a heterogeneous study group, or lacked sufficient 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 later126.

In fact, there are a number of reports of peripheral nerve block and neuraxial techniques that appear to have caused an exacerbation of phantom pain.  These are seen primarily with lower limb amputations, although the phenomenon has been described following brachial plexus block for revision of an arm amputation128.  This ‘reactivated’ phantom pain associated with neural blockade is often severe and unresponsive to parenteral opioids.  However, agents that are usually effective against neuropathic pain, such as lidocaine and carbemazepime, have been used effectively129.  The mechanism by which regional anesthesia provokes this painful response is not completely understood.  One possibility is that an absence of afferent sensory input after spinal anesthesia may decrease the level of inhibition and increase self-sustained neural activity that is common in the spinal cord following deafferentation130.  Since a subanesthetic dose of thiopental (1 mg/kg) is effective at terminating the reactivation phantom pain, a central mechanism is implied131.  While some authors suggest avoiding spinal anesthesia in patients with a history of lower limb amputation132, the benefits of regional anesthesia must be weighed against the potential for this unusual and bizarre event to occur.

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Chronic donor site pain

The occurrence of chronic pain following 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 incision133-136. Although this pain usually resolves over a period of several weeks, it may persist and represent a significant source of postoperative morbidity133-136. In fact, donor site pain has been reported in up to 39% of patients at 3 months, 38% at 6 months, 37% at 1 year, and 19% at 2 years after bone graft harvesting from the iliac crest135-137.

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 ilium133. In addition, the pain may be neuropathic in origin secondary to injury to small sensory nerves at the donor site. One nerve frequently injured while harvesting bone graft from the anterior ilium is the lateral femoral cutaneous nerve, which has been reported in up to 10% of cases134. Injury to the ilioinguinal nerve has also been reported, especially when the bone graft is harvested from the anterior ilium134. The superior cluneal nerves pierce the lumbodorsal fascia and cross the posterior iliac crest 8 cm lateral to the posterior superior iliac spine138. Injury to these nerves may occur while harvesting bone graft from the posterior ilium and may result in transient or permanent numbness and pain over the buttock area.

Two recent studies have demonstrated a significant reduction in the incidence of chronic donor site pain with the preemptive administration of analgesics77,137. Houghton et al.139 have shown that the local application of a low dose of morphine can effectively block the development of hyperalgesia and allodynia in a rat model of bone damage. This analgesic effect was considered to be mediated through µ-opioid receptor action in the bone. Reuben et al.137 subsequently evaluated the analgesic effect of low dose morphine administered to the site of bone graft harvesting in patients undergoing spinal fusion surgery. Sixty patients were randomized to receive either saline infiltration into the harvest site (n=20), intramuscular morphine 5 mg (n=20), or morphine 5 mg infiltrated into the harvest site (n=20). This study revealed that morphine infiltrated into the bone graft harvest site resulted in a significant reduction in pain scores and opioid use for the first 24 hours following surgery. Further, the association of chronic donor site pain was significantly lower in the local morphine group (5%) compared to the intramuscular morphine (37%) or saline infiltration (33%) groups. Another study from the same institution examined the analgesic effect of preemptive COX-2 administration for spinal fusion surgery77. It has been shown that COX-2 plays an integral role in the processes of peripheral and central sensitization140, and it is possible that early and sustained treatment with COX-2 inhibitors may thwart the progression of acute to chronic pain141. Eighty patients scheduled to undergo instrumented posterior spinal fusion were randomized to receive either celecoxib 400 mg 1 hour prior to surgery and then 200 mg every 12 hours postoperatively for the first 5 days or matching placebo at similar time intervals. Patients administered celecoxib reported lower pain scores and had less opioid use during the first 5 postoperative days. Chronic donor site pain was significantly higher in the placebo group (12/40, 30%) compared to the celecoxib group (4/40, 10%) at 1 year following surgery77. The development of neuropathic pain following 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 rats142 and peripheral prostaglandins have been implicated in the pathogenesis of neuropathic pain143. However, after the development of neurogenic inflammation, the responses to mechanical stimuli are not affected by spinal COX-2 inhibition142. Thus, spinal prostaglandin synthesis may be important for the induction and initial expression, but not for the maintenance of spinal cord hyperexcitability70. This may explain the lack of analgesic efficacy of NSAIDs for treatment of chronic donor site pain observed in the study by Reuben et al.

These studies77,137 highlight the importance of utilizing preemptive analgesics for pain management following spinal fusion surgery. It has been suggested that effective treatment of acute pain, particularly when accompanied by a neuropathic element, prevents the development of chronic post-surgical pain syndromes25,144-146. The reduction in chronic donor site pain may be attributed to a preemptive or preventative analgesic effect in which a reduction in spinal cord neuroplasticity derives from prompt reduction in the perioperative noxious afferent input associated with surgery. An early reduction in acute pain may facilitate early postoperative ambulation147 and decrease fear-avoidance behaviors148,149 also contributing to a reduction in chronic post-surgical pain. Further studies are needed to assess the efficacy of preemptive analgesic techniques on reducing chronic donor site pain.

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Postthoracotomy pain syndrome

Pain following thoracic surgery has been reported to be among the most intense clinical experiences known150. The nociceptive pathways that are responsible for postthoracotomy pain are still poorly understood151. Possible sources of nociceptive input that may contribute to postoperative pain following thoracic surgery are multiple and include the site of the surgical incision, disruption of the intercostals nerves, inflammation of the chest wall structures adjacent to the incision, pulmonary parenchyma or pleura, and thoracostomy drainage tubes152. Unrelieved acute pain following thoracic surgery can not only contribute to postoperative pulmonary dysfunction153, but may also contribute to the development of postthoracotomy pain syndrome25,144-146.

Postthoracotomy pain syndrome is defined as pain that recurs or persists along a thoracotomy incision for at least 2 months following the surgical procedure154. The true incidence of postthoracotomy pain syndrome is difficult to determine with a reported range from 5% to 80%155. Different definitions used to describe and assess pain, lack of large, prospective studies, small sample size, varying surgical techniques, varying perioperative management, and different periods of follow-up care have all contributed to the difficulty in determining the true incidence of this post-surgical pain syndrome155. Nonetheless, it has been estimated that half of all patients still alive 1-2 years after thoracotomy will suffer with persistent chest wall pain156. Further, as many as 30% of patients might still experience pain 4 to 5 years after surgery156.

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 neuropathic and myofascial nociceptive pathways contribute to the development of postthoracotomy pain syndrome. While damage to cutaneous or deep (muscle, joint and viscera) tissue is typically associated with peripheral inflammation, damage to neural structures often leads to pathological pain10. Damage to intercostal nerves during thoracic surgery leads to neural degeneration, neuroma formation and the generation of spontaneous neural inputs10. Evidence suggests that although nociceptive and neuropathic pain depend upon separate peripheral mechanisms, they are both significantly influence by changes in central nervous system function10.   The resultant neuroplastic changes in the central nervous system have the capacity to contribute to persistent pathological pain following surgery10.

A variety of preemptive or preventative analgesic techniques have been utilized in an attempt to reduce sustained nociceptive input into the central nervous system and concomitant acute and chronic pain following thoracic surgery. In a retrospective review of 1000 thoracic surgery patients, Richardson et al.157 assessed the efficacy of acute postoperative pain on the incidence of postthoracotomy pain syndrome at two months following surgery. The use of systemic opioids alone was associated with a 23.4% incidence of postthoracotomy pain syndrome157. Interestingly, the use of intraoperative intercostal neurolysis with a cryoprobe increased the incidence of chronic pain to 31.6%157. In contrast, the use of continuous paravertebral infusion of bupivacaine in conjunction with systemic opioids decreased the incidence to 14.8%157. Further, the addition of an NSAID to this analgesic regimen reduced the incidence of postthoracotomy pain syndrome to 9.9%157. These findings highlight the importance of utilizing a multimodal analgesic regimen for the prevention of acute and chronic post-surgical pain. In addition, even when a perioperative local anesthetic block is utilized, nociceptive afferent pathways to the CNS can still be activated leading to central sensitization157. There appears to be two forms of nociceptive input from peripheral inflamed tissue to the CNS140. The first 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 inhibitors140. Thus it has been demonstrated that the addition of a centrally-acting COX-2 inhibitor to a local anesthetic block can result in a significant decrease in CNS prostaglandin E2 (PGE2) levels and improved postoperative analgesia158. McCrory et al.159 confirmed the analgesic benefit of adding a centrally-acting COX-2 inhibitor with neuraxial analgesia for post-thoracotomy pain. This randomized, prospective, double-blind study evaluated the analgesic efficacy of ibuprofen (peripherally-acting NSAID), nimesulide (centrally-acting NSAID), or placebo in conjunction with neuraxial analgesics. This study revealed a significant reduction in postoperative pain and opioid use with the centrally-acting NSAID, nimesulide, compared to either ibuprofen or placebo. This pain reduction correlated with a significant reduction in CSF PGE2 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.160 examined the effects of thoracic epidural analgesia on the incidence of postthoracotomy pain syndrome. One hundred nineteen patients received thoracic epidural anesthesia in conjunction with general anesthesia and 40 patients received only general anesthesia. Thoracic epidural analgesia was initiated prior to surgical incision and maintained intraoperatively with an infusion of bupivacaine 0.5%. Following surgery, these patients were administered epidural morphine every 12 hours for the first 3 days. These authors reported a similar incidence in postthoracotomy pain syndrome in the epidural analgesia group (42%) compared to the general anesthesia group (39%). In contrast to these findings, Obata et al.161, in a prospective, randomized, double-blind study, revealed a significant analgesic benefit when epidural analgesia was initiated prior to thoracic surgery. These investigators compared the analgesic effects of a continuous thoracic epidural infusion of mepivacaine initiated 20 minutes prior to surgery or at the completion of surgery and continued for the first 3 postoperative days. This study revealed a significant reduction in both acute and chronic postthoracotomy pain at 6 months following surgery in the pre- compared to the postincisional epidural analgesia group. The beneficial effects of epidural analgesia following thoracic surgery were confirmed in a more recent prospective, randomized, double-blind study performed by Senturk et al.162. These investigators compared the analgesic effects of three different analgesic techniques : (1) thoracic epidural analgesia initiated before or (2) after surgical incision and (3) intravenous patient controlled analgesia (PCA) on acute postoperative pain and the incidence of postthoracotomy pain syndrome 6 months following surgery. Patients in the pre-thoracic epidural group reported significantly less pain compared with the post-thoracic epidural or the PCA groups for the first 48 hours following surgery. The incidence of postthoracotomy pain syndrome was also significantly lower in the pre-thoracic epidural group (45%) compared to either the post-thoracic epidural (63%) or the PCA (78%) groups. Although both Obata et al.161 and Senturk et al.162 demonstrated a beneficial effect with the preemptive administration of epidural analgesia for thoracic surgery, Ochroch et al.163 were unable to report similar findings. In a prospective, randomized, double-blind study of 157 patients, these investigators examined the analgesic efficacy of thoracic epidural analgesia initiated prior to 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. Further, the number of patients reporting pain 1 year following 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 postthoracotomy pain syndrome. The reason for this variability may be explained by the multiple sources of nociceptive afferent pathways involved in the perception of pain following thoracic surgery152. These pain sources may be conveyed to the central nervous system via somatic nerves (intercostal nerves), phrenic nerve, cranial nerve (vagus nerve), the sympathetic nervous system, the parasympathetic system, and the brachial plexus155. It has been demonstrated that thoracic epidural analgesia is unable to abolish somatosensory evoked potential resulting from thoracic dermatomal stimulation, suggesting that this regional technique may be insufficient in blocking all nociceptive pain pathways164,165. Therefore, the use of regional blockade by itself is insufficient in providing complete pain relief and preventing central sensitization of the nervous system following thoracic surgery. A multimodal analgesic regimen, in which regional blocks are combined with NSAIDS and other analgesics, as described by Richardson et al.157, may provide for a reduction in both acute and chronic pain following thoracic surgery. Future prospective, randomized studies are needed to evaluate the efficacy of utilizing preventative multimodal analgesic techniques on the incidence of postthoracotomy pain syndrome.

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Despite major improvements in our understanding of acute pain physiology, sufficient pain relief that allows normal function has not been achieved during major surgical procedures without the risk of side effects.  Optimal pain relief following surgery is difficult to achieve with the use of just one drug or regimen166.  Many pain experts advocate the use of two or more classes of medications or techniques so as to reduce the side effect profile of any one drug, as well as make use of synergistic analgesic pathways or receptors.  It is possible that, in the search for an ideal technique to provide true preemptive analgesia, a multimodal approach may be employed.  There is already some clinical evidence that this can be an effective technique.  Recently, Reuben et al. demonstrated that a preemptive multimodal regimen consisting of rofecoxib, acetaminophen, femoral nerve block, and an intraarticular injection of morphine, clonidine and bupivacaine led to a reduction in the incidence of pain, opioid use, postoperative nausea and vomiting, length of stay, and unplanned admission to the hospital following anterior cruciate ligament surgery.167.  Further, patients receiving this preemptive analgesic regimen demonstrated a significant reduction in long-term patellofemoral complications including patellofemoral pain, flexion contracture, quadriceps weakness, and CRPS of the knee168.  In addition, these patients were more likely to return to their pre-injury level of activity including full sports participation.

Unfortunately the majority of studies evaluating the long-term benefits of utilizing preventative analgesic techniques failed to document any effect on wound hyperalgesia. Without such data, one cannot comment on the potential mechanisms responsible for a potential reduction in chronic post-surgical pain.169 Recently, Lavand’homme et al. assessed the role of preventative multimodal analgesic techniques in reducing wound hyperalgesia and persistent post-surgical pain following major abdominal surgery.170 In a randomized, double-blind trial these investigators examined the analgesic effects of thoracic epidural analgesia combined with ketamine following neoplastic colon resection. All patients received a thoracic epidural catheter, systemic ketamine (0.5 mg/kg and 0.25 mg . kg-1 . h-1 intraoperatively) and general anesthesia. Patients were allocated to four groups to receive intraoperative intravenous lidocaine-sufentanil-clonidine or epidural bupivacaine-sufentanil-clonidine followed postoperatively by either intravenous (lidocaine-morphine-clonidine) or epidural (bupivacaine-sufentanil-clonidine) patient-controlled analgesia. These analgesics were administered by either intravenous or epidural route as a continuous infusion starting before incision until 72 hours after surgery. This study revealed significantly higher analgesic requirements, pain scores, and area of wound hyperalgesia in the intravenous treatment group (intravenous-intravenous), and more patients reported residual pain from 2 weeks until 1 year (28%). Postoperative epidural treatment (intravenous-epidural) was less effective in preventing residual pain at 1 year (11%) than the intraoperative epidural (epidural-epidural and epidural-intravenous) groups (0%). This landmark study demonstrates a clear benefit of continuous epidural analgesia as a preventative treatment on the development of persistent post-surgical pain. Further, intraoperative use of epidural analgesia seems to provide for a more significant long-term benefit on the presence of residual pain. By demonstrating a reduction in mechanical hyperalgesia with these preventative analgesic techniques, this study highlights the major contribution of central sensitization in both short- and long-term incisional pain.

The pathophysiology of windup has yet to be completely defined, and as our understanding of the pathways involved is enhanced, the use of multiple agents to achieve a more complete and reliable preemptive blockade of sensitization is likely to occur.

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Preemptive analgesia is a tempting concept for practitioners of anesthesia and perioperative pain medicine.  However, despite the compelling experimental evidence, there has been a great deal of difficulty proving its existence in the clinical setting.  This is probably related to multiple methodological factors.  Most importantly, the duration of the noxious afferent input from the surgical wound far exceeds those used for the original animal experiments.  It is futile to attempt to manipulate a complex physiological event such as postoperative pain with a single preoperative intervention that lasts only a few minutes or hours.  Techniques that involve continuous infusions of local anesthetic such as epidurals hold the most promise in this area.  In particular, continuous perineural catheters that are being used to prolong the effect of a peripheral nerve block are very exciting from the point of view of allowing a patient to be discharged home in comfort while at the same time potentially reducing the inflammatory sensitization that would otherwise occur in the spinal cord.  As the popularity of these catheters grows, we are sure to see more clinical trials aimed at defining their role in preemptive analgesia.

Secondly, for a study to prove the efficacy, or even the existence, of preemptive analgesia, the intervention must be compared in three groups –  preincision, postincision, and placebo.  The use of a placebo versus a preincision intervention just serves to support the intuitive notion that ‘some pain medicine is better than none’.  Unfortunately, many studies are allowed to be conducted this way.

Whether or not 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.  Some clinicians are choosing to focus on providing “preventative”, rather than simply “preemptive” analgesia.  The term preventative analgesia was introduced to emphasize the fact that central neuroplasticity is induced by both pre-, intra-, and postoperative nociceptive inputs169.  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.  In other words, the provision of “intensive and prolonged, multimodal analgesic interventions”34 may serve to insulate the susceptible neural pathways from a continuous barrage of nociceptive input over the long term, rather than as just a one-time treatment.  Effective preventative analgesic techniques may not only be useful in reducing acute pain but also chronic post-surgical pain and disability.

As Gottshalk and Raja point out in their recent editorial, it is incumbent upon anesthesiologists to “play a role in preventive medicine”170.  Preemptive analgesia is a good start, and though it remains a controversial subject at present, as our understanding of pain processing and the role of regional anesthesia in pain prevention improves, we can employ it to greater use in helping to keep our patients as comfortable as possible.

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