Chapter 76. Preemptive Analgesia, Regional Anesthesia, & the Prevention of Chronic Postoperative Pain

Foundations

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 locoregional blocks and general anesthesia (GA), especially when the blocks were performed in advance of the painful stimulus, favorably influenced postoperative recovery compared with GA alone. 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 CNS “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 nonpainful 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 on 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 “wind-up.” This is the mechanism by which pain may be prolonged beyond the duration normally expected with an acute insult. Furthermore, 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 wind-up phenomenon.

Physiology of Central & Peripheral Sensitization

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 CNS exhibits a great deal of plasticity. The processing of pain signals is now recognized to be a complex physiologic cascade that involves dozens of different neurotransmitters and chemical substrates at several different anatomic 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 wind-up”) 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 (eg, surgical incision) results in several local responses that affect 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 includes bradykinin, serotonin, histamine, nitric oxide, and several others.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 76–1).

Following transduction, nociceptive signals are carried by myelinated A-δ 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-δ 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”), which 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. Two forms of second-order neurons 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-δ 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 nonnociceptive sources (eg, nonpainful touch). Normally, low-intensity nonpainful stimuli carried by A-β 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 CNS 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 postsurgical pain that is unresponsive to many analgesics.11 The incidence of postsurgical pain that persists well beyond what might be expected (ie, 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 1 month's duration, intensity of acute postoperative pain, psychological 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 postsurgical 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 wind-up from occurring. This has led to the concept of preemptive analgesia (Figure 76–2).

Preemptive Analgesia

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 to 10 min) and a subsequent, prolonged tonic phase lasting 20–65 min.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 and colleagues 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 nonsteroidal antiinflammatory agents (NSAIDs), opioids, α2-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 anatomic sites along the pathway, including the site of injury, peripheral nerve axon, dorsal horn of the spinal cord, and cerebral cortex (Figure 76–3).

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 (eg, 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 (eg, 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 preincisional strategy is employed and compared with placebo (eg, 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. Furthermore, 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 (eg, 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

Evidence in the Literature

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 and coworkers included 80 randomized controlled trials (RCTs) representing 3761 patients published from 1983 to 2000.34 Ong and associates 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 (eg, 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 (eg, 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.

Local Wound Infiltration

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 either surgeon or anesthesiologist, and with the appearance of a skin wheal, it provides a clear endpoint to the intervention. It is also a very safe procedure with few side effects, and low risk for toxicity. In the Moiniche and coworkers' study, 14 trials (736 patients) compared pre- vs postincisional wound infiltration for a variety of abdominal, thoracic, orthopedic, and head and neck procedures. Overall, no difference was found among study groups for all three outcome measures (see Table 76–1). On the other hand, Ong and associates looked at 15 RCTs (671 patients) addressing local infiltration and concluded that local anesthetic infiltration was clinically effective in reducing total analgesic use as well as prolonging the time to rescue analgesia, but did not achieve statistical significance with respect to reducing pain intensity compared with traditional methods.

Other recent randomized trials comparing pre- and postincisional local anesthetic infiltration also suggest no significant difference in pain outcomes. These include studies of infiltration of laparoscopic ports,38,39 intraarticular sites,40 laparotomy wounds,41 and tonsillectomy wounds.42

Preincisional 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 h, 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 wound44 and are unlikely to negatively influence wound healing.45

Peripheral Nerve Blocks

Peripheral nerve blocks (PNBs) are an attractive method of providing postoperative analgesia that, compared with 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 few of studies directly address this issue.

Suresh and colleagues compared the effect of a preincisional great auricular block with 0.25% bupivacaine with postincisional block alone on postoperative pain in children undergoing tympanomastoid surgery.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 and coworkers 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; 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 being 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 postthoracotomy pain compared with blocks performed at the conclusion of surgery.51 Patients were followed for a minimum of 12 months. Pain scores when taking a vital capacity breath during the first 48 h were somewhat decreased in the preincisional group, but no other measure showed a significant difference, including on VAS scores, extent and duration of intercostal nerve block, analgesic consumption, and the incidence of complications.

Huffnagle and associates 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. Although 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 preincisional group.

Several studies examining the effect of intraneural53 or perineural54,55 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 1. 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 decision of when to administer the block, 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.

Epidural & Caudal Analgesia

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 until the catheter is removed, usually 24–72 h 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 and coworkers analyzed 10 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.

Ong and associates' meta-analysis identified 13 studies (653 patients) comparing preincisional versus postincisional epidural analgesia.35 Of these, seven favored pretreatment based on VAS scores, whereas the remaining six were found to be not significant. However, differences were found for total amount of supplemental analgesia—10 vs 3 studies came out in favor of preincisional epidural analgesia.

Both Beilin and colleagues57 and Neustein and coworkers58 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 antiinflammatory 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 h 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

Although 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 a case can 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.

Nonsteroidal Antiinflammatory Drugs

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 antiinflammatory 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 nociceptor.66 Considerable information has emerged in recent years regarding the involvement of prostaglandins and cyclooxygenases in the spinal cord.67

Recent evidence has suggested that COX-2 in the CNS may play a novel role in targeting nociceptive pathways.68,69 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 rats.70,71 It has been suggested that this inflammation-induced central sensitization is the result of an interaction of spinal prostaglandins and NMDA receptors.70 Secondly, the intraspinal administration of COX-2 inhibitors significantly decreases centrally generated inflammatory pain hypersensitivity.69 These results suggest that if COX-2 both inside and outside the brain is inhibited, then better pain relief is achieved.72

NSAIDs have been demonstrated as effective analgesics when administered at the conclusion of surgery.73 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 results.7,34,35,74 Unfortunately, many methodologic problems have been encountered in these studies.33 Reuben et al. were the first investigators to examine the analgesic effects of administering the same dose of an NSAID either before or after arthroscopic knee surgery.75 The results of this study demonstrated that preoperative NSAID administration produced a significantly longer duration of postoperative analgesia, less 24 h opioid use, and lower incidental pain scores than did administering the same drug in the postoperative period.

A review of 18 randomized, single- or double-blinded studies that used an NSAID as the target intervention revealed that only 6 studies (33%) demonstrated a preemptive analgesic effect.74 Furthermore, the beneficial effects of preemptive NSAIDs observed in most studies were minimal. The review by Moniche and coworkers included 20 clinical trials comparing preincisional with postincisional NSAID using a parallel or crossover design.34 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 and associates 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 scores.35

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 pain.76,77

Opioids & Other Pharmacologic Agents

Although 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 wind-up 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 gabapentin.80,81 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 surgery.35,75

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 postsurgical pain syndromes,82 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, or edema.83 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.84 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 76–2.

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 CRPS.86,87 Accordingly, patients should have:

1. At least one symptom in each of the following categories:

   • a. Sensory (hyperesthesia)

   • b. Vasomotor (temperature abnormalities or skin color abnormalities)

   • c. Sudomotor/fluid balance (edema or sweating abnormalities)

   • d. Motor (decreased range of movement, weakness, tremor or neglect)

2. And at least one sign within two or more of the following categories:

   • a. Sensory (allodynia or hyperalgesia)

   • b. Vasomotor (objective temperature abnormalities or skin color abnormalities)

   • c. Sudomotor/fluid balance (objective edema or sweating abnormalities)

   • d. 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 SIP throughout the course of the disease.89

CRPS is a potentially debilitating syndrome that leaves many patients without use of the affected limb. Once diagnosed, treatment should begin immediately. A multifocal approach is often recommended, including a combination of physiotherapy, antidepressant and anticonvulsant medications, steroids, sympathetic blocks, and, in some cases, spinal cord stimulation.89

The incidence of CRPS occurring after surgery varies and may be underreported.90 Approximately 20% of CRPS patients who present to chronic pain clinics have a history of prior surgical procedures in the affected area.91,92 There are accounts of CRPS after such procedures as breast surgery,93,94 radial artery harvesting for cardiac surgery,95 skin nevus excision,96 and lumbar spine surgery.97 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 arthroscopy,98 2.1–5% following carpal tunnel release,99–101 and 0.8–13% following total knee arthroplasty.102–105 There 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 assessed.106 For example, patients assessed 3 months postoperatively are likely to have a different clinical presentation than those assessed 1 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 symptoms.107,108

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. Mitchell.109 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.110

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% and 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 factors.115,116

Typically, phantom pain occurs early in the postamputation course with up to 70% of patients experiencing pain in the first several days after the injury.117,118 Although phantom pain can be constant in some cases, it is predominantly intermittent in nature.112 Some patients report a background low-intensity pain coupled with intermittent episodes of excruciating, debilitating pain.119 It is often characterized as knife-like or stabbing, but sufferers frequently describe other varied sensations, such as shooting, squeezing, burning, aching, and throbbing.119,120 Pain can be perceived anywhere along the absent limb, but is typically reported in distal areas (ie, hands and feet) as opposed to more proximal locations.121 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 12–24 months after loss of the affected limb.112,116,118

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 nervous system 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 CNS, 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 injury.122 For example, a common finding in upper extremity amputees is a shift of the cortical representation of the mouth into the (deafferented) hand area.123 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 pain.124

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 relief.125 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 anticonvulsants.110 Other modalities include nonmedical options such as transcutaneous electrical nerve stimulation (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 surgery.126 Bach and colleagues59 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 and coworkers60 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 effects,54,127 and others demonstrating no long-term benefit.53,55 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 bupivacaine.62 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 that they were not prospective, randomized, or blinded; they utilized either no control group or historical controls; they investigated a heterogeneous study group; or they 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 later.126

In fact, a number of reports of peripheral nerve block and neuraxial techniques 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 amputation.128 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 carbemazepine, have been used effectively.129 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 deafferentation.130 Since a subanesthetic dose of thiopental (1 mg/kg) is effective at terminating the reactivation phantom pain, a central mechanism is implied.131 Although some authors suggest avoiding spinal anesthesia in patients with a history of lower limb amputation,132 the benefits of regional anesthesia must be weighed against the potential for this unusual and bizarre event to occur.

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 incision.133–136 Although this pain usually resolves over a period of several weeks, it may persist and represent a significant source of postoperative morbidity.133–136 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 crest.135–137

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 ilium.133 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 cases.134 Injury to the ilioinguinal nerve has also been reported, especially when the bone graft is harvested from the anterior ilium.134 The superior cluneal nerves pierce the lumbodorsal fascia and cross the posterior iliac crest 8 cm lateral to the posterior superior iliac spine.138 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 analgesics.77,137 Houghton and associates139 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 and colleagues137 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 h following surgery. Furthermore, the association of chronic donor site pain was significantly lower in the local morphine group (5%) than in 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 surgery.77 It has been shown that COX-2 plays an integral role in the processes of peripheral and central sensitization,140 and it is possible that early and sustained treatment with COX-2 inhibitors may thwart the progression of acute to chronic pain.141 Eighty patients scheduled to undergo instrumented posterior spinal fusion were randomized to receive either celecoxib 400 mg 1 h prior to surgery and then 200 mg every 12 h 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%) than in the celecoxib group (4/40, 10%) at 1 year following surgery.77 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 rats,142 and peripheral prostaglandins have been implicated in the pathogenesis of neuropathic pain.143 However, after the development of neurogenic inflammation, the responses to mechanical stimuli are not affected by spinal COX-2 inhibition.142 Thus, spinal prostaglandin synthesis may be important for the induction and initial expression, but not for the maintenance of spinal cord hyperexcitability.70 This may explain the lack of analgesic efficacy of NSAIDs for treatment of chronic donor site pain observed in the study by Reuben and colleagues.

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 postsurgical pain syndromes.25,144–146 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 postsurgical pain. Further studies are needed to assess the efficacy of preemptive analgesic techniques on reducing chronic donor site pain.

Postthoracotomy Pain Syndrome

Pain following thoracic surgery has been reported to be among the most intense clinical experiences known.150 The nociceptive pathways responsible for postthoracotomy pain are still poorly understood.151 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 intercostal nerves; inflammation of the chest wall structures adjacent to the incision, pulmonary parenchyma, or pleura; and thoracostomy drainage tubes.152 Unrelieved acute pain following thoracic surgery may contribute not only to postoperative pulmonary dysfunction,153 but also to the development of postthoracotomy pain syndrome.25,144–146

Postthoracotomy pain syndrome is defined as pain that recurs or persists along a thoracotomy incision for at least 2 months following the surgical procedure.154 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 postsurgical pain syndrome.155 Nonetheless, it has been estimated that half of all patients still alive 1–2 years after thoracotomy will suffer with persistent chest wall pain.156 Furthermore, as much as 30% of patients might still experience pain 4–5 years after surgery.156

The exact mechanism for the pathogenesis of postthoracotomy pain syndrome is still unclear. 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. Although damage to cutaneous or deep (muscle, joint, and viscera) tissue is typically associated with peripheral inflammation, damage to neural structures often leads to pathologic pain.10 Damage to intercostal nerves during thoracic surgery leads to neural degeneration, neuroma formation, and the generation of spontaneous neural inputs.10 Evidence suggests that although nociceptive and neuropathic pain depend on separate peripheral mechanisms, they are both significantly influenced by changes in CNS function.10 The resultant neuroplastic changes in the CNS have the capacity to contribute to persistent pathologic pain following surgery.10

A variety of preemptive or preventative analgesic techniques have been utilized in an attempt to reduce sustained nociceptive input into the CNS and concomitant acute and chronic pain following thoracic surgery. In a retrospective review of 1000 thoracic surgery patients, Richardson and colleagues157 assessed the efficacy of acute postoperative pain on the incidence of postthoracotomy pain syndrome at 2 months following surgery. The use of systemic opioids alone was associated with a 23.4% incidence of postthoracotomy pain syndrome.157 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 Furthermore, 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 postsurgical 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 sensitization.157 There appears to be two forms of nociceptive input from peripheral inflamed tissue to the CNS.140 The first is mediated by neural activity innervating the area of injury which may be reduced with local anesthetic neural blockade or peripherally acting COX-2 inhibitors. The second pathway is humorally mediated, in which interleukins reach the CNS via systemic pathways, resulting in 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.140 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 analgesia.158 McCrory and coworkers159 confirmed the analgesic benefit of adding a centrally acting COX-2 inhibitor with neuraxial analgesia for postthoracotomy 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 with either ibuprofen or placebo. This pain reduction correlated with a significant reduction in PGE2 levels in the cerebrospinal fluid 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 and associates160 examined the effects of thoracic epidural analgesia on the incidence of postthoracotomy pain syndrome. Thoracic epidural anesthesia was given to 119 patients 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 h for the first 3 days. These authors reported a similar incidence in postthoracotomy pain syndrome in the epidural analgesia group (42%) compared with the general anesthesia group (39%). In contrast to these findings, Obata and colleagues,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 min prior to surgery with one begun 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 preincisional compared with 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 and coworkers.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 prethoracic epidural group reported significantly less pain than those receiving the postthoracic epidural or the PCA groups for the first 48 h following surgery. The incidence of postthoracotomy pain syndrome was also significantly lower in the prethoracic epidural group (45%) than for those who received either the postthoracic epidural (63%) or the PCA (78%). Although both Obata and colleagues161 and Senturk and coworkers162 demonstrated a beneficial effect with the preemptive administration of epidural analgesia for thoracic surgery, Ochroch and associates163 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. Furthermore, the number of patients reporting pain 1 year following surgery was similar for 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 surgery.152 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.155 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 for blocking all nociceptive pain pathways.164,165 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 and colleagues,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.

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 regimen.166 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 and to 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 and colleagues 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 Furthermore, 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 knee.168 In addition, these patients were more likely to return to their preinjury 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 postsurgical pain.169 Recently, Lavand'homme and coworkers assessed the role of preventative multimodal analgesic techniques in reducing wound hyperalgesia and persistent postsurgical 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/h 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) PCA. These analgesics were administered by either intravenous or epidural route as a continuous infusion starting before incision until 72 h 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 postsurgical pain. Furthermore, intraoperative use of epidural analgesia seems to provide for more significant long-term prevention 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 wind-up 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.

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 methodologic 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 physiologic 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 vs 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 pre-, intra-, and postoperative nociceptive inputs.171 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 postsurgical pain and disability.

As Gottshalk and Raja point out in their recent editorial, it is incumbent on anesthesiologists to “play a role in preventive medicine.”172 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.