Figure 76–2. Allodynia—Low-intensity sensory stimuli that would normally not cause pain may become painful as a result of peripheral stimulation and its effect on lowering the threshold for activation of the peripheral nociceptors.

        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-δand 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 hyperre- sponsive. 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 windup from occurring. This has led to the concept of preemptive analgesia.

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 maybe 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.

Figure 76-2. Pathophysiologic mechanisms leading to peripheral sensitisation.

Figure 76-3. Pain pathways and levels at which pain transmission and perception can be modulated.

        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 to 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

+ = positive effect, 0 = no effect, ? = equivocal evidence.

       REGIONAL ANESTHESIA

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 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 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 pre- operatively 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 singledose 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 bupi- vacaine/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 methodologie 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 antagonists^78,79 andgabapentin.^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

      CHRONIC PAIN SYNDROMES FOLLOWING SURGERY

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.

CRPS = complex regional pain syndrome.

        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:

        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

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Newer Amide Anesthetics & Sustained-Release Local Anesthetics1. Diagnosis & Management of Intraspinal, Epidural, & Peripheral Nerve Hematoma. Histology of Peripheral Nerves. Supraclavicular Brachial Plexus Block.

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