Introduction

The concept of pre-emptive analgesia originated at a time of growing appreciation for the dynamic characteristics of the pain pathway. Experimental studies made it clear that noxious stimuli could sensitize both the peripheral and central components of the nociceptive pathway. This insight guided the interpretation of several clinical studies that appeared to demonstrate that subjects who underwent surgery having first received opioids or regional blockade experienced less postoperative pain and raised “the possibility that preemptive preoperative analgesia has prolonged effects which outlast the presence of drugs.” Since then, a considerable number of laboratory and clinical studies of pre-emptive analgesia have been performed.

Interpretation of this growing body of data is encumbered by evolving concepts as to what constitutes pre-emptive analgesia. Pre-emptive analgesia in the widest sense recognizes that noxious stimuli at any point throughout the entire perioperative period can sensitize the nervous system. More recently, the term preventive analgesia has been applied to clinical and laboratory studies that seek to demonstrate a beneficial effect of an analgesic intervention that outlasts the pharmacologic presence of the intervention. Such studies typically determine whether some benefit is observed in those who received the analgesic intervention compared with those who did not. In contrast, pre-emptive analgesia in the narrow sense addresses only a small portion of the perioperative period, such as the time of incision or the time of surgery. Clinical and laboratory studies of pre-emptive analgesia defined in this manner typically administer identical analgesic interventions at different times to test and control groups, where typical times would be preincision and postincision or preoperatively and postoperatively. Subjects in such trials could receive considerable benefit from the intervention provided to the control group. Of late, trials like this are considered tests of pre-emptive analgesia as opposed to preventive analgesia. Meta-analyses of clinical trials with a pre-emptive structure have been conflicting, and the most recent is supportive of pre-emptive epidural analgesia, local anesthetic infiltration, and nonsteroidal antiinflammatory drug (NSAID) administration ( Figure 72-1 ). Another meta-analysis demonstrated that studies with a preventive design as opposed to a pre-emptive design were more likely to lead to measurable benefits, particularly for use of N -methyl-D-aspartate (NMDA) antagonists. A summary of gabapentinoid trials indicates the potential of this drug class, apart from its immediate benefits, to reduce chronic postsurgical pain. In interpreting data from any one of these studies, the timing and duration of the analgesic intervention may mean little if the intervention is not capable of preventing sensitization of the nociceptive pathways.

Summary of Results from Recent Meta-Analysis of Preemptive Analgesia. The plot indicates the effect size (standardized mean difference) for pre-emptive treatment compared with control and the 95% confidence interval. For each intervention and outcome measure, the total number of subjects included in the meta-analysis and the significance of the result are indicated. Results when all three outcomes are combined are given at the bottom. NMDA, N -methyl-D-aspartate; NSAIDs, nonsteroidal antiinflammatory drugs.

(Adapted from Figures 1 to 4 of Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005;100(3):757–73.)

Motivation for Pre-Emptive Approaches

The motivation for pre-emptive analgesic strategies is twofold. First, one seeks to minimize perioperative pain as well as pain during the typical recovery period for a given surgical procedure. Apart from the relief offered to patients, there is the expectation of reaping any functional benefits that may be associated with effective analgesic therapy. Second, pre-emptive analgesic approaches recognize that acute painful events can lead to long-term painful consequences, where pain persists even when tissue healing appears complete. Although the best known long-term painful syndromes are associated with limb amputation, in which about 70% of patients report pain 1 year after surgery, long-term painful sequelae are reported for many other types of surgery. In general, prior painful experience is predictive of increased pain and analgesic use after subsequent surgery. Even relatively limited surgery can lead to long-term alterations in the response to noxious stimuli. For example, pain-related behavior is increased during vaccination for boys who previously underwent circumcision compared with those who did not. Pain is reported 1 year after surgery in at least half of patients undergoing major thoracotomy or breast surgery. About half of patients undergoing lower abdominal surgery will still report some degree of residual pain several months after the surgical procedure. Inguinal herniorrhaphy is associated with residual pain in 25% of patients 1 year after surgery. Even low levels of residual pain are associated with decreases in activity and perception of health. Thus long-term alterations in pain perception occur frequently after a broad range of surgical procedures, and these alteration may negatively affect quality of life. These long-term changes in pain perception motivate the use of pre-emptive analgesia. The underlying hypothesis is that such changes can be prevented by initiating an effective analgesic regimen before the onset of the procedure and maintaining it for a sufficient duration.

Options

Therapeutic options for pre-emptive analgesia include virtually all analgesic modalities and pharmacologic classes, individually and in combination. Analgesics can be administered systemically, at the site of surgery, along a peripheral nerve, or neuraxially. Analgesics include opioids, alpha-2 agonists, NMDA antagonists, muscarinic stimulation by administration of an anticholinesterase, NSAIDs, anticonvulsants, and local anesthetics.

Timing of the initiation of the analgesic regimen is central to the use of pre-emptive analgesia. Because most practitioners recognize the need for postoperative analgesia, most studies of pre-emptive analgesia have emphasized interventions initiated before the start of surgery and lasting for some portion of the surgical procedure. However, the quality of postoperative analgesia may be an important factor. Periods of intense pain on emergence or during recovery may lead to sensitization of the nociceptive pathway, overwhelming the benefits of preventing intraoperative sensitization. Conversely, highly effective postoperative analgesic regimens could mask the benefits of intraoperative efforts to prevent sensitization and even limit sensitization in control groups. For procedures characterized by a long and painful postoperative course, preventing sensitization in the postoperative period may be just as important as doing so intraoperatively. For analgesics that can take some time to exert their full effect (e.g., NSAIDs, see further on), initiation of the analgesic regimen well in advance of the start of surgery is required for pre-emption to occur. Along with the decision of when in the perioperative period to initiate analgesic therapy, the necessary dose and duration of analgesic therapy to prevent sensitization during each phase of the perioperative period require elucidation and may vary with the type of surgery.

Laboratory Evidence of Pre-Emptive Analgesia

Laboratory studies have suggested the clinical applicability of pre-emptive analgesia by identifying the underlying mechanisms and the factors that may play important clinical roles. Painful stimuli can sensitize both the peripheral and central components of the nervous system. In the periphery, repeated applications of noxious stimuli increase the magnitude of the response to subsequent applications of the same stimulus. There is a complex interaction between peripheral nociceptors and inflammatory mediators released in response to tissue injury that can enhance the response of peripheral nociceptors. This enhanced response can be attenuated with local anesthetics, opioids, and NSAIDs as described later on.

Neurons in the dorsal horn of the spinal cord exhibit a biphasic response to formalin injection of the skin. Intrathecal opioids are effective at preventing both phases of this response. However, the second phase is still prevented even after administration of an opioid antagonist after the initial response, which indicates that alteration of neural behavior by a noxious stimulus can be prevented. Substance P and excitatory amino acid transmitters acting at NMDA receptors play a crucial role in sensitizing neurons in the dorsal horn. Local anesthetic infiltration before formalin injection can limit longer term pain-related behavior, but when noxious inflammatory stimuli of longer duration are used, longer term reductions in pain-related behavior are seen only with local anesthetics whose duration of action matches that of the noxious stimulus. Administration of local anesthetic before nerve section can decrease pain-related behavior for a considerable period of time. However, in a laboratory model of incisional pain, rats receiving intrathecal opioids or local anesthetic before an incision in their hindpaw exhibited decreased wound hyperalgesia on the day of surgery, but not longer, when compared with those who received the same analgesics immediately after incision.

Many explicit laboratory tests of pre-emptive analgesia have been negative. However, the quality and duration of the pre-emptively administered analgesic relative to the intensity of the experimental stimulus may play an important role in whether pre-emptive analgesic administration is beneficial. Moreover, the extent that laboratory models of surgical pain replicate the nociceptive processing that takes place during major surgical procedures has not been fully determined. For example, a new rat model of thoracotomy has been successful in demonstrating the capacity of systemic and intrathecal analgesics to decrease long-term pain.

Laboratory studies also delineate the contribution of the general anesthetics to pre-emptive analgesic effects. Clinically effective concentrations of volatile anesthetics do not prevent central sensitization, but they can potentiate the effects of neuraxial opioids. Nitrous oxide has been shown to have a pre-emptive analgesic effect that is not realized when a volatile anesthetic is also administered.

Clinical Evidence of Pre-Emptive Analgesia

There are hundreds of studies evaluating the clinical use of pre-emptive analgesia. These vary considerably with respect to timing, intensity, and duration of the intervention, the analgesic used in the control group, and the type of surgery. We will evaluate systemic interventions with opioids, NMDA antagonists, gabapentinoids and NSAIDs, and regional administration of local anesthetics and opioids.

Systemic fentanyl administered as a bolus before incision and maintained with an infusion reduced wound hyperalgesia 24 and 48 hours after surgery when compared with control subjects, all of whom received identical postoperative opioid analgesia. Consequently, it is surprising that multiple studies of pre-emptive opioid administration for hysterectomy have, collectively, been somewhat disappointing; multiple meta-analyses have revealed no benefit of preincisional opioid administration (see Figure 72-1 ) and even a paradoxic effect in favor of analgesics administered postoperatively. However, in all of these studies, the same bolus dose of opioid was administered either before incision or at the conclusion of surgery. Consequently, especially because many of the studies used relatively short-acting opioids, it is conceivable that intraoperative opioid levels were inadequate for preventing sensitization in the intervention group. Furthermore, the group receiving an opioid bolus at the conclusion of surgery would have been relatively comfortable during the often painful period immediately after surgery when sensitization is still ongoing. When intraoperative opioid levels were maintained with an infusion, reduced pain and analgesic consumption were seen for the 48 hours after surgery. An additional potentially confounding factor is that acute opioid tolerance could have developed in the group receiving opioids before incision, rendering analgesics administered in the immediate postoperative period less effective.

NMDA antagonists have the potential to limit central sensitization and, through an additional consequence of their action at the NMDA receptor, decrease the acute tolerance that develops with opioid administration. Systemic ketamine administered before surgery can decrease wound hyperalgesia measured 48 hours after surgery, although this was not always associated with decreases in pain. Other studies with lower doses of ketamine conflict as to whether pre-emptive ketamine administration by itself can lead to reductions in postoperative pain. Systemic ketamine used in combination with epidural analgesics led to persistent reductions in postoperative pain. Preoperative systemic dextromethorphan decreased pain and analgesic consumption in a dose-dependent manner and augmented the efficacy of performing surgery under epidural blockade with a combination of lidocaine and morphine. A meta-analysis of eight trials comparing preincisional administration of ketamine or dextromethorphan with postincisional administration found no consistent benefit of preincisional ketamine administration but did observe a benefit for the two trials of dextromethorphan that were included in the meta-analysis. This negative result for NMDA antagonists was echoed (see Figure 72-1 ) by a more recent meta-analysis. However, studies of NMDA antagonists that were more preventive in their design were associated with beneficial effects. Importantly, systemic NMDA antagonists can also enhance the benefits of epidural analgesia.

Peripheral inflammation in response to tissue injury is painful and can enhance the sensitivity of the peripheral nociceptors, which are themselves a source of proinflammatory mediators. The analgesic effects of NSAIDs are due to both their ability to reduce peripheral nociceptor output by modulating the peripheral inflammatory response and their more central effects. A considerable number of studies demonstrate the ability of NSAIDs to reduce perioperative pain and limit the need for other analgesics. Although the mechanism of action of NSAIDs suggests that administering them before the onset of surgery should be beneficial, the available studies indicate that expectations and strategies for the use of these drugs in a pre-emptive manner need revision.

In an initial meta-analysis of 19 trials of preincisional versus postincisional administration of NSAIDs, only four studies demonstrated any reduction in pain, decreased analgesic consumption, or delay until first analgesic request with preincisional NSAIDs. However, a more recent meta-analysis of 17 studies (see Figure 72-1 ) was more supportive of a pre-emptive analgesic effect. One favorable study not included in the first meta-analysis compared the effects of intravenous NSAID administration 30 minutes before induction to its administration at the conclusion of surgery. Pre-emptive administration resulted in improvement in pain scores, increased time until first analgesic request, and decreased analgesic consumption for the 4-hour period of study. A follow-up study demonstrated similar results when the same NSAID was administered either 30 minutes before induction in the intervention group or at the time of induction, as opposed to the conclusion of surgery, in the control group, which emphasizes the importance of timing in observing a pre-emptive effect.

The gabapentinoids gabapentin and pregabalin appear to contribute to perioperative pain relief in studies in which they were used in a preventive fashion. Decreased pain and opiate sparing have been demonstrated for lumbar spine surgery, breast surgery, and laparoscopic surgery. Preventive use of gabapentin in combination with local anesthetics has demonstrated a reduction in acute pain as well as chronic pain 6 months after breast surgery. A recent meta-analysis supports the hypothesis that gabapentinoids can reduce the incidence of chronic postsurgical pain.

Local anesthetic infiltration is a relatively safe and simple analgesic modality that can decrease peripheral sensitization and reduce or prevent the nociceptor barrage at the spinal cord. A local anesthetic administered before a surgical procedure can have benefits that outlast the duration of action of the local anesthetic. Pain-related behavior by boys during vaccination is reduced in those who previously underwent circumcision after application of a local anesthetic cream compared with those who did not receive a local anesthetic for the procedure. Local anesthetic infiltration with bupivacaine before surgery for inguinal herniorrhaphy reduced wound hyperalgesia compared with general anesthesia alone. This difference was seen 10 days after surgery and was superior to spinal anesthesia. Patients undergoing inguinal herniorrhaphy under general anesthesia who received preincisional infiltration of the incision site with lidocaine waited longer until their first analgesic request and were less likely to request analgesics than those who received lidocaine infiltration at the time of closure. When inguinal herniorrhaphy is performed under spinal anesthesia, subjects who had an ilioinguinal–iliohypogastric nerve block experienced less pain and had decreased analgesic consumption during the first 2 postoperative days. Pre-emptive incisional or peritoneal use of local anesthetic for laparoscopic surgery may also have benefits that can be long-term.

A systematic review of studies using local infiltration that contrasted interventions performed before incision with those performed before the conclusion of the procedure was generally not supportive of preincisional interventions with local anesthetics, except during herniorrhaphy. A subsequent meta-analysis was generally not supportive of preincisional local anesthetic infiltration compared with postincisional infiltration. Another review stressed the importance of using a local anesthetic block of adequate strength and duration. A more recent meta-analysis (see Figure 72-1 ) was more supportive of pre-emptive local anesthetic infiltration of the wound.

Neuraxial blockade with a single dose of local anesthetic placed in the subarachnoid space produces profound but not complete blockade for the duration of surgery and the immediate postoperative period. The use of spinal anesthesia may confer some longer term benefits, but when administration of a spinal anesthetic either before the start of surgery or after its conclusion was compared, only small differences in analgesic use were sometimes seen.

The use of epidural catheters for the neuraxial administration of local anesthetics, opioids, and other drugs continues to be an important technique for perioperative pain control for major surgery. Because epidural catheters are often placed to provide postoperative pain relief and have been shown to do this effectively, studies involving pre-emptive epidural analgesia often focus on the somewhat narrower question of whether there is a benefit to intraoperative use of the epidural catheter. Epidural anesthesia by itself may confer an analgesic benefit that outlasts the duration of the blockade. Neuraxial fentanyl administered immediately before incision reduced pain in the immediate postoperative period compared with the same intervention given shortly after incision. A single preoperative dose of epidural morphine appears to have analgesic benefits that outlast its duration of action for certain types of procedures. When local anesthetic alone or in combination with opioids is administered through epidural catheters during surgery, the impact on postoperative analgesia is often, but not always, limited, as reflected by meta-analyses (see Figure 72-1 ) with different conclusions regarding the benefits of pre-emptive epidural analgesia. However, with the exception of studies addressing long-term pain after amputation or major thoracotomy (see further on), studies addressing pain or functionality after discharge are rare but often favorable.

Given the aforementioned ability of pre-emptively administered local anesthetic to limit long-term pain-related behavior after nerve section in the laboratory, it might be anticipated that a pre-emptive analgesic approach might be particularly effective in preventing the long-term pain syndromes that are associated with thoracotomy and limb amputation. Initiation of epidural blockade before the onset of surgery as compared with after surgery and then maintained for 48 hours in both groups has had a positive long-term impact on the rate of post-thoracotomy pain. In contrast, a study that initiated epidural analgesia before incision or at the start of closure and then maintained the block until thoracostomy tube removal demonstrated only short-term analgesic sparing effects when the two groups were compared. However, this study reported substantially lower rates of post-thoracotomy pain than the prior studies. Several early studies of long-term pain after amputation demonstrated a benefit of pre-emptive approaches that was not observed in a larger study with a somewhat weaker intervention. The editorial that accompanied this last study reviews the related literature in detail and concludes that the likelihood of benefits when epidural analgesia is used to prevent long-term pain after limb amputation varies with the quality and duration of the blockade.

Areas of Controversy and Uncertainty

As already emphasized, pre-emptive analgesia continues to be a controversial area with a large and growing clinical and experimental literature that can be selectively mobilized to support multiple points of view. Whether pre-emptive anesthesia is defined in the wide (preventive analgesia) or narrow sense, there is a relative lack of studies that address long-term outcomes, particularly other than pain and analgesic use. However, even for rather narrow definitions of pre-emptive analgesia, long-term benefits have been demonstrated for major abdominal and thoracic surgery. Apart from the timing of the intervention, there is considerable debate about the magnitude of the intervention. This applies to both the initial drug doses and to whether this level of intervention is maintained throughout surgery and into the postoperative period. Interventions must be capable of preventing sensitization of the pain pathways. Studies defining and testing pre-emptive analgesia in the narrow sense generally use interventions and study designs that permit patients in both the control and intervention groups a comfortable transition to the postoperative period. Consequently, even the control groups often receive an analgesic regimen that might be expected to limit peripheral or central sensitization or both. When consideration is given to outcomes other than pain, it remains uncertain how much any benefit of the intervention is due to reductions in pain and how much is a consequence of other effects of the intervention. For example, intra-articular local anesthetic infiltration reduces postoperative pain, and this pain reduction is associated with improved tissue oxygenation ; on the other hand epidural analgesia modulates a number of physiologic variables that may contribute to favorable outcomes. Lastly, few economic data are available to guide the choice of interventions and to assess the cost of inadequately treated pain.