The understanding of postoperative pain has evolved greatly during the past half century. Many laboratory investigations have established that peripheral tissue injury during surgery can trigger a prolonged state of spinal cord excitation. A reduction in neuronal thresholds in the central nervous system (CNS) is thought to amplify pain in postsurgical patients. Preemptive analgesia is an antinociceptive treatment targeted to block CNS hyperexcitability and leads to a reduced postoperative pain state. This treatment also has the long-term goals of facilitating rapid return to usual baseline function as well as decreasing the risk of chronic pain. However, despite numerous investigations, the clinical relevance of such treatment remains in controversy.

The modern concept of preemptive analgesia was based on experimental animal studies demonstrating CNS plasticity and sensitization after nociception. It was theorized that postoperative pain is amplified by continuous processing of afferent input. The preemptive administration of antinociceptive treatments aims to alter the processing of this afferent input and in turn reduce postoperative pain.¹

An editorial in the 1980s postulated that (1) a reduction in massive small-fiber input into the CNS during surgery would prevent a central sensitization, and (2) analgesia that is present preoperatively has the potential to render prolonged effects, well beyond the known time frame of drug action.² Consistent with this proposal were experimental data by Woolf and Wall demonstrating that low doses of opioids, given before a painful stimulus, can effectively prevent central sensitization.³ In contrast, much higher doses of opioids are required to suppress an already sensitized spinal cord. Since Wall’s editorial, a large number of investigations have been carried out with overall equivocal results. There has been an appreciation for the multiple variables that influence postoperative pain as well as short-term and long-term goals of preemptive analgesia. In the short term, a reduction in pain scores, analgesic consumption (usually opioids) is sought, and in the long run, a quicker return to function and reduction in chronic pain is desired. In the absence of significant preoperative pain, the surgical incision does remain the key stimulus of central sensitization in most operations that triggers multiple mediators, which serve to extend a peripheral and central excited neural state into the postoperative period. Therefore, in the majority of preemptive studies, the preincisional therapy is not continued into the postoperative period.

PERIPHERAL SENSITIZATION

The establishment of sensitization in the periphery involves the transition of high-threshold nociceptors into ones of low threshold, as induced by the release of various chemicals soon after surgical incision.⁴ At the site of damage, a complex array of inflammatory mediators, as outlined in Table 50-1, is mobilized from injured tissue, and others are delivered by the circulation.⁵ Small-diameter primary afferent neurons, Aδ and C fibers innervating the region of insult, subsequently enter a state characterized by ongoing discharge and excitation elicited by suprathreshold stimulation (hyperalgesia).⁶ On a molecular level, it is suggested that the phosphorylation of voltage-gated sodium and potassium channels works to reduce the action potentiation threshold and refractory period while enhancing repetitive firing.⁷ The center of a surgical wound, which is the primary zone of injury, would be expected to demonstrate static mechanical hyperalgesia.

Immediately surrounding the primary zone is an area of erythema, edema, and hyperalgesia initiated by axon reflexes.⁸ Activation of C fibers lead to neurogenic inflammation as a result of antidromic release of neuropeptides (e.g., substance P) from collateral axons.⁹ Substance P release degranulates histamine and serotonin and causes vasodilation to further fuel peripheral sensitization. The skin, muscle, tendons, and other deep somatic structures become sore, achy, and tender. Clinically, patients refrain from movement and deep breathing and guard their surgical sites. With ensuing healing, inflammatory mediators decrease and primary afferent neurons resume their usual high threshold state, emphasizing the normal reversibility of peripheral sensitization.

CENTRAL SENSITIZATION

Peripheral sensitization provoked by surgical incision leads to massive and prolonged afferent nociceptor input into the CNS, particularly the spinal cord.¹⁰ C fibers release neuropeptides (substance P, neurokinin A, calcitonin gene-related peptide) and excitatory amino acids (glutamate, aspartate) on second-order neurons (nociceptive specific and wide dynamic range) in the dorsal horn.¹¹ Second-order neurons enter a state of increased spontaneous firing, prolonged cell discharge (“windup”), reduced thresholds, and expansion of peripheral receptive fields.¹² This process is central sensitization at the level of the spinal cord, which now abnormally amplifies future incoming impulses (Table 50-2).

Sensitized wide-dynamic-range (WDR) neurons receive input not only from Aδ and C fibers but also from low-threshold Aβ fibers (mediating light touch). Such convergence results in an innocuous stimulus being perceived as painful (allodynia).¹³ Receptive fields are expanded to involve normal-appearing areas surrounding the primary site of tissue injury. Such secondary hyperalgesic zones are characteristically painful to light touch, indicating that large Aβ fibers are transmitting impulses to a spinal cord that is sensitized.¹⁴ Dynamic allodynia is established through the convergence of Aβ and C fibers on hyperexcitable WDR cells. It should be noted that peripheral sensitization also causes Aδ and C fibers to respond to low-intensity stimuli. Central sensitization alters dorsal horn cell processing such that impulses from large-diameter, low-threshold, mechanoreceptive afferents fibers (Aβ) produce pain. Under physiologic conditions, central sensitization, similar to peripheral, is reversible.

The persistence of central sensitization has clinical correlation with regards to chronic pain. For example, evidence suggests that patients with fibromyalgia have a dysfunction in the central nociceptive system with extensive disinhibition. Regional blood flow studies, levels of substance P, and NMDA (N-methyl-D-aspartate) receptor activity have all been shown to be altered in those suspected to have fibromyalgia. The ongoing research supports the importance of central sensitization, but the pain mechanisms in this syndrome are still a matter of ongoing study.¹⁵

CELLULAR AND BIOCHEMICAL MECHANISMS OF CENTRAL SENSITIZATION

The prevention of central sensitization forms the basis of preemptive analgesia. Central changes produced by tissue damage and noxious stimulation associated with surgery have been the focus of intense investigation because of the potential to result in prolonged recovery and possibly chronic pain. There is a fair degree of confidence concerning molecular physiology underlying central neuroplasticity deserving of further discussion.

As indicated previously, neuropeptide and excitatory amino acid release in the dorsal horn initiates central sensitization. Both types of ligands lead to increases in intracellular calcium.¹⁶ Neuropeptides bind to neurokinin-G protein–coupled receptors that activate voltage-gated calcium channels to enhance the flux of calcium ion into the dorsal horn cells. Similarly, aspartate interaction with the NMDA receptor leads to increases in intracellular calcium, which is thought to be the predominant mechanism responsible for persistent abnormal neuronal hypersensitivity after noxious stimulation.¹⁷

In addition, glutamate interacts with metabotropic receptors to activate phospholipase C (PLC), a common second messenger system.¹⁸ Receptor-triggered activation of PLC results in hydrolysis of polyphosphatidylinositol (a cell membrane phospholipid) into two intracellular messengers, inositol triphosphate (IP₃) and diacylglycerol (DAG). Whereas IP₃ stimulates the release of calcium from internal cellular stores, DAG activates protein kinase C (PKC). PKC is enzymatically active only in the presence of calcium. Increased calcium concentrations, together with PKC, result in increased expression of proto-oncogenes, such as c-fos and c-jun.¹⁹ The gene products of c-fos and c-jun regulate the encoding of dynorphin and enkephalin peptides. These peptides are then thought to mediate long-term changes in cellular function.^20,21 Finally, PKC itself can phosphorylate NMDA receptors, leading to sustained alterations in cell membrane conduction²² (Table 50-3). Cellular memory for pain (long-term potentiation) results in enhanced response to noxious stimulation.

NMDA ANTAGONISTS

The concept of preemptive analgesia makes ketamine a very suitable candidate for investigation of postoperative pain reduction. Ketamine is a noncompetitive antagonist of the NMDA receptor and thereby reduces associated ion channel conduction.²³ The NMDA receptor is thought to be considerably involved in central pain processing and spinal cord neural plasticity. Preclinical models strongly suggest the importance of administering specific NMDA antagonists before noxious stimulation to effectively block central sensitization.²⁴ Clinical trials have shown significant benefit in the management of acute postoperative pain even when administered after surgical insult.²⁵ Unlike other more selective NMDA antagonists (e.g., MK-801), ketamine does not lead to reduced spinal Fos protein.^26,27

Mechanistically, the neuropharmacology of ketamine is complex. Ketamine may inhibit sodium and L-type calcium channels, a-amino-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), kainate receptors, neuronal uptake of norepinephrine as well as exert agonistic properties at the opioid receptors.²⁸ Ketamine also inhibits the NMDA receptor when the channel is in an open state.^29,30 This latter point may help explain the clinical findings that ketamine is effective not only in reducing central facilitation after an acute noxious input but also in chronic painful conditions (e.g., postherpetic neuralgia).^30,31

A large meta-analysis in 2004 by Subramaniam and colleagues summarized that ketamine certainly has a role as an effective adjuvant to narcotics in postoperative pain control. Intravenous (IV) ketamine infusions decreased IV and opioid requirements in 6 of 11 studies. A majority of studies also demonstrated that bolus ketamine and epidural ketamine have beneficial effects.³² IV ketamine (0.5 mg/kg bolus with 0/25 mg/kg/hr) has also been shown to be an effective complement to traditional epidural analgesia in patients undergoing major digestive surgery.³³

However, ketamine use alone has not consistently been shown to reduce postoperative pain scores or analgesic usage. A preemptive effect would consist of a reduction of secondary hyperalgesia by diminishing or ablating central sensitization. Prolonged analgesic effects would then be appreciated. Tverskoy and colleagues administered preincisional ketamine intravenously and demonstrated a reduction in wound hyperalgesia compared with control participants, by measuring pain threshold to pressure.³⁴ Despite profound reductions in wound hyperalgesia after abdominal hysterectomy, there was no significant effect on postoperative pain or opioid consumption. Similar results in kidney donors have been reported later by Stubhaug and coworkers, which have led investigators to question the relevance of central sensitization in postoperative pain.³⁵

However, studies not assessing secondary hyperalgesia have been able to show a moderate reduction in postoperative opioid consumption lasting between 24 and 48 hours with early administration of low-dose ketamine (0.15 mg/kg).³⁶ Recent attention focused on the effect of preoperative ketamine for patients undergoing laparoscopic procedures. Kwok and colleagues randomized 135 patients to receive 0.15 mg/kg of ketamine bolus preincision versus postclosure bolus and placebo for gynecologic laparoscopic surgery. When assessed postoperatively, the preincision group had lower mean morphine consumption with no change in hemodynamic variables or side effects (P <0.04).³⁷ The extended benefits of ketamine suggest a preemptive effect, yet diminution of secondary hyperalgesia has not correlated with pain reduction. Noncompetitive interaction of ketamine at the NMDA receptor may limit the development of acute opioid tolerance.³⁸ This may offer a partial explanation for the observed decrease in postoperative opioid consumption.

Similarly, epidural ketamine can result in prolongation to first analgesic request, and reduction in postoperative analgesic needs in patients after total knee replacement and hysterectomy.³⁹ These beneficial effects appear to be independent of whether ketamine is administered before or after incision.⁴⁰ Both studies administered generous doses (30–60 mg) and may still be adequate to ablate central sensitization even after it has been initiated. Reduction of wound hyperalgesia was not assessed in either study. Epidural ketamine has also been assessed in patients undergoing lower limb amputation procedures. Postoperative pain was reduced in all patients receiving epidural analgesia preoperatively. However, immediate postoperative pain and mechanical stump sensitivity were lower in a group receiving epidural ketamine. Long-term effects of ketamine at 1-year follow-up were inconclusive.⁴¹

The search for other NMDA antagonists has also recently gained attention. Limited studies using preincisional dextromethorphan showed promise. Helmy and Bali found a statistically significant reduction in postoperative meperidine patient-controlled analgesia (PCA) use in patients undergoing elective upper abdominal surgeries who had received 120 mg of preincisional intramuscular dextromethorphan.⁴² Further research into the efficacy of dextromethorphan in this setting is needed.

OPIOIDS

Preclinical studies have evaluated both systemically and spinally administered opioids in their ability to prevent central facilitation. Neuraxial opioids are known to yield significant dose-dependent analgesia via modulation at the dorsal horn of the spinal cord. Opioids render analgesia at the level of the spinal cord by two distinct mechanisms: (1) preventing the release of excitatory neurotransmitters from small, primary afferent fibers and (2) hyperpolarization of second-order neurons.⁴³ Intraspinal opioids would be reasonable to investigate as agents that may produce preemptive analgesia. Systemically administered opioids are believed to have a more complex mechanism of action that is not fully understood.⁴⁴ Supraspinal sites have been implicated in studies of animals with high-spinal transections. Supraspinal opioid targets activate descending inhibitory pathways, which lead to dorsal horn modulation.⁴⁵ Unknown is the impact of this descending inhibition on the release of excitatory neurotransmitter from primary afferent fibers or the response of dorsal horn cells. CNS modulation is agreed to be the main mechanism of the action of opioids, but peripheral opioid receptors may contribute to analgesia. Aside from intraarticular application, opioid interaction with peripheral receptors does not appear to manifest in clinically significant pain reduction⁴⁵ and would indicate that peripheral sensitization may be modestly affected by systemically or neuraxially administered opioids. Limited new research has been conducted in this area.