Abstract
Postoperative pain remains a significant problem for patients and a challenge for anesthesiologists and acute pain medicine specialists. Despite advancements in the last two decades with increased use of multimodal analgesic regimens, advancements in regional anesthesia, and use of continuous analgesic infusions postoperatively, certain subgroups of patients will go on to develop chronic postoperative pain. Sensitization of peripheral and central pain pathways contribute to the development and perpetuation of pain after surgery. Understanding the potential benefit of preventive analgesia to provide pain relief before, during, and after a noxious insult is necessary to attenuate pain processing in both peripheral and central neurons. Further work is necessary to fully elucidate the mechanisms of these sensitization pathways. Novel therapeutic drug discovery and clinical efficacy trials are necessary to advance the field for improved perioperative pain treatment.
Keywords
central sensitization, chronic postoperative pain, hyperalgesia, NMDA receptor, peripheral sensitization, preemptive analgesia, regional anesthesia
One goal of the perioperative physician anesthesiologist is to provide sufficient analgesia during a surgical procedure so that it can be performed at the highest surgical standard with the least possible impact on the patient. This objective includes the prevention of intraoperative pain, as well as short- (acute) and long-term (chronic/persistent) postoperative pain. Over the past 30 years, many strategies have been employed toward this end; unfortunately, the prevalence of postoperative pain remains problematic, with at least half of patients reporting moderate to severe pain at the time of discharge. Despite many postoperative pain studies in basic science labs and clinical trials, there remains no “best” approach. These failures can be attributed to a multitude of factors, including the study design of clinical trials, an incomplete understanding of the basic neurophysiology of the surgical injury, the semantics of the terminology used to describe the phenomena, and understanding the concept of what constitutes postoperative pain.
Terminology
Preventive analgesia: Preventive analgesia is generally defined as an antinociceptive treatment that attenuates pain from high-intensity noxious stimuli before, during, and after the insult. The goal of preventive analgesia is to attenuate afferent input produced by the peripheral nervous system that can alter peripheral or central sensory processing. This afferent input, left unchecked, can cause central sensitization and subsequent chronic postsurgical pain. There are two phases to the noxious stimuli: the primary phase during which the noxious stimuli is related to the surgical injury itself (cutting, retracting, stretching, etc.), and the secondary phase during which the ongoing noxious stimuli is produced by the release of chemicals, including inflammatory mediators from damaged tissue ( Fig. 11.1 ). The secondary phase can begin during the intraoperative period and extend long into the postoperative recovery period (see Fig. 11.1 ). The duration of the postoperative recovery period and severity of pain depends on many factors, including the type and extent of the surgical operation, the immunological and nutritional status of the patient, the baseline psychological profile, as well as the associated medical comorbidities such as preexisting pain and drugs used to treat pain. The importance of addressing and treating the two phases of the injury is borne out in the literature and has prompted the evolution from “pre-emptive” to “preventive” analgesia.
Many advances have been made toward understanding the pathophysiology of nociceptive pathways. Both physicians and basic science researchers have become more knowledgeable about the nociceptive mediators that act in the periphery and activate the primary nociceptive afferent, as well as those that act centrally at the level of the spinal cord and brain. We now appreciate that tissue injury produces changes in the peripheral afferent neuron and in the spinal cord, both contributing to prolonged excitability. This hypersensitive state can persist for days to months, and contributes to acute and chronic postsurgical pain, a process referred to as peripheral and central sensitization (see Chapter 1 , Chapter 2 for details).
Pathophysiology of Preventive Analgesia
Postinjury Sensitization
Sensitization can occur in both the peripheral and central nervous systems (CNS) following a surgical injury. The relative contribution of each component is a matter of debate. However, following tissue injury, gene expression is altered and mediators are released to activate the peripheral nociceptive afferent. The continued activation of these afferents enhances the patient’s response to further stimuli. The inflammatory mediators can activate and increase the sensitivity of the nociceptors, thereby changing the nociceptive threshold of the afferent. Persistent activation can also lead to alterations in the neurophysiological properties of the primary afferent itself. Peripheral sensitization refers to the summation of these processes.
There are a number of events that occur on the cellular level that are responsible for peripheral sensitization. Transient receptor potential vanilloid (TRPV) receptors on small C fibers are nonselective cation channels. TRPV receptors are known to play an important role in peripheral sensitization and, thus, are prime targets for novel analgesics. They are activated by repeated heat stimulation, acidic environments, and a wide variety of mediators found in postoperative healing tissues (prostaglandin E2, serotonin, bradykinin, epinephrine, adenosine triphosphate, interleukin-1a, interleukin-6, tumor necrosis factor, chemokines, and nerve growth factor). Activation of TRPV channels results in a painful burning sensation. The release of these mediators also increases the magnitude of Na + current in sensory neuron voltage-gated sodium channels. The activation of TRPV and these Na + channels begin a vicious circle that culminates in increased pain. Both sensory neuron-specific sodium channels and TRPV receptors can be phosphorylated by intracellular kinases (protein kinase C or tyrosine kinase), thereby potentiating the release of excitatory amino acids and peptides from sensory afferents and accentuating the pain. The inflammatory activation of TRPV receptors and sensory neuron-specific sodium channels results in vasodilatation and edema. The neurogenic inflammation is mediated by a calcitonin gene-related peptide, substance P, and neurokinin A, and can further sensitize the nociceptive afferents, leading to allodynia or hyperalgesia.
Hypersensitivity and alterations also take place in the CNS, the spinal cord, and supraspinal structures as a result of a surgical injury. Following a tissue injury, such as an incision through the skin, fascia, and muscle, a subset of A-delta and C fibers become spontaneously active and barrage the second-order neurons in the spinal cord. In turn, these neurons release excitatory neurotransmitters, which increase the amplitude of the spinal cord neuron response and lower the response threshold for further stimuli. Therefore the response of the dorsal horn neurons to a particular stimulus—be it noxious (hyperalgesia) and/or innocuous (allodynia)—is altered, and perception of the painful stimulus is increased in intensity as well as duration. The injury also results in alterations of dorsal horn neurons. These neurons react to nonnoxious stimuli as if they were noxious (allodynia) and to noxious stimuli (hyperalgesia) with an exaggerated response, but they also begin to respond to stimuli outside their original receptive field (secondary sites). There is evidence that C fiber input from an injury also causes formation of anatomic connections at the spinal cord level between neurons that respond to A-beta fiber transmission and neurons that respond to A-delta and C fiber transmission. Animal studies have shown that A-beta fibers from injured tissue begin to produce and release substance P, normally found in C fibers, and contribute to pain sensitivity. Central sensitization has two temporally distinct phases. An early phase of hypersensitivity is triggered by changes in glutamate receptor phosphorylation and ion channel properties. The second phase (longer lasting) involves transcriptional changes that result in the formation of new proteins responsible for prolonged pain hypersensitivity.
The development of central and/or peripheral sensitization after traumatic injury or surgical incision can result in amplification of pain, or pain greater than the magnitude anticipated postoperatively. Therefore preventing the establishment of altered central processing by analgesic treatment may, in the short term, reduce postprocedural or traumatic pain and accelerate recovery. In the long term, the benefits may include a reduction in chronic pain and improvement in the patient’s quality of recovery and overall function. Theoretically, providing analgesia to block the initial barrage of afferent produced by the surgical incision can result in a reduction of pain from minor or short-duration surgical procedures. However, surgical procedures that produce substantial tissue injury, resulting in the release of inflammatory mediators and peripheral or central sensitization, will require analgesic techniques that are in effect throughout the period of injury and recovery. Crile first discussed this concept at the turn of the century. Woolf established the neurophysiological basis of central sensitization after injury in a series of animal experiments, and Wall, in an editorial, suggested preinjury analgesia for the reduction of postinjury pain.
Preventive Analgesia in Clinical Investigations
Preventive analgesic studies compare the effects of continuous analgesic therapy when administered throughout the perioperative period versus preemptive analgesia, which refers to the administration in the preoperative period only, or when no treatment is provided.
Many studies and meta-analyses have been performed to determine if aggressive analgesia before surgery impacts postoperative pain scores or prevalence of chronic postoperative pain. Interestingly, in one large study, no benefit was noted in the preemptive group that was treated with nonsteroidal antiinflammatory drugs (NSAIDs), intravenous opioids, intravenous ketamine, peripheral local anesthetics, and caudal analgesia for postoperative pain relief. However, an N-methyl- d -aspartate (NMDA) receptor antagonist, dextromethorphan, did demonstrate a preemptive effect. Single-dose epidural studies showed some benefit, although in most of the trials, improvements were insignificant. The administration of continuous epidural infusion produced statistically improved pain scores, but did not support that preemptive analgesia was of greater benefit than applying the analgesic technique after the onset of surgery. Most of these studies do not support the concept of preemptive analgesia, although several do find a role for preventive analgesia.
A more recent meta-analysis, using more stringent inclusion criteria from the Cochrane collaboration, found a pronounced preventive effect with epidural analgesia, local anesthetic wound infiltration, and systemic NSAID administration, but had mixed results for opioids or systemic NMDA receptor antagonists ( Fig. 11.2 ). This was followed by a randomized controlled study, in which the use of perioperative parecoxib in lumbar spine surgery was shown to reduce postoperative opioid consumption, lower pain scores, and increase patient satisfaction with their analgesic regimen. Similar results in plastic, ambulatory, otolaryngologic surgery have been found with celecoxib. However, a meta-analysis of randomized controlled trials using perioperative NSAIDs or Cox 2 inhibitors demonstrated a reduction in postoperative pain scores with nonselective NSAIDs, but not with Cox 2 inhibitors alone. Cox 2 inhibitors were found to reduce postoperative morphine consumption, but were also associated with an increased risk of renal failure (number required to harm of 73). Additionally, in the trials that used ketamine and Cox 2 inhibitors, no significant difference was noted; however, three trials that used intravenous or intramuscular dextromethorphan and Cox 2 inhibitors had a reduction in either pain intensity or supplemental analgesic use in the postoperative period.
