New Concepts in Acute Pain Therapy

Introduction The pain that accompanies surgical procedures is often inadequately treated, can affect the perception of subsequent noxious stimuli, and can lead to more chronic painful conditions. Moreover, existing painful conditions and prior painful experiences, regardless of whether they are the current indication for surgery, can exacerbate the pain that accompanies surgical procedures. As the neurobiology of pain perception becomes better understood and applied clinically, it becomes clear why patients with chronic painful conditions could be at risk for a more intense pain experience following surgery. It is also becoming clear why patients, even those without preexisting conditions, can and do develop persistent pain following surgery. The neurobiologic principles that demonstrate why this takes place also argue that aggressive perioperative pain management can lead to long-term benefits in the form of decreased pain and speedier recovery following surgery. Studies that support this hypothesis are now becoming available. Several studies over the last decade make it clear that pain control for the more than 23 million surgical procedures performed each year has been and continues to be inadequate,1-3 with excessive pain estimated to be present about half the time and almost two-thirds of patients citing postoperative pain as their primary preoperative fear.4 One reason for this is that many aspects of the perioperative pain experience are transparent to health care workers. Health care personnel routinely underestimate a patient’s pain, and discrepancies between their estimates of pain levels and those reported by the patient tend to be the greatest for severe pain.5 The ability of caregivers to correctly assess pain in the nursing home is also poor,6 and may be further hampered when patients are cognitively impaired.7 Patients’ recollection of painful experiences are for the most part less than those reported at the time of the painful experience.8,9 Patients often do not make their pain known through requests for analgesics for reasons that have yet to be elucidated.10 For many of these reasons, pain is now being emphasized as the “fifth vital sign.” This increased emphasis on pain treatment may also have legal ramifications for physicians failing to properly treat a patient’s pain.11,12 The impact of the pain that accompanies surgery can extend well beyond the time when tissue healing appears complete.13 This can manifest itself in the form of increased sensitivity to noxious stimuli (hyperalgesia) and the experience of painful sensation from previously non-noxious stimuli (allodynia). Prior painful experience is a known predictor of increased pain intensity and analgesic use for subsequent surgery.14,15 Pain levels may be enhanced in patients with elevated levels of depression or anxiety.16 The process whereby the nervous system becomes sensitized to pain is active early in life and appears to persist throughout. Circumcised boys demonstrated a greater degree of pain-related behavior when receiving their vaccinations when compared with boys who were not circumcised.17 Long-term pain is classically known to persist following amputation of an extremity,18 and is often present following thoracotomy,19 mastectomy,20 laparotomy,21 herniorrhaphy,22 and orthopedic procedures.23 Apart from the actual discomfort experienced by the patient, even relatively low levels of persistent pain following surgery have been associated with decreased physical and social function as well as a decreased perception of overall health.16 Physicians who suspect that their patients may be experiencing residual pain following surgery should rule out other possibilities before engaging in long-term treatment of the pain and seek early consultation with a pain specialist if symptoms worsen or persist. Neurobiology of Acute Pain The peripheral nervous system (PNS) and the central nervous system (CNS) jointly contribute to the perception of pain. The PNS, spinal CNS, and supraspinal CNS can all modulate the impact of nociceptor activity through a variety of mechanisms (Figure 1). The extent of these interactions is not fixed and can vary in a use-dependant fashion. Painful sensation generally begins with some degree of stimulation of the peripheral nociceptors with signals that travel along the small myelinated A and unmyelinated C fibers whose soma lie in the dorsal root ganglion. The axons from these nerve fibers synapse in the dorsal horn of the spinal cord, with most interactions occurring in laminae I, II, and V.24 Signals travel from the dorsal horn to the thalamus along the spinothalamic tract. Large fiber input from other somatosensory modalities, as well as descending pathways, can modulate neural activity in the dorsal horn, thus “gating” the response to noxious stimuli.25 Some of the modulatory input to the descending pathways comes from the activation of opiate receptors in the periaqueductal gray matter and the rostroventral medulla of the brain. Signals from the thalamus travel to the primary and secondary somatosensory cortices as well as to the anterior cingulate gyrus. It appears that this region of the limbic system is active when stimuli are perceived as painful, regardless of the extent of activation of somatosensory cortex.26 To appreciate the long-term effects of a severe acute painful experience, it is necessary to understand the extent to which nociceptor activity is known to modulate activity at several points along the pain pathway. The peripheral nociceptors increase their activity in response to repeated stimulation,27 as well as the presence of a large variety of tissue factors that may be present following tissue injury.28,29 It may be that opportunistic opiate receptors are expressed in the periphery in response to chronic inflammatory states.30 The response of neurons in the dorsal horn is biphasic.31 The initial response is relatively brisk and is followed by a more prolonged phase of activity, which is often referred to as “windup” or “central sensitization.” Functionally, the initial pain response corresponds to the sharp well-localized pain that immediately follows the injury. The secondary pain response corresponds to the dull, poorly localized pain that follows sometime after injury. Importantly, if the initial response is prevented with an adequate dose of opiate, the secondary response is substantially attenuated, even if the effects of the opiate are reversed with naloxone. Prevention of the secondary pain response can also be accomplished with local anesthetic blockade.32 Blocking nociceptor input also appears to be an important factor in preventing more chronic pain states.33 Both substance P 34,35 and the excitatory neurotransmitter glutamate36 are known to participate in the process of sensitizing neurons in the dorsal horn. Little is known about how supraspinal portions of the pain pathway adapt to prior experience. Preemptive Multimodal Approach to Pain Relief The neurobiology of acute pain suggests several strategies for effective relief. First, there are several locations along the pain pathway that become sensitized by prior exposure to noxious stimuli, and pain therapy designed to limit sensitization should be targeted at these multiple sites (Figure 1). Pain therapy directed at multiple sites along the pain pathway is known as multimodal analgesia.37,38 Many of the published guidelines for the treatment of longer-term pain embrace this multimodal concept.39-41 Second, it is possible to limit sensitization of the pain pathways by initiating appropriate pain therapy before the onset of a noxious stimulus (Figure 2). This approach is often referred to as preemptive analgesia.42,43 The acute pain that accompanies surgical procedures represents an ideal setting for a preemptive multimodal approach to pain therapy. Not only is the timing of the noxious stimulus known in advance, but sensitization of the pain pathways is ongoing during surgery, despite adequate levels of general anesthesia with one of the volatile anesthetics.44 At the present time, there is no established protocol for a preemptive multimodal approach to acute pain management that encompasses all types of surgery. The strategy must be individualized with respect to the type of surgery, patient needs, and the available resources. Methods for providing acute pain relief include infiltration with local anesthetics, nerve block, neuraxial (subarachnoid or epidural) blockade, and administration of systemic medication (oral, subcutaneous, transdermal, intramuscular, or intravenous). The opioids and local anesthetic drugs are the most common pharmacologic tools for perioperative pain control. However, anti-inflammatory drugs (ketorolac), alpha2 agonists (clonidine or dexmedetomidine), and N-methyl-D-aspartate (NMDA) antagonists (dextromethorphan, ketamine) are playing an increasing role. The mainstay of acute pain therapy is still the opioids. Systemic opioids administered for treatment of acute surgical pain are typically administered intravenously immediately following surgery, and orally once patients are able to take oral medication. More important than the route is the timing of the analgesic dose. It is now accepted that “around-the-clock” dosing is more effective than as-needed dosing since the latter permits pain to return repeatedly, which, apart from the discomfort this causes, could further sensitize the pain pathways. The most effective means of doing this is with patient-controlled analgesia (PCA) where the patient is able to administer additional doses of analgesic, perhaps in addition to a background infusion of the analgesic. Opioids are often administered neuraxially, by themselves or in combination with other drugs, as boluses or infusions, with the duration of action of a single dose varying inversely as the fat solubility of the opioid.45 Local anesthetics are used for infiltration at the surgical site, for nerve block, and for neuraxial blockade. When catheters are left in place, continuous infusions of local anesthetics, often combined with other analgesics, are used for postoperative pain control. The most common of these techniques uses an epidural catheter placed at an appropriate interspace, usually prior to the start of surgery, through which analgesics are administered by a patient-controlled infusion (patient-controlled epidural analgesia). Postoperative analgesia is typically achieved with a mixture of local anesthetic and an opioid. It is not unusual for patients who receive some type of nerve block or neuraxial block to also receive a light general anesthetic during the course of surgery. The use of a regional technique in combination with a general anesthetic permits an extremely light plane of general anesthesia, blunting of the autonomic and endocrine response to surgery, and a smooth, prompt, and comfortable emergence. Impact of Acute Pain Therapy on Outcome There is a growing recognition that aggressive perioperative pain control can lead to improved long-term outcomes.46 However, clinical use of an analgesic regimen in a preemptive manner has been more controversial than the initial laboratory studies may have first suggested.47-49 One of the problems is that it is still debated as to what actually constitutes preemptive analgesia, although there is a growing appreciation that the most comprehensive efforts to prevent sensitization of the pain pathway over the entire perioperative period (Figure 2) are associated with favorable outcomes.50 Because many of the techniques for perioperative pain control involve the use of a regional anesthetic, either alone or in combination with a general anesthetic, some benefit to patients may also arise from properties of regional anesthesia not directly related to pain control.51 The primary example of this is the modulation of sympathetic nervous system activity when a local anesthetic is administered through an epidural catheter.52 Systemic opioids and NMDA antagonists administered prior to incision can lead to decreased wound hyperalgesia several days after surgery,53 and preemptively administered NMDA antagonists can decrease postoperative pain and analgesic requirements.54,55 Other studies have demonstrated that preemptive opioid administration can decrease postoperative pain at rest and, when the dose is sufficient, with activity.56 Administration of opiates targeted at opiate receptors outside of the CNS may be effective under certain circumstances.57 Local anesthetic applied to the surgical site before the onset of surgery can have effects that outlast the presence of local anesthetic at the surgical site. The use of a local anesthetic cream prior to circumcision is associated with a decrease in pain-related behavior at the time of vaccination.58 Local anesthetic infiltration of the surgical site with the long-acting local anesthetic bupivacaine prior to incision can lead to decreased wound hyperalgesia several days following surgery.59,60 Similar results have been obtained for nerve block of the surgical site.61 Local anesthetic infiltration of the incision sites prior to incision reduces postoperative incisional pain following laparoscopic surgery.62 However, local anesthetic infiltration at the conclusion of laparoscopic surgery is no more effective than saline. As indicated above, epidural analgesia is one of the best tools for aggressive perioperative pain control, and is commonly used by itself or in conjunction with general anesthesia for major procedures of the chest, abdomen, and lower extremities. Even if a general anesthetic is planned, the epidural catheter is typically placed prior to induction of general anesthesia, and mixtures of local anesthetic and opioid are administered as boluses or infusions. Because there is some controversy as to the efficacy of preemptive analgesia, many anesthesiologists do not administer medication through an epidural catheter during surgery. Another argument for not using epidural catheters to their fullest effect during surgery is the concern about the loss of sympathetic tone, despite evidence that neuraxial blockade can be beneficial in hemorrhagic shock.63 Preemptive administration of epidural opioid alone has led to benefits after mastectomy, thoracotomy, extremity surgery, and abdominal surgery.64-66 Combinations of epidural opioid and local anesthetic have demonstrated long-term benefits for thoracotomy and abdominal surgery.67 These have included decreased pain during hospitalization,68 reduced length of hospital stay,69 earlier resumption of usual activities, and decreased residual pain. Epidural analgesia is also associated with improved postoperative pulmonary function following thoracic surgery.70,71 Despite these benefits, the routine use of thoracic epidural analgesia for pain relief following major thoracotomy is still debated.72,73 Continuous epidural analgesia or continuous femoral nerve block initiated prior to major knee surgery led to decreased postoperative pain at rest and during mobilization, greater achievement of early milestones for rehabilitation, and shorter admissions to the rehabilitation center.74 The pain that accompanies amputation of an extremity is seen in about 70% of patients presenting for lower extremity amputation. Use of an epidural catheter for analgesia prior to surgery, anesthesia during surgery, and analgesia following surgery led to a reduction in the rate of phantom limb pain by about one-half when compared with systemic opiates.75,76 Subsequent studies have reported mixed results, although an editorial that accompanied one negative study77 indicated in its review of the literature that a favorable outcome was more likely if an aggressive analgesic regimen was used throughout the entire perioperative period.78 Nonsteroidal anti-inflammatory drugs (NSAIDs) can be an important component of a multimodal approach to pain management by helping to limit peripheral nociceptor input,79 and by directly modulating central sensitization at the level of the spinal cord.80 Improved pain control and an opiate-sparing effect have been demonstrated for both systemic81 and epidural82 opiates when used jointly with NSAIDs. NSAID administration in advance of the tissue disruption of surgery has been shown to be beneficial.83-86 The availability of cyclooxygenase-2 (COX-2) selective inhibitors (eg, celecoxib, rofecoxib, and valdecoxib) has enabled greater perioperative NSAID use because of their decreased level of side effects, such as gastric ulceration and bleeding.87 Although often presumed otherwise, the COX-2 selective inhibitors appear to exert similar effects on renal function to the nonselective NSAIDs.88 Moreover, the COX-2 selective inhibitors, particularly rofecoxib, may be associated with greater risk of myocardial infarction89 and congestive heart failure.90 It is important to emphasize that aggressive pain control may directly or indirectly lead to benefits other than decreased pain, and can impact morbidity and mortality. Tissue oxygenation following minor knee surgery is improved in patients receiving better pain treatment.91 The extent that this could lead to improved wound healing has yet to be determined. Decreased morbidity and mortality was demonstrated over a decade ago for a protocol employing epidural analgesia.92 A recent systematic review of the literature revealed that neuraxial blockade was associated with meaningful decreases in deep venous thrombosis, pulmonary embolism, transfusion, pneumonia, respiratory depression, myocardial infarction, renal failure, and death.93 Epidural analgesia is also associated with improvements in exercise tolerance up to 6 weeks following abdominal surgery.94 What Patients Should Do to Optimize Their Care Physicians may frequently be called on to advise their patients about choices for impending surgery and how to cope with the discomfort associated with surgery. Patients should be as completely informed about what to expect in an effort to minimize anxiety. For reasons elucidated above, patients must be made aware that the only way caregivers will know the extent of their pain is by asking or being told. Typically, patients will be asked to rate their pain on a 0-10 scale, where 0 indicates “no pain” and 10 is “worst imaginable pain.” Patients need to express their concern about postoperative pain to both their surgeon and anesthesiologist, and have explicit discussions with each about plans for postoperative pain management. For patients undergoing major procedures, the minimum standard includes PCA or around-the-clock opiate administration since opiate administration as needed (prn) is generally less effective. Depending upon the site of surgery, some type of wound infiltration, peripheral nerve block, or neuraxial block may be feasible, and could be performed in a preemptive manner with long-acting medications and/or a catheter to permit continuous infusions. Conclusion The pain that accompanies surgical procedures is often inadequately treated and continues to be an important health care issue that is often transparent to caregivers. A growing appreciation for the neurobiology of pain perception motivates an aggressive preemptive multimodal approach to pain management. Although there are still many open questions about how to translate this approach to specific clinical scenarios, a growing body of evidence indicates that patients will do better and be more comfortable with this approach. However, the resources to routinely provide outstanding pain relief following surgery may not become available until studies are performed that clearly demonstrate that economic benefits accompany the clinical ones.95 This article was supported in part by National Institutes of Health grant 1-R01-NS41865.