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Preventive Analgesia to Reduce Wound Hyperalgesia and Persistent Postsurgical Pain: Not an Easy Path

Brennan, Timothy J. Ph.D., M.D.*; Kehlet, Henrik M.D., Ph.D.†

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IN perioperative medicine, we continue to examine relatively brief anesthetic treatments during and immediately after surgery for evidence of substantial, sustained postoperative benefits. This preventive concept is being tested against postoperative cognitive dysfunction, deficits caused by neurologic injury, adverse perioperative myocardial events, the systemic inflammatory response, and the risk of developing persistent postsurgical pain. In this issue of Anesthesiology, Lavand’homme et al.1 describe analgesic protocols that decrease the area of hyperalgesia surrounding an incision and influence late, residual pain after colectomy.
The search for preventive analgesic treatments with prolonged benefits continues in part because pain research has emphasized the plasticity of the nociceptive system and pain memory. The perioperative period is ideal for translating concepts such as pain memory, plasticity, and preventive treatments because the nature of the injury (surgery), its onset, duration, and degree are generally known; in addition, the patients can be assessed before the injury to evaluate the role of predisposing factors (hereditary, psychosocial, and others).
The first widespread attempt to translate the concept of plasticity and postoperative pain was in trials of the timing for administration of anesthetic and analgesic treatments. Now, it is generally agreed that starting an analgesic treatment before surgery has minimal benefits compared with starting the treatment after surgery begins or even administering the treatment at the conclusion of surgery.2 However, before we conclude that plasticity has little role in postoperative pain, recognize that clinical plasticity may depend on a variety of factors such as the particular surgery, the type and duration of analgesic treatment, the stimulus modality tested, and the preoperative characteristics of the patients.
Experimentally, plasticity has been described using a variety of models.3,4 Plasticity may be present on nociceptive nerve terminals producing enhanced responses in these primary afferents, i.e., peripheral sensitization; however, a far greater emphasis has been made on plasticity of pain transmission in the central nervous system, from which several models have been described. The question for anesthesiologists and surgeons is how these plasticity models should be applied to perioperative care. Furthermore, what treatments and for how long should we combat neuroplasticity in the perioperative period?
The study by Lavand’homme et al.1 uses a combination of intraoperative, intravenous ketamine administration (an N-methyl-d-aspartate receptor antagonist with other pharmacologic properties) and an intraoperative or postoperative epidural analgesic cocktail in patients undergoing colectomy for malignancy. In addition to the pain assessments, the area of punctate mechanical hyperalgesia was quantified and almost eliminated by each of the preventive analgesic techniques. The area of punctate hyperalgesia is a measurement not typically used in clinical pain management.5 It is thought to represent a measurement of central sensitization and therefore plasticity because the area encompasses uninjured tissue surrounding the incision. However, there was only a modest, although significant reduction in early postoperative pain scores, but no differences between postoperative pain scores with or without intraoperative epidural analgesia or with or without postoperative epidural analgesia.
Other studies using intraoperative and/or postoperative, intravenous ketamine with or without epidural analgesia6–8 have documented suppression of the area of punctate wound hyperalgesia by ketamine. However, despite continuous suppression of the area of hyperalgesia after the ketamine infusion was stopped, the postoperative pain scores were not reduced,6,7 questioning the relation between reduction in the area of wound hyperalgesia and clinical pain. Other studies have also shown a discrepancy between quantitative sensory testing at the incision site compared with pain scores and analgesic effects of opioids9,10 or ketorolac.10 In contrast, Katz et al.11 found wound von Frey pain thresholds and pain scores to be lower after a preventive epidural analgesia versus no epidural, but interpretation is hindered because of more horizontal incisions in the epidural group, which may result in less dermatomal involvement and pain than with a vertical incision. A study of the secondary hyperalgesia response to a preoperative heat injury found no correlation between the quantitative sensory testing findings and the pain response to the subsequent knee operation,12 again questioning the relation between the area of postinjury hyperalgesia and the intensity of clinical pain.
Therefore, the surgical data are not entirely consistent6,7,9–12 compared with studies of other pain models in humans and preclinical incisional pain models where the area of hyperalgesia and secondary hyperalgesia are clearly plastic, modulated by pretreatments, and inhibited for periods extending beyond the expected duration of treatment.13–15 However, with all the popularity associated with plasticity in scientific studies, it is refreshing to discover a few consistencies—this area of secondary hyperalgesia in clinical postoperative pain seems to have commonalities with some aspects of plasticity that have been extensively characterized in preclinical studies. Clearly, further data are required to establish the relation between wound hyperalgesia and clinical pain in various surgical models and with various preventive analgesic techniques.
Given that the area of wound hyperalgesia may be decreased by specific analgesic treatments but inconsistently associated with reduction of clinical pain, the question arises whether these early nociceptive responses are related to the well-established risk of persistent postsurgical pain.16 First, there is agreement that the intensity of early postoperative pain may predict the risk of development of a chronic pain state.16 However, whether this relation is caused by neuroplasticity or preoperative disposing factors12,16,17 remains to be evaluated. Previous studies of various analgesic techniques, including epidural analgesia, have not been consistent to document a clinical meaningful relation between the reduction of acute postoperative pain and persistent pain18–23 despite early reduction in wound hyperalgesia in one study.11,22 Other approaches using venlafaxine,24 gabapentin and mexiletine,25 or a topical local anesthetic26 have reported some positive effects on chronic pain, but these results have not been consistent with a clinically significant reduction in early postoperative pain scores.
However, in all but one11,22 of these studies,18–26 no detailed assessments of wound hyperalgesia were performed, and therefore one cannot comment on the mechanisms for a potential reduction of a chronic pain state. In the study by Lavand’homme et al.,1 follow-up data after 1, 6, and 12 months postoperatively showed an elimination of persistent pain by the preventive epidural analgesic techniques compared with control, which also included ketamine. These findings are somewhat surprising compared with the relatively minor effect on early postoperative pain scores but are consistent with the reduction in the area of early postoperative wound hyperalgesia, whatever the type of preventive analgesia. However, in the studies on persistent postsurgical pain,1,6,18–26 the study design has often been suboptimal and leaves many questions to be answered: In the study by Lavand’homme et al.,1 the patients underwent surgery for rectal cancer, but no specific information is given on tumor state and tumor follow-up, wound complications, stoma application, chemotherapy, radiation therapy, and psychosocial factors or on the site, type, and severity of the chronic pain state.
Although there is agreement that persistent postsurgical pain represents a clinically significant problem,16 much research is needed before we will have a clear answer to its pathogenesis as well as its prevention and treatment. Important topics to be included in future studies are preoperative assessments of pain responses to a nociceptive stimulation, because these may correlate to early postoperative pain responses12,17 and because the intensity of early postoperative pain may correlate with development of chronic postoperative pain.16 In addition, the analgesic intervention should include multimodal techniques with several drugs to combat peripheral and central neuroplasticity27 and with a sufficient duration of treatment as long as significant wound inflammation and hyperalgesia persists. The role of the intensity of an afferent neural blockade must also be assessed, because the dose regimens used in the epidural studies1,6,18–22 probably only provided a limited afferent blockade of the input to the spinal cord.28 Also, a detailed description of the surgical model regarding type of tissue injury, type and length of wound incision, surgical technique, risk of nerve lesions, and disease-specific data (cancer, chemotherapy, radiation therapy, and others) is required. Finally, the late postoperative follow-up should include detailed neurophysiologic assessment of the wound area, detailed characteristics of the chronic pain state and its social consequences, and detailed psychosocial assessment to understand the pathogenesis and treatment possibilities for persistent postsurgical pain. This specifically applies to the role of nerve injury, which may be the most important pathogenic factor leading to persistent postsurgical pain.16,29,30
In summary, factors influencing the area of wound hyperalgesia indicate that this plasticity shares properties with those under intensive study by basic scientists. The relation between the area of wound hyperalgesia, analgesic intervention, and the intensity of acute and persistent postsurgical pain may not appear as an easy path for the anesthesiologist and surgeon but is worthwhile to pursue. Hopefully, future studies will help us to understand in which directions to go to reach the answer.
Timothy J. Brennan, Ph.D., M.D.*
Henrik Kehlet, M.D., Ph.D.†
*Departments of Anesthesia and Pharmacology, The University of Iowa, Iowa City, Iowa. †Section for Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark. henrik.kehlet@rh.dk
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References

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