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Frontiers in Translational Research: The Etiology of Incisional and Postoperative Pain

Brennan, Timothy J. M.D., Ph.D.

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IN many cases, our understanding of fundamental pathophysiologic mechanisms provides the rationale for particular therapies in perioperative medicine. However, this is not yet the case for postoperative pain management. It is in this arena that anesthesiologists can lead and advance the management of postoperative pain. In this issue of Anesthesiology, Kawamata et al.1 subjected volunteers to a small incision in the volar forearm, an area frequently used for sensory testing in humans. By examining the etiology of pain caused by incisions, experiments like these contribute to our understanding of the mechanisms for postoperative pain and make an important link between clinical postoperative pain and basic research in animals on pain mechanisms caused by incisions.
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In the volunteer study conducted by Kawamata et al.1, pain at rest was quantified. Primary mechanical hyperalgesia, exaggerated responses to mechanical stimuli at the incision, and the area of hyperalgesia surrounding the incision were measured. Also, the influence of local anesthetic injection at the wound was studied. In these volunteers, pain at rest decreased and disappeared by 2 h after the experimental incision. Pain in response to mechanical stimuli adjacent to the incision, primary mechanical hyperalgesia, was present for 2 days. The disappearance of pain at rest and persistence of pain with activities and in response to mechanical stimuli at the wound site is also present in patients after surgery. 2 In preclinical studies using an incisional model in rats, 3 investigators observed a temporal pattern of nonevoked pain behaviors and responses to mechanical stimuli similar to the temporal patterns observed in patients after surgery and in the volunteers in the study conducted by Kawamata et al.1 (fig. 1). Together, these studies suggest that pain at rest and evoked pain caused by incisions are likely transmitted by different afferent fiber populations and/or different receptors. Other than using local anesthetics to inhibit these evoked responses, we have discovered few drugs that markedly reduce pain with coughing and movement after surgery. More effective treatment of evoked pain and pain associated with activity will require a better understanding of mechanoreceptor function under normative conditions, mechanoreceptor function after incisions, and the changes in central processing that occur with evoked pain.
Initial pretreatment with a local anesthetic to block the pain during the experimental incision in these volunteers prevented ongoing pain and the primary mechanical hyperalgesia. 1 Pain from the incisions also disappeared when lidocaine was injected after the injury. However, in both cases, as the local anesthetic effect abated, the primary hyperalgesia returned, and for the most part, the hyperalgesia was the same between the preincision and postincision treatments. In patients, local anesthetic injections made before surgery are roughly equivalent for reducing pain to injections made after surgery. 4 Why is preincision local anesthesia equivalent to postincision local anesthesia in patients after surgery and in the volunteers in the study conducted by Kawamata et al.1 ? What is the role of central sensitization if preincision analgesia and postincision analgesia were equal? Such questions cannot be easily answered, and it is here that basic scientific studies provide important insights. In a study combining behavioral and electrophysiologic experiments in rats, the same local anesthetic injections were made, and pain behaviors and central sensitization were examined. 5 Local anesthetic treatment before incision prevented pain behaviors for several hours; injection after incision produced the same effect. One day later, pain behaviors were present and were not different between the groups. In this preclinical study, local anesthetic injection completely blocked activation of the pain transmitting neurons in the spinal cord during incision and prevented central sensitization. Furthermore, injection of a local anesthetic well after incision also reversed dorsal horn neuron sensitization by incision. After the effects of the local anesthetic abated, the sensitization recurred. Therefore, clinical studies, experiments in human volunteers, and a preclinical incision model agree that administration of a local anesthetic before or after the incision are roughly equivalent. Why? Because the activation of central pain transmitting neurons during incision and sensitization are not necessary for pain behaviors several days later. Rather, for incisions, enhanced responsiveness of central neurons and pain require ongoing afferent input from the incision. 6 After the effects of any preincision analgesic treatment abate, the surgical wound appears capable of reinitiating sensitization and regenerating the pain responses.
Kawamata et al.1 also mapped the area of hyperalgesia (including the uninjured zone) caused by incisions. This has also been studied in patients after surgery. Secondary hyperalgesia (hyperalgesia outside of the injured area) is one measure of enhanced responsiveness of the central nervous system, i.e., central sensitization. Kawamata et al.1 noted that the area of flare or redness (possibly a result of axon reflexes) caused by incision was distinct from the area of hyperalgesia. As opposed to pain at rest and primary mechanical hyperalgesia, the large area of hyperalgesia never developed when local anesthetic injection was made before the incision. Moreover, it could not be reversed by local anesthetic injection after incision. In patients after surgery, in some cases, certain treatments greatly reduce the area of hyperalgesia but do not greatly modify clinical measures of postoperative pain (pain scores and opioid consumption). 7 De Kock et al.8 demonstrated that reducing the area of hyperalgesia after colectomy did not greatly reduce acute pain but was associated with a decrease in the number of patients that developed residual pain even as late as 6 months after colectomy. Therefore, the area of hyperalgesia, one measure of central sensitization, could perhaps predict patients likely to develop persistent pain after surgery.
Our armamentarium of drugs for acute pain management is quite limited. The patient with rheumatoid arthritis may be treated with drugs to reduce autoimmune responses or with new agents that block the action of inflammatory mediators like tumor necrosis factor. For acute pain management, we operate using guidelines from the early 1990s that reinforced the generous use of opioids for acute pain, even though effective dosing is limited by deleterious side effects. 9 Anesthesia-based acute pain services popularized continuous epidural analgesia, which controls pain better during activities, and continuous regional techniques for specific surgeries are advancing acute pain management. If the 1990s assured us that opioids should be used with confidence, the last 5 yr have demanded efficacious alternatives to opioids with fewer side effects and perhaps improved outcome. These treatments will follow research based on mechanisms of incisional pain.
So what is causing postoperative pain, and why is pain with movement so difficult to control? At this point, we have no understanding of the algogenic substances that are released to activate and sensitize the nociceptive nerve terminals in a surgical wound. Which classes of nociceptors are activated by these substances? How is this nociception integrated in the central nervous system as acute postoperative pain? The models describing the pathophysiology behind these sensory changes that occur after injury, which were largely developed from studies on inflammation in animals, may not translate well to postoperative pain in humans. For example, pain from incisions may be related to ischemia 10; inflammation may be less critical than originally proposed.
By studying incisions in humans, the results of Kawamata et al.1 allow us to better translate pain in patients after surgery and pain mechanisms studied in basic research. As we discover more about mechanisms for incisional pain, new therapies will advance perioperative medicine. As new sensitizing chemicals and novel receptors on sensory fibers are discovered, our specialty must integrate the new knowledge to problems important for our patients. Mechanisms for pain and hyperalgesia from incisions are not well understood but are relevant to all anesthesiologists. Clinical and basic research can unlock the etiology of incisional pain and, as suggested, 11 point pharmaceutical and biotechnology companies towards treating the problem.
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1. Kawamata M, Watanabe H, Nishikawa K, Takahashi T, Kozuka Y, Kawamata T, Omote K, Namiki A: Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. A nesthesiology 2002; 97: 550–9

2. Moiniche S, Dahl JB, Erichsen CJ, Jensen LM, Kehlet H: Time course of subjective pain ratings, and wound and leg tenderness after hysterectomy. Acta Anaesthesiol Scand 1997; 41: 785–9

3. Brennan TJ, Vandermeulen EP, Gebhart GF: Characterization of a rat model of incisional pain. Pain 1996; 64: 493–501

4. Moiniche S, Kehlet H, Dahl JB: A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: The role of timing of analgesia. A nesthesiology 2002; 96: 725–41

5. Pogatzki E, Vandermeulen E, Brennan T: Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision. Pain 2002; 97: 151–61

6. Pogatzki EM, Gebhart GF, Brennan TJ: Characterization of A delta- and C-fibers innervating the plantar rat hindpaw one day after an incision. J Neurophysiol 2002; 87: 721–31

7. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A: Mapping of punctate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41: 1124–32

8. De Kock M, Lavand'homme P, Waterloos H: ‘Balanced analgesia’ in the perioperative period: Is there a place for ketamine? Pain 2001; 92: 373–80

9. Gould TH, Crosby DL, Harmer M, Lloyd SM, Lunn JN, Rees GAD, Roberts DE, Webster JA: Policy for controlling pain after surgery: Effect of sequential changes in management. BMJ 1992; 305: 1187–93

10. Brennan T, Lee S, Subieta A, Park S: Decreased tissue pH parallels pain behaviors caused by plantar incision. Soc Neurosci 2001; pp 928.1

11. Goldstein JL, Brown MS: The clinical investigator: Bewitched, bothered, and bewildered—but still beloved. J Clin Invest 1997; 99: 2803–12

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