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Anesthesiology:
doi: 10.1097/ALN.0b013e31821c112b
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Stress-induced Hyperalgesia: Any Clinical Relevance for the Anesthesiologist?

Richebé, Philippe M.D., Ph.D.; Rivat, Cyril Ph.D.; Cahana, Alex M.D., D.A.A.P.M., F.I.P.P., M.A.S.

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DURING the last 3 decades, it has been widely reported that intense fear and stress suppress pain. In animals and humans, the typical effect of many stressors was reported as stress-induced analgesia (SIA).1 However, stress was also reported to exacerbate chronic widespread pain syndromes (e.g., in patients with fibromyalgia).2 In animals, repeated exposure to stressors (e.g., swim stress, restraint, and social defeat) were shown to produce hyperalgesia.3 If the mechanisms of SIA have been widely described, those underlying stress-induced hyperalgesia (SIH) remain poorly understood.
In the current issue of Anesthesiology, Donello et al.4 report that adrenoceptor-mediated sympathetic efferent mechanisms contribute to SIH. These data bring novel information regarding the effects of psychologic factors in preclinical pain modeling.
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Mechanisms Supporting SIH

Hyperalgesia can be associated with potentiated adrenergic sensitivity of primary afferent fibers as a result of up-regulation of α2-adrenergic receptors and exacerbation of neurogenic inflammation by α1-adrenergic receptors.
Donello et al.4 enhance our understanding of the sympathetic nervous system and hyperalgesia. They report norepinephrine exacerbated nociception after stress. They also describe how sympathetic postganglionic nerves can facilitate pain hypersensitivity via an α1 adrenoceptor mechanism even when sympathetic outflow is uninhibited. By using α2 A-adrenergic receptor knockout mice or by administering an α2 receptor antagonist, they showed feedback inhibition of norepinephrine release at α2 receptors is likely reduced by stress. This could result in a deregulation and enhanced norepinephrine release from sympathetic postganglionic nerves and significant sensitization of sensory afferents to SIH (see fig. 8 of Donello et al.4).
Other studies indicate other mechanisms may contribute to SIH. For example, epinephrine has been implicated as a factor in SIH. Khasar et al. hypothesized changes in β2-adrenergic receptor signaling and prolonged elevation of circulating epinephrine were responsible for the induction and maintenance of mechanical SIH.5 In addition, the involvement of descending nociceptive pathways in SIH has been described recently in a rat model of social defeat-induced hyperalgesia.6 However, there are limitations to these basic science studies. These preclinical experiments of SIH were performed in animals without any history of pain or opioid use before stress exposure, factors that are common in patients in our daily practice. There is some evidence that endogenous opioid systems paradoxically may trigger SIH. For example, when SIA was observed in naïve rats, 1-h stress exposure induced SIH for several hours in animals with a previous history of nociception and opioid exposure. Such pain nociceptive susceptibility after injury, pain, opioid use, and stress could contribute to central nervous system sensitization and perhaps the development of chronic pain.7
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SIH in a Clinically Relevant Context

In our daily clinical practice, most patients present with a history of chronic pain, and some have a history of chronic opioid use and often associated anxiety and depressive disorders. Depression in chronic pain is an important psychologic parameter in patients requiring pain treatment. Chronic pain and depression are present together in patients, and negative mood can be responsible for worsening pain complaints.8 Whether the same ability to transform SIA into SIH persists in such patients remains to be determined.
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Psychologic Factors Facilitating Persistent Pain after Surgery

Surgery induces a high level of stress in patients. Because chronic exposure to stress markedly exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, psychologic factors are associated with acute pain and the persistence of pain after surgery and could facilitate the development of chronic pain.
Developing animal models for SIH4 is of considerable interest to the pain field. Donello et al. report that nociception and acute stressors could cause a deregulation of the sympathetic nervous system and might have clinical significance in chronic stress conditions. Indeed, disinhibition of sympathetic nervous system outflow and subsequent SIH could exacerbate pain and facilitate the development of chronic pain. In the specific perioperative context, treatments aimed at modifying the development of SIH for the long term after surgery are of interest. For example, in patients scheduled for surgery, interfering with the mechanisms responsible for the transformation of SIA into SIH could reduce not only acute postoperative pain, but also perhaps the likelihood of developing persistent pain and decrease the magnitude of chronic pain after surgery.9 This might be even more appropriate in patients with chronic pain who are scheduled for surgery.
Philippe Richebé, M.D., Ph.D.,
Cyril Rivat, Ph.D.,
Alex Cahana, M.D., D.A.A.P.M., F.I.P.P., M.A.S.
Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, Seattle, Washington. prichebe@u.washington.edu
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References

1. Lewis JW, Cannon JT, Liebeskind JC: Opioid and nonopioid mechanisms of stress analgesia. Science 1980; 208:623–5

2. Adler GK, Manfredsdottir VF, Creskoff KW: Neuroendocrine abnormalities in fibromyalgia. Curr Pain Headache Rep 2002; 6:289–98

3. Vidal C, Jacob J: Hyperalgesia induced by non-noxious stress in the rat. Neurosci Lett 1982; 32:75–80

4. Donello JE, Guan Y, Tian M, Cheevers CV, Alcantara M, Cabrera S, Raja SN, Gil DW: A peripheral adrenoceptor-mediated sympathetic mechanism can transform stress-induced analgesia into hyperalgesia. Anesthesiology 2011; 114:1403–16

5. Khasar SG, Dina OA, Green PG, Levine JD: Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines. J Pain 2009; 10:1073–7

6. Rivat C, Becker C, Blugeot A, Zeau B, Mauborgne A, Pohl M, Benoliel JJ: Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 2010; 150:358–68

7. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: Risk factors and prevention. Lancet 2006; 367:1618–25

8. Bair MJ, Robinson RL, Katon W, Kroenke K: Depression and pain comorbidity: A literature review. Arch Intern Med 2003; 163:2433–45

9. Eisenach JC: Preventing chronic pain after surgery: Who, how, and when? Reg Anesth Pain Med 2006; 31:1–3

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