Postoperative hyperalgesia: evaluation and treatment
B Guignard
Postoperative pain is a complex process influenced by both physiological and psychological factors. Inadequate treatment of pain can affects respiratory, cardiovascular, gastrointestinal, genitourinary, neuroendocrine, musculoskeletal and psychological systems. Because of their potency, opiates are the most commonly used drugs used in this context. Opiates tolerance is a phenomenon known for a long time. Withdrawal signs and symptoms are generally the opposite of the drug's direct effects. In the same way, hyperalgesia is a consequence of the plasticity of the nociceptive nervous system. Our knowledge on the mechanisms of postoperative hyperalgesia has greatly increased during recent years. Refined analysis methods, non-invasive functional brain imaging techniques and genomics have provided new comprehension from peripheral primary afferents to central medullar and cortical processing [1].
Mechanisms of hyperalgesia
Peripherals: apparition of abnormal activity discharges in injured nerves; nociceptors sensitization; pathological activation of c fibers; sympathetic activation. Mediators involved in these reactions are principally kinins, cytokines, lipooxygenases, nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines, and opioids.
Central: sensitization is principally under activation of excitatory amino acid receptors or associated substance-gated slow calcium ion channels.
GABA is the principal neurotransmitter involve in segmentary and descending inhibitory control, it contributes to hyperalgesia. Modification of primaries afferent could involve also new topographic organization in the spinal cord. Central and peripheral mechanisms are linked because ectopics discharges from injured primary afferents could maintain a central state of hyperexcitability that underlies hyperalgesia. Hyperalgesia after incision is principally under influence of spinal non-NMDA receptors, unlike inflammatory hyperalgesia, which is mediated via NMDA receptors [2].
Opioid induced hyperalgesia
For a complete review, see Angst et al. [3]. The use of opioids can be associated not only with loss of analgesic efficacy (tolerance) but also with activation of pronociceptive mechanisms leading to hyperalgesia. The circumstances under which opioid-induced hyperalgesia may occur are not entirely understood but may include high doses, long-term treatment, or abrupt changes in concentrations. Recent observations on changes in neurotransmitter release following acute and chronic exposure to opioids provide potential solutions to comprehension of opioid induced hyperalgesia [4]. Opioids do not excite descending fibres directly but disinhibit them by inhibiting spontaneous GABA release from local GABAergic interneurones. Rebound adenylyl cyclase activity in withdrawal may be the fundamental step in eliciting the withdrawal behaviour. Neuropathic pain and opioid induced hyperalgesia have common pathophysiologic mechanisms. Among these neural mechanisms, the central glutaminergic system plays a pivotal role and N-methyl-d-aspartate (NMDA) receptor has been shown to be critical in the cellular mechanisms of opioid-induced pain sensitivity. Perioperative opioids may increase postoperative pain and opioid requirements [5].
Evaluation of hyperalgesia
The definition of hyperalgesia is more pain accompanying a given stimulus. Diagnosis of hyperalgesia is difficult based on clinical symptoms alone. Its detection is based on comparison of a defined stimulus before and after surgery. The quantification of hyperalgesia requires temporal determination of responses under standardized conditions. This process termed quantitative sensory testing. The postoperative hyperalgesia must be diagnosed in order to be treated [6].. Hyperalgesia must be distinguished from allodynia: pain due to non-noxious stimulus to the normal skin. Allodynia involves a change in the quality of a sensation, whether tactile, thermal, or of any other sort. The original response to a stimulus was not pain, but the present response is. One way of testing postoperative tactile and pain thresholds is with a Von Frey Anesthesiometer. This device has fibers that applies calibrated pressure to the skin. This technique gives an evaluation of nociceptive threshold near the site of surgery and could be repeated for days. Von Frey hair stimulation could serve to mapping surgical wound hyperalgesia [7]. Another way to determine postoperative pain thresholds is pressure algometer which consist of a hand-held force transducer. Quantitation of thermal hyperalgesia and tactile allodynia in postoperative patients have been performed in few studies [8]. More studies are needed in order to characterize the intensity and the impact of postoperative hyperalgesia. It is assume that primary hyperalgesia occurs from hours up to 3-5 days postoperatively. Secondary mechanical hyperalgesia has been seen from hours up to 7 days after surgery. Questionnaires send to patients could help to characterize pain and neurological aspects of late postoperative pain.
Treatment of hyperalgesia
Prevention
Avoid unnecessary prolonged exposition to opioids. Avoid rapid decreases in opioid doses combined with procedural pain leads to excess pain in the postoperative period. Anticipation and prolonged preemptive analgesia could contribute to reduce hyperalgesia. Prolonged, preemptive nerve block reduced late hyperalgesia after thermal injury [9].
* Blockade of NMDA receptors has been shown in animal studies to prevent the development of increased pain sensitivity and opioid tolerance. Ketamine is a non-competitive NMDA receptor antagonist and there is evidence that it could lower postoperative hyperalgesia and reduce wind-up and central sensitization. Dosage varies between 0.15 and 0.5 mg.kg-1. Continuous infusion is still in debate [10].
* Gabapentin is similar in structure to the neurotransmitter GABA but not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated calcium ions channels. It has demonstrated efficacy in patients with neuropathic pain and reduces elements of central sensitization in human experimental hyperalgesia. Dosage and mode of administration are not well defined [11].
* Epidural anesthesia combined with ketamine reduced early but not late (one year) wound area of punctuate hyperalgesia [12]
Antihyperalgesic effects of IV lidocaine in patients with peripheral nerve injury have been demonstrated. Topical or conduction block by local anesthesia reduces hyperalgesia.
* In future studies, other medications to be tested in hyperalgesia treatment are (non-limitative) vinlafaxine, amitriptylin, nitric oxide, nitrous oxide [13], clonidine, pregabalin, nefopam, anti-parkinsonian agents and halogenated anesthetics.
Conclusion
Postoperative hyperalgesia is a complex phenomenon with many possible triggers. Diagnostic is essential More studies are needed to determine the prevalence and the characteristics of this pain after surgery. Pre and postoperative assessment of pain response, individual factors should be including in future. Medications and treatments to give are numerous, but their place, alone or in combination are still not defined.
references
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