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doi: 10.1097/ALN.0b013e3181650edd
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Preemptive Antihyperalgesia to Improve Preemptive Analgesia

Simonnet, Guy Ph.D.

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BASED on the rationale that gabapentin effectively treats neuropathic pain and that there are many similarities in mechanisms between neuropathic pain and hyperalgesia from opioid administration,1 Van Elstraete et al.2 tested whether gabapentin could also reduce hyperalgesia induced by a short-term use of fentanyl in rats, and reported in this issue of Anesthesiology that it was effective, although no analgesic effect per se was observed. These observations agree with a recent study in human volunteers showing that pregabalin, a gabapentin analog, has no effect on electrically evoked pain but significantly reduces the areas of punctuate mechanical hyperalgesia.3 Numerous experimental and clinical studies suggest that gabapentin is unlikely to be a conventional analgesic and may have a selective effect on pain processes involving central sensitization, such as that which occurs with opioid exposure. This result highlights new ways of thinking to improve the management of postoperative pain.
Although opioids are well recognized as unsurpassed analgesics for relieving moderate to severe pain, clinical studies have reported for more than a century that hyperresponsiveness to noxious stimuli is the most common symptom of withdrawal after prolonged opioid administration. More recently, the paradoxical phenomenon of opioid-induced hyperalgesia (OIH) has been described to develop rapidly after a single opioid exposure in animals, human volunteers, and surgical patients.4 OIH is now recognized to reflect a sustained sensitization of the nervous system in which excitatory amino-acid neurotransmitter systems play a critical role, especially via N-methyl-d-aspartate (NMDA) receptors. From a medical viewpoint, abnormal persistence of excitatory neuroplasticity is now considered to be a major, if largely unrecognized, candidate mechanism for the development of chronic pain.5 One hypothesis is that the administration of large doses of opioids, as used for surgery in humans, increases the risk to induce not only early exaggerated postoperative pain, but also the development of postoperative chronic pain. This does not mean that opioid use must be eliminated for surgical analgesia in humans (certainly not!) but provides yet another rationale to reduce opioid dose to avoid unidentified and then unevaluated long-lasting deleterious effects on pain sensitivity. Moreover, therapies that can oppose early postoperative hyperalgesia and reduce postoperative opioid consumption should be developed, because these are perhaps linked phenomena. Several points should be considered.
From a mechanistic viewpoint, experiments in animals and human volunteers show that drugs that affect NMDA receptor functioning directly, such as NMDA receptor antagonists like ketamine, memantine, dextromethorphan, magnesium, or nitrous oxide, or indirectly by reducing the spinal release of excitatory amino acid neurotransmitters, such as the cyclooxygenase inhibitors, prevent OIH by inhibiting an overactivation of pronociceptive systems and antiopioid systems that directly oppose the analgesic effects of opioids.5 Gabapentin acts via different mechanisms than NMDA receptor antagonists or cyclooxygenase inhibitors because it presynaptically binds to the α2δ1 subunit of voltage-gated calcium channel (Cavα2δ1). Elevated Cavα2δ1 at the spinal cord level has been proposed to contribute to pain hypersensitivity in neuropathic pain models.6 Interestingly, gabapentin effects on voltage-gated calcium channel currents are minimal in wild-type mice as compared with significant inhibition in transgenic mice that constitutively overexpress Cavα2δ1 in neuronal tissues.7 Voltage-gated calcium channel current blockade by pregabalin leads to a decrease of release of the excitatory neurotransmitters substance P and glutamate, which are themselves known to be involved in pain hypersensitivity. One hypothesis (which does not exclude other mechanisms) is that gabapentin indirectly prevents OIH via inhibition of overactivation of NMDA receptors like other antihyperalgesic drugs. However, an up-regulation of neuronal Cavα2δ1 in this OIH experimental model has not been investigated. When this information is taken together, it is conceivable indirect modulation of NMDA receptor functioning by gabapentin is more useful clinically than direct receptor blockade by NMDA receptor antagonists for opposing OIH because side effects are more limited with the former approach. This is also supported by our recent observation that a polyamine-deficient diet, which negatively modulates overactivation of NMDA receptors via an NMDA allosteric polyamine site, is an efficacious strategy devoid of any noticeable side effects to relieve pain hypersensitivity.8
From a therapeutic viewpoint, these data could lead us to reevaluate preemptive analgesia. Preemptive analgesia is defined as a treatment initiated before the surgical procedure to prevent pain and sensitization. Numerous clinical studies indicate that the level of preoperative pain is correlated with the development of early postoperative pain and with the subsequent development of chronic pain, which may persist for months or years after surgery. Indeed, even though the best way to prevent pain sensitization might be to block completely any pain signal originating from the surgical wound from the time of incision (or opioid administration) until final wound healing, it is noteworthy that analgesic drugs used for surgery have different pharmacologic profiles. Therefore, opioids, though potent analgesics, are typically “false friends” for preemptive analgesia because they also induce delayed and long-lasting pain hypersensitivity. As indicated by Eisenach9 in an Editorial View in this journal, opioids might induce “Preemptive hyperalgesia, not analgesia.” Indeed, the study by Van Elstraete et al.2 and related OIH studies suggest that analgesia is necessary but not sufficient to develop good preemptive analgesia and that a preemptive antihyperalgesic is also needed. Among available therapies, the early administration of antihyperalgesic agents that are not antinociceptive per se, such as gabapentin; polyamine-deficient diet; or analgesics with specific antihyperalgesic properties, such as buprenorphine, nitrous oxide, cyclooxygenase inhibitors, or nefopam might be fruitful strategies for improving preemptive analgesia. These agents may be also preferentially used during the postoperative period to reinforce this antihyperalgesic strategy.
Finally, from a medical viewpoint, patients with high intensity of early postoperative pain are known to have a higher risk of developing a chronic pain state.5 Opioids might reinforce this deleterious phenomenon. Experimental10 and clinical studies11 indicate that preoperative and perioperative therapies that are efficacious to prevent early exaggerated postoperative hyperalgesia also oppose long-lasting pain hypersensitivity, i.e., pain vulnerability. This phenomenon, which is paradoxically facilitated by opioids, has been referred to as a “latent pain sensitization”10 because it may aggravate preexisting pain that could have gone unnoticed in the absence of subsequent nociceptive inputs. Gabapentinoids have demonstrated promising antihyperalgesic potential in a number of clinical trials of early postoperative pain. However, the ability of gabapentin to prevent the development of postoperative chronic pain must be evaluated in combination with different classes of “traditional” analgesics. Indeed, we must reevaluate analgesics, especially opioids, independently of their own analgesic potencies because OIH studies indicate that certain opioids, especially fentanyl and remifentanil, induce hyperalgesic effects, whereas others, such as buprenorphine or methadone, exert a lasting antihyperalgesic effect.12 Attempting to combine preemptive analgesia with preemptive antihyperalgesia could be a fascinating challenge for modern anesthesiology because chronic pain occurs in 10–50% of patients after surgery, especially when it is associated with nerve injury. Other therapies, such as continuous local anesthetic wound infusion or systemic antiinflammatory corticosteroid therapy, might reinforce preemptive antihyperalgesia. Although the possibilities are exciting, application of such therapeutic strategies will also need to apply Hippocrates’ dictum, primum non nocere—first, do no harm.
Guy Simonnet, Ph.D.
Universite Victor Segalen-Bordeaux 2, Université Bordeaux 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Homéostasie-Allostasie-Pathologie-Réhabilitation, Bordeaux, France.
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