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The development of chronic pain is considered a major complication after surgery. Basic science research in animal models helps us understand the transition from acute to chronic pain by identifying the numerous molecular and cellular changes that occur in the peripheral and central nervous systems. It is now well recognized that inflammation and nerve injury lead to long-term synaptic plasticity that amplifies and also maintains pain signaling, a phenomenon referred to as pain sensitization. In the context of surgery in humans, pain sensitization is both responsible for an increase in postoperative pain via the expression of wound hyperalgesia and considered a critical factor for the development of persistent postsurgical pain. Using specific drugs that block the processes of pain sensitization reduces postoperative pain and prevents the development of persistent postoperative pain. This narrative review of the literature describes clinical investigations evaluating different preventative pharmacologic strategies that are routinely used by anesthesiologists in their daily clinical practices for preventing persistent postoperative pain. Nevertheless, further efforts are needed in both basic and clinical science research to identify preclinical models and novel therapeutics targets. There remains a need for more patient numbers in clinical research, for more reliable data, and for the development of the safest and the most effective strategies to limit the incidence of persistent postoperative pain.

Purpose of review The aim of the present review is to describe how regional anaesthesia might oppose neuronal changes that surgery and opioids cause in the central nervous system to block both pain sensitization and chronicization following surgery. This might help anaesthesiologists to better understand the impact of their practice on the development of postoperative chronic pain. Recent findings Even though there are more evidences from animals and clinical trials showing that regional anaesthesia might impact the acute pain/hyperalgesia and chronic postsurgical pain, the controversy on how and when to use regional anesthesia to avoid chronic pain persists. Animal studies brought only a very partial answer on what to do in our daily clinical practice. Clinical studies were performed in different types of surgery with various protocols so that a strong conclusion on whether or not using regional anesthesia might benefit the patient to decrease the risk of postoperative chronic pain remains unclear. Studies performed with neuraxial anaesthesia seem to bring better evidences than those with nerve blocks. Future studies will have to specifically evaluate acute hyperalgesia and postoperative chronic pain and not only the classical pain scores and analgesic consumption to bring us the answer we all need. Summary Regional anaesthesia is able to reduce postoperative acute hyperalgesia and long-term chronic pain by decreasing pain sensitization induced by the surgery itself, and intraoperative use and opioid-induced hyperalgesia. Nevertheless, clinical studies on neuraxial anaesthesia and nerve blocks did not bring so far a strong conclusion to this question, and further better designed studies are necessary.

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold. These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.

There is a compelling body of evidence that N-methyl-d-aspartate receptors (NMDA-R) play a critical role in the development and maintenance of pain hypersensitivity. However, long-term treatments with NMDA-R antagonists are limited by unacceptable side effects. Since polyamines modulate the functioning of NMDA-R and mainly originate from normal dietary intake and bacterial metabolism in the gut, we developed a nutritional therapy based on dietary polyamine deficiency. Here, we reported that a polyamine deficient diet (PD diet) for 7 days prevented the enhancement of tyrosine phosphorylation of the spinal NR2B subunit-containing NMDA-R associated with inflammation in rats. Based on these data, we studied the ability of PD diet to prevent long-lasting pain hypersensitivity associated with tissue injury on one hind paw by evaluating long-lasting changes in both mechanical nociceptive threshold and weight bearing. A PD diet strongly reduced long-lasting hyperalgesia induced by inflammation or incision, especially in fentanyl-treated rats. Moreover a PD diet also prevented the exaggerated hyperalgesia induced by a second inflammation performed 7 days after the first one. A PD diet also opposed paradoxical hyperalgesia induced by non-nociceptive environmental stress in rats with pain and opioid experiences. A PD diet reversed pain hypersensitivity associated with monoarthritis or neuropathy and restored the analgesic effect of morphine. Since PD diet was devoid of any noticeable side effects, this nutritional therapy could be part of an effective and safe strategy for pre-emptive analgesia and for reducing the transition from acute to chronic pain and its outcomes in various pain syndromes.

Background Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. Methods First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats. Results When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. Conclusions Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.

Background Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. Methods During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 microg/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. Results Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. Conclusions By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness.Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.

Background Tissue damage may produce hyperalgesia, allodynia, and persistent pain. The authors recently reported that fentanyl elicits analgesia but also activates N-methyl-D-aspartate-dependent pain facilitatory processes opposing analgesia. In nonsuffering rats, this leads to a long-lasting enhancement in pain sensitivity. The current study assessed whether fentanyl could amplify carrageenan-induced hyperalgesia. Methods First, rats were injected once with carrageenan in a hind paw, with fentanyl (60 or 100 microg/kg each given four times at 15-min intervals [4 x 60 or 4 x100]) or saline. Second, rats were injected with carrageenan twice without fentanyl (7-day interval), with the second injection either in the previously injected paw or in the other paw. Third, rats were injected twice with carrageenan in the same hind paw: the first ketamine injection was given (10 mg/kg each given three times at 5-h intervals) with or without fentanyl (4 x 60 microg/kg), and second injection was given without ketamine or fentanyl. The consequences of treatments on long-term hyperalgesia were examined by the paw-pressure vocalization test. Results The long-lasting hyperalgesia induced by the first carrageenan injection was dose-dependently enhanced in both duration and magnitude in 4 x 60 or 4 x 100 microg/kg fentanyl-treated rats: 5 or 10 days, respectively, as compared with 2 days in saline-treated rats. Hyperalgesia observed in the hind paw contralateral to the first carrageenan injection was enhanced in fentanyl-treated rats. The second carrageenan injection, performed in any hind paw, induced an exaggerated hyperalgesia, especially in fentanyl-treated rats. Pretreatment with ketamine totally prevented the carrageenan- and fentanyl-induced enhancement of the long-lasting hyperalgesia. Conclusion Central sensitization in inflammatory pain states is reinforced by an opiate treatment, which could be prevented by N-methyl-D-aspartate receptors blockade.

Background It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity. Methods The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed. Results Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia. Conclusions Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.