A randomized phase I trial evaluating the effects of inhaled 50–50% N<sub>2</sub>O–O<sub>2</sub> on remifentanil‐induced hyperalgesia and allodynia in human volunteers

Wehrfritz, Andreas; Schaefer, Susan L.; Troester, Alexander M; Noel, N.; Bessière, Baptiste; Apiou-Sbirlea, Gabriela; Simonnet, Guy; Schuettler, J.; Richebé, Philippe

doi:10.1002/ejp.870

Cited by 7 publications

(13 citation statements)

References 37 publications

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“…Intradermal capsaicin and electrical HFS models induce a very unpleasant stinging sensation, which may reach 7–9/10 on VAS but rapidly abates after stimulus application. On the other hand, the low‐frequency (LFS) electrical models use repetitive noxious stimuli during all the duration of the experiment, and necessarily induce a combination of ongoing pain and secondary hyperalgesia during minutes to hours (Bandschapp et al., 2010 ; Koppert et al., 2001 ; Nickel et al., 2011 ; Wehrfritz et al., 2016 ). Topical capsaicin and contact‐heat models produce secondary hyperalgesia with only moderate pain on application, which makes them attractive on the condition that the experiments do not exceed several hours.…”

Section: Discussionmentioning

confidence: 99%

Human surrogate models of central sensitization: A critical review and practical guide

Quesada

Kostenko

et al. 2021

European Journal of Pain

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Background: As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. Data treatment: We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. Results: From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low-or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower.The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. Conclusions: While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. Significance: Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogateThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Human surrogate models of central sensitization: A critical review and practical guide

Quesada

Kostenko

et al. 2021

European Journal of Pain

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“…15,34 The potentiation of analgesic effects in our patients receiving opioids may depend on similar mechanisms. However, in contrast with the previous studies conducted in patients 25,32 or healthy volunteers 34 with acute pain and receiving strong opioids, our data may indicate that these processes could also be at play in patients receiving long-term opioid treatment and also in patients receiving weak opioids. This has not been directly demonstrated so far, and therefore further experimental studies are needed to verify whether similar mechanisms are involved when EMONO is combined with strong or weak opioids administered chronically or acutely.…”

Section: Patients Treated With Opioidsmentioning

confidence: 95%

“…They are also antagonized by N 2 O, which has been shown to decrease opioid-induced hyperalgesia and therefore restore opioid analgesia, in both in animal 7,30 and humans. 15,34 The potentiation of analgesic effects in our patients receiving opioids may depend on similar mechanisms. However, in contrast with the previous studies conducted in patients 25,32 or healthy volunteers 34 with acute pain and receiving strong opioids, our data may indicate that these processes could also be at play in patients receiving long-term opioid treatment and also in patients receiving weak opioids.…”

Section: Patients Treated With Opioidsmentioning

confidence: 95%

“…11,13,23 Of interest, similar to other NMDA receptor antagonists, N 2 O can strongly inhibit these phenomena in both animals 7,30 and humans. 15,34 On the basis of these experimental data suggesting that the combination of N 2 O and opiates could result in additive or even multiplicative analgesic effects, we hypothesized that the effects of N 2 O/O 2 mixture inhalation in patients with neuropathic pain would be larger in patients receiving opioids as a concomitant treatment. To verify this hypothesis, we performed exploratory post hoc analyses of our ProtoTOP study data 10 to compare the effects of EMONO between patients receiving and patients not receiving a concomitant opioid treatment during the course of the study.…”

Section: Introductionmentioning

confidence: 99%

“…11,13,23 Of interest, similar to other NMDA receptor antagonists, N 2 O can strongly inhibit these phenomena in both animals 7,30 and humans. 15,34…”

Section: Introductionmentioning

confidence: 99%

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Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses

Bouhassira

Perrot

Attal

et al. 2021

Pain

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Experimental studies have suggested that nitrous oxide-induced analgesia depends on interactions with opioids. On the basis of these results, we hypothesized that the effects of inhaled nitrous oxide/oxygen (N 2 O/O 2 ) 50%-50% equimolar mixture (EMONO) on patients with neuropathic pain would be higher in those receiving concomitant opioids. To test this hypothesis, we did exploratory post hoc analyses of our recently published ProtoTOP study to compare the effects of EMONO and placebo in patients with or without concomitant opioid treatment. A total of 92 patients of the 221 (ie, 41.6%) included in the ProtoTOP study were concomitantly treated with opioids. In contrast with our previous analyses, average pain intensity was significantly decreased in comparison with placebo one week after the last treatment administration in patients treated with opioids, but not in those treated without opioid, and this effect was maintained over the 4-week follow-up period. Neuropathic pain symptom inventory (NPSI total and subscores) was also significantly more decreased after inhalation of EMONO in comparison with placebo only in patients receiving opioids. The proportion of patients with at least 30% pain reduction and of those reporting an overall improvement with the Patient Global Impression of Change were significantly higher only in this population of patients. In conclusion, these results complement our previous analyses with the identification of a specific population of responders to EMONO inhalation in patients with neuropathic pain. As suggested by experimental studies, we hypothesized that these long-lasting analgesic effects could depend on the anti-N-methyl-D-aspartate properties of N 2 O.

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Withdrawal from spinal application of remifentanil induces long-term potentiation of c-fiber-evoked field potentials by activation of Src family kinases in spinal microglia

Yang¹,

Du²,

Liu

et al. 2018

Neurochem Res

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It is well known that remifentanil, a widely used intravenous anesthesia drug, can paradoxically induce hyperalgesia. The underlying mechanisms are still not clear despite the wide investigations. The present study demonstrated that withdrawal from spinal application of remifentanil could dose-dependently induce long term potentiation (LTP) of C-fiber evoked field potentials. Remifentanil withdrawal could activate Src family kinases (SFKs) in microglia, and upregulate the expression of tumor necrosis factor alpha (TNFα) in spinal dorsal horn. Furthermore, pretreatment with either microglia inhibitor Minocycline, SFKs inhibitor PP2 or TNF αneutralization antibody could block remifentanil withdrawal induced spinal LTP, whereas supplement of recombinant rat TNFα to the spinal cord could reverse the inhibitory effect of Minocycline or PP2 on remifentanil withdrawal induced LTP. Our results suggested that TNFαrelease following SFKs activation in microglia is involved in the induction of LTP induced by remifentanil withdrawal.

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A randomized phase I trial evaluating the effects of inhaled 50–50% N₂O–O₂ on remifentanil‐induced hyperalgesia and allodynia in human volunteers

Cited by 7 publications

References 37 publications

Human surrogate models of central sensitization: A critical review and practical guide

Human surrogate models of central sensitization: A critical review and practical guide

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses

Withdrawal from spinal application of remifentanil induces long-term potentiation of c-fiber-evoked field potentials by activation of Src family kinases in spinal microglia

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A randomized phase I trial evaluating the effects of inhaled 50–50% N2O–O2 on remifentanil‐induced hyperalgesia and allodynia in human volunteers

Cited by 7 publications

References 37 publications

Human surrogate models of central sensitization: A critical review and practical guide

Human surrogate models of central sensitization: A critical review and practical guide

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses

Withdrawal from spinal application of remifentanil induces long-term potentiation of c-fiber-evoked field potentials by activation of Src family kinases in spinal microglia

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A randomized phase I trial evaluating the effects of inhaled 50–50% N₂O–O₂ on remifentanil‐induced hyperalgesia and allodynia in human volunteers