Peripherally applied opioids for postoperative pain: evidence of an analgesic effect? A systematic review and meta‐analysis

Nielsen, Bendt; Henneberg, Steen Winther; Schmiegelow, Kjeld; Friis, Susanne Molin; Rømsing, Janne

doi:10.1111/aas.12529

“…38 In humans, a meta-analysis of peripherally-delivered opioids for postoperative pain found that preoperative inflammation was a key factor in determining postoperative analgesic outcomes. 39 Accordingly, we report here that the potencies of both loperamide and oxymorphindole were increased following inflammation, such that ED 50 values following complete Freund's adjuvant are approximately three-to six-fold lower in inflamed than in naïve mice. This holds true for both drugs, as well as for both intraplantar and subcutaneous routes of administration.…”

Section: Discussionmentioning

confidence: 70%

Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice

Bruce

¹

,

Peterson

²

,

Kitto

³

et al. 2019

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Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background The long-term use of opioids for analgesia carries significant risk for tolerance, addiction, and diversion. These adverse effects are largely mediated by μ-opioid receptors in the central nervous system. Based on the authors’ previous observation that morphine and δ-opioid receptor agonists synergize in spinal cord in a protein kinase Cε–dependent manner, they predicted that this μ-opioid receptor–δ-opioid receptor synergy would take place in the central terminals of nociceptive afferent fibers and generalize to their peripheral terminals. Therefore, the authors hypothesized that loperamide, a highly efficacious μ-opioid receptor agonist that is excluded from the central nervous system, and oxymorphindole, a δ-opioid receptor agonist that was shown to synergize with morphine spinally, would synergistically reverse complete Freund’s adjuvant–induced hyperalgesia. Methods Using the Hargreaves assay for thermal nociception, the von Frey assay for mechanical nociception and the complete Freund’s adjuvant–induced model of inflammatory pain, we tested the antinociceptive and antihyperalgesic effect of loperamide, oxymorphindole, or the loperamide–oxymorphindole combination. Animals (Institute for Cancer Research [ICR] CD1 strain mice; n = 511) received drug by systemic injection, intraplantar injection to the injured paw, or a transdermal solution on the injured paw. Dose–response curves for each route of administration and each nociceptive test were generated, and analgesic synergy was assessed by isobolographic analysis. Results In naïve animals, the loperamide–oxymorphindole combination ED50 value was 10 times lower than the theoretical additive ED50 value whether given systemically or locally. In inflamed animals, the combination was 150 times more potent systemically, and 84 times more potent locally. All combinations showed statistically significant synergy when compared to the theoretical additive values, as verified by isobolographic analysis. The antihyperalgesia was ablated by a peripherally-restricted opioid antagonist. Conclusions From these data we conclude that the loperamide–oxymorphindole combination synergistically reverses complete Freund’s adjuvant–induced inflammatory hyperalgesia. The authors also conclude that this interaction is mediated by opioid receptors located in the peripheral nervous system.

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“…Carrageenan elicits an endogenous inflammatory response that mimics that which occurs naturally, suggesting that the nonresponsive state of the peripheral DOR system could also occur in inflammatory conditions where 12-/15-LOX metabolites of AA are generated, such as rheumatoid arthritis (Deleuran et al, 1994;Liagre et al, 1997) and osteoarthritis (Kelly et al, 2015). It is possible that a LOX-dependent nonresponsive state of peripheral opioid receptor systems may underlie the cases where some clinical studies have failed to demonstrate effectiveness of peripherally restricted opioids for the treatment of pain (for reviews, see Vadivelu et al, 2011;Nielsen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid–Dependent 12/15-Lipoxygenase Metabolites

Sullivan¹,

Chavera²,

Gao³

et al. 2017

J Pharmacol Exp Ther

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The function of opioid receptors (DOR) expressed by peripheral pain-sensing neurons (nociceptors) is regulated by both cyclooxygenase- and lipoxygenase (LOX)-dependent arachidonic acid (AA) metabolites. Whereas cyclooxygenase metabolites enhance responsiveness, LOX metabolites elicit a refractory, nonsignaling state of the DOR receptor system for antinociceptive signaling. In this study, using high-performance liquid chromatography-tandem mass spectrometry analyses, we have found that the 12-/15-LOX metabolites, 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, were elevated after treatment of adult rat primary sensory neuron cultures with AA. Exogenously applied 12-HETE and 15-HETE, but not 5-HETE, completely prevented DOR and opioid receptor (KOR) agonist-mediated inhibition of prostaglandin E2 (PGE)-stimulated cAMP accumulation, but not inhibition, by the 5-HT receptor agonist 5-carboxamidotryptamine in cultured peripheral sensory neurons and in Chinese hamster ovary (CHO) cells heterologously expressing DOR or KOR. Similarly, intraplantar injection of 12- or 15-HETE, either alone or in combination, prevented DOR agonist-mediated inhibition of PGE-evoked thermal allodynia. Further, both AA- and carrageenan-mediated induction of the nonresponsive state of the DOR system was blocked by an intraplantar coinjection of the 12-/15-LOX inhibitors baicalein and luteolin. In contrast to the regulation of cAMP signaling, pretreatment with 12- and 15-HETE had no effect on either DOR or KOR agonist- mediated activation of extracellular signal-regulated kinase in peripheral sensory neurons or CHO cells. These results suggest that the analgesic efficacy of peripherally restricted opioids for treatment of inflammatory pain may be enhanced by adjunct inhibition of LOX activity.

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“…e increased concentration of GLU and cortisol after operation indicated that besides nerve conduction regulating stress response, local inflammatory response was also related to cytokine release. erefore, a variety of measures were taken to reduce stress response after surgery [22,23]. e results of this study showed that preoperative analgesia could effectively reduce stress state of patients and oxycodone could effectively inhibit stress response.…”

Section: Discussionmentioning

confidence: 86%

Efficacy of Different Preemptive Analgesia on Postoperative Analgesia, Oxidative Stress, and Inflammatory Response after Gynecological Laparoscopic Surgery

Sun

¹

,

Yang²,

Wang

³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. To observe and compare the analgesic effects of oxycodone, pentazocine, and ketorolac tromethamine pre-emptive analgesia on gynecological laparoscopic patients after operation and the effects on oxidative stress and inflammatory reaction. Methods. A total of 64 patients who underwent elective gynecological laparoscopic surgery in Yiwu Central Hospital from June 2019 to December 2020 were randomly divided into four groups (n = 16). Before anesthesia induction, oxycodone (group A), pentazocine (group B), ketorolac tromethamine (group C), and normal saline (group D) were, respectively, administered. Patients’ mean arterial pressure (MAP) and heart rate (HR) changes, visual analogue scale (VAS), Bruggemann comfort scale (BCS), serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), blood glucose (CLU), serum cortisol level, postoperative adverse reactions, and additional analgesia were recorded at each time point. Results. The MAP levels of T2 (immediate intubation), T3 (immediate catheter removal), and T4 (5 min after catheter removal) in the four groups were higher than those of T1 (quiescent state), and the HR levels T2, T3, and T4 were lower than those of T1 P < 0.05 . The MAP and HR levels of T2, T3, and T4 in patients of groups A, B, and C were lower than those of group D in the same period P < 0.05 . The VAS and BCS scores of groups A, B, and C at 1, 6, 12, and 24 h after operation were better than those of group D at the same time, and the scores of group A at 1 h and 6 h after operation were better than those of groups B and C at the same time P < 0.05 . The levels of serum TNF-α, IL-6, and CRP in the four groups of patients at 6, 12, and 24 h after operation were higher than those before operation, but those in groups A, B, and C were lower than those in group D, and those in group A were higher than those in groups B and C at 12 h and 24 h after operation P < 0.05 . The CLU and serum cortisol levels in the four groups were significantly higher at 6, 12, and 24 h after operation, but those in groups A, B, and C were lower than those in group D, and those in group A were lower than those in groups B and C at 6 and 12 h after operation P < 0.05 . There was no significant difference in the incidence of adverse reactions within 24 h between the four groups P > 0.05 . The incidence of additional analgesia in groups A, B, and C was lower than that in group D P < 0.05 . Conclusion. Oxycodone, pentazocine, and ketorolac tromethamine are effective and safe in inhibiting postoperative pain and the generation of inflammatory factors and relieving inflammatory state in gynecological laparoscopic pre-emptive analgesia. Oxycodone has better postoperative analgesic effect because it can effectively alleviate stress reaction.

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Peripherally applied opioids for postoperative pain: evidence of an analgesic effect? A systematic review and meta‐analysis

Abstract: Evidence of a clinically relevant analgesic effect of peripherally applied opioids for acute postoperative pain is lacking. The analgesic effect of peripherally applied opioids may depend on the presence of preoperative inflammation.

Cited by 11 publications

References 73 publications

Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice

Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice

Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid–Dependent 12/15-Lipoxygenase Metabolites

Efficacy of Different Preemptive Analgesia on Postoperative Analgesia, Oxidative Stress, and Inflammatory Response after Gynecological Laparoscopic Surgery

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