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    Can dexmedetomidine reduce postoperative pain?

    Authors: Jasmina Markovic-Bozic

    Coauthors : Alenka Spindler Vesel

    Keywords EN: Perioperative pain control. Multimodal analgesia. Dexmedetomidine

    Abstract EN: Adequate perioperative pain control improves surgical outcome and prevents development of chronic pain. Opioids are still the main stay of perioperative analgesia. Non-opioid analgesics are used to provide better pain control with less opioid-related side effects. Dexmedetomidine has a potential role in multimodal analgesia strategy. It can be used in all perioperative stages. It improves postoperative analgesia, decreases perioperative opioid consumption and opioid related side effects, such as PONV. Potential use of dexmedetomidine for treatment of chronic and neuropathic pain and in rehabilitation is suggested. Preliminary safety data for perineuraly route of dexmedetomidine administration may be encouraging, but only its intravenous route is approved by FDA and EMA.


    Citation: Jasmina Markovic-Bozic, Alenka Spindler Vesel. Can dexmedetomidine reduce postoperative pain?. https://:doi.org/10.24175/sbd.2019.000008
    Received: April 23, 2019  Accepted: May 10, 2019  Published: May 10, 2019
    Copyright: © 2019 Markovic-Bozic et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC), which allows, distribution, reproduction in any medium, provided the original author and source are credited and non-commercial use.
    Funding: I certify that no funding has been received for the conduct of this study and/or preparation of this manuscript.
    Conflicts of Interest: I have no conflicts of interest to declare

    

    Can dexmedetomidine reduce postoperative pain?

    Jasmina Markovic-Bozic;1 Alenka Spindler Vesel2

    1,2MD, PhD, assist.

    Clinical department of anaesthesiology and surgical intensive therapy, University medical centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia

    Correspondence authors:

    jasmina.markovic1@kclj.si

    alenka.spindler@guest.arnes.si

    Abstract

    Adequate perioperative pain control improves surgical outcome and prevents development of chronic pain. Opioids are still the main stay of perioperative analgesia. Non-opioid analgesics are used to provide better pain control with less opioid-related side effects.

    Dexmedetomidine has a potential role in multimodal analgesia strategy. It can be used in all perioperative stages. It improves postoperative analgesia, decreases perioperative opioid consumption and opioid related side effects, such as PONV.

    Potential use of dexmedetomidine for treatment of chronic and neuropathic pain and in rehabilitation is suggested.

    Preliminary safety data for perineuraly route of dexmedetomidine administration may be encouraging, but only its intravenous route is approved by FDA and EMA.

    Key words: Perioperative pain control. Multimodal analgesia. Dexmedetomidine


    Introduction

    Management of acute postoperative pain is an important health care issue. The poor control of perioperative pain may lead to increased morbidity and postoperative complications (PONV, ileus), delayed mobilization and prolonged hospital stays (1-5).

    Adequate perioperative pain control improves surgical outcome and prevents development of chronic pain. It also prevents agitation and delirium perioperatively. Implementation of assessment-driven and standardized pain management protocols and PAD (pain, agitation, delirium) guidelines in a mixed medical/surgical intensive care unit (ICU) significantly decreased ventilator time, ICU stay and the length of hospitalization that consequently reduces costs for the health care system (6).

    Opioids are still the main stay of perioperative analgesia but are associated with adverse events. Therefore, non-opioid analgesics are used to provide better pain control with less opioid-related side effects (7-10).

    Multimodal analgesia is a strategy employing more than one type of analgesic or technique resulting in additive or synergistic analgesia while reducing side effects encountered with the sole use of one analgesic. Dexmedetomidine have a potential role in perioperative multimodal analgesia strategy (8).

    Dexmedetomidine characteristics

    Dexmedetomidine was first approved by the Food and Drug Administration (FDA) in 1999 for short- term use as an analgesic and sedative in the intensive care unit (9).

    Compared to clonidine, dexmedetomidine is eight times more specific for α-2 adrenoreceptors, with a α2:α1 selectivity ratio of 1,600:1,7. As a highly selective α-2 adrenoreceptor agonist, with no respiratory depressive effect and with short-term half-life of 2 hours, dexmedetomidine is useful in clinical practice to produce anxyolysis, sedation and analgesia. It augments anaesthetic effect and regional blockade. Beneficial effects are also neuroprotection, maintenance of respiratory function, sympatholysis, cardiovascular stabilizing effect and reduction of oxygen consumption. Its most notable side effects are bradycardia and hypotension. Hypertension is observed only with higher doses.

    European medicines agency (EMA) authorised its use to sedate adult patients in the hospital intensive care units and before or during diagnostic or surgical procedures where the patient remains awake (awake sedation) (10). In clinical studies it is used also off label, as adjuvant analgesic intravenously with general or regional anaesthesia or with local anaesthetics (LA) mixtures in central or peripheral nerve blocks. Systemic administration includes intravenous, intramuscular, intranasal, buccal, transdermal and subcutaneous routes. Local or regional application of dexmedetomidine into mixtures with LA involves different anatomic locations (spinal, caudal, epidural, perineural, intraarticular) (7).

    The analgesic mechanism of dexmedetomidine and its use for perioperative pain

    Dexmedetomidine can be applied directly into the peripheral nervous system and inhibits nociceptive neurotransmission through C and A fibres. Its central action is exerted through alpha-2 adrenergic receptors, located in the locus coeruleus and dorsal horn of spinal cord. It inhibits the release of norepinephrine on the presynaptic membrane and induces hyperpolarization with inhibition of pain signals to the brain. It is also proposed that dexmedetomidine induces the release of acetylcholine from spinal neurons and consequently increases the synthesis of nitric oxide which is involved in the pain modulation (7,11,12).

    Several studies have investigated the potential benefits of perioperative use of intravenous, perineural, and neuraxial administration of dexmedetomidine and its impact on perioperative outcomes (13-16). The results showed reduced postoperative pain, opioid use and opioid related side effects. Perioperative dexmedetomidine use has also a trend toward decreased adverse side effects such as PONV when compared with other commonly prescribed analgesic medications.

    Dexmedetomidine reduced perioperative pain and need for analgesics when using preoperatively (premedication, sedation, and adjuvant to LA). Its usage was safe and effective, with side effects only with higher doses.

    Intraoperatively, it prevented opioid induced hyperalgesia, reduced opioids and anaesthetics requirements, hemodynamic changes, respiratory depression and coughing. It increased patient satisfaction. Usually initial dose of 1µg/kg is given, followed by infusion of 0,2-0,7µg/kg/h.

    Dexmedetomidine has also been used as an adjuvant to LA. Intrathecaly or epiduraly, it provided better postoperative analgesia. As an adjuvant in peripheral nerve block and intravenous regional anaesthesia, it caused early onset time of analgesia, superior intraoperative and postoperative analgesia, better block quality and comfort of the patients. Dexmedetomidine 0,5-1µg/kg is usually added into analgesic mixture for the spinal, epidural, paravertebral, caudal and peripheral blocks. The prolongation of motor blockade may offset the benefits of dexmedetomidine if it delays rehabilitation or discharge, especially in the ambulatory setting.

    Neurotoxicity of dexmedetomidine

    Conclusive neurotoxicity data on perineural dexmedetomidine use are lacking. In animal studies dexmedetomidine epiduraly can demyelinize oligodendrocytes in the white matter, suggesting its harmful effects on the myelin sheath (17).

    Brachial plexus block in neonate rats at a high dose of dexmedetomidine decreased levels of IL-6 and TNF-α suggested minimal neurotoxicity (18). In recent study, intrathecal single dose of dexmedetomidine did not produce histological evidence of neurotoxicity (19).

    Future studies

    Most of the existing literature relating to perineural dexmedetomidine is limited by small sample sizes, dosing inconsistencies, and unreliable block assessment protocols. It is still uncertain whether perineural and intravenous dexmedetomidine have the same effectiveness in all peripheral blocks. It was reported recently that perineural and intravenous dexmedetomidine can both effectively prolong the interscalene block analgesic duration and reduce the opioid consumption without prolonging motor blockade (20).

    More research will establish the efficacy and safety of perioperative dexmedetomidine in the acute pain management and analgesia, especially its utility postoperatively and in the ambulatory setting.

    Future studies should therefore focus on optimal doses (safe, effective, minimal side effects), larger sample sizes, long term outcomes evaluation (chronic pain, rehabilitation, neurotoxicity) and patient satisfaction.

    Conclusions

    Dexmedetomidine decreases perioperative opioid consumption and improves postoperative analgesia.

    Successful application of dexmedetomidine with central and peripheral blocks suggests its potential use for treatment of chronic and neuropathic pain and in rehabilitation.

    Preliminary safety data for perineuraly route of dexmedetomidine administration may be encouraging, but only its intravenous route is approved by FDA and EMA.

    References

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    2.      Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol 2009; 22:588-93.

    3.      Apfelbaum JL, Ashburn MA, Connis RT, et al. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012; 116(2):248-73.

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    7.      Grewal A. Dexmedetomidine: new avenues. J Anaesthesiol Clin Pharmacol. 2011; 27(3):297–302.

    8.      Tang C, Xia Z. Dexmedetomidine in perioperative acute pain management: a non-opioid adjuvant analgesic. J Pain Res 2017; 10:1899–1904.

    9.      Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR and Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet 2017; 56: 893-913.

    10.  https://www.ema.europa.eu/en/medicines/human/EPAR/dexdor

    11.  Khasar SG, Green PG, Chou B, Levine JD. Peripheral nociceptive effects of alpha 2-adrenergic receptor agonists in the rat. Neuroscience 1995; 66(2):427-32.

    12.   Liang F, Liu M, Fu X, Zhou X, Chen P, Han F. Dexmedetomidine attenuates neuropathic pain in chronic constriction injury by suppressing NR2B, NF-kB, and iNOS activation. Saudi Pharm J 2017; 25(4):649-54.

    13.  Jin C, Cheng Y, Sun Y. The effects of continuous intravenous infusion of dexmedetomidine and remifentanil on postoperative pain: a systematic review and meta-analysis. Int J Clin Exp Med 2019; 12(1):1165-78.

    14.  Hussain N, Grzywacz VP, Ferreri CA, et al. Investigating the efficacy of dexmedetomidine as an adjuvant to local anaesthesia in brachial plexus block: a systematic review and meta-analysis of 18 randomized controlled trials. Reg Anesth Pain Med 2017; 42:184-96.

    15.  Wang K, et al. Dexmedetomidine combined with local anesthetics in thoracic paravertebral block. A systematic review and meta-analysis of randomized controlled trials. Medicine 2018; 97:46(e13164).

    16.  Peng K, et al. Optimization of postoperative intravenous patient-controlled analgesia with opioid-dexmedetomidine combinations: An updated meta-analysis with trial sequential analysis of randomized controlled trials. Pain Physician 2017; 20:569-95.

    17.  Konakci S, Adanir T, Yilmaz G, Rezanko T. The efficacy and neurotoxicity of dexmedetomidine administered via the epidural route. Eur J Anaesthesiol 2008; 25:403-9.

    18.  Kang Z, et al. Comparison of neurotoxicity of dexmedetomidine as an adjuvant in brachial plexus block in rats of different age. Neurotoxicol Teratol 2018; 69:21-6. doi: 10.1016/j.ntt.2018.07.001.

    19.  Ozdamar D, et al. Evaluation of the neurotoxicity of intrathecal dexmedetomidine on rat spinal cord (electromicroscopic observations). Saudi J Anaesth 2018; 12/1:10-15.

    20.   Abdallah FW, Dwyer T, et al. IV and perineural dexmedetomidine similarly prolong the duration of analgesia after interscalene brachial plexus block. A randomized, three-arm, triple-masked, placebo-controlled trial. Anesthesiology 2016; 124: 683-95.

About The Author/s
Jasmina Markovic-Bozic
jasmina.markovic1@kclj.si
Clinical department of anaesthesiology and surgical intensive therapy, University medical centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia


Alenka Spindler Vesel
Clinical department of anaesthesiology and surgical intensive therapy, University medical centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia


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DOI: 10.24175/sbd.2019.000008

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