Short- and long-term impact of remifentanil on thermal detection and pain thresholds after cardiac surgery: A randomised controlled trial

Sjoerd de Hoogd, Abraham J Valkenburg, Eric P A van Dongen, Edgar J Daeter, Joost van Rosmalen, Albert Dahan, Dick Tibboel, Catherijne A J Knibbe, Sjoerd de Hoogd, Abraham J Valkenburg, Eric P A van Dongen, Edgar J Daeter, Joost van Rosmalen, Albert Dahan, Dick Tibboel, Catherijne A J Knibbe

Abstract

Background: The clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term.

Objective: The current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing.

Design: A single-blind, randomised controlled trial.

Setting: A tertiary care teaching hospital in The Netherlands, from 2014 to 2016.

Patients: A total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy.

Interventions: Patients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points.

Main outcome measures: Warm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery.

Results: Both warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified.

Conclusion: Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems.

Trial registration: The study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://ichgcp.net/clinical-trials-registry/NCT02031016).

Figures

Fig. 1
Fig. 1
Flow chart of study.
Fig. 2
Fig. 2
Detection and pain thresholds at baseline (n=126), 3 days after surgery (n=124) and 12 months after surgery (n=121). Whiskers represent the 5th to 95th percentiles. Black, fentanyl group; grey, remifentanil group.

References

    1. Macrae WA. Chronic postsurgical pain: 10 years on. Br J Anaesth 2008; 101:77–86.
    1. Bruce J, Drury N, Poobalan AS, et al. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain 2003; 104:265–273.
    1. Ho SC, Royse CF, Royse AG, et al. Persistent pain after cardiac surgery: an audit of high thoracic epidural and primary opioid analgesia therapies. Anesth Analg 2002; 95:820–823.
    1. Meyerson J, Thelin S, Gordh T, et al. The incidence of chronic poststernotomy pain after cardiac surgery – a prospective study. Acta Anaesthesiol Scand 2001; 45:940–944.
    1. Berger A, Dukes EM, Oster G. Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 2004; 5:143–149.
    1. Leadley RM, Armstrong N, Reid KJ, et al. Healthy aging in relation to chronic pain and quality of life in Europe. Pain Pract 2014; 14:547–558.
    1. Andrew R, Derry S, Taylor RS, et al. The costs and consequences of adequately managed chronic noncancer pain and chronic neuropathic pain. Pain Pract 2014; 14:79–94.
    1. Haroutiunian S, Nikolajsen L, Finnerup NB, et al. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain 2013; 154:95–102.
    1. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German research network on neuropathic pain (DFNS): standardized protocol and reference values. Pain 2006; 123:231–243.
    1. Zaslansky R, Yarnitsky D. Clinical applications of quantitative sensory testing (QST). J Neurol Sci 1998; 153:215–238.
    1. Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009; 10:556–572.
    1. Werner MU, Mjobo HN, Nielsen PR, et al. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology 2010; 112:1494–1502.
    1. Grosen K, Fischer IW, Olesen AE, et al. Can quantitative sensory testing predict responses to analgesic treatment? Eur J Pain 2013; 17:1267–1280.
    1. Lundblad H, Kreicbergs A, Jansson KA. Prediction of persistent pain after total knee replacement for osteoarthritis. J Bone Joint Surg Br 2008; 90:166–171.
    1. Wylde V, Sayers A, Lenguerrand E, et al. Preoperative widespread pain sensitization and chronic pain after hip and knee replacement: a cohort analysis. Pain 2015; 156:47–54.
    1. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 2014; 112:991–1004.
    1. Yu EH, Tran DH, Lam SW, et al. Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia 2016; 71:1347–1362.
    1. de Hoogd S, Ahlers SJ, van Dongen EP, et al. Is intraoperative remifentanil associated with acute or chronic postoperative pain after prolonged surgery? An update of the literature. Clin J Pain 2016; 32:726–735.
    1. van Gulik L, Ahlers SJ, van de Garde EM, et al. Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy. Br J Anaesth 2012; 109:616–622.
    1. de Hoogd S, Ahlers SJGM, van Dongen EPA, et al. Randomized controlled trial on the influence of intraoperative remifentanil versus fentanyl on acute and chronic pain after cardiac surgery. Pain Pract 2018; 18:443–451.
    1. Torensma B, Thomassen I, van Velzen M, et al. Pain experience and perception in the obese subject systematic review (revised version). Obes Surg 2016; 26:631–639.
    1. de Hoogd S, Ahlers SJ, van Dongen EP, et al. Remifentanil versus fentanyl during cardiac surgery on the incidence of chronic thoracic pain (REFLECT): study protocol for a randomized controlled trial. Trials 2014; 15:466.
    1. Ahlers SJ, van Gulik L, van Dongen EP, et al. Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial. Anaesth Intensive Care 2012; 40:417–426.
    1. van den Bosch GE, van Dijk M, Tibboel D, et al. Thermal quantitative sensory testing in healthy Dutch children and adolescents standardized test paradigm and Dutch reference values. BMC Pediatr 2017; 17:77.
    1. Valkenburg AJ, van den Bosch GE, de Graaf J, et al. Long-term effects of neonatal morphine infusion on pain sensitivity: follow-up of a randomized controlled trial. J Pain 2015; 16:926–933.
    1. Rolke R, Magerl W, Campbell KA, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain 2006; 10:77–88.
    1. van Gulik L, Janssen LI, Ahlers SJ, et al. Risk factors for chronic thoracic pain after cardiac surgery via sternotomy. Eur J Cardiothorac Surg 2011; 40:1309–1313.
    1. Cleeland CS, Ryan KM. Pain assessment: global use of the brief pain inventory. Ann Acad Med Singapore 1994; 23:129–138.
    1. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005; 103:147–155.
    1. Schmidt S, Bethge C, Forster MH, et al. Enhanced postoperative sensitivity to painful pressure stimulation after intraoperative high dose remifentanil in patients without significant surgical site pain. Clin J Pain 2007; 23:605–611.
    1. Salengros JC, Huybrechts I, Ducart A, et al. Different anesthetic techniques associated with different incidences of chronic postthoracotomy pain: low-dose remifentanil plus presurgical epidural analgesia is preferable to high-dose remifentanil with postsurgical epidural analgesia. J Cardiothorac Vasc Anesth 2010; 24:608–616.
    1. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 2014; 13:924–935.
    1. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14:145–161.
    1. Li Y, Wang H, Xie K, et al. Inhibition of glycogen synthase kinase-3beta prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-d-aspartate receptors in vivo and vitro. PLoS One 2013; 8:e77790.
    1. Yuan Y, Wang JY, Yuan F, et al. Glycogen synthase kinase-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating N-methyl-d-aspartate receptor trafficking. Anesth Analg 2013; 116:473–481.
    1. Arout CA, Edens E, Petrakis IL, et al. Targeting opioid-induced hyperalgesia in clinical treatment: neurobiological considerations. CNS Drugs 2015; 29:465–486.
    1. Zhao Q, Zhang L, Shu R, et al. Involvement of spinal PKMzeta expression and phosphorylation in remifentanil-induced long-term hyperalgesia in rats. Cell Mol Neurobiol 2017; 37:643–653.
    1. Chaparro LE, Smith SA, Moore RA, et al. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013; CD008307.
    1. Martinez V, Pichard X, Fletcher D. Perioperative pregabalin administration does not prevent chronic postoperative pain: systematic review with a meta-analysis of randomized trials. Pain 2017; 158:775–783.
    1. Granot M. Can we predict persistent postoperative pain by testing preoperative experimental pain? Curr Opin Anaesthesiol 2009; 22:425–430.
    1. Marcuzzi A, Dean CM, Wrigley PJ, et al. Prognostic value of quantitative sensory testing in low back pain: a systematic review of the literature. J Pain Res 2016; 9:599–607.
    1. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010; 23:611–615.
    1. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic postoperative pain: preoperative DNIC testing identifies patients at risk. Pain 2008; 138:22–28.
    1. Nothnagel H, Puta C, Lehmann T, et al. How stable are quantitative sensory testing measurements over time? Report on 10-week reliability and agreement of results in healthy volunteers. J Pain Res 2017; 10:2067–2078.
    1. Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 2017; 158:261–272.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe