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Managing chronic whiplash associated pain with a combination of low-dose opioid (remifentanil) and NMDA-antagonist (ketamine)
Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
Center for Sensory-Motor Interaction (SMI), Laboratory for Experimental Pain Research, Aalborg University, Denmark.
Department of Anesthesiology, University Hospital, Bern, Switzerland.
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2007 (English)In: European Journal of Pain, ISSN 1090-3801, Vol. 11, no 7, 719-732 p.Article in journal (Refereed) Published
Abstract [en]

The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study.

Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2 ng/ml (stepwise) for remifentanil and 100 ng/ml for ketamine.

Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA.

KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1 ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2 ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain.

KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used.

Place, publisher, year, edition, pages
2007. Vol. 11, no 7, 719-732 p.
Keyword [en]
WAD, Neck pain, Remifentanil, Ketamine, Experimental pain, Pain assessment
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-12920DOI: 10.1016/j.ejpain.2006.11.002OAI: diva2:17396
Available from: 2008-01-30 Created: 2008-01-30 Last updated: 2009-08-19
In thesis
1. Experimental Aspects on Chronic Whiplash-Associated Pain
Open this publication in new window or tab >>Experimental Aspects on Chronic Whiplash-Associated Pain
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: Chronic pain after whiplash trauma (chronic WAD) to the neck is still a common clinical problem in terms of pain management, rehabilitation and insurance claims. In contrast to the increased knowledge concerning mechanisms of chronic pain in general, no clinical guidelines exist concerning assessment, pain control and rehabilitation of patients with chronic WAD.

Aim: The general aim of this thesis was to use experimental techniques to better understand the complex mechanisms underlying chronic pain after whiplash trauma. The specific aims of papers I and II were mainly to use analgesic drugs with different target mechanisms alone or in combinations to assess their effects on pain intensity (VAS). Experimental pain techniques were used in all studies to assess deep tissue sensitivity (electrical, mechanical and chemical stimuli). Paper IV aimed at assessing deep tissue sensitivity to mechanical and chemical stimulation. The aim in paper III was to investigate if biochemical changes in interstitial muscle tissue (trapezius muscle) could be detected in WAD patients.

Materials and Methods: The thesis is based on three different groups of patients with chronic WAD. In paper III and IV two different groups of healthy controls also participated. All patients were initially assessed in the pain and rehabilitation centre. In paper I (30 patients) and II (20 patients) two different techniques of drug challenges were used. In paper I: morphine, ketamine and lidocaine were used as single drugs. In paper II: remifentanil, ketamine and placebo were used in combinations and together with experimental pain assessments. Microdialysis technique was used in paper III (22 patients from study IV and 20 controls). In paper IV (25 patients and 10 controls) a new quantitative method, computerized cuff pressure algometry, was used in combination with intramuscular saline. In all papers, experimental pain techniques for deep tissue assessment (except cutaneous electrical stimulation in paper I) were used in different combinations: intramuscular hypertonic saline infusion, intramuscular electrical stimulation and pressure algometry.

Results and Conclusion: There are multiple mechanisms behind chronic whiplash-associated pain, opioid sensitive neurons, NMDA-receptors and even sodium channels might play a part. A significant share of the patients were pharmacological non-responders to analgesic drugs targeting the main afferent mechanisms involved in pain transmission, this implies activation of different pain processing mechanisms (i.e. enhanced facilitation or changes in the cortical and subcortical neuromatrix). Experimental pain assessments and drug challenges together indicate a state of central hyperexcitability. Ongoing peripheral nociception (paper III), central sensitization and dysregulation of pain from higher levels in the nervous system may interact. These findings are likely to be present early after a trauma, however it is not possible to say whether they are trauma-induced or actually represents pre-morbid variations. Clinical trials with early assessments of the somatosensory system (i.e., using experimental pain) and re-evaluations, early intervention (i.e. rehabilitation) and intensified pain management could give further knowledge.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008. 88 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1035
Neck injury, whiplash-associated disorders, chronic pain, central sensitization, pain assessment, drug challenges
National Category
Anesthesiology and Intensive Care
urn:nbn:se:liu:diva-10693 (URN)978-91-85895-19-9 (ISBN)
Public defence
2008-02-22, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2008-01-30 Created: 2008-01-30 Last updated: 2015-11-19

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