CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome

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CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome
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  CNS Measures of Pain Responses Pre- and Post-AnestheticKetamine in a Patient with Complex Regional Pain Syndrome L. Becerra, PhD,* R. J. Schwartzman, MD, † R. T. Kiefer, MD, ‡ P. Rohr, M MD, ‡ E. A. Moulton, PhD,*D. Wallin, BS,* G. Pendse, MA, MS,* S. Morris, BA,* and David Borsook, MD, PhD* *Pain/Analgesia Imaging Neuroscience (PAIN) Group, Brain Imaging Center, McLean Hospital, Harvard Medical School,Belmont, Massachusetts;  † Drexel University College of Medicine, Department of Neurology, Philadelphia, Pennsylvania,USA; and  ‡ Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University, Tuebingen, Germany A B S T R A C T Background.  Previous reports have indicated that ketamine anesthesia may produce significant improvement if not complete recovery of patients with complex regional pain syndrome (CRPS).  Aims.  Here we report on a patient who had CRPS affecting mainly the right side of her body whounderwent functional magnetic resonance imaging (fMRI) scans prior to and in the months fol-lowing apparent successful treatment with anesthetic doses of ketamine.  Materials and Methods.  The patient underwent two imaging sessions: one during her pain state(CRPS + ) and 1 month after her ketamine treatment in her pain-free state (CRPS - ).Both spontaneous and evoked (brush, cold, and heat) pain scores decreased from 7–9/10 on a visual analog scale prior to the treatment to 0–1 immediately following and for months after thetreatment. For each imaging session, the identical mechanical (brush) and thermal (cold and heat)stimuli were applied to the same location (the skin of the dorsum of the right hand).  Results.  Comparison of CRPS +  vs CRPS - for the three stimuli showed significant changes through-out the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcorticalregions such as caudate nucleus, and in the cerebellum. In addition, resting state network analysisshowed a reversal of brain network state, and the recovered state paralleled specific default networksin healthy volunteers. Discussion.  The observed changes in brain response to evoked stimuli provide a readout for thesubjective response. Conclusion.  Future studies of brain function in these patients may provide novel insight into brainplasticity in response to this treatment for chronic pain.  Key words.  CRPS; Neuropathic Pain; Imaging; Clinical; fMRI; Ketamine Coma Introduction C omplex regional pain syndrome (CRPS) isconsidered to be a disease of the peripheraland central nervous systems [1,2]. It may follow peripheral nerve injury [3,4] or even minor trauma[5]. The condition affects women more frequently than men, and the upper extremities more oftenthan the lower [6]. The only population-basedstudy reports an incidence of 5.46/100,000person-years at risk but other more recent studiessuggest higher incidences ranging from 15 to26/100,000 [6,7]. The syndrome has been vali-dated and characterized into four major clusters:1) pain (allodynia, hyperalgesia, hyperpathia); 2)edema and sudomotor dysfunction (i.e., sweating);3) vasomotor dysfunction (i.e., skin color and tem-perature changes); and 4) motor and trophic dys-function (i.e., dystonia and tremor) accompanied  Reprint requests to:  David Borsook, MD, PhD, Pain/  Analgesia Imaging Neuroscience (P.A.I.N.) Group, BrainImaging Center, McLean Hospital, 115 Mill Street,Belmont, MA 02478, USA. Tel: 617-855-2691; Fax: 617-855-3772; E-mail: PAIN MEDICINE Volume *  •  Number *  •  2009 © American Academy of Pain Medicine 1526-2375/09/$15.00/** **–** doi:10.1111/j.1526-4637.2009.00559.x  by atrophy and dystrophy [8]. Early in the courseof the illness, it remains peripheral, but with timecentralizes and spreads to the brain [1,2,9]. A significant number of patients with CRPSare refractory to the usual therapeutic modalities.However,manycasesofCRPShaveresolvedspon-taneously [10,11]. Ketamine has been successfully utilized for both early cases and those that are late,generalized, and refractory [12–15]. The drug hasa complex mode of action both pre- and post-synaptically, but its major effect is thought to be itsblocking action of n-methyl-d-aspartate (NMDA)receptors on neurons that transmit pain-relatedneural signals [16]. The discovery that a CRPSpatient completely recovered following regularketamine infusions led to the usage of ketamine inanesthetic doses for a series of refractory patients[12]. Extensive neuropsychological testing in nineof these patients who had undergone 5 days of anesthetic ketamine and midazolam infusionsrevealed that pain was reduced with no adversepsychological or cognitive effects [17]. Completerecovery from intractable CRPS using anestheticdoses of ketamine has previously been reported[12,18].In this case report, using fMRI, we evaluatedfunctional central nervous system (CNS) changesin response to evoked stimuli and resting statenetworks (RSNs) in a patient with CRPS afterreceiving ketamine-induced coma in KlinikumSaarbruecken, Saarbruecken Germany. RSNs arean evaluation of functional brain connectivity during a resting state [19] and reflect an organizedbaseline level of activity characterized by low frequency blood-oxygenation level dependent (BOLD) signal fluctuations [20]. The patient wasimaged twice, once prior to the treatment (painstate) and once following her treatment (pain-freestate as reported by the subject including the use of quantitative sensory testing [QST]). The ability toevaluate CNS changes in a pre-existing condition(i.e., patients with severe pain due to CRPS) and asubsequent state of significantly reduced pain,offers the potential for novel insights into thedisease. Methods Patient History   The patient is a 27-year-old woman who was diag-nosed with CRPS in 1999 (see Details of ClinicalHistory Appendix). Her CRPS followed a motor vehicle accident that resulted in the development of pain in her right arm. She underwent a numberof treatments including sympathetic blocks andnumerous medications (carbamazepine, celeco- xib, amitriptyline, lidocaine infusions, lidocainepatches, gabapentin, and diphenhydramine). Fol-lowing the onset of her pain, it spread up the armas well as down to the right leg (see Figure 1). A review of medical systems was otherwise unre-markable. She was seen at the brain-imagingcenter on 1/11/06 (visit 1) prior to going toGermany for the ketamine infusions and then on2/23/07 (visit 2); at this later time she had no pain. Ethics Approval   The study on fMRI evaluation of the subjects priorto and following their treatment was approved by the McLean Hospital institutional review boardethics committee and this study met the standardsfor the principles for medical research in humansubjects [21]. No therapy was administered at theimaging site. Figure 1  Distribution of pain pre-and post-ketamine coma. The figureshowsself-reporteddistributionofpain(shadedregion)performedpriorto(leftpanels;CRPS + )andafter(rightpanels;CRPS - ) the ketamine treatment. Becerra et al. 2  Pre-Imaging Assessment On both visits, she underwent a battery of ques-tionnaires (Table 1) and testing (Figure 2):1.  Galer/Jensen neuropathy pain scale (NPS):  Thescores for the NPS, each rated on a scale forpain quality for visit one (CRPS + ) and two(CRPS - ) respectively were: intense—8 vs 0,sharp—6 vs 0, hot—8 vs 0, dull—1 vs 0, cold 0 vs 0, sensitive—7 vs 1; itchy—0 vs 0, pain withstanding or walking—7 vs 0, unpleasant—8 vs0, deep pain rating 9 vs 0, and surface painrating—8 vs 0.2.  Beck depression scale—Beck Depression Index(BDI-II):  She scored 4/63 on the first visit and7/63 on the second visit.3.  McGill pain questionnaire (MPQ):  At the time of her first visit, the patient scored a 20/78 on thepainratingindex(PRI)sectionoftheMPQ,anda 4–5/5 on the present pain intensity (PPI)section.Thepatientindicatedthatthefollowing wordsfromthequestionnairebestdescribedherpain during her first visit: pain level now   = “excruciating,” worst level  =  “excruciating,”lowestlevel  =  “discomforting,”worsttoothache =  “distressing,” worst headache  =  “horrible,”and worst stomachache  =  “distressing.” On hersecond visit, she scored 0/78 on PRI and 0/5 onPPI. Word use that best described her pain onher second visit: pain level now   =  “mild,” worst level  =  “discomforting,” lowest level  =  “mild,” worst toothache  =  “horrible,” worst headache =  “excruciating,” and worst stomachache  = “horrible.”4.  QST:  QST was performed outside of themagnet prior to each MR scanning session todetermine cold and heat pain detection thresh-olds (Figure 2), and to determine sensitivity tonormally innocuous brushing. An ascendingmethod of limits approach was used to deter-mine the subject’s thresholds. From a baselinetemperature of 32°C, decreasing cold orincreasing heat stimuli were delivered at a rateof 2°C/s. She was instructed to tap the mousebutton at the first perception of pain. For heat and cold, this was performed three times; theaverage temperature was recorded by thethermal sensory analyzer (TSA) program.During the second visit (QST and Neuroimag-ing II), the QST determined temperatures of the first visit were again used for scanning, but QST measures were recorded to detect any changes in her pain thresholds. On her first  visit (CRPS + ), her detection threshold for heat pain was 36.9°C and for cold pain was 29.0°C Table 1  Pain and depression questionnaires pre- andpost-treatment Test range CRPS + CRPS - Neuropathy pain scaleIntense 0–10 8 0Sharp 0–10 6 0Hot 0–10 8 0Dull 0–10 1 0Cold 0–10 0 0Sensitive 0–10 7 1Itchy 0–10 0 0Pain w/ standing/walking 0–10 7 0Unpleasant 0–10 8 0Deep pain 0–10 9 0Surface pain 0–10 8 0McGill pain questionnairePain rating index 0–78 20 0Present pain intensity 0–5 4.5 0Pain level now 0–5 5 1Worst level 0–5 5 2Lowest level 0–5 2 1Worst toothache 0–5 3 4Worst headache 0–5 4 5Worst stomachache 0–5 3 4BDI-II 0–63 4 7 CPRS  =  complex regional pain syndrome; BDI-II  =  Beck Depression Index. Figure 2  Heat and cold pain detec-tion thresholds. Mean pain detectionthresholds based on ascending ordescending method of limits. For eachcondition, thresholds for hot and coldpain were recorded three times each.At rest, the thermode maintained32°C. The unaffected limb was testedonly during the CRPS - state. Errorbars denote standard deviation. Ketamine, Pain, CRPS, and the Brain   3  for her affected hand. Brushing of her affectedarm evoked a pain intensity rating of 8/10, while brushing her unaffected arm evoked nopain (0/10). On her second visit (CRPS - ), herpain thresholds were 47.5°C for heat and14.8°C for cold on her affected hand and45.1°C for heat and 16.2°C for cold for herunaffected hand. For both arms, brushingevoked no pain (0/10). fMRI  Magnetic resonance imaging (MRI) was carriedout in a 3.0 T Siemens Trio scanner (Erlangen,Germany) with a quadrature coil. For anatomicallocalization, a Magnetization Prepared RApidGradient Echo (MPRAGE) was used (1  ¥  1 mmin-plane resolution, 1.3 mm slice thickness). Mag-nitude and phase images were acquired on thesame orientation as the functional scans to correct for susceptibility distortions. Pre- and post-treatment sessions involved the acquisition of ana-tomical and functional scans (Figure 3). Sevenfunctional scans were obtained: six evoked scans(two scans each for brush, heat, and cold stimuli)and one resting state/default network state scan.Functional scans were acquired using a gradient-echo echo-planar imaging (GE EPI) sequence with isotropic resolution of 3.5 mm, 41 slices (no-gaps) were prescribed obliquely along the brain-stem axis. For functional scans using stimuli,repetition time/time to echo (TR/TE)  =  3.0 s/ 30 ms and 404 volumes were acquired. For theresting state functional scan, TR/TE  =  3.0 s/ 30 ms and 202 volumes were acquired. In order todetermine brain areas activated by pain, fMRI wasused to measure regional hemodynamic changesrelated to the brush, heat, and cold stimuli. Stimuli in the Scanner For each functional scan using stimulation, fourstimuli were delivered as explained above for25 seconds with interstimulus intervals of 60 seconds. 1) Brush: brush stimuli was applied by a Velcro-topped stick administered to the skin of the dorsum of the hand at 1–2 Hz (1–2 strokes persecond) on the affected limb; 2) for cold, a3  ¥  3 cm Peltier probe was used to deliver coldstimuli 2°C below pain threshold to the dorsumof the hand using a Food and Drug Administration(FDA) approved TSA device (MEDOC Advanced Medical Systems, Ltd., Haifa, Israel); and 3) forheat, the same probe was used to deliver heat stimuli 2°C above pain threshold to the dorsum of the hand. After the fMRI scans (with the applica-tion of sensory stimuli), the subject used a visualanalog scale (VAS) to rate her perceived painintensity (0  =  “no pain” and 10  =  “worst painimaginable”) and pain unpleasantness (0  =  “Min”and 10  =  “Max”). Ketamine Infusion Treatment and Followup Anesthesia Protocol  The patient was treated at outside hospitals. Stan-dard pharmacological and interventional therapy had failed to produce any pain relief or halt thespread of CRPS in trials at Drexel University Hos-pital (Dr. Schwartzman). As a last treatment option, the patient was transferred to the intensivecare unit and treated on a compassionate care basis with anesthetic doses of ketamine in the Depart-ment of Anesthesiology and Intensive Care Medi-cine at Eberhard-Karls University, Tuebingen,Germany (Dr. Kiefer and Dr. Rohr) as previously reported [12,15]. Anesthesia was induced by bolus injections of ketamine (1.5 mg/kg) and midazolam (7.5 mg). Tracheal intubation was facilitated by vecuronium(0.1 mg/kg). Treatment was maintained by infu-sions of ketamine over 5 days, starting at 3 mg/ kg/h, followed by gradual daily titration upto a final dose of 7 mg/kg/h. Midazolam was co-administered and adjusted as clinically required(0.15–0.4 mg/kg/h) to maintain a stable deep seda-tion(Ramsayscore4–5),andtoattenuateketaminespecific side effects, that is, agitation. Figure 3  Imaging paradigm. Func-tional scans using brush, cold, or heatinvolved the presentation of fourstimulus cycles of 25 s on/60 s off.Two functional scans for each stimulustype were acquired. The resting statescan did not involve the application ofstimuli. Identical imaging paradigmswere performed at each session. Becerra et al. 4  In addition, standardized additional drugs wereadministered as follows:1. Deep Venous Thrombosis and Ulcer Prophy-laxis: The patient received intravenous unfrac-tionated low dose heparin 7.500–15.000 I.E./d(Liquemin ® , Roche, Germany) under regularactivated partial thromboplastin time (aPTT)monitoring, and the proton pump inhibitorpantoprazole 40 mg/d (Pantozol ® , AltanaPharma, Germany).2. Clonidine: Clonidine (Catapresan ® , Boe-hringer Ingelheim, Germany) was administeredintravenously (0.20–0.85  m g/kg/h) to controlthe hemodynamic stimulating ketamine effects,to attenurate psychomimetic and potential neu-rotoxic side effects of ketamine. Dosage wasadjusted as clinically required (0.20–0.85  m g/ kg/h) to control tachycardia and hypertension. The infusion of clonidine was maintained at aminimum dose of 0.15  m g/kg/h throughout theintensive care treatment. Clinical Follow-up She was also seen at her treatment center (Dr.Schwartzman) at 2 weeks, 4 weeks and 3 monthsafter her treatment in Germany and reported not pain (including no dynamic or static allodynia, nohyperalgesia, deep muscle sensitization or hyper-pathia). No movement disorder or autonomicdysregulation was noted on clinical examination.She was seen 12 months after her treatment inGermany for the second scan. At this time shereported no pain since her ketamine treatment inGermany. Image Processing   Analysis of fMRI data was carried out using fMRIExpert Analysis Tool Version 5.43, part of OxfordCenterforFunctionalMRIoftheBrain’s(FMRIB)Software Library (FSL, The following pre-processing steps wereapplied; high-pass filtering for trend removal andspatial smoothing full width at half maximum(FWHM)  =  10 mm to improve signal to noiseratio. General linear model (GLM)-based time-series statistical analysis was carried out usingFMRIB’s improved linear model with local auto-correlation correction. Statistical maps corre-sponding to evoked pain were created, and a linearcontrastwasrun.Statisticalmapswerethresholdedusing Gaussian mixture modeling with automaticmodel order selection using Bayes informationcriterion. The contrast analysis consisted of single-level voxel-wise  t  -tests between the scans acquired inthe pathological pre-treatment state (CRPS + ) andanother in the pain-free post-treatment state(CRPS - ). With a contrast analysis, three results arepossible (Figure 4): 1) increased response of thetest condition A (CRPS + ) vs control condition B Figure 4  Contrastanalysisoutcomes.Summary of the three main outcomesof the contrast analysis: increasedresponse, decreased response, andvalence change. Increased and de-creased responses can be describedin terms of changed signal magnitude,whereas valence change represents areversal in the sign of the response.Condition A  =  CRPS + ; Condition B  = CRPS - . Under the column for signalpattern, red indicates positive res-ponses and blue indicates negative. Ketamine, Pain, CRPS, and the Brain   5
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