Brush-evoked allodynia predicts outcome of spinal cord stimulation in Complex Regional Pain Syndrome type 1

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Brush-evoked allodynia predicts outcome of spinal cord stimulation in Complex Regional Pain Syndrome type 1
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  Brush-evoked allodynia predicts outcome of spinal cord stimulationin Complex Regional Pain Syndrome type 1 Frank van Eijs a , Helwin Smits a , José W. Geurts a, * , Alfons G.H. Kessels b , Marius A. Kemler a ,Maarten van Kleef  a , Elbert A.J. Joosten a , Catharina G. Faber c a Maastricht University Medical Centre, Department of Anesthesiology and Pain Management, The Netherlands b Maastricht University Medical Centre, Department of Clinical Epidemiology and Medical Technology Assessment, The Netherlands c Maastricht University Medical Centre, Department of Neurology, The Netherlands a r t i c l e i n f o  Article history: Received 2 July 2009Received in revised form 1 October 2009Accepted 19 October 2009Available online 25 November 2009 Keywords: Spinal cord stimulation (SCS)Complex Regional Pain Syndrome type 1(CRPS-1)Brush-evoked allodyniaMechanical hypoesthesiaPrognostic factors a b s t r a c t Background:  Spinal cord stimulation (SCS) has proven to be an effective however an invasive and rela-tively expensive treatment of chronic Complex Regional Pain Syndrome type 1(CRPS-1). Furthermore,in one third of CRPS-1 patients, SCS treatment fails to give significant pain relief and 32–38% of treatedpatients experience complications. The aim of the current study was to develop effective prognostic fac-tors for prediction of successful outcome of SCS. Methods and results:  Thestudypopulationconsistedof36chronicCRPSpatientsenrolledinarandomizedcontrolled trial of SCS efficacy. We analyzed various prognostic factors in the group of patients treatedwith SCS and compared baseline values of possible predictors of outcome in the successfully treatedand the not successfully treated group. Success was defined as Patient Global Perceived Impression of Change score of at least ‘‘much improved” and pain reduction of at least 2.5 on a visual-analogue scale(VAS score 0–10). Univariate analyses showed that patient age, duration of the disease, localization of the disease, intensity of the pain, and the presence of mechanical hypoesthesia did not predict SCS suc-cess. The mean and maximum value of brush-evoked allodynia proved to be statistically significant pre-dictors of outcome. Using Receiver-Operating Characteristic (ROC) curve analyses of maximumallodyniavalues, the diagnostic sensitivity for successful SCS was 0.75 and the specificity 0.81. Conclusion:  Brush-evokedallodynia maybeasignificant negativeprognostic factor of SCStreatment out-come after 1 year in chronic CRPS-1.   2009 European Federation of International Association for the Study of Pain Chapters. Published byElsevier Ltd. All rights reserved. 1. Introduction CRPS-1 is a syndrome that describes an array of painful condi-tions that are characterized by a continuing regional pain whichisseeminglydisproportionateintimeordegreetotheusualcourseof any known trauma or other lesion, as defined by the clinicaldiagnostic criteria of the International Association for the Studyof Pain (IASP) (Merskey, 1994). Common symptoms in CRPS-1 pa-tientsarethepresenceofpain,edema,trophicchangesandsensorydisturbances, with mechanical hypoesthesia being present in 74%and mechanical allodynia in 85% of cases (Kemler et al., 2000b;Maihofner and Birklein, 2007; Maihofner et al., 2006).Spinal cord stimulation (SCS) is an accepted, effective therapyfor chronic pain in Complex Regional Pain Syndrome (CRPS) pa-tients who fail to improve with medication, physical therapy orless invasive procedures and who require additional or moreaggressive pain therapy (Grabow et al., 2003; Taylor et al., 2006).It is considered general practice in SCS treatment to begin with atest stimulation period of about one week with an external stimu-latingdevicebeforeapermanentSCSdeviceisimplanted.Bothteststimulation and subsequent implantation of a SCS device are inva-sive procedures, with common complications such as electrodedisplacement and pain from the pulse generator pocket, requiringreoperation. These complications are reported in 31–38% of pa-tients within the first 2 years of stimulation (Kemler et al., 2004;Kumar et al., 2006).About two thirds of CRPS-1 patients undergo implantation of apermanent spinal cord stimulating system (Kemler et al., 2001;North et al., 1991; Spiegelmann and Friedman, 1991). The effectof the permanent SCS on pain may gradually decline over time(Farrar et al., 2001; Kemler et al., 2008; Kumar et al., 1998).There have been few reports on the prognostic factors in suc-cessful stimulation in CRPS-1 (Sindou et al., 2003; Smits et al., 1090-3801/$36.00    2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ejpain.2009.10.009 *  Corresponding author. Address: Department of Anesthesiology and PainManagement, Maastricht University Medical Centre, Mail Box 5800, 6202 AZMaastricht, The Netherlands. Tel.: +31 043 3877673. E-mail address: (J.W. Geurts).European Journal of Pain 14 (2010) 164–169 Contents lists available at ScienceDirect European Journal of Pain journal homepage:  2006; Taylor et al., 2006). Absent or significantly altered neuralconductivity in the dorsal column-lemniscal system as measuredbysomatosensoryevokedpotentials(SSEPs)wasanegativepredic-tor of SCS success in patients with intractable chronic neuropathicpain (Sindou et al., 2003). A differential effect of SCS related to theseverity of the allodynia was reported in an experimental neuro-pathic pain model in rats (Smits et al., 2006). In this model SCSled to a better and faster pain relief in mildly allodynic rats thanin those with severe allodynia.The present study is part of our participation in a randomizedcontrolled trial of SCS efficacy for CRPS patients out of whichdemographic criteria and a variety of reliable and validated painand sensory measurement were used to asses changes in outcomein the SCS treated group (Kemler et al., 2001).For identification of predictors for successful pain relief afterSCS treatment, we analyzed pretreatment responses to the abovementioned criteria and correlated each with the reported pain sta-tus aftertrial stimulationandafter 1yearof SCStreatment. Specialattention was paid to two clinically useful and common sensorycharacteristics in CRPS-1, namely mechanical hypoesthesia andbrush-evoked allodynia. 2. Methods  2.1. Patients Thestudypopulationwasdrawnfromaseriesof54consecutiveCRPS-1 patients who underwent a randomized trial of SCS at theUniversity Medical Centre of Maastricht, The Netherlands (Kemleret al., 2000a). Of these trial patients only the 36 patients treatedwith SCS were considered for this study.Patientswereeligibleforthestudyiftheywerebetween18and65years old and met the diagnostic criteria for CRPS-1 establishedbytheIASPwithimpairedfunctionandsymptomsbeyondtheareaof trauma (Table 1) (Merskey, 1994). Additional criteria for enrolment included disease which wasclinically restricted to one hand or foot and affected the entirehand or foot, and which had lasted for at least 6 months. Further-more, patients should not have a sustained response to standardtherapy (6 months of physical therapy, sympathetic blockade,transcutaneous electrical nerve stimulation, and pain medication),and suffer a mean pain intensity of at least 5cm on a visual-ana-logue scale from 0 (no pain) to 10cm (worst imaginable pain).Exclusion criteria were the presence of Raynaud’s disease,current or previous neurologic abnormalities unrelated to reflexsympathetic dystrophy, another condition affecting the functionof the diseased or contra lateral extremity, a blood-clotting disor-der, or use of an anticoagulant drug, and implanted cardiac pace-maker. The study was approved by the Medical Ethics Committeeof Maastricht University Medical Centre, Maastricht, The Nether-lands.Allpatientsgavewritteninformedconsentpriortoinclusionin the study.Ofthe36patients,24patientswereresponderstoSCStrialther-apyandsubsequentlyunderwentimplantationofapermanentSCSdevice. In 12 patients the trial stimulation was unsuccessful andthe percutaneous trial electrode was removed. All 36 patients re-ceived a standardized physical therapy program.  2.2. Materials All 36 patients considered for this study had a trial stimulationperiod of at least one week of home-testing during which painhad to be scored in a pain diary, three times a day ( Jensen andMcFarland, 1993). If there was less than 50% pain reduction, pa-tients were considered non-responders, and subsequently the testelectrode was removed. A spinal cord stimulator was implantedpermanently if the visual-analogue score for the intensity of painduring the last four days of the testing period was at least 50%lower than the baseline score, or if there was a score of at least6 (‘‘much improved”) on a seven-point scale for patients globalimpression of change (PGIC). PGIC is a seven-point ordinal scale,used after treatment, as an external criterion of clinically impor-tant change. A score of 4 means no change in the condition, andscores >4 denotes an improvement indicating ‘‘improved”, ‘‘muchimproved” and ‘‘very much improved”, and a score of 3 or lessmeans a worsening, ‘‘ minimally worse”, ‘‘much worse”, ‘‘verymuch worse” (Forouzanfar et al., 2003). PGIC measures are validindicators of important change in CRPS patients (Farrar et al.,2001; Forouzanfar et al., 2003).  2.3. Implantation of the Spinal Cord Stimulator System After the prophylactic administration of cefuroxime (1500mggiven intravenously), the patient was placed in the prone positionand a 5-cm vertical midline incision was made in the skin overly-ing the thoracic spine (if the hand was affected) or the lumbarspine (if the foot was affected). An electrode (model 3487A, Med-tronic) was implanted in a fashion similar to the implantation of the temporary lead and was fixed with special clips. The patientwas then placed in a lateral position, and a sedative was adminis-  Table 1 Diagnostic criteria for CRPS-1 in the study related to implant effect. a R.I. b N   =20 (%)N.N. N   =12 (%)N.I. N   =4 (%)Total36 (%)  Absolute criteria Pain 20 12 4Impaired function 20 12 4Symptoms beyond the area of trauma 20 12 4 Relative criteria Cold, warm, or intermittently cold/warm 15 (75) 8 (67) 4 (100) 27 (75)Edema 16 (80) 10 (83) 4 (100) 30 (83)Increased nail growth 8 (40) 8 (67) 3 (75) 19 (53)Increased hair growth 4 (20) 2 (17) 2 (50) 8 (22)Hyperhidrosis 15 (75) 10 (83) 2 (50) 27 (75)Abnormal skin color 18 (90) 11 (92) 4 (100) 33 (92)Hypoesthesia 14 (70) 6 (50) 1 (25) 21 (58)Hyperalgesia 15 (75) 11 (92) 4 (100) 30 (83)Mechanical or thermal allodynia or both 15 (75) 11 (92) 4 (100) 30 (83) a All the absolute criteria, together with at least three of the relative criteria, were required for this study. b R.I., responders implanted; N.N., non-responders not implanted; N.I., non-responders implanted. F. van Eijs et al./European Journal of Pain 14 (2010) 164–169  165  tered (1mg of propofol per kilogramof body weight). A pulse gen-erator (Itrel III, model 7425, Medtronic) was implanted subcutane-ously in the left lower anterior abdominal wall and connected tothe electrode by a tunnelled extension lead (model 7495-51/66,Medtronic). After the skin had been closed, the pulse generatorwas activated (rate, 85Hz; pulse width, 210 l s) with the use of aconsole programmer (model 7432, Medtronic). The patient couldcontrol the intensity of stimulation by adjusting the amplitudefrom 0 to 10V with a programmer (model 7434-NL, Medtronic).The patient remained in the hospital for 24h after the implanta-tion, during which time two doses of cefuroxime (750mg each)were given intravenously. If no change in the position of the elec-trode was evident on an X-ray filmobtained the following day, thepatient was discharged.  2.4. Physical therapy Physical therapy, which both groups of patients received, con-sisted of a standardized program of graded exercises designed toimprove the strength, mobility, and function of the affected handor foot. Pain during the exercises was considered acceptable, butif it had not returned to the pre-session level within 24h, theintensity of the exercises was reduced. Physical therapy wasadministered for 30min twice a week, with a minimum of twodays between sessions. The total duration of the physical therapywas 6 months, starting after the second assessment. To ensurestandardization, selected physical therapists were trained to pro-vide the program of exercises. The coordinating physical therapistfrom our institution visited the other therapists regularly to makesure the treatment was uniform.  2.5. Data collection and follow up Outcome measures were assessed at baseline. The effect of SCSon pain intensity VAS and PGIC was measured at 1, 3, 6, and12months after implantation.  2.6. Methods Semmes–Weinstein pressure filaments (Smith and NephewRolyan Inc., Germantown, WI) were used to measure mechanicaldetection thresholds (i.e. mechanical hypoesthesia). Measure-ments at hands and feet were done at nine standardized sites. Thisprocedure has been described earlier (Kemler et al., 2001). Handswere examined in sitting position, while the feet were examinedin the supine position. Subjects were required to keep their eyesclosed while being tested.We classified the amount of mechanical hypoesthesia into fourcategories of intensity according to the Semmes–Weinstein con-versiontables. Thesecategoriesare:normalsensibility,diminishedsensibility to light touch, diminished protective sensation and lossof protective sensation.Brush-evoked allodynia was assessed by transiently strokingthe skin of subject’s hands and feet with a soft standardized brushat nine sites (Kemler et al., 2001). This procedure is not painful innormalsubjects.Iftheprocedurewasperceivedaspainful,thissig-nifiesthepresenceofallodyniaandsubjectswereaskedtoverballyratetheevokedpainonanumericalratingscale(NRS)from0to10(0=no pain and 10=worst imaginable pain). The mean brush-evoked allodynia was then calculated by dividing the total scoreby nine.Demographic characteristics, spontaneous pain VAS, localiza-tion of the CRPS-1, duration of the disease, medication use,Semmes–Weinstein QST measurements and brush-evoked allo-dynia were all measured before implantation as baseline values.Subjects were tested in a quiet room maintained at 21–23  C andafter having received explanation of the procedure.  2.7. Statistical analysis Patients who in the first year of their treatment with SCS had asustained effect on their pain reduction, as defined by pain reduc-tionof at least 2.5 on their VAS score and/or a PGICscore of ‘‘muchimproved” or ‘‘very much improved” in at least 3 out of the 4 fol-low up assessments are considered to be successfully treated(Forouzanfar et al., 2003). Implanted patients with significant de-cline in pain reduction during the evaluation period as definedby not meeting the above mentioned criteria for successful treat-ment are considered to be unsuccessfully treated with SCS.Thefrequencyofoccurrenceatbaselineofthedifferentpossiblepredictors of SCSoutcomewas determinedinthe successful andinthe non-successful group. The predictive performance of allodynia(maximum value and average of nine measurements), hypoesthe-sia, age, gender, localization of the disease, duration of the disease,andbaselineintensityofthepainwasinvestigated. Duetothelim-itednumberofpatientsthisanalysiswasdonewithaunivariatelo-gisticregressionanalysis.Thiswayonlytwostatisticallysignificantpredictors (  p  <0.10) remained and these were entered in a multi-variate logistic regression model with a forward stepwise proce-dure. The results of this regression analysis were used toconstruct a ROC curve and calculate an Area Under the Curve(AUC). Non-parametric testing, i.e. Mann–Whitney, was used forthe hypoesthesia and allodynia parameters due to the non-sym-metrical distribution of results. Analyses were performed withthe Statistical Package for the Social Sciences, version 16.0 (SPSSInc.,Chicago,IL). Two-tailed  p  valuesoflessthan0.05wereconsid-ered statistically significant. 3. Results Thirty-six patients, aged 40–65years, 22 women and 14 men,with chronic CRPS-1 in one extremity, who had been referred toour department andtook part in thepreviouslydescribedrandom-ized clinical trial and who subsequently underwent SCS trial stim-ulation were part of this predictor study.All 36 chronic CRPS-1 patients underwent SCS trial stimulationwith a screening electrode. Following the trial period 12 patientsdidnotreceiveapermanentimplantduetoinsufficientpainreduc-tion. Twenty-four patients received an implant after a positivetrial.Table 1 shows the diagnostic criteria for CRPS-1 as assessed inthisstudyinrelationtoimplanteffect. Therearenodifferencesbe-tween the separate groups in all aspects of the absolute and rela-tive criteria for CRPS-1.Baseline characteristics and the distribution of patients in rela-tion to treatment effect are shown in Table 2. Furthermore, itshows the results of the chi square tests for patient age, gender,disease duration, localization of the disease, allodynia, hypoesthe-sia and pain intensity measured by the success rate of SCS aftertrial stimulation and 1 year of SCS treatment. The average age of patients included in this study was 40, SD11.7, range 21–65years.The lower limb was affected in 14 patients and 22 patients hadupper limb involvement. The mean duration of the disease was40months, SD 27.5, range 9–120. The mean patient baseline painintensity VAS score was 71mm, SD 15, range 50–90. Chi squareanalysis showed no significant correlation between age, locationof the affection, baseline pain intensity VAS score, gender, andsuccess of SCS. Medication use included peripheral analgesics likenon-steroidal anti-inflammatory drugs and acetaminophen,antidepressants and antiepileptic drugs and weak opioids like 166  F. van Eijs et al./European Journal of Pain 14 (2010) 164–169  tramadol or buprenorphine. Thirteen out of twenty allodynia pa-tients used one or more of these drugs and ten out of sixteen pa-tients in the non-allodynia group. Only one patient used oralmorphine sulfate and two used an antidepressant or antiepileptic.So there was no clinical relevant difference in the use of medica-tion between the groups. Our data indicate that the absence orpresence of hypoesthesia, light or severe, does not predict SCS out-come ( P  , 0.55). In our patient sample, only allodynia was signifi-cantly correlated with success of treatment after 1 year. A trendcould be seen after the trial period towards the negative associa-tion of allodynia and treatment success ( P  , 0.06). The differenceinsuccessrateafter1year(Mann–Whitneytest)isstatisticallysig-nificant ( P  , 0.017) between the groups with and without allodynia.In the successfully treatedgroup five patients had severe allodynia(5/20;25%)comparedto11patientsinthenotsuccessfullytreatedgroup (11/16; 69%).After 1 year, 20 out of the 24 (83%) SCS-implanted patientsmaintained their significant pain reduction.Of the 24 patients who underwent definitive implantation, fourshowed a significant loss of pain reduction after 1 year. These fourpatients together with the 12 patients not receiving a permanentimplant were considered to be unsuccessfully treated after 1 year(16/36 patients; 41%). Table 3 shows the baseline characteristicsof the unsuccessfully treated group in separate categories andcombined. Of the 4 patients implanted but longer term non-responding to SCS treatment, 3 patients suffered severe allodynia.In all other aspects the baseline variables did not differ.The univariate logistic regression analysis shows that themaximum value as well as the mean value of brush-evoked allo-dynia are statistically significant predictors of outcome after SCStrial and even more significant after 1 year of SCS treatment.These two predictors were entered in a multivariate logisticregression model with a forward stepwise procedure. The resultof this regression analysis were used to construct a ROC curveand calculate an Area Under the Curve (AUC) and is displayedin Fig. 1. The corresponding tables belonging to Fig. 1 show that the cutoff point can be set at a brush-evoked allodynia painintensity NRS score of 2.5 with a sensitivity of 0.75 and a spec-ificity of 0.81. 4. Discussion Spinal cord stimulation is an established and effective treat-ment option for controlling chronic pain in CRPS-1 patients, butit is also an invasive and expensive therapy. The selection of opti-mal candidates is a very important factor for increasing SCS treat-ment success rates. In this study we showed that the presence of brush-evoked allodynia may be a negative predictor for successfulSCS treatment.Not every patient achieves an acceptable reduction of pain fol-lowing treatment with SCS. Patients with paraplegic pain, stump  Table 2 Baseline characteristics of 36 CRPS-1 patients in relation to implant effect. Characteristic Implant effect  P   valuesTrial effect ( N  %) 1 year effect ( N  %) Trial 1 yearSuccessful N   =24Unsuccessful N   =12Successful N   =20Unsuccessful N   =16Age  6 40 15 (65%) 8 (35%) 13 (65%) 7 (35%) 0.81 0.20>40 9 (69%) 4 (31%) 7 (44%) 9 (56%)Gender Male,  N   =14 9 (64%) 5 (36%) 6 (43%) 8 (57%) 0.81 0.22Female,  N   =22 15 (68%) 7 (32%) 14 (64%) 8 (36%)Localization Arm 15 (68%) 7 (32%) 12 (55%) 10 (45%) 0.81 0.88Leg 9 (64%) 5 (36%) 8 (57%) 6 (43%)Disease duration in months <40 15 (68%) 7 (32%) 13 (62%) 8 (38%) 0.45 0.36 P 40 9 (64%) 5 (36%) 7 (47%) 8 (53%)Pain intensity VAS 6 7.1 12 (75%) 4 (25%) 12 (57%) 9 (43%) 0.34 0.20VAS>7.1 12 (60%) 8 (40%) 8 (53%) 7 (47%)Allodynia Absent 14 (88%) 2 (12%) 13 (81%) 3 (19%) 0.06 0.017Moderate 2 (50%) 2 (50%) 2 (50%) 2 (50%)Severe 8 (50%) 8 (50%) 5 (31%) 11 (69%)Hypoesthesia Absent/light a 11 (69%) 5 (31%) 8 (50%) 8 (50%) 0.81 0.55Severe b 13 (65%) 7 (35%) 12 (60%) 8 (40%) a Normal sensibility or diminished sensibility to light touch. b Diminished sensibility or loss of protective sensation.  Table 3 Baseline characteristics of CRPS-1 patients non-responding to SCS therapy. Characteristic Non-responders after 1 year of treatment N I. N   =4 N N. N   =12 N C. N   =16Age, mean(SD) range 46 (9)33–5541 (14)21–6542 (13)21–65Disease duration in months,mean (SD) range39 (29)11–7643 (24)14–9942 (24)11–99Pain intensity VAS in mm,mean (SD) range75 (11)60–8572 (12)54–9573 (12)54–95Gender,  N   (%) Male 3 (75%) 5 (42%) 8 (50%)Female 1 (25%) 7 (58%) 8 (50%)Localization,  N   (%) Arm 3 (75%) 7 (58%) 10 (63%)Leg 1 (25%) 5 (42%) 6 (37%)Allodynia,  N   (%) Absent 1 (25%) 2 (17%) 3 (19%)Moderate 0 (0%) 2 (17%) 2 (12%)Severe 3 (75%) 8 (66%) 11 (69%)Hypoesthesia,  N   (%) Absent/light a 3 (75%) 5 (42%) 8 (50%)Severe b 1 (25%) 7 (58%) 8 (50%) N I., non-responders implanted.  N N., non-responders not implanted.  N C., combinedgroup of non-responders. a Normal sensibility or diminished sensibility to light touch. b Diminished sensibility or loss of protective sensation. F. van Eijs et al./European Journal of Pain 14 (2010) 164–169  167  pain, and phantom limb pain do not respond to SCS, whereas pa-tients having pain attributable to failed back syndrome, ischemiclower limb pain, painful peripheral neuropathy or CRPS-1 in gen-eral do (Kumar et al., 1998). In patients with failed back syndromewhohaveundergonesurgicalproceduresithasbeendemonstratedthat, witha shorter duration of the pain syndrome, greater rates of successcouldbeachieved(Kumaretal.,1998).InthepresentstudywithchronicCRPS-1patients,wecouldnotconfirmthiscorrelationbetween disease duration and SCS success. Others found that in-creased patient age was inversely correlated with SCS success, ina patient population consisting mainly of failed back surgery syn-drome;however,inourpopulationofCRPS-1patientsweobservedno effect of patient age on outcome (Burchiel et al., 1995).SCS has evolved as a clinical application of Melzack and Wall’sgate-control theory (Melzack and Wall, 1965). The general mech-anism of pain relief by SCS is still understood in these gatingterms. The pain alleviating effect is generally seen to be causedby activation of large-diameter afferents in the dorsal columns.The fact that chronic neuropathic pain patients, even those withsevere hypoesthesia, can still show a successful response to SCSmight be explained by the presence of remaining intact large fi-bers in the dorsal column which can be recruited for stimulation.Pain in an affected extremity provoked by the normally non-pain-ful stimulus of a brush is regarded as a sign of central sensitiza-tion (Vaneker et al., 2005). Our results show that brush-evokedallodynia seems to be associated with a lower chance of achievinglong-term pain reduction with SCS treatment. This phenomenonis probably due to central sensitization which makes it difficultto suppress the total experienced pain, both spontaneous andevoked, even when stimulating the spinal cord dorsal columns.Central sensitization on spinal level occurs in the dorsal hornand is probably caused by repetitive high frequency stimulationof peripheral C-fibres leading to an amplification and prolonga-tion of the response of the dorsal horn neurons, a phenomenoncalled ‘wind up’. This process may be linked to increased releaseof substance P and the excitatory neurotransmitter glutamate,mediated through voltage gated N-calcium channels, leading topostsynaptic  N  -methyl-D-aspartate (NMDA) receptor interactionand hyperexcitability. Furthermore the amount of inhibitory neu-rotransmitter Gamma-aminobutyric acid (GABA) and GABAergicinterneurones within the spinal cord may increase or decreasethe output of the dorsal horn. These mechanisms cause increasedsensitivity to pain (hyperalgesia) and input from non-nociceptiveAß-fibres to be perceived as pain (allodynia) (Baron, 2009; D’Mel-lo and Dickenson, 2008). So far, neurochemical and electrophysi-ological evidence from experimental studies has suggested thatthe effects of SCS on the dorsal columns are mediated centrallyin the dorsal horns of the spinal cord, by altering the release of neurotransmitters (e.g. increased release of GABA) and suppres-sion of hyperexcitable Wide Dynamic Range neurons (WDR)(Cui et al., 1996). In experimental SCS the amount of pain relief is related to the severity of allodynia (Smits et al., 2006; Yakhn-itsa et al., 1999). The non-response to SCS in animals with severeallodynia may well relate to a severe form of central neuropathicderangement and may imply a disability to produce appropriateamounts of GABA, either alone or accompanied by the increasedloss of inhibitory interneurons. In this scenario modulation of dorsal horn neurons by SCS could have either little or no effect.Other animal studies showed that the combination of SCS withpharmacological therapy, in rats not responsive to SCS, canbecome effective when combined with intrathecal or intravenousmedication like baclofen, adenosine, gabapentin and pregabalin(Wallin et al., 2002).None of these medications were being used by the describedpatients. CRPS patients who fulfil the criteria for SCS are ratherscarce and, although the sample sizes of our study are small, weconsider the present study of interest because it can provide newinsights into pain mechanism and treatment in CRPS-1 patients.Because of these small sample sizes we adjusted our statisticaltests for small and non-parametric data.In the most ideal situation, when comparing different possiblepredictors,allpatientsinonegroupshouldhaveundergoneexactlythe same treatment. In this study 12 patients who did not showpain reduction after one week of trial stimulation and the 4 pa-tients who did receive an implant but showed significant loss of pain reduction after 1 year were both considered non-responders.These16patientswerecomparedtotherespondergroupwhereallpatients received an SCS implant. Because both groups did not re-ceive exactly the same treatment which is preferable in predictorstudies, we analyzed the groups according to success of the trialversus failure of the trial and the association with allodynia. Thisreflectswidelyacceptedroutineclinicalpracticewherepatientsin-deed have the device removed, or permanent stimulating treat-ment is not considered, if they do not have significant painreduction after the trial period.To our knowledge the predictive effect of mechanical allodyniaon the outcome of SCS therapy in neuropathic pain syndromessuch as CRPS-1 has never been investigated. We tested for brush-evoked allodynia in nine standardized places of the hand or footand calculated the mean. However, the ROC curve shows thatbrush-evoked allodynia at the area of maximal pain is an equallyeffective indicator as the average of nine individual allodynia mea-surements. This has clinical relevance since the attention of clini-cian and patient in routine clinical assessment of CRPS-1 patientsis typically directed towards the area of maximal pain and allo-dynia. As in diabetic neuropathy, severe hypoesthesia of the plan-tar aspect of the foot can easily be detected by bed side testingusing the 10g filament and severe hypoesthesia of the hand anddorsal aspect of the foot can easily be detected using the 4g fila-ment (Perkins et al., 2001). We showed that there was no correla-tion between the severity of hypoesthesia and the success of SCS.Hence testing for the presence of hypoesthesia, despite its impor-tanceinthediagnosisofCRPS-1,seemstobeofnovalueinpredict-ing SCS success. ROC Curve and Area Under the Curve 1 - Specificity        S     e     n     s      i      t      i     v      i      t     y Fig. 1.  ROC curve and Area Under the Curve of the maximal and mean value of thebrush-evokedallodynia measurementsonthe CRPSeffectedlimbinpatientsafter1year of SCS treatment.168  F. van Eijs et al./European Journal of Pain 14 (2010) 164–169
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