Efficacy of Ketamine in Anesthetic Dosage for the ... · with CRPS have concomitant peripheral...

Efficacy of Ketamine in Anesthetic Dosage for the Treatment ofRefractory Complex Regional Pain Syndrome: An Open-LabelPhase II Study

Ralph-Thomas Kiefer, MD,* Peter Rohr, MD,† Annette Ploppa, MD,* Hans-Jürgen Dieterich, MD,*John Grothusen, PhD,§ Sandra Koffler, PhD,¶ Karl-Heinz Altemeyer, MD,† Klaus Unertl, MD,* andRobert J. Schwartzman, MD§

*Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany; †Departmentof Anesthesiology, Intensive Care and Emergency Medicine and Pain Therapy, Klinikum Saarbrücken, Teaching HospitalUniversity of the Saarland, Saarbrücken, Germany; Departments of §Neurology, ¶Psychiatry, Drexel University College ofMedicine, Hahneman University Hospital, Philadelphia, PA, USA

A B S T R A C T

Objective. Advanced complex regional pain syndrome (CRPS) remains very difficult to treat. Whilesubanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advancedCRPS has not been as effective. Since ketamine’s analgesic potency and duration of effect inneuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anestheticdosage in refractory CRPS patients that had failed available standard therapies.

Methods. Twenty ASA I-III patients suffering from refractory CRPS received ketamine in anestheticdosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality oflife, and ability to work at baseline and up to 6 months following treatment.

Results. Significant pain relief was observed at 1, 3, and 6 months following treatment(93.5 � 11.1%, 89.4 � 17.0%, 79.3 � 25.3%; P < 0.001). Complete remission from CRPS wasobserved at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapseoccurred, significant pain relief was still attained at 3 and 6 months (59.0 � 14.7%, P < 0.004;50.2 � 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to worksignificantly improved in the majority of patients at 3 and 6 months.

Conclusions. This open-label trial suggests benefit in pain reduction, associated CRPS symp-toms, improved quality of life and ability to work following anesthetic ketamine in previouslyrefractory CRPS patients. However, a randomized controlled trial will be necessary to prove itsefficacy.

Key Words. Complex Regional Pain Syndrome; Ketamine; NMDA-Receptor; Reflex SympatheticDystrophy; Pain Therapy; Quality of Life

Introduction

The understanding of the pathophysiology ofmechanisms underlying complex regional

pain syndrome (CRPS) has vastly progressed inthe recent years [1]. Recent evidence has beenpresented that suggests focal small-fiber axonaldegeneration and alteration of the cutaneous

Reprint requests to: Robert J. Schwartzman, MD, Depart-ment of Neurology, Drexel Universtity, College of Medi-cine, Hahneman University Hospital, Broad and VineStreets, Mail Stop 423, Philadelphia, PA 19102-1192,USA. Tel: 215-762-7090; Fax: 215-762-3161; E-mail:[email protected].

Financial Disclosure: The study was financed by depart-mental resources.

PAIN MEDICINEVolume * • Number * • 2007

© American Academy of Pain Medicine 1526-2375/07/$15.00/** **–** doi:10.1111/j.1526-4637.2007.00402.x

mailto:[email protected]

innervation by small-diameter afferent and post-ganglionic sympathetic efferent fibers are impor-tant for its induction and maintenance [2,3].Caveats of this hypothesiz have been raised byJanig and Baron [4], who propose that patientswith CRPS have concomitant peripheral changesin the microenvironment at the site of injury thatinduce peripheral afferent sensitization, neuro-genic inflammation, and sympathetic afferent cou-pling in addition to functional reorganization ofthe somatosensory, motor, and autonomic circuitsin the central nervous system (CNS) [5–7].

There is general agreement that the pain inCRPS is disproportionate to the extent of theprimary triggering injury that does not respect aroot or nerve territory. Characteristic symptomsinclude severe unrelenting burning and deep pain,associated with mechano- and thermal allodynia,hyperalgesia, and hyperpathia. Swelling, auto-nomic dysregulation, a movement disorder,atrophy, and dystrophy are associated to varyingdegrees [8]. The syndrome may progress withtime, and signs and symptoms may spread to sitesthat were not primarily affected. In some patients,it is generalized [9,10]. Current standard therapyconsists of a variety physical, psychological, behav-ioral, pharmacological and interventional treat-ments [11–13]. Unfortunately, a subgroup ofCRPS patients remains refractory to all standardtherapy. For these refractory patients, no effectivetreatment exists [8].

Ketamine, the currently most potent clinicallyavailable N-methyl-D-aspartate (NMDA)-antagonist, has a well-established role in thetreatment of acute and chronic pain [14,15]. Itsmain action is through inhibition of NMDA-receptors, which are thought to play a crucial rolein the generation and maintenance of chronicpain [16,17]. In addition to its acute analgesiceffects, systemic ketamine modulates correlates ofcentral sensitization in chronic pain states on along-term basis. Wind-up and punctuate hyperal-gesia were shown to be significantly reduced upto 7 days after surgery [18]. Ketamine adminis-tered at higher intraoperative dosage for majorabdominal surgery reduced the area of woundhyperalgesia and significantly prevented the ini-tiation and maintenance of chronic pain [19,20].Possible mechanisms are that these effects aremediated through NMDA-receptor inhibition,which may be critical for central sensitization,and anti-inflammatory modulation of the immunesystem [17,21]. Proinflammatory cytokines areinvolved in the processes of peripheral and central

sensitization and are inhibited by ketamine [22].In the management of chronic pain, the use ofketamine at higher dosages has been limited bypsychotropic side effects. The incidence andseverity of ketamine side effects are dose-dependent as are its analgesic potency and dura-tion of action [15].

Several series and case reports have docu-mented reduction of pain intensity, allodynia andassociated CRPS signs of autonomic dysregulationand motor dysfunction following the admini-stration of subanesthetic systemic, epidural, andtopical ketamine [23–26]. A recent case report andlarger series demonstrated long-term pain relieffrom subanesthetic ketamine infusions, particu-larly in early and well localized CRPS [27,28].However, in a subgroup of refractory CRPS withspreading disease, subanesthetic continuous S(+)-ketamine infusions were ineffective [29].

This suggested that ketamine in anestheticdosages might be effective in this refractory CRPSsubgroup. Excellent clinical results were obtainedwith anesthetic doses of ketamine administered ona compassionate care basis to several refractoryCRPS patients (unpublished). Based on thislimited clinical experience, a standardized treat-ment regime was developed, and utilized in thepresent trial. The therapeutic efficacy of ketaminein anesthetic dosage was studied in a Phase II studyin 20 refractory CRPS-patients, who sufferedeither longstanding or rapidly progressive diseasethat had failed standard therapy. The primaryoutcome parameter was acute and long-term reliefof pain. Other measures included effects on themovement disorder, quality of life, social integra-tion, and the ability to work at 6 months followingtreatment.

Methods

PatientsThe human investigation committees in Tübingenand Saarbrücken, Germany, approved the study.Patients were recruited in the pain clinics of theDepartment of Neurology of Drexel UniversityCollege of Medicine (Philadelphia, PA) and painclinics of the Teaching Hospital University ofthe Saarland (Saarbrücken, Germany). Informedconsent emphasized the experimental nature ofthis treatment. Special emphasis was placed on therisks associated with the intensive care componentof this treatment which includes respiratory andurinary tract infections and other infectious

Kiefer et al.2

complications such as systemic inflammatoryresponse syndrome and sepsis. Organ failure(single or multi-organ failure), cardiovascularcomplications as well as the associated high mor-bidity and mortality rates of all of these seriouscomplications were stressed. All patients gave theirinformed written consent.

Inclusion CriteriaAll patients fulfilled the 1993 IASP–CRPS diag-nostic criteria, the 1999 modified research diag-nostic CRPS criteria, and the proposed modifiedresearch diagnostic criteria of the 2005 Budapestconference in at least one limb [30–32]. Otherassociated CRPS factors [1–4] were noted tovarying degrees in contiguous areas of the extrem-ity, the face or in a mirror distribution. Clusteranalysis placed all patients in subgroup; and [3] aflorid CRPS syndrome [32].

The average daily pain intensity had to be 7points or greater on a numerical rating scale(Numeric Rating Scale [NRS] endpoints 0: nopain, 10: worse pain imaginable) over a period of atleast 6 months while on standard therapy. TheCRPS symptomatology had to be either long-standing and spreading, or rapidly progressive.Standard conventional nonmedical (physicaltherapy, psychological approaches), or pharmaco-logical and interventional treatment modalitieshad to have failed. Failure of therapy was definedas: 1) no benefit from treatment, or 2) no lastingpain relief (>2 months). The designation “refrac-tory” included documented failure of: 1) nonmedi-cal; 2) pharmacological mono-, or combinedtherapy with nonsteroidal antiinflammatory drugs,tricyclic antidepressants, anticonvulsants, low orhigh potency opioids; 3) at least three inter-ventional procedures, including selective nerveblocks, epidural analgesia, brachial plexus blocks,sympathetic ganglion blocks, intravenous regionalsympathetic blocks, spinal cord stimulation, surgi-cal sympathectomy, or intrathecal drug deliverysystems; and 4) unchanged or progressing state ofdisease despite these efforts.

Inclusion was limited to ASA I-III patients(ASA: American Society of AnesthesiologistsPhysical Status Classification), which apart fromtheir pain-related disability, did not suffer fromclinically relevant systemic disease. Patients thatpresented with a history of significant cardiovas-cular, pulmonary, renal disease or mental disorderswere excluded. Further exclusion criteria includedknown contraindications to ketamine use (severearterial hypertension, hyperthyroidism, ischemic

heart disease or heart failure), as well as allergies toketamine or midazolam. All patients during thecourse of their treatments were evaluated by apsychiatrist for counseling and support and 9underwent detailed neuropsychological testingprior to and following treatment [33]. All patientshad difficulty falling and staying asleep but thisfeature of their illness was not studied systemati-cally. Patients with a history of substance or drugabuse, or a suspected somatoform pain disorderwere excluded. The inclusion criteria were evalu-ated by three physicians, a neurologist (RJS), andtwo anesthesiologists (RTK, PR).

Ketamine Treatment ProtocolAnesthesia was induced by bolus injection of ket-amine (1–1.5 mg/kg) and midazolam (2.5–7.5 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 up toa final dose of 7 mg/kg/h. Midazolam wasco-administered and adjusted as clinically required(0.15–0.4 mg/kg/h) to obtain a stable level of deepsedation (Ramsay-Score 4–5), and to attenuateketamine-specific side effects, i.e., agitation [34].The first three patients were not intubated andspontaneous ventilation was allowed. The re-maining 17 patients were electively intubated,to limit the risk of aspiration. These 17 patientswere mechanically ventilated. After 5 days,infusions were slowly tapered, first by reducingthe ketamine dosage by 20% every four hours,followed by gradual reduction of midazolam in thesame manner. Patients were then weanedfrom mechanical ventilation and extubated onceadequate spontaneous ventilation, sufficient gasexchange, and the appropriate level of conscious-ness together with intact protective reflexes wasattained.

Ketamine and Norketamine Plasma ConcentrationsBlood samples were drawn into prefabricatedEDTA-tubes (S-Monovette®, Sarstedt AG & Co.,Nürnbrecht, Germany) from all patients everyeight hours to determine ketamine and norket-amine (the primary ketamine metabolite) plasmaconcentrations during anesthesia and for 3 daysfollowing treatment. Blood samples were centri-fuged and plasma aliquots stored until analysis at-80°C. Ketamine and norketamine plasma con-centrations were analyzed by simultaneous high-pressure liquid chromatography (HPLC) [35].

Efficacy of Ketamine in Anesthetic Dosage 3

Standardized Additional DrugsDeep Venous Thrombosis and Ulcer ProphylaxisAll patients received intravenous unfractionatedlow-dose heparin 7.500–15.000 I.E./day (Liq-uemin®, Roche, Germany) under regular aPTTmonitoring, and the proton pump inhibitor pan-toprazole 40 mg/day (Pantozol®, Altana Pharma,Germany).

ClonidineClonidine (Catapresan®, Boehringer Ingelheim,Germany) was administered intravenously (0.20–0.85 mg/kg/h) to control cardiovascular stimula-tion and the psychomimetic and potentialneurotoxic side effects of ketamine. It was dosed asclinically required (0.20–0.85 mg/kg/h) to controltachycardia and hypertension. The coadministra-tion of clonidine at a minimum dose of 0.15 mg/kg/h was maintained throughout the intensive caretreatment.

Alimentation and Glycemic ControlAlimentationThe first three unintubated patients receivedfull parenteral nutrition (25 kcal/kg/day) witha ternary mixture of aminoacids (40 g/L), glucose(160 g/L), and fat (40 g/L), containing1040 kcal/L glucose-fat calories (Oliclinomel®

4.0% GF-E Baxter, Germany). Intubated patientsreceived full enteral nutrition (25 kcal/kg/day) vianasogastral tube (Nutrison Standard®, NutrisoneMultifibre®, Pfrimmer Nutrica, Germany, con-taining 1.000 kcal/L, proteins 40 g/L, carbohy-drates 123 g/L, fat 39 g/L).

Glycemic ControlIntensified insulin-therapy (Actrapid®, NovoNordisk A/S, Denmark) was applied, and insulindosed as clinically needed to maintain normogly-cemia (blood glucose concentrations: 90–150 mg/dL) [36].

Patient SafetyMonitoringContinuous standard intensive care monitoring(arterial blood pressure monitoring, ECG andST-segment analysis, core temperature, pulseoximetry, capnometry, central venous pressure)was performed in all patients. All patients hadbladder catheterization.

Blood Gas Analysis and Blood ChemistryBlood gas analysis was routinely performed every8 hours and additionally when clinically warrantedto adjust mechanical ventilation, insulin therapy,

acid-base balance, and electrolytes. Detailed bloodtests were performed before the treatment, dailyduring treatment, and for the first 2 weeksthereafter. Laboratory evaluation included cellcounts, electrolytes, coagulation parameters, liverenzymes, C-reactive protein (CRP), creatinephosphokinase (CPK), and CKMB-isoenzymeactivity.

Screening for Infectious ComplicationsWhen admitted patients were screened with pha-ryngeal, nose and rectal swabs for the presence ofmultiresistant pathogens (methycillin resistantS. aureus [MRSA]; vancomycin resistant entero-cocci [VRE]). During the treatment screeningincluded continuous monitoring of core bodytemperature, and laboratory parameters (daily leu-kocyte count, CRP), urine status, and trachealsecretion and urine cultures on the first day oftreatment and when respiratory or urinary tractinfection was suspected clinically. In the presenceof fever blood cultures were collected.

Outcome CriteriaThe patients’ progress during the study, the timesand nature of assessments at baseline, 1 week, 1, 3,and 6 months after treatment are summarized in aflow chart shown in Figure 1.

Pain Assessment and Degree of Pain ReliefThe degree of a patient’s subjective pain intensi-ties was rated by a numeric scale (NRS, endpoints:0—no pain, 10—worst pain imaginable) at base-line and at follow-up examinations. The degreeof pain relief following treatment was calculatedas: percent pain relief = (NRSbaseline - NRSfollow up)/NRSbaseline ¥ 100.

Movement DisorderData were obtained at baseline and 1, 3, and 6months after treatment for both upper and lowerextremities.

Upper Extremity Motor EvaluationAssessment of active range of motion was based onnorms described by Kendall et al. [37]. Arm move-ment was quantified by utilizing a combination ofthe performance of specific motor tasks (placinga book in a shelf above shoulder level, abilityto comb one’s hair, putting on a sweater, tying anapron) in addition to the results of the range ofmotion evaluation. Hand movement assessmentcombined grip function (gripping and holding acup) and pinch grip ability (gripping, holding anduse of a key, pencil and writing). Based on the

Kiefer et al.4

observed range of movement combined with per-formance in the described functional tasks, themovement disorder was quantified utilizing a4-point rating scale: 0: normal movement; 1: mod-erate disability (moderately reduced active rangeof motion, muscular strength, initiation, andcompletion of motor tasks); 2: severe disability(severely restricted active range of motion, weak-ness, poor initiation, and completion of motortasks); 3: total disability (only residual movement,severe weakness, and inability to perform motortasks).

Lower Extremity Motor EvaluationThe assessment of motor function of the lowerextremity was based on the ability to walk and wasscored on a 4-point rating scale: 0: normal move-ment (unimpaired walking); 1: moderate disabi-

lity (inability to walk 500 meters); 2: severe disabi-lity (inability to walk 200 meters); 3: total disability(ability to walk <50 meters or inability to walk).

Quality of LifeThe assessments to estimate disease-relatedimpairments in activities of daily living, socialintegration, and the ability to work represent rec-ognized aspects of quality of life. The assessmentswere performed at baseline and at 3, and 6 monthsfollowing therapy.

Activities of Daily LivingPatients were asked to rate their performance oftypical activities of daily living. The representativetasks of everyday life were based on selected keyitems contained in valid questionnaires, such asthe West Haven-Yale Multidimensional Pain

Figure 1 Flow chart summarizingpatients’ progress through the study.The left side of the diagram shows thetiming of the assessment of patientsand the investigated treatment withanesthetic ketamine. The right side ofthe diagram shows he investigatedoutcome parameters at the differentassessment times throughout thestudy. CRPS = complex regional painsyndrome; ICU = intensive care unit.

Patient Screening

Neuropsychological Screening

Ketamine Treatment (Day 1)

End of Ketamine Treatment (Day 5)

Discharge ICU (Days 8-10)

Peripheral Ward (Days 8-14)

Followup: 1 Week (Day 12) (N=20)

Followup: 1 Month (N=20)

Followup: 3 Months (N=20)

Hospital Discharge (Days 10-16)

Followup: 6 Months (N=20)

• Patient Characteristics/Medical History

• CRPS-Specific Medical History

MedicationTherapeutic interventions

• Pain Intensities

• CRPS-Related Disabilities:

Motor dysfunctionActivities of daily livingSocial integrityAbility to work


• Degree of Pain Relief

• CRPS-Related Disabilities:

Motor dysfunctionActivities of dailylivingSocial integrityAbility to work


• Degreeof Pain Relief

• Ketamine Side Effects

• Documentation of Complications

• Continuous ICU-Monitoring

• Screening for Infectious Complications

• Ketamine Plasma Levels

• Ketamine Side Effects

• Documention of Complications


• Degree of Pain Relief

Recruitment/Inclusion (N=20)

Baseline (N=20)


Inventory (WHYMPI) and the Stanford HealthAssessment Questionnaire (HAQ) [38,39].Patients were instructed to rate their abilityto independently perform the following tasks:self-care (preparing meals and eating [cuttingfood], drinking, dressing, washing, drying, andcombing), and household activities (house clean-ing, grocery shopping, washing dishes, and gar-dening). The degree of impairment was ratedusing a 4-point numeric scale: 0: no impairment(all tasks can be performed independently), 1:moderate impairment (tasks can be accomplishedbut with difficulty), 2: severe impairment (<50% ofactivities can be performed independently); 3: totalimpairment (majority of tasks cannot be per-formed; dependent on the help of others).

Social IntegrationPatients were queried in regard to their abilityto function socially and rated their overall im-pairment. Representative activities were chosenfrom the aforementioned validated questionnaires(WHYMPI, HAQ). Patients were asked to ratetheir ability to perform recreational activities (pur-suing hobbies, playing sports, taking trips, seeingfriends/relatives, reading, going out), culturalactivities (attending concerts, movies, theatre).The degree of impairment was rated using a4-point numeric rating scale: 0: no impairment, 1:moderate impairment (all activities can be per-formed, but with difficulty), 2: severe impairment(<50% of activities can be performed indepen-dently), 3: total impairment (majority of activitiescannot be performed and the patient is dependenton the help of others).

Ability to WorkThe ability to work was rated on a 4-point scale: 0:no impairment, 1: moderate impairment (able towork more than 4 h/day but less than 8 h/day), 2:severe disability (able to work up to 4 h/day), 3:total impairment (able to work only 2 h/day ortotally unable to work).

Side Effects of TreatmentKetamine-Specific Side EffectsPsychotomimetic side effects: the occurrence,duration, and severity of ketamine-specific psy-chotomimetic side effects were documentedfollowing treatment. These included: anxiety, hal-lucinations, restlessness, difficulty in concentra-tion, disruption of sleep, dizziness, dysphoria,euphoria, and disorientation.

Other Adverse Treatment EffectsThese included all potential adverse effects asso-ciated with the intensive care nature of the treat-ment, such as respiratory, urinary tract or systemicinfection, and cardiovascular and pulmonary com-plications. The occurrence of these complications,their treatment and resolution were documented.

StatisticsData were analyzed using the statistical softwarepackage JMP IN (Version 5.1.2, SAS Institute,Cary, NC). The Kolmogorov-Smirnov test wasused to assess normality. Nonparametric pairedt-tests on ranks were used to analyze differencesbetween baseline and those obtained during andfollowing therapy for not normally distributeddata. Normally distributed data were analyzed bypaired t-tests. Alpha was set at 0.05. For multiplecomparisons the alpha correction of Bonferroniwas performed.

Results

Patient DemographicsTwenty ASA-Class I–III patients were enrolledand completed the study (18 female and two male;mean age 30.4 � 10.4 years, range: 14–48 years).The mean duration of CRPS was 49.4 � 25.0months (range: 6–84 months). All patients sufferedfrom severe or spreading CRPS. Two had rapidcontiguous spread affecting the entire extremity,two suffered from mirror spread, and 16 had gen-eralized CRPS. All patients had been unresponsiveto multiple conventional treatments and had failedstandard pharmacological therapy and numerousinvasive procedures (Tables 1–4).

Pain Intensities and Pain reliefPain IntensitiesPain intensities were analyzed for the entiregroup, as well as for the subgroup of patients withrecurring initiating or maintaining pain (nocicep-tive or neuropathic, but without associated CRPSsigns or symptoms) and the subgroup with relaps-ing CRPS (neuropathic pain and associated CRPSsigns and symptoms).

At baseline, pain intensity of the entire group(N = 20), and of the subgroups with later recurringpain, and relapsing CRPS were NRS 8.9 � 0.3,8.8 � 0.2, and 9.2 � 0.2 (mean � SD), respec-tively, and no statistically significant differencesbetween the groups were detected.

Kiefer et al.6

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ths)

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the

stat

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dise

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base

line,

and

the

pain

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nopa

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pain

imag

inab

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Pat

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Age

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AS

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Sca

le.


Following ketamine treatment, a significantreduction of pain intensity was observed at 1 weekand 1 month for the entire group (NRS 0.5 � 0.8,and 0.6 � 1.0), and the subgroup with recurringpain (1.4 � 0.7, and 1.7 � 1.1, N = 7) (P < 0.001).At 3 months, pain intensity was significantly(P < 0.001) reduced compared with baseline in theentire group (NRS 0.9 � 1.6) and the subgroupwith recurring pain (2.0 � 0.9, N = 4). Threepatients had a CRPS relapse, but had significantlyreduced pain compared with baseline (NRS3.8 � 1.4, P < 0.004). Pain intensity at 6 monthswas significantly reduced for the entire group ofpatients (2.0 � 2.4, P < 0.001), the subgroups withrecurring pain (3.6 � 2.0, P < 0.001, N = 6), andthose with a CRPS relapse (4.6 � 1.1, P < 0.002,N = 4). The results are summarized in Figure 2.

Pain ReliefThe calculated percentage of pain relief was sig-nificant following ketamine treatment at 1 week(mean � SD: 94.5% � 8.9, and at 1, 3, and 6months (93.5% � 11.1, 89.4% � 17.0, 79.3% �25.3) in the entire group of patients (P < 0.001).Analyses for the subgroup with recurring painshowed significant pain relief at 1 week (84.4% �8.22, N = 7, P < 0.001), and 1, 3, and 6 months(81.4% � 11.5, 77.8% � 10.1, and 64.32% �23.8, N = 7, 4, and 6, P < 0.001 in all), respectively.

Pain relief in the subgroup of CRPS patientwith relapse was maintained at 3, and 6 months(59% � 14.7, N = 3, P < 0.004, and 50.21% �10.6, N = 4, P < 0.002). Figure 2 summarizes theresults.

Movement DisorderUpper ExtremityFor statistical analyses, the separately assessedscores the impairment of movement in the armand hand of each side of the body was added to atotal score for hands and arms. Thus, the minimalsum score was 0 (normal bilateral movement) andmaximal 6 (total bilateral impairment). All patients(N = 20) showed impaired movement in the upperextremities.

At baseline a sum score of 3.2 � 1.2(mean � SD) for movement in the arms, and3.7 � 1.2 for movement in the hands was docu-mented (N = 20). At 1, 3, and 6 months, a sig-nificant (P < 0.001) reduction of the sum scorewas noted for the movement impairment in thearms (1.4 � 0.83, 0.5 � 0.8, and 0.4 � 0.8),and hands (1.6 � 0.8, 0.5 � 0.9, and 0.5 � 0.8),respectively.

Lower ExtremityStatistical analyses of scores for decreased move-ment in the lower extremities were based on thedirect scores of the aforementioned 4-point-basednumeric rating scale. Of the entire group, onlythose with a movement disorder in the lowerextremity were included for statistical analyses. Atbaseline, patients with movement disorder of thelower extremity (N = 15) had a score of 2.3 � 0.7(mean � SD). Following treatment, their im-pairment was significantly reduced at 1, 3, and 6months (1.3 � 0.9, 0.6 � 0.7, and 0.6 � 0.6;N = 15, P < 0.001). Figure 3 summarizes theresults.

Table 2 Demographics: summarizes statistic data of patients’ demographics for the entire group of patients, and theanalyzed subgroups: recurring pain (all patients with recurring pain, either neuropathic, nociceptive, or both at one of thefollow-ups), CRPS-relapse (all patients with a CRPS-relapse), and results of the statistical comparison of differencesbetween the entire group and the subgroups (exact p-values)

N

Entire GroupSubgroup: Recurring Painfrom Initial Injury Subgroup: CRPS-Relaspse

20 9 4

Age (years) (Mean � SD) 30.4 � 10.7 30.7 � 8.2 33.7 � 11.9Range (min–max) 34 (14–38) 23 (19–42) 26 (20–46)P Value 0.95 0.58

Weight (kg) (Mean � SD) 68.4 � 18.7 68.6 � 15.9 68.7 � 31.6Range (min–max) 67.3 (48.5–115.8) 49 (48.5–97.5) 66.0 (49.8–115.8)P Value 0.99 0.98

Height (cm) (Mean � SD) 167.6 � 10.7 168.9 � 12.6 168.0 � 12.6Range (min–max) 42.0 (152–194) 42.0 (152–194) 29.0 (154–183)P Value 0.78 0.95

Duration of CRPS (months) (Mean � SD) 49.4 � 25.6 49.7 � 22.8 60.0 � 19.6Range (min–max) 78 (6–84) 60 (24–84) 48 (36–84)P Value 1.0 0.59

CRPS = complex regional pain syndrome.

Kiefer et al.8

Tab

le3

Fai

led

phys

ioth

erap

yan

dph

arm

acot

hera

py:

sum

mar

izes

the

indi

vidu

alpa

tient

s’fa

iled

phys

ioth

erap

eutic

and

phar

mac

othe

rape

utic

appr

oach

esat

base

line

Pat

ient

No.

Phy

siot

hera

py

Pha

rmac

othe

rapy

Topi

calP

harm

ca

NS

AID

Ant

idep

ress

ants

Ant

icon

vuls

ants

Spa

smol

ytic

sS

odiu

m-C

hann

el-B

lock

erLo

w-P

oten

tO

pioi

dsH

igh-

Pot

ent

Opi

oids

Lido

cain

eD

MS

O

1+

++

++

2+

++

++

++

+3

++

++

++

4+

++

++

++

++

5+

++

++

++

+6

++

++

++

++

7+

++

++

++

8+

++

++

++

++

9+

++

++

10+

++

++

+11

++

++

++

12+

++

++

+13

++

++

++

14+

++

++

+15

++

++

++

16+

++

++

17+

++

++

++

+18

++

++

++

19+

++

++

+20

++

++

++

++

The

“+”

indi

cate

s,w

hich

trea

tmen

tsha

vebe

enpe

rfor

med

and

faile

d,de

fined

asbe

ing

with

out

prim

ary

effe

ct,

orno

last

ing

(>2

mon

ths)

onpa

inre

lief.

NS

AID

=no

nste

roid

alan

ti-in

flam

mat

ory

drug

s;D

MS

O=

dim

ethy

lsul

foxi

dco

ntai

ning

oint

men

t;IV

RS

B=

intr

aven

ous

regi

onal

sym

path

etic

bloc

kade

.


Tab

le4

Fai

led

Inte

rven

tiona

lthe

rapi

es:

sum

mar

izes

for

the

indi

vidu

alpa

tient

s’fa

iled

inte

rven

tiona

ltre

atm

ents

atba

selin

e

Pat

ient

No.

Trig

ger-

Poi

nt-

Infil

trat

ions

Ner

ve-B

lock

sS

ympa

thet

icB

lock

s

i.v.

Lido

cain

e

Spi

nal

Cor

dS

timul

atio

nIn

trat

heca

lS

yste

ms

Sel

ectiv

eN

erve

Blo

cks

Bra

chia

lP

lexu

sB

lock

IVR

SB

Intr

aple

ural

Blo

ck

Ste

llate

Gan

glio

nB

lock

sC

ervi

cal

Epi

dura

lT

hora

cic

Epi

dura

lLu

mba

rE

pidu

ral

Lum

bar

Sym

path

etic

Cha

inB

lock

12

21

32

23

33

24

>8>4

22

>4>3

35

>10

>2>3

36

>4>4

24

24

+7

>6>4

22

++

8>8

21

19

>4>5

22

2>6

210

5>6

2>3

12

+11

>4>5

22

>62

112

>6>6

2>4

>41

2+

13>8

>83

>51

11

114

>8>8

21

>62

11

15>6

>82

>61

32

+16

>4>6

2>4

117

>10

>82

>8>3

218

>6>4

22

119

31

11

20>8

>11

23

22

++

The

perf

orm

edin

terv

entio

ns,w

hich

had

faile

d,ar

ein

dica

ted

bya

num

ber,

indi

catin

gth

efr

eque

ncy

offa

iled

inte

rven

tions

,or

bya

“+.”

Fai

lure

was

defin

edas

bein

gw

ithou

tprim

ary

effe

cton

pain

,or

nola

stin

gef

fect

(>2

mon

ths)

onpa

inre

lief.

IVR

SB

=in

trav

enou

sre

gion

alsy

mpa

thet

icbl

ocka

de.

Kiefer et al.10

Quality of LifeActivities of Daily LivingAt baseline, the ability to independently accom-plish activities of daily living was rated as severelyimpaired by seven, and as totally impaired by 13patients, with a mean score of 2.35 � 0.4(mean � SD) for the entire group. At 3 months,the impairment was rated as severe by one, asmoderate by 12, and as not impaired by seven

patients, with a mean score of 0.7 � 0.6, and asignificant difference compared with baseline(P < 0.001). At 6 months, there was a significantdifference in the ability to perform activities ofdaily living compared with baseline. One patientrated total impairment, three severe impairment,six moderate impairment, and 10 patients noimpairment for a mean score of 0.7 � 0.9(P < 0.001). Results are shown in Figure 4.

-2

0

2

4

6

8

10

baseline

follow-up times

NR

S:

0-1

0 [

po

ints

]

entire group recurring pain CRPS - relapses

* **

*

+#

** *

*

(A)

0

20

40

60

80

100

120

1 week

follow-up times

pain

relie

f

entire group recurring pain CRPS - relapses[ % ]

* ** *

+

#

****

(B)

1 week 1 month 3 months 6 months1 month 3 months 6 months

Figure 2 The pain intensities (A) and the degree of pain relief (B) before and following the treatment. Part (A) shows the painintensities (NRS: 0–10, data presented as mean � SD) of the entire treatment group (N = 20) for baseline, at 1 week, and1, 3, and 6 months following treatment and significant differences compared with baseline (*P < 0.001), and the results of thesubgroup analyses for patients with recurring pain (N = 7 at 1 week, and 1 month, N = 4 at 3, and N = 6 at 6 months) andsignificant differences compared with baseline, as well as results for the subgroup with relapsing CRPS (N = 3 at 3 months,N = 4 at 6 months) and significant differences compared with baseline (+P < 0.004; #P < 0.0029). Part (B) summarizes thepercentage of pain relief following the treatment. Data are presented as means � SD for the entire group and the subgroupswith recurring pain, and relapsing pain, respectively. Significant degrees in the percentage of pain relief are indicated(*P < 0.001; +P < 0.004; #P < 0.002). NRS = Numeric Rating Scale; CRPS = complex regional pain syndrome.

0

1

2

3

4

5

6

baseline

follow-up times

mo

ve

me

nt

dis

ab

ilit

y s

co

re [

po

ints

]

arms hands

0

0,5

1

1,5

2

2,5

3

follow-up times

mo

ve

me

nt

dis

ab

ilit

y s

co

re [

po

ints

]

∗

∗

∗ ∗

∗ ∗

1 month 3 months 6 months baseline 1 month 3 months 6 months

(A) Upper Extremity (B) Lower Extremity

Figure 3 The changes for the movement disability score (4-point rating scale: 0: normal movement, 3: total impairment) ofthe different assessment times. Data are presented as means � SD for baseline, and the follow-ups at 1, 3, and 6 months.(A) Upper extremity: data show the results of a sum-score (movement disability scores of both body sides were added, thusa minimal score of 0 (normal bilateral movement), and 6 (total impaired bilateral movement) for impairment of movement inarms and hands, and significant differences compared with baseline (*P < 0.001). (B) Lower extremity: results and significantdifferences in the movement disability score for the lower extremity at baseline and the follow up assessments (P < 0.001).


Social IntegrationThe impairment in social integration prior totreatment was rated as complete by 11 patients andsevere by nine. Their mean impairment score was2.5 � 0.5. At 3 months, their impairment wasrated as severe by one, as moderate by 10, and ninewere unimpaired. Their mean score of 0.6 � 0.6,was significantly improved compared with theirpretreatment baseline (P < 0.001). At 6 months,there was significant improvement in the groupwith one patient rating total impairment, twosevere impairment, six moderate impairment,and 11 patients no impairment (mean score of0.6 � 0.8 (P < 0.001). Results are shown inFigure 4.

Ability to WorkThe impairment in the ability to work prior totreatment was rated as complete by 11, severe by 5,and as moderate by four patients (mean impairmentscore of 2.3 � 0.8). At 3 months, the impairment inability to work was rated as complete and severe byone patient in each category, as moderate by eight,and as not impaired by 10 patients (mean score of0.6 � 0.8), which was significantly improved com-pared with their baseline (P < 0.001). At 6 months,

there was significant improvement in the abilityto work as only two patients in the cohort wereunable to work, four had moderate impair-ment, and 14 patients had no impairment (meanscore of 0.5 � 0.9) (P < 0.001). Results are shownin Figure 4 and Table 5.

Ketamine and Norketamine Plasma ConcentrationsHigh-pressure liquid chromatography analysis ofketamine and norketamine plasma levels was in 18patients. The sampling and analysis of two patientswas incomplete, because of initial technical diffi-culties and therefore were not included in theanalyses. Figure 5 summarizes the plasma concen-trations for ketamine and norketamine.

Side Effects

Ketamine-Specific Side EffectsPsychotropic Ketamine Side EffectsPsychotropic side effects that included anxiety,dysphoria, nightmares, and difficulties with sleepwere observed in the majority of patients uponemergence from ketamine anesthesia. The inten-sity of these ketamine-specific side effects was

Figure 4 The results for the assess-ments of quality of life: the impairmentin activities of daily living, the impair-ment in social integration, and theability to work. Patients rated theirimpairment on a 4-point rating scale (0:no impairment, 3: total impairment).Part (A) shows the absolute number(N) of patients in each category ofimpairment at baseline and the follow-ups, and significant differences com-pared with baseline (*P < 0.001). (B)Severity of impairment: the impairmentscores for the entire group for impair-ment of activities of daily living, socialintegration, and the ability to work atbaseline, 3, and 6 months and signifi-cant differences compared with base-line (*P < 0.001).

0

2

4

6

8

10

12

14

16

activities of

daily living

social

integrity

ability to

work

activities of

daily living

social

integrity

ability to

work

activities of

daily living

social

integrity

ability to

work

baseline 3 months 6 months

disability domain / follow-up time

nu

mb

er

of

pa

tie

nts

No Impairment Moderate Impairment Severe Impairment Total Impairment

**

[ N ]

(A)

0

0,5

1

1,5

2

2,5

3

3,5

baseline 3 months 6 months

follow-up times

dis

ab

ilit

y s

co

re

activities of daily living social integrity ability to work

* **

* * *

[points]

(B)

Kiefer et al.12

Tab

le5

Indi

vidu

alou

tcom

efo

llow

ing

anes

thet

icke

tam

ine:

the

indi

vidu

alpa

tient

s’ou

tcom

efo

r:pa

inre

spon

se(d

ata

show

nfo

rth

efo

llow

-ups

at1,

3,an

6m

onth

s),

mov

emen

tdi

sord

er(d

ata

show

nfo

rba

selin

e,3,

6m

onth

s;nu

mbe

rsgi

ven

indi

cate

:su

msc

ore

mov

emen

tdi

sabi

lity

inth

ear

ms

(0:

bila

tera

lnor

mal

mov

emen

t–6:

bila

tera

lto

tali

mpa

irmen

t)/s

umsc

ore

mov

emen

tdis

abili

tyin

the

hand

s(0

:bila

tera

lnor

mal

mov

emen

t–6:

bila

tera

ltot

alim

pairm

ent)

/mov

emen

tdis

abili

tysc

ore

for

the

low

erex

trem

ities

(0:

norm

alw

alki

ng–3

:to

tali

mpa

irmen

t),

and

the

impa

irmen

tin

the

asse

ssed

aspe

cts

ofqu

ality

oflif

e:ev

ery

day

activ

ities

,so

cial

life

activ

ities

,an

dw

orki

ngca

paci

ty

Pat

ient

No.

Pai

nM

ovem

ent

Dis

orde

rsA

ctiv

ities

ofD

aily

Livi

ngS

ocia

lInt

egra

tion

Abi

lity

toW

ork

1M

onth

3M

onth

6M

onth

Bas

elin

e3

Mon

ths

6M

onth

sB

asel

ine

3M

onth

s6

Mon

ths

Bas

elin

e3

Mon

ths

6M

onth

sB

asel

ine

3M

onth

s6

Mon

ths

1F

RF

RF

R3/

3/0

0/0/

00/

0/0

TI

NI

NI

TI

NI

NI

TI

NI

NI

2F

RF

RF

R4/

5/0

0/0/

00/

0/0

SI

NI

NI

SI

NI

NI

SI

NI

NI

3R

PF

RF

R4/

4/0

0/0/

00/

0/0

SI

MI

NI

SI

MI

NI

SI

NI

NI

4R

PC

RP

SC

RP

S4/

5/2

2/2/

12/

2/1

SI

MI

SI

TI

MI

SI

TI

MI

TI

5F

RF

RR

P2/

3/0

1/0/

01/

1/0

SI

MI

SI

SI

NI

SI

TI

MI

NI

6F

RF

RF

R5/

5/3

0/0/

00/

0/0

TI

MI

MI

TI

MI

NI

TI

MI

NI

7R

PC

RP

SC

RP

S4/

5/3

2/3/

32/

3/3

TI

SI

TI

TI

SI

TI

TI

TI

TI

8F

RF

RR

P2/

4/2

0/0/

10/

0/1

SI

MI

MI

SI

MI

MI

MI

NI

NI

9F

RF

RF

R2/

3/1

0/0/

00/

0/0

SI

NI

NI

SI

NI

NI

SI

NI

NI

10R

PF

RF

R2/

3/2

0/0/

00/

0/0

TI

NI

NI

TI

NI

NI

MI

NI

NI

11R

PC

RP

SC

RP

S2/

3/3

2/2/

12/

2/1

SI

MI

SI

SI

MI

MI

MI

MI

MI

12R

PR

PR

P5/

5/3

2/2/

22/

2/2

TI

MI

MI

TI

MI

MI

TI

MI

MI

13R

PF

RF

R5/

6/3

1/0/

00/

0/0

TI

MI

NI

TI

MI

NI

TI

MI

NI

14F

RF

RR

P4/

2/2

1/1/

00/

1/0

SI

MI

NI

TI

NI

NI

MI

NI

NI

15F

RR

PR

P2/

2/1

0/0/

00/

0/0

SI

MI

MI

TI

MI

MI

SI

MI

NI

16F

RF

RF

R3/

3/2

0/0/

00/

0/0

SI

NI

NI

SI

NI

NI

SI

NI

NI

17F

RF

RF

R1/

1/0

0/0/

00/

0/0

SI

MI

NI

SI

NI

NI

TI

NI

NI

18R

PR

PC

RP

S4/

4/2

0/1/

10/

0/1

SI

MI

MI

TI

MI

MI

TI

MI

MI

19F

RF

RF

R4/

4/3

0/0/

00/

0/0

TI

NI

NI

TI

NI

NI

TI

NI

NI

20F

RR

PR

P3/

4/2

0/0/

10/

0/1

SI

NI

MI

SI

MI

MI

TI

MI

MI

FR

=fu

llre

mis

sion

;R

P=

recu

rrin

gpa

in;

CR

PS

=co

mpl

exre

gion

alpa

insy

ndro

me-

rela

pse;

NI=

noim

pairm

ent;

MI=

mod

erat

eim

pairm

ent;

SI=

seve

reim

pairm

ent;

TI=

tota

lim

pairm

ent.


most severe in the initial days following emer-gence from anesthesia and resembled an acutewithdrawal. These symptoms were successfullytreated with small doses of clonidine and/or ben-zodiazepines. The psychotropic side effects fadedwithin the first week following treatment in themajority of patients. However, five patientsreported difficulties with sleeping and recurringnightmares for a month following treatment.Muscular weakness was reported in all patients foras long as 4–6 weeks following treatment.

Adverse Treatment EffectsInfectious ComplicationsNo major or life threatening complications wereobserved. The majority of complications wereinfections associated with the intensive care natureof treatment. Seven patients had respiratory infec-tions, tracheobronchitis in five, and pneumonia intwo patients. Fever was observed early (within24–48 hours) following the initiation of anestheticdoses of ketamine, with concomitant leucocytosis(12,000–16,000/mL) and elevation of the CRP(6–25 mg/dL). Culture of tracheal secretionsrevealed S. aureus (methycillin sensible S. aureus,N = 6), Klebsiella pneumoniae (N = 2), and Proteusmirabilis (N = 1), as the pathogens in these cases.Lower urinary tract infections were seen in sixpatients, and urine cultures revealed enterococcusspecies (E. faecium, E. faecalis), and E. coli as thepathogens. These infectious complications weresuccessfully treated with antibiogram-guided anti-biotic therapy.

Laboratory EvaluationDuring treatment, transient rises in liver enzymes,CPK and CKMB were observed. Blood tests priorto the start of therapy revealed elevated liverenzymes (g-GT: 20–60 U/L in five patients, andGOT: 20–38 U/L in five patients), all of whomhad been taking combinations of analgesics, anti-depressants, and seizure medications. Under anes-thesia, elevations of liver enzymes were noted in16 patients for g-GT (range: 30–94 U/L), GOT(range 30–98 U/L), and GPT (20–94 U/L), themaximal elevations occurred on days 5–6 of treat-ment. Elevations in CPK (range: 20–800 U/L)were observed in 16 patients, all of whom hadnormal ratios for CPK/CKMB which wherebelow 10%. Both the elevation of liver enzymesand CPK decreased following treatment andreturned to reference values within 10–14 days.

Discussion

This open-label study suggests an impressiveeffect of anesthetic ketamine in advanced andrefractory CRPS patients. Pain scores were signifi-cantly improved and long-term complete painrelief was observed in 50% of patients. Patientsthat suffered recurring pain alone and recurringpain in conjunction with a CRPS relapse alsomaintained significant relief during the courseof the study. In addition, there was significantimprovement of the movement disorder, ability toperform activities of daily living, and the abilityto work in concert with the decrement in pain.

Figure 5 Ketamine and norketamineplasma concentrations. Summarizesby the HPLC determined plasma con-centrations for racemic ketamine andthe primary active metabolite norket-amine (mg/mL) over the five treatmentdays with anesthetic days and sub-siding in the three consecutivedays after anesthetic ketamine treat-ment. HPLC = high-pressure liquidchromatography.

0

1

2

3

4

5

6

7

8

9

10

Day 1

Ketamine Treatment

co

nc

en

tra

tio

n [

µg

/ml

]

Ketamine [µg/ml] Norketamine [µg/ml]

Following Ketamine

Day 2 Day 3 Day 4 Day 5 Day 1 Day 2 Day 3

Kiefer et al.14

However, the dramatic nature of the interventionwould be expected to cause a strong placeboresponse and the nonrandomized uncontrolleddesign of this study leave its results suggestive butunproven.

There are many possible mechanisms thatunderlie the marked and long-lasting effects ofanesthetic ketamine in these severely affectedCRPS patients. Because this is an open-label phaseII study with lack of controls, the results may not becompletely attributable to ketamine. Anestheticdoses of ketamine have not been studied in thetherapy of chronic pain states. Existing evidence forthe efficacy of ketamine in chronic pain disorderswas obtained by utilizing low subanesthetic doseprotocols primarily for neuropathic pain statesother than CRPS. The first data on the beneficialeffects of ketamine for CRPS were obtained fromcase reports and small case series [23–26,28]. Inthese studies, subanesthetic ketamine was adminis-tered via systemic, epidural or topical routes andprovided dramatic relief from pain and associatedCRPS symptoms in some patients. However, thesestudies differ in the routes of ketamine administra-tion, dosage, treatment time, patient clinical pro-files, and the duration of observation followingtreatment. The main limitations in determiningthe benefit of ketamine in these studies are samplesize, lack of a control population and standardiza-tion of the treatment and measurement protocols.Long-term pain relief for 8 months was observedfollowing a 10-day course of epidural ketamine(0.25 mg/kg/h) in a patient with lower extremityCRPS [23]. Harbut utilized continuous subanes-thetic ketamine for 6 days in a patient that hadsuffered 9 years of CRPS and achieved pain relieffor 5 months [28]. Recently, a larger-scale retro-spective case series described long-term relief frompain following continuous low-dose ketamine [27].In this series, the best response to ketamine wasobserved in patients with early CRPS whose symp-toms and signs were well localized to the distalaspects of one extremity. In a subgroup of refrac-tory CRPS patients, we recently showed subanes-thetic continuous S(+)-ketamine (500 mg/day)administered over 10 days (exceeding the equian-algesic ketamine dosages used by Correll) was inef-fective in relieving pain or attenuating severethermal and mechanical allodynia [29]. To ourknowledge, there are no randomized controlledtrials on the efficacy of ketamine in the treatmentof CRPS.

Complex regional pain syndrome is generallythought to be a subset of neuropathic pain [2,4].

Although as noted above, inflammatory compo-nents are often predominant in early stages [40,41],the exact pathophysiology is unknown but strideshave been made in the understanding of possiblemechanisms that underlie the generation andmaintenance of this possible neuropathic pain[8,17]. A critical role for NMDA-receptors thatcontribute to central sensitization in chronic neu-ropathic pain is well established [16,17]. Conse-quently, the efficacy of several NMDA-receptorantagonists has been investigated in various neuro-pathic pain conditions. In human and animalstudies, ketamine was shown to have a dose-dependent effect on neuropathic pain features,such as secondary hyperalgesia, allodynia, long-term potentiation, and wind-up [42–46]. Severalclinical trials in neuropathic pain conditions haveconfirmed beneficial effects of ketamine in thetherapy of chronic pain. In a randomized con-trolled trial of postherpetic neuralgia, iv ketaminesignificantly reduced pain, allodynia, and hyper-pathia [47]. Similarly, intravenous ketamine hasbeen shown to produce significant pain relief andreduction of wind-up pain in a randomized con-trolled trial of chronic phantom pain [48]. A ran-domized trial of intramuscular ketamine provided24 hours of significant pain relief in patients withfacial neuralgia [49]. Several trials have noted long-term affects of ketamine that outlast its pharmaco-logical profile [18–20,49]. In addition, animal andclinical studies have demonstrated that the efficacyof ketamine is dose-dependent [19,43,44,50]. Asthe incidence and degree of ketamine side effectsalso depends on dosage, most trials in pain medi-cine have been performed with low doses [14]. Thistrial of anesthetic dosage of ketamine in refractoryCRPS, as well as the first patient treated on acompassionate care basis [51] demonstrated long-term significant pain relief that outlasts its pharma-cological profile.

Many aspects of the pathophysiology of CRPSremain unclear. Recently, CRPS has been positedto be a disease of the CNS [7]. The molecularmechanisms underlying CRPS are hindered bylack of an exact animal model that is completelyvalid for this complex clinical entity [52]. Its char-acteristic signs and symptoms may occur as a con-sequence of dysregulated efferent central controlof several systems (i.e., somatosensory, motor, andsympathetic) and appears to be maintained from aperipheral sensitizing afferent nociceptive barrage.The molecular mechanisms responsible forinducing and maintaining these lasting and self-maintaining neuroplastic changes in CRPS are not


known but there is evidence for NMDA-receptormediated neuronal plasticity and facilitation ofcentral pain processing [8]. Another potentialmechanism underlying the syndrome is injuryinduced activation of central microglia that secreteinflammatory cytokines which activate centralpain projecting neurons [53]. The relative impor-tance of mechanisms for central sensitizationmediated by the NMDA-receptor and subsequentcalcium cascades or effects of inflammatory cytok-ines on pain transmission neurons or both inconcert is not known [17,21]. Recent evidence in arat model of neuropathic pain demonstrated acomparable long-term suppression of allodynia byketamine that outlasted the duration of its NMDAblockade [50]. Thus, down-regulation of centralsensitization mediated by NMDA-receptor block-ade might explain in part long-term effects of ket-amine in neuropathic pain.

Other relevant mechanisms mediated by ket-amine that contribute to pain relief in thesepatients must be considered. These include poten-tial modulation of peripheral NMDA- and non-NMDA-receptors. Ketamine inhibits peripheralglutamate receptors which play a role in bothperipheral and subsequent central sensitization[54]. In addition, ketamine interacts with variousreceptors involved in nociception that includeAMPA and kainate glutamate receptors, voltage-dependent ion channels, sodium and L-typecalcium channels, opioid receptors (m-, k-, andd-opioid receptors), GABAA-receptors, and nico-tinic and muscarinic acetylcholine receptors [15].Ketamine induced inhibition of nitric-oxide syn-thase might also contribute to its analgesic effects[15]. As noted above, proinflammatory mediatorsare known to play an essential role in the processesof peripheral and central sensitization [55].Ketamine induces a profound inhibition of pro-inflammatory cytokines and other inflammatorymediators, both in experimental and clinicalstudies [15,22]. A recent study demonstrated sig-nificant increases in proinflammatory cytokines inthe cerebrospinal fluid of CRPS patients, whichsuggests a potential role of neuroimmune activa-tion in CRPS [56]. The anti-inflammatory effectsof ketamine administered in anesthetic doses mayalso play a role in its effects on these patients.Alternatively or in addition to ketamine, mida-zolam and clonidine may also contribute to theeffectiveness of this treatment. Clonidine, acentral a2-adrenergic agonist, has analgesic prop-erties [57]. Its analgesic potency is weak but haseffect when administered by epidural, intrathecal

or a transdermal route. Although the analgesiceffects of intravenous clonidine are controversial,a synergistic interaction with ketamine in ourpatients is possible [57]. Another synergistic effectof this treatment may be due to midazolam, ashort-acting GABAA agonist. In the course ofcentral sensitization, GABA-ergic inhibitorytransmission is depressed by NMDA-dependentmechanisms which leads to prolonged depressionof inhibitory transmission and thus potentiation ofcentral pain projecting neuron hyperexcitability[17,58]. The large doses of midazolam adminis-tered during treatment would be expected toenhance GABA-ergic induced inhibition duringthis treatment while its role as an analgesic isunclear [17,58]. The possible contributions of theplacebo effect and or resetting of pain processingmechanisms due to 5 days of anesthesia in thebeneficial effects of this treatment are unknown.

A most relevant concern of this invasive proce-dure is patient safety. Modern intensive care medi-cine standards achieve a high level of patientsafety. Ketamine has been safely used for over 30years in clinical anesthesia and also in intensivecare. However, a potential concern is NMDAR-antagonist induced neurotoxicity that has beendemonstrated in animal experimental work in thedeveloping and adult rat brain [59]. Neurotoxiceffects are prevented by administration of cloni-dine and GABAA-agonists [60,61]. To the best ofour knowledge, neurotoxicity of ketamine to datehas not been demonstrated in humans [62]. Initialstudies investigating ketamine sedation in braininjured patients in the intensive care setting werenot associated with significant morbidity or mor-tality [63,64]. However, these studies were notpowered for a valid assessment of safety. Thereported duration of ketamine sedation (6.1 � 3.2days) and the dosage of ketamine (maximal dose:94 � 23 mg/kg/min) are comparable to our study(5 days of sedation; maximal dose: ~84 mg/kg/min)[63].

Nonetheless, it must be emphasized that thisprotocol is associated with serious risks. Themajor complications observed in this study wererespiratory and urinary tract infections, represent-ing typical infections in intensive care. Although,in this series, infections resolved under antibiotictreatment, it must be emphasized that infectiouscomplications still represent the main source ofmorbidity and mortality in modern intensive caremedicine. Transient ketamine-specific psychotro-pic side effects occurred on emergence from ket-amine anesthesia and were successfully controlled

Kiefer et al.16

by benzodiazepines and clonidine. There were nolong-term psychiatric or cognitive impairments inany patient [65]. Moderate muscle weakness per-sisted for a month to 6 weeks.

In addition to all of the limitations inherent ina nonrandomized uncontrolled trial, there areseveral other limitations of this study: 1) the move-ment disorder, social integration, activities of dailyliving and ability to work measures were subjectiveand have not been validated in CRPS patient; 2)the CRPS patient population studied is not repre-sentative of that seen in most pain centers as it isdrawn from the entire USA; 3) the mechanism ofthe spread of other validated factors of CRPS fromthe area of original injury is not known. The sever-ity of this clinical component in these patients isunusual and may represent or be a consequence ofthe role of central glia pathophysiology in chronicpain states, central sensitization, functional reor-ganization of pain processing systems or dysfunc-tion of descending pain control mechanisms. Thearea of primary CRPS may be maintaining a moregeneralized pain state.

A complete double blind placebo controlledrandomized clinical trial would be logistically andethically at least difficult, but its realization repre-sents a major challenge of future work to possiblyconfirm the observed effect.

Conclusion

This phase II open-label study utilizing anestheticdoses of ketamine with midazolam and clonidinesuggests possible effectiveness for severe CRPSpatients that have failed all available standardtherapies. A definitive, large multicenter random-ized controlled trial is needed to confirm theseresults.

Acknowledgments

PR and RTK wish to thank Prof. Robert J. Schwartzman,Prof. Karl-Heinz Altemeyer, and Prof. Klaus Unertl fortheir belief and support in a new clinical concept and theirsupport, which enabled the clinical realization of this study.

The authors wish to thank the nursing staff and physi-cians of the intensive care units: Station 43, KlinikumSaarbrücken, Germany, and A5-Nord/A5-Ost, UniverstiyHospital Tübingen, Germany, for their support of thisstudy and especially the excellent clinical care of thepatients, which highly contributed to the success and aboveall the safe treatment of the patients.

The authors sincerely thank Dr. Birgit Schönfisch, PhD(Institute of Medical Biometry, Eberhard-Karls University,Tübingen, Germany) for her statistical expertise, and

Professor Marcel E. Durieux (Department of Anesthe-siology, University of Virginia, Charlottesville, VA) forstimulating discussions of the data and his expertiseand constructive criticism in preparing and revising thismanuscript.

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neou

sbu

rnin

gpa

in;

evok

edsh

ootin

gpa

in;

mec

hani

cal

allo

dyni

a(d

ynam

ican

dst

atic

);th

erm

alal

lody

nia

toco

ld

Tem

pera

ture

asym

met

ry:

incr

ease

drig

htar

man

dfa

ce>

left;

eryt

hem

atou

srig

htar

man

dfa

ce;

fluct

uatin

ger

ythe

ma

right

arm

and

face

Ede

ma

ofrig

htar

man

dfa

ce;

hype

rhid

rosi

sgr

eate

rrig

htar

mth

anle

ft

Dec

reas

edra

nge

ofm

otio

nrig

htha

nd(u

nabl

eto

com

plet

ely

flex

finge

rs);

wea

knes

sof

dist

alha

ndm

uscl

es;

decr

ease

dab

ility

toin

itiat

efin

ger

mov

emen

ts;

incr

ease

dna

ilrid

ging

;lo

ssof

hair

right

hand

and

fore

arm

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

am

irror

dist

ribut

ion

Pos

itive

inup

per

trun

kle

ftbr

achi

alpl

exus

dist

ribut

ion

(hyp

eral

gesi

ato

pinp

rick;

mec

hani

cald

ynam

ican

dst

atic

allo

dyni

a;co

ldal

lody

nia)

Dec

reas

edab

ility

toin

itiat

em

ovem

ent

offin

gers

ofle

ftha

nd

No.

325

yom

ale

CR

PS

24m

onth

sB

asel

ine

Pai

nN

RS

9A

SA

Cla

ssII

Rig

htbr

achi

alpl

exus

;H

odgk

in’s

dise

ase;

com

pres

sion

ofth

ebr

achi

alpl

exus

byly

mph

oma

Rig

htbr

achi

alpl

exus

;V

1-V

3H

yper

alge

sia

topi

npric

k;sp

onta

neou

sbu

rnin

gpa

in;

evok

edla

ncin

atin

gan

dtin

glin

gpa

in;

deep

ache

;m

echa

nica

lallo

dyni

a(d

ynam

ican

dst

atic

);jo

int

pain

(sm

allj

oint

sof

the

finge

rs);

ther

mal

allo

dyni

ato

cold

Tem

pera

ture

asym

met

ry:

incr

ease

din

the

right

arm

and

face

>th

ele

ftar

man

dfa

ce;

eryt

hem

atou

sen

tire

right

arm

and

face

;no

fluct

uatio

nof

eryt

hem

ain

right

arm

and

face

Sev

ere

edem

aof

the

face

;m

oder

ate

edem

aof

the

right

arm

and

hand

;hy

perh

idro

sis

bila

tera

llyof

the

arm

san

drig

htfa

ce;

edem

ast

atic

inrig

htar

man

dfa

ce

Diff

icul

tyin

itiat

ing

fine

finge

rm

ovem

ents

right

hand

;w

eakn

ess

ofdo

rsal

and

vola

rin

tero

ssei

and

abdu

ctor

polli

cis

brev

isrig

htha

nd;

supr

aspi

natu

san

din

fras

pina

tus

wea

knes

sof

the

right

arm

;oc

casi

onal

myo

clon

icje

rkof

right

arm

;in

crea

sed

nail

grow

th,

ridgi

ngan

dth

ickn

ess

offin

gers

ofrig

htha

nd

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

the

left

arm

and

hand

Hyp

eral

gesi

ato

pinp

rick;

mec

hani

cal

dyna

mic

and

stat

ical

lody

nia;

cold

allo

dyni

a;le

ssse

vere

spon

tane

ous

burn

ing

pain

;le

ssse

vere

evok

edla

ncin

atin

gpa

in

Nor

mal

tem

pera

ture

arm

and

face

;sl

ight

eryt

hem

aof

the

left

ear;

stat

icco

lor

chan

geof

the

ear

(ery

rhem

a)

Slig

htly

slow

initi

atio

nof

mov

emen

t;fu

llst

reng

th;

noad

vent

itial

mov

emen

t;fu

llra

nge

ofm

ovem

ent

Kiefer et al.20

No.

446

yofe

mal

eC

RP

S60

mon

ths

Bas

elin

eP

ain

NR

S9.

5A

SA

Cla

ssII

Rig

htbr

achi

alpl

exus

trac

tion

inju

ryH

yper

alge

sia

topi

npric

krig

htfa

ce,

arm

,an

terio

rch

est

and

tota

lleg

;sp

onta

neou

sbu

rnin

gpa

in,

deep

ache

entir

erig

htsi

deof

the

body

;se

vere

right

L5-S

1di

strib

utio

nla

ncin

atin

gpa

in;

mec

hani

cal,

dyna

mic

and

stat

ical

lody

nia

ofen

tire

right

side

ofth

ebo

dy;

ther

mal

allo

dyni

ato

both

cold

and

heat

;co

ldal

lody

nia

spre

adsi

xin

ches

toei

ther

side

ofth

est

imul

us(t

unin

gfo

rk)

Tem

pera

ture

asym

met

ry;

right

arm

and

face

>th

anle

ft(h

ighe

r);

eryt

hem

aof

the

right

arm

and

face

;no

rmal

skin

colo

rof

the

left

arm

and

face

;flu

ctua

ting

colo

rch

ange

ofth

erig

htar

man

dfa

ce

Con

stan

ted

ema

ofth

erig

htha

nd,

arm

and

face

;hy

perh

idro

sis

ofrig

htar

man

dfa

ce;

cons

tant

edem

aof

right

face

and

hand

;sy

mpt

oms

oftig

htne

ssin

the

hand

Dec

reas

edra

nge

ofm

otio

nof

all

finge

rsof

right

hand

;un

able

tofle

xth

efin

gers

fully

;w

eakn

ess

ofal

ldi

stal

mus

cles

ofrig

htha

nd;

exag

gera

tion

ofph

ysio

logi

ctr

emor

ofrig

htup

per

extr

emity

;oc

casi

onal

myo

clon

icje

rkof

right

uppe

rex

trem

ity;

flexi

ondy

ston

icpo

stur

eof

arm

and

wris

t;m

otor

negl

ect

ofrig

htar

m;

loss

ofha

iron

the

right

fore

arm

;th

icke

ned

ridge

dan

dbr

ittle

nails

ofrig

htha

nd

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

othe

rth

anpr

imar

yar

eas

ofin

volv

emen

trig

htar

mC

linic

alcr

iterio

nfa

ctor

sth

atw

ere

posi

tive

inot

her

than

prim

ary

area

sof

invo

lvem

ent

right

leg

Tact

ilem

echa

nica

ldyn

amic

and

stat

ical

lody

nia

(upp

eran

dlo

wer

trun

k,br

achi

alpl

exus

dist

ribut

ions

onth

ele

ft);

hype

ralg

esia

topi

npric

k(u

pper

and

low

ertr

unk

brac

hial

plex

usdi

strib

utio

ns);

cold

allo

dyni

a(u

pper

and

low

ertr

unk)

;le

ftar

mM

echa

noal

lody

nia

(sta

tican

ddy

nam

ic)

ofth

erig

htup

per

leg

inre

gion

aldi

strib

utio

n

Min

imal

hype

rhid

rosi

sof

left

arm

;no

rmal

tem

pera

ture

ofle

ftar

mM

inim

aler

ythe

ma

(rar

ely)

ofth

ele

ftar

mS

light

diffi

culty

initi

atin

gan

dm

aint

aini

ngle

ftha

ndfin

ger

mov

emen

ts

Add

ition

alfe

atur

esS

ever

eno

n-flu

ctua

ting

veno

usdi

sten

tion

inha

ndan

dfo

rear

mve

ins;

L4-L

5;L5

-S1

radi

cula

rm

otor

and

sens

ory

chan

ges

onth

ele

ftsi

de;

eryt

hem

atou

sea

ron

the

right

;up

per

trun

kof

brac

hial

plex

us;

low

ertr

unk

brac

hial

plex

us

No.

529

yofe

mal

eC

RP

S30

mon

ths

Bas

elin

eP

ain

NR

S8.

5A

SA

Cla

ssII

Rig

htbr

achi

alpl

exus

(ele

ctric

alin

jury

;te

arof

the

labr

umof

the

glen

oid

foss

aof

the

hum

erus

)

Sev

ere

hype

ralg

esia

topi

npric

kre

gion

aldi

strib

utio

nof

the

right

uppe

rex

trem

ity;

spon

tane

ous

burn

ing

pain

;lig

hten

ing-

like

pain

right

uppe

rex

trem

ity;

mec

hani

cal

dyna

mic

and

stat

ical

lody

nia;

cold

allo

dyni

a;de

epm

uscl

ese

nsiti

zatio

nto

pres

sure

ofrig

htup

per

extr

emity

inre

gion

aldi

strib

utio

n

Hig

her

tem

pera

ture

right

uppe

rex

trem

ityth

anle

ftup

per

extr

emity

;er

ythe

ma

ofen

tire

right

uppe

rex

trem

ity;

left

trap

eziu

srid

geha

dco

lor

chan

ge;

eryt

hem

ast

atic

inaf

fect

edar

eas

Ede

ma

ofth

erig

htup

per

extr

emity

and

face

;hy

perh

idro

sis

ofrig

htup

per

extr

emity

;sw

olle

nst

iffrig

htha

nd

Rig

htha

ndde

mon

stra

ted

diffi

culty

initi

atin

gfin

ger

mov

emen

ts;

wea

knes

sof

alld

ista

lrig

htha

ndm

uscu

latu

re;

spas

mof

the

right

uppe

rex

trem

ity;

loss

ofha

ir;br

ittle

atro

phic

nails

with

ridgi

ng;

loss

ofin

tegu

men

tof

the

4than

d5th

finge

rsrig

htha

nd;

shin

yth

insk

inof

the

right

hand

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

cont

iguo

usar

eas

Mec

hano

allo

dyni

a,(s

tatic

and

dyna

mic

)of

the

right

face

Allo

dyni

aan

dhy

pera

lges

iato

pinp

rick

inth

esa

me

dist

ribut

ion;

spon

tane

ous

burn

ing

pain

inth

efa

cean

dth

igh

Incr

ease

dte

mpe

ratu

refa

ceV

1-V

3,an

dre

gion

ally

inth

eup

per

thig

h;er

ythe

ma

ofth

efa

ce;

noflu

ctua

tion

ofer

ythe

ma

ofth

efa

ce

Ede

ma

and

hipe

rhid

rosi

sof

the

right

face

V1-

V3

dist

ribut

ion;

com

plai

nts

ofna

rrow

ing

ofpa

lpeb

ralfi

ssur

efr

omed

ema

right

V1

Add

ition

alfe

atur

esP

ain

inbi

occi

pita

lten

don;

seve

reTi

nels

igns

with

com

pres

sion

ofth

esu

prar

adic

ular

foss

a,pr

onat

orca

nal,

Arc

ade

ofF

rohs

ean

dca

rpal

tunn

el;

ante

rior

shou

lder

inst

abili

ty;

touc

hon

the

arm

spre

adto

the

face


Ap

pen

dix

1:C

ontin

ued

Dem

ogra

phic

sTr

igge

ring

Inju

ryS

iteof

Prim

ary

CR

PS

Abn

orm

aliti

esin

Pai

nP

roce

ssin

gF

acto

r1

Ski

nC

olor

and

Tem

pera

ture

Cha

nges

Fac

tor

2

Fac

tor

Vas

omot

oran

dS

udom

otor

/Ede

ma

Cha

nges

Fac

tor

3

Mot

orD

ysfu

nctio

nan

dTr

ophi

cF

eatu

res

Fac

tor

4

No.

646

yofe

mal

eC

RP

S72

mon

ths

Bas

elin

eP

ain

NR

S8.

5A

SA

Cla

ssIII

Cru

shin

jury

ofth

erig

htan

kle

and

foot

;op

erat

ive

oste

osyn

thes

isof

the

right

foot

Hyp

eral

gesi

ato

pinp

rick

ofrig

htlo

wer

extr

emity

,bu

rnin

gpa

inm

ost

seve

reat

the

site

ofth

eor

igin

alfo

otsu

rger

y;jo

int

pain

right

foot

;lig

hten

ing-

like

pain

srig

htfo

otan

dle

g

Col

der

right

leg

toth

ekn

eeth

anle

ft;er

ythe

ma

ofth

erig

htlo

wer

extr

emity

Ede

ma

ofrig

htlo

wer

extr

emity

and

face

;st

iffne

ssan

dde

crea

sed

mob

ility

from

swel

ling

ofrig

htfo

otan

dha

nd;

hype

rhid

rosi

sof

the

right

low

erex

trem

ity,

hype

rhid

rosi

san

ded

ema

ofth

erig

htle

gto

the

thig

h,va

som

otor

and

sudo

mot

orch

ange

sV

1-V

3rig

htfa

ce

Diff

icul

tyin

itiat

ing

mov

emen

t;w

eakn

ess

ofin

vers

ion,

dors

iflex

ion

and

ever

sion

ofth

erig

htde

crea

sed

rang

eof

mot

ion

toal

lpla

nes

ofth

erig

ht;

feel

ing

asif

the

right

leg

wou

ldlo

sest

abili

ty;

thic

kene

d,br

ittle

nails

;lo

ssof

hair

over

the

dist

allo

wer

third

ofth

ele

gan

dfo

ot

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

cont

iguo

usip

sila

tera

lext

rem

ities

(leg

and

uppe

rex

trem

ity),

face

and

mirr

orfo

otdi

strib

utio

n

Rig

htco

ntig

uous

leg,

uppe

rex

trem

ityan

dfa

ce);

hype

ralg

esia

topi

npr

ick;

spon

tane

ous

burn

ing,

lanc

inat

ing

and

deep

pain

;m

echa

nica

l,dy

nam

ican

dst

atic

allo

dyni

a;de

epm

uscl

ese

nsiti

zatio

n;co

ldal

lody

nia

(rig

htfa

ce>

left

arm

)

Incr

ease

dte

mpe

ratu

reof

the

right

face

;de

crea

sed

tem

pera

ture

ofth

erig

htup

per

extr

emity

and

right

low

erex

trem

ity

Hyp

erhi

dros

is;

dusk

ycy

anos

isrig

htar

man

dup

per

thig

hP

oor

initi

atio

nan

dm

aint

enan

ceof

fine

mov

emen

ts;

wea

knes

sof

exte

rnal

halli

ces

long

usrig

htup

per

extr

emity

;de

crea

sed

initi

atio

nof

mov

emen

tle

ftto

esan

dan

kle

Add

ition

alfe

atur

esS

ever

ete

nder

ness

inar

eaof

surg

ical

scar

;sp

read

ofst

imul

us(p

inpr

ick

and

cold

)fr

omth

erig

htfo

otto

the

right

face

;V

2,ed

ema

and

hype

rhid

rosi

sof

right

face

,m

ost

seve

re;

spon

tane

ous

burn

ing

pain

No.

728

yofe

mal

eC

RP

S60

mon

ths

Bas

elin

eP

ain

NR

S9.

5A

SA

Cla

ssIII

Trau

ma

toth

elo

wer

back

and

right

leg

Hyp

eral

gesi

arig

htlo

wer

extr

emity

topi

npric

k;se

vere

spon

tane

ous

burn

ing

pain

ofrig

htlo

wer

extr

emity

(reg

iona

ldis

trib

utio

n);

deep

knee

join

tpa

in;

pain

atth

ein

jury

site

ofth

erig

htlo

wer

back

;m

echa

nica

l,dy

nam

ican

dst

atic

allo

dyni

arig

htle

g;co

ldal

lody

nia

right

low

erex

trem

ity

Rig

htle

gsl

ight

lyco

lder

than

left

leg;

both

cold

erth

anno

rmal

;flu

ctua

ting

eryt

hem

aof

the

right

low

erex

trem

ity

Ede

ma

ofrig

htle

g(s

ever

e);

hype

rhid

rosi

sof

right

leg

>le

ft;ed

ema

not

fluct

uatin

g(c

ompo

unde

d)by

the

patie

ntbe

ing

whe

elch

air

boun

d

Una

ble

toin

itiat

em

ovem

ent

ofth

eto

es;

wea

knes

sof

allm

uscl

egr

oups

ofth

erig

htle

g;de

crea

sed

rang

eof

mot

ion

ofth

erig

htfo

ot,

myo

clon

icje

rks;

dyst

onia

right

foot

;po

stur

e(p

lant

arfle

xed

and

inve

rted

);th

icke

ned

nails

;br

awny

edem

a;ar

eas

ofdy

stro

phic

skin

Kiefer et al.22

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

cont

iguo

usar

eas

ofth

eip

sila

tera

lext

rem

ity,

face

and

cont

rala

tera

lleg

Ipsi

late

rala

rmhy

pera

lges

iato

pinp

rick;

dyna

mic

and

stat

icm

echa

noal

lody

nia;

cold

and

hot

allo

dyni

a;jo

int

pain

;de

epm

uscl

eal

lody

nia

topr

essu

re;

spon

tane

ous

burn

ing

pain

,lig

hten

ing-

like

pain

;tin

glin

gpa

inF

ace

right

side

(V1-

V3)

hype

ralg

esia

topi

npric

k;dy

nam

ican

dst

atic

mec

hano

allo

dyni

a;co

ldal

lody

nia

Rig

htup

per

extr

emity

war

mer

than

left

uppe

rex

trem

ity;

eryt

hem

atou

srig

htar

man

dha

nd;

varie

dw

ithpa

in,

mov

emen

tan

dem

otio

nals

tres

s

War

mer

than

the

left

face

(par

ticul

arly

V2)

;er

ythe

mat

ous

chee

kan

drig

htea

r;no

n-va

ryin

ger

ythe

ma

Mod

erat

eed

ema

ofth

erig

htha

nd;

hype

rhid

rosi

sco

mpa

red

tole

ftup

per

extr

emity

;no

nvar

ying

degr

eeof

edem

aof

right

uppe

rex

trem

ity

Ede

ma

ofrig

ht>

left

uppe

rex

trem

ity;

hype

rhid

rosi

s>

left

uppe

rex

trem

ity;

cons

tant

edem

aof

the

face

Poo

rin

itiat

ion

and

mai

nten

ance

offin

ger

mov

emen

t;w

eakn

ess

ofal

lm

uscl

egr

oups

ofth

erig

htup

per

extr

emity

;m

yocl

onic

jerk

san

dsp

asm

spr

ovok

edw

ithex

erci

se

Add

ition

alfe

atur

esTi

nels

igns

very

posi

tive

atsu

prac

lavi

cula

rfo

ssa,

Arc

ade

ofF

rohs

e,pr

onat

orca

nala

ndca

rpal

tunn

elbi

late

rally

;st

imul

ussp

read

from

arm

tofa

cerig

htsi

de;

leg

tofa

cerig

htsi

de

Mirr

ordi

strib

utio

nof

left

leg

hype

ralg

esia

topi

npric

k;dy

nam

ican

dst

atic

mec

hano

allo

dyni

a;co

ldal

lody

nia

(equ

alth

roug

hout

the

leg)

Coo

ler

than

right

leg;

min

imal

eryt

hem

aco

mpa

red

torig

htle

g;co

lor

chan

geva

ried

with

emot

iona

lstr

ess

and

cold

Ede

ma

ofth

ele

ftle

g>

dist

ally

(com

poun

ded

bybe

ing

whe

elch

air

boun

d);

non-

vary

ing

edem

a;sl

ight

lyle

sshy

perh

idro

ticth

anrig

htsi

de

Una

ble

toin

itiat

em

ovem

ent

ofth

eto

esor

low

erle

g;m

inim

alm

ovem

ent

ofili

opso

as;

myo

clon

icje

rks;

dyst

onia

ofth

ele

ftfo

ot(in

vert

edan

dpl

anta

rfle

xed)

;th

icke

ned,

ridge

dan

dbr

ittle

nails

,sh

iny

thin

skin

ofth

efo

ot

No.

842

yofe

mal

eC

RP

S30

mon

ths

Bas

elin

eP

ain

NR

S8.

5A

SA

Cla

ssII

Cru

ciat

elig

amen

tte

ar;

tibia

lpl

ate

frac

ture

ofth

erig

htkn

eeH

yper

alge

sia

ofth

erig

htkn

eean

dle

gin

are

gion

aldi

strib

utio

n;dy

nam

ican

dst

atic

mec

hano

allo

dyni

aof

the

skin

;de

epse

nsiti

zatio

nof

the

quad

ricep

sm

uscl

e;sp

onta

neou

sbu

rnin

gpa

inof

the

knee

that

was

cont

inuo

us;

evok

edlig

hten

ing-

like

pain

and

deep

ache

with

wei

ght

bear

ing

Tem

pera

ture

asym

met

ry(w

arm

er)

than

left

knee

;er

ythe

ma

ofrig

htkn

ee;

lived

ore

ticul

aris

and

dusk

ycy

anos

is;

incr

ease

der

ythe

ma

with

exer

cise

and

heat

ofth

erig

htkn

eear

eaan

dup

per

leg

Ede

ma

ofrig

htkn

eear

ea;

min

imal

edem

aof

the

right

uppe

rle

g;sw

eatin

gas

ymm

etry

>th

anle

ftkn

eean

dle

g;va

riabl

eed

ema

afte

rex

erci

se(s

wim

min

gan

dw

alki

ng)

Poo

rin

itiat

ion

and

mai

nten

ance

offin

em

ovem

ent

ofto

eson

the

right

;de

crea

sed

rang

eof

mot

ion

ofrig

htkn

ee;

wea

knes

sof

quad

ricep

san

dex

tens

orha

lluci

slo

ngus

onth

erig

ht;

min

imal

nail,

hair

and

skin

chan

geof

the

right

leg

and

foot

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

ipsi

late

rala

rman

dfa

ceas

wel

las

ina

mirr

ordi

strib

utio

n

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

inth

eup

per

extr

emiti

esof

the

supr

acla

vicu

lar

foss

a;C

2-C

3ex

itfo

ram

ina;

Arc

ade

ofF

rohs

e;pr

onat

orca

nal,

cubi

tala

ndca

rpal

tunn

el;

stim

ulus

appl

ied

toR

knee

(pin

pric

k)at

times

felt

inth

eR

orL

face

.

Ipsi

late

ralr

ight

arm

;ip

si-

late

ralf

ace;

mirr

orle

ftle

g,hy

pera

lges

iaan

dal

lody

nia

(sta

tican

ddy

nam

ic)

V1-

V3

edem

aan

dhy

perh

idro

sis

right

face

Ipsi

late

ralr

ight

arm

;le

ftle

gpo

orin

itiat

ion

ofm

ovem

ent


Ap

pen

dix

1:C

ontin

ued

Dem

ogra

phic

sTr

igge

ring

Inju

ryS

iteof

Prim

ary

CR

PS

Abn

orm

aliti

esin

Pai

nP

roce

ssin

gF

acto

r1

Ski

nC

olor

and

Tem

pera

ture

Cha

nges

Fac

tor

2

Fac

tor

Vas

omot

oran

dS

udom

otor

/Ede

ma

Cha

nges

Fac

tor

3

Mot

orD

ysfu

nctio

nan

dTr

ophi

cF

eatu

res

Fac

tor

4

No.

922

yofe

mal

eC

RP

S72

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Tend

onru

ptur

edi

git

IV;

oper

ativ

ere

pair

inth

erig

htha

ndH

yper

alge

sia

topi

npric

kof

right

uppe

rex

trem

ity;

dyna

mic

and

stat

icm

echa

noal

lody

nia

ofth

een

tire

right

uppe

rex

trem

itybu

tm

ore

seve

rein

the

late

ralh

and;

spon

tane

ous

deep

ache

and

burn

ing

lanc

inat

ing

pain

ofth

erig

htha

ndan

drig

htup

per

extr

emity

Tem

pera

ture

asym

met

ry,

prim

arily

war

mer

ofrig

htve

rsus

left

hand

;er

ythe

ma

ofrig

htha

nd;

colo

rch

ange

varie

dfr

omer

ythe

ma

todu

sky

cyan

osis

;liv

edo

retic

ular

isof

right

uppe

rex

trem

itym

ost

seve

rein

the

med

ialf

orea

rm

Ede

ma

ofrig

htha

nd(a

llfin

gers

);sw

eatin

gas

ymm

etry

right

>le

ftup

per

extr

emity

;m

ost

seve

rein

the

hand

;no

n-va

ryin

grig

htha

nded

ema

Wea

knes

sof

alli

ntrin

sic

hand

mus

cles

onth

erig

ht;

decr

ease

dra

nge

ofm

otio

nrig

htha

nd;

unab

leto

clos

efin

gers

into

afis

t;in

crea

sed

phys

iolo

gic

and

inte

ntio

ntr

emor

;sp

onta

neou

sdr

oppi

ngob

ject

s;sh

iny

skin

ofth

edo

rsum

ofth

erig

htha

nd;

loss

ofsu

bcut

aneo

ustis

sue

digi

tIV

,V

;br

ittle

,rid

ged

and

thic

kene

dna

ilsrig

htha

nd

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

the

ipsi

late

ral

uppe

ran

dlo

wer

extr

emity

;ip

sila

tera

lfac

ean

dco

ntra

late

ral

hand

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

insu

prac

lavi

cula

rfo

ssa,

Arc

ade

ofF

rohs

e,pr

onat

orca

nal,

cubi

tal

tunn

elrig

ht>

left;

spre

adof

pinp

rick

from

the

hand

toth

efa

cean

dar

m

Ipsi

late

rala

rman

dle

g;ip

sila

tera

lfa

ce(V

1-V

3)sp

onta

neou

sbu

rnin

gpa

in,

hype

ralg

esia

topi

npr

ick

Ipsi

late

rala

rman

dle

g;ip

sila

tera

lfac

e(V

1-V

3)hy

perh

idro

sis

and

war

mer

;co

ntra

late

ralh

and

(muc

hle

ssde

gree

than

Rha

nd)

Ipsi

late

rala

rman

dle

g;ip

sila

tera

lfac

e(V

1-V

3)hy

perh

idro

sis

and

edem

a;co

ntra

late

ralh

and

(muc

hle

ssde

gree

than

right

hand

)

Ipsi

late

rala

rman

dle

g;co

ntra

late

ral

hand

(poo

rin

itiat

ion

offin

ger

and

toe

mov

emen

t)

No.

1019

yofe

mal

eC

RP

S60

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Fra

ctur

eof

met

atar

salV

ofth

erig

htfo

otH

yper

alge

sia

topi

npric

kof

the

right

leg

and

right

foot

atar

eaof

inju

ry(m

ost)

seve

re;

dyna

mic

and

stat

icm

echa

no-a

llody

nia

ofth

erig

htfo

ot;

cold

allo

dyni

aof

the

right

foot

;sp

onta

neou

sbu

rnin

gpa

inof

the

foot

;m

ost

seve

repa

inat

the

area

ofth

eor

igin

alfr

actu

re;

evok

edla

ncin

atin

gpa

inan

dde

epac

hew

ithw

alki

ng;

occa

sion

alsp

onta

neou

ssq

ueez

ing

pain

ofth

erig

htfo

otan

dle

g

Tem

pera

ture

asym

met

ryrig

htfo

otco

lder

than

left;

fluct

uate

sw

ithoc

casi

onal

right

foot

war

mer

than

left;

colo

rch

ange

with

eryt

hem

aal

tern

atin

gw

ithdu

sky

cyan

osis

ofrig

htfo

ot>

left

foot

;he

atan

dco

ldev

oked

eryt

hem

aor

cyan

osis

resp

ectiv

ely

Ede

ma

ofdo

rsum

ofrig

ht>

left

foot

;sw

eatin

gas

ymm

etry

right

>le

ftfo

ot;

posi

tion

(dep

ende

nt)

incr

ease

ded

ema

but

alw

ays

pres

ent

right

>le

ftfo

ot

Dec

reas

edex

tens

ion

and

flexi

onof

the

right

foot

;st

iffne

ssof

the

right

foot

;sl

ight

dyst

onia

atre

stw

ithpl

anta

rfle

xion

and

inve

rsio

nof

right

foot

;ra

rem

yocl

onic

jerk

ofth

erig

htsi

de

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

the

ipsi

late

ral

face

and

extr

emiti

es

Left

leg;

right

arm

;rig

htfa

ce(V

1-V

3)sp

onta

neou

spa

inan

dm

echa

noal

lody

nia

(sta

tican

ddy

nam

ic)

Left

leg;

right

face

(V1-

V3)

usua

llyer

ythe

mat

ous

but

alte

rnat

ing

blan

ched

Left

leg;

right

face

(V1-

V3)

edem

atou

san

dus

ually

dusk

yan

dcy

anot

ic

Left

leg;

right

arm

;le

ftar

m;

left

foot

;po

orin

itiat

ion

ofm

ovem

ent;

wea

knes

sof

left

intr

insi

cha

ndm

uscl

es

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

bila

tera

llysu

prac

lavi

cula

rfo

ssa,

Arc

ade

ofF

rohs

e,pr

onat

orca

nal,

fora

min

aex

itar

eas

C2–

C3;

spre

adof

pinp

rick,

hype

ralg

esia

and

cold

stim

ulus

toth

een

tire

right

side

from

ast

imul

usto

right

foot

.

Kiefer et al.24

No.

1120

yofe

mal

eC

RP

S36

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Trau

ma

torig

htsh

ould

eran

drig

htar

m(b

lunt

trau

ma

from

falli

ngob

ject

)

Hyp

eral

gesi

ato

pinp

rick

right

uppe

rex

trem

ity;

dyna

mic

and

stat

icm

echa

noal

lody

nia

ofrig

htup

per

extr

emity

;co

ldan

dw

arm

allo

dyni

aof

right

uppe

rex

trem

ity;

spon

tane

ous

burn

ing

pain

;de

epac

he;

evok

edla

ncin

atin

gpa

in;

pain

fult

ingl

ing

ofen

tire

right

uppe

rex

trem

ity;

spon

tane

ous

pain

wor

serig

htbr

achi

alpl

exus

dist

ribut

ions

Tem

pera

ture

asym

met

ryrig

ht>

left

uppe

rex

trem

ity;

eryt

hem

aof

right

>le

ftup

per

extr

emity

;va

riabl

eco

lor

chan

gew

ithem

otio

nals

tres

s,ex

erci

sean

dco

ld

Ede

ma

ofth

erig

htup

per

extr

emity

;hy

perh

idro

sis

right

>le

ftup

per

extr

emity

;pi

tting

edem

a(m

ild)

offo

rear

m

Dec

reas

edra

nge

ofm

otio

nof

right

hand

inex

tens

ion;

inab

ility

tocl

ose

hand

into

afis

t;po

orin

itiat

ion

offin

efin

ger

mov

emen

t;sp

asm

and

myo

clon

us(v

aria

ble

ofrig

htup

per

extr

emity

wea

knes

sof

dors

alan

dvo

lar

inte

ross

eian

dab

duct

orpo

llice

sbr

evis

;sl

ight

delto

id.

bice

ps,

tric

eps,

supr

aspi

natu

sw

eakn

ess;

britt

le,

ridge

dna

ils;

loss

ofin

tegu

men

tdi

git

IV,

V

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

the

ipsi

late

ral

face

,le

gan

dco

ntra

late

rala

rm

Spo

ntan

eous

pain

inip

sila

tera

lfac

e(V

1-V

33)

;ip

sila

tera

lleg

;co

ntra

late

ralu

pper

extr

emity

both

ina

regi

onal

dist

ribut

ion;

dyna

mic

and

stat

icm

echa

noal

lody

nia

inth

esa

me

dist

ribut

ions

Ede

ma

and

hype

rhid

rosi

sV

1-V

3of

ipsi

late

ralf

ace,

ipsi

late

rall

eg;

uppe

rex

trem

ityex

trem

itypr

imar

ilyth

eha

nd

Ipsi

late

rall

eg;

cont

rala

tera

lupp

erex

trem

ityde

crea

sed

abili

tyto

initi

ate

mov

emen

ts,

wea

knes

sof

intr

insi

cha

ndan

dfo

otm

uscl

es

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

inth

esu

prac

lavi

cula

rfo

ssa;

exit

fora

min

aof

C2-

CV

asom

otor

and

Sud

omot

or/E

dem

aC

hang

es,

CV

asom

otor

and

Sud

omot

or/E

dem

aC

hang

es-C

4;pr

onat

orca

nal,

cubi

tala

ndca

rpal

tunn

el;

dyst

roph

icpu

nche

dou

tsk

inul

cers

;br

own

papu

lar

skin

lesi

ons

ofrig

htup

per

extr

emity

No.

1235

yofe

mal

eC

RP

S72

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

III

Trau

ma

torig

htsh

ould

eran

drig

htar

mH

yper

alge

sia

topi

npric

kof

the

entir

eup

per

extr

emity

;dy

nam

ican

dst

atic

mec

hano

allo

dyni

aen

tire

right

uppe

rex

trem

ity;

cold

allo

dyni

arig

htup

per

extr

emity

;al

lody

nia

tode

epso

mat

icpr

essu

re;

pain

fulj

oint

mov

emen

t(b

oth

smal

land

larg

ejo

ints

ofrig

htup

per

extr

emity

)

Tem

pera

ture

asym

met

ry;

right

uppe

rex

trem

ityco

lder

than

left;

cyan

otic

,bl

uish

,liv

edo

retic

ular

isrig

ht>

left

uppe

rex

trem

ity

Ede

ma

ofrig

htup

per

extr

emity

;ha

nd>

fore

arm

;hy

perh

idro

sis

ofha

ndan

dfo

rear

m;

varia

tion

ined

ema

due

tode

pend

ency

and

hand

use

Dec

reas

edra

nge

ofm

otio

nof

flexo

rsof

the

hand

and

prox

imal

shou

lder

gird

lem

uscl

es;

mot

orne

glec

tof

the

right

;in

crea

sed

phys

iolo

gic

trem

or;

atro

phy

ofin

tegu

men

tof

digi

tIV

,V

;br

ittle

ridge

nails

onrig

htha

nd;

loss

ofrig

htfo

rear

mha

ir

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

right

face

and

leg

and

left

arm

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

bila

tera

llysu

prac

lavi

cula

rfo

ssa,

pron

ator

cana

l,cu

bita

land

carp

altu

nnel

s;sp

read

ofpi

npric

kan

dco

ldst

imul

usco

ntig

uous

lyfr

omar

eaof

appl

icat

ion

(12–

14in

ches

).

Ery

them

aan

din

crea

sed

tem

pera

ture

ofV

1-V

3of

right

face

Ede

ma

and

hype

rhid

rosi

sof

the

right

face

(V1-

V3)

Rig

htle

gde

crea

sed

initi

atio

nof

mov

emen

t


Ap

pen

dix

1:C

ontin

ued

Dem

ogra

phic

sTr

igge

ring

Inju

ryS

iteof

Prim

ary

CR

PS

Abn

orm

aliti

esin

Pai

nP

roce

ssin

gF

acto

r1

Ski

nC

olor

and

Tem

pera

ture

Cha

nges

Fac

tor

2

Fac

tor

Vas

omot

oran

dS

udom

otor

/Ede

ma

Cha

nges

Fac

tor

3

Mot

orD

ysfu

nctio

nan

dTr

ophi

cF

eatu

res

Fac

tor

4

No.

1338

yofe

mal

eC

RP

S24

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

III

Cru

shin

jury

digi

tIII

right

hand

,po

stop

erat

ive

wou

ndin

fect

ion

and

ampu

tatio

nof

the

digi

t

Hyp

eral

gesi

ato

pinp

rick

ofth

een

tire

Rha

ndan

dar

m,

site

ofam

puta

tion

scar

mos

tse

vere

;dy

nam

ican

dst

atic

mec

hano

allo

dyni

aof

the

entir

eR

arm

;de

epso

mat

icse

nsiti

zatio

nan

dal

lody

nia

offo

rear

man

dup

per

arm

mus

cula

ture

;jo

int

pain

inth

eha

ndw

ithm

ovem

ent

Tem

pera

ture

asym

met

ryrig

htha

ndco

lder

than

left;

dusk

ycy

anos

isof

the

right

hand

>le

ft;liv

edo

retic

ular

isrig

htfo

rear

m>

left;

colo

rch

ange

right

hand

varia

ble

with

emot

iona

lstr

ess,

cold

and

exer

cise

Ede

ma

ofrig

htha

nd>

left

hand

;hy

perh

idro

sis

ofth

erig

htup

per

extr

emity

>th

anle

ft;sw

ellin

gof

the

hand

incr

ease

dw

ithus

ean

dde

pend

ency

Dec

reas

edra

nge

ofm

otio

nof

all

join

tsin

right

hand

;de

crea

sed

abili

tyto

clen

chth

eha

ndin

toa

fist;

wea

knes

sof

intr

insi

cha

ndm

uscl

es;

poor

initi

atio

nan

dm

aint

enan

ceof

frac

tiona

ted

finge

rm

ovem

ent;

dyst

onic

hand

post

ure

(flex

ion)

;th

inat

roph

icsk

in;

britt

le,

thic

kene

dan

dat

roph

icna

ils

Clin

ical

crite

rion

fact

ors

that

wer

epo

sitiv

ein

right

face

and

right

leg;

left

arm

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

bila

tera

llyin

supr

acl

avic

ular

foss

a;A

rcad

eof

Fro

hse,

pron

ator

cana

l,cu

bita

ltu

nnel

and

carp

altu

nnel

;sp

read

ofco

ldst

imul

usap

prox

imat

ely

12in

ches

from

the

hand

upth

ear

m;

spre

adof

pinp

rick

from

the

Rha

ndto

the

ipsi

late

ralf

ace

onth

eR

Rig

htfa

ce(V

1-V

3)er

ythe

mat

ous,

war

mer

than

leg

Ede

ma

and

hype

rgid

rosi

sof

right

face

,rig

htle

gan

dle

ftar

mR

ight

leg;

poor

initi

atio

nan

dfin

em

ovem

ents

No.

1419

yom

ale

CR

PS

84m

onth

sB

asel

ine

Pai

nN

RS

9A

SA

Cla

ssII

Spr

ain

inju

ryof

the

right

hand

Hyp

eral

gesi

ato

pinp

rick

over

the

entir

erig

htup

per

quad

rant

;sp

onta

neou

sbu

rnin

gpa

inin

right

brac

hial

plex

usdi

strib

utio

ns;

chro

nic

deep

som

atic

achi

ngpa

in;

evok

edpa

roxy

smal

pain

inrig

htbr

achi

alpl

exus

dist

ribut

ions

;m

echa

nica

l,dy

nam

ican

dst

atic

tact

ileal

lody

nia

ofth

ebr

achi

alpl

exus

dist

ribut

ions

and

V1-

V3

Tem

pera

ture

asym

met

ry,

the

right

hand

and

arm

war

mer

than

the

left;

eryt

hem

aof

the

right

arm

and

face

toa

grea

ter

degr

eeth

anth

ele

ft;er

ythe

ma

incr

ease

dw

ithpr

ovoc

ativ

em

aneu

vers

ofst

ress

and

cold

Ede

mat

ous

right

arm

and

face

;hy

perh

idro

sis

ofrig

htar

man

dfa

ce;

tight

ness

ofso

fttis

sues

ofha

ndan

dfo

rear

m;

eye

alm

ost

swol

len

shut

durin

gse

vere

exac

erba

tions

Wea

knes

sof

intr

insi

crig

htha

ndm

uscl

es;

decr

ease

dra

nge

ofm

otio

nof

right

finge

rsan

drig

htw

rist;

inab

ility

toin

itiat

efin

em

ovem

ents

;in

crea

sed

phys

iolo

gic

trem

orof

right

hand

;br

ittle

,rid

ged

nails

ofrig

htha

nd;

som

eha

irth

icke

ned

onrig

htfo

rear

m

Clin

ical

crite

rion

fact

ors

inot

her

area

ofC

RP

Sin

volv

emen

t

Add

ition

alfe

atur

esS

prea

ding

pain

from

aco

ldst

imul

us6–

7in

ches

from

site

ofap

plic

atio

nrig

htsi

de;

spre

adin

gpa

infr

ompi

npric

kst

imul

usfr

omth

ear

mto

the

face

Rig

htfa

ce(V

1-V

3)er

ythe

mat

ous

Ede

ma

prim

arily

dors

umof

the

fore

arm

and

hand

onth

ele

ftsi

de

Left

arm

wea

knes

sof

intr

insi

cha

ndm

uscl

es;

decr

ease

din

itiat

ion

ofm

ovem

ent

ofle

ftto

es

Kiefer et al.26

No.

1536

yofe

mal

eC

RP

S60

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Par

aven

ous

IVlin

ein

filtr

atio

nof

the

left

fore

arm

Hyp

eral

gesi

ato

pinp

rick

over

the

entir

ele

ftup

per

extr

emity

;sp

onta

neou

sbu

rnin

gpa

inov

erth

een

tire

left

uppe

rqu

adra

ntin

clud

ing

neck

,fa

ce,

arm

and

ches

t(a

bdom

ensp

ared

);m

echa

nica

ltac

tile

dyna

mic

and

stat

ical

lody

nia

over

the

left

uppe

rqu

adra

ntan

dfa

ce;

tric

eps,

fore

arm

mus

cles

;co

ldal

lody

nia

over

the

left

uppe

rqu

adra

ntin

clud

ing

the

neck

and

face

;sm

alla

ndla

rge

join

tpa

inw

ithm

ovem

ent

Tem

pera

ture

asym

met

ryle

ftup

per

quad

rant

>th

anrig

ht;

redn

ess

ofth

ele

ftup

per

extr

emity

and

face

(prim

arily

V2-

V3)

;er

ythe

ma

incr

ease

dw

ithpr

ovok

ing

fact

ors

ofst

ress

Ede

ma

ofle

ftfa

ce,

arm

and

hand

;hy

perh

idro

sis

ofle

ftfa

ce,

arm

and

hand

;ed

ema

ofaf

fect

edar

eas

varie

sw

ithem

otio

nals

tres

san

dpo

sitio

nof

extr

emity

Dec

reas

edra

nge

ofm

ovem

ent

ofle

ftfin

ger

and

wris

tex

tens

oran

dfle

xor

mus

cles

;in

abili

tyto

fully

mak

ea

fist

inle

ftha

nd;

poor

initi

atio

nof

mov

emen

tof

the

left

hand

;w

eakn

ess

ofdo

rsal

and

vola

rin

tero

ssei

,ab

duct

orpo

llice

sbr

evis

ofth

ele

ftha

nd;

britt

le,

thic

kene

dna

ilsof

allfi

nger

sof

the

left

hand

;sl

ight

loss

ofha

iron

the

left

fore

arm

Clin

ical

crite

rion

fact

ors

inot

her

area

ofC

RP

Sin

volv

emen

tR

ight

uppe

rtr

unk

brac

hial

plex

us;

left

leg

(mec

hani

cala

ndth

erm

alal

lody

nia)

;rig

htar

m,

hype

ralg

esia

topi

npric

kan

dm

echa

noal

lody

nia

(sta

tican

dm

echa

nic)

Wea

knes

sof

dors

alan

dvo

lar

inte

ross

ei;

left

leg;

right

arm

;

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

atsu

prac

lavi

cula

rfo

ssa,

pron

ator

cana

l,cu

bita

ltun

nela

ndA

rcad

eof

Fro

hse;

spre

adin

gpa

infr

omco

ldst

imul

usan

dpi

npric

kfr

omth

ele

ftha

ndto

face

No.

1625

yofe

mal

eC

RP

S25

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Arn

old

Chi

arir

epai

rop

erat

ion;

trac

tion

ofth

ebr

achi

alpl

exus

left

shou

lder

Hyp

eral

gesi

ato

pinp

rick

over

the

entir

ele

ftup

per

quad

rant

;sp

onta

neou

sbu

rnin

gan

dla

ncin

atin

gpa

inle

ftbr

achi

alpl

exus

dist

ribut

ions

;ev

oked

tingl

ing

pain

with

mov

emen

t;m

echa

nica

l,dy

nam

ican

dst

atic

allo

dyni

ain

brac

hial

plex

usdi

strib

utio

ns

Tem

pera

ture

asym

met

ryle

ftar

m,

face

and

hand

war

mer

than

right

;er

ythe

ma

left

arm

and

face

;co

lor

chan

geal

way

spr

esen

tbe

cam

em

ore

evid

ent

with

cold

and

emot

iona

lstr

ess

Ede

ma

ofL

hand

,ar

m;

swea

ting

asym

met

ryw

ithhy

perh

idro

sis

ofth

eL

arm

and

uppe

rex

trem

ity;

edem

aal

way

spr

esen

t;ev

oked

toa

grea

ter

degr

eew

ithde

pend

ency

and

use

Dec

reas

edra

nge

ofm

otio

nof

all

finge

rsin

flexi

onan

dex

tens

ion

left

hand

;w

eakn

ess

ofin

trin

sic

hand

mus

cles

;m

otor

negl

ect

ofth

ele

ftsi

de;

britt

le,

thic

kene

d,rid

ged

nails

inth

ele

ftha

nd;

shin

yth

insk

inof

left

hand

Clin

ical

crite

rion

fact

ors

inot

her

area

sof

CR

PS

invo

lvem

ent

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

atsu

prac

lavi

cula

rfo

ssa,

neur

ovas

cula

rbu

ndle

,Arc

ade

ofF

rohs

ean

dpr

onat

orca

nal;

cold

allo

dyni

aan

dpi

npric

kst

imul

ussp

read

from

the

hand

toth

esh

ould

eran

dfa

ce

Left

face

(V1-

V3)

eryt

hem

atou

san

dw

arm

erLe

ftfa

ce(V

1-V

3)ed

emat

ous

and

slig

hthy

perh

idro

sis

Rig

htar

mde

crea

sed

initi

atio

nof

mov

emen

t


Ap

pen

dix

1:C

ontin

ued

Dem

ogra

phic

sTr

igge

ring

Inju

ryS

iteof

Prim

ary

CR

PS

Abn

orm

aliti

esin

Pai

nP

roce

ssin

gF

acto

r1

Ski

nC

olor

and

Tem

pera

ture

Cha

nges

Fac

tor

2

Fac

tor

Vas

omot

oran

dS

udom

otor

/Ede

ma

Cha

nges

Fac

tor

3

Mot

orD

ysfu

nctio

nan

dTr

ophi

cF

eatu

res

Fac

tor

4

No.

1748

yofe

mal

eC

RP

S72

mon

ths

Bas

elin

eP

ain

NR

S8.

5A

SA

Cla

ssII

Ext

ensi

on/d

iste

ntio

ntr

aum

aof

the

right

hand

Hyp

eral

gesi

ato

pinp

rick

ofth

erig

htar

min

are

gion

aldi

strib

utio

n;sp

onta

neou

sbu

rnin

gpa

in,

deep

ache

,tin

glin

gof

right

arm

;ev

oked

lanc

inat

ing

pain

with

mov

emen

t;dy

nam

ican

dst

atic

mec

hano

allo

dyni

aof

the

right

arm

;de

epso

mat

icse

nsiti

zatio

nof

right

arm

;sm

allj

oint

pain

ofth

erig

htha

nd;

cold

allo

dyni

aof

the

right

arm

Tem

pera

ture

asym

met

ry,

right

arm

war

mer

than

the

left;

min

imal

eryt

hem

aof

the

right

hand

;co

lor

chan

gein

crea

sed

with

use,

depe

nden

cyan

dte

mpe

ratu

rech

ange

Ede

ma

ofrig

htha

nd;

swea

ting

asym

met

ryrig

ht>

left

hand

;m

inim

alch

ange

(incr

ease

)of

edem

aw

ithde

pend

ency

and

use

Dec

reas

edra

nge

ofm

otio

n(fl

exio

nan

dex

tens

ion

offin

gers

and

wris

t)of

right

hand

;w

eakn

ess

ofrig

htha

nddo

rsal

and

vola

rin

tero

ssei

,fle

xor

polli

cis

long

usan

dop

pone

nspo

llici

s;in

crea

sed

phys

iolo

gic

trem

orof

right

hand

and

arm

;br

ittle

nails

and

shin

ysk

inof

right

hand

Clin

ical

crite

rion

fact

ors

inot

her

area

sof

CR

PS

invo

lvem

ent

Add

ition

alfe

atur

esP

ositi

veTi

nels

igns

supr

aan

din

frac

lavi

cula

rfo

ssa;

neur

ovas

cula

rbu

ndle

,pr

onat

orca

nal;

spre

adof

pinp

rick

stim

ulus

from

the

right

hand

toth

erig

htar

man

dfa

ce(V

2)

Rig

htfa

ce(V

1-V

3)er

ythe

mat

ous

and

war

mer

and

uppe

rth

igh

ofth

erig

htle

gw

arm

erth

anle

ft

Rig

htfa

ce(V

1-V

3)ed

emat

ous

and

slig

hthy

perh

idro

sis

Rig

htle

g;le

ftar

m;

wea

knes

sof

intr

insi

cha

ndm

uscl

esrig

htha

nd;

poor

initi

atio

nof

toe

mov

emen

tsrig

htle

g

No.

1841

yofe

mal

eC

RP

S84

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Mot

orve

hicl

eac

cide

nt;

exte

nsio

n/fle

xion

inju

ryof

the

brac

hial

plex

uson

the

right

Hyp

eral

gesi

ato

pinp

rick

right

arm

ina

regi

onal

dist

ribut

ion;

spon

tane

ous

burn

ing

pain

;de

epso

mat

icpa

in;

join

tpa

inof

the

right

hand

;ev

oked

tingl

ing

and

hand

pain

with

mov

emen

t;dy

nam

ican

dst

atic

mec

hano

allo

dyni

aof

allb

rach

ial

plex

usdi

strib

utio

nsof

the

right

uppe

rex

trem

ity;

cold

allo

dyni

aan

dhe

atal

lody

nia

right

arm

and

hand

>th

anth

esh

ould

er

Tem

pera

ture

asym

met

ryrig

htar

mco

lder

than

left;

eryt

hem

aof

right

arm

and

hand

;co

lor

chan

geva

ries

thro

ugho

utth

eda

y;at

times

spon

tane

ousl

yan

dat

othe

rtim

esby

emot

iona

lstr

ess;

mov

emen

tan

dte

mpe

ratu

rech

ange

Sw

ellin

gof

dors

um>

vent

ral

area

sof

the

hand

;sw

ellin

gof

the

arm

and

shou

lder

;hy

perh

idro

sis

>rig

htth

anle

ftup

per

extr

emity

;sw

ellin

gin

crea

sed

with

arm

use

Wea

knes

sof

alli

ntrin

sic

mus

cles

ofth

eha

nd;

poor

abili

tyto

oppo

seth

umb

and

fore

finge

r;sp

onta

neou

sm

yocl

onic

jerk

s;ex

agge

ratio

nof

her

phys

iolo

gica

ltre

mor

ofth

erig

htar

m

Clin

ical

crite

rion

fact

ors

inot

her

area

sof

CR

PS

invo

lvem

ent

Rig

htfa

ce(V

1-V

3)hy

pera

lges

iaan

dm

echa

noal

lody

nia

(dyn

amic

and

stat

ic)

War

mer

and

eryt

hem

atou

srig

htfa

ceR

ight

face

(V1-

V3)

edem

atou

san

dhy

perh

idro

ticR

ight

leg;

left

arm

poor

initi

atio

nof

mov

emen

t

Add

ition

alfe

atur

esS

prea

ding

pain

from

pinp

rick

and

cold

stim

ulif

rom

the

hand

toen

tire

extr

emity

and

toco

ntra

late

ralf

ace;

posi

tive

Tine

lsi

gns

supr

aan

din

frac

lavi

cula

rfo

ssa,

neur

ovas

cula

rbu

ndle

,A

rcad

eof

Fro

hse,

pron

ator

cana

l,cu

bita

ltun

nell

eft>

right

arm

Kiefer et al.28

No.

1914

yofe

mal

eC

RP

S7

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

III

Bro

wn

recl

use

spid

erbi

teof

the

inne

rrig

htth

igh

Hyp

eral

gesi

ato

pinp

rick

ofth

een

tire

right

leg

ina

regi

onal

dist

ribut

ion;

mos

tse

vere

surr

ound

ing

the

area

ofth

esp

ider

bite

;sp

onta

neou

sbu

rnin

gpa

inof

the

entir

eth

igh;

seve

rebu

rnin

gin

the

six

inch

essu

rrou

ndin

gth

een

veno

mat

ion

site

;de

epso

mat

icpa

in;

join

tpa

inat

the

knee

;ta

ctile

and

dyna

mic

mec

hano

allo

dyni

aof

the

right

leg;

cold

allo

dyni

am

ost

seve

resi

xin

ches

surr

ound

ing

the

site

ofen

veno

mat

ion

but

affe

ctin

gth

een

tire

thig

h;de

epso

mat

icse

nsiti

zatio

nof

allm

uscl

esof

the

thig

h

Tem

pera

ture

asym

met

ryrig

htle

gw

arm

erth

anth

ele

ft;er

ythe

mat

ous

right

leg;

fluct

uatin

gco

lor

chan

gedu

eto

activ

ity,

cold

and

emot

iona

lstr

ess

Ede

ma

ofth

erig

htle

g(t

high

>lo

wer

leg)

;hy

per

hidr

osis

ofrig

htle

g;ed

ema

cons

tant

Wea

knes

sof

iliop

soas

,qu

adric

eps;

diffi

culty

initi

atin

gm

ovem

ents

ofrig

htle

g;dy

ston

icpl

anta

rfle

xed

inve

rted

foot

;pa

tient

unab

leto

bear

wei

ght

onrig

htle

g;th

icke

ned

and

britt

lena

ilsrig

htfo

ot

Clin

ical

crite

rion

fact

ors

inar

eas

othe

rth

anpr

imar

yC

RP

Sre

gion

Rig

htfa

ce;

right

arm

;rig

htle

gsp

onta

neou

spa

in,

mec

hano

allo

dyni

a(S

tatic

and

dyna

mic

)an

dth

erm

oallo

dyni

ato

cold

stim

uli

Rig

htfa

ce;

right

arm

;rig

htle

ger

ythe

mat

ous

Rig

htar

m;

right

leg

poor

initi

atio

nof

mov

emen

tof

dist

alm

uscl

es

Add

ition

alfe

atur

esP

ositi

veTi

nels

ign

ofth

esc

iatic

nerv

ein

the

right

scia

ticno

tch;

post

erio

rpo

plite

alpo

sitiv

eTi

nel

sign

onth

erig

ht;

abno

rmal

spre

adin

gpa

infr

omco

ldor

pinp

rick

stim

uliu

pth

een

tire

leg

ifth

epa

tient

rece

ives

the

stim

ulus

near

the

site

ofth

eor

igin

alin

jury

No.

2033

yofe

mal

eC

RP

S63

mon

ths

Bas

elin

eP

ain

NR

S9

AS

AC

lass

II

Tibi

alto

rsio

nfr

actu

re;

oste

osyn

thes

isop

erat

ion,

left

low

erle

g

Hyp

eral

gesi

ato

pinp

rick

left

knee

and

low

erle

g;sp

onta

neou

sbu

rnin

gpa

in,

deep

ache

ofm

uscl

esan

djo

ints

;pr

ovok

edla

ncin

atin

gpa

inw

ithm

ovem

ent

orw

eigh

tbe

arin

g;m

echa

nica

land

ther

mal

allo

dyni

ale

ftle

g

Tem

pera

ture

asym

met

ry;

left

leg

cold

erth

anrig

ht;

slig

hter

ythe

ma

ofth

ele

ftfo

ot;

fluct

uatio

nof

colo

rch

ange

with

mov

emen

tan

dw

eigh

tbe

arin

gof

left

foot

Ede

ma

ofle

ftlo

wer

extr

emity

belo

wth

ekn

ee(m

ore

seve

rein

the

foot

);sw

eatin

gas

ymm

etry

left

low

erle

g>

than

right

;hy

perh

idro

sis

fluct

uate

dm

ildly

with

exer

cise

,co

ldan

dem

otio

nals

tres

s

Wea

knes

sof

ante

rior

tibia

lis,

exte

nsor

hallu

cis

long

usan

dga

stro

cnem

ius

mus

cle

left

leg;

decr

ease

dra

nge

ofm

otio

nat

the

ankl

ean

dkn

eejo

int;

poor

initi

atio

nan

dm

aint

enan

ceof

mov

emen

trig

htle

gan

dto

es;

thic

kene

d,rid

ged,

britt

lena

ilsle

ftfo

ot;

atro

phy,

shin

ysk

inle

ftfo

ot

Crit

erio

nfa

ctor

sin

othe

rth

anpr

imar

yar

eaof

CR

PS

Add

ition

alfe

atur

esS

prea

ding

pain

from

cold

stim

uli

from

foot

toth

ekn

ee;

and

from

pinp

rick

stim

ulif

rom

the

foot

toth

ele

ftfa

ce

Left

face

(V1-

V3)

,le

ftar

m;

right

leg

spon

tane

ous

pain

,m

echa

noal

lody

nia

(sta

tican

ddy

nam

ic)

and

ther

moa

llody

nia

toco

ldst

imul

i

Left

face

(V1-

V3)

;rig

htle

ger

ythe

mat

ous;

cyan

otic

buis

hrig

htle

gLe

ftar

m;

right

leg

poor

initi

atio

nof

mov

emen

tof

dist

alm

uscl

es


Efficacy of Ketamine in Anesthetic Dosage for the ... · with CRPS have concomitant peripheral...

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Transcript of Efficacy of Ketamine in Anesthetic Dosage for the ... · with CRPS have concomitant peripheral...