mpnp recommendations complex regional pain syndrome crps aug 2005

376 Medical Progress August 2005

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Recommendations for the Management

of Complex Regional Pain SyndromeThe Multidisciplinary Panel on Neuropathic Pain*

I. Pathophysiology, Prevalence andSymptoms

Complex regional pain syndrome (CRPS),previously referred to as reflex sympatheticdystrophy, causalgia, algodystrophy, Sudeck’satrophy and shoulder-hand syndrome, is anuncommon and poorly understood neuropa-thy that normally affects the limbs. CRPS ischaracterized by pain and altered sensation;motor dysfunction and soft tissue change;vasomotor and autonomic alterations; andpsychosocial disturbance.1

Women are more likely to develop CRPSthan men. CRPS can affect all age groups, butmost commonly occurs between the ages of40 and 60 years. It has been reported thatCRPS occurs in 1% to 2% of postfracturepatients and after peripheral nerve injury in2% to 5% of patients.2 No precipitating causecan be identified in 10% to 26% of cases.2,3

The International Association for theStudy of Pain (IASP) has developed the following classifications for CRPS4:• CRPS type I occurs after minor injury

that may be unnoticed by the patient.

* Panel members: Chen Phoon Ping, MBBS, FANZCA, FFPMANZCA, FHKCA, FHKAM, DipPainMgtConsultant, Department of Anaesthesiology, Intensive Care and Operating Services, Alice Ho Miu Ling Nethersole Hospital, and Adjunct AssociateProfessor, The Chinese University of Hong Kong, Hong Kong SAR.Josephine WY Ip, MBBS, MS, FRCS(Ed), FHKAM(Ortho), DipHandSurg(FESSH)Chief, Division of Hand and Foot Surgery, Department of Orthopaedic Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.Joseph MK Lam, MBChB, FRCS(Edin), FCSHK, FHKAM(Surg)Consultant Neurosurgeon and Adjunct Associate Professor, Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong,Prince of Wales Hospital, Hong Kong SAR.Lee Tsun Woon, MBBS, FANZCA, FFPMANZCA, FHKCA, FHKAM(Anaesthesiology), DipPainMgtChief of Service and Service Director (Clinical & Ambulatory Care), Department of Anaesthesia & Intensive Care, Tuen Mun Hospital, Hong Kong SAR.Tsoi Tak Hong, MBBS, MRCP, FRCP(Edin), FRCP(Glas), FHKCP, FHKAM(Med)Specialist in Neurology and Consultant Physician, Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR.Wong Chun Por, MBBS, FHKAM(Med), FRCP(Lond), FRCP(Glas), FRCP(Edin), FHKCPChief of Service, Integrated Medicine Service, Consultant Geriatrician, and Head, Department of Geriatrics, Ruttonjee Hospital, Hong Kong SAR.Lawrence KS Wong, MBBS, MD, MRCP, FHKAM(Med), FRCPAssociate Professor, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital,Hong Kong SAR.

The Multidisciplinary Panel on Neuropathic Pain is supported by an educational grant from Pfizer Corporation Hong Kong Limited.

© 2005 CMPMedica Pacific Ltd. Reprinted with permission from Medical Progress 2005 Vol. 32 No. 8.

Medical Progress August 2005 377

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There may not be any obviousassociated nerve injury. Type Inerve lesions are undetectedbecause they are partial, or pre-dominantly affect unmyelinatedaxons.

• CRPS type II is associated withan identifiable nerve injury, oftenfollowing trauma or surgery.CRPS is attributed to both

peripheral and central mechanisms.Peripherally, α-receptor upregula-tion and neurotransmitter releasemay increase sensitivity to sympa-thetic stimulation,5-8 while persistentinflammation may lead to continu-ous stimulation and hyperexcitabil-ity.9,10 Central neuronal sensitization,maintained by N-methyl-D-aspar-tate (NMDA)-receptor activation,also contributes to post-injury painhypersensitivity.11

The following are signs and/orsymptoms of CRPS4:• Pain: burning or aching pain in

the affected limb; hyperaesthesia,hyperalgesia and allodynia;

• Autonomic dysfunction: changesin skin temperature and colour;changes in sweating patterns;oedema;

• Trophic changes: thin, shiny skin;thickened nails; coarse hair; mus-cle wasting; and

• Motor dysfunction: weakness,

tremor or dystonia; decreasedrange of motion.Signs and symptoms progress if

left untreated, and the patient mayexperience debilitating pain, muscleatrophy and permanent joint andskin damage with advanced disease.Psychological disturbances such as anxiety, depression and fear-avoidance often accompany CRPS.

II. Diagnosis

The diagnosis of CRPS is often com-plicated by variations in presentingsymptoms and the difficulty in iden-tifying causative lesions. CRPS typesI and II may or may not be associ-ated with sympathetic-maintainedpain (SMP). Patient evaluationshould include:• Review of medical history,

including onset of CRPS symp-toms, associated injury anddetails of pain patterns to differentiate the neuropathic features;

• Physical examination of skin,nails, muscles and joints to revealany trophic and sudomotorchanges and to determine the siteof pain;

• Neurological examination toassess and exclude reversible neu-rological pathology; electrodiag-

nostic testing may be necessary;• Bone scintigraphy or x-ray to

identify any bone changes;• Thermography, to detect changes

in blood flow and skin tempera-ture; and

• Sudomotor evaluation measuringsweat output may be helpful.In 1994, the International Asso-

ciation for the Study of Pain (IASP)published consensus-based diagnos-tic criteria for CRPS.4 The criteriafor the diagnosis of CRPS type 1 areas follows:1. The presence of an initiating nox-

ious event or a cause of immobi-lization. For CPRS type II, aknown nerve injury should bepresent.

2. Continuing pain, allodynia orhyperalgesia disproportionate tothe injury’s severity.

3. Evidence at some time of oedema,changes in skin blood flow orabnormal sudomotor activity inthe region of pain.

4. CRPS is excluded by the presenceof conditions that would other-wise account for the degree ofpain or dysfunction. A validation study of the IASP

criteria, however, indicated signifi-cant overdiagnosis of CRPS andproposed a set of more specific diag-nostic criteria.12 These modified cri-teria, set out in Table 1, discriminatebetween CRPS and other types ofneuropathic pain.

III.Management

Early identification of at-risk patients(e.g. injury type, presence of anxietyor depression) can prevent progres-sion of CPRS and worsening ofCRPS signs and symptoms. Thegoals of treatment are to promoterehabilitation and restore motorfunction. Patients should be referred

Table 1. Modified diagnostic criteria for CRPS

1. Continuing pain that is disproportionate to any inciting event;

2. The patient must report at least one symptom in each of the four categories below; and

3. The patient must display at least one sign in two or more of the four categories below.

Sensory Hyperalgesia and/or allodynia

Vasomotor Temperature asymmetry; and/or skin colour changes and/or asymmetry

Sudomotor/oedema Oedema and/or sweating changes and/or sweating asymmetry

Motor/trophic Decreased range of motion and/or motor dysfunction (weakness, tremor,dystonia) and/or trophic changes (hair, nail, skin)


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as soon as possible to pain specialistsor physicians with experience inmanaging CRPS; outcome isimproved if treatment is started at anearlier stage.

In cases of CRPS associated withtrauma, surgical restoration is bene-ficial (e.g. decompression of a com-promised neural structure) and,when appropriate, should be per-formed immediately.

Most children with recent-onsetCRPS will improve spontaneouslyand need conservative managementonly. In adults, a holistic programmecombining both pharmacologicaland nonpharmacological techniquesmay achieve remission. The rehabili-tation pathway in Figure 1 providesa stepwise approach that combinesdifferent modalities to optimizeCRPS management.

Guidelines for the Management of CRPS• An early programme of physical

and occupational therapy, espe-cially for at-risk patients, is essen-tial to treat the secondarycomplications of CRPS, such asdecreased joint and tendon move-ment. This will improve paincontrol and mobility.

• Psychological support and cogni-tive behavioural managementprogrammes can help patientsmanage their pain, and reducedepression and dependence onhealth care.

• For patients with SMP, sympa-thetic blocks are effective pain-relief techniques to facilitatephysical rehabilitation.

• Whenever appropriate, anti-inflammatory medications areuseful in the acute phase follow-ing injury to minimize pain andswelling.

• Primary pain management should

include tricyclic antidepressants(TCAs, e.g. amitriptyline) or anti-convulsants (e.g. gabapentin, car-bamazepine, phenytoin). Slowdosage titration (up to 8 weeks) isnecessary to minimize side effectsof both TCAs and anticonvul-sants; pain relief may not beapparent for 3 weeks at the max-imum tolerated dosage.

• When the response to TCAs andanticonvulsants is unsatisfactory,a trial of combined TCA andanticonvulsant may be effective.

• Rescue therapy with opioids maybe necessary, but this should onlybe used for short-term treatment.

• For patients remaining refractoryto trials of pharmacotherapy andphysiotherapy, invasive proce-dures can be considered. Neu-rostimulation of the spinal cordor peripheral nerves may be effec-tive; however, there is no evi-dence it improves long-termprognosis. Destructive or ablativesurgery is not recommended andonly has a limited role in provid-ing relief for patients with a shortlife expectancy.

IV. Appendix on Evidence-basedManagement of CRPS

Pharmacological ManagementPublished evidence for drug efficacyin CRPS is lacking; however, thedrugs mentioned in these recommen-dations are effective in a variety ofneuropathic pain syndromes. Whereappropriate, trials using CRPSpatients have been described below;however, some of the evidence isderived from patients with otherneuropathies. Some agents are notlicensed for use in any type of neuro-pathic pain. Full prescribing infor-mation should be consulted beforeinitiating therapy.

1. Nonsteroidal Anti-inflammatoryDrugsAs persistent inflammation is impli-cated in the development of CRPS,anti-inflammatory drugs may have arole in the early management ofCRPS, particularly in cases wherethere is considerable inflamma-tion.14,15 However, clinical trial dataon the benefit of NSAIDs for CRPS islacking. A critical literature reviewsuggested that NSAIDs have signifi-cant activity against bradykinin andprostacyclin (e.g. ketoprofen) may bemore useful than those with conven-tional antiprostaglandin effects.Cyclooxygenase-2 selective inhibitorshave not been evaluated in CRPS.

2. Gabapentin and OtherAnticonvulsantsGabapentin is approved for use in allneuropathic pain conditions basedon evidence from randomized,placebo-controlled trials primarily inpatients with painful diabetic neu-ropathy (PDN)16,17 and postherpeticneuralgia (PHN).18,19 Phantom limbpain,20 Guillain-Barré syndrome21

and pain from spinal cord injury22

have also been managed successfullywith gabapentin.

To demonstrate further its appli-cability to other neuropathies, a randomized, double-blind, placebo-controlled study examined the safetyand efficacy of gabapentin in a widevariety of neuropathic pain syn-dromes.23 Patients were selected onthe basis of specific symptoms,rather than specific syndromes, toreflect the realities of clinical prac-tice. Of the 305 patients included inthe study, 28% had been diagnosedwith CRPS. Gabapentin was admin-istered at 900 mg/day (titrated upover 3 days) for 5 weeks, with esca-lation to 1,800 or 2,400 mg/day, asrequired. After 8 weeks, patients


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MANAGEMENT OF CRPS

Multidisciplinary approach

SMP involvement

Psychological and cognitive behavioural

management

Occupational therapy

Physiotherapy

1. TENS2. Laser therapy3. Ultrasound treatment

Interventional pain management

Sympathetic blocks:1. Ganglion sympathetic

block2. IV sympathetic block3. IV regional

sympathetic block

Neurosurgical management:1. Spinal cord stimulation 2. Peripheral nerve

stimulation3. Intrathecal therapy

Pain management

1st line treatment1. NSAIDs and/or2. TCAs or anticonvulsant

(e.g. gabapentin)3. TCA + anticonvulsant4. TCA + rotation of anticonvulsant

2nd line treatment (rescue medication)

Opioids

3rd line treatmentCorticosteroids

4th line treatment1. Lignocaine, capsaicin or transdermal

fentanyl2. Calcitonin, bisphosphonates

Figure 1. The rehabilitation pathway.

NSAID = nonsteroidal anti-inflammatory drug; SMP = sympathetic-maintained pain; TCA = tricyclic antidepressant; TENS = transcutaneous electrical nerve stimulationAdapted from Ref. 13.


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treated with gabapentin had a 21%decrease in the average daily paindiary score, compared with 14% inthe placebo group (p=0.048). Signif-icant improvements with gabapentinwere also seen in the Clinician andPatient Global Impression ofChange (p<0.05) and in somedomains of the Short-Form-McGillPain Questionnaire. Quality of life,determined using the Short-Form-36Health Survey, also improved forpatients treated with gabapentin.

In addition, a double-blind, randomized, placebo-controlledcrossover trial with two 3-weektreatment periods separated by a 2-week washout period examined theefficacy of gabapentin (up-titrated to600 mg t.i.d.) in CRPS I patients(n=58).24 Using a visual analoguescale (VAS), there was a significantpain relief in favour of gabapentin inthe first period. Using a seven-pointscale to determine global perceivedeffect on pain, significantly moregabapentin-patients experienced painrelief compared with placebo (43%vs. 17%, p=0.002). Gabapentin ther-apy also significantly reduced CRPS-associated sensory deficits in theaffected limb (measured as Von Freymonofilament skin applicationscores) more effectively than placebo(25.0 vs. 16.8, p=0.027).

Adverse effects of gabapentin aretolerable and mostly transient,occurring during the titrationphase.23 The most commonlyreported adverse events are dizzinessand somnolence.23,24 Gabapentin hasa more acceptable side effect profilethan the older anticonvulsants, suchas phenytoin and carbamazepine.25

The theoretical benefit of olderanticonvulsants for CRPS has notbeen demonstrated in clinical trials.Phenytoin was the first anticonvul-sant to be used as an antinociceptive

agent, but there is no sound evi-dence for its efficacy in relievingneuropathic pain.26 Clinical trialssupport the use of carbamazepine inthe treatment of trigeminal neural-gia27 and PDN,28 but evidence of itsefficacy in CRPS, PHN, phantomlimb pain and other neuropathicconditions is limited.26

3. Tricyclic AntidepressantsAntidepressants have been the main-stay of therapy for many types ofneuropathic pain. The number-needed-to-treat for antidepressantsin neuropathic pain is between 2.3to 3.29 The efficacy of TCAs, espe-cially amitriptyline, in the treatmentof PDN and PHN is well establishedby numerous clinical trials.30

A randomized, double-blind,crossover trial compared clomi-pramine with acetylsalicylic acid(ASA) in patients with painful mono-and polyneuropathies, 48 of whomhad CRPS.31 The starting dose ofclomipramine was 50 mg o.d.increasing to t.i.d. (n=23), or ASA500 mg o.d. increasing to t.i.d.(n=23) for 2 weeks. Patients werecrossed over to the alternative groupafter a 1-week washout period.Patients with dysaesthesia, hyper-pathia and CRPS had significantimprovements in pain if they weretreated with clomipramine (p<0.001).However, adverse events, includinghypotension, tachycardia, tremor andsweating, were more pronouncedwith clomipramine. Side effects fromTCAs occur commonly; therefore,TCAs may not be suitable forpatients who tolerate them poorly.

4. OpioidsLike NSAIDs, opioids lack soundevidence of benefit for CRPS. How-ever, a literature review recom-mended the addition of opioids to

ongoing treatment regimens if theinitial medications do not providesufficient analgesia, especially if thepersistent pain prevents patientsfrom undergoing physical therapy.32

5. CorticosteroidsThe anti-inflammatory effect of corti-costeroids can also be particularlyuseful in the acute phases of CRPS. Aprospective study on 36 hemiplegicpoststroke patients who developedshoulder-hand syndrome revealedlow-dose corticosteroid therapy givenwithin 2 to 3 months of the neuro-logic insult could relieve CRPS.33 Ofthe 36 patients, 31 (86.1%) werealmost symptom-free after 10 days oforal corticosteroid therapy. The effi-cacy of long-term corticosteroid ther-apy is also established, but longercourses may have a questionable risk-benefit ratio.14,34 However, a 12-weektreatment using oral prednisone 10 mg t.i.d. produced a 75% clinicalimprovement in patients diagnosedwith reflex dystrophy syndrome,according to a small randomized,placebo-controlled study.35

Furthermore, plasma metenke-phalin levels were increased in CRPSpatients after 2 weeks of steroidtherapy, suggesting that, in additionto its anti-inflammatory effects, cor-ticosteroid therapy may also have astimulatory action on the endoge-nous opioid system and, thus, mayfurther enhance analgesia.36

6. Lignocaine, Capsaicin andTopical FentanylA case report on nine CRPS patientstreated with continuous 4- to 8-weeksubcutaneous infusion of 10% ligno-caine indicated significant alleviationof pain, dysaesthesia, allodynia,hyperpathia, skin colour and tem-perature changes, decreased range ofmotion of involved extremities and


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changes in hair and nail growth.37

Upon discontinuation of infusion,patients had sustained pain relief. Inaddition, in a randomized, double-blind, placebo-controlled study inCRPS patients with profound allody-nia, intravenous infusion of ligno-caine caused a significant elevationof hot pain thresholds and decreaseof allodynic response to stroking andcool stimuli, together with a signifi-cant decrease in pain scores to coolstimuli.38 However, in many cases,the duration of effect is brief. More-over, there is no oral preparation forlignocaine. Mexiletine, despite hav-ing pharmacological properties simi-lar to lignocaine, has no evidence ofefficacy in CRPS.

Capsaicin 5% to 10% may beeffective for CRPS – 90% of patientsachieved substantial analgesia lasting1 to 18 weeks in a study on 10patients with CRPS and other neuro-pathic pain syndromes.39 A meta-analysis also showed the pooledodds ratio for benefit from capsaicintherapy was 2.35.34 However, the useof capsaicin is limited due to itsmessy application and the associatedintolerable burning pain.14

According to a 12-month multi-centre, open-label trial, transdermalfentanyl (TDF) is effective as long-term treatment for moderate-to-severe chronic noncancer pain,possibly including CRPS. Using amean dose of 48 to 90 µg/hour,67% of patients reported substantialpain control with TDF.40 Forty-twopercent reported either good or verygood global satisfaction and 86%reported a preference for TDF overtheir previous treatment (p<0.001,binomial test).

7. Calcitonin and bisphosphonatesCalcitonin and bisphosphonates cancontrol pain in patients with early

CRPS, but the mechanism is not yetunderstood. In a study in whichpatients were administered 300 IUcalcitonin within 8 to 10 weeks ofCRPS onset, pain relief and improvedrange of motion were reported.25

However, another study did notshow any benefit of calcitonin afterremoval of cases for Colles’ fracture.Intravenous pamidronate and clo-dronate have also demonstrated painrelief in some studies.25

Procedures1. Sympathetic BlocksThe efficacy of sympathetic blocks inthe treatment of CRPS is poorlydefined.41 A systematic review of theliterature found 29 studies that evalu-ated 1,144 patients (19 retrospective,5 prospective case series, 3 random-ized and 2 nonrandomized controlledstudies). Twenty-nine percent ofpatients achieved a full response and41% achieved a partial response,while 32% did not respond.42 Theauthors concluded that the evidencesupporting the use of sympatheticblocks in CRPS is poor. It is possiblethat sympathectomy may selectivelyshow more effective pain relief inpatients with SMP, thus facilitatingphysical rehabilitation.

Procedures commonly used forsympathetic blockade are sympa-thetic ganglion blocks (e.g. stellateganglion block and lumbar sympa-thetic block), IV sympathetic blocks(e.g. IV phentolamine and IV ligno-caine infusions, IV regional sympa-thetic block with guanethidine orbretylium and subcutaneous ligno-caine). Pain management specialistsusually perform these procedures;however, they tend to be used morefor diagnosis, as the response isoften brief. In some cases, effectsmay persist for longer periods andprovide therapeutic benefit.

2. Spinal-cord Stimulation When the pain of CRPS is refractoryto usual pharmacological treatmentand conservative pain managementprocedures, spinal-cord stimulation(SCS), implantable intrathecal drug-delivery systems or peripheral nervestimulation may also be considered.Severe pain, which may hinder phys-ical rehabilitation and result in long-term functional disability, may bemore effectively controlled throughthese methods and facilitate func-tional recovery.

A recent literature reviewshowed that SCS is effective in themanagement of CRPS; most studiesreported success rates of between60% and 91%.43 However, thereview noted that many of the stud-ies on CRPS have poor methodolog-ical quality. When considering thisprocedure, a thorough medical andpsychological assessment should beperformed to ensure optimal patientselection for favourable outcomes.

3. Intrathecal Drug AdministrationSystemsLong-term intraspinal morphineadministration has been reported tobe effective in patients withintractable CRPS.44 As in SCS, athorough medical and psychologicalassessment should be performed toensure optimal patient selectionwhen considering intrathecal mor-phine administration.

4. NeuroablationNeurolytic or surgical sympathec-tomy may be considered when diag-nostic sympathectomy shows a briefbut favourable response. However,the role of these procedures is notclear, thus these procedures are notrecommended. Although someimprovement is often achieved in theshort term, the risks associated with


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more invasive and destructive proce-dures often outweigh their benefits.Ablative and destructive proceduresmay be more appropriate to relievepain in patients with terminal cancerwho have short life expectancy.

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mpnp recommendations complex regional pain syndrome crps aug 2005

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