Treatment

Only a few evidence-based treatment regimens for CRPS are available so far; these are summarized in Box 20.1. In fact, three literature reviews of outcome studies found discouragingly little consistent information regarding the pharmacologic agents and methods for treatment of CRPS [90-93]. Moreover, the methodology is often poor and patient numbers are low. Although CRPS shows a different phenotype in

Box 20.1 Interventions supported by evidence

Modality of pain relief

Analgesics

Administration

Evidence

route

level

Pharmacologic treatment

Steroids

Prednisolone

po

B

Calcium-regulating drugs

Calcitonin

IN

B

Clodronate

IV

B

Alendronate

IV/po

B

Pamidronate

IV

B

Free radical scavengers

DMSO

Topical

B

NAC

po

B

Calcium channel-blocking anticonvulsants

Gabapentin

po

C

Spinal drug application

GABA agonists

Baclofen

IT (in dystonia)

C

a2-receptor agonist

Clonidine

Epidural

C

Stimulation techniques

Spinal cord stimulation

Epidural

B

Physical and occupational therapy

B

Physical or occupational therapy, mirror visual

feedback treatment, hand laterality recognition

training, movement imagination

Psychologic therapy

B

Cognitive behavioral treatment, graded

exposure, disease education

DMSO, dimethylsulfoxide; GABA, gamma aminobutyric acid; IN, intranasal; IV, intravenous; IT, intrathecal; NAC, N-acetylcysteine;

po, oral.

comparison to other neuropathic pain syndromes like postherpetic neuralgia or painful polyneuropathy, clinicians extrapolate the results of clinical trials in these disease entities to guide therapy in CRPS. However, since functional imaging and neuropyhsiologic studies indicate that a reduction of pain does not only reduce the burden of illness but also contributes to the reversibility of cortical reorganization and improvement of function, the standard analgesics to treat neuropathic pain also become part of CRPS therapy.

Pharmacologic therapy

Interventions supported by evidence

Steroids

Orally administered prednisone, 10 mg three times daily, has clearly demonstrated efficacy in the improvement of the entire clinical status (up to 75%) of acute CRPS patients (<13 weeks) [36]. In CRPS I following stroke 40 mg prednisolone for 14 days followed by tapering significantly improved the signs and symptoms compared to piroxicam 20 mg daily [94]. In this randomized controlled trial in 60 patients, baseline scores for sensory, motor and autonomic symptoms improved significantly in the prednisolone group (drop of mean 10.7 to 4.3; score 0 -14) whereas piroxicam did not show any significant change when assessed 1 month after therapy initiation.

Calcium-regulating drugs

Calcitonin administered three times daily intranasally demonstrated a significant pain reduction in CRPS patients [95]. In 2001 Perez and co-workers conducted a blinded meta-analysis on randomized trials using calcitonin in CRPS I. The meta-analysis of the five trials available evaluating the efficacy of calci-tonin demonstrated a significant analgesic effect [96]. In contrast, the review of Albazaz and co-workers could not show a definite efficacy of calcitonin [97].

Clodronate 300 mg daily IV and daily alendronate 7.5 mg IV or 40 mg orally showed a significant improvement in pain, swelling and movement range in acute CRPS [98, 99]. Alendronate 40 mg daily for 8 weeks and a single infusion of pamidronate showed beneficial effects on pain and physical function [100, 101]. A nonplacebo-controlled trial showed the same efficacy of calcitonin 200 IU/day together with physiotherapy as the combination of paracetamol

1500 mg/day and physiotherapy [102]. The mode of action of these compounds in CRPS is unknown. Bisphosphonates may interact with CRPS-related bone resorption and showed some analgesic effect themselves. However, a recent meta-analysis showed a potential to reduce pain in CRPS associated with bone loss but the authors stated that there are insufficient data to recommend their use in practice [103].

Free radical scavengers

One placebo-controlled trial was performed, using the free radical scavengers dimethylsulfoxide (DMSO) 50% topically or N-acetylcysteine (NAC) orally for the treatment of CRPS I [104]. Both drugs were found to be equally effective; however, DMSO seemed more favorable for "warm" and NAC for "cold" CRPS I. The results were negatively influenced by longer disease duration. A previous trial with DMSO failed to show a positive result in CRPS [105]; however, DMSO applied in patients suffering from CRPS I of the upper extremity has been shown to be more effective than regional blocks with guanethidine in an uncontrolled trial in a small population of CRPS patients [106]. Interestingly, vitamin C has been shown to be effective in the prevention of CRPS after surgery (see below).

Gabapentin

Promising preliminary evidence was revealed by two studies on patients with CRPS that showed an analgesic effect of gabapentin [107-109]. A randomized double-blind placebo-controlled cross-over trial was performed in 58 patients with CRPS I. In half of the patients gabapentin was uptitrated to 600 mg tid and taken for 21 days before washout and placebo intake. The second group received placebo first and gabapentin thereafter. The change of pain intensity, assessed as the primary endpoint, demonstrated a mild but not statistically significant effect of gabapentin on pain compared to placebo. However, gabapentin demonstrated a significant reversal of mechanical hypoesthe-sia but no superior effect on motor, autonomic and positive sensory signs, such as dynamic mechanical allodynia, compared to placebo [110]. Pregabalin has not been studied in CRPS so far.

Interventions refuted by evidence

Since there is only limited evidence on the pharmaco-logic treatment of CRPS, there is no clear indication that any specific interventions are ineffective.

Commonly used interventions currently unproven

Nonsteroidal anti-inflammatory drugs (NSAIDs) Naproxen has not been effective in a very small number of patients [111]. This trial assessed the ratio of bone to soft tissue uptake with scintigraphy in eight patients with CRPS I. After 3 months' intake of 500 mg naproxen bid, the uptake showed no statistically significant improvement. The effect on pain was not assessed properly in this trial. Other NSAIDs have not been investigated in the treatment of CRPS to date. However, clinical experience suggests that they can control mild to moderate pain.

Opioids

Opioids are clearly effective in postoperative, inflammatory and cancer pain. The use of opioids in CRPS has not been studied. In other neuropathic pain syndromes, compounds such as tramadol, morphine, oxycodone and levorphanol are clearly analgesic when compared to placebo. However, there are no long-term studies of oral opioid use regarding efficacy and safety for treatment of neuropathic pain generally or CRPS in particular. Even without solid scientific evidence, derived as an analogy from recent treatment recommendations for neuropathic pain, opioids could be and should be used as part of a comprehensive pain treatment program [112-114]. Opioids enable the clinician to use (potentially) fast-acting potent analgesics that might be necessary in the beginning of therapy, e.g. while uptitrating co-analgesics, but also in the long term. The definite efficacy in CRPS still remains to be determined.

Antidepressants

Tricyclic antidepressants (TCAs) have been intensively studied in different neuropathic pain conditions as published in recent treatment algorithms, but not in CRPS [112-114]. There is solid evidence that reuptake blockers of serotonin and noradrenaline (e.g. amitriptyline) and selective noradrenaline blockers (e.g. desipramine) produce pain relief in neuropathic pain. The effectiveness of selective serotonin reuptake inhibitors in neuropathic pain states is still discussed and the controlled trials conducted so far have shown limited or no efficacy [112-114]. Selective serotonin noradrenaline reuptake inhibitors, however, are effective in painful diabetic polyneuropathy [112-114]. None has been studied in CRPS patients [93].

Sodium channel-blocking agents Lidocaine administered intravenously is effective in CRPS I and II for spontaneous and evoked pain [115]. Within this randomized double-blind placebo-controlled trial on 16 CRPS patients with predominant mechanical allodynia, lidocaine was infused once intravenously to reach three different plasma levels of 1, 2 and 3 ^g/ml in each patient. Compared to baseline, lidocaine achieved a statistically significant reduction of spontaneous pain intensity at the highest plasma level and a decrease of cold and less mechanical hyperalgesia as well as dynamic mechanical allodynia.

The orally administered lidocaine analog mexili-tene has not been evaluated in the treatment of CRPS and is not included in the recent therapy algorithms of neuropathic pain due to lack of efficacy or poor tolerability [112-114].

Systemic sodium channel-acting anticonvulsants, such as carbamazepine, oxcarbazepine and lamotrig-ine, have not been tested in CRPS. However, there is evidence for their effectiveness in various neuropathic pain conditions although recent trials using oxcar-bazepine and lamotrigine failed to prove consistent efficacy [112-114].

N-methyl-D-aspartate (NMDA) receptor blockers Clinically available compounds that are demonstrated to have NMDA receptor-blocking properties and at least in part are effective in neuropathic pain include ketamine, dextromethorphan and memantine [112-114]. An uncontrolled prospective open-label trial using low-dose ketamine infusion (40-80 mg/day) for 10 days reported pain reduction in a heterogeneous group of 40 CRPS I or II patients [116]. A combination of ketamine and midazolam in anesthetic dosages in an ICU setting over 6 days led to a full recovery in the case report of a CRPS I patient [117]. However, the trial results are inconsistent. There are only results of small trials available and accordingly these compounds are only third-line recommendations in neuropathic pain [114]. Further studies that would help clinicians to fully utilize these agents are not yet available.

Immune-modulating drugs

Only one case report showed a favorable effect of a TNF-a antagonist [118]. No solid evidence has been obtained with other immune-modulating therapies except steroids, such as immunoglobulins or immunosuppressive drugs.

Transdermal application of the a 2-adrenoceptor agonist clonidine, which is though to prevent the release of catecholamines by a presynaptic action, may be helpful when small areas of hyperalgesia are present [119]. However, this uncontrolled observation was made in a small group of four patients and only three of these reported efficacy.

Invasive interventional therapy

Interventions supported by evidence

Stimulation techniques and spinal drug application Epidural spinal cord stimulation (SCS) in one randomized study in selected chronic CRPS patients [120] improved pain and health-related quality of life but not functional outcome assessed 2 years later. Interestingly, these patients had previously undergone unsuccessful surgical sympathectomy. The pain-relieving effect was not associated with peripheral vasodilation, suggesting that central disinhibition processes are involved. Sensory detection thresholds were not affected by the stimulation. At a 5-year follow-up pain intensity, global perceived effect, treatment satisfaction and health-related quality of life in the group who received SCS and physiotherapy did not differ from those who received physiotherapy only [121](Figure 20.1). A meta-analysis showed that in selected patients SCS can relieve pain and allodynia and improve quality of life [122] but further studies are warranted since trials on larger groups of patients assessing short- and long-term efficacy on pain and motor functioning are still missing [123]. Moreover, safety data show that about 30% of the patients who received stimulation experienced treatment-related adverse events [121, 123]. Cervical and lumbar devices seem to be equally effective [124]. SCS was also effective in selected CRPS patients with sympathetically maintained pain [125] but further predicting factors beside test stimulations are still under investigation [126]. Other stimulation techniques, e.g. peripheral nerve stimulation with implanted electrodes, repetitive transcranial magnetic stimulation, and deep brain stimulation (sensory thalamus and medial lemniscus, motor cortex), have been reported to be effective in selected cases of CRPS [4, 127, 128]. In summary, there is limited evidence for the use of SCS in selected cases of CRPS but there is no evidence for using other invasive stimulation techniques as part of commonly used therapy algorithms.

Intrathecal baclofen is effective in some patients with CRPS-related dystonia [129]. Within a randomized double-blind placebo-controlled cross-over study in seven female patients with localized or generalized dystonia, baclofen, a potent GABAb receptor agonist, was applied intrathecally. After receiving 50 and 75 ^g baclofen, six patients experienced complete or partial reversal of the dystonic posture of the hands but much less reversal of the dystonic posture of the legs. In these six patients a pump for continuous therapy was implanted. The follow-up showed high variability in long-term efficacy, ranging from nearly complete recovery to fading resolution of dystonia.

In selected patients with severe refractory CRPS, the epidural application of clonidine showed a greater

□ SCS + PT (n = 31) □ PT (n = 13) ■ Implant (n = 20)

Follow-up (years)

Figure 20.1 Bar graph demonstrating the mean (± SD) VAS pain scores in patients with complex CRPS I. The groups in the main analysis are represented by white and gray bars, whereas the subgroup of patients with an implant at the final follow-up is represented by black bars. Reproduced from Kemler et al. [121].

pain reduction in higher dosages (700 p,g) than in lower dosages (300 p,g) [130]. However, the drug was associated with marked side effects (e.g. sedation and hypotension).

Interventions refuted by evidence

Since proven effectiveness is lacking in large trials of interventional treatment of CRPS, there is no clear evidence for a priori omission of specific interventions.

Commonly used interventions currently unproven

Interventional therapy at the sympathetic nervous system level

Currently, two therapeutic techniques for blocking sympathetic activity are used:

• injections of local anesthetic around sympathetic paravertebral ganglia that project to the affected body part (sympathetic ganglion blocks)

• regional intravenous application of guanethidine, bretylium or reserpine (which all deplete noradrenaline in the postganglionic axon) to an isolated extremity blocked with a tourniquet (intravenous regional sympatholysis, IVRS).

Epidural blocks have not been investigated in CRPS within controlled studies so far.

There are many uncontrolled surveys in the literature reviewing the effect of sympathetic interventions in CRPS patients, about 70% of whom report full or partial response [131]. The efficacy of these procedures is, however, still controversial and has been questioned in the past [91, 132]. In fact, the specificity and the long-term results as well as the techniques used have rarely been adequately evaluated.

One controlled study in patients with CRPS I has shown that sympathetic ganglion blocks with local anesthetic have the same immediate effect on pain as a control injection with saline [133]. However, after 24 hours patients in the local anesthetic group were much better, indicating that nonspecific effects are important initially and that evaluating the efficacy of sympatholytic interventions is best done after 24 hours. With these data in mind, the uncontrolled studies mentioned above must be interpreted cautiously. Only 10 out of the 24 studies we reviewed assessed long-term effects.

No improvement compared with baseline was found for reserpine (IVRS) and guanethidine

(IVRS) [134]. No differences were obtained between guanethidine (IVRS) or lidocaine (lignocaine) (IVRS)

[135]. Guanethidine and pilocarpine versus placebo showed no difference after application of four blocks

[136]. However, stellate blocks with bupivacaine as well as regional blocks with guanethidine (IVRS) demonstrated a significant improvement of pain compared with baseline but no differences between these two therapies [137]. One study demonstrated that IVRS bretylium plus lidocaine (lignocaine) produce significantly longer pain relief than lidocaine (lignocaine) alone [138]. No effect was obtained by droperidol (IVRS) [139]. Hanna & Peat [140] demonstrated a significant improvement in pain due to a single (IVRS) bolus of ketanserin. Bounameaux et al. [141] failed to show any significant effect with the same procedure. Bier's block with methylprednisolone and lidocaine in CRPS I did not provide a short- or long-lasting benefit compared to placebo [142].

Although no straightforward conclusion on the efficacy of IVRS in CRPS can be drawn from the above data, the evaluation of this intervention is also limited by small sample sizes ranging from six to 21 only, insufficient trial designs and short observation periods. A meta-analysis of studies assessing the effect of intravenous regional sympathetic blockade for CRPS failed to draw conclusions concerning the effectiveness of this procedure, mainly due to small sample sizes [134].

There is a desperate need for controlled studies that assess the acute as well as the long-term effect of sympathetic blockade and IVRS on pain and other CRPS symptoms, in particular motor function. Although evidence is sparse, interventions at the sympathetic efferent system are part of therapy algorithms in CRPS that are based mainly on clinical experience and on the limited evidence of controlled trials. Well-performed sympathetic ganglion blocks should be performed rather than IVRS [143].

TENS

Transcutaneous electrical nerve stimulation (TENS) may be effective in some cases and has few side effects. No sufficient clinical trials are available.

Surgical sympathectomy

There is only limited evidence regarding the efficacy of thoracoscopic or surgical sympathectomy. Four open studies report partly long-lasting benefits in

CRPS I and II [144-147]. The most important independent factor in determining a positive outcome of sympathectomy is a time interval of less than

12 months between inciting event and sympathec-tomy [144, 147]. The videoscopic lumbar sympathec-tomy is as effective as the open surgical intervention [148]. However, one study [149] showed lower efficacy of thoracic sympathectomy in CRPS compared to other diseases. The irreversible sympathectomy may be effective in selected cases. Because of the risk of developing adaptive supersensitivity even on noci-ceptive neurones and consequent pain increase and prolongation, these procedures should not be recommended on a broad indication basis.

Physical therapy and occupational therapy

Physical therapy and occupational therapy are supported by the results of several trials. It should be stressed that clinical experience clearly indicates that physiotherapy is of the utmost importance in achieving recovery of function and rehabilitation. Standardized physiotherapy has shown long-term relief in pain and physical dysfunction in children [150]. Recent developments of mirror and limb recognition techniques have advanced this field.

Physical and, to a lesser extent, occupational therapy are able to reduce pain and improve active mobility in CRPS I [151]. Lymph drainage provides no benefit when applied together with physiotherapy in comparison with physiotherapy alone [152]. Patients with initially less pain and better motor function are predicted to benefit to a greater degree than others. Physical therapy of CRPS is both more effective and less costly than either occupational therapy or control treatment [153].

Mirror visual feedback treatment in CRPS I has been shown to reduce pain and improve function in a controlled trial in eight patients [62]. After a 6-week treatment phase including no-mirror control phases, pain reduction and gain of function were documented in patients with a disease duration < 1year. Although these results were obtained in a preliminary trial, recent studies have demonstrated that the combination of hand laterality recognition training, imagination of movements and mirror movements, called a motor imagery program, reduces pain and disability in CRPS patients [63- 65]. Initially,

13 CRPS I patients were randomly allocated to a motor imagery program or to continuation of their previous treatment. After 12 weeks the control group crossed over to the motor imagery program [65]. As a result, a NNT of 3 for a 6-month period can be achieved. It is important to recognize that the order of training - laterality recognition, movement imagination followed by mirror movements - is important. Thus, adding the motor imagery program might be more effective than physiotherapy sparing these techniques. However, it is important to acknowledge that this conclusion is based on a small sample size only. However, physical and occupational therapy and attentional training have become an important part of successful therapy in CRPS patients.

Psychologic therapy

Although there is evidence of a psychologic impact on CRPS patients, only one study has addressed the efficacy of psychologic treatment. A prospective, randomized, single-blind trial of cognitive behavioral treatment (CBT) was conducted together with physical therapy of different intensities in children and adolescents. Twenty-eight patients were randomly assigned to two groups, both receiving six sessions of CBT, including pain management strategies, relaxation training, biofeedback, guided imagery, and physical therapy once or three times a week within a 6-week treatment period. At the end, long-lasting reduction of all symptoms in both arms in both treatment groups was demonstrated [154]. Fear of injury or reinjury by moving the affected limb is thought to be a possible predictor of chronic disability. Thus, in a small group of patients graded exposure therapy was successful in decreasing pain-related fear, pain intensity and consequent disability [155]. Beside the lack of well-controlled studies, a sequenced protocol for psychologic treatment has been proposed recently by Bruehl & Chung [156]: 1. education regarding the nature of the disease for all patients and their families, 2. if disease duration exceeds 6-8 weeks, patients should be evaluated psychologically and treated with cognitive behavioral techniques, 3. in case of psychiatric co-morbidities or major ongoing life stressors, these issues should be addressed additionally with general CBT [156].

Prevention studies

Only two reliable randomized placebo-controlled prevention studies have been conducted to date. Zollinger

Box 20.2 Commonly used interventions currently unproven

Modality of pain relief

Analgesics

Administration

route

Pharmacologic treatment

NSAIDs

e.g. naproxen, ibuprofen, diclofenac

po

Opioids

e.g. tramadol, morphine, oxycodone

po

Antidepressants

e.g. amitryptiline, desipramine,

po

duloxetine

Calcium channel-blocking anticonvulsants

Pregabalin

po

Sodium channel-blocking agents/anticonvulsants

Lidocaine

IV

Carbamazepine

po

NMDA receptor blockers

Ketamine

po/IV

Dextrometorphan

po

Immune-modulating drugs

Intravenous immunoglobulin

IV

a2-receptor agonist

Clonidine

Topical

Interventional treatment

Electrical nerve stimulation

TENS

Local

Intervention at the sympathetic nervous

Sympathetic ganglion blocks

Local

system level

Intravenous regional sympatholysis

IV

Surgical sympathectomy

IV, intravenous; NMDA, N-methyl-D-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs; po, oral; TENS, transcutaneous electrical

nerve stimulation.

et al. [157] proved a significantly reduced incidence of CRPS following Colles' fracture with vitamin C (500 mg/day) treatment. In this study, 123 patients who were treated conservatively for wrist fractures were randomized to a double-blind trial receiving 500 mg vitamin C or placebo. Within the observation period of 1 year, only 7% of the treatment group developed a CRPS, compared to 22% in the placebo group. A recent trial confirmed this result and determined 500 mg as a sufficient dosage [158]. Preoperatively administered guanethidine (20 mg, RIS) did not prevent CRPS in patients undergoing fasciotomy for Dupuytren's disease [159].

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