Interventions for treating pain and disability in adults with complex regional pain syndrome‐ an overview of systematic reviews

Abstract

Background

Complex regional pain syndrome (CRPS) is a chronic pain condition that usually occurs in a limb following trauma or surgery. It is characterised by persisting pain that is disproportionate in magnitude or duration to the typical course of pain after similar injury. There is currently no consensus regarding the optimal management of CRPS, although a broad range of interventions have been described and are commonly used. This is the first update of the original Cochrane review published in Issue 4, 2013.

Objectives

To summarise the evidence from Cochrane and non‐Cochrane systematic reviews of the efficacy, effectiveness, and safety of any intervention used to reduce pain, disability, or both, in adults with CRPS.

Methods

We identified Cochrane reviews and non‐Cochrane reviews through a systematic search of Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews, CINAHL, PEDro, LILACS and Epistemonikos from inception to October 2022, with no language restrictions. We included systematic reviews of randomised controlled trials that included adults (≥18 years) diagnosed with CRPS, using any diagnostic criteria. 

Two overview authors independently assessed eligibility, extracted data, and assessed the quality of the reviews and certainty of the evidence using the AMSTAR 2 and GRADE tools respectively. We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes quality of life, emotional well‐being, and participants' ratings of satisfaction or improvement with treatment. 

Main results

We included six Cochrane and 13 non‐Cochrane systematic reviews in the previous version of this overview and five Cochrane and 12 non‐Cochrane reviews in the current version. Using the AMSTAR 2 tool, we judged Cochrane reviews to have higher methodological quality than non‐Cochrane reviews. The studies in the included reviews were typically small and mostly at high risk of bias or of low methodological quality. We found no high‐certainty evidence for any comparison. 

There was low‐certainty evidence that bisphosphonates may reduce pain intensity post‐intervention (standardised mean difference (SMD) ‐2.6, 95% confidence interval (CI) −1.8 to −3.4, P = 0.001; I2 = 81%; 4 trials, n = 181) and moderate‐certainty evidence that they are probably associated with increased adverse events of any nature (risk ratio (RR) 2.10, 95% CI 1.27 to 3.47; number needed to treat for an additional harmful outcome (NNTH) 4.6, 95% CI 2.4 to 168.0; 4 trials, n = 181). 

There was moderate‐certainty evidence that lidocaine local anaesthetic sympathetic blockade probably does not reduce pain intensity compared with placebo, and low‐certainty evidence that it may not reduce pain intensity compared with ultrasound of the stellate ganglion. No effect size was reported for either comparison.

There was low‐certainty evidence that topical dimethyl sulfoxide may not reduce pain intensity compared with oral N‐acetylcysteine, but no effect size was reported.

There was low‐certainty evidence that continuous bupivacaine brachial plexus block may reduce pain intensity compared with continuous bupivacaine stellate ganglion block, but no effect size was reported.

For a wide range of other commonly used interventions, the certainty in the evidence was very low and provides insufficient evidence to either support or refute their use. Comparisons with low‐ and very low‐certainty evidence should be treated with substantial caution. We did not identify any RCT evidence for routinely used pharmacological interventions for CRPS such as tricyclic antidepressants or opioids.

Authors' conclusions

Despite a considerable increase in included evidence compared with the previous version of this overview, we identified no high‐certainty evidence for the effectiveness of any therapy for CRPS. Until larger, high‐quality trials are undertaken, formulating an evidence‐based approach to managing CRPS will remain difficult. Current non‐Cochrane systematic reviews of interventions for CRPS are of low methodological quality and should not be relied upon to provide an accurate and comprehensive summary of the evidence.

Author(s)

Michael C Ferraro, Aidan G Cashin, Benedict M Wand, Keith M Smart, Carolyn Berryman, Louise Marston, G Lorimer Moseley, James H McAuley, Neil E O'Connell

Abstract

Plain language summary

Which treatments are effective for the management of complex regional pain syndrome in adults?

Key messages

There is a critical lack of high‐quality evidence for the benefits and risks of most treatments for adults with complex regional pain syndrome (CRPS). Larger, well‐designed studies and higher‐quality reviews are needed to provide accurate evidence for benefits and risks of treatments for adults with CRPS.

What is complex regional pain syndrome?

CRPS is a disabling chronic pain condition. People with CRPS experience persistent pain, usually in the hands or feet, that is not proportionate in severity to any underlying injury. It often involves a variety of other symptoms in the affected body part such as swelling, discolouration, stiffness, weakness, and changes to skin quality. 

What did we want to find out?

A broad range of therapies are used to treat CRPS. The effects of these therapies are summarised across a number of Cochrane and non‐Cochrane reviews. Our aim was to combine the information from these reviews into one accessible document. We specifically wanted to find out which treatments are effective in reducing pain and disability in adults with CRPS. We also wanted to find out whether these treatments cause any unwanted effects.

What did we do?

We searched for Cochrane and non‐Cochrane reviews in the medical literature using online databases, from their beginning to October 2011, in the previous version of this overview, and between October 2011 and October 2022 in the current version. We included reviews that evaluated any treatment aiming to reduce pain intensity and disability in adults with CRPS. We judged the quality of the included reviews and summarised their results. We also rated our confidence in the evidence included in the reviews, based on factors such as study methods and size.

What did we find?

We included six Cochrane and 13 non‐Cochrane systematic reviews in the previous version of this overview and five Cochrane and 12 non‐Cochrane reviews in the current version. These reviews included evidence relating to a large range of treatments, including drugs, surgical procedures, rehabilitation, and complementary and alternative therapies. For most treatments, there were only a small number of published studies and the quality of these studies was low. The review evidence suggests the following:

     •   Compared with placebo (or 'dummy') treatment, bisphosphonates (a class of medicines that slow down bone loss) may reduce pain intensity shortly after treatment, but they are probably associated with some side effects.

   •   Compared with a placebo (or sham) treatment, blocking the branches of the sympathetic nervous system with an anaesthetic probably does not reduce pain intensity.

   •   There may not be any differences in the pain‐reducing effects of a topical cream called dimethyl sulfoxide (DMSO) and an amino acid supplement called N‐acetyl cysteine, but it is unclear whether either treatment works at all.

   •   One type of nerve block, called a brachial plexus block, may reduce pain intensity more than another type of block, called a bupivacaine stellate ganglion block.

For the majority of the commonly used drug, surgical, rehabilitation, and complementary and alternative therapies for CRPS, we found only very low‐quality evidence or no evidence at all. As a result, we cannot be certain about their effects on pain and disability in CRPS.  - 

What are the limitations of the evidence?

All of the included non‐Cochrane reviews were conducted in a way that affects the reliability of their findings. The studies included within both the Cochrane and non‐Cochrane reviews had several limitations, particularly due to the small number of included participants. The results presented within this overview demonstrate unclear benefits and risks for most treatments for adults with CRPS.- 

How up‐to‐date is this evidence?

This overview updates our previous overview. The evidence is up‐to‐date to October 2022.

Author(s)

Michael C Ferraro, Aidan G Cashin, Benedict M Wand, Keith M Smart, Carolyn Berryman, Louise Marston, G Lorimer Moseley, James H McAuley, Neil E O'Connell

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For adults with CRPS

The evidence regarding the effectiveness of most interventions used to treat pain and disability in CRPS is very uncertain. 

We found low‐certainty evidence that, on average, treatment with bisphosphonates may reduce pain intensity compared with placebo, but is probably associated with an increased risk of experiencing an adverse effect. 

We found moderate‐certainty evidence that, on average, blocking the activity of the sympathetic nerves using lidocaine anaesthetic probably does not reduce pain intensity more than a placebo intervention, and low‐certainty evidence that it may not be more effective than ultrasound. 

We also found that other commonly used treatments such as ketamine infusions, spinal cord stimulation, graded motor imagery and mirror therapy may reduce pain intensity more than placebo or other active controls, however the evidence is very uncertain. 

While there is a lack of evidence for adverse events, the risk of harm likely varies between invasive, drug and non‐drug treatments and may be an may be an important consideration to guide the choice of management.

For clinicians

There is insufficient high‐certainty evidence on which to base comprehensive clinical guidance on the management of CRPS. Current non‐Cochrane systematic reviews are unlikely to provide an unbiased representation of the available RCT evidence. 

We found moderate‐ or low‐certainty evidence for only two placebo‐controlled comparisons: 

  • There was low‐certainty evidence bisphosphonates may reduce pain intensity post‐intervention, and moderate‐certainty evidence that they are probably associated with increased adverse events of any nature. The included studies used a range of bisphosphonates with different routes of administration, and were primarily used in early onset CRPS I. As such, it is unclear whether the observed effects are likely to apply to long‐standing CRPS, or CRPS with associated neural tissue injury. Further investigations of this medicine class are warranted. 
  • There was moderate‐certainty evidence that lidocaine local anaesthetic sympathetic blockade probably does not reduce pain intensity compared with placebo. 

We found only low‐certainty evidence for three effectiveness comparisons: 

  • compared with oral N‐acetylcysteine, topical DMSO may not reduce pain intensity.
  • compared with ultrasound of the stellate ganglion, lidocaine stellate ganglion may not reduce pain intensity.
  • compared with continuous bupivacaine stellate ganglion block, continuous brachial plexus block may reduce pain intensity.  

While there was evidence of efficacy or effectiveness for routinely used interventions for CRPS such as intravenous ketamine, spinal cord stimulation, graded motor imagery and mirror therapy, the very low‐certainty of the evidence suggests that the true effects of these interventions are likely to be substantially different from the estimates of effect. These results should be interpreted with caution and do not reliably aid clinical decision‐making. We did not identify any RCT evidence for commonly used pharmacological interventions such as tricyclic antidepressants or opioids.  

While adverse event data are lacking for most included interventions, consideration of the probable risk of treatment‐related harms may be important for guiding patient management. Based on findings from this overview, managing CRPS using an evidence‐based approach will remain difficult until further larger, well‐conducted trials are undertaken.

For policy‐makers and funders

The available evidence relating to treatments for CRPS is very uncertain. Policy and funding decisions should not be made on the basis of findings from current non‐Cochrane reviews due to their low methodological quality. There is insufficient evidence to support or refute the use of the majority of routinely used interventions for pain intensity and disability in CRPS. Funders might prioritise CRPS research calls that enable consortia of researchers to leverage funding for high‐quality clinical trials that aim to meaningfully resolve key clinical uncertainties. Until such research is undertaken, clinical guidelines for the treatment of CRPS will continue to be informed largely by consensus.

Implications for research 

Design of future systematic reviews

There is a clear need to improve the methodological quality of systematic reviews of treatments for CRPS. In planning for future reviews, authors should follow methodological guidance for systematic reviews outlined in the Cochrane Handbook (Higgins 2021). Careful consideration of the review Population, Intervention, Comparison(s), Outcome and Time (PICOT) is required when formulating the review question. Rather than limiting the scope of a review to a single CRPS subtype, authors should aim to include evidence on all CRPS subtypes, and report results separately. This will ensure no important evidence is excluded. In order to minimise duplication of reviews and reporting bias, methods should be established in a protocol prior to the conduct of the review and registered on open databases such as PROSPERO (Cashin 2021). To facilitate transparent, complete and accurate reporting of what was done, reviews should adhere to the PRISMA reporting guideline (Page 2021). Authors should clearly describe the included interventions in accordance with published guidance (Hoffmann 2017) in order to improve the usability of the review by clinicians, patients and policy makers. 

Design of randomised trials

We have identified that there is very low‐certainty evidence for most interventions used to treat pain and disability in CRPS. It is unlikely that further small, short‐term studies testing poorly‐defined interventions will meaningfully improve this uncertainty. There is an urgent need for adequately powered, high‐quality randomised controlled trials, tested over clinically‐relevant time frames. There are many challenges to addressing this problem. Given the relatively low incidence of CRPS, it remains difficult to recruit adequate numbers into clinical trials. The best chance of solving this issue may be through multicentre, international collaborative research projects which recruit from much larger clinical populations. The use of telehealth trials could facilitate this. Recruitment targets may be more easily met through alterations to trial design parameters (Parmar 2016) and Bayesian approaches to increase statistical power (Partington 2022), and efficiency could be maximised by testing two or more interventions in a single factorial trial (Kahan 2022). 

Future trials should use established diagnostic criteria (Harden 2010) and specify the type and aetiology of CRPS under investigation (Goebel 2021). Comprehensive reporting of participant characteristics, including those that stratify health opportunities and outcomes (O'Neill 2014), will help to assess the generalisability of findings. Trial interventions must be carefully selected based on major clinical uncertainty or rigorous pilot research. There is a critical need for industry‐independent placebo‐controlled replication trials of intravenous ketamine and bisphosphonates, and trials of routinely used pharmacological interventions such as tricyclic antidepressants and opioids. Trials testing pragmatic, multimodal models of functional restoration, such as those endorsed by clinical guidelines (Bruehl 2022), against minimal or no care should be also prioritised. Trialists should consider optimal strategies for reporting pain in clinical trials (Busse 2015) and measure outcomes specified in the core set for CRPS (Grieve 2017). There is also a clear need to improve the measurements and reporting of adverse events in the field. Trial reports should fully adhere to CONSORT guidance (Schulz 2010) and interventions should be described in sufficient detail to allow replication by using the TIDIER guidelines (Hoffmann 2014).

Get full text at The Cochrane Library