Harmful or safe? Exposure and pain provocation during physiotherapy of complex regional pain syndrome I: a narrative review

1.Introduction

Complex regional pain syndrome (CRPS) is a pain syndrome that can develop after trauma, surgery, immobilization, minimal injuries and possibly even spontaneously [1, 2, 3]. CRPS has also been associated with soft-tissue injuries to the shoulder after a stroke [4]. A typical feature of CRPS is pain disproportionate to any inciting event and that CRPS primarily affects the limbs. Further, although the pain is often described with characteristics typical of neuropathic pain, peripheral nerve lesions have typically not been proven in type I CRPS [1, 2, 3, 4]. CRPS is a clinical diagnosis with a controversial history that covers a relatively heterogeneous group of clinical manifestations with not fully explained etiopathogenesis [5, 6]. CRPS is now predominately being associated with functional and structural changes in the neurological and immune systems, however, the results of different authors are often contradictory [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. Currently, the Budapest Criteria are used in the diagnosis of CRPS [1], which are described in Table 1. Differential diagnosis is paramount since CRPS is a diagnosis based on exclusion [1, 19]. For this reason, additional assessment methods facilitating diagnosis and treatment incl. diagnostic imaging should be used in selected patients [1, 5, 7]. Regarding prognosis, recent prospective study shows that only 5.5% of individuals with CRPS are asymptomatic 12 months after the onset even with treatment, although the majority showed significant improvements in pain (average decrease of 50%) and disability (average decrease of 60%) [20]. Unfortunately, it seems that in a minority of individuals with CRPS symptoms persist or even worsen and progress over time [21].

There is generally a lack of robust evidence for the use of any physiotherapy management approach and for this reason, existing management strategies are mostly based only on insufficient evidence or expert opinions while the mechanism of action is not fully understood [22, 23, 24, 25]. According to clinical practice guidelines [1, 19, 26, 27], early diagnosis and timely treatment are paramount and patients must have access to rehabilitation treatment as soon as possible. There is also consensus that physiotherapy should be goal-oriented and focus should be placed on restoration or preservation of function as well as on pain management. Earlier guidelines promote pain-contingency [26] while more recent guidelines de-emphasize a pain-contingent approach and point out that therapy should be graded and function-oriented while an optimal balance between “doing too much” or “doing too little” must be sought [1, 19, 27]. There is an ongoing debate whether a reduction in pain facilitates an increase in function or an increase in a function facilitates pain reduction or when one is more important than the other. Because of this, there is a spectrum of opinions regarding the balance between these seemingly contradictory approaches [28]. Unfortunately, there is huge uncertainty involved as there is no evidence to guide us in the exact dosing, intensity, order or a suitable combination of approaches, nor to tell us who will respond better to which regimen. In summary, it can be recommended that “(1) no single-treatment approach should be preferred for management of this client group and (2) therapists should not blindly apply all treatment approaches” [29].

2.Objectives

Even though clinical practice guidelines de-emphasize pain contingency [1, 19, 27] and there is some evidence that exposure-based approaches and desensitization are being implemented in clinical practice [40, 41, 42, 43], pain aggravation during physiotherapy of individuals with CRPS is commonly perceived as dangerous by clinicians [43] and patients. This could be problematic because it is hypothesized that increased pain-related fear resulting in excessive focus on pain control and any associated avoidance of activity perpetuates a vicious cycle leading to more disability and pain [33, 37]. Since pain provocation during movement or exercise is standardized in the form of exposure to valued but painful activities in the so-called exposure-based approaches, results of studies regarding exposure-based approaches could be used as a proxy for evaluation, whether or not pain provocation during movement is harmful for individuals living with CRPS. Thus, the main objective of this narrative review is to answer the following PICO question [44]: Are exposure-based approaches associated with any harms in adult individuals diagnosed with CRPS? A related secondary goal was to also evaluate to what extent and quality are harms reported in studies regarding exposure-based therapies.

3.Methods

This narrative review was conducted in accordance with a Scale for the Quality Assessment of Narrative Review Articles (SANRA) [45] and secondarily with the PRISMA harms checklist [46] since its focus is on harms. This study, as a literature review, is exempt from Institutional Review Board approval. The main author identified articles using keyword database searches and then by a manual search through reference lists of identified eligible studies. Eligibility criteria were based on a PICO(S) format suggested by PRISMA statements [44]:

Further, only studies written in English were eligible and this review searched only for published data. Exposure-based approaches were defined as any approach where a) exposure to painful activities or exercises is explicitly implemented and promoted, b) pain-contingency is de-emphasized and c) where pain provocation or aggravation is not a signal to cease the intervention. For this review, we followed the definition of harms by CONSORT extension [47] defining harms as “the totality of possible adverse consequences of an intervention or therapy”. Specifically, this review was focused on a) any reported adverse events, b) any reported deterioration in functional state and c) any reported long-term increase in pain intensity (> 1.5/10 increase at follow-ups [48, 49]). Since adverse events and deterioration in functional state or long-term increase in pain intensity could be reported also in studies primarily focused on efficacy, these studies were included as well as studies focusing primarily on harms. This discrepancy between primary and secondary study goals will be distinguished in the results section.

PubMed, Cochrane Library, PEDro and Web of Science databases were searched using the terms ‘complex regional pain syndrome’ and ‘exposure’ from inception to January 2022. The last search was performed in July 2022. The search strategy is described in Table 2. The records located were screened for relevance by title. Duplicates and not relevant records were removed. After that, the identified reports were retrieved and assessed for eligibility. Further, reference lists of these reports were screened for additional studies. The main author extracted the following relevant data from each eligible study: first author and year of publication, study design and setting, intervention description, characteristics of participants, duration of follow-up, outcome measures (pain, disability, quality of life), medication use, drop-outs and adverse events reports. Since the aim of this narrative review was not to evaluate the effectiveness of exposure-based approaches over other therapies but only associated harms and their safety, an extension of the CONSORT statement for reporting harms [47] was used for all included studies. Even though CONSORT harms extension was developed for evaluation of randomized clinical trials, it was also used for any prospective interventional study included in this review, as it was used by some authors for evaluation of observational studies previously [50, 51]. Further, to summarize to what extent the harms are reported overall in the studies regarding exposure-based approaches, CONSORT harms extension [47] was used also for studies primarily investigating efficacy, despite of being intended for studies primarily investigating harms. Both these discrepancies will be distinguished in the results section.

4.Results

A total of 107 records were identified through the search. Duplicates (n= 32) and not relevant records (n= 57) were removed. After an assessment of the eligibility of the retrieved reports, twelve were removed (n= 12) and six articles meeting the inclusion criteria were included [30, 31, 36, 37, 52, 53]. Thus, the total number of included studies was six (n= 6) with 201 participants in single-case experimental studies and randomized controlled trials (those allocated in exposure treatment arms). Figure 1 presents this process in more detail.

Figure 1.

Flow diagram.

Only one study reported “safety” as a primary goal [37] and one study reported “efficacy and safety” as a primary goals but focused on efficacy only [31]. Only two identified studies were randomized controlled trials [36, 52]. Regarding adverse events associated with PEPT and its safety, van de Meent et al. [37] actively collected data about the severity of predefined CRPS signs and symptoms as well as functioning and disability 3–4 times per treatment phase and specified that a 30% change was determined as a minimal clinically important change (MCID), but no grading was implemented. Even though described, fluctuations in symptoms on an individual level were unfortunately not numerically presented and only some measurement methods were previously validated. Further, Barnhoorn et al. [52] stated that serious adverse events during PEPT treatment were collected through the use of a standardized form, but without sufficient details – in the trial protocol [54] it was found that exacerbations of signs and symptoms leading to medical consultation were monitored with this form but it was not clear whether an active or passive approach was implemented. Two other studies mentioned the absence of adverse events or harms but did not specify anything about their collection or interpretation [31, 36]. It can be speculated that in these studies the absence of adverse events or safety was referring to disability and pain outcomes but this was not explicitly specified and necessary details were lacking. Further, in two studies adverse events or harms were not mentioned at all [30, 53]. No study specified how severity or seriousness was measured nor whether and how causality was assessed or determined. On the other hand, all the included studies provided sufficient descriptions of withdrawals that were due to harm and the experience of the allocated treatment. Although drop-out rates were significant (25 out of 201, i.e. 12%), most of them occurred prior to the treatment or after education about the treatment (n= 14 (7%)) or were not adversely related to the treatment (n= 5 (2.5%)). Only four participants withdrew during the treatment period (PEPT) specifically for the reason that the intervention was too painful and strenuous (n= 4 (2%)) and two were lost to follow-up without any given reason (n= 2 (1%)). In the only study investigating “safety” as a primary goal, which was of multiple single-case design [37], the quality of reporting of harms based on the 10-items of extended CONSORT criteria [47] was sufficient (9/10). In the other included studies [30, 31, 36, 52, 53] without this primary aim the quality of reporting of harms [47] was clearly insufficient or absent (1–4/10). Details can be found in Table 3.

Follow-ups in the included studies ranged between 2–9 months and the mode was 6 months. Although fluctuation of symptoms during the intervention phase as well as a temporary increase in pain and other symptoms during and after physiotherapy sessions were common, this was expected and explained to patients. No study reported any long-lasting increase in symptoms or deterioration of function at follow-up. It is of interest, that all the included studies that presented numerical data for pain intensity (sample means) [31, 36, 37, 52] reported a decrease in pain at follow-up which was clinically significant, despite the fact that pain reduction was not the main aim of these approaches. Of interest is also the

observation that positive change in symptoms and function is more pronounced with longer follow-up after the treatment phase [30, 36, 37, 52] which indicates that the effects of exposure-based therapies seem rather to increase over time and that early short-term increases in symptoms can precede improvement in some patients. It should be noted, however, that in both included RCTs medication was used together with the exposure-based approach in some patients (36% in PEPT [52] and 65% in GEXP [36]). In the other two included PEPT studies no report on adherence with medication cessation was present and in the other two included GEXP studies no mention of medication use was found.

Taken together, no adverse events were reported outside temporary fluctuations in CRPS-related symptoms but which were regarded as expected non-harmful side-effects. No withdrawals due to pain increase were reported during the treatment for GEXP and only 2% for PEPT. Summary of extracted data can be found in Tables 4 and 5.

5.Discussion

Even though only one included study evaluated “safety” as its primary goal and the reporting of harms in the rest of the included studies was of insufficient quality or absent, taken together with outcome measures, the available data does not point to any major adverse reactions by way of pain provocation during physiotherapy of individuals with CRPS outside of temporary increases in CRPS-related symptoms during the treatment period. But it has to be emphasized that absence of evidence should not be interpreted as evidence of absence, since only very few relevant studies were identified and only one focused primarily on safety. This insufficiency in harms reporting is surprising since these exposure-based approaches are not widely accepted [43]. But the included studies are not an exception, since a recent Cochrane review [22] reports that most studies regarding physiotherapy for CRPS did not report on adverse events and generally we are uncertain if any of the physiotherapy treatments investigated in the Cochrane review of RCTs (including PEPT [52] a GEXP [36]) caused any unwanted side effects [22]. For this reason, comparison with other approaches is not possible. But inadequate reporting of harms is generally problematic across clinical areas and types of interventions [55, 56].

It should be emphasized that the results of this review must not be generalized to any pain provocation in CRPS patients. For example, even though based mainly on expert opinion for lack of robust evidence, elective surgery is recommended to be performed no less than 12 months after symptoms have settled or at least after the symptoms are well controlled because of the expected risk of exacerbation or recurrence of CRPS [57, 58, 59]. In cases when surgery is indicated, careful patient selection and appropriate pre-, peri- and post-operative management may lower this risk, but a number of the presented studies used older diagnostic criteria or combined CRPS types I and II [60, 61, 62, 63].

What needs consideration is that drop-out rates indicate that ∼10% of participants were not willing to participate or complete these treatments due to treatment characteristics, but only 2% withdrew during the treatment phase from the seemingly more aggressive PEPT because of the intervention being too painful. This indicates that the majority of patients motivated enough to initiate participation in these exposure-based treatments tolerated temporary fluctuations in symptoms and were able to perform the proposed exercises. Drop-outs during exposure-based treatments are not an exception limited to CRPS – e.g. in low back pain trial with exposure [64] it was reported that 16% of participants withdrew during the exposure treatment period for reasons related to treatment, which is even a higher rate.

For future research, it should be recommended that reporting of harms and data about symptom fluctuation should be of higher quality and detail. Open or semi-structured questions may provide additional information about both expected and unexpected adverse events and harms. Also, reporting of psychological impact outside pain-related fears might be valuable as well (distress, anxiety, depression, etc.). Even though not based on any evidence, some authors argue that only activities in the full control of CRPS patients should be implemented because of the potential for psychologically traumatizing events due to insensitive handling or interventions against the will of the individual with CRPS [65]. Higher quality of harm reporting should lead to more realistic expectations and set boundaries about what is a common and normal reaction to these approaches and how to prevent any unintended harms. In terms of treatment effectiveness, comparison is also not possible since only two of the involved studies were RCTs and there are some methodological concerns in both of them [66]. Generally, there is a lack of higher-quality evidence to inform clinical decision-making [22, 29].

6.Limitations

The main limitation of this narrative review is that available evidence is sparse and generally of low quality – only one identified study evaluated “safety” as the primary goal. Further, in almost all the included studies the treatment was delivered in a CRPS-specialized setting and/or by specifically trained therapist, which decreases any external validity for common practice. A significant risk for bias is that evaluation based on extended CONSORT criteria for reporting of harms [47] was performed by only one author. This is of importance because the subjective nature of assessment of harms reporting (e.g. multiple components in only one item) probably causes inconsistencies in assessments across assessors and reviews [55, 56]. Further, even though the Scale for the Quality Assessment of Narrative Review Articles (SANRA) [45] was followed, narrative reviews are generally more prone to bias than systematic reviews, but for which significant resources are necessary.

7.Conclusion

Even though only very few relevant studies were identified and the reporting of harms in the included studies was generally of insufficient quality and therefore our confidence in the evidence is very low, taken together with outcome measures, available data does not point to any major harms associated with exposure-based approaches and related pain provocation during physiotherapy of CRPS. No deterioration in symptoms or function was reported at follow-ups and the majority of patients motivated enough to initiate participation in these pain-provoking treatments were able to perform the proposed exercises despite temporary fluctuations in CRPS-related symptoms. Comparison with other approaches is not possible since harms reporting is generally lacking and therefore should be a priority in future research.

Funding

The author reports no funding.

Ethical approval

Not applicable.

Informed consent

Not applicable.