Pain Practice - 2023 - Berg - The Efficacy of Oral Corticoids in Treating Complex Regional Pain Syndrome A Retrospective
Pain Practice - 2023 - Berg - The Efficacy of Oral Corticoids in Treating Complex Regional Pain Syndrome A Retrospective
Pain Practice - 2023 - Berg - The Efficacy of Oral Corticoids in Treating Complex Regional Pain Syndrome A Retrospective
13310
Corinne van den Berg MD | Frank J. P. M. Huygen MD, PhD | Jitske Tiemensma PhD
K EY WOR DS
complex regional pain syndrome, corticoids, treatment
I N T RODUC T ION Over the years, it has become clear that several mech-
anisms play a role in the development and maintenance
Complex regional pain syndrome (CRPS) is generally of CRPS. Increasing evidence supports an exaggerated
characterized by continuing pain combined with sen- inflammatory response as one of the major mechanisms.
sory, vasomotor, sudomotor, motor, and trophic symp- Studies documented increased concentrations of pro-in-
toms.1 The pain is disproportional in relation to the flammatory cytokines and neuropeptides in systemic cir-
initial trauma and the incidence varies between 5.5 and culation, cerebrospinal fluid, and in artificial skin blister
26.2 per 100.000 person years.2,3 CRPS is diagnosed fluid on the affected limb of CRPS patients.5–7 Likewise,
based on the International Association for the Study of median soluble IL-2 receptor (sIL-2R) was increased in
Pain (IASP) clinical diagnostic criteria, assessing pa- CRPS patients' serum compared to healthy blood do-
tient's symptoms and signs.4 nors, indicating increased T-cell activity in CRPS.8
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© 2023 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.
394 |
wileyonlinelibrary.com/journal/papr Pain Practice. 2024;24:394–403.
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van den BERG et al. | 395
Historically, CRPS was treated in an all fits one codes are used to classify the reason for the visit, given
manner. Today, treatment is mostly tailored to the most diagnoses, and treatment for a patient. Specific codes are
prominent mechanism(s) present in a specific CRPS used for CRPS: G90.5, G90.6, and G90.7 as ICD-10 codes
case, so-called mechanism-based treatment.9 No causal and 150 for DBC. Based on these codes, a search was
therapy for CRPS is available. The mechanism(s) pres- conducted in electronic patient records. Subsequently,
ent may be relevant to predict responses to individual all identified patients were approached by letter, email,
treatment options. Corticoids, as most effective anti-in- and/or phone to provide permission to view their medi-
flammatory drugs, are a natural treatment option in cal records, according to the General Data Protection
cases with prominent inflammation.10 Corticoids are Regulation.15 Only adult patients (>18 years) were ap-
widely used in treating inflammatory diseases and act proached. After permission, a single researcher (CvdB)
anti-inflammatory by interfering with various processes, viewed the medical files to assess whether a patient was
causing upregulation of the anti-inflammatory genes eligible for inclusion in this retrospective study. The in-
and downregulation of the pro-inflammatory genes.11 clusion criteria involved a CRPS diagnosis, based on the
Additionally, corticoids inhibit transcription factors IASP clinical diagnostic criteria, and the patient has to be
that control synthesis of pro-inflammatory mediators. treated at our center for pain medicine. In cases of uncer-
Corticoids also inhibit phospholipase A2, causing pro- tainty, the other authors were consulted and it was jointly
duction of inflammatory mediators.12,13 determined whether the patient was eligible. Medical files
A recent review showed corticoid treatment to be suc- from eligible patients were viewed entirely from the start
cessful in treating CRPS, especially regarding pain relief of treatment and cases who were treated at our tertiary
and improvement in range of motion.14 However, the op- referral center before the age of 18 remained in the study.
timal route of administration and optimal dose are still Patients referred for a second opinion or preoperative ad-
unknown. Today, in our clinic, a standardized moderate vice were excluded. Due to the lack of medical informa-
dose regimen is conducted in patients with clinical signs tion, patients who continued treatment started in another
of inflammation and an elevated sIL-2R level. We con- hospital were also excluded. Only patients who were
ducted this retrospective study to evaluate the effective- treated with corticoids were included in the present study.
ness of our oral corticoid treatment protocol for CRPS
in our expert center.
Data collection
Symptomsa Signsb
One hundred fifty-three patients were treated for CRPS Global perceived effect
in our expert center between January 2015 and January
2020. All patients were approached to request permis- In total 24 patients completed the GPE. Two patients
sion to view their medical records. In total, 123 patients (1 responder and 1 nonresponder) indicated that they
gave consent of which nine patients did not meet eligi- no longer sufficiently remember the treatment. In ad-
bility criteria after viewing medical records. A total of dition, one patient (responder) could not be reached
114 patients were eligible for inclusion in the current by telephone. Resulting in a response rate of 88.9%.
study. Corticoid treatment was given to 29 (25.4%) of Based on GPE we distinguished three groups; improve-
the patients. However, one outlier was excluded and ment (GPE 1–3), no change (GPE 4), and deterioration
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van den BERG et al. | 397
Responder Nonresponder
N = 14 N = 13 Significance
Gender 1.00
Female 13 (92.9%) 12 (92.3%)
Male 1 (7.1%) 1 (7.7%)
BMI 26.99 ± 4.61 26.68 ± 4.36 0.861
Age at the start corticoid treatment, years 40.28 ± 15.01 43.07 ± 15.53 0.639
CRPS duration at start treatment, months (median, IQR) 53.28 (15.75–110.25) 42.38 (6.5–49.0) 0.369
Affected limb 0.154
Upper limb 2 (14.3%) 4 (30.8%)
Lower limb 12 (85.7%) 9 (69.2%)
Affected side 0.915
Left 8 (57.1%) 7 (53.8%)
Right 6 (42.9%) 5 (38.5%)
Both 0 1 (7.7%)
Initiating event 0.661
Trauma 11 (78.6%) 7 (53.8%)
Surgery 2 (14.3%) 5 (38.5%)
Spontaneous 1 (7.1%) 1 (7.7%)
Note: Values are presented as number (%) for categorical variables and mean ± SD or median (IQR) for continuous variables.
Abbreviations: BMI, body mass index; IQR, interquartile range; SD, standard deviation.
TA BL E 4 Comparison of treatment specifications and side effects between responders and nonresponders.
Responder Nonresponder
N = 14 N = 13 Significance
but the difference showed to be both positive and nega- at the time of visit and 24 h before the visit were compa-
tive. Meaning in some patients sIL-2R level after treat- rable between both groups. Two symptoms (i.e., subjec-
ment was higher than before treatment, and in others, tive symptoms reported by patients) were significantly
levels fell. higher in the nonresponder group than in the responder
group: affected side colder (p = 0.035) and nail changes
(p = 0.029). Affected side warmer was significantly higher
CRPS severity score in the responder group (p = 0.037). In signs (i.e., objective
signs observed by the physician) no significant differ-
Table 6 shows the proportion of symptoms and signs in ences between both groups were found. In addition, the
responders and nonresponders according to the CSS at mean CRPS severity score was comparable between both
first outpatient visit in our center. Median pain scores groups.
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van den BERG et al. | 399
FIGURE 2 Boxplot of the mean sIL-2R levels before and after corticoid treatment between the responders and nonresponders.
TA BL E 6 CRPS severity score: presence of symptoms and signs of CRPS in each group.
Responder Nonresponder
N = 14 N = 13 Significance
TA BL E 6 (Continued)
Responder Nonresponder
N = 14 N = 13 Significance
All patients treated with corticoids in this study re- hypothalamic–pituitary–adrenal axis (HPA axis). HPA-
ceived a moderate dose (between 7.5 and 40 mg/day) of axis impairments are present in inflammatory and auto-
oral prednisolone. Treatment was shown to be effective in immune diseases such as rheumatoid arthritis, Crohn's
51.9% of the patients. Patients in this study already suffer disease, multiple sclerosis, and asthma.28,29 All diseases
from CRPS for 1–58 months at the first visit to our expert associated with increased inflammatory activity—just
center, and the CRPS duration at the start of corticoid like CRPS. In addition to stress, both physical and psy-
treatment is between 6.5 and 110 months. Therefore, it is chological, the HPA axis can also be activated by in-
likely that the longer duration of CRPS in our patients flammatory mediators.30 Activation of the HPA axis
plays an important role in the shown treatment effective- causes endogenous cortisol production, which has an
ness. Especially in the acute stage of CRPS, the classical inhibitory effect on the HPA axis, also known as nega-
signs of peripheral inflammation are described: pain, tive feedback. Subsequently, activated negative feedback
increased temperature, swelling, redness, and loss of can ensure suppressed inflammation. Only one study re-
function.23,24 In this phase, corticoid treatment is likely garding the functioning of the HPA axis in CRPS exists.
to be effective. However, at least in the majority of pa- Park and Ahn showed that a relatively high frequency of
tients with longer-existing CRPS the acute inflammation spontaneous pain attacks was associated with a reduced
extinguished and there is residual damage. In this stage cortisol awakening response and flattened slope of the
with residual damage, which may be both peripheral and diurnal cortisol decline.31 Reduced cortisol levels indi-
central, the anti-inflammatory effect of given corticoid cate dysfunction of the HPA axis, which also can influ-
treatment will be minimal or even absent. Barbalinardo ence the effect of corticoid treatment.
et al. indeed showed limited efficacy in CRPS patients In addition to the possible dysfunction of the HPA
with a duration of more than 3 months.25 axis, forms of glucocorticoid resistance could also be re-
In addition to CRPS duration, warm and cold CRPS lated. The response to corticoids is not only determined
subtypes may also play a role.26 Looking at CSS we found by the concentration of corticoids but also by differences
significant differences in some symptoms related to in- in individual glucocorticoid sensitivity. In the general
flammation. The affected side was significantly warmer population, it is estimated that around 30% of people
in responders, while the affected side was significantly are nonresponders or “glucocorticoid resistant.”32 This
colder in nonresponders. This may indicate warm CRPS glucocorticoid sensitivity causes a variety of clinical re-
in the responder group and cold CRPS in the nonre- sponses and therefore may also influence the shown effi-
sponder group. However, in other symptoms related to cacy of corticoid treatment in this study.
inflammation: color asymmetry, sweating asymmetry, We found variable sIL-2R values with both positive
and edema no differences were found. Furthermore, the and negative differences in sIL-2R levels before and after
signs related to inflammation were comparable between corticoid treatment. Meaning in some patients sIL-2R
both groups. In addition, it is known that inflammation level after treatment was higher than before treatment,
still plays a role in cold CRPS, with present levels of and in others, levels fell. In addition to a possible role
pro-inflammatory cytokines.27 for glucocorticoid resistance, this variation is probably
The increased inflammatory activity in because the sIL-2R was not determined immediately be-
CRPS could also be related to dysfunction of the fore and after treatment. For example, sIL-2R before was
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402 | ORAL CORTICOIDS IN CRPS
measured 117–0 days before start of treatment. In four the patients. Future research should examine the effi-
patients sIL-2R level was measured during treatment cacy of oral corticoids in a controlled study. To estab-
and not afterward. Where the sIL-2R level of another lish potential predictors of treatment response, it would
patient was determined 99 days after ending treatment. be helpful to focus on mechanism-based treatment and
It is also suggested that the effect of corticoid adminis- thus focus on CRPS patients with clinically prominent
tration on circulating sIL-2R levels depends on the state inflammation.
of immune activation and the duration of the corticoid
exposure.33 Therefore, we postulate dosage of corticoid AU T HOR C ON T R I BU T ION S
treatment probably also plays a role. Corinne van den Berg drafted the manuscript. Jitske
Corticoid treatment can cause side effects, which are Tiemensma and Frank J. P. M. Huygen co-authored this
often dose and time dependent.12,34 In this study, side ef- manuscript. All authors critically edited, read, and ap-
fects were described in only five patients (17.9%). Despite proved the final manuscript.
the not well-documented nature of these side effects the
reported effects showed to be mild: vomiting, dizziness, F U N DI NG I N F OR M AT ION
and occurrence of a wound. The results of this study thus No funding was received to assist with the preparation
showed treatment with oral corticoids appears to be rel- of this manuscript.
atively safe.
This study has several limitations. First, the retro- C ON F L IC T OF I N T E R E ST STAT E M E N T
spective design and the associated reliance on what Frank J. P. M. Huygen reports personal fees from Abbott;
was reported in the medical records. Therefore, we en- grants and personal fees from Saluda; and personal fees
countered missing data. Due to a lack of clear specifi- from Boston Scientific, Grunenthal, and Pfizer outside
cation of clinician-reported treatment effects in medical the submitted work. Corinne van den Berg and Jitske
records, we were unable to indicate which effect (pain Tiemensma report no conflicts of interest.
relief, improvement of inflammatory features, and im-
proved function) was shown in the responder group. For DATA AVA I L A B I L I T Y STAT E M E N T
example, NRS before and after corticoid treatment was Research data are not shared.
only reported in two responders. Before treatment, both
patients reported pain NRS 8 and both showed a de- ORC I D
crease in NRS: 1 and 3 points decrease. Also, the results Corinne van den Berg https://orcid.
of GPE could be biased by patients' memory. The more org/0000-0003-0017-7204
so, given the relatively the long period between treatment
and completion of the questionnaire. In addition, GPE
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