Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04667364 |
| Other study ID # |
CRPSprojekt |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 25, 2021 |
| Est. completion date |
January 1, 2023 |
Study information
| Verified date |
April 2023 |
| Source |
Hospital of South West Jutland |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
CRPS is a complex pain condition that usually develops in response to trauma and
immobilization which is very painful and debilitating. There is no consensus about the
underlying mechanisms which might be a combination of mentally and physically factors. At the
moment, better diagnostic clarification and better pain relieving treatment is needed. The
aim of this study is to investigate changes in the perception of pain in patients with
Complex Regional Pain Syndrome (CRPS), and whether this perception can be affected by
treatment with transcutaneous electrical nerve stimulation (TENS) on the painful area. The
study will consist of two parts. One in which patients' perception of pain will be compared
to the perception of pain in healthy controls. Another in which the included patients are
randomly allocated into a group receiving medical treatment plus treatment with
transcutaneous electrical nerve stimulation on the painful area or in a group receiving
medical treatment as usual (MED).Patients will be evaluated four times. At the start of the
study, immediately after treatment, and again at 6 and 12 months after treatment. The
evaluation consists of an overall assessment of pain, response to standardized sensory
stimuli, and questionnaires about quality of life, physical capacity and mentally/socially
well-being.
Description:
BACKGROUND Chronic pain represents a major challenge worldwide, with significant clinical,
social and economic implications. Complex regional pain syndrome (CRPS) is a chronic pain
condition that usually, but not exclusively, develops in response to acute trauma or surgery.
It is characterized by pain disproportionate to the preceding trauma, in addition to sensory
abnormalities and autonomic disturbances, trophic changes and impaired motor function.
Reports indicate that the incidence of CRPS is 26.2/100.000 life-years, with a 3.5:1 female
male ratio, and with a mean age at diagnosis 52.7y. The condition is complex and is probably
the result of multimodal pathogenesis, that has a significant impact on daily functioning and
quality of life (QoL). In addition, few cases resolve completely within 12 months of onset,
has a large impact on work ability and some develop chronic pain and disability. The
socioeconomic consequences are therefore substantial and an increased focus on CRPS diagnosis
and treatment is needed. Because of the complexity of the condition, treatment is difficult
and include physiotherapy, education, spinal cord stimulation (SCS) and medical treatment.
Primary treatment involves medical treatment which might include important adverse effects
such as fatigue, insomnia, anxiety and weight gain, to name a few. Regardless, results vary
significantly. One explanation is the multimodality of pain that involves both peripheral
nerves, the spinal cord and higher brain centers, modulated by immune cells, interneurons,
descending pathways, cognitive and psychosocial factors. Changes in pain sensitization has
been proposed to be a driving factor in CRPS and is the result of distorted somatosensory
signaling in the central nervous system. Pain normally reflects damaging peripheral input,
acting as an important protective function, however, this concept might get distorted so that
pain no longer represent peripheral noxious stimuli but rather functional changes of the
central nervous system. The pain in these situations arises spontaneously, can be elicited by
normally innocuous stimuli (allodynia), is exaggerated and prolonged in response to noxious
stimuli (hyperalgesia), and spreads beyond the site of injury (secondary hyperalgesia).
Testing some of the underlying mechanisms provides the means to directly evaluate these pain
symptoms suggested to be among the primary complaints in CPRS. Accordingly, a range of
sensory changes has been suggested including thermal and mechanical hyperalgesia and
hypoesthesia. A study found hyperalgesia to blunt pressure in patients with CRPS and with
peripheral nerve injury, which has been confirmed by others, suggesting an importance of deep
somatic structures such as muscles and bones. Another study showed changes in thermal
sensitivity with both heat and cold hyperalgesia in the acute phase of CRPS and a modulation
of thermal detection thresholds as the CRPS progressed. In addition, a study reported changes
in endogenous pain modulation, implying a shift towards facilitation, whereas others found
limited change. These differential results alongside heterogeneous mechanisms associated with
diverse clinical features complicates treatment significantly which might only affect a small
portion of patients. It is crucial to establish whether patients can be identified and
distinguished to facilitate optimal decisions and effects of treatment strategies. This
project applies a psychophysical method, based on conventional quantitative sensory testing
(QST), to quantify somatosensory function in CRPS patients, to provide a mechanisms-based
approach to diagnosis and treatment. Recently QST has been used to complement traditional
neurological testing, with greater precision and reliability when assessing somatosensory
aberrations and its clinical value is well recognized. Nevertheless, because of a lack of
standardization and a paucity in normative data, the application of QST in clinical settings
remains scarce. The current project applies QST methodology developed at the Spine center of
Southern Denmark, Lillebaelt Hospital, specifically designed to meet clinical demands and
will be part of a novel initiative to implement and standardize QST in clinical practice in
Denmark. The methodology might prove valuable in a range of different pathologies such as
headache, fibromyalgia and diabetic neuropathy. In addition, the current project will combine
QST measurement with functional measurements and patient reported outcomes on depression,
anxiety and sleep using a national database on pain in collaboration with Pain Center South,
University Hospital Odense. The modulation of QST, their interaction and time course together
with functional measurements and PRO-data might be a powerful combination for the diagnosis
of patients, monitoring and prediction of therapy success. A therapy often used as an adjunct
to medication is transcutaneous electrical nerve stimulation (TENS) which is an inexpensive,
noninvasive and safe treatment for pain. Electrical stimulation is delivered to peripheral
sensory nerves using surface electrodes and has been shown to have a beneficial effect on
centralized pain, showing normalized hyperalgesia post intervention. Nevertheless, the
beneficial effects remain controversial as more high-quality studies are needed. In addition,
pain is complex and depends on contextual, social, psychological and biological factors not
necessarily attributed to a specific pathology. These are rarely considered concurrently. The
current project will evaluate the effect of TENS, in respect to patients psychological,
functional and somatosensory profile, adding valuable information to the existing body of
literature.
The aim of the current project is three-fold; 1) to test the feasibility and validity of
standardized quantitative sensory testing for CRPS in clinical practice, 2) to evaluate
changes in sensitization and 3) to evaluate the effectiveness of transcutaneous electrical
nerve stimulation (TENS) and identify subgroups that benefit the most.
The investigators hypothesize that quantitative sensory testing is feasible in a clinical
setting and will in combination with functional measurements and PRO-data be a valuable tool
for the diagnosis of patients and for the monitoring and prediction of therapy success.
TRIAL DESIGN The project will utilize quantitative methods and strong randomized controlled
research designs. The project will consist of two parts; 1) Evaluation of CRPS patient
compared to healthy controls, and validation of method. Participants will be assessed at
baseline prior to treatment with QST (mechanical stimulation, pain thresholds, cold/heat
sensitivity) as outcome measure to identify somatosensory profiles of CRPS patients compared
to normative data. 2) Evaluation of treatment with TENS compared to treatment as usual.
Patients will be randomly allocated to either a TENS intervention group (TENS) or a treatment
as usual group (MED) and will be assessed at baseline, re-test pre TENS, post intervention
and 3 month post intervention. Outcomes include QST and patient reported outcomes (pain,
quality of life, depression, anxiety, sleep, a.m.). Subsequent analysis of data is planned,
to evaluate its ability to predict therapeutic outcomes of TENS.
RECRUITMENT AND SAMPLE SIZE Patients will be recruited from the clinic for CRPS and
neuropathic pain, Hospital of South West Jutland, (SVS), University Hospital of Southern
Denmark. The clinic functions as a specialized CRPS clinic in the Region of Southern Denmark.
Healthy controls will be recruited amongst staff at SVS and partners, relatives or friends.
The planned number of trial participants is based on the assumed superiority of TENS
treatment over control. Estimating the sample size for a two-sample means test with a level
of significance at 0.05, assuming a common standard deviation (SD) of 2 in NRS pain intensity
scores indicates that for the intention-to-treat (ITT) population, 34 individuals is required
to obtain a power of at least 80% to establish a minimal clinically significant difference
(MCSD) of 2 in NRS pain scores. The MCSD and common standard deviation is based on previous
findings with a similar patient group and intervention. With an expected drop-out rate of
20%, a total of 46 individuals will be included in the project, 23 in each group.
ALLOCATION All patients will be evaluated at baseline and their QST data will be compared to
a group of healthy controls (Part 1). Subsequently, in part 2, patients will be randomized
with a computer-generated block randomization with a 1:1 allocation ratio using random block
sizes of 2, 4 and 6 in either group TENS or group MED. The randomization restrictions will
not be disclosed, and the sequence will be performed by an external party.
INTERVENTIONS TENS. Conventional TENS will be performed using two electrodes placed on the
involved extremity and with the following stimulation parameters; a frequency of 100 Hz,
pulse duration 50-100 ms, and at an intensity gradually increased until the patient feels a
strong, tolerable and non-painful sensation. The intensity is incrementally increased based
on patient feedback. Patients will receive guidelines on how to use the TENS device at home
and will over a period of 30 days self-administer TENS as needed. Patients is to fill out a
predefined schedule on paper each day to monitor dose (see appendix).
Treatment as usual. Consist of medicinal treatment, prescribed by a specialist doctor
(Carsten Kock-Jensen, MD) from the CRPS clinic and will be monitored using patients'
medicinal records.
STATISTICAL METHODS To evaluate the empirical distributions of the continuous outcomes,
visual inspection of the studentized residuals will be applied to evaluate whether the
assumption of normality is reasonable. The treatment groups will be examined for
comparability based on baseline demographic and prognostic measures. An Intention-To-Treat
(ITT) analysis will be used for all allocated patients and a mixed effects model will be used
on the continuous outcome measures to determine the effects of TENS treatment from baseline
to post treatment and follow-ups [Between groups factor: TENS vs MED, within groups factor:
time]. The model will use robust estimation methods to account for outliers. Finally, a
multiple imputation approach will be used in case of missing data. All p-values < 0.05 will
be considered statistically significant.
ETHICS AND SIGNIFICANCE The project is to be approved by the Regional Committee on Health
Research Ethics for Southern Denmark and will be conducted according to the declaration of
Helsinki.
The combination of quantitative pain measurements and PRO-data might be a powerful
combination for the diagnosis of patients and monitoring and prediction of therapy success.
It might have the potential to provide patients with individualized mechanism-based pain
therapy and clarify to what extend and to whom TENS is beneficial. This might result in
increased functional capacity and quality of life as a result of significant pain relief.
This could have a significant impact on patients' lives as well as significant socioeconomic
consequences.
