Clinical trial NCT04439669: CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation
Official title: Complex Regional Pain Syndrome - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Transcranial Magnetic Stimulation
Complex Regional Pain Syndrome of Upper Limb (Disorder)
Keywords: TMS
CRPS
pain
fMRI
quality of life
mood
cognitive function
DNA
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Turku University Hospital
First posted: 2020-06-19
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The patients are first randomized to receive either sham stimulation or right "S2" for three week period (10 stimulation sessions). Thereafter, a 3 month followup period (clinical checkup at a research visit at 1 month, RN structured telephone interviews at 2 and 3 months). If pain ≥5/10 at 3 month interview, the patient is offered an open label nrTMS treatment phase, in which the protocol depends on the first protocol of the RCT phase.
Primary purpose: TREATMENT

Brief summary: This is a sham controlled, randomized, double-blind, navigated repetitive Transcranial Magnetic Stimulation (nrTMS) study for the treatment of complex regional pain syndrome (CRPS types 1 and 2). The investigators study factors that may contribute to development, maintenance, or treatment responses with clinical, sleep, and psychiatric questionnaires and clinical examinations, quantitative sensory testing and neurophysiologic recordings, genetics, and MRI techniques.

Detailed description: rTMS hypothetically disrupts the default networks related to chronic pain and renders the brain more susceptible to drugs, rehabilitation, or cognitive behavioral therapy. In addition, there is experimental evidence that rTMS releases factors that are involved in endogenous top-down modulation of pain and neural plasticity. Thus, the analgesic effect of rTMS may be mediated via enforcing endogenous pain control systems at the brain level, in addition to its effects on neuroplastic effects.

For active, navigated stimulation targets the investigators have the parietal opercular cortex overlying the secondary somatosensory cortex ("S2") and the primary motor cortex (M1).

The investigators randomize participants to first receive nrTMS to the right "S2" or sham stimulation. After ten sessions the investigators follow up the participants up to three months. At three months, if the average pain is ≥5/10 in numeric rating scale (NRS), the participant is offered an active, open nrTMS treatment phase depending on which treatment the participant first received. If the participant benefits from the open label treatment, a maintenance therapy is offered (6 months with gradually reducing nrTMS treatment frequency). The symptoms and quality of life are followed with questionnaires and diaries. After the maintenance period, the RN calls a structured interview at 1, 3, and 6 months.

Eligibility criteria: Inclusion Criteria:

* CRPS 1 or 2 of the upper limb
* Duration ≥ 6 months
* Mean pain (NRS) intensity ≥5/10
* Medical and other therapies have failed

Exclusion Criteria:

* Other stimulation therapies apart from transcutaneous nerve stimulation
* psychotic disorder
* severe depression
* use of strong opioids
* epilepsy
* any contraindication for MRI
* abuse of alcohol or drugs
* ongoing insurance or other entitlement cases

Primary outcomes:
measure: 15-item quality of life measure
timeFrame: Change from baseline at one month
Secondary outcomes:
measure: Mean pain intensity and interference
timeFrame: Baseline, during stimulation, and two weeks after the intervention
measure: Weekly pain intensity and interference
timeFrame: Up to 3 months after intervention
measure: Sleep interference and quality
timeFrame: Baseline and 1,2,and 3 months after intervention
measure: Clinical neurophysiology measures
timeFrame: Baseline and one week after intervention
measure: Cognitive assessment A
timeFrame: Baseline and one month after the intervention
measure: Hand strength
timeFrame: Baseline and one week after the intervention.
measure: Biochemical tests
timeFrame: At baseline
measure: Brain imaging: Default mode networks
timeFrame: Baseline and one week after intervention
measure: CRPS symptom severity
timeFrame: Baseline and at one month
measure: Patient global impression of change
timeFrame: 1, 2, and 3 months and through study completion, an average of 1 year
measure: Screening of psychiatric symptoms and diagnostics
timeFrame: Up to 24 weeks
measure: Hand mobility
timeFrame: Baseline and one week after intervention
measure: Cognitive assessment B
timeFrame: Baseline and one month after the intervention
measure: Cognitive assessment C
timeFrame: Baseline and one month after the intervention
measure: Cognitive assessment D
timeFrame: Baseline and one month after the intervention
measure: Cognitive assesment E
timeFrame: Baseline and one month after the intervention
measure: DNA
timeFrame: At baseline
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Pain Clinic
state: Uusimaa
city: Turku
country: Finland
facility: Turku University Hospital, Pain Clinic
state: Varsinais-Suomi
Study officials:
affiliation: Helsinki University Hospital, Pain Clinic
name: Eija Kalso, Professor
role: STUDY_CHAIR
affiliation: Turku University Hospital, Dept. of Clinical Neurophysiology
name: Satu Jääskeläinen, Professor
role: STUDY_CHAIR
affiliation: Helsinki University Hospital, Pain Clinic
name: Hanna Harno, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jaaskelainen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorova I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol. 2020 Feb;131(2):474-528. doi: 10.1016/j.clinph.2019.11.002. Epub 2020 Jan 1.
citation: Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5.
citation: Jaaskelainen SK, Lindholm P, Valmunen T, Pesonen U, Taiminen T, Virtanen A, Lamusuo S, Forssell H, Hagelberg N, Hietala J, Pertovaara A. Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation. Pain. 2014 Oct;155(10):2180-7. doi: 10.1016/j.pain.2014.08.029. Epub 2014 Aug 29.