CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

Transcranial Magnetic Stimulation Clinical Trial

Official title:

Complex Regional Pain Syndrome - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04439669
• Other study ID #: TYH20162222
• Status: Active, not recruiting
• Phase: N/A
• Start date: August 28, 2017
• Est. completion date: December 2024

Study information

• Verified date: May 2023
• Source: Helsinki University Central Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Complex Regional Pain Syndrome of Upper Limb (Disorder)
• Complex Regional Pain Syndromes
• Reflex Sympathetic Dystrophy
• Syndrome
• Transcranial Magnetic Stimulation

Intervention

Device:
• Sham nrTMS and open phase
Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to sham. In the following open phase stimulation the treatment targets are the right "S2"-contralateral M1-left "S2".
• Active nrTMS and open phase
Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to "S2". In the following open phase stimulation the treatment targets are contralateral M1 and left "S2". If the patient benefited from active "S2" stimulation, but the treatment effect faded in follow-up, the open phase stimulation starts with right "S2".

Locations

Country	Name	City	State
Finland	Helsinki University Hospital, Pain Clinic	Helsinki	Uusimaa
Finland	Turku University Hospital, Pain Clinic	Turku	Varsinais-Suomi

Sponsors (2)

Lead Sponsor	Collaborator
Helsinki University Central Hospital	Turku University Hospital

Country where clinical trial is conducted

Finland, 

References & Publications (3)

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. — View 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. Erratum In: Clin Neurophysiol. 2020 May;131(5):1168-1169. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	15-item quality of life measure	Quality of life (15D questionnaire) with 15 question items with 5 alternatives in each. The scores range between 15 to 75 with 15 the best and 75 the worst quality of life.	Change from baseline at one month
Secondary	Mean pain intensity and interference	Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)	Baseline, during stimulation, and two weeks after the intervention
Secondary	Weekly pain intensity and interference	Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)	Up to 3 months after intervention
Secondary	Sleep interference and quality	Insonnia severity index (ISI). There are seven questions with scale 0 to 4 (0 with no symptoms and 4 with the worst symptoms). The scores are added up to get a total score ranging from 0 to 28. A higher score means a worse outcome.	Baseline and 1,2,and 3 months after intervention
Secondary	Clinical neurophysiology measures	Quantitative sensory testing (QST) with standardized reporting	Baseline and one week after intervention
Secondary	Cognitive assessment A	Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting.	Baseline and one month after the intervention
Secondary	Hand strength	Hand motor function measured e.g. by Jamar (kg)	Baseline and one week after the intervention.
Secondary	Biochemical tests	Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting	At baseline
Secondary	Brain imaging: Default mode networks	Resting state fMRI	Baseline and one week after intervention
Secondary	CRPS symptom severity	CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)	Baseline and at one month
Secondary	Patient global impression of change	Global impression of change (GIC, 1=very much improved, 7= very much worse)	1, 2, and 3 months and through study completion, an average of 1 year
Secondary	Screening of psychiatric symptoms and diagnostics	Psychiatric interveiw (SCID II) with symptom and diagnostic description. Nine questions, answers yes or no, standard reporting. The more "yes"-answers, the worse the outcome.	Up to 24 weeks
Secondary	Hand mobility	Angles of the joints in the hand (degrees)	Baseline and one week after intervention
Secondary	Cognitive assessment B	Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting.	Baseline and one month after the intervention
Secondary	Cognitive assessment C	Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting.	Baseline and one month after the intervention
Secondary	Cognitive assessment D	Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.	Baseline and one month after the intervention
Secondary	Cognitive assesment E	Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting.	Baseline and one month after the intervention
Secondary	DNA	DNA analysis. Standard reporting.	At baseline