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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Transcranial Magnetic Stimulation; Complex Regional Pain Syndrome of Upper Limb (Disorder)
• Intervention / Treatment: Device: Active nrTMS and open phase; Device: Sham nrTMS and open phase

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hanna Harno, MD, PhD; Phone Number: +358 094711; Email: hanna.harno@hus.fi
• Study Contact Backup: Name: Juhani Ojala, MD; Phone Number: +358 094711; Email: juhani.ojala@hus.fi

Study Locations

• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00029
      • Helsinki University Hospital, Pain Clinic
  • Varsinais-Suomi
    • Turku, Varsinais-Suomi, Finland, 20014
      • Turku University Hospital, Pain Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Starts with active stimulation; Active nrTMS is given to "S2" at the right side (10 sessions in a three week period). Thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to M1 contralateral to the side of pain. After 5 stimulation sessions the response is evaluated. If pain is still ≥510, the investigators change the target to the "S2" on the left side for five sessions. If there is response with pain relief, a maintenance therapy with this target is offered for 6 months with gradually reducing stimulation sessions.	Device: 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".; Other Names: Starts with active stimulation
Placebo Comparator: Starts with sham stimulation; Sham nrTMS will be targeted to the "S2" on the right side, but using a sham box/coil. Stimulation period is similar than for the active comparator. Similarly, thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to "S2" at the right side. After 5 stimulation sessions the response is evaluated. If pain is still ≥5/10, the investigators change the target to M1 on the contralateral side of the pain and furthermore to "S2" at the left side after 5 stimulation sessions, if pain is still ≥5/10.	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".; Other Names: Starts with sham stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Clinical neurophysiology measures	Quantitative sensory testing (QST) with standardized reporting	Baseline and one week after intervention
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
Hand strength	Hand motor function measured e.g. by Jamar (kg)	Baseline and one week after the intervention.
Biochemical tests	Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting	At baseline
Brain imaging: Default mode networks	Resting state fMRI	Baseline and one week after intervention
CRPS symptom severity	CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)	Baseline and at one month
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
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
Hand mobility	Angles of the joints in the hand (degrees)	Baseline and one week after intervention
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
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
Cognitive assessment D	Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.	Baseline and one month after the intervention
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
DNA	DNA analysis. Standard reporting.	At baseline

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Turku University Hospital
• Investigators: Study Chair: Eija Kalso, Professor, Helsinki University Hospital, Pain Clinic; Study Chair: Satu Jääskeläinen, Professor, Turku University Hospital, Dept. of Clinical Neurophysiology; Study Director: Hanna Harno, MD, PhD, Helsinki University Hospital, Pain Clinic

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2017
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: June 17, 2020
• First Posted (Actual): June 19, 2020

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 29, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: pain; DNA; quality of life; cognitive function; fMRI; CRPS; TMS; mood
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Disease; Neuromuscular Diseases; Peripheral Nervous System Diseases; Autonomic Nervous System Diseases; Syndrome; Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy
• Other Study ID Numbers: TYH20162222

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The Ethics committee doesn't allow that due to privacy agreements.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No