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| Name | Class |
|---|---|
| Turku University Hospital | OTHER_GOV |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Starts with active stimulation | Active Comparator | 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. |
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| Starts with sham stimulation | Placebo Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sham nrTMS and open phase | Device | 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". |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eija Kalso, Professor | Helsinki University Hospital, Pain Clinic | Study Chair |
| Satu Jääskeläinen, Professor | Turku University Hospital, Dept. of Clinical Neurophysiology | Study Chair |
| Hanna Harno, MD, PhD | Helsinki University Hospital, Pain Clinic | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Turku University Hospital, Pain Clinic | Turku | Southwest Finland | 20014 | Finland | ||
| Helsinki University Hospital, Pain Clinic |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31901449 | Background | 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. | |
| 25034472 |
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The Ethics committee doesn't allow that due to privacy agreements.
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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.
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The participant does not know whether the stimulation is sham or active. The doctor or nurse giving the stimulation knows the target and whether the stimulation is sham or active. The RN and the clinician (conducting screening and 1 month clinical visit) do not know the stimulation type or target until month 3, when the code is opened.
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| Active nrTMS and open phase | Device | 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". |
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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 |
| Helsinki |
| Uusimaa |
| 00029 |
| Finland |
| Background |
| 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. |
| 25180011 | Background | 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. |
| 40626344 | Derived | Liesto S, Aho T, Jaaskelainen SK, Hietanen M, Kalso E. Cognitive Function in Patients With Complex Regional Pain Syndrome (CRPS). Eur J Pain. 2025 Jul;29(6):e70070. doi: 10.1002/ejp.70070. |
| ID | Term |
|---|---|
| D012019 | Reflex Sympathetic Dystrophy |
| D010146 | Pain |
| ID | Term |
|---|---|
| D020918 | Complex Regional Pain Syndromes |
| D001342 | Autonomic Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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