Small Fiber Neuropathy
Conditions
Keywords
repetitive transcranial magnetic stimulation, rTMS, small fiber neuropathy, SFN, pain management
Brief summary
Small fiber neuropathy (SFN) is a condition in which the smallest nerve fibers are damaged. This leads to severe pain and disturbances in the body's automatic functions. As a result, quality of life is often substantially reduced. Pain is one of the main symptoms of small fiber neuropathy. Unfortunately, the effects of currently available pain medications are often disappointing and may be accompanied by unacceptable side effects. Although the smallest nerve fibers do not function properly in SFN, the brain also appears to play a role in the symptoms. Specialized brain imaging studies have shown that brain activity and certain neural connections differ between patients with SFN and healthy individuals. Therefore, the brain may also represent a suitable target for treatment. In several chronic pain conditions, it has been demonstrated that stimulation of specific brain regions using magnetic pulses delivered through a specialized coil can reduce pain. This treatment can be administered using repetitive Transcranial Magnetic Stimulation (rTMS), a safe and non-invasive technique that is already available in the Netherlands for people with severe depression. The effectiveness of rTMS has never been investigated in patients with small fiber neuropathy. In addition, the pain-relieving effects of treatment are often temporary. Maintenance treatment may offer a potential solution to this problem.
Detailed description
Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by invalidating neuropathic pain, leading to a substantial decline of quality of life (QOL). Pharmacological treatment is often ineffective and causes debilitating side effects. Interestingly, while constituting a peripheral nerve condition, SFN is also characterized by changes in brain network connectivity as demonstrated by structural and functional brain imaging, making the brain a promising treatment target for SFN. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been proven to be effective in chronic neuropathic pain treatment, by inducing changes in cortical excitability. However, the number of neuropathy patients that has been studied is limited, and induced analgesic effects were rather short-lived in duration. We hypothesize that rTMS is an effective treatment strategy for neuropathic pain in SFN compared to sham stimulation. The primary objective is to evaluate the efficacy of rTMS for pain alleviation in SFN patients. Secondary objectives are to assess the effect of providing repeated maintenance rTMS treatment on prolonged pain relief, and to study the effect of rTMS on pain intensity, pain qualities, other SFN-related complaints, daily functioning and QoL, as well as safety features of rTMS in SFN.
Interventions
DEVICETranscranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) is arguably the most versatile noninvasive neuromodulation technique. TMS is the transcranial delivery of magnetic pulses to a brain region, inducing electric current that can depolarize neurons and induce action potentials. When multiple electromagnetic pulses are applied repetitively (rTMS) to the brain, longer lasting neuroplastic changes can be induced
DEVICETranscranial Magnetic Stimulation Sham
A placebo version of the active repetitive transcranial magnetic stimulation. The coil mimics sound and sensation of a real treatment without active stimulation.
Sponsors
Maastricht University Medical Center
Princess Beatrix Muscle Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Randomized controlled trial, single blind.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older. * Skin-biopsy proven idiopathic SFN. * Pain intensity (maximum pain) rated ≥5 on the PI-NRS, that must have existed for at least 12 weeks before the study. * Written informed consent.
Exclusion criteria
* Signs of large nerve fiber dysfunction (i.e., weakness, loss of vibration sense, hyporeflexia or areflexia, abnormal nerve conduction studies). * Identifiable underlying cause of SFN (diabetes, SCN9A/SCN10A/SCN11A mutations, hypothyroidism, vitamin B12 deficiency, monoclonal gammopathy, alcohol abuse (more than 5 IU/day), malignancies, or drugs that cause neuropathy). * Implanted ferromagnetic devices or other magnetic-sensitive metal implants close to the magnetic coil. * History of epilepsy. * Using pain medication that has changed in the 30 days prior to randomization. * Pregnancy. * Mentally challenged subjects unable to give independent informed consent. * Clinically significant or unstable psychiatric disorder including major depression, (history of) substance abuse and other major disorders in accordance with DSM-V,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of responders, defined as ≥ 1-point improvement in the mean weekly peak pain measured with the PI-NRS after the 6-week treatment period. | From enrolment until 6 weeks of active rTMS treatment | As pain is the main future of SFN, the primary outcome measure will be based on pain intensity. This will be evaluated using the 11-point PI-NRS (0 = no pain to 10 = worst imaginable pain). The primary outcome parameter is defined as the difference in the mean weakly peak pain intensity. A responder is defined as ≥ 1-point decline on the PI-NRS at week 6 compared to baseline. The primary outcome measure is based on the IMMPACT criteria.12 The primary efficacy endpoint is the proportion of responders of rTMS compared to the proportion of responders of sham stimulation after the 6-week treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in daily pain intensity using the PI-NRS | From enrolment until month 6 | The daily pain intensity (defined as the mean pain experienced during the day: from waking up to 6 pm), the nocturnal pain intensity (6 pm until waking up), and the average of these two, using the PI-NRS. |
| Proportion of responders defined as ≥ 2-point decline on the PI-NRS at week 6 compared to baseline. | From enrolment until 6 weeks of treatment | A secondary efficacy endpoint is a comparison between the percentage responders treated by rTMS and sham stimulation, when the responder is defined as ≥ 2-point decline on the PI-NRS at week 6 compared to baseline. |
| Pain changes on the Patient Global Impression of Change (PGIC) | From enrolment until 6 months | Pain symptoms, using the patients' global impression of change (PGIC) on a 7-point Likert scale. Subsequent scores of the PGIC are 1) worse than ever; 2) much worse; 3) little worse; 4) no change; 5) little improved; 6) much improved; 7) very much improved. 'Very much improved and 'much improved' are considered as a relevant improvement. Clinically relevant pain reduction on PGIC for pain will be defined as score 6 ('much improved') or 7 ('very much improved'). |
| Severity of various pain qualities, using the neuropathic pain scale (NPS). | From enrolment until 6 months | Severity of various pain qualities, using the neuropathic pain scale (NPS). |
| SFN related symptoms on the SFN-SIQ | From enrolment until month 6 | SFN-related symptoms, measured by the Rasch-transformed 13 items SFN symptoms inventory questionnaire (RT-SFN-SIQ). |
| Activity and participation level using SFN-RODS | From enrolment until month 6 | Activity and participation level, measured by the Rasch-built Overall disability Outcome Scale specifically designed for SFN (SFN-RODS). |
| Quality of Life using EuroQoL 5D | From enrolment until month 6 | QoL, using EQ5D (EuroQol 5D) |
| Efficacy of maintenance treatment based on pain intensity. | From enrolment until week 12 | Also, the efficacy of the maintenance treatment is based on pain intensity. The maintenance period is successful, if the PI-NRS at week 12 is still ≥ 1-point lower compared to baseline. |
| Adverse events | From enrolment up until 12 weeks and 6 months | Adverse events and vital signs will be registered for safety evaluation |
Countries
Netherlands
Contacts
CONTACTEva C.M. Gruintjes, MD
CONTACTJanneke G.J. Hoeijmakers, MD, PhD
PRINCIPAL_INVESTIGATORJanneke G.J. Hoeijmakers, MD, PhD
Maastricht University Medical Centre +
Outcome results
None listed