tDCS and Pain Associated With Diabetic Neuropathy

Chronic Pain Clinical Trial

Official title:

Effects of Transcranial Direct Current Stimulation (tDCS) on Pain Associated With Diabetic Neuropathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04306289
• Other study ID #: University of Rome Tor Vergata
• Status: Recruiting
• Phase: N/A
• Start date: June 1, 2020
• Est. completion date: September 1, 2022

Study information

• Verified date: August 2021
• Source: University of Rome Tor Vergata
• Contact: Silvia Natoli, MD, PhD
• Phone: +393451690925
• Email: silvia.natoli[@]uniroma2.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the effects of anodal transcranial direct current stimulation (tDCS) on pain intensity associated with diabetic neuropathy. The investigators will conduct real tDCS or sham, over the left dorsolateral prefrontal cortex (DLPFC) during 6 separated days. They will evaluate pain intensity, sleep quality, quality of life and anxiety and depression symptoms via clinical validated scales. The research question is whether tDCS can lessen neuropathic pain and improve sleep, psychological status and quality of life in patients with diabetic neuropathy. It is hypothesized, that less neuropathic pain and improved sleep, psychological status and quality of life after the tDCS sessions.

Description:

Background: Worldwide, the prevalence of diabetes mellitus (DM) and its chronic complications are reaching epidemic proportions. By 2045 DM expected to affect 629 million persons. Diabetic neuropathy is one of the most common complications of DM and is actually the set of heterogeneous clinical forms. Among diabetic neuropathies, generalized, focal or multifocal forms are distinguished. The most typical and most common form (up to 80% of cases is sensory-motor polyneuropathy. It has recently been redefined as a length-dependent symmetric sensory-motor polyneuropathy attributable to metabolic and microvascular alterations following exposure to chronic hyperglycemia and cardiovascular risk cofactors. Painful diabetic peripheral neuropathy (PDPN) may be considered a variant; about 15-25% of patients have painful diabetic polyneuropathy. According to the definition of neuropathic pain of the International Association for the Study of Pain (IASP), PDPN is considered as asymmetric sensory-motor polyneuropathy chronic in which neuropathic pain has been present, for at least 3 months, as direct consequence abnormalities of the peripheral somatic-sensitive system following diabetic pathology. Sensory symptoms are more evident than motor symptoms; which is appear in the most distal portions of the limbs and progress proximally according to a "glove" or "sock" distribution associated with paresthesias and dysesthesias. The clinical symptoms are related to the type of nerve fiber involved and typically there are "positive" (tingling, burning, pain, allodynia) or "negative" sensory symptoms (loss of sensitivity, numbness). The involvement of small sensitive fibers causes a reduction in thermal sensitivity and pain and this, in turn, contributes to the deficits in tactile and proprioceptive sensitivity to increase the risk of a foot injury. The PDPN is associated with negative repercussions on the quality of life (QoL), activities of daily livings, sleep disorders, and is the major determinant of depressive symptoms in patients with PDNP. In fact, depression and sleep disturbances play a negative prognostic role in the general and diabetic population, and sleep disturbances are associated with glycated hemoglobin levels higher than 0.35% in type 2 diabetes. The presence of PDPN determines an increase in the use of medical care and social costs, both directly related to treatments, and indirect secondary to the reduction of working capacity. The presence of chronic pain of any nature increases the risk of difficulties in the self-management of diabetes, in relation to taking therapy, physical activity, adherence to the diet, foot care and even glycemic self-monitoring. Transcranial Direct Current Stimulation (tDCS) has shown promising results for the treatment of chronic pain in several types of diseases, being a good and non-invasive alternative to treat pain in PDPN patients. Also, based on studies that showed changes in the brain activity of chronic pain patients and on the difficulties faced to treat PDPN, there is a need to conduct clinical trials using new techniques, such as neuromodulation, to help these patients to control their pain. Therefore, tDCS emerges as a new tool to be coupled with other effective treatments already used for these patients. The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region as well as a key area of numerous brain networks involved in the processing of cognition effect. Numerous studies have shown that some chronic pain syndromes are associated with a reduction in the volume of the gray matter of DLPFC. Some studies show that pain relief manages to reverse these structural changes PDPN. Moreover, previous studies reported that DLPFC stimulation induces a significant analgesic and antidepressant effect. Hypothesis: The investigators believe that neuromodulation by tDCS over the left DLPFC would decrease the pain intensity and improve the general quality of life in patients with PDPN. Objectives: general PURPOSE Investigate if anodal tDCS over left DLPFC has analgesic effects in patients with PDPN. Specifics purposes 1- Evaluate the tDCS effects over pain intensity; 2- Evaluate if tDCS has any effect on sleep quality, depression, anxiety, and quality of life. Randomization: The subjects will be allocated consecutively to randomization as an intervention order using the tool from the randomization.com website (Dallal GE, http://www.randomization.com). The investigators will use the second generation suggested for crossover studies. Data Collection Procedure: All subjects will be treated using two different interventions (groups respecting the washout period of six weeks to avoid residual effects. The intervention order will be determined by randomization per group of interventions. Subjects will be contacted by phone and asked if they want to participate in the study. Those who wish to participate and qualify according to the selection criteria after completing the pre-screening questionnaire will be scheduled after reading and signing the consent form (2 copies). During the second visit, all clinical and neurological assessments will be performed before and after tDCS stimulation phase. Each patient will be clinically and neurologically assessed before and after the stimulation, allowing data to be collected 4 times (T0, T1, T2, and T3). tDCS protocol: Group Real tDCS: The participant will receive anodal tDCS over the left DLPFC and the reference electrode will place over the right forearm. The stimulation intensity will be 2mA DC delivered for 20 min (30 s step-up ramp, 30 s step-down ramp), repeated six times, during two weeks (Mon, Wed, Frid). Group sham tDCS: Identical to the real tDCS, except the participants will only receive the initial 30 seconds of ramp-up, after which the current will be set to 0 for the remainder of the 20 minutes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: September 1, 2022
• Est. primary completion date: June 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patient diagnosed with painful diabetic peripheral neuropathy (PDPN) components with DN4 score = 4/10, and chronic pain with an intensity of at least VAS> 4/10.
• Onset of neuropathic PDPN pain for at least 6 months.
• Pain intensity as measured by VAS> 4/10 in the week preceding inclusion in the study.
• drug-resistant patients who have no pain reduction of 50% or an improvement of at least 2 points in the Patient Global Impression of Change, having used all the classes of drugs indicated as a first, second or third line.
• Absence of glycemic de-compensation with HbA1c values <9% in the previous 6 months.
• Stability of glycemic control with changes in HbA1c in the last 6 months of less than 2%. Exclusion Criteria
• Neurological comorbidities.
• Presence of contraindications to the use of electrotherapy (pacemaker, epilepsy, etc ...).
• Pregnancy.
• Previous neurosurgical interventions.
• psychiatric conditions.
• Cognitive impairments ( Mini-Mental Status exam (MMSE) <24).
• Presence of red flags for pain: tumors, spine fractures, non-neuropathic pain difficult to distinguish from that of the PDPN, neuropathic pain from a cause other than the PDPN.
• Severe comorbidities such as advanced renal failure, heart failure, respiratory failure.

Related Conditions & MeSH terms

• Chronic Pain
• Diabetic Neuropathies
• Peripheral Nervous System Diseases

Intervention

Device:
• transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) is a noninvasive technique of neuronal modulation that has been used in different neurological conditions, neuropathic pain.

Locations

Country	Name	City	State
Italy	Prof. Silvia Natoli	Roma	Lazio

Sponsors (1)

Lead Sponsor	Collaborator
University of Rome Tor Vergata

Country where clinical trial is conducted

Italy, 

References & Publications (15)

Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011 Oct;34(10):2220-4. doi: 10.2337/dc11-1108. Epub 2011 Aug 18. — View Citation

Alleman CJ, Westerhout KY, Hensen M, Chambers C, Stoker M, Long S, van Nooten FE. Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: A review of the literature. Diabetes Res Clin Pract. 2015 Aug;109(2):215-25. doi: 10.1016/j.diabres.2015.04.031. Epub 2015 May 6. Review. — View Citation

Binns-Hall O, Selvarajah D, Sanger D, Walker J, Scott A, Tesfaye S. One-stop microvascular screening service: an effective model for the early detection of diabetic peripheral neuropathy and the high-risk foot. Diabet Med. 2018 Jul;35(7):887-894. doi: 10.1111/dme.13630. Epub 2018 May 10. — View Citation

D'Amato C, Morganti R, Greco C, Di Gennaro F, Cacciotti L, Longo S, Mataluni G, Lauro D, Marfia GA, Spallone V. Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities. Diab Vasc Dis Res. 2016 Nov;13(6):418-428. Epub 2016 Jun 22. — View Citation

Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabet Med. 2004 Sep;21(9):976-82. — View Citation

Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ 3rd, Service FJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993 Apr;43(4):817-24. Erratum in: Neurology 1993 Nov;43(11):2345. — View Citation

Kim YJ, Ku J, Kim HJ, Im DJ, Lee HS, Han KA, Kang YJ. Randomized, sham controlled trial of transcranial direct current stimulation for painful diabetic polyneuropathy. Ann Rehabil Med. 2013 Dec;37(6):766-76. doi: 10.5535/arm.2013.37.6.766. Epub 2013 Dec 23. — View Citation

Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29. Review. — View Citation

Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Jan;40(1):136-154. doi: 10.2337/dc16-2042. Review. — View Citation

Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285-93. doi: 10.2337/dc10-1303. Review. Erratum in: Diabetes Care. 2010 Dec;33(12):2725. — View Citation

Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005 Jan 27;352(4):341-50. — View Citation

Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008 Apr 29;70(18):1630-5. Epub 2007 Nov 14. — View Citation

Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K, Raemen H, Mathieu C, Colin IM. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 2009 Jun;35(3):206-13. doi: 10.1016/j.diabet.2008.11.004. Epub 2009 Mar 17. — View Citation

Wu YJ, Lin CC, Yeh CM, Chien ME, Tsao MC, Tseng P, Huang CW, Hsu KS. Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats. Brain Stimul. 2017 Nov - Dec;10(6):1079-1087. doi: 10.1016/j.brs.2017.08.007. Epub 2017 Aug 24. — View Citation

Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A; KORA Study Group. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med. 2009 Mar;10(2):393-400. doi: 10.1111/j.1526-4637.2008.00555.x. Epub 2009 Jan 16. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Pain severity	Changes in Pain severity will be measured by Brief Pain Inventory (BPI) to determine the effect of anodal Transcranial direct current stimulation (tDCS) in reducing pain of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention
Secondary	Changes in Depression severity	Changes in depression severity will be measured by Hamilton Depression scale (HAM-D) to determine the effect of anodal Transcranial direct current stimulation (tDCS) in reducing depression severity of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention
Secondary	Changes in Anxiety severity	Changes in Anxiety severity will be measured by Hamilton Anxiety scale (HAM-A) to determine the effect of anodal Transcranial direct current stimulation (tDCS) in reducing anxiety severity of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention
Secondary	Changes in sleep quality	Changes in Sleep quality will be measured by Pittsburgh sleep quality index (PSQI) to determine the effect of anodal Transcranial direct current stimulation (tDCS) in improving sleep quality of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention
Secondary	Changes in Quality of Life	Changes in quality of life will be measured by SF-36 to determine the effect of anodal Transcranial direct current stimulation (tDCS) in improving quality of life of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention
Secondary	Changes in Pain related to disability	The investigators will use the Pain Disability Index (PDI) to assess changes in pain related to disability.	Measured at baseline and immediately after the intervention
Secondary	Changes in Pain Catastrophizing	The investigators will use the Pain Catastrophizing Scale (PCS) to assess changes in pain Catastrophizing.	Measured at baseline and immediately after the intervention
Secondary	Changes in Neuropathic Pain Symptom	Changes in neuropathic pain symptoms will be measured by Neuropathic Pain Symptom Inventory (NPSI) to determine the effect of anodal Transcranial direct current stimulation (tDCS) in improving and/or reducing neuropathic pain symptom of subjects with pain associated with diabetic neuropathy.	Measured at baseline and immediately after the intervention