Helena Knotkova

Capsaicin (trpv1 Agonist) Therapy for Pain Relief: Farewell or Revival?

ObjectiveIn this review, we explain our current understanding of the molecular basis for pain relief by capsaicin and other transient receptor potential vanilloid subfamily, member 1 (TRPV1) agonists. We summarize disease-related changes in TRPV1 expression and its implications for therapy and potential adverse effects. Last, we provide an overview of the current clinical uses of topical and injectable TRPV1 agonist preparations in both oncologic and nononcologic populations. MethodSearch of MEDLINE and other databases. ResultsThe capsaicin receptor TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of activation that could be lowered under inflammatory conditions. Consistent with this model, TRPV1 knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV1 desensitization of primary sensory neurons is a powerful approach to relieve symptoms of nociceptive behavior in animal models of chronic pain. However, over-the-counter capsaicin creams have shown moderate to poor analgesic efficacy. This is in part related to low dose, poor skin absorption, and compliance factors. Recently developed site-specific capsaicin therapy with high-dose patches and injectable preparations seem to be safe and reportedly provide long-lasting analgesia with rapid onset. ConclusionsWe argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complimentary pharmacologic approaches for pain relief and we predict a “revival” for capsaicin and other TRPV1 agonists in the clinical management of pain associated with inflammation, metabolic imbalances (eg, diabetes), infections (HIV), and cancer, despite the current focus of the pharmaceutical industry on TRPV1 antagonists.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016.

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

Current and future options for the management of phantom-limb pain

Phantom-limb pain (PLP) belongs among difficult-to-treat chronic pain syndromes. Treatment options for PLP are to a large degree implicated by the level of understanding the mechanisms and nature of PLP. Research and clinical findings acknowledge the neuropathic nature of PLP and also suggest that both peripheral as well as central mechanisms, including neuroplastic changes in central nervous system, can contribute to PLP. Neuroimaging studies in PLP have indicated a relation between PLP and the neuroplastic changes. Further, it has been shown that the pathological neuroplastic changes could be reverted, and there is a parallel between an improvement (reversal) of the neuroplastic changes in PLP and pain relief. These findings facilitated explorations of novel neuromodulatory treatment strategies, adding to the variety of treatment approaches in PLP. Overall, available treatment options in PLP include pharmacological treatment, supportive non-pharmacological non-invasive strategies (eg, neuromodulation using transcranial magnetic stimulation, visual feedback therapy, or motor imagery; peripheral transcutaneous electrical nerve stimulation, physical therapy, reflexology, or various psychotherapeutic approaches), and invasive treatment strategies (eg, surgical destructive procedures, nerve blocks, or invasive neuromodulation using deep brain stimulation, motor cortex stimulation, or spinal cord stimulation). Venues of further development in PLP management include a technological and methodological improvement of existing treatment methods, an implementation of new techniques and products, and a development of new treatment approaches.

Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols

The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user’s capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population’s level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations.

Non-invasive Transcranial Direct Current Stimulation for the Study and Treatment of Neuropathic Pain

In the last decade, radiological neuroimaging techniques have enhanced the study of mechanisms involved in the development and maintenance of neuropathic pain. Recent findings suggest that neuropathic pain in certain pain syndromes (e.g., complex regional pain syndrome/reflex sympathic dystrophy, phantom-limb pain) is associated with a functional reorganization and hyperexitability of the somatosensory and motor cortex. Studies showing that the reversal of cortical reorganization in patients with spontaneous or provoked pain is accompanied by pain relief stimulated the search for novel alternatives how to modulate the cortical excitability as a strategy to relieve pain. Recently, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) were proposed as suitable methods for modulation of cortical excitability. Both techniques (TMS and tDCS) have been clinically investigated in healthy volunteers as well as in patients with various clinical pathologies and variety of pain syndromes. Although there is less evidence on tDCS as compared with TMS, the findings on tDCS in patients with pain are promising, showing an analgesic effect of tDCS, and observations up to date justify the use of tDCS for the treatment of pain in selected patient populations. tDCS has been shown to be very safe if utilized within the current protocols. In addition, tDCS has been proven to be easy to apply, portable and not expensive, which further enhances great clinical potential of this technique.

Using Transcranial Direct Current Stimulation to Treat Depression in HIV-Infected Persons: The Outcomes of a Feasibility Study

Transcranial direct current stimulation (tDCS) is a novel non-invasive neuromodulatory method that influences neuronal firing rates and excitability of neuronal circuits in the brain. tDCS has been shown to relieve Major Depressive Disorder (MDD) in the general population, suggesting its potential for other vulnerable populations with high MDD prevalence. Aims: This study evaluated the feasibility, safety, acceptability, and clinical outcomes of a 2-week tDCS antidepressant treatment in HIV-MDD co-diagnosed patients, and the feasibility of collecting serum and saliva for analysis of immunity biomarkers. Methods: Ten enrolled patients underwent baseline evaluation and started the tDCS treatment (Monday–Friday for 2 weeks) delivered with Phoresor II 850 PM for 20 min at 2 mA at each visit, using two saline-soaked sponge electrodes placed over the F3 position of EEG 10–20 system and the contralateral supraorbital region. Outcome measures were collected at baseline, after the last tDCS and 2 weeks later. A quantitative microarray (Ray Bio Tech Inc.) for TH1/TH2 cytokines was used for saliva and plasma analysis. Results: Analyzable outcome-data were obtained from eight subjects. Depression scores significantly decreased (p < 0.0005) after the treatment. No serious adverse events occurred. Several transient minor AEs and occasional changes of blood pressure and heart rate were noted. Mini-mental state examination scores remained unchanged or increased after the treatment. All subjects were highly satisfied with the protocol and treatment results and described the desire to find new treatments for HIV-MDD as motivating participation. Conclusion: Findings support feasibility and clinical potential of tDCS for HIV-MDD patients, and justify larger-sample, sham-controlled trials.

A qualitative study to explore psychological distress and illness burden associated with opioid-induced constipation in cancer patients with advanced disease

Background: Constipation affects many patients receiving long-term opioid therapy for cancer pain. Little is known about the nature of psychological distress and the burden associated with this problem. This information may inform the development of effective treatment strategies and ameliorate distress. Aim: The objective was to use qualitative research methods to better understand psychological distress and the burden associated with opioid-induced constipation and its treatment in advanced cancer patients. Design: In this qualitative study, semi-structured interviews explored perceptions of psychological distress and burden from opioid-induced constipation. Interviews were analyzed using a thematic content analysis approach involving descriptive and interpretive coding and identification of recurring themes. Setting/participants: Twelve advanced cancer patients with opioid-induced constipation were recruited from a large urban hospital. Results: Patients experienced various types of negative affect and cognitions associated with opioid-induced constipation. Analyses indicated three major themes: (1) irrational thoughts and educational needs; (2) psychological distress from constipation and (3) the effects of constipation on the decision to use opioid analgesics. Irrational thoughts and educational needs included beliefs that nutrition could improve constipation, the supposition that constipation indicated deteriorating health, and catastrophic beliefs. Psychological distress included depressive symptoms and anticipatory anxiety related to constipation. Decision-making revealed cognitive dissonance about using opioids and conflicting preferences about continuing use. Conclusions: Future investigation of the multiple components of cognitive and affective burden from opioid-induced constipation is warranted. Understanding the varied nature of this burden may improve clinical recognition and assessment and promote more intensive management consistent with the distress it produces.

Putative physiological mechanisms underlying tDCS analgesic effects

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that induces changes in excitability, and activation of brain neurons and neuronal circuits. It has been observed that beyond regional effects under the electrodes, tDCS also alters activity of remote interconnected cortical and subcortical areas. This makes the tDCS stimulation technique potentially promising for modulation of pain syndromes. Indeed, utilizing specific montages, tDCS resulted in analgesic effects in experimental settings, as well as in post-operative acute pain and chronic pain syndromes. The promising evidence of tDCS-induced analgesic effects raises the challenging and complex question of potential physiologic mechanisms that underlie/mediate the accomplished pain relief. Here we present hypotheses on how the specific montages and targets for stimulation may affect the pain processing network.

Transcranial direct current stimulation (tDCS) relieved itching in a patient with chronic neuropathic pain.

Abstract:Itching is often called the second modality of nociception besides pain, and affects many chronic pain patients. Objectives:This case report presents a first note on beneficial effects of transcranial direct current stimulation (tDCS) on itching associated with chronic neuropathic pain in a patient diagnosed with syringomyelia. Methods:tDCS is a novel noninvasive neuromodulatory method with promising therapeutic potential in pain and symptom management. The primary mechanism of tDCS is subthreshold modulation of the neuronal resting membrane potential that induces a polarity-dependent modification of N-Methyl-D-aspartate receptor function that plays a role in neuroplasticity. The patient, a 46-year-old white male diagnosed with syringomyelia 2 decades ago, continuously reported weakness in the arms and dyesthesias including pain and itch that fluctuated in severity. Pharmacological treatment with baclofen, duloxetine, and bupropion was partially helpful; however, did not prevent flares of pain and other dysesthesias, including itch. The patient underwent 3 tDCS treatment courses consisting of 20 minutes of tDCS on 5 consecutive days at each course over 13 months. Results:Although there was no change in pain intensity or quality during or after tDCS, the treatment resulted in a reduction in itch to a mild, tolerable intensity that persisted for 3 to 4 months after each course, before returning to the pretreatment level. The patient has agreed to a plan of care that will incorporate neurostimulation every 4 to 6 months, as long as its effectiveness continues. Discussion:This case provides a rationale for future studies of neuromodulatory treatments for itch, and indicates a potential clinical use of neuromodulation in patients with unrelieved itching.