Mechanism-based Treatment Approach Research Articles

Emerging therapies for childhood-onset movement disorders.

We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

Tapentadol treatment results in long-term pain relief in patients with chronic low back pain and associates with reduced segmental sensitization.

Chronic low back pain (CLBP) is one of the most common chronic pain conditions in pain practice. In the current study, we describe phenotypes of patients with CLBP based on the status of their endogenous pain modulatory system. Conditioned pain modulation (a measure of central pain inhibition), temporal summation (TS, a measure of pain facilitation), and offset analgesia (a measure of temporal filtering of nociception) were evaluated in 53 patients with CLBP at painful and nonpainful sites. Next, in a double-blind, randomized, placebo-controlled trial, 40 patients with defective conditioned pain modulation responses received treatment with tapentadol prolonged-release or placebo for 3 months. The majority of patients (87%) demonstrated loss of central pain inhibition combined with segmentally increased TS and reduced offset analgesia at the lower back region. During treatment, tapentadol reduced pain intensity more than placebo (tapentadol -19.5 ± 2.1 mm versus placebo -7.1 ± 1.8 mm, P = 0.025). Furthermore, tapentadol significantly decreased pain facilitation by reduction of TS responses at the lower back (tapentadol -0.94 ± 1.9 versus placebo 0.01 ± 1.5, P = 0.020), which correlated with pain reduction (P < 0.001). Patients with CLBP demonstrated different phenotypes of endogenous pain modulation. In patients with reduced conditioned pain modulation, tapentadol produced long-term pain relief that coincided with reduction of signs of pain facilitation. These data indicate that the endogenous pain system may be used as a biomarker in the pharmacological treatment of CLBP, enabling an individualized, mechanism-based treatment approach.

Pain-autonomic interaction: A surrogate marker of central sensitization.

Central sensitization represents a key pathophysiological mechanism underlying the development of neuropathic pain, often manifested clinically as mechanical allodynia and hyperalgesia. Adopting a mechanism-based treatment approach relies highly on the ability to assess the presence of central sensitization. The aim of the study was to investigate potential pain-autonomic readouts to operationalize experimentally induced central sensitization in the area of secondary hyperalgesia. Pinprick evoked potentials (PEPs) and sympathetic skin responses (SSRs) were recorded in 20 healthy individuals. Three blocks of PEP and SSR recordings were performed before and after heat-induced secondary hyperalgesia. All measurements were also performed before and after a control condition. Multivariate analyses were performed using linear mixed-effect regression models to examine the effect of experimentally induced central sensitization on PEP and SSR parameters (i.e. amplitudes, latencies and habituation) and on pinprick pain ratings. The noxious heat stimulation induced robust mechanical hyperalgesia with a significant increase in PEP and SSR amplitudes (p<0.001) in the area of secondary hyperalgesia. Furthermore, PEP and SSR habituation were reduced (p<0.001) after experimentally induced central sensitization. The findings demonstrate that combined recordings of PEPs and SSRs are sensitive to objectify experimentally induced central sensitization and may have a great potential to reveal its presence in clinical pain conditions. Corroborating current pain phenotyping with pain-autonomic markers has the potential to unravel central sensitization along the nociceptive neuraxis and might provide a framework for mechanistically founded therapies. Our findings provide evidence that combined recordings of sympathetic skin responses (SSRs) and pinprick evoked potentials (PEPs) might be able to unmask central sensitization induced through a well-established experimental pain model in healthy individuals. As such, these novel readouts of central sensitization might attain new insights towards complementing clinical pain phenotyping.

Identifying Primary Immune Deficiencies in Patients with Autoimmune Cytopenias

Objective: The purpose of this study is to increase awareness and improve diagnosis of primary immune deficiency (PID) in the heterogenous group of patients with autoimmune cytopenia (AIC) by identifying clinical characteristics and laboratory biomarkers that distinguish PID patients from patients with AIC alone. This is especially relevant in genetically-defined PIDs which may be resistant to conventional therapy and mechanism-based treatment approach is required. Evans syndrome, defined by multi-lineage autoantibodies (two or more positive anti-platelet, anti-neutrophil, or direct Coombs test) is a known risk factor for PID; therefore we also investigate the incidence of PID in a broad cohort of AIC patients with single and multi-lineage cytopenias. Methods: Patients with autoimmune cytopenias (autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), or autoimmune neutropenia (AIN)) were referred to our Immune Dysregulation clinical team and prospectively enrolled in the study period of 2016-2019. Detailed immune phenotyping (IgG, IgA, IgM, lymphocyte subsets, vaccine titers, lymphocyte proliferation to mitogens/antigens), serum lipopolysaccharide (LPS) and autoantibodies were measured and/or collected by chart review and genetic testing for PID was pursued. Results: From 2016 to 2019, 78 patients were enrolled to our study. The patients were predominantly children (ages 1-82 years, average age 16.82 years). Of 78 patients with AIC, 48 (61%) were diagnosed with underlying PID based on immune phenotyping and/or genetic testing. Of 39 patients with genetic testing to date, 19 (49%) have been diagnosed with genetically-defined PID (pathogenic variants in CTLA-4, NFKB1, ALPS-related genes, WAS, POLE-1, PI3K, CYBB, or 22q11 [partial DiGeorge syndrome]); the remainder were classified as combined immune deficiency or common variable immune deficiency based on immune phenotyping; an additional two patients were classified as ALPS based on clinical history/flow cytometry/family history of ALPS. Lymphocyte subsets (CD4+ T, CD8+ T, CD19+ B, CD56+ NK) and immune globulins (IgG, IgA, IgM) tended to be lower in AIC-PID patients vs AIC-only (p&lt;0.05). Evans syndrome was more commonly found in AIC-PID patients (13/31, 42%) compared to AIC-only (4/42, 10%). LPS was significantly elevated in the serum of AIC patients compared to healthy controls (mean 719 vs 87 pg/mL, p&lt;0.001). Excluding partial DiGeorge syndrome patients (average LPS 222pg/mL), LPS levels were significantly higher in genetically-defined untreated PID patients (average 1463 pg/mL) vs. other PID (average 444 pg/mL) (p=0.02) or patients with AIC alone (average 667 pg/mL) (p=0.03). Studies are ongoing on specific subsets that are linked to immune dysregulation (T-regulatory cells, double negative T cells, T follicular helper cells). Conclusions: An unexpectedly high fraction of patients with AIC were identified with underlying PID in our Immune Dysregulation program. Routine basic immune evaluation with immunoglobulin levels and lymphocyte subsets expedited diagnosis of PID. Genetic evaluation distinguished a group of patients with AIC-PID and highly elevated LPS level, reflecting high bacterial load, and this may distinguish them from the rest of patients with AIC. The source of bacterial LPS can be multifactorial and is yet to be determined. Our studies continue focusing on biomarkers that can be applied to the heterogenous group of patients with AIC. This will allow early detection and timely initiation of targeted therapies. Disclosures No relevant conflicts of interest to declare.

Neuropathic Pain: Epidemiology, Classification, Mechanisms, and Therapy

Neuropathic pain develops because of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful polyneuropathy, post herpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterized by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Methods such as questionnaires for screening and assessment focus on the presence and quality of neuropathic pain. Basic research is enabling the identification of different pathophysiological mechanisms, and clinical assessment of symptoms and signs can help to determine which mechanisms are involved in specific neuropathic pain disorders. Management of neuropathic pain requires an interdisciplinary approach, centered on pharmacological treatment. A better understanding of neuropathic pain and, in particular, of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.

A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.

A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.

Overview of the Pharmacological Management of Neuropathic Pain

Neuropathic pain refers lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterized by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. neuropathic pain is treated as a ‘blanket condition’ in this guideline regardless of its aetiologies, unless there is valid and robust clinical and health economics evidence that shows the clinical efficacy and cost effectiveness of a particular treatment for a specific neuropathic pain condition. Management of neuropathic pain requires an interdisciplinary approach, centered around pharmacological treatment. A better understanding of neuropathic pain and in particular of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.

Cold Hyperalgesia Associated With Poorer Prognosis in Lateral Epicondylalgia

Predictors of outcome in lateral epicondylalgia, which is mainly characterized as a mechanical hyperalgesia, are largely limited to sociodemographic and symptomatic factors. Quantitative sensory testing is used to study altered pain processing in various chronic pain conditions and may be of prognostic relevance. The predictive capacity of early measures of physical and psychological impairment on pain and disability and mechanical hyperalgesia, were examined using data from 41 patients assigned to placebo in a prospective randomized controlled trial of unilateral lateral epicondylalgia. Quantitative sensory testing (pressure, cold pain thresholds), motor function (pain-free grip), and psychological factors (Tampa Scale of Kinesiophobia, Hospital Anxiety and Depression Scale) were measured at baseline. The outcome measures were the Patient-rated Tennis Elbow Evaluation (PRTEE) scale and pressure pain threshold (PPT) measured by digital algometry at the affected elbow. Backward stepwise linear regression was used to predict PRTEE and PPT scores at 2 and 12 months. Cold pain threshold was the only consistent predictor for both PRTEE (P<0.034) and PPT (P<0.048). Initial PRTEE was the strongest single predictor of PRTEE at 2 months, whereas female sex was the strongest single predictor of PPT (P<0.002). At 1 year, final models explained 9% to 52% of the variability in pain and disability and mechanical hyperalgesia, respectively. Early assessment of cold pain threshold could be a useful clinical tool to help identify patients at risk of poorer outcomes and might provide direction for future research into mechanism-based treatment approaches for these patients.

Pathophysiologie des neuropathischen Schmerzes - Optimale Behandlungsstrategien anhand der pathophysiologischen Mechanismen

Neuropathic pain syndromes are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked pain (hyperalgesia, allodynia). Neuropathic pain syndromes develop after lesion or disease of the peripheral or the central nervous system. Multiple pathophysiological mechanisms take place on different levels of the nociceptive pathways. Therapy often remains unsatisfactory with a need for optimized treatment-strategies. It is suggested that clinical symptoms and signs reflect the underlying pain mechanisms. Therefore, understanding pathopysiology is essential and may lead to a mechanism-based treatment approach. This means an optimized treatment-strategy for each patient, according to what mechanisms are at play in the individual case.

Chronic neuropathic pain: mechanisms, drug targets and measurement

Neuropathic pain is common in many diseases or injuries of the peripheral or central nervous system, and has a substantial impact on quality of life and mood. Lesions of the nervous system may lead to potentially irreversible changes and imbalance between excitatory and inhibitory systems. Preclinical research provides several promising targets for treatment such as sodium and calcium channels, glutamate receptors, monoamines and neurotrophic factors; however, treatment is often insufficient. A mechanism-based treatment approach is suggested to improve treatment. Valid and reliable tools to assess various symptoms and signs in neuropathic pain and knowledge of drug mechanisms are prerequisites for pursuing this approach. The present review summarizes mechanisms of neuropathic pain, targets of currently used drugs, and measures used in neuropathic pain trials.

Symptom Profiles Differ in Patients With Neuropathic Versus Non-neuropathic Pain

The distinction between neuropathic and non-neuropathic pain reflects partially distinct mechanisms and patterns of treatment response. It was therefore hypothesized that patients with neuropathic and non-neuropathic pain have different profiles of symptoms and signs. To test this hypothesis, pain intensity, unpleasantness, quality, and spatial characteristics were examined in 618 patients with 1 of 3 peripheral neuropathic pain conditions (painful diabetic peripheral neuropathy, painful idiopathic sensory polyneuropathy, or postherpetic neuralgia), osteoarthritis pain, or low back pain. These assessments were conducted before treatment had begun in clinical trials of lidocaine patch 5% administered alone or with stable dosages of other analgesics. Patients with osteoarthritis pain and low back pain did not differ in their profile of pain quality and spatial characteristics and were combined to form a group of patients with non-neuropathic pain. In univariate analyses, patients with peripheral neuropathic pain reported significantly more intense hot, cold, sensitive, itchy, and surface pain and significantly less intense dull and deep pain than patients with non-neuropathic pain. In a multivariate analysis, the overall pattern of pain quality and spatial characteristics differed significantly between patients with neuropathic and non-neuropathic pain. In addition, specific pain quality and spatial characteristics improved the discrimination of patients with neuropathic and non-neuropathic pain in a logistic regression model that adjusted for demographic covariates and overall pain intensity and unpleasantness. Perspective The results indicate that the distinction between neuropathic and non-neuropathic pain is reflected in different profiles of pain quality and spatial characteristics and suggest that the assessment of patterns of pain symptoms might contribute to the identification of distinct pathophysiologic mechanisms and the development of mechanism-based treatment approaches.