Roi Treister

Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.

ABSTRACT Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n = 192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 °C) and phasic heat pain (47 °C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine‐related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30‐bp repeat in the promoter region of the monoamine oxidase‐A gene (MAO‐A), 40‐bp repeat in the 3′‐untranslated region of the dopamine transporter gene (DAT‐1), and 48‐bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT‐1 (p = 0.008) and MAO‐A (p = 0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.

Differentiating between heat pain intensities: The combined effect of multiple autonomic parameters

Summary Autonomic parameters differentiate between the presence and absence of pain; yet, their linear combination discriminates between pain intensities better than each parameter alone. Abstract Although it is well known that pain induces changes in autonomic parameters, the extent to which these changes correlate with the experience of pain is under debate. The aim of the present study was to compare a combination of multiple autonomic parameters and each parameter alone in their ability to differentiate among 4 categories of pain intensity. Tonic heat stimuli (1 minute) were individually adjusted to induce no pain, low, medium, and high pain in 45 healthy volunteers. Electrocardiogram, photoplethysmogram, and galvanic skin response were recorded, and the following parameters were calculated: heart rate; heart rate variability—high frequency (0.15 to 0.4 Hz) spectral power; skin conductance level; number of skin conduction fluctuations; and photoplethysmographic pulse wave amplitude. A combination of parameters was created by fitting an ordinal cumulative logit model to the data and using linear coefficients of the model. Friedman test with post‐hoc Wilcoxon test were used to compare between pain intensity categories for every parameter alone and for their linear combination. All of the parameters successfully differentiated between no pain and all other pain categories. However, none of the parameters differentiated between all 3 pain categories (i.e., low and medium; medium and high; low and high). In contrast, the linear combination of parameters significantly differentiated not only between pain and no pain, but also between all pain categories (P < .001 to .02). These results suggest that multiparameter approaches should be further investigated to make progress toward reliable autonomic‐based pain assessment.

Factors affecting – And relationships between – Different modes of endogenous pain modulation in healthy volunteers

Endogenous analgesia (EA) can be reflected by diffuse noxious inhibitory control (DNIC), non‐noxious inhibitory control (NNIC) and habituation to repeated painful stimuli. However, the coexistence of these phenomena in a given individual and the degree to which various factors predict their magnitudes have not been fully investigated. Using experimental paradigms of DNIC, NNIC and habituation, the present study explored the relationships between – and the contribution factors to – the magnitude of EA exhibited by healthy volunteers (n = 191; 104 F, 87 M) exposed to these three experimental paradigms. Each subject was assigned to all three paradigms (DNIC‐tested by co‐administering repeated short painful heat stimuli and a conditioning tonic cold pain stimulation; NNIC – tested similarly with the exception of using a painless conditioning stimulation; habituation – tested by applying repeated painful heat stimuli only) in a random order. Pain intensities decreased from baseline in all three paradigms. However, DNIC produced significantly more pain reduction than the other two modes (RM‐ANOVA). The magnitude of pain reduction of DNIC was found to be highly correlated with that of NNIC and habituation (r = 0.56, p < 0.001 for both correlations). A hierarchical regression analysis showed that baseline (p < 0.001) and conditioning pain scores (p = 0.043) predicted the magnitude of DNIC. A gender split analysis showed that conditioning pain scores served as a predictive factor for men only. Conclusions: Under these experimental conditions, different EA conditions seem to be related to each other. High initial pain intensities predict ‘effective’ DNIC and habituation, whereas intensity of the conditioning stimulus determines the magnitude of DNIC in men only.

Transcranial magnetic stimulation of the brain: guidelines for pain treatment research

Abstract Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvards Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIHs PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

Association between polymorphisms in serotonin and dopamine-related genes and endogenous pain modulation.

UNLABELLED Genetic studies have become indispensable in understanding pain mechanisms, shedding light on the role of monoamine pathways in pain modulation. The present study was aimed to explore the relationship between functional polymorphisms in serotonin and dopamine-related genes and pain modulation. Two paradigms of pain modulation were administered to 191 healthy participants in a random order: Conditioned Pain Modulation in response to painful stimuli (CPM(painful)) tested by the coadministration of repeated short painful heat stimuli and a conditioning tonic cold pain stimulation; and Conditioned Pain Modulation in response to nonpainful stimuli (CPM(nonpainful)) tested similarly, except for using a painless conditioning stimulation. Using the Transmission Disequilibrium Test (TDT), functional variable number of tandem repeat (VNTR) polymorphisms of the following candidate genes were studied: 1) serotonin transporter (5-HTTLPR); 2) dopamine transporter (DAT1); 3) dopamine receptor 4 (DRD4); and 4) monoamine oxidase A (MAOA). DNA samples from both participants and their parents were analyzed. A significant association was found between CPM(nonpainful) and the 5-HTTLPR polymorphism (P = .001). More specifically, carriers of the long allele exhibited a significantly higher magnitude of CPM(nonpainful) than carriers of the short allele. No associations were found between the dopamine-related genes and both types of pain modulation. These results highlight the importance of serotonin in endogenous analgesia. PERSPECTIVE This article presents an association between the serotonin transporter gene polymorphism (5-HTTLPR) and pain modulation derived by nonpainful conditioned pain modulation (CPM(nonpainful)), rather than painful conditioned pain modulation (CPM(painful)). These findings emphasize the complex role of serotonin in pain modulation, and highlight the importance of genetic studies in the understanding of interindividual differences in sensitivity to pain.

Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is characterized by dysregulation of sensory processing and neurobiology of dopamine. Although cumulative evidence suggests that dopamine is involved in pain processing, pain perception in ADHD subjects and the effect of dopamine agonists such as methylphenidate (MP, Ritalin) on it have rarely been studied.

Validation of the composite autonomic symptom scale 31 (COMPASS-31) in patients with and without small fiber polyneuropathy

The recently developed composite autonomic symptom score 31 (COMPASS‐31) is a questionnaire that assess symptoms of dysautonomia. It was distilled from the well‐established Autonomic Symptom Profile questionnaire. COMPASS‐31 has not yet been externally validated. To do so, its psychometric properties and convergent validity in patients with and without objective diagnosis of small fiber polyneuropathy (SFPN) were assessed.

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?

The term “neuropathic pain” (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain’s surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuronal plasticity to produce long-lasting therapeutic benefit. Repeated TMS already has US and European regulatory approval for treating refractory depression, and multiple small studies report efficacy for neuropathic pain. Recent improvements include “frameless stereotactic” neuronavigation systems, in which patients’ head MRIs allow TMS to be applied to precise underlying cortical targets, minimizing variability between sessions and patients, which may enhance efficacy. Transcranial magnetic stimulation appears poised for the larger trials necessary for regulatory approval of a NP indication. Since few clinicians are familiar with TMS, we review its theoretical basis and historical development, summarize the neuropathic pain trial results, and identify issues to resolve before large-scale clinical trials.

Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia.

&NA; Under specific experimental conditions, oxycodone seems to exert spinal (temporal summation) rather than supraspinal (conditioned pain modulation) analgesic effects in humans. &NA; Opioid analgesia is mediated primarily by modulating (inhibiting and enhancing) pain mechanisms at the spinal and supraspinal levels. Advanced psychophysical paradigms of temporal summation (TS) and conditioned pain modulation (CPM) likely represent pain mechanisms at both levels. Therefore, the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans. The current randomized, double‐blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects. TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli. CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone. These paradigms were tested before and at 60, 120, and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo. Repeated‐measures analysis of variance revealed significant effects of oxycodone, but not placebo, on the magnitude of TS (F = 7.196, P < .001). Pairwise comparisons revealed that relative to baseline, TS was significantly reduced at 60 minutes (P = .008) and at 180 minutes (P = .017) after oxycodone administration. In contrast, no significant effects of either oxycodone (F = 0.871, P = .458) or placebo (F = 2.086, P = .106) on the magnitude of CPM were found. These results suggest that under the current experimental conditions, oxycodone exerted spinal, rather than supraspinal, analgesic effects. Furthermore, compared with CPM, TS seems more suitable for studying the mechanisms of opioid analgesia in humans.

Pain Intensity Recognition Rates via Biopotential Feature Patterns with Support Vector Machines

Background The clinically used methods of pain diagnosis do not allow for objective and robust measurement, and physicians must rely on the patient’s report on the pain sensation. Verbal scales, visual analog scales (VAS) or numeric rating scales (NRS) count among the most common tools, which are restricted to patients with normal mental abilities. There also exist instruments for pain assessment in people with verbal and / or cognitive impairments and instruments for pain assessment in people who are sedated and automated ventilated. However, all these diagnostic methods either have limited reliability and validity or are very time-consuming. In contrast, biopotentials can be automatically analyzed with machine learning algorithms to provide a surrogate measure of pain intensity. Methods In this context, we created a database of biopotentials to advance an automated pain recognition system, determine its theoretical testing quality, and optimize its performance. Eighty-five participants were subjected to painful heat stimuli (baseline, pain threshold, two intermediate thresholds, and pain tolerance threshold) under controlled conditions and the signals of electromyography, skin conductance level, and electrocardiography were collected. A total of 159 features were extracted from the mathematical groupings of amplitude, frequency, stationarity, entropy, linearity, variability, and similarity. Results We achieved classification rates of 90.94% for baseline vs. pain tolerance threshold and 79.29% for baseline vs. pain threshold. The most selected pain features stemmed from the amplitude and similarity group and were derived from facial electromyography. Conclusion The machine learning measurement of pain in patients could provide valuable information for a clinical team and thus support the treatment assessment.