Pain Inhibition Research Articles

Suppression of neuropathic pain and comorbidities by recurrent cycles of repetitive transcranial direct current motor cortex stimulation in mice

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.

FMRI findings in MTBI patients with headaches following rTMS

Mild Traumatic Brain Injury (MTBI) patients with persistent headaches are known to have diminished supraspinal modulatory connectivity from their prefrontal cortices. Repetitive transcranial magnetic stimulation (rTMS) is able to alleviate MTBI-related headache (MTBI-HA). This functional magnetic resonance imaging (fMRI) study assessed supraspinal correlates associated with the headache analgesic effect of rTMS at left prefrontal cortex (LPFC), hypothesizing real rTMS would significantly increase modulatory functions at LPFC in comparison to sham treatment. Subjects with MTBI-HA were randomized to receive either real or sham rTMS treatments and subjected to pre- and post-treatment resting state and evoked heat-pain fMRI as described in a prior study. Real rTMS consisted of 2000 pulses delivered at 10 Hz and 80% of the resting motor threshold at left dorsolateral prefrontal cortex, whereas sham treatment was delivered with same figure-of-eight coil turned 180 degrees. Follow-up fMRI was performed one-week post-treatment. All fMRI data was processed using BrainVoyager QX Software. 14 subjects receiving real and 12 subjects receiving sham treatments completed the study. The REAL group demonstrated significant (P < 0.02) decreases in headache frequency and intensity at one week following treatment. fMRI scans in the REAL group showed increased evoked heat pain activity (P < 0.002) and resting functional connectivity (P < 0.0001) at the LPFC after rTMS. Neither this significant analgesic effect nor these fMRI findings were seen in the sham group. Sham treatment was, however, associated with a decrease in resting state activity at the LPFC (P < 0.0001). This study correlates the demonstrated analgesic effect of rTMS in the treatment of MTBI-HA with enhanced supraspinal functional connectivity in the left prefrontal cortex, which is known to be involved in “top-down” pain inhibition along the descending midbrain-thalamic-cingulate pathway.Trial Registration: This study was registered on September 24, 2013, on ClinicalTrials.gov with the identifier: NCT01948947. https://clinicaltrials.gov/ct2/show/NCT01948947.

BKCa Channel Inhibition by Peripheral Nerve Injury Is Restored by the Xanthine Derivative KMUP-1 in Dorsal Root Ganglia.

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BKCa current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BKCa currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BKCa. Real-time PCR was used to measure BKCa mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BKCa currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BKCa channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BKCa-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BKCa mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BKCa current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain.

Neurophysiological mechanisms of chiropractic spinal manipulation for spine pain

AbstractTogether, neck pain and back pain are the first cause of disability worldwide, accounting for more than 10% of the total years lived with disability. In this context, chiropractic care provides a safe and effective option for the management of a large proportion of these patients. Chiropractic is a healthcare profession mainly focused on the spine and the treatment of spinal disorders, including spine pain. Basic studies have examined the influence of chiropractic spinal manipulation (SM) on a variety of peripheral, spinal and supraspinal mechanisms involved in spine pain. While spinal cord mechanisms of pain inhibition contribute at least partly to the pain‐relieving effects of chiropractic treatments, the evidence is weaker regarding peripheral and supraspinal mechanisms, which are important components of acute and chronic pain. This narrative review highlights the most relevant mechanisms of pain relief by SM and provides a perspective for future research on SM and spine pain, including the validation of placebo interventions that control for placebo effects and other non‐specific effects that may be induced by SM.SignificanceSpinal manipulation inhibits back and neck pain partly through spinal segmental mechanisms and potentially through peripheral mechanisms regulating inflammatory responses. Other mechanisms remain to be clarified. Controls and placebo interventions need to be improved in order to clarify the contribution of specific and non‐specific effects to pain relief by spinal manipulative therapy.

From acute to long-term alterations in pain processing and modulation after spinal cord injury: mechanisms related to chronification of central neuropathic pain.

A severe and debilitating consequence of a spinal cord injury (SCI) is central neuropathic pain (CNP). Our aim was to investigate the processes leading to CNP emergence and chronification by analyzing causal relationship over time between spinothalamic function, pain excitability, and pain inhibition after SCI. This longitudinal follow-up study included 53 patients with acute SCI and 20 healthy controls. Spinothalamic, pain excitability, and intrasegmental and extrasegmental pain inhibition indices were repeatedly evaluated at 1.5, 3, and 6 months post-SCI. Between- and within-group analyses were conducted among those patients who eventually developed CNP and those who did not. Healthy controls were evaluated twice for repeatability analysis. Patients who developed CNP, compared with those who did not, exhibited increased thermal thresholds (P < 0.05), reduced pain adaptation (P < 0.01), and conditioned pain modulation (P < 0.05), early post-injury, and the CNP group's manifestations remained worse throughout the follow-up. By contrast, allodynia frequency was initially similar across SCI groups, but gradually increased in the subacute phase onward only among the CNP group (P < 0.001), along with CNP emergence. Early worse spinothalamic and pain inhibition preceded CNP and predicted its occurrence, and early worse pain inhibition mediated the link between spinothalamic function and CNP. Crossover associations were observed between early and late pain inhibition and excitability. Inefficient intrasegmental and extrasegmental inhibition, possibly resulting from spinothalamic deafferentation, seems to ignite CNP chronification. Pain excitability probably contributes to CNP maintenance, possibly via further exhaustion of the inhibitory control. Preemptive treatment promoting antinociception early post-SCI may mitigate or prevent CNP.

The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and γ-aminobutyric acid in fibromyalgia and healthy subjects: a multimodal neuroimaging study.

A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene (rs6971) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). The influence of TSPO on endogenous pain modulation presented in the form of TSPO HABs, as opposed to MLABs, displaying less efficient descending pain inhibition and expectancy-induced reduction of pain. Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non-FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.

D2 Receptors in the Periaqueductal Gray/Dorsal Raphe Modulate Peripheral Inflammatory Hyperalgesia via the Rostral Ventral Medulla

Dopamine neurons in the periaqueductal gray (PAG)/dorsal raphe are key modulators of antinociception with known supraspinal targets. However, no study has directly tested whether these neurons contribute to descending pain inhibition. We hypothesized that PAG dopamine neurons contribute to the analgesic effect of D-amphetamine via a mechanism that involves descending modulation via the rostral ventral medulla (RVM). Male C57BL/6 mice showed increased c-FOS expression in PAG dopamine neurons and a significant increase in paw withdrawal latency to thermal stimulation after receiving a systemic injection of D-amphetamine. Targeted microinfusion of D-amphetamine, L-DOPA, or the selective D2 agonist quinpirole into the PAG produced analgesia, while a D1 agonist, chloro APB, had no effect. In addition, inhibition of D2 receptors in the PAG by eticlopride prevented the systemic D-amphetamine analgesic effect. D-amphetamine and PAG D2 receptor-mediated analgesia were inhibited by intra-RVM injection of lidocaine or the GABAA receptor agonist muscimol, indicating a PAG-RVM signaling pathway in this model of analgesia. Finally, both systemic D-amphetamine and local PAG microinjection of quinpirole, inhibited inflammatory hyperalgesia induced by carrageenan. This hyperalgesia was transiently restored by intra-PAG injection of eticlopride, as well as RVM microinjection of muscimol. We conclude that D-amphetamine analgesia is partially mediated by descending inhibition and that D2 receptors in the PAG are responsible for this effect via modulating neurons that project to the RVM. These results further our understanding of the antinociceptive effects of dopamine and elucidate a mechanism by which clinically available dopamine modulators produce analgesia.

Efficacy of Anodal Suboccipital Direct Current Stimulation for Endogenous Pain Modulation and Tonic Thermal Pain Control in Healthy Participants: A Randomized Controlled Clinical Trial.

The aim of this study was to assess whether anodal DCS applied to the suboccipital (SO) target area could potentiate antinociception assessed primarily with conditioned pain modulation of tonic thermal test stimuli. Randomized double-blinded control trial. Rehabilitation hospital. Healthy participants. Forty healthy participants were randomized to receive either SO-DCS or M1-DCS. The 20-minute 1.5 mA anodal or sham DCS intervention were applied to each participant in randomized order during two test sessions. The primary outcome measure included heterotopic cold-pressor conditioned pain modulation (CPM) of tonic heat pain. Secondary measures included pressure pain threshold and tonic thermal pain intensity. Heterotopic CPM of tonic heat pain intensity was unaffected by either SO-DCS or active M1, including the secondary measures of pressure pain threshold and tonic thermal pain intensity. Although low-power non-significant interactions were identified for DCS intervention (active versus sham) and time (before and after), a significant within-group inhibition of tonic cold pain was identified following SO-DCS (P = .011, mean [SD]: -0.76 ± 0.88 points) and M1-DCS (P < .002: -0.84 ± 0.82 points), without a significant change following sham DCS. Although heterotopic CPM was not facilitated with either SO-DCS or M1-DCS, a general significant inhibition of tonic cold pain intensity was demonstrated following both interventions. The general effects of active DCS compared to sham on tonic cold pain-irrespective of the M1 or SO target-need to be confirmed using standard quantitative sensory testing.

The Relationship Between Adverse Life Events and Endogenous Inhibition of Pain and Spinal Nociception: Findings From the Oklahoma Study of Native American Pain Risk (OK-SNAP)

Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. PerspectiveThis study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.

Central synthesis of temporomandibular dysfunction

Introduction Temporomandibular dysfunction (TMD) is a group of conditions that affect bone structures and soft tissues of the orofacial region and are characterised mainly by pain [1]. Patients with TMD often have chronic pain, which in turn results from the mechanisms of sensitisation which is thus responsible for the hypersensitivity of pain [2]. Central sensitisation can be examined experimentally using a conditioned pain modulation paradigm; it can function as a form of inhibition of pain in humans [3]. This study aim to evaluate the conditioned modulation of pain in patients with temporomandibular dysfunction and chronic pain, and also to relate the influence that it has on anxiety and quality of life. Materials and methods An analytic observational study was carried out, involving a group of 19 individuals with chronic pain (34.1 ± 14.9 yrs), and sample selection was performed using Research Diagnostic Criteria for Temporomandibular Disorder. (RDC/TMD). The subjects were submitted to the application of a mechanical (algometer) and thermal stimulus (ice) alone and to two mechanical and thermal stimuli simultaneously and independently. The interval application between stimulus, isolated and simultaneously was 5 min. All participants signed informed consent. The study was approved by the Ethics Committee of the Egas Moniz. Results It was verified that the intensity of the pain perceived by the patients in the orofacial region during the simultaneous application of the two mechanical stimuli was in 100% of the cases lower than that perceived during the application of one stimulus. Regarding the thermal stimuli, it was verified that the intensity of the pain perceived in the orofacial region during the simultaneous application of the two thermal stimuli was 47% of the times inferior to that perceived during the application of one stimulus. Discussion and conclusions The decrease in pain prediction in the orofacial region when two simultaneous stimuli were applied is in agreement with the principles of conditioned pain modulation, which seems to indicate that individuals with TMD have central sensitisation [3]. Given the small size of the sample and the small number of studies carried out on the present theme, it is suggested to carry out new studies with larger samples in the future.

No added value of duloxetine for patients with chronic pain due to hip or knee osteoarthritis

Purpose: The currently prescribed analgesics for OA related pain do not always sufficiently reduce pain and can be associated with side-effects or can be contra-indicated. Other treatment options are therefore needed. An option may be duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI). Duloxetine is hypothesized to reduce chronic pain by central inhibition of pain. Several placebo-controlled studies showed small to moderate effect of duloxetine. However, the effectiveness in a primary care setting is unknown.

Is Therapeutic Exercise Clinically Effective in Reducing Pain Intensity in Patients With Knee Osteoarthritis? A Systematic Review

Objective: This systematic review aimed to evaluate and summarize the effects of therapeutic exercise clinically in reducing pain intensity in patients with knee osteoarthritis. Methods: A search of PubMed, Web of Science, Scopus, EBSCO, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of inception to December 15, 2019, was conducted. Primary outcome of interest was pain measurement using the visual analog scale. The methodological quality of the studies was assessed using the Physiotherapy Evidence Database (PEDro) scale. Results: Sixteen studies were included in this systematic review. These studies reported that therapeutic exercise is clinically effective in reducing pain intensity in patients with knee osteoarthritis. In addition, compared with a short-term and low-intensity therapeutic exercise, there was strong evidence that therapeutic exercise, in combination with pain inhibition interventions, may play a significant role in reducing pain intensity. Conclusion: The systematic review provides evidence for the use of therapeutic exercises, which is high-intensity, long-term, and combined with other interventions, for reducing pain intensity clinically.

Study of the analgesic effect of the aqueous extract of the leaves of Citrus aurantifolia (Rutaceae) in mice

Citrus aurantifolia (Rutaceae) is a plant used in traditional medicine in the treatment of inflammatory and analgesic pathologies. The objective of this study was to evaluate the analgesic activity of the aqueous extract of the leaves of Citrus aurantifolia in mice. The phytochemical study revealed flavonoids, tannins, polyphenols, coumarins, saponosides and polyterpene sterols and the absence of alkaloids. Concerning the acute toxicity study at the single dose of 2000 mg/ Kg pc orally, it revealed that the aqueous extract of the leaves of Citrus aurantifolia is not toxic. Thus, according to OECD guideline 423, the oral LD50 of this extract is in the range of 2000-5000 mg/kg bw. The analgesic activity of the aqueous extract of Citrus aurantifolia orally was determined by evaluating the rate of inhibition of pain caused by acetic acid. The 250 mg/kg bw and 500 mg/kg bw doses of the aqueous extract administered orally all showed analgesic activity. The best analgesic activity was obtained with an inhibition rate of 88.64% for the 250 mg/kg bw dose. The best analgesic activity was obtained with an inhibition rate of 88.64% for the 250 mg/kg bw dose, while with the 500 mg/kg bw dose, the inhibition rate of pain sensation was 47.57%. Therefore, the extract has an analgesic effect at low doses.

Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways

New therapeutic approaches to resolve persistent pain are highly needed. We tested the hypothesis that manipulation of cytokine receptors on sensory neurons by clustering regulatory cytokine receptor pairs with a fusion protein of interleukin (IL)-4 and IL-10 (IL4-10 FP) would redirect signaling pathways to optimally boost pain-resolution pathways. We demonstrate that a population of mouse sensory neurons express both receptors for the regulatory cytokines IL-4 and IL-10. This population increases during persistent inflammatory pain. Triggering these receptors with IL4-10 FP has unheralded biological effects, because it resolves inflammatory pain in both male and female mice. Knockdown of both IL4 and IL10 receptors in sensory neurons in vivo ablated the IL4-10 FP-mediated inhibition of inflammatory pain. Knockdown of either one of the receptors prevented the analgesic gain-of-function of IL4-10 FP. In vitro, IL4-10 FP inhibited inflammatory mediator-induced neuronal sensitization more effectively than the combination of cytokines, confirming its superior activity. The IL4-10 FP, contrary to the combination of IL-4 and IL-10, promoted clustering of IL-4 and IL-10 receptors in sensory neurons, leading to unique signaling, that is exemplified by activation of shifts in the cellular kinome and transcriptome. Interrogation of the potentially involved signal pathways led us to identify JAK1 as a key downstream signaling element that mediates the superior analgesic effects of IL4-10 FP. Thus, IL4-10 FP constitutes an immune-biologic that clusters regulatory cytokine receptors in sensory neurons to transduce unique signaling pathways required for full resolution of persistent inflammatory pain.

A psychophysical study comparing massage to conditioned pain modulation: A single blind randomized controlled trial in healthy participants

IntroductionPain-inducing massage results in greater pain inhibition than pain free massage, suggesting a mechanism dependent on conditioned pain modulation (CPM). The purpose of this study was to test the hypothesis that pain inducing massage produces similar magnitude of reduction in pain sensitivity as a cold pressor task and that baseline conditioned pain modulation efficiency predicts pain inducing massage related hypoalgesia. MethodsSixty healthy participants were randomly assigned to receive either pain inducing massage to the neck, cold pressor task to the hand, or pain free massage to the neck. Participants also underwent pre and immediate post-intervention quantitative sensory testing. A repeated measures ANCOVA determined between group differences in pain sensitivity changes. ResultsPain inducing massage used as a conditioning stimulus resulted in comparable experimental pain sensitivity changes as a cold pressor task (p > 0.05). Pain intensity during the intervention demonstrated a weak correlation (r = 0.20, p = 0.12) with changes in pain sensitivity at a remote site. Individuals with an efficient CPM at baseline who received the pain inducing massage displayed greater increases in pressure pain threshold compared to individuals with a less efficient CPM indicating the potential benefit of treatment stratification by mechanism. ConclusionAlthough pain inducing massage resulted in less self-reported pain than a cold pressor task, both resulted in similar magnitude of the CPM response, suggesting shared underlying mechanisms. Understanding mechanisms of interventions can move us closer to mechanistic based treatments for pain which is consistent with a personalized medicine approach to care.

Macrophage regulator of G-protein signaling 12 contributes to inflammatory pain hypersensitivity.

BackgroundPain is a predominant symptom in rheumatoid arthritis (RA) patients that results from joint inflammation and is augmented by central sensitization. Regulator of G-protein signaling 12 (RGS12) is the largest protein in the RGS protein family and plays a key role in the development of inflammation. This study investigated the regulation of RGS12 in inflammatory pain and explored the underlying mechanisms and potential RA pain targets.MethodsMacrophage-specific RGS12-deficient (LysM-Cre+;RGS12fl/fl) mice were generated by mating RGS12fl/fl mice with LysM-Cre+ transgenic mice. Collagen antibody-induced arthritis (CAIA) models were induced in LysM-Cre+;RGS12fl/fl mice by the administration of a cocktail of five monoclonal antibodies and LPS. Mouse nociception was examined using the von Frey and heat plate tests. Primary macrophages and RAW264.7 cells were used to analyze the regulatory function and mechanism of RGS12 in vitro. The expression and function of RGS12 and COX2 (cyclooxygenase 2) were determined by real-time PCR, ELISA, and luciferase assays.ResultsAblation of RGS12 in macrophages decreased pain-related phenotypes, such as paw swelling, the clinical score, and the inflammatory score, in the CAIA model. LysM-Cre+;RGS12fl/fl mice displayed increased resistance to thermal and mechanical stimulation from day 3 to day 9 during CAIA, indicating the inhibition of inflammatory pain. Overexpression of COX2 and PGE2 in macrophages enhanced RGS12 expression, and PGE2 regulated RGS12 expression through the G-protein-coupled receptors EP2 and EP4. Furthermore, RGS12 or the RGS12 PTB domain strengthened the transcriptional regulation of COX2 by NF-κB, whereas inhibiting NF-κB suppressed RGS12-mediated regulation of COX2 in macrophages.ConclusionsOur results demonstrate that the deletion of RGS12 in macrophages attenuates inflammatory pain, which is likely due to impaired regulation of the COX2/PGE2 signaling pathway.

Conditioned Pain Modulation (CPM) Effects Captured in Facial Expressions.

PurposeConditioned pain modulation (CPM) is most often assessed using self-report of pain. However, self-report of pain is not always available (eg in individuals with cognitive impairment) and is susceptible to report bias. In comparison, the facial expression of pain is more reflex-like and represents one of the most sensitive and specific non-verbal signals of pain. The aim of the present study was to investigate whether the facial expression of pain is sensitive enough to capture endogenous pain inhibition as elicited during CPM paradigms.Patients and MethodsIn total, 26 female participants took part in this study. Facial and verbal responses to phasic heat pain were assessed once while participants immersed their hand in a hot water bath and once without additional stimulation. Facial responses were analyzed using the Facial Action Coding System (FACS). Verbal responses were assessed using a Numerical Rating Scale (NRS).ResultsPain-relevant facial responses as well as pain ratings to phasic heat pain were significantly reduced when participants simultaneously immersed their hand in a hot water bath compared to baseline. Thus, CPM effects could be demonstrated both on subjective as well as on facial responses. Moreover, CPM-induced changes in pain-relevant facial responses and in NRS ratings were significantly correlated.ConclusionThe present study shows that facial expressions of pain are sensitive enough to capture CPM effects. Given the proven clinical usefulness of assessing CPM, the parallel assessment of verbal and facial CPM effects might be a promising approach with wider scope of applications. Further research in other demographic healthy participant and clinical cohorts is warranted.

Screening of novel 2-4methylphenylimino-3-carboxamide substituted thiophene compound for peripheral analgesic activity

Background: Pain is an unpleasant sensation that can range from mild, localized discomfort to agony. The mechanism of pain perception involves dedicated subsets of peripheral and central neurons. For management of pain, currently, available treatment regimens are opioid analgesics and NSAIDs which are easily available over the counter drugs. Long term use of analgesics can lead to significant impact on human renal system, cardiovascular system and analgesic abuse etc. So, there is a need for novel, safe and cost effective analgesic compound. Hence a study on 2-4methylphenylimino-3-carboxamide substituted thiophene compound, a novel thiophene compound has been carried out in different experimental animal models.Methods: Two methods were used to evaluate the peripheral analgesic activity of 2-4methylphenylimino-3-carboxamide substituted thiophene compound. First method was Acetic acid induced writhing and compared to standard drug aspirin. Second method was late phase of formalin induced paw licking in mice and compared to a standard drug, aspirin.Results: With Acetic acid induced writhing, 40mg/kg dose of 2-4methylphenylimino-3-carboxamide substituted thiophene compound has shown maximum Pain Inhibition Percentage (PIP) of 78 % compared to 91% by Aspirin. Whereas with late phase of Formalin test, 40mg/kg dose of 2-4methylphenylimino-3-carboxamide substituted thiophene compound has shown maximum PIP of 58% in late phase compared to 86% by aspirin. The results were statistically significant with p&lt;0.05.Conclusions: It can be concluded that 2-4methylphenylimino-3-carboxamide substituted thiophene compound found to have moderate peripheral analgesic activity as evident in acetic acid induced writhing and late phase of formalin tests.

Screening of novel 2-4 methylphenylimino-3-carboxamide substituted thiophene compound for central analgesic activity

Background: Pain is an unpleasant sensation that can range from mild, localized discomfort to agony. The mechanism of pain perception involves dedicated subsets of peripheral and central neurons. For management of pain, currently, available treatment regimens are opioid analgesics and NSAIDs which are easily available over the counter drugs. Long term use of analgesics can lead to significant impact on human renal system, cardiovascular system and analgesic abuse etc. So, there is a need for novel, safe and cost-effective analgesic compound. Hence a study on 2-4 methylphenylimino-3-carboxamide substituted thiophene compound, a novel thiophene compound has been carried out in different experimental animal models.Methods: Two methods were used to evaluate the central analgesic activity of 2-4 methylphenylimino-3-carboxamide substituted thiophene compound. First method was Eddy’s hot plate method and compared to standard central analgesic, morphine. Second method was early phase of formalin induced paw licking in mice and compared to a standard drug, aspirin.Results: With eddy’s hot plate method, 40mg/kg dose of 2-4 methylphenylimino-3-carboxamide substituted thiophene compound has shown maximum pain inhibition percentage (PIP) of 45% at 60 min compared to 125% by morphine. Whereas with early phase of formalin test, 40 mg/kg dose of 2-4 methylphenylimino-3-carboxamide substituted thiophene compound has shown maximum PIP of 44% in early phase compared to 60% by aspirin. The results were statistically significant with p&lt;0.05.Conclusions: It can be concluded that 2-4 methylphenylimino-3-carboxamide substituted thiophene compound found to have minimal central analgesic activity as evident in eddy’s hot plate and early phase of formalin tests.

Comparison of the Efficacy of Intravenous Ketorolac to that of Intravenous Pethidine in Pain Suppression in Patients with Biliary Colic

Aim: The study aimed to compare the effect of intravenous administration of the NSAID (Non-steroidal anti-inflammatory drugs) ketorolac to that of intravenous administration of the opioid pethidine in the suppression of pain in patients with biliary colic.&#x0D; Methodology: The present study is a trial study. Among all the biliary colic patients in Mashhad Referral Hospital Emergency in Iran, 58 patients with inclusion criteria were selected using convenience sampling. They were randomly divided into two groups of 29 patients. In the first group, 1 mg/kg IV pethidine, and in the second group, 30 mg IV ketorolac was injected. The pain severity was assessed prior to the treatment and 15, 30, and 60 minutes after the onset of the treatment using the Visual Analogue Scale (VAS). The data were analyzed using SPSS 20 and Chi-square tests.&#x0D; Findings: The patients' mean age was 45±15 years old (age ranged from 30 to 60 years old). The results showed no significant relationship between pain suppression and medicine type after 15 minutes (P=0.5), 30 minutes (P=0.6), and 1 hour (P=0.7). It means that pethidine and ketorolac have an equal effect on pain suppression in patients with biliary colic. Also, the more time passes from the injection, the more the medicines suppress pain.&#x0D; Conclusion: the results of this study show that the efficacy of NSAIDs in the suppression of moderate to severe pain; therefore, a plan to use NSAIDs instead of narcotics for this purpose is essential.