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The diagnostic criteria for small fibre neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources, and the design of clinical trials. To address these issues, we performed a reappraisal study of 150 patients with sensory neuropathy and a prospective and follow-up validation study of 352 new subjects with suspected sensory neuropathy. Small fibre neuropathy diagnostic criteria were based on deep clinical phenotyping, quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD). Small fibre neuropathy was ruled out in 5 of 150 patients (3.3%) of the reappraisal study. Small fibre neuropathy was diagnosed at baseline of the validation study in 149 of 352 patients (42.4%) based on the combination between two clinical signs and abnormal QST and IENFD (69.1%), abnormal QST alone (5.4%), or abnormal IENFD alone (20.1%). Eight patients (5.4%) had abnormal QST and IENFD but no clinical signs. Further, 38 patients complained of sensory symptoms but showed no clinical signs. Of those, 34 (89.4%) had normal QST and IENFD, 4 (10.5%) had abnormal QST and normal IENFD, and none had abnormal IENFD alone. At 18-month follow-up, 19 of them (56%) reported the complete recovery of symptoms and showed normal clinical, QST and IENFD findings. None of those with one single abnormal test (QST or IENFD) developed clinical signs or showed abnormal findings on the other test. Conversely, all eight patients with abnormal QST and IENFD at baseline developed clinical signs at follow-up. The combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of small fibre neuropathy than the combination of abnormal QST and IENFD findings in the absence of clinical signs. Sensory symptoms alone should not be considered a reliable screening feature. Our findings demonstrate that the combined clinical, functional and structural approach to the diagnosis of small fibre neuropathy is reliable and relevant both for clinical practice and clinical trial design.
Learn More >Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve-injured mice.
Mu and delta opioid receptors (MOP, DOP) limit pain perception in physiological conditions, but their relative contribution to the manifestations of pathological pain is not completely understood. Here we used a genetic approach to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations.
Learn More >Medical treatments typically occur in the context of a social interaction between healthcare providers and patients. Although decades of research have demonstrated that patients' expectations can dramatically affect treatment outcomes, less is known about the influence of providers' expectations. Here we systematically manipulated providers' expectations in a simulated clinical interaction involving administration of thermal pain and found that patients' subjective experiences of pain were directly modulated by providers' expectations of treatment success, as reflected in the patients' subjective ratings, skin conductance responses and facial expression behaviours. The belief manipulation also affected patients' perceptions of providers' empathy during the pain procedure and manifested as subtle changes in providers' facial expression behaviours during the clinical interaction. Importantly, these findings were replicated in two more independent samples. Together, our results provide evidence of a socially transmitted placebo effect, highlighting how healthcare providers' behaviour and cognitive mindsets can affect clinical interactions.
Learn More >We present structures of mouse TRPV3 in temperature-dependent open, closed and intermediate states that suggest two-step activation of TRPV3 by heat. During the strongly temperature-dependent first step, sensitization, the channel pore remains closed while S6 helices undergo α-to-π transitions. During the weakly temperature-dependent second step, channel opening, tight association of the S1-S4 and pore domains is stabilized by changes in the carboxy-terminal and linker domains.
Learn More >The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
Learn More >Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feed-forward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain-of-function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feed-forward inhibitory microcircuit were altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance towards excitation and the widening of the integration time window were both smaller in FHM1 compared to wild-type mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed towards inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feed-forward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feed-forward inhibitory microcircuit, whereby the balance is relatively skewed towards inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.
Learn More >Chronic pain and anxiety symptoms are frequently encountered clinically, but the neural circuit mechanisms underlying the comorbid anxiety symptoms in pain (CASP) in context of chronic pain remain unclear. Using viral neuronal tracing in mice, we identified a previously unknown pathway whereby glutamatergic neurons from layer 5 of the hindlimb primary somatosensory cortex (S1) (Glu), a well-known brain region involved in pain processing, project to GABAergic neurons in the caudal dorsolateral striatum (GABA). In a persistent inflammatory pain model induced by complete Freund's adjuvant injection, enhanced excitation of the Glu→GABA pathway was found in mice exhibiting CASP. Reversing this pathway using chemogenetic or optogenetic approaches alleviated CASP. In addition, the optical activation of Glu terminals in the cDLS produced anxiety-like behaviors in naive mice. Overall, the current study demonstrates the putative importance of a novel Glu→GABA pathway in controlling at least some aspects of CASP.
Learn More >Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Since sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic-nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin and parvalbumin positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naïve mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.
Learn More >Despite evidence of broad impact on daily functioning in adolescence, little is known regarding the life course effects of childhood chronic pain. This is the first nationally representative study to characterize the disruptive impact of chronic pain in adolescence on key educational, vocational, and social outcomes in young adulthood (12 years later). Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) was used, including 3,174 youth with chronic pain and 11,610 without chronic pain. Multivariate regression analyses controlling for sociodemographic factors and adolescent depression found that chronic pain in adolescence was associated with long-term risk for a constellation of impairments indicative of socioeconomic disparities. Specifically, adolescent chronic pain was subsequently associated with reduced educational attainment (e.g., lower odds of attaining a high school diploma and bachelor's degree), poor vocational functioning (e.g., lower odds of receiving employer-provided benefits, higher odds of receiving public aid), and social impairments (e.g., early parenthood, lower self-reported romantic relationship quality) in young adulthood. These findings provide a window into the future of adolescents with chronic pain, contributing to the limited knowledge base of the scope of adverse long-term outcomes during the transition to adulthood. However, several questions remain. Increased research attention is needed to understand the life course impact of pediatric chronic pain, including early risk factors and underlying mechanisms that drive adverse outcomes as they unfold across the lifespan.
Learn More >Two recent studies suggest that experimental pain sensitivity is associated with low-grade systemic inflammation. However, only two biomarkers have been identified and the studies were conducted in adult individuals where confounding effects of comorbid diseases cannot be excluded. We therefore tested associations between pain sensitivity and 119 inflammation-related serum biomarkers in 827 healthy adolescents (15-19 years) in the population-based Tromsø Study: Fit Futures. The main outcome measure was cold-pressor pain tolerance (CPT), tested by placing the dominant hand in circulating cold (3°C) water for a maximum of 105s. Secondary outcomes were heat and pressure pain threshold and tolerance. Twelve proteins and six fatty acids were significantly associated with CPT after adjustment for possible confounding factors and correction for multiple comparisons. Of these, all fatty acids and 10 proteins were protective, i.e. higher biomarkers levels were associated with increased CPT, whereas two biomarkers were associated with lower tolerance. Taken together these biomarkers predicted completion of the tolerance test with a C-statistic of 0.65. Results for heat and pressure pain tolerance were remarkably similar, strengthening the generalizability of our findings. In this cohort of young healthy individuals, we found a relationship between inflammation-related biomarkers and pain tolerance and thresholds. Biomarkers with anti-inflammatory and analgesic effects predominated, suggesting that the development of prophylactic dietary or pharmaceutical treatments may be possible.
Learn More >Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating". The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have employed a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia (TN), a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. While many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement and for some there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and TN cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.
Learn More >African Americans experience an increased burden of motor vehicle collision (MVC), post-MVC musculoskeletal pain (MSP) and Vitamin D insufficiency. In this prospective multicenter study, we tested the hypothesis that African Americans (n=133) presenting to the ED after MVC with low peritraumatic Vitamin D levels would have worse chronic MSP outcomes compared to individuals with sufficient Vitamin D. Vitamin D levels were assessed in the early aftermath of MVC via enzyme-linked immunosorbent assay, and pain severity was assessed via the 0-10 numeric rating scale at 6 weeks, 6 months and 1 year. In repeated-measures analysis, African American MVC survivors with vitamin D insufficiency experienced more severe chronic pain (β=1.18, p=0.031). In secondary analyses, we assessed for evidence that the effect of Vitamin D on post-MVC pain outcomes is mediated, at least in part, by the influence of Vitamin D on genetic variants in genes involved in immune system regulation (IL-10 and NLRP3). Genotyping was performed using a genome-wide microarray using collected DNA samples. Secondary analyses suggest that the effect of Vitamin D on post-MVC pain outcomes may be influenced by genetic variation in IL-10 and NLRP3. Further studies are needed to assess the impact of Vitamin D insufficiency on pain outcomes in African Americans experiencing MVC and other common trauma exposures, to assess factors affecting this relationship, and to assess the efficacy of administering Vitamin D in the immediate aftermath of MVC to prevent chronic pain. Such low-cost, non-opioid interventions are urgently needed to address chronic pain development following MVC.
Learn More >Premature infants in the Neonatal Intensive Care Unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects' left plantar paw surface which occurred four times daily during the first week of life (PND 1 – 7). Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND 6) and fluorescent hybridization (FISH) for corticotropin releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND 24 and PND 25) and underwent innate anxiety testing utilizing an elevated plus maze protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage. This report expands on current rodent model research performed to assess the long-term effects of highly utilized neonatal intensive care unit (NICU) procedures. The NICU plays an integral role in pediatric medicine by significantly reducing infant mortality and providing necessary procedures to preterm or unwell newborns. However, procedures in the NICU are often stressful and painful. A common procedure performed in the NICU is heel lances to monitor blood composition. This, along with numerous other painful procedures, are often performed on NICU babies without the benefit of analgesics. Our study identifies key neurological indicators which are altered in response to neonatal pain. Additionally, we explore the later anxiety of subjects exposed to neonatal pain.
Learn More >A person's concept of pain can be defined as how they understand what pain actually is, what function it serves and what biological processes are thought to underpin it. This study aimed to explore the concept of pain in children with and without persistent pain.
Learn More >The flavoring agent menthol elicits complex orosensory and behavioral effects including perceived cooling at low concentrations, and irritation and ingestive avoidance at higher intensities. Oral menthol engages the cold-activated transient receptor potential (TRP) ion channel TRP melastatin 8 (TRPM8) on trigeminal fibers, although its aversive feature was discussed to involve activation of TRP ankyrin 1 (TRPA1) associated with nociceptive processing. Here we studied the roles of TRPM8 and TRPA1 in orosensory responding to menthol by subjecting mice gene-deficient for either channel to brief-access exposure tests, which measure immediate licking responses to fluid stimuli to capture sensory/tongue control of behavior. Stimuli included aqueous concentration series of (-)-menthol (0 [water], 0.3, 0.5, 0.7, 1.0, 1.5, and 2.3 mM) and the aversive bitter taste stimulus quinine-HCl (0, 0.01, 0.03, 0.1, 0.3, 1, and 3 mM). Concentration-response data were generated from daily brief-access tests conducted in lickometers, which recorded the number of licks water-restricted mice emitted to a randomly selected stimulus concentration over a block of several 10 sec stimulus presentations. Wild-type mice showed aversive orosensory responses to menthol above 0.7 mM. Oral aversion to menthol was reduced in mice deficient for TRPA1, but not TRPM8. Oral aversion to quinine was similar between TRPA1 mutant and control mice but stronger than avoidance of menthol. This implied menthol avoidance under the present conditions represented a moderate form of oral aversion. These data reveal TRPA1 contributes to the oral sensory valence of menthol and have implications for how input from TRPA1 and TRPM8 shapes somatosensory-guided behaviors. Menthol is used in confectionery, tobacco, and oral consumer products to add a pleasant "coolness" to their flavor appeal. Yet menthol's sensation is complex and includes coolness at low but irritation at high concentrations. Elucidating mechanisms that underlie menthol's aversive flavor component would facilitate understanding of how trigeminal circuits distinguish noxious from innocuous stimuli. Although engaging the cold receptor TRPM8, menthol was discussed to induce oral irritation through its activation of TRPA1, which is expressed on nociceptive fibers usually devoid of TRPM8. Here we found mice gene-deficient for TRPA1, but not TRPM8, show reduced aversion to menthol in an oral sensory-guided behavioral task. These results have implications for how TRPM8 and TRPA1 afferents contribute to hedonic tone during somatosensory-influenced behaviors.
Learn More >A fundamental organizing principle in the somatosensory and motor systems is somatotopy, where specific body parts are represented separately and adjacently to other body parts, resulting in a body map. Different terminals of the sensorimotor network show varied somatotopic layouts, in which the relative position, distance and overlap between body-part representations differ. Since somatotopy is best characterized in the primary somatosensory (S1) and motor (M1) cortices, these terminals have been the main focus of research on somatotopic remapping following loss of sensory input (e.g. arm amputation). Cortical remapping is generally considered to be driven by the layout of the underlying somatotopy, such that neighboring body-part representations tend to activate the deprived brain region. Here, we challenge the assumption that somatotopic layout restricts remapping, by comparing patterns of remapping in humans born without one hand (hereafter, one-handers, n=26) across multiple terminals of the sensorimotor pathway. We first report that in the cerebellum of one-handers, the deprived hand region represents multiple body parts. Importantly, the representations of some of these body parts do not neighbor the deprived hand region. We further replicate our previous finding, showing a similar pattern of remapping in the deprived hand region of the cerebral cortex in one-handers. Finally, we report preliminary results of a similar remapping pattern in the putamen of one-handers. Since these three sensorimotor terminals (cerebellum, cerebrum, putamen) contain different somatotopic layouts, the parallel remapping they undergo demonstrates that the mere spatial layout of body-part representations may not exclusively dictate remapping in the sensorimotor systems.When a hand is missing, the brain region that typically processes information from that hand may instead process information from other body-parts, a phenomenon termed remapping. It is commonly thought that only body-parts whose information is processed in regions neighboring the hand region could "take up" the resources of this now deprived region. Here we demonstrate that information from multiple body-parts is processed in the hand regions of both the cerebral cortex and cerebellum. The native brain regions of these body-parts have varying levels of overlap with the hand region across multiple terminals in the sensorimotor hierarchy, and do not necessarily neighbor the hand region. We therefore propose that proximity between brain regions does not limit brain remapping.
Learn More >Genome-wide association studies have implicated dozens of genes with migraine susceptibility, but it remains unclear in which nervous system cell types these genes are expressed.
Learn More >To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy.
Learn More >The objective of this study was to evaluate the efficacy, tolerability, and safety of 120 mg DFN-15 vs placebo for the acute treatment of migraine.
Learn More >Migraine and major depressive disorder show a high rate of comorbidity, but little is known about the associations between the subtypes of major depressive disorder and migraine. In this cross-sectional study we aimed at investigating a) the lifetime associations between the atypical, melancholic, combined and unspecified subtype of major depressive disorder and migraine with and without aura and b) the associations between major depressive disorder and its subtypes and the severity of migraine.
Learn More >Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodeling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARβ agonist, C286, currently under clinical research, in NP. A 4-week treatment initiated 2 days after the injury normalized pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286-mediated pain modulation, suggests that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore.
Learn More >PACAP and other neuropeptides link chronic migraine and opioid-induced hyperalgesia in mouse models.
Chronic use of opioids can produce opioid-induced hyperalgesia (OIH), and when used to treat migraine, these drugs can result in increased pain and headache chronicity. We hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. Using label-free, non-biased liquid chromatography-mass spectrometry to identify and measure changes in more than 1500 neuropeptides under these two conditions, we observed only 16 neuropeptides that were altered between the two conditions. The known pro-migraine molecule, calcitonin-gene related peptide, was among seven peptides associated with chronic migraine, with several pain-processing neuropeptides among the nine other peptides affected in OIH. Furthermore, composite peptide complements Pituitary adenylate cyclase-activating polypeptide (PACAP), Vasoactive intestinal peptide (VIP) and Secretogranin (SCG) showed significant changes in both chronic migraine and OIH. In a follow-up pharmacological study, we confirmed the role of PACAP in models of these two disorders, validating the effectiveness of our peptidomic approach, and identifying PACAP as a mechanistic link between chronic migraine and OIH. Data are available via ProteomeXchange with identifier PXD013362.
Learn More >Observing pain in others can enhance our own pain. Two aspects of this effect remain unknown or controversial: first, whether it depends on the 'painfulness' of the visual stimulus; second, whether it reflects a genuine bias in perception or rather a bias in the memory encoding of the percept. Pain ratings and vegetative skin responses were recorded while 21 healthy volunteers received electric nociceptive shocks under three experimental conditions: (i) observing a painful contact between the body and a harmful object; (ii) observing a non-painful body contact, (iii) observing a control scene where the body and the object are not in contact. Pain reports and vegetative responses were enhanced exclusively when the subjects observed a painful body contact. The effect on perception was immediate, abated 3 sec after the shock, and positively correlated with the magnitude of vegetative arousal. This suggests that (a) hyperalgesia during observation of painful scenes was induced by their pain-related nature, and not by the simple body contact, and (b) hyperalgesia emerged from a very rapid bias in the perceptual encoding of the stimulus, and was not the result of a retrospective bias in memory recollection. Observing pain-depicting scenes can modify the processing of concomitant somatic stimuli, increasing their arousal value and shifting perception toward more painful levels.
Learn More >Cortical areas including the anterior cingulate cortex (ACC) play critical roles in different types of chronic pain. Most of previous studies focus on the sensory inputs from somatic areas, and less information about plastic changes in the cortex for visceral pain. In this study, chronic visceral pain animal model was established by injection with zymosan into the colon of adult male C57/BL6 mice. Whole cell patch-clamp recording, behavioral tests, Western blot, and Cannulation and ACC microinjection were employed to explore the role of adenylyl cyclase 1 (AC1) in the ACC of C57/BL6 and AC1 knock out (AC1 KO) mice. Integrative approaches were used to investigate possible changes of neuronal adenylyl cyclase 1 (AC1) in the ACC after the injury. We found that AC1, a key enzyme for pain-related cortical plasticity, was significantly increased in the ACC in an animal model of irritable bowel syndrome. Inhibiting AC1 activity by a selective AC1 inhibitor NB001 significantly reduced the upregulation of AC1 protein in the ACC. Furthermore, we found that AC1 is required for NMDA GluN2B receptor upregulation and increases of NMDA receptor-mediated currents. These results suggest that AC1 may form a positive regulation in the cortex during chronic visceral pain. Our findings demonstrate that the upregulation of AC1 protein in the cortex may underlie the pathology of chronic visceral pain; and inhibiting AC1 activity may be beneficial for the treatment of visceral pain.
Learn More >This study investigated if repeated buffered acidic saline infusions into the masseter muscles induced muscle pain and mechanical sensitization. Fourteen healthy men participated in this double-blind, randomized, and placebo-controlled study. Two repeated infusions (day 1 and 3) were given in the masseter muscles with either a buffered acidic saline solution (pH 5.2) or an isotonic saline solution (pH 6) as control. After 10 days of wash-out, the experiment was repeated with the other substance. Pressure pain thresholds (PPT), pain intensity, maximum unassisted mouth opening (MUO), and pain drawings were assessed before, directly following, and after each infusion at 5, 15, and 30 min and on day 4 and 7. Fatigue and pain intensity were assessed after a one-minute chewing test 30 min after infusions and day 4 and 7. Acidic saline induced higher pain intensity than control day 3 up to 5 min after infusions, but did not affect PPT. The chewing test did not evoke higher fatigue during chewing or MUO or after acidic saline infusion compared to control. Repeated acidic saline infusions in the masseter muscles induced a short-lasting muscle pain without mechanical hyperalgesia or functional pain. Hence, this model might not be superior to already existing experimental muscle pain models.
Learn More >Addiction neuroscience models posit that recurrent drug use increases reactivity to drug-related cues and blunts responsiveness to natural rewards, propelling a cycle of hedonic dysregulation that drives addictive behavior. Here, we assessed whether a cognitive intervention for addiction, Mindfulness-Oriented Recovery Enhancement (MORE), could restructure reward responsiveness from valuation of drug-related reward back to valuation of natural reward. Before and after 8 weeks of MORE or a support group control, prescription opioid users ( = 135) viewed opioid and natural reward cues while an electroencephalogram biomarker of target engagement was assessed. MORE was associated with decreased opioid cue-reactivity and enhanced capacity to regulate responses to opioid and natural reward cues. Increased positive affective responses to natural reward cues were associated with decreased craving and mediated MORE's therapeutic effects on opioid misuse. This series of randomized experiments provide the first neurophysiological evidence that an integrative behavioral treatment can remediate hedonic dysregulation among chronic opioid users.
Learn More >This updated systematic review evaluated the efficacy, acceptability and safety of long-term opioid therapy (LTOT) for chronic non-cancer pain (CNCP).
Learn More >Little are known about the effects of non-pharmacological interventions among medication-overuse headache (MOH) patients, although non-pharmacological approaches combined with pharmacological treatment are recommended. The objective was to evaluate the effect of an educational program as an add-on to standard treatment.
Learn More >The King-Devick test is a timed rapid number naming task that involves complex cerebral functions. The objective of this pilot exploratory study is to determine whether there is a difference in the King-Devick test during a migraine attack compared to the interictal phase.
Learn More >Douleur Neuropathique 4 (DN4) is a screening questionnaire to help identify neuropathic pain (NP) in clinical practice and research. We tested the accuracy of the DN4 questionnaire in stratifying possible NP (pNP) and definite NP (dNP) in patients operated for breast cancer.
Learn More >The gamma-aminobutyric acid type B (GABA) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABA receptor agonists is limited by their undesirable side-effects. To clarify whether GABA receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABA receptor agonist in FM, we investigated the potential of a novel GABA receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABA receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABA receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABA receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABA receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABA receptor agonists in patients with FM.
Learn More >Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major toxicity of cancer treatment, leading to dose reduction and premature treatment cessation, potentially affecting patient function, and quality of life. The development of accurate and sensitive assessment tools for CIPN is essential to enable clinical monitoring during treatment, follow-up of long-term outcomes and measurement of toxicity in clinical trials. This review examines CIPN clinical assessment scales incorporating clinician-based, composite, and patient-reported outcomes (PROs), providing a systematic review of their properties and an updated critical analysis of recommendations on current evidence for their use. This systematic review of CIPN assessment tools identified 50 papers containing 41 assessment tools, across 4 categories (common toxicity criteria; composite neurological scale; PROs; pain scale). The majority of these tools were PROs, underscoring the importance of patient-based assessment of symptoms. While there has been considerable work in the field over the past 10 years, this review highlights significant gaps, including a lack of evaluation of responsiveness and problematic neuropathic pain evaluation. There remains a need for consensus on the best available tool and the need to modify existing instruments to improve utility.
Learn More >Neuropeptide Y (NPY) signaling plays an important role in inhibiting chronic pain in the spinal cord of mice. However, little is known about the respective roles of two major NPY receptors, Y1R and Y2R, in evoked, and spontaneous, pain behavior under normal physiological condition. Using intrathecal (i.t.) administration approach, we found that pharmacological inhibition of Y2R, unexpectedly, gave rise to spontaneous pain behavior. In addition, Y2R antagonism also resulted in long-lasting mechanical but not thermal hypersensitivity. By contrast, no overt spontaneous pain behavior, nor mechanical and thermal hypersensitivity were detected after pharmacological inhibition of Y1R. Remarkably, activation of Y1R produced powerful analgesic effect: blocking both evoked and spontaneous pain behavior resulted from Y2R antagonism. These findings highlight the pivotal role of endogenous Y2R in gating mechanical and spontaneous pain transmission. Importantly, our results suggest that Y1R could be a therapeutic target that may be exploited for alleviating spontaneous pain without affecting acute pain transmission.
Learn More >Post-traumatic Stress Disorder (PTSD) commonly co-occurs with chronic pain. Although PTSD symptoms are associated with negative health outcomes in patients with chronic pain, PTSD is typically under-detected and under-treated in outpatient pain settings. There is a need for rapid, brief screening tools to identify those at greatest risk for severe PTSD symptoms. To achieve that goal, our aim was to use item response theory (IRT) to identify the most informative PTSD symptoms characterizing severe PTSD in patients with chronic pain.
Learn More >Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.
Learn More >Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.
Learn More >To compare the effectiveness of deep tissue massage, supervised strengthening and stretching exercises, and a combined therapy (exercise followed by massage) (index groups), with advice to stay active (control group).
Learn More >Peripheral neuropathies result in adaptation in primary sensory and other regions of cortex, and provide a framework for understanding the localized and widespread adaptations that arise from altered sensation. Mesoscale cortical imaging achieves high temporal resolution of activity using optical sensors of neuronal activity to simultaneously image across a wide expanse of cortex and capture this adaptation using sensory-evoked and spontaneous cortical activity. Saphenous nerve ligation in mouse is an animal model of peripheral neuropathy that produces hyperalgesia circumscribed to the hindlimb. We performed saphenous nerve ligation or sham, followed by mesoscale cortical imaging using voltage sensitive dye (VSD) after ten days. We utilized subcutaneous electrical stimulation at multiple stimulus intensities to characterize sensory responses after ligation or sham, and acquired spontaneous activity to characterize functional connectivity and large scale cortical network reorganization. Relative to sham animals, the primary sensory-evoked response to hindlimb stimulation in ligated animals was unaffected in magnitude at all stimulus intensities. However, we observed a diminished propagating wave of cortical activity at lower stimulus intensities in ligated animals after hindlimb, but not forelimb, sensory stimulation. We simultaneously observed a widespread decrease in cortical functional connectivity, where midline association regions appeared most affected. These results are consistent with localized and broad alterations in intracortical connections in response to a peripheral insult, with implications for novel circuit level understanding and intervention for peripheral neuropathies and other conditions affecting sensation.
Learn More >The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Ca2.2, Itgam/Cd11b, Scn9a/Na1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.
Learn More >Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC ) and maximum observed concentration (C ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC and C were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC and C remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC and C were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.
Learn More >Individuals with chronic pain commonly report significant functional impairment and reduced quality of life. Despite this, little is known about psychological processes and mechanisms underpinning enhancements in well-being within this population. The study aimed to investigate whether (1) increased levels of pain intensity and interference were associated with lower levels of mental well-being, (2) increased positive goal engagement was associated with higher levels of mental well-being and (3) whether the relationships between pain characteristics and mental well-being were mediated by increased positive goal engagement. A total of 586 individuals with chronic pain participated in the cross-sectional, online study. Participants completed self-report measures to assess pain intensity and interference, mental well-being and goal motivation variables. Results showed that pain interference and positive goal engagement were associated with mental well-being. Moreover, the relationship between pain interference and mental well-being was partially mediated by positive goal engagement. The results provide tentative evidence for the protective role of positive goal engagement in enabling individuals with chronic pain to maintain a sense of mental well-being. The study develops the biopsychosocial model of chronic pain by examining the roles and relationships of relevant yet previously unexplored psychological constructs. The promotion of mental well-being through the enhancement of positive goal engagement is discussed, offering a platform for further research and clinical interventions.
Learn More >Potential protective effects of nonpharmacological treatments (NPT) against long-term pain-related adverse outcomes have not been examined.
Learn More >Diabetic neuropathy is a serious complication for diabetic patients involving the nervous system. This disease is a quiet but painful condition caused by chronically high blood glucose levels. It is reported that high mobility group box 1 protein (HMGB1) participates in the development of neuropathic pain. This study aimed to explore the role of microRNA (miR)-193a in diabetic neuropathic pain through the regulation of HMGB1.
Learn More >Listening to self-chosen, pleasant and relaxing music reduces pain in fibromyalgia (FM), a chronic centralized pain condition. However, the neural correlates of this effect are fairly unknown. In our study, we wished to investigate the neural correlates of music-induced analgesia (MIA) in FM patients. To do this, we studied 20 FM patients and 20 matched healthy controls (HC) acquiring rs-fMRI with a 3T MRI scanner, and pain data before and after two 5-min auditory conditions: music and noise. We performed resting state functional connectivity (rs-FC) seed-based correlation analyses (SCA) using pain and analgesia-related ROIs to determine the effects before and after the music intervention in FM and HC, and its correlation with pain reports. We found significant differences in baseline rs-FC between FM and HC. Both groups showed changes in rs-FC after the music condition. FM patients reported MIA that was significantly correlated with rs-FC decrease between the angular gyrus, posterior cingulate cortex and precuneus, and rs-FC increase between amygdala and middle frontal gyrus. These areas are related to autobiographical and limbic processes, and auditory attention, suggesting MIA may arise as a consequence of top-down modulation, probably originated by distraction, relaxation, positive emotion, or a combination of these mechanisms.
Learn More >The aim of this systematic review with meta-analysis is to evaluate the clinical efficacy of transcutaneous electrical nerve stimulation (TENS) for any type of acute and chronic pain in adults.
Learn More >Pain in animals is typically assessed using reflexive and physiological responses. These measures allow inferences regarding nociception but provide little basis for conclusions about the affective component of pain (i.e. how negatively the experience is perceived). Calves routinely undergo painful procedures on commercial farms, including hot-iron disbudding, providing a convenient model to study pain in animals. The aim of this study was to investigate the affective component of post-procedural pain due to hot-iron disbudding, using conditioned place aversion. Calves ( = 31) were subjected to two procedures (one bud at a time): one without post-procedural pain control and the other with the use of a nonsteroidal anti-inflammatory drug (either meloxicam ( = 16) or ketoprofen ( = 15)). All procedures included the use of local anaesthesia (lidocaine). Place conditioning was tested 2 days after the last treatment by allowing calves to freely roam between the pens where they had previously been disbudded. Calves spent more time, and lay down more frequently, in the pen where they received meloxicam compared with the pen where they only received a local block. Surprisingly, calves avoided the pen where they received ketoprofen compared with the control treatment pen. We hypothesize that the shorter duration of action of ketoprofen resulted in increasing pain at the end of the conditioning period, explaining the increased aversion to this treatment. These results illustrate the value of place conditioning paradigms to assess the affective component of pain in animals, and suggest that the animal's evaluation of painful events depends upon the time course of when the pain is experienced.
Learn More >Pain during vaginal intercourse in pregnancy has largely been ignored despite physiological and psychological components of pregnancy that may be associated with its onset and persistence.
Learn More >As professional health care personnel we are well educated in anatomy, physiology, clinical medicine and so forth. Our patients present with various symptoms and signs that we use this knowledge to diagnose and treat. But sometimes the patient case contradicts our knowledge. Since the patient is the terrain and our knowledge is the map, these patient cases are anomalies that give us the opportunity to update our maps. One such anomaly is how time restricted amnesia can improve or even eradicate an underlying chronic pain condition and eliminate the patient's dependence on daily opioid consumption. In this short communication I will use amnesia as a starting point to briefly review chronic pain from a learning and memory perspective. I will introduce, for many readers, new concepts like degeneracy and criticality, and together with more familiar concepts like habits and brain network activity, we will end with overarching principles for how chronic pain treatment in general can be crafted and individualized almost independently of the chronic pain condition at hand. This introductory article is followed by a review series that elaborates on the fundamental biological principles for chronic pain, treatment options, and testing the theory with real world data.
Learn More >Observational studies have implicated migraine as a risk factor for coronary artery disease (CAD) and atrial fibrillation (AF), however it is unclear whether migraine is causal in this relationship. We investigated potential causality between genetically instrumented liability to migraine and cardiovascular disease outcomes using two-sample Mendelian randomization.
Learn More >Prospective cohort study OBJECTIVE.: The aims of this study were to evaluate the outcome of surgical as well as non-surgical treatment for patients with lumbar herniated disc (LHD) or lumbar spinal stenosis (LSS) after two years and to identify predictors for non-success.
Learn More >The current study aimed to validate the parent-proxy IMPACT-III (IMPACT-III-P) in a sample of youth diagnosed with inflammatory bowel disease (IBD). Parent-proxy report measures are standard for pediatric psychosocial assessment, and the IMPACT-III-P will provide a more comprehensive representation of HRQOL. Reliability and validity analyses were conducted.
Learn More >The 'Paracetamol and Ibuprofen in Combination' (PANSAID) trial showed that combining paracetamol and ibuprofen resulted in lower opioid consumption than each drug alone and we did not findan increase in risk of harm when using ibuprofen versus paracetamol. The aim of this subgroup analysis was to investigate differences in benefits and harms of the interventions in different subgroups. We hypothesized the intervention effects would differ in subgroups with different risk of pain or adverse events.
Learn More >Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine.
Learn More >Dupilumab, a fully human monoclonal antibody targeting the alpha subunit of IL-4 was recently approved for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients. To assess dupilumab effectiveness and safety in adults with moderate-to-severe AD in a real-life Italian multicentre retrospective cohort. Adult moderate-to-severe AD patients, referring to 39 Italian centres, received dupilumab in the context of a national patient access program. Disease assessment was performed at baseline, after 4 and 16 weeks of treatment using Eczema-Area-and-Severity-Index (EASI) score, itch and sleep numerical-rating-score (itch-NRS, sleep-NRS) and Dermatology-Life-Quality-Index (DLQI). A total of 109 (71M/38F) patients was studied. There was a significant reduction in EASI score, itch-NRS, sleep-NRS and DLQI from baseline to week 4 and a further significant decline to week 16. EASI 50, EASI75 and EASI90 were achieved by 59.6%, 28.4% and 9.3% of patients at 4 weeks and by 87.2%, 60.6% and 32.4% of them at 16 weeks, respectively. Adverse events were experienced by 19.2% (21/109) of the patients and they were all mild in intensity, being conjunctivitis the most common side effect. Dupilumab significantly improved disease severity, pruritus, sleep loss and quality of life with an acceptable safety profile.
Learn More >The World Health Organization Disability Assessment Schedule (WHODAS) 2.0 is a generic instrument to assess disability. Pain and psychological factors seem to play a pronounced disabling role in fibromyalgia (FM). There are few studies that investigate the factors associated with disability in patients with fibromyalgia from the patient's perspective. Information about FM disability using self-reported questionnaires is limited. This study aimed to assess the relationship between the ordinal response variable (degree of disability), and four explanatory variables: pain intensity, depression, anxiety, and alexithymia.
Learn More >Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length-dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre-existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs-induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.
Learn More >Chronic pain is mainly treated with opioid analgesics such as morphine. However, the use of these substances can cause adverse effects, including dependence and tolerance, necessitating the discovery of a new approach to analgesic therapies. The transient receptor potential vanilloid 1 (TRPV1) is linked to thermal sensibility and has been considered as a new therapeutic option for pain treatment. This study aims to investigate the antinociceptive effect and toxicity of SB-366791, a TRPV1 antagonist. Morphine-tolerant and morphine non-tolerant Swiss mice were submitted to the hot plate and thermal tail flick tests. Toxicological evaluations of the genotoxic and mutagenic activities of SB-366791 were assessed using a comet assay and micronucleus test, and the Salmonella/microsome mutagenicity assay. In the hot plate test, intrathecal injection of SB-366791 or morphine resulted in significantly increased antinociception in non-tolerant mice. SB-366791 also led to an analgesic effect in the tail flick test. Tolerant mice that received SB-366791 demonstrated a central antinociceptive effect in both thermal tests. No genotoxic effects were observed in the comet assay and no mutagenic effects were detected in the micronucleus test or in the Salmonella/microsome assay. Behavioral results of the thermal nociception tests show that SB-366791 has antinociceptive potential in both morphine-tolerant and non-tolerant mice and does not cause genotoxic or mutagenic effects. Nevertheless, new studies should be performed to clarify the activity and participation of vanilloid channels in the antinociception of SB-366791.
Learn More >Previous studies have shown that α7 nicotinic acetylcholine receptor (nAChR) has a critical role in the regulation of pain sensitivity and neuroinflammation. However, pharmacological effects of α7 nAChR activation in the hippocampus on neuroinflammatory mechanisms associated with allodynia and hyperalgesia remain unknown. We have determined the effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an α7 nAChR positive allosteric modulator, on lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in mice. We also evaluated the effects of TQS on immunoreactivity of microglial marker ionized-calcium binding adaptor molecule 1 (Iba-1), phospho-nuclear factor-κB (p-NF-κB p), tumor necrosis factor-alpha (TNF-α), and norepinephrine (NE) level.
Learn More >Most patients with IBD experience pain, especially during acute disease exacerbations. Opioid use continues to be more prevalent in IBD than any other chronic gastrointestinal condition, and the majority of IBD patients consume narcotics during hospitalization despite the risks of infection and death.
Learn More >Prostatodynia is the main symptom of chronic prostatitis and the main reason that patients go to the hospital for treatment. Although a variety of factors, including inflammatory immune response, nervous system sensitization, and psychological factors, have been shown to play important roles in the induction and development of chronic pain in prostatitis, the underlying cause of chronic prostatodynia maintenance in prostatitis patients remains unclear.
Learn More >The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract-TRP channels interactions.
Learn More >Osteoarthritis (OA) is a leading cause of chronic pain and disability in older adults, which most commonly affects the joints of the knee, hip, and hand. To date, there are no established disease modifying interventions that can halt or reverse OA progression. Therefore, treatment is focused on alleviating pain and maintaining or improving physical and psychological function. Rehabilitation is widely recommended as first-line treatment for OA as, in many cases, it is safer and more effective than the best-established pharmacological interventions. In this article, we describe the presentation of OA pain and give an overview of its peripheral and central mechanisms. We then provide a state-of-the-art review of rehabilitation for OA pain-including self-management programs, exercise, weight loss, cognitive behavioral therapy, adjunct therapies, and the use of aids and devices. Next, we explore several promising directions for clinical practice, including novel education strategies to target unhelpful illness and treatment beliefs, methods to enhance the efficacy of exercise interventions, and innovative, brain-directed treatments. Finally, we discuss potential future research in areas, such as treatment adherence and personalized rehabilitation for OA pain.
Learn More >Opioids are frequently prescribed for the management of patients with chronic non-cancer pain (CNCP). Previous meta-analyses of efficacy and harms have combined treatment effects across all opioids; however, specific opioids, pharmacokinetic properties (ie, long acting vs short acting), or the type of formulation (ie, immediate vs extended release) may be a source of heterogeneity for pooled effects.
Learn More >Patients who have limb amputation are at risk of chronic pain, including phantom limb pain, that can be challenging to treat. The aim of this study was to describe the incidence of preoperative opioid usage and the incidence and risk factors for new persistent postoperative opioid usage in opioid-naïve patients after limb amputation.
Learn More >Multimodal analgesia (MMA) is the simultaneous use of multiple analgesic medications that work in a synergistic manner to provide pain control. In recent years, spine surgery has seen the growth of multimodal perioperative protocols for managing pain. Postoperative pain following spinal procedures is a common complaint, with persistent pain even after the immediate convalescent period leading to negative impacts on health. A multidisciplinary approach is essential in reducing postoperative morbidity and complication rates. This review demonstrates the efficacy in the combined use of opioid-alternative medications such as NSAIDs, gabapentinoids, local anesthetics, acetaminophen, and other neuromodulatory pharmacologic agents. Continued research will be essential in the optimization of the MMA protocol for treating patients who undergo spine procedures.
Learn More >Chronic pelvic pain (CPP) – defined as intermittent or constant pain in the lower abdomen or pelvis of at least 6 months' duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy – is estimated to affect 6-27% of women worldwide. In the United Kingdom, over 1 million women suffer from CPP, which has been highlighted as a key area of unmet need. Current medical treatments for CPP are often associated with unacceptable side effects. A specific style of acupuncture, the meridian balance method electro-acupuncture (BMEA) and traditional Chinese medicine health consultation (TCM HC (BMEA + TCM HC = BMEA treatment)), may be effective for CPP in women.
Learn More >Pain is a widely experienced symptom of inflammatory bowel disease (IBD), which has significant psychological and functional impacts on patients. Understanding the aetiology and management of chronic pain is a poorly understood area of IBD research. This qualitative study aimed to explore the experiences of individuals with IBD and pain, the pain management strategies they use and any needs for future pain management interventions.
Learn More >Half of individuals with a whiplash injury experience ongoing pain and disability. Many are insufficiently active for good health, increasing their risk of preventable morbidity and mortality, and compounding the effects of the whiplash injury. This paper describes a protocol for evaluating the efficacy of a physical activity promotion intervention in adults with whiplash associated disorders. A multiple-baseline, single case experimental design will be used to evaluate the effects of a physical activity (PA) intervention that includes evidence-based behaviour change activities and relapse prevention strategies for six adults with chronic whiplash. A structured visual analysis supplemented with statistical analysis will be used to analyse: accelerometer-measured PA, confidence completing PA in the presence of neck pain, and pain interference.
Learn More >Accumulating evidence from neuroimaging studies has supported that chronic pain could induce changes in brain function. However, few studies have focused on the dynamic regional homogeneity (dReHo) of trigeminal neuralgia (TN). In this study, twenty-eight TN patients and 28 healthy controls (HC) were included. Based on the resting-state fMRI (rsfMRI), we detected abnormalities in dReHo in the TN patients. Patients with TN had decreased dReHo in the left middle temporal gyrus, superior parietal lobule, and precentral gyrus, and increased dReHo in the thalamus. Furthermore, the increase in dReHo in the thalamus was positively correlated with duration of TN ( = 0.485, = 0.012). These results provide compelling evidence for abnormal resting-state brain activity in TN and suggest that the duration of TN may play a critical role in brain function.
Learn More >Chronic musculoskeletal pain in adolescence is a significant public health concern with 3-5% of adolescents suffering from significant pain-related disability. Pain-related fear and avoidance of activities has been found to have a significant influence on pain outcomes in children and adolescents and is a risk factor for less favorable response to treatment. To address this need, we developed graded exposure treatment for youth with chronic pain (GET Living). We describe the rationale, design, and implementation of a two-group randomized controlled trial (RCT) enhanced with single-case experimental design (SCED) methodology with a sample of 74 adolescents with chronic musculosketal pain and their parent caregivers. GET Living includes education, behavioral exposures, and parent intervention jointly delivered by pain psychology and physical therapy providers. The multidisciplinary pain management control group includes pain psychology delivered education and pain self-management skills training (e.g., relaxation, cognitive skills) and separate physical therapy. Assessments include brief daily diaries (baseline to discharge, 7-days at 3-month and 6-month follow-up), comprehensive in-person evaluations at baseline and discharge, and questionnaire across all time points (baseline, discharge, 3-month and 6-month follow-up). Primary outcome is pain-related fear avoidance. Secondary outcome is functional disability. We also outline all additional outcomes, exploratory outcomes, covariates, and implementation measures. The objective is to offer a mechanism-based, targeted intervention to youth with musculoskeletal pain to enhance likelihood of return to function.
Learn More >