Interrelations between pain and alcohol: An integrative review.
Clinical psychology review
Pain and alcohol use are both highly prevalent in the general population, and pain-alcohol interrelations are of increasing empirical interest. Previous research has identified associations between pain and alcohol dependence, and the current review provides novel contributions to this emerging domain by incorporating studies that have tested relations between pain and low-to-moderate alcohol consumption, and by identifying potential psychosocial mechanisms of action. Specifically, we sought to integrate evidence of pain-alcohol relations derived from two directions of empirical inquiry (i.e., effects of alcohol on pain and effects of pain on alcohol use) across psychological, social, and biological literatures. We observed converging evidence that associations between alcohol consumption and pain may be curvilinear in nature. Whereas moderate alcohol use was observed to be associated with positive pain-related outcomes (e.g., greater quality of life), excessive drinking and alcohol use disorder appear to be associated with deleterious pain-related outcomes (e.g., greater pain severity). We also observed evidence that alcohol administration confers acute pain-inhibitory effects, and that situational pain may motivate alcohol consumption (e.g., drinking for pain-coping). Future research can inform theoretical and clinical applications through examination of temporal relations between pain and alcohol consumption, tests of hypothesized mechanisms, and the development of novel interventions.
10.1016/j.cpr.2015.02.005
Calcium-permeable ion channels in pain signaling.
Bourinet Emmanuel,Altier Christophe,Hildebrand Michael E,Trang Tuan,Salter Michael W,Zamponi Gerald W
Physiological reviews
The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic pain states. Many of the channels involved in the afferent pain pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.
10.1152/physrev.00023.2013
Clinical presentation, management, and pathophysiology of neuropathic itch.
Steinhoff Martin,Schmelz Martin,Szabó Imre Lőrinc,Oaklander Anne Louise
The Lancet. Neurology
Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch.
10.1016/S1474-4422(18)30217-5
Maximizing treatment efficacy through patient stratification in neuropathic pain trials.
Nature reviews. Neurology
Treatment of neuropathic pain remains inadequate despite the elucidation of multiple pathophysiological mechanisms and the development of promising therapeutic compounds. The lack of success in translating knowledge into clinical practice has discouraged pharmaceutical companies from investing in pain medicine; however, new patient stratification approaches could help bridge the translation gap and develop individualized therapeutic approaches. As we highlight in this article, subgrouping of patients according to sensory profiles and other baseline characteristics could aid the prediction of treatment success. Furthermore, novel outcome measures have been developed for patients with neuropathic pain. The extent to which sensory profiles and outcome measures can be employed in routine clinical practice and clinical trials and across distinct neuropathic pain aetiologies is yet to be determined. Improvements in animal models, drawing on our knowledge of human pain, and robust public-private partnerships will be needed to pave the way to innovative and effective pain medicine in the future.
10.1038/s41582-022-00741-7
TRPA1: A gatekeeper for inflammation.
Bautista Diana M,Pellegrino Maurizio,Tsunozaki Makoto
Annual review of physiology
Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract.
10.1146/annurev-physiol-030212-183811
Frontostriatal Gating of Tinnitus and Chronic Pain.
Rauschecker Josef P,May Elisabeth S,Maudoux Audrey,Ploner Markus
Trends in cognitive sciences
Tinnitus and chronic pain are sensory-perceptual disorders associated with negative affect and high impact on well-being and behavior. It is now becoming increasingly clear that higher cognitive and affective brain systems are centrally involved in the pathology of both disorders. We propose that the ventromedial prefrontal cortex and the nucleus accumbens are part of a central 'gatekeeping' system in both sensory modalities, a system which evaluates the relevance and affective value of sensory stimuli and controls information flow via descending pathways. If this frontostriatal system is compromised, long-lasting disturbances are the result. Parallels in both systems are striking and mutually informative, and progress in understanding central gating mechanisms might provide a new impetus to the therapy of tinnitus and chronic pain.
10.1016/j.tics.2015.08.002
Pathological pain and the neuroimmune interface.
Grace Peter M,Hutchinson Mark R,Maier Steven F,Watkins Linda R
Nature reviews. Immunology
Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs--which focus on suppressing aberrant neuronal activity--new strategies to manipulate neuroimmune pain transmission hold considerable promise.
10.1038/nri3621
Neuroinflammation and comorbidity of pain and depression.
Walker A K,Kavelaars A,Heijnen C J,Dantzer R
Pharmacological reviews
Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.
10.1124/pr.113.008144
Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus.
Science translational medicine
Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light-mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino-ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)-positive neurons in the vLGN (vLGN). Moreover, green light analgesia was prevented by knockdown of in the vLGN or by ablation of vLGN neurons. In addition, activation of the projections from vLGN neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGN-DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.
10.1126/scitranslmed.abq6474
Spinal Circuits for Touch, Pain, and Itch.
Koch Stephanie C,Acton David,Goulding Martyn
Annual review of physiology
The exteroceptive somatosensory system is important for reflexive and adaptive behaviors and for the dynamic control of movement in response to external stimuli. This review outlines recent efforts using genetic approaches in the mouse to map the spinal cord circuits that transmit and gate the cutaneous somatosensory modalities of touch, pain, and itch. Recent studies have revealed an underlying modular architecture in which nociceptive, pruritic, and innocuous stimuli are processed by distinct molecularly defined interneuron cell types. These include excitatory populations that transmit information about both innocuous and painful touch and inhibitory populations that serve as a gate to prevent innocuous stimuli from activating the nociceptive and pruritic transmission pathways. By dissecting the cellular composition of dorsal-horn networks, studies are beginning to elucidate the intricate computational logic of somatosensory transformation in health and disease.
10.1146/annurev-physiol-022516-034303
Meningeal Mechanisms and the Migraine Connection.
Annual review of neuroscience
Migraine is a complex neurovascular pain disorder linked to the meninges, a border tissue innervated by neuropeptide-containing primary afferent fibers chiefly from the trigeminal nerve. Electrical or mechanical stimulation of this nerve surrounding large blood vessels evokes headache patterns as in migraine, and the brain, blood, and meninges are likely sources of headache triggers. Cerebrospinal fluid may play a significant role in migraine by transferring signals released from the brain to overlying pain-sensitive meningeal tissues, including dura mater. Interactions between trigeminal afferents, neuropeptides, and adjacent meningeal cells and tissues cause neurogenic inflammation, a critical target for current prophylactic and abortive migraine therapies. Here we review the importance of the cranial meninges to migraine headaches, explore the properties of trigeminal meningeal afferents, and briefly review emerging concepts, such as meningeal neuroimmune interactions, that may one day prove therapeutically relevant.
10.1146/annurev-neuro-080422-105509
Nerve Growth Factor and Pain Mechanisms.
Denk Franziska,Bennett David L,McMahon Stephen B
Annual review of neuroscience
Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy.
10.1146/annurev-neuro-072116-031121
Behavioral Conceptualization and Treatment of Chronic Pain.
Vlaeyen Johan W S,Crombez Geert
Annual review of clinical psychology
Pain is considered a hardwired signal of bodily disturbance belonging to a basic motivational system that urges the individual to act and to restore the body's integrity, rather than just a sensory and emotional experience. Given its eminent survival value, pain is a strong motivator for learning. Response to repeated pain increases when harm risks are high (sensitization) and decreases in the absence of such risks (habituation). Discovering relations between pain and other events provides the possibility to predict (Pavlovian conditioning) and control (operant conditioning) harmful events. Avoidance is adaptive in the short term but paradoxically may have detrimental long-term effects. Pain and pain-related responses compete with other demands in the environment. Exposure-based treatments share the aim of facilitating or restoring the pursuit of individual valued life goals in the face of persistent pain, and further improvements in pain treatment may require a paradigm shift toward more personalized approaches.
10.1146/annurev-clinpsy-050718-095744
Headache in people with epilepsy.
Nature reviews. Neurology
Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.
10.1038/s41582-021-00516-6
Pain in amyotrophic lateral sclerosis.
Chiò Adriano,Mora Gabriele,Lauria Giuseppe
The Lancet. Neurology
Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies.
10.1016/S1474-4422(16)30358-1
Drugging the pain epigenome.
Niederberger Ellen,Resch Eduard,Parnham Michael J,Geisslinger Gerd
Nature reviews. Neurology
More than 20% of adults worldwide experience different types of chronic pain, which are frequently associated with several comorbidities and a decrease in quality of life. Several approved painkillers are available, but current analgesics are often hampered by insufficient efficacy and/or severe adverse effects. Consequently, novel strategies for safe, highly efficacious treatments are highly desirable, particularly for chronic pain. Epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs (miRNAs) strongly affect the regulation of gene expression, potentially for long periods over years or even generations, and have been associated with pathophysiological pain. Several studies, mostly in animals, revealed that inhibitors of DNA methylation, activators and inhibitors of histone modification and modulators of miRNAs reverse a number of pathological changes in the pain epigenome, which are associated with altered expression of pain-relevant genes. This epigenetic modulation might then reduce the nociceptive response and provide novel therapeutic options for analgesic therapy of chronic pain states. However, a number of challenges, such as nonspecific effects and poor delivery to target cells and tissues, hinder the rapid development of such analgesics. In this Review, we critically summarize data on epigenetics and pain, focusing on challenges in clinical development as well as possible new approaches to the drug modulation of the pain epigenome.
10.1038/nrneurol.2017.68
Neural Mechanisms of Itch.
Lay Mark,Dong Xinzhong
Annual review of neuroscience
Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch.
10.1146/annurev-neuro-083019-024537
Insights into migraine attacks from neuroimaging.
The Lancet. Neurology
Migraine is one of the most common neurological diseases and it has a huge social and personal impact. Although head pain is the core symptom, individuals with migraine can have a plethora of non-headache symptoms that precede, accompany, or follow the pain. Neuroimaging studies have shown that the involvement of specific brain areas can explain many of the symptoms reported during the different phases of migraine. Recruitment of the hypothalamus, pons, spinal trigeminal nucleus, thalamus, and visual and pain-processing cortical areas starts during the premonitory phase and persists through the headache phase, contributing to the onset of pain and associated symptoms. Once the pain stops, the involvement of most brain areas ends, although the pons, hypothalamus, and visual cortex remain active after acute treatment intake and resolution of migraine symptoms. A better understanding of the correlations between imaging findings and migraine symptomatology can provide new insight into migraine pathophysiology and the mechanisms of novel migraine-specific treatments.
10.1016/S1474-4422(23)00152-7
Neocortical circuits in pain and pain relief.
Nature reviews. Neuroscience
The sensory, associative and limbic neocortical structures play a critical role in shaping incoming noxious inputs to generate variable pain perceptions. Technological advances in tracing circuitry and interrogation of pathways and complex behaviours are now yielding critical knowledge of neocortical circuits, cellular contributions and causal relationships between pain perception and its abnormalities in chronic pain. Emerging insights into neocortical pain processing suggest the existence of neocortical causality and specificity for pain at the level of subdomains, circuits and cellular entities and the activity patterns they encode. These mechanisms provide opportunities for therapeutic intervention for improved pain management.
10.1038/s41583-021-00468-2
Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis.
The lancet. Psychiatry
BACKGROUND:The left dorsolateral prefrontal cortex is a prime target for repetitive transcranial magnetic stimulation (TMS) to treat neuropsychiatric disorders; thus, abundant efficacy data from controlled trials are available. A cross-diagnostic meta-analysis was conducted to identify the symptom domains susceptible to repetitive TMS to the left dorsolateral prefrontal cortex. METHODS:This systematic review and meta-analysis investigated the effects of repetitive TMS to the left dorsolateral prefrontal cortex on neuropsychiatric symptoms presenting across diagnoses. We searched PubMed, MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for randomised and sham controlled trials published from inception to Aug 17, 2022. Included studies assessed symptoms using clinical measures and reported sufficient data to calculate effect sizes pooled with a random effects model. Two independent reviewers conducted screening and used the Cochrane risk-of-bias tool for quality assessment. Summary data were extracted from published reports. The main outcome was the therapeutic effects of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains. This study is registered with PROSPERO (CRD42021278458). FINDINGS:Of 9056 studies identified (6704 from databases and 2352 from registers), 174 were included in the analysis including 7905 patients. 163 of 174 studies reported gender data; 3908 (52·35%) of 7465 patients were male individuals, and 3557 (47·65%) were female individuals. Mean age was 44·63 years (range 19·79-72·80). Ethnicity data were mostly not available. Effect size was large for craving (Hedges'g -0·803 [95% CI -1·099 to -0·507], p<0·0001; I=82·40%), medium for depressive symptoms (-0·725 [-0·889 to -0·561], p<0·0001; I=85·66%), small for anxiety, obsessions or compulsions, pain, global cognition, declarative memory, working memory, cognitive control, and motor coordination (Hedges'g -0·198 to -0·491), and non-significant for attention, suicidal ideation, language, walking ability, fatigue, and sleep. INTERPRETATION:The cross-diagnostic meta-analysis shows the efficacy of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains, providing a novel framework for assessing target or efficacy interactions of repetitive TMS, and informing personalised applications for conditions for which regular trials are uninformative. FUNDING:The University Grants Committee of Hong Kong and the Mental Health Research Center, The Hong Kong Polytechnic University.
10.1016/S2215-0366(23)00026-3
Narcotic bowel syndrome.
Farmer Adam D,Gallagher Jayne,Bruckner-Holt Caroline,Aziz Qasim
The lancet. Gastroenterology & hepatology
Narcotic bowel syndrome is characterised by worsening abdominal pain in the context of escalating or continuous opioid therapy. Although narcotic bowel syndrome is rarely diagnosed, given the current epidemic of opioid use, it is likely to be under-recognised. The underlying pathophysiological mechanisms of narcotic bowel syndrome are incompletely understood; however, opioid-induced hyperalgesia is likely to be a central facet. The putative mechanisms of hyperalgesia include activation of bimodal opioid regulatory systems, counter-regulatory mechanisms, neuroinflammation, opioid facilitation, and interactions of the N-methyl D-aspartate receptor with opioids at the level of the spinal cord. The cornerstone of management is the development of a therapeutic alliance with the patient, education of the patient as to the mechanisms by which opioids might paradoxically worsen pain, and implementation of an opioid detoxification programme. Opioid detoxification regimens vary between centres, but frequently include tapering or substitution of opioids and concomitant co-administration of antidepressants, anxiolytics, and psychological therapies. Despite these interventions, recidivism rates remain high. Further prospective research is warranted to determine the epidemiology of narcotic bowel syndrome and delineate the most efficacious detoxification programmes.
10.1016/S2468-1253(16)30217-5
The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice.
Murthy Swetha E,Loud Meaghan C,Daou Ihab,Marshall Kara L,Schwaller Frederick,Kühnemund Johannes,Francisco Allain G,Keenan William T,Dubin Adrienne E,Lewin Gary R,Patapoutian Ardem
Science translational medicine
The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of -expressing sensory neurons induced nociception in mice. Mice lacking in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Aδ-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin-induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury-induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia.
10.1126/scitranslmed.aat9897
Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects.
Cell research
Both opioids and nonsteroidal anti-inflammatory drugs (NSAIDS) produce deleterious side effects and fail to provide sustained relief in patients with chronic inflammatory pain. Peripheral neuroinflammation (PN) is critical for initiation and development of inflammatory pain. A better understanding of molecular mechanisms underlying PN would facilitate the discovery of new analgesic targets and the development of new therapeutics. Emerging evidence suggests that peripheral sensory neurons are not only responders to painful stimuli, but are also actively engaged in inflammation and immunity, whereas the intrinsic regulatory mechanism is poorly understood. Here we report the expression of proton-selective ion channel Hv1 in peripheral sensory neurons in rodents and humans, which was previously shown as selectively expressed in microglia in mammalian central nervous system. Neuronal Hv1 was up-regulated by PN or depolarizing stimulation, which in turn aggravates inflammation and nociception. Inhibiting neuronal Hv1 genetically or by a newly discovered selective inhibitor YHV98-4 reduced intracellular alkalization and ROS production in inflammatory pain, mitigated the imbalance in downstream SHP-1-pAKT signaling, and also diminished pro-inflammatory chemokine release to alleviate nociception and morphine-induced hyperalgesia and tolerance. Thus, our data reveal neuronal Hv1 as a novel target in analgesia strategy and managing opioids-related side effects.
10.1038/s41422-022-00616-y
Long-lasting analgesia via targeted in situ repression of Na1.7 in mice.
Science translational medicine
Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in Na1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between Na subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of Na1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of Na1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of Na1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.
10.1126/scitranslmed.aay9056
Effect of Osteopathic Manipulative Treatment vs Sham Treatment on Activity Limitations in Patients With Nonspecific Subacute and Chronic Low Back Pain: A Randomized Clinical Trial.
Nguyen Christelle,Boutron Isabelle,Zegarra-Parodi Rafael,Baron Gabriel,Alami Sophie,Sanchez Katherine,Daste Camille,Boisson Margaux,Fabre Laurent,Krief Peggy,Krief Guillaume,Lefèvre-Colau Marie-Martine,Rannou François
JAMA internal medicine
Importance:Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations. Objective:To compare the efficacy of standard OMT vs sham OMT for reducing LBP-specific activity limitations at 3 months in persons with nonspecific subacute or chronic LBP. Design, Setting, and Participants:This prospective, parallel-group, single-blind, single-center, sham-controlled randomized clinical trial recruited participants with nonspecific subacute or chronic LBP from a tertiary care center in France starting February 17, 2014, with follow-up completed on October 23, 2017. Participants were randomly allocated to interventions in a 1:1 ratio. Data were analyzed from March 22, 2018, to December 5, 2018. Interventions:Six sessions (1 every 2 weeks) of standard OMT or sham OMT delivered by nonphysician, nonphysiotherapist osteopathic practitioners. Main Outcomes and Measures:The primary end point was mean reduction in LBP-specific activity limitations at 3 months as measured by the self-administered Quebec Back Pain Disability Index (score range, 0-100). Secondary outcomes were mean reduction in LBP-specific activity limitations; mean changes in pain and health-related quality of life; number and duration of sick leaves, as well as number of LBP episodes at 12 months; and consumption of analgesics and nonsteroidal anti-inflammatory drugs at 3 and 12 months. Adverse events were self-reported at 3, 6, and 12 months. Results:Overall, 200 participants were randomly allocated to standard OMT and 200 to sham OMT, with 197 analyzed in each group; the median (range) age at inclusion was 49.8 (40.7-55.8) years, 235 of 394 (59.6%) participants were women, and 359 of 393 (91.3%) were currently working. The mean (SD) duration of the current LBP episode was 7.5 (14.2) months. Overall, 164 (83.2%) patients in the standard OMT group and 159 (80.7%) patients in the sham OMT group had the primary outcome data available at 3 months. The mean (SD) Quebec Back Pain Disability Index scores for the standard OMT group were 31.5 (14.1) at baseline and 25.3 (15.3) at 3 months, and in the sham OMT group were 27.2 (14.8) at baseline and 26.1 (15.1) at 3 months. The mean reduction in LBP-specific activity limitations at 3 months was -4.7 (95% CI, -6.6 to -2.8) and -1.3 (95% CI, -3.3 to 0.6) for the standard OMT and sham OMT groups, respectively (mean difference, -3.4; 95% CI, -6.0 to -0.7; P = .01). At 12 months, the mean difference in mean reduction in LBP-specific activity limitations was -4.3 (95% CI, -7.6 to -1.0; P = .01), and at 3 and 12 months, the mean difference in mean reduction in pain was -1.0 (95% CI, -5.5 to 3.5; P = .66) and -2.0 (95% CI, -7.2 to 3.3; P = .47), respectively. There were no statistically significant differences in other secondary outcomes. Four and 8 serious adverse events were self-reported in the standard OMT and sham OMT groups, respectively, though none was considered related to OMT. Conclusions and Relevance:In this randomized clinical trial of patients with nonspecific subacute or chronic LBP, standard OMT had a small effect on LBP-specific activity limitations vs sham OMT. However, the clinical relevance of this effect is questionable. Trial Registration:ClinicalTrials.gov Identifier: NCT02034864.
10.1001/jamainternmed.2021.0005
Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice.
Science translational medicine
Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express , the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.
10.1126/scitranslmed.abd7702
Single-cell transcriptomic analysis of somatosensory neurons uncovers temporal development of neuropathic pain.
Cell research
Peripheral nerve injury could lead to chronic neuropathic pain. Understanding transcriptional changes induced by nerve injury could provide fundamental insights into the complex pathogenesis of neuropathic pain. Gene expression profiles of dorsal root ganglia (DRG) in neuropathic pain condition have been studied. However, little is known about transcriptomic changes in individual DRG neurons after peripheral nerve injury. Here we performed single-cell RNA sequencing on dissociated mouse DRG cells after spared nerve injury (SNI). In addition to DRG neuron types that are found under physiological conditions, we identified three SNI-induced neuronal clusters (SNIICs) characterized by the expression of Atf3/Gfra3/Gal (SNIIC1), Atf3/Mrgprd (SNIIC2) and Atf3/S100b/Gal (SNIIC3). These SNIICs originated from Cldn9/Gal, Mrgprd and Trappc3l DRG neurons, respectively. Interestingly, SNIIC2 switched to SNIIC1 by increasing Gal and reducing Mrgprd expression 2 days after nerve injury. Inferring the gene regulatory networks after nerve injury, we revealed that activated transcription factors Atf3 and Egr1 in SNIICs could enhance Gal expression while activated Cpeb1 in SNIIC2 might suppress Mrgprd expression within 2 days after SNI. Furthermore, we mined the transcriptomic changes in the development of neuropathic pain to identify potential analgesic targets. We revealed that cardiotrophin-like cytokine factor 1, which activates astrocytes in the dorsal horn of spinal cord, was upregulated in SNIIC1 neurons and contributed to SNI-induced mechanical allodynia. Therefore, our results provide a new landscape to understand the dynamic course of neuron type changes and their underlying molecular mechanisms during the development of neuropathic pain.
10.1038/s41422-021-00479-9
Sex differences in the epidemiology, clinical features, and pathophysiology of migraine.
Vetvik Kjersti Grøtta,MacGregor E Anne
The Lancet. Neurology
Migraine is two to three times more prevalent in women than men, and women report a longer attack duration, increased risk of headache recurrence, greater disability, and a longer period of time required to recover. Conditions recognised to be comorbid with migraine include asthma, anxiety, depression, and other chronic pain conditions, and these comorbidities add to the amount of disability in both sexes. Migraine-specifically migraine with aura-has been identified as a risk factor for vascular disorders, particularly in women, but because of the scarcity of data, the comparative risk in men has yet to be established. There is evidence implicating the role of female sex hormones as a major factor in determining migraine risk and characteristics, which accounts for sex differences, but there is also evidence to support underlying genetic variance. Although migraine is often recognised in women, it is underdiagnosed in men, resulting in suboptimal management and less participation of men in clinical trials.
10.1016/S1474-4422(16)30293-9
Acute inflammatory response via neutrophil activation protects against the development of chronic pain.
Science translational medicine
The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcriptomic changes were compared between patients whose LBP was resolved at 3 months with those whose LBP persisted. We found thousands of dynamic transcriptional changes over 3 months in LBP participants with resolved pain but none in those with persistent pain. Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain. In mouse pain assays, early treatment with a steroid or nonsteroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic in the short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils delayed resolution of pain in mice, whereas peripheral injection of neutrophils themselves, or S100A8/A9 proteins normally released by neutrophils, prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs. Thus, despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers.
10.1126/scitranslmed.abj9954
PIEZO2 mediates injury-induced tactile pain in mice and humans.
Szczot Marcin,Liljencrantz Jaquette,Ghitani Nima,Barik Arnab,Lam Ruby,Thompson James H,Bharucha-Goebel Diana,Saade Dimah,Necaise Aaron,Donkervoort Sandra,Foley A Reghan,Gordon Taylor,Case Laura,Bushnell M Catherine,Bönnemann Carsten G,Chesler Alexander T
Science translational medicine
Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.
10.1126/scitranslmed.aat9892
Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease.
Talavera Karel,Startek Justyna B,Alvarez-Collazo Julio,Boonen Brett,Alpizar Yeranddy A,Sanchez Alicia,Naert Robbe,Nilius Bernd
Physiological reviews
The transient receptor potential ankyrin (TRPA) channels are Ca-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.
10.1152/physrev.00005.2019
Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.
Bliss Tim V P,Collingridge Graham L,Kaang Bong-Kiun,Zhuo Min
Nature reviews. Neuroscience
The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.
10.1038/nrn.2016.68
The physiological function of different voltage-gated sodium channels in pain.
Nature reviews. Neuroscience
Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant - which most of those developed to date are not.
10.1038/s41583-021-00444-w
A sleep-active basalocortical pathway crucial for generation and maintenance of chronic pain.
Nature neuroscience
Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral nerve injury, cholinergic neurons in the anterior nucleus basalis (aNB) of the basal forebrain are increasingly active during nonrapid eye movement (NREM) sleep in a mouse model of neuropathic pain. These neurons directly activate vasoactive intestinal polypeptide-expressing interneurons in the primary somatosensory cortex (S1), causing disinhibition of pyramidal neurons and allodynia. The hyperactivity of aNB neurons is caused by the increased inputs from the parabrachial nucleus (PB) driven by the injured peripheral afferents. Inhibition of this pathway during NREM sleep, but not wakefulness, corrects neuronal hyperactivation and alleviates pain. Our results reveal that the PB-aNB-S1 pathway during sleep is critical for the generation and maintenance of chronic pain. Inhibiting this pathway during the sleep phase could be important for treating neuropathic pain.
10.1038/s41593-022-01250-y
Gastrointestinal pain.
Nature reviews. Disease primers
Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.
10.1038/s41572-019-0135-7
A Clinical Overview of Off-label Use of Gabapentinoid Drugs.
Goodman Christopher W,Brett Allan S
JAMA internal medicine
Background:The gabapentinoid drugs gabapentin and pregabalin were originally developed as antiseizure drugs but now are prescribed mainly for treatment of pain. For gabapentin, the only pain-related indication approved by the US Food and Drug Administration (FDA) is postherpetic neuralgia. For pregabalin, FDA-approved indications related to pain are limited to postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia. Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for various other pain syndromes. Such use is growing, possibly because clinicians are searching increasingly for alternatives to opioids. Observations:This report summarizes the limited published evidence to support off-label gabapentinoid uses, describes clinical cases in which off-label use is problematic, and notes how review articles and guidelines tend to overstate gabapentinoid effectiveness. Conclusions:Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses.
10.1001/jamainternmed.2019.0086
Structural plasticity and reorganisation in chronic pain.
Kuner Rohini,Flor Herta
Nature reviews. Neuroscience
Chronic pain is not simply a temporal continuum of acute pain. Studies on functional plasticity in neural circuits of pain have provided mechanistic insights and linked various modulatory factors to a change in perception and behaviour. However, plasticity also occurs in the context of structural remodelling and reorganisation of synapses, cells and circuits, potentially contributing to the long-term nature of chronic pain. This Review discusses maladaptive structural plasticity in neural circuits of pain, spanning multiple anatomical and spatial scales in animal models and human patients, and addresses key questions on structure-function relationships.
10.1038/nrn.2016.162
Effectiveness of Electroacupuncture or Auricular Acupuncture vs Usual Care for Chronic Musculoskeletal Pain Among Cancer Survivors: The PEACE Randomized Clinical Trial.
JAMA oncology
IMPORTANCE:The opioid crisis creates challenges for cancer pain management. Acupuncture confers clinical benefits for chronic nonmalignant pain, but its effectiveness in cancer survivors remains uncertain. OBJECTIVE:To determine the effectiveness of electroacupuncture or auricular acupuncture for chronic musculoskeletal pain in cancer survivors. DESIGN, SETTING, AND PARTICIPANTS:The Personalized Electroacupuncture vs Auricular Acupuncture Comparative Effectiveness (PEACE) trial is a randomized clinical trial that was conducted from March 2017 to October 2019 (follow-up completed April 2020) across an urban academic cancer center and 5 suburban sites in New York and New Jersey. Study statisticians were blinded to treatment assignments. The 360 adults included in the study had a prior cancer diagnosis but no current evidence of disease, reported musculoskeletal pain for at least 3 months, and self-reported pain intensity on the Brief Pain Inventory (BPI) ranging from 0 (no pain) to 10 (worst pain imaginable). INTERVENTIONS:Patients were randomized 2:2:1 to electroacupuncture (n = 145), auricular acupuncture (n = 143), or usual care (n = 72). Intervention groups received 10 weekly sessions of electroacupuncture or auricular acupuncture. Ten acupuncture sessions were offered to the usual care group from weeks 12 through 24. MAIN OUTCOMES AND MEASURES:The primary outcome was change in average pain severity score on the BPI from baseline to week 12. Using a gatekeeping multiple-comparison procedure, electroacupuncture and auricular acupuncture were compared with usual care using a linear mixed model. Noninferiority of auricular acupuncture to electroacupuncture was tested if both interventions were superior to usual care. RESULTS:Among 360 cancer survivors (mean [SD] age, 62.1 [12.7] years; mean [SD] baseline BPI score, 5.2 [1.7] points; 251 [69.7%] women; and 88 [24.4%] non-White), 340 (94.4%) completed the primary end point. Compared with usual care, electroacupuncture reduced pain severity by 1.9 points (97.5% CI, 1.4-2.4 points; P < .001) and auricular acupuncture reduced by 1.6 points (97.5% CI, 1.0-2.1 points; P < .001) from baseline to week 12. Noninferiority of auricular acupuncture to electroacupuncture was not demonstrated. Adverse events were mild; 15 of 143 (10.5%) patients receiving auricular acupuncture and 1 of 145 (0.7%) patients receiving electroacupuncture discontinued treatments due to adverse events (P < .001). CONCLUSIONS AND RELEVANCE:In this randomized clinical trial among cancer survivors with chronic musculoskeletal pain, electroacupuncture and auricular acupuncture produced greater pain reduction than usual care. However, auricular acupuncture did not demonstrate noninferiority to electroacupuncture, and patients receiving it had more adverse events. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02979574.
10.1001/jamaoncol.2021.0310
Qualitative sex differences in pain processing: emerging evidence of a biased literature.
Mogil Jeffrey S
Nature reviews. Neuroscience
Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.
10.1038/s41583-020-0310-6
The Role of Voltage-Gated Sodium Channels in Pain Signaling.
Bennett David L,Clark Alex J,Huang Jianying,Waxman Stephen G,Dib-Hajj Sulayman D
Physiological reviews
Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Na1.1, Na1.6, Na1.7, Na1.8, and Na1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Na1.7, Na1.8, and Na1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.
10.1152/physrev.00052.2017
Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential.
Inoue Kazuhide,Tsuda Makoto
Nature reviews. Neuroscience
Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside.
10.1038/nrn.2018.2
Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy.
Nature reviews. Endocrinology
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
10.1038/s41574-021-00496-z
Medication overuse headache.
Nature reviews. Disease primers
Medication overuse headache (MOH) is a secondary headache disorder attributed to overuse of acute headache medications by a person with an underlying headache disorder, usually migraine or tension-type headache. MOH is common among individuals with 15 or more headache days per month. Although MOH is associated with substantial disability and reductions in quality of life, this condition is often under-recognized. As MOH is both preventable and treatable, it warrants greater attention and awareness. The diagnosis of MOH is based on the history and an unremarkable neurological examination, and is made according to the diagnostic criteria of the International Classification of Headache Disorders third edition (ICHD-3). Pathophysiological mechanisms of MOH include altered descending pain modulation, central sensitization and biobehavioural factors. Treatment of MOH includes the use of headache preventive therapies, but essential to success is eliminating the cause, by reducing the frequency of use of acute headache medication, and perhaps withdrawing the overused medication altogether. Appropriate treatment is usually highly effective, leading to reduced headache burden and acute medication consumption.
10.1038/s41572-022-00415-0
Emerging targets in neuroinflammation-driven chronic pain.
Ji Ru-Rong,Xu Zhen-Zhong,Gao Yong-Jing
Nature reviews. Drug discovery
Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This Review focuses on emerging targets - such as chemokines, proteases and the WNT pathway - that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders.
10.1038/nrd4334
Calcitonin gene-related peptide: physiology and pathophysiology.
Physiological reviews
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.
10.1152/physrev.00034.2013
Central neuropathic pain.
Nature reviews. Disease primers
Central neuropathic pain arises from a lesion or disease of the central somatosensory nervous system such as brain injury, spinal cord injury, stroke, multiple sclerosis or related neuroinflammatory conditions. The incidence of central neuropathic pain differs based on its underlying cause. Individuals with spinal cord injury are at the highest risk; however, central post-stroke pain is the most prevalent form of central neuropathic pain worldwide. The mechanisms that underlie central neuropathic pain are not fully understood, but the pathophysiology likely involves intricate interactions and maladaptive plasticity within spinal circuits and brain circuits associated with nociception and antinociception coupled with neuronal hyperexcitability. Modulation of neuronal activity, neuron-glia and neuro-immune interactions and targeting pain-related alterations in brain connectivity, represent potential therapeutic approaches. Current evidence-based pharmacological treatments include antidepressants and gabapentinoids as first-line options. Non-pharmacological pain management options include self-management strategies, exercise and neuromodulation. A comprehensive pain history and clinical examination form the foundation of central neuropathic pain classification, identification of potential risk factors and stratification of patients for clinical trials. Advanced neurophysiological and neuroimaging techniques hold promise to improve the understanding of mechanisms that underlie central neuropathic pain and as predictive biomarkers of treatment outcome.
10.1038/s41572-023-00484-9
Pain and immunity: implications for host defence.
Nature reviews. Immunology
Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain.
10.1038/s41577-019-0147-2
Paediatric functional abdominal pain disorders.
Thapar Nikhil,Benninga Marc A,Crowell Michael D,Di Lorenzo Carlo,Mack Isabelle,Nurko Samuel,Saps Miguel,Shulman Robert J,Szajewska Hania,van Tilburg Miranda A L,Enck Paul
Nature reviews. Disease primers
Paediatric functional abdominal pain disorders, currently referred to as disorders of gut-brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3-16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota-gut-brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.
10.1038/s41572-020-00222-5
Clinical Evidence for Association of Acupuncture and Acupressure With Improved Cancer Pain: A Systematic Review and Meta-Analysis.
He Yihan,Guo Xinfeng,May Brian H,Zhang Anthony Lin,Liu Yihong,Lu Chuanjian,Mao Jun J,Xue Charlie Changli,Zhang Haibo
JAMA oncology
Importance:Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent. Objective:To evaluate the existing randomized clinical trials (RCTs) for evidence of the association of acupuncture and acupressure with reduction in cancer pain. Data Sources:Three English-language databases (PubMed, Embase, and CINAHL) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through March 31, 2019. Study Selection:Randomized clinical trials that compared acupuncture and acupressure with a sham control, analgesic therapy, or usual care for managing cancer pain were included. Data Extraction and Synthesis:Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. Random-effects modeling was used to calculate the effect sizes of included RCTs. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. Main Outcomes and Measures:The primary outcome was pain intensity measured by the Brief Pain Inventory, Numerical Rating Scale, Visual Analog Scale, or Verbal Rating Scale. Results:A total of 17 RCTs (with 1111 patients) were included in the systematic review, and data from 14 RCTs (with 920 patients) were used in the meta-analysis. Seven sham-controlled RCTs (35%) were notable for their high quality, being judged to have a low risk of bias for all of their domains, and showed that real (compared with sham) acupuncture was associated with reduced pain intensity (mean difference [MD], -1.38 points; 95% CI, -2.13 to -0.64 points; I2 = 81%). A favorable association was also seen when acupuncture and acupressure were combined with analgesic therapy in 6 RCTs for reducing pain intensity (MD, -1.44 points; 95% CI, -1.98 to -0.89; I2 = 92%) and in 2 RCTs for reducing opioid dose (MD, -30.00 mg morphine equivalent daily dose; 95% CI, -37.5 mg to -22.5 mg). The evidence grade was moderate because of the substantial heterogeneity among studies. Conclusions and Relevance:This systematic review and meta-analysis found that acupuncture and/or acupressure was significantly associated with reduced cancer pain and decreased use of analgesics, although the evidence level was moderate. This finding suggests that more rigorous trials are needed to identify the association of acupuncture and acupressure with specific types of cancer pain and to integrate such evidence into clinical care to reduce opioid use.
10.1001/jamaoncol.2019.5233
Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: A Randomized Clinical Trial.
JAMA psychiatry
Importance:Chronic back pain (CBP) is a leading cause of disability, and treatment is often ineffective. Approximately 85% of cases are primary CBP, for which peripheral etiology cannot be identified, and maintenance factors include fear, avoidance, and beliefs that pain indicates injury. Objective:To test whether a psychological treatment (pain reprocessing therapy [PRT]) aiming to shift patients' beliefs about the causes and threat value of pain provides substantial and durable pain relief from primary CBP and to investigate treatment mechanisms. Design, Setting, and Participants:This randomized clinical trial with longitudinal functional magnetic resonance imaging (fMRI) and 1-year follow-up assessment was conducted in a university research setting from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Clinical and fMRI data were analyzed from January 2019 to August 2020. The study compared PRT with an open-label placebo treatment and with usual care in a community sample. Interventions:Participants randomized to PRT participated in 1 telehealth session with a physician and 8 psychological treatment sessions over 4 weeks. Treatment aimed to help patients reconceptualize their pain as due to nondangerous brain activity rather than peripheral tissue injury, using a combination of cognitive, somatic, and exposure-based techniques. Participants randomized to placebo received an open-label subcutaneous saline injection in the back; participants randomized to usual care continued their routine, ongoing care. Main Outcomes and Measures:One-week mean back pain intensity score (0 to 10) at posttreatment, pain beliefs, and fMRI measures of evoked pain and resting connectivity. Results:At baseline, 151 adults (54% female; mean [SD] age, 41.1 [15.6] years) reported mean (SD) pain of low to moderate severity (mean [SD] pain intensity, 4.10 [1.26] of 10; mean [SD] disability, 23.34 [10.12] of 100) and mean (SD) pain duration of 10.0 (8.9) years. Large group differences in pain were observed at posttreatment, with a mean (SD) pain score of 1.18 (1.24) in the PRT group, 2.84 (1.64) in the placebo group, and 3.13 (1.45) in the usual care group. Hedges g was -1.14 for PRT vs placebo and -1.74 for PRT vs usual care (P < .001). Of 151 total participants, 33 of 50 participants (66%) randomized to PRT were pain-free or nearly pain-free at posttreatment (reporting a pain intensity score of 0 or 1 of 10), compared with 10 of 51 participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual care. Treatment effects were maintained at 1-year follow-up, with a mean (SD) pain score of 1.51 (1.59) in the PRT group, 2.79 (1.78) in the placebo group, and 3.00 (1.77) in the usual care group. Hedges g was -0.70 for PRT vs placebo (P = .001) and -1.05 for PRT vs usual care (P < .001) at 1-year follow-up. Longitudinal fMRI showed (1) reduced responses to evoked back pain in the anterior midcingulate and the anterior prefrontal cortex for PRT vs placebo; (2) reduced responses in the anterior insula for PRT vs usual care; (3) increased resting connectivity from the anterior prefrontal cortex and the anterior insula to the primary somatosensory cortex for PRT vs both control groups; and (4) increased connectivity from the anterior midcingulate to the precuneus for PRT vs usual care. Conclusions and Relevance:Psychological treatment centered on changing patients' beliefs about the causes and threat value of pain may provide substantial and durable pain relief for people with CBP. Trial Registration:ClinicalTrials.gov Identifier: NCT03294148.
10.1001/jamapsychiatry.2021.2669
Innovations and advances in modelling and measuring pain in animals.
Nature reviews. Neuroscience
Best practices in preclinical algesiometry (pain behaviour testing) have shifted over the past decade as a result of technological advancements, the continued dearth of translational progress and the emphasis that funding institutions and journals have placed on rigour and reproducibility. Here we describe the changing trends in research methods by analysing the methods reported in preclinical pain publications from the past 40 years, with a focus on the last 5 years. We also discuss how the status quo may be hampering translational success. This discussion is centred on four fundamental decisions that apply to every pain behaviour experiment: choice of subject (model organism), choice of assay (pain-inducing injury), laboratory environment and choice of outcome measures. Finally, we discuss how human tissues, which are increasingly accessible, can be used to validate the translatability of targets and mechanisms identified in animal pain models.
10.1038/s41583-021-00536-7
Astrocytes in chronic pain and itch.
Ji Ru-Rong,Donnelly Christopher R,Nedergaard Maiken
Nature reviews. Neuroscience
Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte 'gliopathy'. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal-glial and glial-glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.
10.1038/s41583-019-0218-1
Fibromyalgia.
Häuser Winfried,Ablin Jacob,Fitzcharles Mary-Ann,Littlejohn Geoffrey,Luciano Juan V,Usui Chie,Walitt Brian
Nature reviews. Disease primers
Fibromyalgia is a common illness characterized by chronic widespread pain, sleep problems (including unrefreshing sleep), physical exhaustion and cognitive difficulties. The definition, pathogenesis and treatment are controversial, and some even contest the existence of this disorder. In 1990, the American College of Rheumatology (ACR) defined classification criteria that required multiple tender points (areas of tenderness occurring in muscles and muscle-tendon junctions) and chronic widespread pain. In 2010, the ACR preliminary diagnostic criteria excluded tender points, allowed less extensive pain and placed reliance on patient-reported somatic symptoms and cognitive difficulties. Fibromyalgia occurs in all populations worldwide, and symptom prevalence ranges between 2% and 4% in the general population. The prevalence of people who are actually diagnosed with fibromyalgia ('administrative prevalence') is much lower. A model of fibromyalgia pathogenesis has been suggested in which biological and psychosocial variables interact to influence the predisposition, triggering and aggravation of a chronic disease, but the details are unclear. Diagnosis requires the history of a typical cluster of symptoms and the exclusion of a somatic disease that sufficiently explains the symptoms by medical examination. Current evidence-based guidelines emphasize the value of multimodal treatments, which encompass both non-pharmacological and selected pharmacological treatments tailored to individual symptoms, including pain, fatigue, sleep problems and mood problems. For an illustrated summary of this Primer, visit: http://go.nature.com/LIBdDX.
10.1038/nrdp.2015.22
Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain.
Kuner Rohini,Kuner Thomas
Physiological reviews
Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.
10.1152/physrev.00040.2019
Visceral Pain.
Grundy Luke,Erickson Andelain,Brierley Stuart M
Annual review of physiology
Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for >20% of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs. In this review, we highlight key mechanisms underlying chronic abdominal and pelvic pain associated with functional and inflammatory disorders of the gastrointestinal and urinary tracts. This includes how the colon and bladder are innervated by specialized subclasses of spinal afferents, how these afferents become sensitized in highly dynamic signaling environments, and the subsequent development of neuroplasticity within visceral pain pathways. We also highlight key contributing factors, including alterations in commensal bacteria, altered mucosal permeability, epithelial interactions with afferent nerves, alterations in immune or stress responses, and cross talk between these two adjacent organs.
10.1146/annurev-physiol-020518-114525
Cluster headache.
May Arne,Schwedt Todd J,Magis Delphine,Pozo-Rosich Patricia,Evers Stefan,Wang Shuu-Jiun
Nature reviews. Disease primers
Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that female patients describe each attack as worse than childbirth. The past decade has seen remarkable progress in the understanding of the pathophysiological background of cluster headache and has implicated the brain, particularly the hypothalamus, as the generator of both the pain and the autonomic symptoms. Anatomical connections between the hypothalamus and the trigeminovascular system, as well as the parasympathetic nervous system, have also been implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves excluding other primary headaches and secondary headaches and is based primarily on the patient's symptoms. Remarkable progress has been achieved in developing effective treatment options for single cluster attacks and in developing preventive measures, which include pharmacological therapies and neuromodulation.
10.1038/nrdp.2018.6
Genetic pain loss disorders.
Nature reviews. Disease primers
Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.
10.1038/s41572-022-00365-7
CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022.
MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports
This guideline provides recommendations for clinicians providing pain care, including those prescribing opioids, for outpatients aged ≥18 years. It updates the CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016 (MMWR Recomm Rep 2016;65[No. RR-1]:1-49) and includes recommendations for managing acute (duration of <1 month), subacute (duration of 1-3 months), and chronic (duration of >3 months) pain. The recommendations do not apply to pain related to sickle cell disease or cancer or to patients receiving palliative or end-of-life care. The guideline addresses the following four areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Recommendations are based on systematic reviews of the scientific evidence and reflect considerations of benefits and harms, patient and clinician values and preferences, and resource allocation. CDC obtained input from the Board of Scientific Counselors of the National Center for Injury Prevention and Control (a federally chartered advisory committee), the public, and peer reviewers. CDC recommends that persons with pain receive appropriate pain treatment, with careful consideration of the benefits and risks of all treatment options in the context of the patient's circumstances. Recommendations should not be applied as inflexible standards of care across patient populations. This clinical practice guideline is intended to improve communication between clinicians and patients about the benefits and risks of pain treatments, including opioid therapy; improve the effectiveness and safety of pain treatment; mitigate pain; improve function and quality of life for patients with pain; and reduce risks associated with opioid pain therapy, including opioid use disorder, overdose, and death.
10.15585/mmwr.rr7103a1
Etiology and Pharmacology of Neuropathic Pain.
Alles Sascha R A,Smith Peter A
Pharmacological reviews
Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na, K, Ca, hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the 2-1 subunit of voltage-gated Ca channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.
10.1124/pr.117.014399
Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation.
Pinho-Ribeiro Felipe A,Verri Waldiceu A,Chiu Isaac M
Trends in immunology
Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.
10.1016/j.it.2016.10.001
Vulvodynia.
Nature reviews. Disease primers
Vulvodynia is a condition that occurs in 8-10% of women of all ages and is characterized by pain at the vulva that is present during sexual and/or non-sexual situations. Diagnosis is established through careful medical history and pelvic examination, including the cotton-swab test. The onset and maintenance of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression and childhood maltreatment as well as cognitive-affective, behavioural and interpersonal factors. Given the absence of empirically supported treatment guidelines, a stepwise approach of pelvic floor physical therapy and cognitive behavioural therapy as well as medical management is suggested, with surgery as the last option. Vulvodynia has a negative effect on the quality of life of women and their partners, and imposes a profound personal and societal economic burden. In addition, women with vulvodynia are more likely to report other chronic pain conditions, which further alters their quality of life. Future efforts should aim to increase girls', women's and healthcare professionals' education and awareness of vulvodynia, phenotype different subgroups of women based on biopsychosocial characteristics among more diverse samples, conduct longitudinal studies and improve clinical trial designs.
10.1038/s41572-020-0164-2
Endogenous and Exogenous Opioids in Pain.
Corder Gregory,Castro Daniel C,Bruchas Michael R,Scherrer Grégory
Annual review of neuroscience
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
10.1146/annurev-neuro-080317-061522
Low back pain.
Vlaeyen Johan W S,Maher Chris G,Wiech Katja,Van Zundert Jan,Meloto Carolina Beraldo,Diatchenko Luda,Battié Michele C,Goossens Marielle,Koes Bart,Linton Steven J
Nature reviews. Disease primers
Low back pain affects individuals of all ages and is a leading contributor to disease burden worldwide. Despite advancements in assessment and treatment methods, the management of low back pain remains a challenge for researchers and clinicians alike. One reason for the limited success in identifying effective treatments is the large variation in the manifestations, possible causes, precipitating and maintaining factors, course, prognosis and consequences in terms of activity interference and quality of life. However, despite these challenges, steady progress has been achieved in the understanding of back pain, and important steps in the understanding of the psychological and social risk factors, genetics and brain mechanisms of low back pain have been made. These new findings have given impetus to the development of new diagnostic procedures, evidence-based screening methods and more targeted interventions, which underscore the need for a multidisciplinary approach to the management of low back pain that integrates biological, psychological and social aspects.
10.1038/s41572-018-0052-1
Brain circuits for pain and its treatment.
Science translational medicine
Pain is a multidimensional experience with sensory-discriminative, affective-motivational, and cognitive-evaluative components. Pain aversiveness is one principal cause of suffering for patients with chronic pain, motivating research and drug development efforts to investigate and modulate neural activity in the brain’s circuits encoding pain unpleasantness. Here, we review progress in understanding the organization of emotion, motivation, cognition, and descending modulation circuits for pain perception. We describe the molecularly defined neuron types that collectively shape pain multidimensionality and its aversive quality. We also review how pharmacological, stimulation, neurofeedback, surgical, and cognitive-behavioral interventions alter activity in these circuits to relieve chronic pain.
10.1126/scitranslmed.abj7360
Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms.
Jensen Troels S,Finnerup Nanna B
The Lancet. Neurology
Allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) are prominent symptoms in patients with neuropathic pain. Both are seen in various peripheral neuropathies and central pain disorders, and affect 15-50% of patients with neuropathic pain. Allodynia and hyperalgesia are classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation. Peripheral sensitisation and maladaptive central changes contribute to the generation and maintenance of these reactions, with separate mechanisms in different subtypes of allodynia and hyperalgesia. Pain intensity and relief are important measures in clinical pain studies, but might be insufficient to capture the complexity of the pain experience. Better understanding of allodynia and hyperalgesia might provide clues to the underlying pathophysiology of neuropathic pain and, as such, they represent new or additional endpoints in pain trials.
10.1016/S1474-4422(14)70102-4
Pain-resolving immune mechanisms in neuropathic pain.
Nature reviews. Neurology
Interactions between the immune and nervous systems are of central importance in neuropathic pain, a common and debilitating form of chronic pain caused by a lesion or disease affecting the somatosensory system. Our understanding of neuroimmune interactions in pain research has advanced considerably. Initially considered as passive bystanders, then as culprits in the pathogenesis of neuropathic pain, immune responses in the nervous system are now established to underpin not only the initiation and progression of pain but also its resolution. Indeed, immune cells and their mediators are well-established promoters of neuroinflammation at each level of the neural pain pathway that contributes to pain hypersensitivity. However, emerging evidence indicates that specific subtypes of immune cells (including antinociceptive macrophages, pain-resolving microglia and T regulatory cells) as well as immunoresolvent molecules and modulators of the gut microbiota-immune system axis can reduce the pain experience and contribute to the resolution of neuropathic pain. This Review provides an overview of the immune mechanisms responsible for the resolution of neuropathic pain, including those involved in innate, adaptive and meningeal immunity as well as interactions with the gut microbiome. Specialized pro-resolving mediators and therapeutic approaches that target these neuroimmune mechanisms are also discussed.
10.1038/s41582-023-00777-3
Mindfulness Meditation and Psychopathology.
Wielgosz Joseph,Goldberg Simon B,Kral Tammi R A,Dunne John D,Davidson Richard J
Annual review of clinical psychology
Mindfulness meditation is increasingly incorporated into mental health interventions, and theoretical concepts associated with it have influenced basic research on psychopathology. Here, we review the current understanding of mindfulness meditation through the lens of clinical neuroscience, outlining the core capacities targeted by mindfulness meditation and mapping them onto cognitive and affective constructs of the Research Domain Criteria matrix proposed by the National Institute of Mental Health. We review efficacious applications of mindfulness meditation to specific domains of psychopathology including depression, anxiety, chronic pain, and substance abuse, as well as emerging efforts related to attention disorders, traumatic stress, dysregulated eating, and serious mental illness. Priorities for future research include pinpointing mechanisms, refining methodology, and improving implementation. Mindfulness meditation is a promising basis for interventions, with particular potential relevance to psychiatric comorbidity. The successes and challenges of mindfulness meditation research are instructive for broader interactions between contemplative traditions and clinical psychological science.
10.1146/annurev-clinpsy-021815-093423
Cognitive and emotional control of pain and its disruption in chronic pain.
Bushnell M Catherine,Ceko Marta,Low Lucie A
Nature reviews. Neuroscience
Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states - important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.
10.1038/nrn3516
Neuropathic pain.
Nature reviews. Disease primers
Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.
10.1038/nrdp.2017.2
Neuropathic Pain: From Mechanisms to Treatment.
Finnerup Nanna Brix,Kuner Rohini,Jensen Troels Staehelin
Physiological reviews
Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on αδ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.
10.1152/physrev.00045.2019