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Chronic pain is a prevalent medical problem, and its molecular basis remains poorly understood. Here, we demonstrate the significance of the transmembrane protein (Tmem) 160 for nerve injury-induced neuropathic pain. An extensive behavioral assessment suggests a pain modality- and entity-specific phenotype in male Tmem160 global knockout (KO) mice: delayed establishment of tactile hypersensitivity and alterations in self-grooming after nerve injury. In contrast, Tmem160 seems to be dispensable for other nerve injury-induced pain modalities, such as non-evoked and movement-evoked pain, and for other pain entities. Mechanistically, we show that global KO males exhibit dampened neuroimmune signaling and diminished TRPA1-mediated activity in cultured dorsal root ganglia. Neither these changes nor altered pain-related behaviors are observed in global KO female and male peripheral sensory neuron-specific KO mice. Our findings reveal Tmem160 as a sexually dimorphic factor contributing to the establishment, but not maintenance, of discrete nerve injury-induced pain behaviors in male mice.
Learn More >Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na1.8 or Advillin neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.
Learn More >Several bone conditions e.g., bone cancer, osteoporosis and rheumatoid arthritis (RA) are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and leads not only to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been thought to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here we have addressed the disconnection between inflammation, pain and bone erosion by using a combination of two monoclonal antibodies isolated from B-cells of RA patients. We have found that mice injected with B02/B09 mAbs developed a long-lasting mechanical hypersensitivity which was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. In contrast, we found that inhibiting osteoclast activity and ASIC3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified phospholipase A2 (sPLA2) and lysophospatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with sPLA2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases like RA.
Learn More >We deployed an online pain sensitivity questionnaire (PSQ) and an at-home version of the cold pressor test (CPT) in a large genotyped cohort. We performed genome-wide association studies (GWAS) on the PSQ score (25,321 participants) and CPT duration (6,853). We identified one new genome-wide significant locus associated with the PSQ score, which was located in the TSSC1 (also known as EIPR1) gene (rs58194899, OR = 0.950 [0.933-0.967], P-value = 1.9*10-8). Although high pain sensitivity measured by both PSQ and CPT was associated with individual history of chronic and acute pains, genetic correlation analyses surprisingly suggested an opposite direction: PSQ score was inversely genetically correlated neck and shoulder pain (rg = -0.71), rheumatoid arthritis (-0.68), and osteoarthritis (-0.38), and with known risk factors, such as the length of working week (-0.65), smoking (-0.36), or extreme BMI (-0.23). Gene-based analysis followed by pathway analysis showed that GWAS results were enriched for genes expressed in the brain and involved in neuronal development and glutamatergic synapse signaling pathways. Finally, we confirmed that females with red hair were more sensitive to pain and found that genetic variation in the MC1R gene was associated with an increase in self-perceived pain sensitivity as assessed by the PSQ.
Learn More >To understand a putative causal link for depression and pain, we retrieved summary statistics from genome-wide association studies conducted for pain at 7 different body sites (N = 151,922-226,683) and major depression disorder (MDD, Ncase/control = 246,363/561,190). We conducted a bidirectional Mendelian randomization analysis using distinct genome-wide association studies-identified single nucleotide polymorphisms for each trait as instrumental variables and performed several sensitivity analyses to verify Mendelian randomization assumptions. We also conducted functional annotation analysis using 396 tissue-specific annotations from the roadmap project. Across 7 different body sites, genetic predisposition to depression was associated with pain at the neck/shoulder (odds ratio [OR] = 1.08 per one log-unit increase in depression risk, 95% confidence interval [CI]: 1.06-1.10), back (OR = 1.05, 95% CI: 1.04-1.07), abdominal/stomach (OR = 1.03, 95% CI: 1.02-1.04), as well as headache (OR = 1.10, 95% CI: 1.07-1.12), but not with pain on the face, hip, and knee. In the reverse direction, genetically instrumented multisite chronic pain (OR = 1.78 per one increment in the number of pain site, 95% CI: 1.51-2.11) and headache (OR = 1.55 per one log-unit increase in headache risk, 95% CI = 1.13-2.10) were associated with MDD. Functional annotation analysis showed differential clustering patterns where depression clustered closely with headache and neck/shoulder pain, exhibiting substantial brain tissue enrichment. Our study indicates that depression is a causal risk factor for headache and pain localized at neck/shoulder, back, and abdominal/stomach, rather than pain at face, hip, and knee, and suggests common neurological pathologies underlying the development of depression, headache, and neck/shoulder pain.
Learn More >Early neuronal processing of thermal noxious information relies mostly on molecular detectors of the transient receptor potential family expressed by specific subpopulation of sensory neurons. This information may converge to second-order wide-dynamic-range (WDR) neurons located in the deep layer of the dorsal horn of the spinal cord.
Learn More >People with chronic shoulder pain commonly report pain during arm movements in daily-life activities. Pain related to movement is commonly viewed as an accurate representation of tissue damage. Thus, when a person reports pain across a variety of movements, this is often understood as indicative of greater damage.
Learn More >Chronic pain causes disability and is prevalent in the general population. Opioids are a part of a multimodal strategy for pain management. Methadone, a cheap and long-acting synthetic opioid, may represent an option for those who have limited access to the aforementioned class of analgesics. We aimed to provide a real-world evidence for the analgesic use of methadone, compared with morphine.
Learn More >Pharmacological treatments of chronic pain can lead to numerous and sometimes serious adverse effects. Drawing on a social science approach to chronic illness, this study aimed to understand the experiences of people living with chronic pain and community pharmacists regarding the definition, prevention and management of analgesic adverse effects.
Learn More >The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.
Learn More >There is a pressing need for more effective nonaddictive treatment options for pain. Pain signals are transmitted from the periphery into the spinal cord via dorsal root ganglion (DRG) neurons, whose excitability is driven by voltage-gated sodium (Na) channels. Three Na channels (Na1.7, Na1.8, and Na1.9), preferentially expressed in DRG neurons, play important roles in pain signaling in humans. Blockade of these channels may provide a novel approach to the treatment of pain, but clinical translation of preclinical results has been challenging, in part due to differences between rodent and human DRG neurons. Human DRG neurons and iPSC-derived sensory neurons (iPSC-SNs) provide new preclinical platforms that may facilitate the development of novel pain therapeutics.
Learn More >Occipital headache, the perception of pain in the back of the head, is commonly described by patients diagnosed with migraine, tension-type headache, and occipital neuralgia. The greater and lesser occipital nerves play central role in the pathophysiology of occipital headache. In the clinical setup, such headaches are often treated with onabotulinumtoxinA, a neurotoxin capable of disrupting ability of nociceptors to get activated and/or release proinflammatory neuropeptides. Attempting to understand better onabotulinumtoxinA mechanism of action in reducing headache frequency, we sought to determine its effects on expression of inflammatory genes in injected occipital tissues. To achieve this goal, we injected 40 units of onabotulinumtoxinA into 4 muscle groups (occipitalis, splenius capitis, semispinalis capitis, and trapezius muscles – all located on one side of the occiput) of patients with chronic bilateral occipital headache scheduled for occipital nerve decompression surgery 1-month latter. At the time of surgery, we collected discarded muscle, fascia and periosteum tissues from respective locations on both sides of the neck and occiput and performed targeted transcriptome analyses to determine expression level of inflammatory genes in onabotulinumtoxinA-injected and onabotulinumA-uninjected tissues. We found that (a) onabotulinumtoxinA alters expression of inflammatory genes largely in periosteum, minimally in muscle and not at all in fascia; (b) expression of inflammatory genes in uninjected periosteum and muscle is significantly higher in historical onabotulinumA responders than historical non-responders; (c) in historical responders' periosteum, onabotulinumA decreases expression of nearly all significantly altered genes, gene sets that define well-recognized inflammatory pathways (e.g., pathways involved in adaptive/innate immune response, lymphocyte activation, and cytokine, chemokine, NF-kB, TNF and interferon signaling), and abundance of 12 different immune cell classes (e.g., neutrophils, macrophages, cytotoxic T-, NK-, Th1-, B- and dendritic-cells), whereas in historical non-responders it increases gene expression but to a level that is nearly identical to the level observed in the uninjected periosteum and muscle of historical responders, and surprisingly, (d) that the anti-inflammatory effects of onabotulinumA are far less apparent in muscles and absent in fascia. These findings suggest that in historical responders' periosteum – but not muscle or fascia – inflammation contributes to the pathophysiology of occipital headache, and that further consideration should be given to the possibility that onabotulinumA mechanism of action in migraine prevention could also be achieved through its ability to reduce pre-existing inflammation, likely through localized interaction that lead to reduction in abundance of immune cells in the calvarial periosteum.
Learn More >Persistent postsurgical pain (PPSP) is a common complication that impacts quality of life, often necessitating long-term opioid treatment. Certain neurocognitive factors, including reduced performance on cognitive flexibility tasks, are associated with increased risk for PPSP. We examine perceptions of surgical patients and clinicians regarding perioperative pain management activities and needs; patient acceptance and use of a perioperative neurocognitive training intervention; and implementation feasibility.
Learn More >Neuropathic pain induces changes in neuronal excitability and synaptic connectivity in deep layers of the anterior cingulate cortex (ACC) that play a central role in the sensory, emotional and affective consequences of the disease. However, how this impacts ACC in vivo activity is not completely understood. Using a mouse model, we found that neuropathic pain caused an increase in ACC in vivo activity, as measured by the indirect activity marker c-Fos and juxtacellular electrophysiological recordings. The enhanced firing rate of ACC neurons in lesioned animals was based on a change in the firing pattern towards bursting activity. Despite the proportion of ACC neurons recruited by noxious stimuli was unchanged during neuropathic pain, responses to noxious stimuli were characterized by increased bursting. Thus, this change in coding pattern may have important implications for the processing of nociceptive information in the ACC and could be of great interest to guide the search for new treatment strategies for chronic pain.
Learn More >The primary aim of this study was to review the effect of exercise in comparison with a non-active treatment on pain intensity, frequency of headache episodes, headache duration, quality of life, medication use, and psychological symptoms, in patients with migraine or tension-type headache (TTH). A systematic search was conducted in various electronic databases to identify all relevant studies: Medline (PubMed), PEDro, EBSCO and Google Scholar. Clinical trials assessing the effects of exercise interventions in patients with primary headaches were selected. Methodological quality was evaluated using the Cochrane Risk of Bias Tool and PEDro scale and qualitative analysis was based on classifying the results into levels of evidence according to the GRADE. 19 studies (2776 participants; 85% female) were included. The meta-analysis showed statistically significant differences in pain intensity for aerobic training in patients with migraine (SMD=-0.65; 95% CI=-1.07 to -0.22, very low certainty evidence) and for strength training in patients with TTH (SMD=-0.84; 95% CI=-1.68 to -0.01, very low certainty evidence). Statistically significant differences were also found in the medication use (SMD=-0.51; 95% CI=-0.85 to -0.17, low certainty evidence). Low transparency, replicability and high risk of bias were found. Aerobic training has a small to moderate clinical effect on pain intensity and medication use on migraine patients, with very low to low certainty of evidence. Strength training showed a moderate clinical effect with very low quality of evidence in patients with TTH. Exercise could be considered as clinically relevant for the management of patients with primary headaches, but the presence of low certainty of evidence and low transparency and replicability limited its clinical application. Perspective: This article presents current evidence about exercise interventions in patients with primary headaches, including migraine and tension-type headache. Existing findings are reviewed, and relevant data are provided on the effectiveness of each exercise modality, as well as its certainty of evidence and clinical applicability.
Learn More >Previous studies targeting inter-individual differences in pain processing in migraine mainly focused on the perception of pain. Our main aim was to disentangle pain anticipation and perception using a classical fear conditioning task, and investigate how migraine frequency and pre-scan cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio as an index of neurobiological stress response would relate to neural activation in these two phases. Functional Magnetic Resonance Imaging (fMRI) data of 23 participants (18 females; mean age: 27.61± 5.36) with episodic migraine without aura were analysed. We found that migraine frequency was significantly associated with pain anticipation in brain regions comprising the midcingulate and caudate, whereas pre-scan cortisol-to DHEA-S ratio was related to pain perception in the pre-supplementary motor area (pre-SMA). Both results suggest exaggerated preparatory responses to pain or more general to stressors, which may contribute to the allostatic load caused by stressors and migraine attacks on the brain.
Learn More >Endometriosis is a condition characterised by the presence of ectopic deposits of endometrial-like tissue outside the uterus, usually in the pelvis. The impact of laparoscopic treatment on overall pain is uncertain and a significant proportion of women will require further surgery. Therefore, adjuvant medical therapies following surgery, such as the levonorgestrel-releasing intrauterine device (LNG-IUD), have been considered to reduce recurrence of symptoms. OBJECTIVES: To determine the effectiveness and safety of post-operative LNG-IUD in women with symptomatic endometriosis.
Learn More >Migraine with aura may respond differently to therapies than migraine without aura. Individuals with migraine with aura have an elevated vascular risk, necessitating a safety assessment of migraine preventive treatments in this patient subgroup.
Learn More >Chronic pelvic pain (CPP) is a common gynaecological condition accounting for 20% of all gynaecological referrals. There are wide ranges of causes with overlapping symptomatology, therefore the management of the condition is a formidable challenge for clinicians. The aetiology of CPP is heterogeneous and in many cases, no clear diagnosis can be reached. It is in this scenario that the label of chronic pelvic pain syndrome (CPPS) can be applied. We defined women with CPPS as having a minimum duration of pain of at least 6 months, including with a diagnosis of pelvic congestion syndrome, but excluding pain caused by a condition such as endometriosis. Many surgical interventions have been tried in isolation or in conjunction with non-surgical interventions in the management with variable results. Surgical interventions are invasive and carry operative risks. Surgical interventions must be evaluated for their effectiveness prior to their prevalent use in the management of women with CPPS.
Learn More >Aquaporins (AQPs) play critical physiological roles in water balance in the central nervous system (CNS). Aquaporin-4 (AQP4), the principal aquaporin expressed in the CNS, has been implicated in the processing of sensory and pain transmission. Akt signaling is also involved in pain mediation, such as neuroinflammatory pain and bone cancer pain. Previously, we found that expression of AQP4 and p-Akt was altered in the rat spinal cord after spinal nerve ligation (SNL). Here, we further investigated the effects of the AQP4 and Akt pathways in the spinal dorsal horn (SDH) on the pathogenesis of neuropathic pain (NP). Spinal AQP4 was significantly upregulated after SNL and was primarily expressed in astrocytes in the SDH. Inhibition of AQP4 with TGN-020 attenuated the development and maintenance of NP by inhibiting glial activation and anti-neuroinflammatory mechanisms. Moreover, inhibition of AQP4 suppressed astrocyte activation both in the SDH and in primary cultures.Similar to AQP4, we found that p-Akt was also significantly elevated after SNL. Inhibition of Akt with MK2206 suppressed AQP4 upregulation and astrocyte activation both in vivo and in vitro. Furthermore, Akt blockade with MK2206 alleviated neuropathic pain in the early and late phases after SNL. These results elucidate the mechanisms involved in the roles of Akt/Aquaporin-4 signaling in the development and maintenance of NP. AQP4 is likely to be a novel therapeutic target for neuropathic pain management.
Learn More >Chronic Whiplash Associated Disorders (CWAD) are characterized by long-lasting symptoms of neck pain occurring after an acceleration-deceleration injury. Central sensitization (CS) has been suggested as the possible underlying mechanism for these symptoms, and is characterized by changes in the central nervous system. Besides CS, psychological factors are believed to play an important role in the experience of (chronic) pain.
Learn More >There is a high prevalence of posttraumatic stress disorder (PTSD) in patients with chronic pain. However, different patients are identified depending on the diagnostic system used. Moreover, it is unclear if the conceptualizations of PTSD are differently associated with outcomes of pain rehabilitation. Hence, the aims of the present study were first to explore the prevalence rates and diagnostic agreement of probable PTSD according to the ICD-11 and the DSM-5 screening tools (International Trauma Questionnaire [ITQ] vs. PTSD Checklist [PCL-5]), and secondly, to explore the associations of probable PTSD determined by ITQ and PCL-5 with psychological distress measures at baseline, and thirdly, the associations with pain and disability after pain rehabilitation adjusting for psychological covariates.
Learn More >Although pain-related fear and catastrophizing are predictors of disability in low back pain (LBP), their relationship with guarded motor behavior is unclear. The aim of this meta-analysis was to determine the relationship between pain-related threat (via pain-related fear and catastrophizing) and motor behavior during functional tasks in adults with LBP.
Learn More >This paper will emphasize the necessity to improve education about pain, its close relationship with suicide, and effective suicide screening as well as management strategies for medical providers.
Learn More >Psychological trauma (e.g., abuse, neglect) and posttraumatic stress symptoms (PTSS) commonly occur in pediatric pain populations and may be related to various maladaptive coping strategies, which may in turn affect short- and long-term pain-related outcomes in youth. Accordingly, the current scoping review and conceptual framework seeks to identify important gaps in the field's current understanding of how coping impacts outcomes in youth who have experienced trauma/PTSS and pediatric chronic pain and explores avenues for future investigation.
Learn More >This study aimed to investigate the association between sociodemographic data, physical activity, depression, anxiety and stress, sleep, and self-reported symptoms of central sensitization at baseline, in asymptomatic adolescents, and the onset of pain at 6-months follow-up.
Learn More >This study aims to observe the effects of direct suppression of the parabrachial nucleus (PBN) on chronic neuropathic pain (CNP) and CNP-related behaviors in mice.
Learn More >Severe gastrointestinal (GI) manifestations have been sporadically reported in children with COVID-19; however, their frequency and clinical outcome are unknown.
Learn More >Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.
Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).
Learn More >The study had been initiated because of restrictions put in place to control the spread of coronavirus in Milan in March 2020 that impacted clinical activities at our tertiary headache center in Milan (Foundation IRCSS Carlo Besta Neurological Institute). Treatment efforts were modified to make use of telephonic and internet communication to maintain care of our patients.
Learn More >Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes.
Learn More >To investigate what format for providing patient information (i.e. written summary, infographic or video animation) is most effective for promoting correct beliefs about imaging and inevitable consequences of low back pain (LBP).
Learn More >Chronic exertional compartment syndrome (CECS) is a condition occurring most frequently in the lower limbs and often requires corrective surgery to alleviate symptoms. Amongst military personnel, the success rates of this surgery can be as low as 20%, presenting a challenge in determining whether surgery is worthwhile. In this study, the data of 132 fasciotomies for CECS was analysed and using combinatorial feature selection methods, coupled with input from clinicians, identified a set of key clinical features contributing to the occupational outcomes of surgery. Features were utilised to develop a machine learning model for predicting return-to-work outcomes 12-months post-surgery. An AUC of 0.85 ± 0.08 was achieved using a linear-SVM, trained using 6 features (height, mean arterial pressure, pre-surgical score on the exercise-induced leg pain questionnaire, time from initial presentation to surgery, and whether a patient had received a prior surgery for CECS). To facilitate trust and transparency, interrogation strategies were used to identify reasons why certain patients were misclassified, using instance hardness measures. Model interrogation revealed that patient difficulty was associated with an overlap in the clinical characteristics of surgical outcomes, which was best handled by XGBoost and SVM-based models. The methodology was compiled into a machine learning framework, termed AITIA, which can be applied to other clinical problems. AITIA extends the typical machine learning pipeline, integrating the proposed interrogation strategy, allowing to user to reason and decide whether to trust the developed model based on the sensibility of its decision-making.
Learn More >Rheumatoid arthritis (RA) is a chronic autoimmune disease that can result in considerable disability and pain. The metacarpophalangeal (MCP) joint is the most common diseased joint in RA. In clinical practice, MCP synovitis is commonly diagnosed on the basis of musculoskeletal ultrasound (MSUS) images. However, because of the vague criteria, the consistency in grading MCP synovitis based on MSUS images fluctuates between ultrasound imaging practitioners. Therefore, a new method for diagnosis of MCP synovitis is needed. Deep learning has developed rapidly in the medical area, which often requires a large-scale data set. However, the total number of MCP-MSUS images fell far short of the demand, and the distribution of different medical grades of images was unbalanced. With use of the traditional image augmentation methods, the diversity of the data remains insufficient. In this study, a high-resolution generative adversarial network (HRGAN) method that generates enough images for network training and enriches the diversity of the training data set is described. In comparison experiments, our proposed diagnostic system based on MSUS images provided more consistent results than those provided by clinical physicians. As the proposed method is image relevant, this study might provide a reference for other medical image classification research with insufficient data sets.
Learn More >Pruritus is a recurring, long-lasting skin disease with few effective treatments. Many patients have unsatisfactory responses to currently available antipruritic treatments, and effective therapeutics are urgently needed to relieve symptoms. A previous study reported that mesenchymal stem cell (MSC)-mediated immune regulation could be used to treat skin inflammatory diseases. Multilineage-differentiating stress-enduring (Muse) cells are a new type of pluripotent stem cell that may also have the potential to treat inflammatory skin diseases.
Learn More >Greater trochanteric pain syndrome (GTPS) is a musculoskeletal condition which can cause disability and reduce quality of life. However, limited evidence is available on the long-term outcomes of people with GTPS. Our aims were to determine the long-term prevalence of GTPS; to calculate the proportion of people with GTPS who had developed hip osteoarthritis (OA); and to determine the level of function and quality of life, 11-years after initial GTPS diagnosis.
Learn More >Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for migraine prevention in adults. Real-world data on the effectiveness of fremanezumab are limited. This retrospective, observational cohort study assessed patient-reported migraine symptoms, health care resource utilization (HCRU), and direct medical costs before and after fremanezumab treatment initiation.
Learn More >Musculoskeletal disorders (MSKDs) are the most common causes of disabilities for older adults. The aim of this systematic review and meta-analysis is to assess the effectiveness of multimodal interventions including exercise rehabilitation for older adults with chronic MSKDs.
Learn More >At present, the mechanism of siSCN9A in Vincristine (VCR)-induced neuropathic pain (NP) is still unclear. This study aimed to explore the analgesic mechanism of lentivirus-siSCN9A (LV-siSCN9A) infected neurons against NP. 40 male Sprague-Dawley (SD) rats were divided into a control group (injected with normal saline), a model group (VCR-induced NP model), a LV-SC group (NP model mice were injected with LV-SC-infected dorsal root ganglia (DRG) neuron cells under the microscope), and a LV-siSCN9A group (NP model mice were injected with LV-siSCN9A-infected DRG neuron cells under the microscope, with 10 rats in each group. The changes of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats in different groups were detected by behavior testing, the Nav1.7 changes in each group were detected by immunofluorescence double standard and Western-blot method. It was found that compared with the control group, the MWT and TWL of the rats in model group were significantly decreased ( < 0.05), and the expression levels of Nav1.7 messenger ribonucleic acid (mRNA) and proteins were significantly increased ( < 0.05). Compared with LV-SC group, the MWT and TWL of rats in LV-siSCN9A group were significantly increased ( < 0.05), the expression levels of Nav1.7 mRNA and proteins were significantly decreased ( < 0.05), and the CGRP expression of spinal dorsal horn was significantly decreased. It was concluded that the LV-siSCN9A infected neurons could play an analgesic role by down-regulating Nav1.7 expression induced by VCR in NP model.
Learn More >The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10A gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10a mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10a mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10a mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10a mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.
Learn More >Calcitonin gene-related peptide receptor (CGRPR) is a heterodimer protein complex consisting of a class-B G protein-coupled receptor (GPCR) named calcitonin receptor-like receptor (CLR) and an accessory protein, receptor activity modifying protein type 1 (RAMP1). Here in this study, with several molecular modeling approaches and molecular dynamics (MD) simulations, the structural and dynamical effects of RAMP1 on the binding of small molecule CGRPR inhibitors (namely rimegepant and telcagepant) to the CGRPR extracellular ectodomain complex site (site 1) and transmembrane binding site (site 2) are investigated. Results showed that although these molecules stay stable at site 1, they can also bind to site 2, which may be interpreted as non-specificity of the ligands, however, most of these interactions at transmembrane binding site are not sustainable or are weak. Furthermore, to examine the site 2 for gepant binding, different in silico experiments (i.e., alanine scanning mutagenesis, SiteMap, ligand decomposition binding free energy analyses) are also conducted and the results confirmed the putative binding pocket (site 2) of the gepants at the CGRPRs.
Learn More >Monoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients.
Learn More >Sumatriptan was introduced in 1983, as the first of the triptans, selective 5-hydroxytryptamine (5-HT ) receptor agonists, to treat moderate to severe migraine. Migraine predominates in females. Although there have been reports of sex differences in migraine-associated features and pharmacokinetics (PKs) of some triptans, sex differences in the PKs of oral sumatriptan have never been evaluated in Korean. We conducted this study of oral sumatriptan to assess the sex differences in Korean population. Thirty-eight healthy Korean subjects who participated in two separate clinical studies receiving a single oral dose of 50 mg sumatriptan with the same protocols were included in this analysis. A total of 532 sumatriptan concentration observations were used for a population PK modeling. Validation of final population PK model of sumatriptan was performed using bootstrap and visual predictive check. The PK profile of oral sumatriptan was adequately described by a one-compartmental model with combined transit compartment model and a first-order absorption. The covariate analysis showed that the clearance of oral sumatriptan was significantly higher in males than in females (male: 444 L/h, female: 281 L/h). Our results showed that there were sex differences in the clearance of oral sumatriptan. These results encourage further studies to establish the sumatriptan pharmacokinetic-pharmacodynamic (PK-PD) model considering sex-related PK differences, which may help to determine optimal dosing regimens for effective treatment of migraine in males and females. This article is protected by copyright. All rights reserved.
Learn More >Basic pain research has shed light on key cellular and molecular mechanisms underlying nociceptive and phenomenological aspects of pain. Despite these advances, [[we still yearn for] the discovery of novel therapeutic strategies to address the unmet needs of about 70% of chronic neuropathic pain patients whose pain fails to respond to opioids as well as to other conventional analgesic agents. Importantly, a substantial body of clinical observations over the past decade cumulatively suggests that the psychedelic class of drugs may possess heuristic value for understanding and treating chronic pain conditions. The present review presents a theoretical framework for hitherto insufficiently understood neuroscience-based mechanisms of psychedelics' potential analgesic effects. To that end, searches of PubMed-indexed journals were performed using the following Medical Subject Headings' terms: pain, analgesia, inflammatory, brain connectivity, ketamine, psilocybin, functional imaging, and dendrites. Recursive sets of scientific and clinical evidence extracted from this literature review were summarized within the following key areas: (1) studies employing psychedelics for alleviation of physical and emotional pain; (2) potential neuro-restorative effects of psychedelics to remediate the impaired connectivity underlying the dissociation between pain-related conscious states/cognitions and the subcortical activity/function leading to the eventual chronicity through immediate and long-term effects on dentritic plasticity; (3) anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics as the may pertain to the role of these factors in the pathogenesis of neuropathic pain; (4) safety, legal, and ethical consideration inherent in psychedelics' pharmacotherapy. In addition to direct beneficial effects in terms of reduction of pain and suffering, psychedelics' inclusion in the analgesic armamentarium will contribute to deeper and more sophisticated insights not only into pain syndromes but also into frequently comorbid psychiatric condition associated with emotional pain, e.g., depressive and anxiety disorders. Further inquiry is clearly warranted into the above areas that have potential to evolve into further elucidate the mechanisms of chronic pain and affective disorders, and lead to the development of innovative, safe, and more efficacious neurobiologically-based therapeutic approaches.
Learn More >Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18-45 years and > 45 years) and sex.
Learn More >The pain of survival: Prevalence, patterns, and predictors of pain in survivors of childhood cancer.
Survivors of childhood cancer experience late effects as a result of their cancer treatment. Evidence for the prevalence of pain as a late effect has been equivocal. This study aimed to describe the prevalence and patterns of pain and biospsychosocial variables that may be related to pain in this population.
Learn More >Although the interrupting effect of chronic pain on voluntary-directed attention is well-documented, research on the impact of chronic pain on involuntary-directed attention remains incomplete. This study aimed to investigate the influence of chronic pain on involuntary as well as voluntary allocation of attention as, respectively, indexed by the P3a and P3b components in the event-related potential derived from the electroencephalogram. Both involuntary and voluntary captures of attention were compared between 33 patients with chronic pain and 33 healthy controls using an auditory three-stimulus oddball task (with standard, target, and unexpected distractor tones). The results revealed a reduced P3a amplitude as well as a reduced P3b amplitude in patients with chronic pain compared to healthy controls, indicating a detrimental effect of chronic pain on involuntary and voluntary attention, respectively. This study extends the picture of the impairing effects of chronic pain on attentional allocation to a current task and attentional allocation to information outside the focus of attention. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Learn More >Botulinum toxin type A (BTX-A) has been proposed as a treatment for painful diabetic peripheral neuropathy (DPN). This systematic review and meta-analysis aimed to assess the effect and safety of BTX-A for treating DPN pain.
Learn More >Sleep disturbance is prevalent among patients with chronic low back pain (CLBP). This systematic review aimed to summarize the evidence regarding the: (1) temporal relations between changes in sleep quality/quantity and the corresponding changes in pain and/or disability; and (2) role of baseline sleep quality/quantity in predicting future pain and/or disability in patients with CLBP.
Learn More >To explore pain-specific, general health-related quality of life (HRQoL), and safety outcomes of chronic pain patients prescribed cannabis-based medicinal products (CBMPs).
Learn More >In hemochromatosis, causes of abdominal pain and its associations with cirrhosis are poorly understood.
Learn More >To assess risk factors for persistent neuropathic pain in subjects recovered from COVID-19 and to study the serum level of neurofilament light chain (NFL) in those patients.
Learn More >The purpose of this narrative review is to examine the literature investigating a causal relationship between stress and migraine and evaluate its implications for managing migraine.
Learn More >Multiple Sclerosis (MS) is a debilitating autoimmune disease often accompanied by severe chronic pain. The most common type of pain in MS, called neuropathic pain, arises from disease processes affecting the peripheral and central nervous systems. It is incredibly difficult to study these processes in patients, so animal models such as experimental autoimmune encephalomyelitis (EAE) mice are used to dissect the complex mechanisms of neuropathic pain in MS. The pleiotropic cytokine tumor necrosis factor α (TNFα) is a critical factor mediating neuropathic pain identified by these animal studies. The TNF signaling pathway is complex, and can lead to cell death, inflammation, or survival. In complex diseases such as MS, signaling through the TNFR1 receptor tends to be pro-inflammation and death, whereas signaling through the TNFR2 receptor is pro-homeostatic. However, most TNFα-targeted therapies indiscriminately block both arms of the pathway, and thus are not therapeutic in MS. This review explores pain in MS, inflammatory TNF signaling, the link between the two, and how it could be exploited to develop more effective TNFα-targeting pain therapies.
Learn More >This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN.
Learn More >Osteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis of OA. We propose that the tight junction disruption may be due to an increase in zonulin activity as already demonstrated for many other chronic inflammatory disorders. After years of unreliable quantification, one study optimised the methodology, showing a positive validated correlation between plasma lipopolysaccharide (LPS), obesity, joint inflammation, and OA severity. Chemokines show a prominent role in pain development. Our systematic review confirms preliminary evidence supporting a gut-joint axis in OA pathogenesis and progression. Being modifiable by several factors, the gut microbiota is a promising target for treatment. We propose a pathogenetic model in which dysbiosis is correlated to the bipartite graph of tight junctions and bacterially-produced products, aiming to direct future studies in the search of other bacterial products and tight junction disassembly regulators.KEY MESSAGESPrevious studies and methods have underestimated the impact of the gut-joint axis in osteoarthritis and have focussed on the characterisation of microbiota phenotypes rather than clear molecular mediators of disease.Gut dysbiosis is related to higher levels of bacterial toxins that elicit cartilage and synovium inflammatory pathways.Future research may benefit from focussing on both tight junctions and bacterially-produced products.
Learn More >Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone (TT) and associated symptoms. The effect of testosterone replacement therapy (TRT) on muscle function in men with chronic pain and low TT remains to be investigated.
Learn More >The reliability of the Nordic Musculoskeletal Questionnaire (NMQ) has not been evaluated in an unselected general population. The aim of this population-based follow-up study was to estimate the reliability between a self-administered NMQ-based questionnaire and a face-to-face interview performed approximately two months later. To interpret the results, we assessed the 1-year prevalence of various pain musculoskeletal pain locations.
Learn More >Based on promising effects seen in a pilot study evaluating a generic mindfulness-based program for migraine, we developed a migraine-specific adaptation of the Mindfulness-Based Cognitive Therapy (MBCT) program. The aim of this study was to evaluate this program for feasibility and effectiveness in a randomized controlled trial.
Learn More >Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP).
Learn More >Low-grade inflammation is a possible contributing factor in the development and persistence of chronic primary pain syndromes. Related to inflammatory activity is sickness behavior, a set of behavioral responses including increased pain sensitivity, fatigue, malaise, fever, loss of appetite, as well as depressive behavior and anhedonia. To capture these behavioral responses and their relation to longstanding pain, psychometrically sound self-report questionnaires are needed. The Sickness Questionnaire (SicknessQ) was developed to assess self-reported sickness behavior based on studies on acute immune activation while maintaining relevance for persistent conditions. The aim of the current study was to evaluate aspects of the validity and reliability of the SicknessQ in a Swedish sample of persons with longstanding pain.
Learn More >Within physical therapy, manual therapy is known to be effective for managing temporomandibular disorders (TMDs). However, manual therapy is a broad term including different approaches applied to different body regions. This is the first systematic review that aims to evaluate the effectiveness of manual therapy applied specifically to the craniomandibular structures (Cranio-Mandibular Manual Therapy (CMMT)) on pain and maximum mouth opening in people with TMD. This systematic review was developed based on a pre-determined published protocol which was prospectively registered with PROSPERO (CRD42019160213). A search of MEDLINE, Embase, CINAHL, ZETOC, Web of Science, SCOPUS, PEDro, PubMed, Cochrane Library and Best Evidence, EBM reviews-Cochrane Central Register of Controlled Trials, Index to Chiropractic Literature ChiroAccess and Google Scholar databases was conducted from inception until October 2020. Randomised controlled trials comparing the effect of CMMT on pain and maximum mouth opening versus other types of treatment in TMDs were included. Two reviewers independently screened articles for inclusion, extracted data, assessed risk of bias with the revised Cochrane risk of bias tool for randomised trials and evaluated the overall quality of evidence with the Grading of Recommendations, Assessment, Development and Evaluations. A total of 2720 records were screened, of which only 6 (293 participants) satisfied the inclusion criteria. All studies showed some concerns in risk of bias, except for one, which was high risk of bias. The overall quality of evidence was very low for all outcomes because of high heterogeneity and small sample sizes. All studies showed a significant improvement in pain and maximum mouth opening for CMMT from baseline in the mid-term, but only two showed superiority compared to other interventions. Given the high heterogeneity and small sample sizes of the included studies, a quantitative synthesis was not performed. There is the need for future high methodology research investigating different manual therapy techniques applied to different regions and different populations (e.g., chronic versus acute TMD) to determine what is most effective for pain and maximum mouth opening in patients with TMDs.
Learn More >Chronic lower back pain is a common report in the general population. A dysfunctional sacroiliac joint (SIJ) is estimated to be responsible for one in five patients with lower back pain. Minimally invasive sacroiliac joint fusion (MISJF) is a surgical procedure to treat SIJ dysfunction. During the procedure, the SIJ is stabilised by implants inserted percutaneously under fluoroscopy guidance. Postoperatively, patients often report a lot of pain, which contributes to patients taking high doses of painkillers (opioids for example,) and preventing early mobilisation. In several orthopaedic procedures, intraoperative infiltration of the wound bed results in decreased consumption of analgesics, earlier mobilisation and shorter hospitalisation time. The aim of this study is to investigate the effectiveness of intraoperative SIJ infiltration with analgesia in reducing postoperative pain after MISJF.
Learn More >Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.
Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.
Learn More >One in five patients report chronic pain following total knee arthroplasty (TKA) and are considered non-improvers. Psychological interventions such as cognitive behavioral therapy (CBT), combined with exercise therapy and education may contribute to reduced pain an improved function both for patients with OA or after TKA surgery, but the evidence for the effectiveness of such interventions is scarce. This randomized controlled trial with three arms will compare the clinical effectiveness of patient education and exercise therapy combined with internet-delivered CBT (iCBT), evaluated either as a non-surgical treatment choice or in combination with TKA, in comparison to usual treatment with TKA in patients with knee OA who are considered candidates for TKA surgery.
Learn More >Diabetic peripheral neuropathy (DPN) is a common condition that is associated with neuromuscular dysfunction and peripheral sensory impairment. These deficits predispose patients to sensory and motor system limitations, foot ulcers and a high risk of falls. Exercise training has been proposed as an effective tool to alleviate neural deficits and improve whole-body function. Here we review the effects of DPN on neuromuscular function, the mechanisms underlying this impairment, and the neural and muscular adaptations to exercise training. Muscle dysfunction is an early hallmark of DPN. Deficits in muscle strength, power, mass and a greater fatigability are particularly severe in the lower extremity muscles. Non-enzymatic glycation of motor proteins, impaired excitation-contraction coupling and loss of motor units have been indicated as the main factors underlying muscular dysfunction. Among the exercise-based solutions, aerobic training improves neural structure and function and ameliorates neuropathic signs and symptoms. Resistance training induces marked improvement of muscle performance and may alleviate neuropathic pain. A combination of aerobic and resistance training (i.e., combined training) restores small sensory nerve damage, reduces symptoms, and improves muscle function. The evidence so far suggests that exercise training is highly beneficial and should be included in the standard care for DPN patients.
Learn More >Post-mastectomy pain syndrome (PMPS) is a surgical complication of breast surgery characterized by chronic neuropathic pain. The development of PMPS is multifactorial and research on its prevention is limited. The objective of this systematic review is to synthesize the existing evidence on interventions for lowering the incidence of persistent neuropathic pain after breast surgery.
Learn More >Chronic low back pain is the second leading cause of disability in the United States and is related to greater risk of opioid misuse. Research suggests that severe fatigue may be a relevant factor for better understanding the greater rates of opioid and misuse among adults with chronic low back pain. Therefore, the current study sought to examine differences in opioid misuse, risk for opioid use disorder, and hazardous alcohol use in two different groups: one group with clinically significant fatigue, and one group without clinically significant fatigue.
Learn More >Headache disorders are disabling, with major consequences for productivity, yet the literature is silent on the relationship between headache-attributed disability and lost productivity, often erroneously regarding the two as synonymous. We evaluated the relationship empirically, having earlier found that investment in structured headache services would be cost saving, not merely cost-effective, if reductions in headache-attributed disability led to > 20% pro rata recovery of lost productivity.
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