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Chronic pain is a widespread and complex set of conditions that are often difficult and expensive to treat. Comparative effectiveness research (CER) is an evolving research method that is useful in determining which treatments are most effective for medical conditions such as chronic pain. An underutilized mechanism for conducting CER in pain medicine involves combining patient-reported outcomes (PROs) with electronic health records (EHRs). Patient-reported pain and mental and physical health outcomes are increasingly collected during clinic visits, and these data can be linked to EHR data that are relevant to the treatment of a patient's pain, such as diagnoses, medications ordered, and medical comorbidities. When aggregated, this information forms a data repository that can be used for high-quality CER. This review provides a blueprint for conducting CER using PROs combined with EHRs. As an example, the University of Pittsburgh's patient outcomes repository for treatment is described. This system includes PROs collected via the Collaborative Health Outcomes Information Registry software and cross-linked data from the University of Pittsburgh Medical Center EHR. The requirements, best practice guidelines, statistical considerations, and caveats for performing CER with this type of data repository are also discussed.
Learn More >Oxycodone is one of the options for the management of CLBP in patients with an inadequate response to other analgesics. However, oxycodone is not yet approved for noncancer pain in Japan. Here, we assessed the efficacy and long-term safety of S-8117, a controlled-release oxycodone formulation, for the management of Japanese CLBP patients.
Learn More >The transmission of visceral nociception can be inhibited by electroacupuncture (EA) at the spinal level. However, relationships between current intensity and EA-induced analgesia are still lacking. This study compares the effects of different intensities of EA at local acupoints and heterotopic acupoints on nociceptive responses of spinal wide dynamic range (WDR) neurons induced by noxious colorectal distension (CRD).
Learn More >Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos.The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context.
Learn More >Chronic headache is one of the most common pain conditions, often leading to symptomatic drug overuse. The aim of this study was to provide data on symptomatic drug consumption in an Italian outpatient population and to describe how the clinical picture of headache may change after headache experts take charge of the care of affected individuals. A total of 199 adults complaining of chronic headache were recruited through 32 pharmacies in the Pavia health district. Participants underwent four evaluations: a baseline assessment (T0) and three follow-up evaluations performed by a neurologist at 3, 6, and 12 months (T3, T6, and T12, respectively). On each occasion, they underwent a complete neurological assessment and received therapeutic adjustments to achieve better management of their headache. On the basis of a preliminary telephone interview, the prevalence rates of chronic headache and medication overuse headache (MOH) were 16 and 12%, respectively. At 12 months of follow-up, we observed a significant decrease in the frequency of attacks (T0: 9 ± 9/month vs. T12: 2 ± 2/month; < 0.001), in the number of days/month with headache (T0: 11 ± 9 vs. T12: 4 ± 4; < 0.001) and in single attack duration (T0: 34 ± 30 h vs. T12: 10 ± 19 h; < 0.001). Careful headache management resulted in a significant decrease in analgesic consumption (T0: 12 ± 16 vs. T12: 4 ± 6 doses/month; = 0.014) and a significant increase in quality of life, measured using the Migraine Disability Assessment Scale (MIDAS) and Headache Under-Response to Treatment (HURT) scales ( < 0.001). Headache management by a specialist is more effective than self-treatment, resulting in an overall benefit for headache patients.
Learn More >The remodeling of functional neuronal connectivity in chronic widespread pain (CWP) patients remains largely unexplored. This study aimed to investigate functional connectivity in CWP patients in brain networks related to chronic pain for changes related to pain sensitivity, psychological strain, and experienced pain. Functional connectivity strength of the default mode network (DMN) and the salience network (SN) was assessed with functional magnetic resonance imaging. Between-group differences were investigated with an independent component analysis for altered connectivity within the whole DMN and SN. Then, changes in connectivity between nodes of the DMN and SN were investigated with the use of a seed-target analysis in relation to the covariates clinical pain intensity, pressure pain sensitivity, psychological strain, and as an effect of experienced experimental cuff-pressure pain. CWP patients showed decreased connectivity in the inferior posterior cingulate cortex (PCC) in the DMN and increased connectivity in the left anterior insula/superior temporal gyrus in the SN when compared to controls. Moreover, higher pain sensitivity in CWP when compared to controls was related to increased connectivity within the SN (between left and right insula) and between SN and DMN (between right insula and left lateral parietal cortex). This study shows that connectivity within the DMN was decreased and connectivity within the SN was increased for CWP. Furthermore, we present a novel finding of interaction of pain sensitivity with SN and DMN-SN functional connectivity in CWP.
Learn More >Sensitive skin is a clinical syndrome defined by the occurrence of unpleasant sensations such as burning, stinging, tingling, pricking, or itching in response to various normally innocuous physical, chemical, and thermal stimuli. These particular symptoms have led the consideration of a potential dysfunction of the intra-epidermal nerve fibers (IENF) that are responsible for pain, temperature, and itch perception. This neuronal hypothesis has just been reinforced by recent studies suggesting that sensitive skin could become assimilated to small fiber neuropathy. Meanwhile, the involvement of keratinocytes, the pre-dominant epidermal cell type, has so far mainly been considered because of their role in the epidermal barrier. However, keratinocytes also express diverse sensory receptors present on sensory neurons, such as receptors of the transient receptor potential (TRP) family, including Transient Receptor Potential Vallinoid 1 (TRPV1), one of the main transducers of painful heat which is also involved in itch transduction, and Transient Receptor Potential Vallinoid 4 (TRPV4) which is depicted as a heat sensor. While TRPV1 and TRPV4 are expressed both by sensory neurons and keratinocytes, it has recently been demonstrated that the specific and selective activation of TRPV1 on keratinocytes is sufficient to induce pain. Similarly, the targeted activation of keratinocyte-expressed TRPV4 elicits itch and the resulting scratching behavior. So, contrary to classical conception, the IENF are not the exclusive transducers of pain and itch. In light of these recent advances, this review proposes to consider the putative role of epidermal keratinocytes in the generation of the unpleasant sensations characteristic of sensitive skin syndrome.
Learn More >Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase "rearranged during transfection"), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100(left-right)/right)]. Intra-group differences were studied by paired -tests. For inter-group comparisons ANOVA test followed by LSD test (when < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation.
Learn More >Despite recent advances in understanding and treating trigeminal neuralgia, its management remains a considerable challenge. Better classification of different types of facial pain and the identification of prognostic factors for different treatment options lead the way toward better quality of life for the individual patient. Although the principles of treating trigeminal neuralgia remain basically the same, antiepileptic drugs, muscle relaxants, and neuroleptic agents are widely used medical treatment options. They were not originally developed for treating trigeminal neuralgia. Carbamazepine was studied in adequate placebo-controlled clinical trials in the 1960s and is still considered the most effective drug. Among emerging treatment options currently under clinical investigation are local botulinum neurotoxin type A injections and a novel sodium channel blocker (CNV1014802) that selectively blocks the Na 1.7 sodium channel. Non-pharmacological treatment options are non-invasive electrical stimulation with either transcranial direct-current stimulation or repetitive transcranial magnetic stimulation which both require further evaluation in regard to applicability. Surgical options remain a valid choice for patients not responding to medical treatment and include Gasserian ganglion percutaneous techniques, gamma knife surgery, and microvascular decompression. There is continual effort to improve these techniques and predict the outcome for better patient selection.
Learn More >Migraine is a primary headache disorder which has complex neurogenic pathophysiological mechanisms still requiring full elucidation. The sensory nerves and meningeal mast cell couplings in the migraine target tissue are very effective interfaces between the central nervous system and the immune system. These couplings fall into three categories: intimacy, cross-talk and a shared fate. Acting as the immediate call-center of the neuroimmune system, mast cells play fundamental roles in migraine pathophysiology. Considerable evidence shows that neuroinflammation in the meninges is the key element resulting in the sensitization of trigeminal nociceptors. The successive events such as neuropeptide release, vasodilation, plasma protein extravasation, and mast cell degranulation that form the basic characteristics of the inflammation are believed to occur in this persistent pain state. In this regard, mast cells and sensory neurons represent both the target and source of the neuropeptides that play autocrine, paracrine, and neuro-endocrine roles during this inflammatory process. This review intends to contribute to a better understanding of the meningeal mast cell and sensory neuron bi-directional interactions from molecular, cellular, functional points of view. Considering the fact that mast cells play a role in expanding the opportunities for targeted new migraine therapies, it is of crucial importance to explore these multi-faceted interactions.
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