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Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABA, 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABA, 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.
Learn More >Accessibility of evidence-based behavioral health interventions is one of the main challenges in health care and effective treatment approaches are not always available for patients that would benefit from them. Digitization has dramatically changed the health care landscape. Although mHealth has shown promise in addressing issues of accessibility and reach, there is vast room for improvements. The integration of technical innovations and theory driven development is a key concern. Digital solutions developed by industry alone often lack a clear theoretical framework and the solutions are not properly evaluated to meet the standards of scientifically proven efficacy. On the other hand, mHealth interventions developed in academia may be theory driven but lack user friendliness and are commonly technically outdated by the time they are implemented in regular care, if they ever are. In an ongoing project aimed at scientific innovation, the mHealth Agile Development and Evaluation Lifecycle was used to combine strengths from both industry and academia in the development of ACTsmart – a smartphone-based Acceptance and Commitment Therapy treatment for adult chronic pain patients. The present study describes the early development of ACTsmart, in the process of moving the product from alpha testing to a clinical trial ready solution.
Learn More >Melatonin is a pleiotropic hormone synthesized and secreted mainly by the pineal gland in vertebrates. Melatonin is an endogenous regulator of circadian and seasonal rhythms. Melatonin is involved in many physiological and pathophysiological processes demonstrating antioxidant, antineoplastic, anti-inflammatory, and immunomodulatory properties. Accumulating evidence has revealed that melatonin plays an important role in pain modulation through multiple mechanisms. In this review, we examine recent evidence for melatonin on pain regulation in various animal models and patients with pain syndromes, and the potential cellular mechanisms.
Learn More >Infants spending extended time in the neonatal intensive care unit are at greater risk of developing a variety of mental health problems later in life, possibly due to exposure to painful/stressful events. We used a rodent model of inflammatory neonatal pain to explore effects on fear conditioning, somatosensory function and maternal behavior. Hindpaw injections of 2% λ-carrageenan on postnatal days 1 and 4 produced an attenuation in conditioned freezing during the postweaning period, similar to our previous work with acute pain, but did not cause lasting impacts on contextual freezing nor somatosensory function. Additionally, we assessed maternal behavior to observe dam-pup interactions during the neonatal period. Results showed dams of litters which experienced pain spent similar amounts of time with pups as undisturbed controls. However, the specific behaviors differed per condition. Dams of pain litters exhibited less time licking/grooming, but more time nursing than controls. These results suggest changes in maternal care following pain could be a contributing factor underlying the long-term effects of neonatal trauma. Furthermore, our laboratory has previously shown acute, but not inflammatory pain, disrupted conditioned freezing; the current experiment observed the long-term effects of neonatal inflammatory pain on conditioned fear using a weak conditioning protocol.
Learn More >A child maltreatment history is reported more frequently among adults with chronic pain compared to the general population; unfortunately, studies have primarily relied upon retrospective maltreatment reports by adults with chronic pain. This prospective study assessed pain symptoms in a cohort of young adult women with a documented history of child maltreatment, compared with a matched cohort of women who did not experience childhood maltreatment. Young women (N = 477) were recruited between ages 14-17 years and followed annually to age 19. Of these women, 57% experienced maltreatment (i.e., physical, sexual, or emotional abuse, neglect; n = 273) substantiated by child welfare record. Maltreated women were demographically-matched to non-maltreated women, also confirmed by child welfare record. In adolescence, post-traumatic stress was assessed. Women were contacted as young adults (Mage = 24.76; n = 383) and surveyed about their pain experiences, including the presence of pain in the past week, pain severity (0-10), and number of body areas with pain. Mediation path analyses examining the impact of maltreatment and adolescent post-traumatic stress on young adult pain were estimated via structural equation modeling. As adults, women who had experienced child maltreatment reported higher pain intensity, a greater number of pain locations, and were more likely to experience pain in the previous week than non-maltreated women. Adolescent post-traumatic stress partially explained the effects of maltreatment on pain. Young adult women who experienced child maltreatment are at higher risk for pain, particularly when they also experienced post-traumatic stress as adolescents.
Learn More >CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes.
Learn More >Fatigue is commonly reported by people with chronic pain. The purpose of the current study was to examine Acceptance and Commitment Therapy (ACT), based on the Psychological Flexibility (PF) model, for fatigue in chronic pain. This study included 354 adults attending an interdisciplinary ACT-oriented treatment for chronic pain. T-tests and analyses of clinically meaningful change were used to investigate participant improvements in fatigue interference after the treatment. Pearson's correlations and hierarchical regressions were conducted to investigate associations between improvement in fatigue interference and improvements in PF processes. Finally, mixed effects models were used to explore associations between baseline fatigue interference and changes in treatment outcome measures. Participants improved in fatigue interference (d=.37), pain, some PF processes, and daily functioning (d=.18-1.08). 39.7% of participants demonstrated clinically meaningfully improvements in fatigue interference. Changes in fatigue interference was associated with changes in pain, PF processes and daily functioning, |r|= .20-.46. Change in fatigue interference was associated with change in pain acceptance independent of change in pain, β=-.36, p<.001. However, baseline fatigue interference did not predict any treatment outcome. Overall, people with fatigue appeared to benefit from the ACT-oriented interdisciplinary treatment for chronic pain, and relatively higher levels of fatigue did not appear to impede this benefit. ACT-based treatments may benefit people with chronic pain and fatigue. Future studies including experimental designs, and studies investigating other PF processes, are needed to better understand the utility of ACT for co-morbid fatigue and pain.
Learn More >The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena. Yet, the majority of studies involve healthy participants. As the pain modulatory system may differ in healthy participants and patients with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each of these populations. PubMed, Embase, Scopus databases, and the Cochrane Library were searched for articles investigating the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokinergic (CCKergic) systems in placebo and nocebo effects in pain. Twenty-eight placebo and two nocebo studies were included. Vote counting was used to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid and vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were mixed. In patients with chronic pain, only four studies investigated neurotransmitters showing no involvement of the endogenous opioid system and mixed findings regarding the dopaminergic system. As to nocebo effects, two studies suggest that the CCKergic system is involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.
Learn More >Although burst and high-frequency (HF) spinal cord stimulation (SCS) relieve neuropathic pain, their effects on neuronal hyperexcitability have not been compared. Specifically, it is unknown how the recharge components of burst SCS-either actively balanced or allowed to passively return-and/or different frequencies of HF SCS compare in altering neuronal activity. Neuronal firing rates were measured in the spinal dorsal horn on day 7 after painful cervical nerve root compression in the rat. Motor thresholds (MTs) and evoked neuronal recordings were collected during noxious stimuli before (baseline) and after delivery of SCS using different SCS modes: 10 kHz HF, 1.2 kHz HF, burst with active recharge, or burst with passive recharge. Spontaneous firing rates were also evaluated at baseline and after SCS. The average MT for 10 kHz SCS was significantly higher (p < 0.033) than any other mode. Burst with passive recharge was the only SCS mode to significantly reduce evoked (p = 0.019) and spontaneous (p = 0.0076) firing rates after noxious pinch. This study demonstrates that HF and burst SCS have different MTs and effects on both evoked and spontaneous firing rates, indicating they have different mechanisms of providing pain relief. Since burst with passive recharge was the only waveform to reduce firing, that waveform may be important in the neurophysiological response to stimulation.
Learn More >To investigate the influence of clinical and demographic features on diagnostic delay in cluster headache patients, in order to discuss diagnostic pitfalls and raise disease awareness.
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