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Post-traumatic headache (PTH) is a condition that frequently affects individuals after traumatic brain injury (TBI). Inflammation is one of the major causes of this disability. However, little is known about the trigger for, and endurance of, this painful process. Thus, the involvement of fibers containing the transient receptor potential vanilloid 1 (TRPV1) channels on the PTH and inflammation after TBI through neonatal treatment with capsaicin are investigated. Fluid percussion injury (FPI) in adult male Wistar rats caused periorbital allodynia in one, three and seven days after injury, and the neonatal treatment reversed the painful sensation in seven days. The lack of TRPV1 channels reduced the activation of macrophages and glial cells induced by TBI in the trigeminal system, which were characterized by glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1) immune content in the ipsilateral trigeminal ganglion, brainstem, and perilesional cortex. Immunofluorescence analyses of the ipsilateral Sp5C nucleus demonstrated a hypertrophic astrocytes profile after TBI which was reduced with treatment. Moreover, effects of succinate sumatriptan (SUMA – 1 mg/kg), TRPV1 selective antagonist capsazepine (CPZ – 2 mg/kg), and TRP non-selective antagonist ruthenium red (RR – 3 mg/kg) were evaluated. Although all mentioned drugs reduced the painful sensation, SUMA and CPZ demonstrated a stronger effect compared to the RR treatment, reinforcing the involvement of TRPV1 channels in periorbital allodynia after TBI. Hence, this report suggests that TRPV1-containing fibers and TRPV1 channels are able to induce inflammation of the trigeminal system and maintain the painful sensation after TBI.
Learn More >Methadone is increasingly being used for its analgesic properties. Despite the increasing popularity, many healthcare providers are not familiar with methadone's complex pharmacology and best practices surrounding its use. The purpose of this narrative review article is to discuss the pharmacology of methadone, the evidence surrounding methadone's use in acute pain management and both chronic cancer and non-cancer pain settings, as well as highlight pertinent safety, monitoring, and opioid rotation considerations. Methadone has a unique mechanism of action when compared with all other opioids and for this reason methadone has come to hold a niche role in the management of opioid-induced hyperalgesia and central sensitization. Understanding of the mechanisms of variability in methadone disposition and drug interactions has evolved over the years, with the latest evidence revealing that CYP 2B6 is the major determinant of methadone elimination and plays a key role in methadone-related drug interactions. From an acute pain perspective, most studies evaluating the use of intraoperative intravenous methadone have reported lower pain scores and post-operative opioid requirements. Oral methadone is predominantly used as a second-line opioid treatment for select chronic pain conditions. As a result, several oral morphine to oral methadone conversion ratios have been proposed, as have methods in which to rotate to methadone. From an efficacy standpoint, limited literature exists regarding the effectiveness of methadone in the chronic pain setting with most of the available efficacy data pertaining to methadone's use in the treatment of cancer pain. Many of the prospective studies that exist feature low participant numbers. Few clinical trials investigating the role of methadone as an analgesic treatment are currently underway. The complicated pharmacokinetic properties of methadone and risks of harm associated with this drug highlight how critically important it is that healthcare providers understand these features before prescribing/dispensing methadone. Particular caution is required when converting patients from other opioids to methadone and for this reason only experienced healthcare providers should undertake such a task. Further randomized trials with larger sample sizes are needed to better define the effective and safe use of methadone for pain management.
Learn More >Epigenetics of neurotrophic factors holds the potential to unravel the mechanisms underlying the pathophysiology of complex conditions such as chronic fatigue syndrome (CFS). This study explored the role of brain-derived neurotrophic factor (BDNF) genetics, epigenetics, and protein expression in patients with both CFS and comorbid fibromyalgia (CFS/FM).
Learn More >Tremendous progress has been made in the past decades for the treatment of headache disorders. Chronic migraine is the most disabling type of headache and requires the use of acute and preventive medications, many of which are associated with adverse events that limit patient adherence. Botulinum toxin (BoNT) serotype A, a neurotoxin derived from certain strains of Clostridium, disrupts neuropeptide secretion and receptor translocation related to trigeminal nociception, thereby preventing pain sensitization through peripheral and possibly central mechanisms. Ever since the first randomized controlled trial on onabotulinumtoxinA (onabotA) for migraine was published two decades ago, onabotA has been the only BoNT formulation approved for use in the prevention of chronic migraine. Superior tolerability and efficacy have been demonstrated on multiple migraine endpoints in many controlled trials and real-life studies. OnabotA is a safe and efficacious treatment for chronic migraine and possibly high-frequency episodic migraine. Further research is still needed to understand its mechanism of action to fully develop its therapeutic potential.
Learn More >The development of antinociceptive morphine tolerance is a clinically intractable problem. Previous studies clarified the pivotal roles of platelet-derived growth factor (PDGF) and its receptor PDGFRβ in morphine tolerance. Herein, we investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFRβ activation.
Learn More >The International Association for the Study of Pain has released a new classification scheme for chronic pain. This classification scheme describes chronic pain as either a symptom of a disease (chronic secondary pain) or as the disease itself (chronic primary pain). Chronic temporomandibular disorders have many similarities to other proposed chronic overlapping pain disorders, but are classified and managed by dental practitioners as a localized pain condition of the orofacial region. We review the literature to describe the similarities between chronic temporomandibular disorders and chronic overlapping pain disorders, and discuss how this evolving concept may affect the way that dentists approach the diagnosis and management of chronic temporomandibular disorders.
Learn More >The present study explores the benefits of an 8-week mindfulness-based stress reduction (MBSR) program to white matter integrity among breast cancer survivors experiencing chronic neuropathic pain (CNP).
Learn More >Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ∼7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006-2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs.
Learn More >Luminal distention and abdominal pain are major clinical hallmarks of obstructive bowel disorders and functional bowel disorders linked to gut dysbiosis. Our recent studies found that chronic lumen distention increased visceral sensitivity and decreased abundance of gut commensal Lactobacillus reuteri in a rodent model of partial colon obstruction (OB). To establish causation, we performed precision microbial therapy to assess whether recolonization of L. reuteri prevents visceral hypersensitivity in lumen distention, and if so, to identify the gut-microbiota mechanism. Lumen distention was induced in Sprague-Dawley rats by implanting an obstruction band in the distal colon for up to 7 days. L. reuteri strains or vehicle were gavage ingested 1X10 CFU/g daily starting 2 days prior to obstruction. L. reuteri rat strains that were able to recolonize obstructed colon significantly improved food intake and body weight in OB rats, and attenuated referred visceral hyperalgesia measured by the withdrawal response to von Frey filament applications to the abdomen. Mechanistically, L. reuteri treatment attenuated hyper-excitability of the dorsal root ganglia neurons projecting to the distended colon by promoting opioid receptor function in affected tissues. The expression of µ, δ, and κ opioid receptors was significantly downregulated in colonic muscularis externae and sensory neurons in OB rats. However, L. reuteri treatment prevented the loss of opioid receptors. Further, administration of peripheral opioid receptor antagonist naloxone methiodide abolished the analgesic effect of L. reuteri in OB. In conclusion, precision L. reuteri therapy prevents lumen distention-associated visceral hypersensitivity by local bacterial induction of opioid receptors.
Learn More >Acute pain that persists for a few days is associated with a reduction in patients' quality of life. Orofacial persistent pain promotes psychological disorders such as anxiety, impairs daily essential activities such as eating, and results in decreased social interaction. Here, we investigated whether rats subjected to orofacial formalin injection or intraoral incision surgery display persistent facial heat hyperalgesia, ongoing pain, anxiety-like behavior and changes in ultrasonic vocalization. Orofacial formalin injection or intraoral incision caused facial heat hyperalgesia for 3 days compared to saline-injected and sham animals. Additionally, both experimental groups showed a reduction in the number of entries and in the time spent in the open arms in the elevated plus maze test on day 3, suggesting that anxiety-like behavior developed as a consequence of persistent pain. At this time point, both groups also displayed a reduction in the number of 50-kHz calls, specifically in the flat subtype, which suggests a decrease in social communication. Moreover, on day 3 after surgery, systemic morphine produced robust conditioned place preference in rats subjected to intraoral incision compared to sham, and the former group also presented increased spontaneous facial grooming, revealing the presence of ongoing pain. Finally, western blot and immunohistochemistry analysis showed a reduction in tyrosine hydroxylase expression in the nucleus accumbens (NAc), which may reflect a decrease in mesolimbic dopaminergic activity. Altogether, the results demonstrate that acute orofacial pain causes prolonged changes in behavioral and affective pain components, which may be related to dopaminergic changes in the NAc.
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