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Cannabinoid 1 (CBR) and delta opioid receptors (DOR) associate to form heteromers that exhibit distinct pharmacological properties. Not much is known about CBR-DOR heteromer location or signaling along the pain circuit in either animal models or patients with chemotherapy-induced peripheral neuropathy (CIPN). Here, we use paclitaxel to induce CIPN in mice and confirm the development of mechanical allodynia. Under these conditions, we find significant increases in CBR-DOR heteromers in the dorsal spinal cord of mice with CIPN as well as in postmortem spinal cords from human subjects with CIPN compared to controls. Next, we investigated receptor signaling in spinal cords of mice with CIPN and found that treatment with a combination of low signaling doses of CBR and DOR ligands leads to significant enhancement in G-protein activity that could be selectively blocked by the CBR-DOR antibody. Consistent with this, administration of subthreshold doses of a combination of ligands (CBR agonist, Hu-210, and DOR agonist, SNC80) leads to significant attenuation of allodynia in mice with CIPN that is not seen with the administration of individual ligands, and this could be blocked by the CBR-DOR antibody. Together, these results imply that CBR-DOR heteromers upregulated during CIPN-associated mechanical allodynia could serve as a potential target for treatment of neuropathic pain including CIPN.
Learn More >Chronic non-malignant pain has a major impact on the well-being, mood and productivity of those affected. Opioids are increasingly prescribed to manage this type of pain, but with a risk of other disabling symptoms, when their effectiveness has been questioned. This trial is designed to implement and evaluate a patient-centred intervention targeting withdrawal of strong opioids in people with chronic pain.
Learn More >Deaths associated to tramadol, a synthetic opioid, are rising globally. Herein, we characterize prescription patterns of tramadol relative to other opioids in the USA from 2012 to 2015, by geographic region and physician specialty.
Learn More >A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.
Learn More >Time pressure to provide a quick fix is commonly cited as a reason why opioids are frequently prescribed in the United States, but there is little evidence of an association between appointment timing and clinical decision-making. As the workday progresses and appointments run behind schedule, physicians may be more likely to prescribe opioids.
Learn More >High rates of chronic non-cancer pain (CNCP), concerns about adverse effects including dependence among those prescribed potent pain medicines, the recent evidence supporting active rather than passive management strategies and a lack of funding for holistic programme have resulted in challenges around decision making for treatment among clinicians and their patients. Discrete choice experiments (DCEs) are one way of assessing and valuing treatment preferences. Here, we outline a protocol for a study that assesses patient preferences for CNCP treatment.
Learn More >An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted.
Learn More >The Centers for Disease Control and Prevention guidelines in 2016 recommended avoiding concurrent use of opioids and benzodiazepines.
Learn More >The American College of Rheumatology (ACR) 2016 criteria for fibromyalgia (FM) is recommended for use in primary and referral setting. However, neither the ACR 2016 nor its predecessor ACR 2010 criteria have been validated in a referral setting. We hypothesized that the presence of higher comorbidities in the referral care setting may affect the performance of the ACR 2016. All patients referred to a tertiary care hospital with widespread pain for more than 3 months were screened using (1) the ACR 2016 criteria and (2) by a blinded expert physician (using ACR 1990 criteria). Using the ACR 1990 as reference standard, the sensitivity and specificity were calculated. Also, concomitant depression (BPHQ: Brief Patient Health Questionnaire), anxiety disorder (GAD7: Generalized Anxiety Disorder-7) and alexithymia (TAS-20: Toronto Alexithymia Scale-20) were screened for using standardized instruments. Other central sensitization syndromes were also screened clinically. Of 147 patients (132 females; median age 36 [30-45] years, median symptom duration 4 [1-6] years), 112 met the ACR 1990 criteria while 93 met the ACR 2016 criteria. There was disagreement between the two criteria in 47 patients. The sensitivity and specificity of ACR 2016 were 71% and 60%, respectively. Patients diagnosed by ACR 2016 criteria alone, had higher GAD7 scores than those diagnosed by the ACR 1990 alone. However, BPHQ and TAS-20 did not differ between the groups. Patients diagnosed by the ACR 2016 criteria had a greater odds (OR 5.2 CI 1.3-21.7, p = 0.022) of having concomitant restless leg syndrome or post-traumatic stress disorder or chronic fatigue syndrome. The sensitivity/specificity of the ACR 2016 in tertiary settings matched those found in previous primary care-based studies. Thus, the ACR 2016 criteria are valid for use in the tertiary setting. However, patients diagnosed by only the ACR 2016 criteria (and not by the ACR 1990) have high probability of having another concomitant comorbidity.
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