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Endogenous opioid peptides and exogenous opioids modulate immune function and animal and human studies have shown that some have a depressant immunomodulatory effect. This is potentially of high clinical significance for example in cancer patients and surgery.The primary objective of this pilot study was to evaluate the effect of morphine and oxycodone on immune pathways associated with immunosuppression in gynecological laparotomy patients.Gene expression was analyzed in CD4+, CD8+ and NK cells using the 3' Affymetrix microarray. Patients were randomized to receive morphine, oxycodone, or non-opioid 'control' analgesia during and after surgery. Genes demonstrating differential expression were those with a ≥±2-fold difference and p-value≤0.05 following ANOVA. Cytometric bead array and NK cell degranulation assay were used to investigate changes in serum cytokine concentration and in NK cell cytotoxicity, respectively. Forty patients had satisfactory RNA which was hybridized to gene chips. Genes were identified (Partek® Genomics Suite® 6.6) at baseline, 2 h, 6 h and 24 h and were either ≥2-fold up or down-regulated from baseline.At 2 h, a large number of genes were down-regulated with morphine but not with control analgesia or oxycodone. Statistically significant increases in IL-6 concentrations were induced by morphine only; NK cell activity was suppressed with morphine, but maintained with oxycodone and epidural analgesia.Gene expression profiles suggest that at 2 h post-incision morphine appeared to be immunosuppressive as compared to oxycodone and non-opioid control analgesia.
Learn More >Triptans are 5-HT receptor agonists (that also display 5-HT receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity and in vitro/in vivo vascular effects of lasmiditan, and compared it to sumatriptan.
Learn More >Calcitonin gene-related peptide (CGRP) is a neuronal transmitter present in intracranial sensory nerves, where it is involved in migraine pathophysiology as well as other biological functions. Recently, the fully human monoclonal antibody erenumab (AMG 334), which targets the canonical calcitonin gene-related peptide receptor, showed significant prophylactic efficacy and favourable safety in phase II and III clinical trials for episodic and chronic migraine and is now approved for migraine prevention in several countries.
Learn More >A pilot-randomised controlled trial (RCT) examined the effects of a brief mindfulness-based intervention (MBI) on persistent pain patients and assessed the feasibility of conducting a definitive RCT. A brief (15 min) mindfulness body-scan audio was compared with an active control administered in a clinic and then used independently over 1 month. Immediate effects of the intervention were assessed with brief measures of pain severity, distraction and distress. Assessments at baseline, 1 week and 1 month included pain severity and interference, mood, pain-catastrophizing, mindfulness, self-efficacy, quality of life and intervention acceptability. Of 220 referred patients, 147 were randomised and 71 completed all assessments. There were no significant immediate intervention effects. There were significant positive effects for ratings of intervention 'usefulness' at 1 week (p = 0.044), and pain self-efficacy at 1 month (p = 0.039) for the MBI group compared with control. Evidently, it is feasible to recruit persistent pain patients to a brief MBI study. Strategies are needed to maximise retention of participants.Trial registration Current controlled trials ISRCTN61538090. Registered 20 April 2015.
Learn More >CGRP plays a major role in the pathophysiology of migraine. Concomitant, CGRP plays a role in endogenous neurovascular protection from severe vasoconstriction associated with e.g. cerebral or cardiac ischemia. The CGRP antagonistic antibodies Fremanezumab (TEVA Pharmaceuticals) and Erenumab (Novartis/Amgen) have successfully been developed for the prevention of frequent migraine attacks. Whereas these antibodies might challenge endogenous neurovasular protection during severe cerebral or coronary vasoconstriction, potential future therapeutic CGRP agonists might induce migraine-like headaches in migraineurs. In the current study segments of cerebral artery have been used to obtain mechanistic insight of the CGRP-neutralizing anti-body Fremanezumab in neurovascular regulation in vitro. The basilar artery was selected due to its relevance in subarachnoid hemorrhage (SAH). Erenumab is known to block the human CGRP receptor and Fremanezumab to neutralize both human and rat CGRP. Results confirmed that Erenumab does not block the rat CGRP receptor and that Fremanezumab inhibits the vasodilatory effect induced by both human CGRP, rat CGRP and the metabolically stable CGRP analog, SAX in rat basilar artery. Fremanezumab also inhibits the vasodilatory effect of capsaicin in constricted segments of basilar artery. Capsaicin is used as a pharmacological tool to induce secretion of endogenous perivascular CGRP and our studies confirm that the antibody reach the perivascular sensory synaptic cleft and blocks the vasodilatory response of released CGRP in the present in vitro model. Thus, CGRP neutralization might have the mechanistic potential to block vasoprotective responses to severe vasoconstriction provided they reach the site of action and Fremanezumab is an important tool for future investigations of the impact of CGRP physiology.
Learn More >Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants.
Learn More >Pain catastrophizing has been shown to predict greater pain and less physical function in daily life for chronic pain sufferers, but its effects on close social partners have received much less attention. The overall purpose of the present study was to examine the extent to which pain catastrophizing is an interpersonal coping strategy that is maladaptive for patients and their spouses. A total of 144 older knee osteoarthritis patients and their spouses completed baseline interviews and a 22-day diary assessment. Multilevel lagged models indicated that, on days when patients reported greater catastrophizing in the morning, their spouses experienced more negative affect throughout the day. In addition, a higher level of punishing responses from the spouse predicted greater pain catastrophizing the next morning, independent of patient pain and negative affect. Multilevel mediation models showed that patients' morning pain catastrophizing was indirectly associated with spouses' negative affect and punishing responses via patients' own greater negative affect throughout the day. There was no evidence that spouses' empathic or solicitous responses either followed or preceded patients' catastrophizing. These findings suggest that cognitive-behavioral interventions that reduce pain catastrophizing should be modified for partnered patients to address dyadic interactions and the spouse's role in pain catastrophizing.
Learn More >To assess the prevalence and characteristics of chronic neck pain, chronic low back pain, and migraine or frequent headaches among Spanish adults in 2014 according to gender, to identify predictors for each of these types of pains, and to compare the prevalence with those found in 2009.
Learn More >Exercise therapy (ET) is advocated as a treatment for chronic nonspecific low back pain (CNSLBP). However, therapy effect sizes remain low. In other chronic disorders, training at higher intensity has resulted in greater improvements on both general health related and disease specific outcomes compared to lower intensity ET. Possibly, high intensity training also improves effect sizes in CNSLBP.
Learn More >Neuroimaging studies have shown that chronic pain is maladaptive and influences brain function and behavior by altering the flexible cerebral information flow. We utilized power spectral analysis to investigate the impact of classic trigeminal neuralgia (TN) on the oscillation dynamics of intrinsic brain activity in humans. The amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) were measured in 29 TN patients and 34 age- and sex-matched healthy controls (HCs) via resting-state functional MRI (R-fMRI). Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. Differences in blood oxygen level-dependent (BOLD) signal fluctuations and related resting-state functional connectivity (rsFC) between the TN patients and HCs were identified. The TN patients had reduced ALFF/fALFF in the posterior cingulate cortex (PCC), left insula, left dorsolateral prefrontal cortex (DLPFC), left putamen and bilateral temporal lobe, exclusively in the frequency of the slow-5 band. Whole brain rsFC analyses with these six different regions as seeds revealed two weaker circuits including the PCC-medial prefrontal cortex (mPFC) and DLPFC-hippocampus circuits, indicating abnormal interactions with the default mode network (DMN) in TN patients. The functional connectivity between the default-mode regions (mPFC and PCC) in the slow-5 band tracked pain intensity. Together, our results provide novel insights into how TN disturbs the cortical rhythms and functional interactions of the brain. These insights may have implications for the understanding and treatment of brain dysfunction in chronic pain patients, including TN patients.
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