Browse by Audience
We aimed to determine the burden of opioid consumption in a cohort of patients with functional gastrointestinal disorders. All patients diagnosed with functional gastrointestinal disorders and referred to our university hospital were evaluated from 2013 to the beginning of 2019. Irritable bowel syndrome and functional dyspepsia diagnoses were determined according to Rome criteria and severity according to irritable bowel syndrome severity scoring system. Vomiting was quantified using a 5-point Likert scale, and constipation severity was measured using the Knowles-Eccersley-Scott-Symptom questionnaires. Quality of life was quantified by the GastroIntestinal Quality of Life Index. Patients were categorized as being treated on a chronic basis with either tramadol, step II opioids, step III opioids or as being opioid-free. 2933 consecutive patients were included. In our cohort, 12.5% had only irritable bowel syndrome, 39.3% had only functional dyspepsia, 24.9% had a combination of both, and 23.4% had other functional gastrointestinal disorders. Among them, the consumption of tramadol, step II (tramadol excluded) and step III opioids was 1.8, 1.3 and 0.3 % respectively in 2013 and 4.3, 3.4 and 1.9% in 2018 ( < 0.03). Opioid consumption was associated with increased vomiting ( = 0.0168), constipation ( < 0.0001), symptom severity ( < 0.001), more altered quality of life ( < 0.0001) and higher depression score ( = 0.0045). In functional gastrointestinal disorders, opioid consumption has increased in the last years and is associated with more GI symptoms (vomiting, constipation and GI severity), higher depression and more altered quality of life.
Learn More >Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.
Learn More >Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of and remained unchanged in contrast to that of , which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy.
Learn More >Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs.
Learn More >There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague-Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients.
Learn More >It is often assumed that there are two types of pain patients: those who respond well to efficacious pain therapies and those who do not respond at all, with few people in the middle. This assumption is based on research that claims that changes in pain intensity have a bimodal distribution. The claim of bimodality has led to calls for a change in how pain clinical trials are designed and analyzed, for example, performing "responder" analyses instead of comparing group means to evaluate the treatment effect. We analyzed data from four clinical trials, two each of duloxetine and pregabalin, for chronic musculoskeletal and neuropathic pain conditions to critically examine the claim of bimodality of the distribution of change in pain intensity. We found that the improper construction of histograms, using unequal bin widths, was the principal flaw leading to the bimodality claim, along with the use of the oft-criticized baseline observation carried forward (BOCF) method for imputing missing data also serving as a contributing factor. Properly constructed histograms of absolute change in pain intensity using equal bin widths, combined with more principled methods for handling missing data, resulted in distributions that had a more unimodal appearance. While our findings neither support nor refute the hypothesis that distinct populations of "responders" and "non-responders" to pain interventions exist, the analyses presented in earlier work do not provide support for this hypothesis, nor for the recommendation that pain clinical trials prioritize "responder" analyses, a less efficient analysis strategy.
Learn More >Opioid-induced hyperalgesia is a state of nociceptive sensitization secondary to opioid administration. The objective of this meta-analysis was to test the hypothesis that high-dose intraoperative opioids contribute to increased postoperative pain and hyperalgesia when compared with a low-dose regimen in patients under general anaesthesia.
Learn More >Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side-effects of opioid analgesics. We developed a novel multifunctional agonist named DN-9. Here, we studied the analgesic profiles and related side-effects of peripheral DN-9 in various pain models.
Learn More >The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.
Learn More >