Rejected

As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

Glomus tumors, also called paragangliomas, are challenging lesions, demanding accurate knowledge of complex anatomy and pertinent approaches. We present the case of a 39-year-old male presenting with headache, vertigo, tinnitus, hearing loss, and hoarseness. Neurological assessment showed facial paralysis House-Brackmann IV and lower cranial nerves deficits. Preoperative magnetic resonance imaging (MRI) demonstrated two large lesions, suggestive of a glomus jugulare, and carotid body paragangliomas. Considering worsening of the symptoms and the important mass effect of both lesions over the neurovascular structures, microsurgical excision was offered, after preoperative tumor embolization. We preferred to approach both lesions in the same operation, starting by the cervical tumor. Initially there was not an easily identifiable dissection plane between the tumor and the carotid artery, but it was achieved after performing a subadventitial dissection, being possible to resect the entire lesion. The jugular foramen lesion was approached through a postauricular transtemporal approach, skeletonizing the sigmoid sinus, jugular bulb, and facial nerve, following a complete mastoidectomy. The tumor, extending to the intradural compartment, middle ear, internal auditory canal, petrous internal carotid artery, and internal jugular vein was completely removed. Postoperative MRI demonstrated complete resection of both lesions, and pathology confirmed to be paragangliomas. In the immediate postoperative period, the facial paralysis evolved to House-Brackmann grade VI, improving to grade III during follow-up. The patient underwent a vocal cord medialization in order to improve voice quality and swallowing. These are challenging lesions and extensive laboratory training is mandatory to be familiarized with the regional anatomy and its various surgical approaches. The link to the video can be found at: https://youtu.be/gA_ckwFq_9c .

: Purinergic P2X3-P2X2/3 receptors are placed in nociceptive neurons' strategic location and show unique desensitization properties, hence they represent an attractive target for many pain related diseases. Therefore a broad interest from academic and pharmaceutical scientists has focused on the search for P2X3 and P2X2/3 receptor ligands and has led to the discovery of numerous new selective antagonists. Some of them have been studied in clinical trials for the treatment of pathological conditions such as bladder disorders, gastrointestinal and chronic obstructive pulmonary diseases.: This review provides a summary of the patents concerning the discovery of P2X3 and/or P2X2/3 receptor antagonists published between 2015 and 2019 and their potential clinical use. Thus, the structures and biological data of the most representative molecules are reported.: The 2016 publication of the crystallographic structure of the human P2X3 receptor subtype gave an improvement of published patents in 2017. Hence, a great number of small molecules with dual antagonist activity on P2X3-P2X2/3 receptors, a favorable pharmacokinetic profile, and reasonable oral bioavailability was discovered. The most promising compounds are the phenoxy-diaminopyrimidines including gefapixant (AF-219), and the imidazo-pyridines like BLU-5937, which are in phase III and phase II clinical trials, respectively, for refractory chronic cough.

Remifentanil infusion is used as an intraoperative anesthetic for thyroidectomy, but has been associated with acute opioid tolerance and hyperalgesia. A national shortage of remifentanil provided an opportunity to study postoperative pain in patients undergoing thyroidectomy.

Dexmedetomidine (DEX) is a highly selective alpha-2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic tone inhibition. Here we report a systematic review and meta-analysis of its effects on stress, inflammation, and immunity in surgical patients during the perioperative period.

The mechanisms underlying temporomandibular disorders following orofacial pain remain unclear. Hydrogen sulfide (HS), a newly identified gasotransmitter, has been reported to modulate inflammation. Cystathionine γ-lyase (CSE) is responsible for the systemical production of HS, which exerts both pro- and antinociceptive effects through inflammation. In the current study, we investigated whether the endogenous HS production pathway contributes to arousal and maintenance of orofacial inflammatory pain, through the investigation of the effects of a CSE inhibitor, propargyglycine (PAG), in a rat CFA (Complete Freund Adjuvant)-induced temporomandibular inflammation model to mimic persistent pain in the orofacial region. For this, rats received either CFA or saline in the temporomandibular joints (TMJs), and after 3 or 14 days, they received a single injection of PAG or saline and were evaluated for nociception with the von Frey and formalin test. Also, pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were analyzed in TMJs and trigeminal ganglion (TG). In this last one, glial cells reactivity was also verified. Endogenous HS production rate were measured in both, TMJ and TG. Our results indicated decreased allodynia and hyperalgesic responses in rats submitted to CFA after injection of PAG. Moreover, PAG inhibited leucocyte migration to temporomandibular synovial fluid after 3 and 14 days of inflammation. PAG was able to reduce levels of CBS, CSE, TNF-α, and IL-1β in the TMJ and TG, after 13 days of CFA injection. The observed increased activation of glial cells in the trigeminal ganglia on the 14th day of inflammation can be prevented by the highest dose of PAG. Finally, CBS and CSE expression, and endogenous HS production rate in the TMJ and TG was found higher in rats with persistent temporomandibular inflammation compared to rats injected with saline and PAG was able to prevent this elevation. Our results elucidated the molecular mechanisms by which HS exerts its pro-inflammatory and pro-nociceptive role in the orofacial region by alterations in both local tissue and TG.

Ketamine, a phencyclidine analog and dissociative anesthetic, has been used in anesthesia since the 1960s. Serial subanesthetic administration has been explored for treatment of depression and chronic pain; however, there has been a recent surge in its intraoperative and perioperative use among anesthesia providers. As ketamine becomes an important addition to multimodal acute pain regimens, it important that anesthesia providers review the physiologic underpinnings of ketamine administration. Herein, we review the primary scientific literature and discuss recent studies that have implicated ketamine in inflammation and oxidative stress, inhibition of ion channels in dorsal horn neurons, and in disruption of frontoparietal communication. Also discussed are the potential clinical implications these effects may have for patients.

Pre-hospital analgesic treatment of injured children is suboptimal, with very few children in pain receiving analgesia. Studies have identified a number of barriers to pre-hospital pain management in children which include the route of analgesia administration. The aim of this review is to critically evaluate the pre-hospital literature, exploring the safety and efficacy of intranasal (IN) analgesics for children suffering pain.

Ultrasound-guided popliteal blocks for postoperative pain management have grown in popularity within foot and ankle surgery. The purpose of this study was to evaluate the efficacy of popliteal block in preventing postoperative emergency department visits after foot and ankle surgery. We compared rates of presentation to the emergency department for pain following foot and ankle surgery between surgeries with a popliteal block and those with local field block alone. We identified 101 charts, of which 26 presented to the emergency department for postoperative pain following popliteal block. Our results demonstrated that popliteal blocks did not perform better than local blocks, and that there is no statistically significant difference between the 2 methods of postoperative pain control in terms of rates of presentation to the emergency department for pain. Levels of Evidence: Level III, All statistical analyses were carried out using the R statistical package by the primary author (NS) (R Developmental, Core Team. R: A Language and Environment for Statistical Computing, 2012. http://www.R-project.org ).