Comparing the Risk of Infusion-Related Reactions and Tolerability in Patients Given Cetirizine or Diphenhydramine Prior to Ocrelizumab Infusion (PRECEPT).

Background: Ocrelizumab is an effective medication for multiple sclerosis. However, infusion-related reactions (IRRs) are a concern for patients and may lead to discontinuation of ocrelizumab. To minimize IRRs, pre-medications are administered. However, from our experience, these medications, especially diphenhydramine, can cause marked drowsiness. The primary objective of this study was to evaluate whether cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity of reactions from ocrelizumab infusions. Methods: Twenty participants were serially randomized in a 1:1 ratio to receive 10 mg of cetirizine or 25 mg of diphenhydramine orally prior to their first three ocrelizumab infusions. Results: The rate of IRRs in this study was similar across both treatment groups with no increase in the risk of severity, and no grade 3 IRRs. Further, patients receiving cetirizine experienced a reduction in fatigue. While there was not a significant difference in global satisfaction, this score increased over time in the cetirizine arm while it remained unchanged in the diphenhydramine arm. Conclusions: Overall, our results suggest that cetirizine does not increase the risk of infusion-related reactions compared to diphenhydramine.

A randomized study of IV prochlorperazine plus diphenhydramine versus IV hydromorphone for migraine-associated symptoms: A post hoc analysis.

OBJECTIVE: We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine-associated symptoms of hydromorphone, an opioid, versus prochlorperazine, an antidopaminergic antiemetic. METHODS: This was a post hoc analysis of data from a double-blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia. RESULTS: A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction [ARR] = 38.8%, 95% CI: 20.5%-57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%-37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%-34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness. CONCLUSIONS: Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine-associated symptoms.

Localized muscle spasm as a manifestation of pembrolizumab-induced infusion reaction.

INTRODUCTION: As immune checkpoint inhibitors increasingly gain oncological utility, the incidence of unique adverse events may rise as well. The description and management of localized, recurrent muscle spasms secondary to pembrolizumab infusions has not previously been reported. CASE REPORT: A 64-year-old male receiving pembrolizumab infusions experienced acute-onset, isolated spasms and pain occurring in cycles 2 through 5.Management and outcome: Pretreatment with intravenous lorazepam, diphenhydramine, famotidine, ondansetron, and fluids have led to spasm-free pembrolizumab infusions. DISCUSSION: The purpose of this report is to provide the first known incidence and successful corrective measures taken for localized muscle spasms secondary to pembrolizumab infusion.

Premedication with montelukast and rupatadine decreased rituximab infusion time, rate, severity of reactions and use of rescue medications.

Rituximab-associated infusion reactions (IRs) are significant burdens on oncology patients, caregivers and healthcare providers. We evaluated whether montelukast and rupatadine improve rituximab delivery, decrease frequency/severity of IRs and the number of medications used to control IRs. Using a nonrandomized clinical study design, we assessed adult rituximab naïve patients with B-cell lymphoid malignancies from January 2017 to July 2019. Prior to the first rituximab infusion patients received one of the premedication regimens: (i) standard premedications, diphenhydramine hydrochloride and acetaminophen ("SP" group); (ii) SP + montelukast ("M" group); (iii) SP + rupatadine ("R" group); (iv) SP + rupatadine + montelukast Schedule 1 ("M + R Schedule 1" group); (v) SP + rupatadine + montelukast Schedule 2 ("M + R Schedule 2" group). A total of 223 patients with a median age of 69 years were assessed. Demographics and treatment groups were comparable among all five groups. Mean rituximab infusion time was 290 min in the SP group versus 273, 261, 243 and 236 min in the M, R, M + R Schedule 1 and M + R Schedule 2 groups, respectively. The incidence of rituximab IRs was 75% in the SP group versus 44, 41, 22 and 22% in the M, R, M + R Schedule 1 and M + R Schedule 2 groups, respectively. The median reaction grade was 2 in the SP group and 0 in all other groups. The median number of rescue medications was 3 in the SP group and 0 in all other groups. In conclusion, montelukast and rupatadine significantly improved rituximab delivery, decreased the rate and severity of IRs and reduced the need for rescue medications.

Intravenous Cetirizine Versus Intravenous Diphenhydramine for the Treatment of Acute Urticaria: A Phase III Randomized Controlled Noninferiority Trial.

STUDY OBJECTIVE: Acute urticaria is a frequent presentation in emergency departments (EDs), urgent care centers, and other clinical arenas. Treatment options are limited if diphenhydramine is the only intravenous antihistamine offered because of its short duration of action and well-known adverse effects. We evaluate cetirizine injection, the first second-generation injectable antihistamine, for acute urticaria in this multicenter, randomized, noninferiority, phase 3 clinical trial. METHODS: Adult patients presenting to EDs and urgent care centers with acute urticaria requiring an intravenous antihistamine were randomized to either intravenous cetirizine 10 mg or intravenous diphenhydramine 50 mg. The primary endpoint was the 2-hour pruritus score change from baseline, with time spent in treatment center and rate of return to treatment centers as key secondary endpoints. Frequency of sedation and anticholinergic adverse effects were also recorded. RESULTS: Among 262 enrolled patients, the 2-hour pruritus score change from baseline for intravenous cetirizine was statistically noninferior to that for intravenous diphenhydramine (-1.6 versus -1.5; 95% confidence interval -0.1 to 0.3), and in favor of cetirizine. Treatment differences also favored cetirizine for mean time spent in treatment center (1.7 versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), lower change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), and adverse event rate (3.9% versus 13.3%). CONCLUSION: Intravenous cetirizine is an effective alternative to intravenous diphenhydramine for treating acute urticaria, with benefits of less sedation, fewer adverse events, shorter time spent in treatment center, and lower rates of revisit to treatment center.

I-FiBH trial: intravenous fluids in benign headaches-a randomised, single-blinded clinical trial.

BACKGROUND: Many emergency physicians use an intravenous fluid bolus as part of a 'cocktail' of therapies for patients with headache, but it is unclear if this is beneficial. The objective of this study was to determine if an intravenous fluid bolus helps reduce pain or improve other outcomes in patients who present to the ED with a benign headache. METHODS: This was a randomised, single-blinded, clinical trial performed on patients aged 10-65 years old with benign headaches who presented to a single ED in Las Vegas, Nevada, from May 2017 to February 2019. All patients received prochlorperazine and diphenhydramine, and they were randomised to also receive either 20 mL/kg up to 1000 mL of normal saline (the fluid bolus group) or 5 mL of normal saline (the control group). The primary outcome was the difference between groups in mean pain reduction 60 min after the initiation of treatment. Secondarily, we compared groups with regards to pain reduction at 30 min, nausea scores, the use of rescue medications and disposition. RESULTS: We screened 67 patients for enrolment, and 58 consented. Of those, 35 were randomised to the fluid bolus group and 23 to the control group. The mean pain score dropped by 48.3 mm over 60 min in the fluid bolus group, compared with 48.7 mm in the control group. The between groups difference of 0.4 mm (95% CI -16.5 to 17.3) was not statistically significant (p=0.96). Additionally, no statistically significant difference was found between groups for any secondary outcome. CONCLUSION: Though our study lacked statistical power to detect small but clinically significant differences, ED patients who received an intravenous fluid bolus for their headache had similar improvements in pain and other outcomes compared with those who did not. TRIAL REGISTRATION NUMBER: NCT03185130.

Multiple cranial nerve injury in Ramsay Hunt Syndrome: a case report.

Herpes zoster oticus (Ramsay Hunt Syndrome) is characterized by facial nerve paralysis, ear pain and auricular skin rash. It occurs as a result of reactivation oflatent varicella zoster virus infection in the geniculate ganglion of the facial nerve. Major clinical symptoms include 7th nerve paralysis or cranial nerve paralysis and vesicles along the nerve with cocomitant ear pain. Other cranial nerve involvement although uncommon, can be found in some cases. In this study, a 74-year-old female patient had ipsilateral 8th, 9th and 10th cranial nerves injury. Cranial nerve paralysis accompanied with injury has been repor ted in R amsay Hunt Syndrome.

Initial Development toward Non-Invasive Drug Monitoring via Untargeted Mass Spectrometric Analysis of Human Skin.

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.

Intravenous Fluid for the Treatment of Emergency Department Patients With Migraine Headache: A Randomized Controlled Trial.

STUDY OBJECTIVE: The objective of this pilot study is to assess the feasibility and necessity of performing a large-scale trial to measure the effect of intravenous fluid therapy on migraine headache pain. METHODS: This was a single-center, pilot randomized controlled trial. We randomized adult emergency department migraine headache patients to receive 1 L of normal saline solution during 1 hour (fluid group) or saline solution at 10 mL/hour for 1 hour (control group). All patients received intravenous prochlorperazine and diphenhydramine at the start of fluid administration. Participants and outcome assessors were blinded; nurses administering the intervention were not. Outcomes were assessed at 60 and 120 minutes, and 48 hours. The primary outcome was the difference in the verbal pain rating (on a scale of 0 to 10) between 0 and 60 minutes. Key secondary outcomes included additional clinical endpoints, the rate of protocol completion, and the effectiveness of blinding. RESULTS: Fifty patients consented to participate; one withdrew, leaving 25 patients randomized to the fluid group and 24 in the no fluid group. The mean improvement in 0- to 60-minute pain score was 4.5 (95% confidence interval 3.7 to 5.3) in the fluid group and 4.9 (95% confidence interval 3.5 to 6.2) in the control group. Primary outcome data were collected for 49 of 50 enrolled patients, and only one participant correctly identified the group assignment. CONCLUSION: This pilot study showed no statistically significant treatment effect from fluid administration, but does not exclude the possibility of a clinically important treatment effect. The study protocol and approach to blinding are both feasible and effective.

The feasibility of dexamethasone omission in weekly paclitaxel treatment for breast cancer patients.

OBJECTIVES: Patients with breast cancer who receive weekly paclitaxel therapy may experience deleterious effects associated with prophylactic dexamethasone use for 12 consecutive weeks. Approximately 90% of paclitaxel hypersensitivity reactions (HSRs) occur within the first 10 to 15 min of the first two infusions. We investigated the feasibility of dexamethasone withdrawal between weeks 3 and 12 (W3 and W12) in early stage breast cancer patients treated with weekly paclitaxel at the standard dose (80 mg/m2). METHODS: All patients received intravenous prophylaxis of dexamethasone 20 mg, ranitidine 50 mg, and diphenhydramine 50 mg in the first 2 weeks (W1 and W2) of treatment. Provided that no serious (G3/G4) HSRs events occurred, dexamethasone was omitted between W3 and W12, while ranitidine and diphenhydramine were continued. The primary end point was the incidence of any grade HSRs during the treatment period, and the secondary end points were quality of life and weight changes. RESULTS: Twenty-five patients were included in the study, and 300 infusion cycles of paclitaxel were evaluated for HSRs. The overall incidence of HSRs was 0.6% (2 events), and both of these events occurred in the first week. There were no incidents of serious HSRs or anaphylaxis and no G3 or G4 toxicities. Scores from the EORTC QLQ-C30 questionnaire did not change significantly for the global health status/quality of life scale or for the symptoms scales, although changes in scores differed significantly for the functional scales. There were no clinically relevant weight changes during the treatment period. CONCLUSIONS: Dexamethasone withdrawal from W3 to W12 in early stage breast cancer patients treated with weekly paclitaxel is feasible. The incidence of all grades of HSRs was comparable to that reported in trials with dexamethasone for 12 consecutive weeks, and no serious events (G3/G4) occurred. Studies with larger sample sizes are needed to confirm our results which are important, especially for patients for whom corticosteroids are contraindicated.

Intravenous lidocaine in the management of chronic peripheral neuropathic pain: a randomized-controlled trial.

PURPOSE: Neuropathic pain, resulting from injury to the peripheral or central nervous system, is due to upregulation of aberrant sodium channels with neuronal hyperexcitability. Lidocaine blocks these channels and several studies show that intravenous (IV) lidocaine infusion provides significant relief in patients with chronic peripheral neuropathic pain in the short term (for up to six hours). Our objective was to determine if IV lidocaine provides significant pain relief and overall improvement in quality of life in the longer term (for up to four weeks). METHODS: This single site randomized double-blind, crossover trial compared IV lidocaine infusion (5 mg·kg-1) with active placebo infusion containing diphenhydramine (50 mg) in patients with chronic neuropathic pain of peripheral nerve origin of at least six months duration. The primary outcome was average pain intensity reduction from IV lidocaine relative to placebo at four weeks post-infusion. Secondary outcome measures included parameters of physical function, mood, and overall quality of life. RESULTS: We enrolled 34 subjects in this trial-mostly with painful diabetic neuropathy and post-herpetic neuralgia. There were no significant differences between IV lidocaine and placebo infusions at any time point involving any of the outcome measures. Mean (standard deviation) pain intensity at week 4 for the placebo and lidocaine groups were not different [6.58 (1.97) vs 6.78 (1.56), respectively; between-group difference, 0.17; 95% confidence interval, - 0.50 to 0.84]. CONCLUSION: We found no significant long-term analgesic or quality of life benefit from IV lidocaine relative to control infusion for chronic peripheral neuropathic pain. TRIAL REGISTRATION: clinicaltrials.gov (NCT01669967); registered 22 June, 2012.

RéSUMé: OBJECTIF: La douleur neuropathique, résultat d'une lésion du système nerveux périphérique ou central, est due à l'augmentation de canaux sodiques aberrants accompagnée d'une hyperexcitabilité neuronale. La lidocaïne bloque ces canaux et plusieurs études ont démontré qu'une perfusion intraveineuse (IV) de lidocaïne offrait un important soulagement à court terme (pour une durée maximale de six heures) aux patients atteints de douleur neuropathique périphérique chronique. Notre objectif était de déterminer si la lidocaïne IV procurait un soulagement significatif de la douleur et une amélioration globale de la qualité de vie à plus long terme (pour une durée maximale de quatre semaines). MéTHODE: Cette étude randomisée croisée à double insu et mono-site a comparé une perfusion de lidocaïne IV (5 mg·kg−1) à une perfusion de placebo actif contenant de la diphenhydramine (50 mg) chez des patients atteints de douleur neuropathique chronique provenant du système nerveux périphérique et durant depuis au moins six mois. Le critère d'évaluation principal était la réduction moyenne de l'intensité de la douleur procurée par la lidocaïne IV par rapport au placebo à quatre semaines post-perfusion. Les critères d'évaluation secondaires comprenaient divers paramètres pour mesurer la capacité physique fonctionnelle, l'humeur et la qualité de vie globale. RéSULTATS: Nous avons recruté 34 patients pour cette étude, la plupart souffrant de neuropathie diabétique douloureuse et de névralgie post-herpétique. Aucune différence significative n'a été observée entre les perfusions de lidocaïne IV et de placebo, quel que soit le point de mesure dans le temps, pour aucun de nos critères d'évaluation. L'intensité de la douleur moyenne (écart type) à la semaine 4 était similaire dans les groupes placebo et lidocaïne [6,58 (1,97) vs 6,78 (1,56), respectivement; différence intergroupe, 0,17; intervalle de confiance 95 %, − 0,50 à 0,84]. CONCLUSION: Nous n'avons trouvé aucun bienfait significatif sur l'analgésie à long terme ou la qualité de vie d'une perfusion de lidocaïne IV par rapport à une perfusion témoin pour soulager la douleur neuropathique périphérique chronique. ENREGISTREMENT DE L'éTUDE: clinicaltrials.gov (NCT01669967); enregistrée le 22 juin 2012.

The becoming-methadone-body: on the onto-politics of health intervention translations.

In this paper, we reflect on health intervention translations as matters of their implementation practices. Our case is methadone treatment, an intervention promoted globally for treating opioid dependence and preventing HIV among people who inject drugs. Tracing methadone's translations in high-security prisons in the Kyrgyz Republic, we notice the multiple methadones made possible, what these afford, and the onto-political effects they make. We work with the idea of the 'becoming-methadone-body' to trace the making-up of methadone treatment and its effects as an intra-action of human and nonhuman substances and bodies. Methadone's embodied effects flow beyond the mere psycho-activity of substances incorporating individual bodies, to material highs and lows incorporating the governing practices of prisoner society. The methadone-in-practice of prisoner society is altogether different to that imagined as being in translation as an intervention of HIV prevention and opioid treatment, and has material agency as a practice of societal governance. Heroin also emerges as an actor in these relations. Our analysis troubles practices of 'evidence-based' intervention and 'implementation science' in the health field, by arguing for a move towards 'evidence-making' intervention approaches. Noticing the onto-politics of health intervention translations invites speculation on how intervening might be done differently.

The THINK (Treatment of Headache with Intranasal Ketamine) Trial: A Randomized Controlled Trial Comparing Intranasal Ketamine with Intravenous Metoclopramide.

BACKGROUND: Headache is a common chief complaint in the emergency department (ED) setting. OBJECTIVES: To compare analgesia with metoclopramide and diphenhydramine vs. intranasal ketamine among ED patients with primary headache. METHODS: We enrolled a convenience sample of adults with a primary headache in a randomized, single-blind, placebo-controlled trial. We randomized patients to either a control arm (intravenous metoclopramide and diphenhydramine) or intranasal ketamine. The primary outcome was change in pain 0-100 mm visual analog scale (VAS) score measured at study start and 30 min post completion of initial medication administration. Secondary outcomes included side effects, hospital admission, and return to care within 48-72 h. RESULTS: All 53 enrolled subjects completed the study, 26 of whom were allocated to the control arm and 27 to intranasal ketamine. The mean change in pain VAS score at 30 min post intervention was 22.2 mm in the control arm vs. 29.0 in the intranasal ketamine arm (effect size difference 6.8 mm, 95% confidence interval -5.8-19.4). The incidence of reported side effects was 65.4% in the control arm vs. 66.7% in the ketamine arm. Three patients (11.5%) allocated to the control arm required admission for headache pain control vs. 1 patient (3.7%) in the intranasal ketamine arm. Three (11.5%) additional patients in the control arm returned to the ED within 48-72 h for headache pain vs. none in the ketamine arm. CONCLUSIONS: In this small randomized study, intranasal ketamine was not superior to standard therapy among ED patients with primary headache syndromes.

Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine-induced wheal formation: a pilot study.

BACKGROUND: Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine. HYPOTHESIS/OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (≈5 mg/kg diphenhydramine). ANIMALS: Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design. METHODS AND MATERIALS: Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation. RESULTS: There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (± 20) and 124 (± 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (± 7.1) and 11.6 (± 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs. CONCLUSION: Oral absorption of diphenhydramine was approximately three times greater with a longer half-life when it was administered as the combination product dimenhydrinate.

Successful mast-cell-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding.

Dyspareunia, vaginitis and dysfunctional uterine bleeding (DUB) are common problems which, despite their polygenicity, commonly appear idiopathic and treatment-refractory. Mast cell (MC) activation syndrome (MCAS) is a newly-recognised, prevalent, chronic multisystem polymorbidity of general themes of inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues. MCs produce significant quantities of heparin, too. As such, MCAS may underlie some cases of chronic dyspareunia, vaginitis or DUB. We report five such patients; all who responded well to MC-targeted treatment. We review aspects of MC biology and pathobiology of potential relevance to otherwise idiopathic persistent inflammatory or coagulopathic genital tract problems. Diagnostic testing for MCAS may be warranted in some patients with chronic dyspareunia, vaginitis or DUB (especially patients whose histories well fit the general profile of MCAS), and prospective therapeutic trials of MC-directed topical and/or systemic therapies may be warranted in such populations. Impact statement What is already known on this subject? Chronic, idiopathic, treatment-refractory female genital tract inflammation or bleeding are common problems for which mast cell (MC) disease, previously generally thought to consist of just rare cases of mastocytosis, and is seldom considered in the differential diagnosis. What do the results of this study add? The substantial prevalence of the newly recognised 'mast cell activation syndrome' (MCAS), featuring chronic inappropriate MC activation with little-to-no MC neoplasia, and its clinical presentation with chronic multisystem inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues, raises the possibility that MCAS might underlie the aforementioned genital tract problems, especially in patients whose larger clinical presentations fit the MCAS profile. We report five example patients (among many more we have similarly treated) who enjoyed excellent responses to safe, inexpensive MC-targeted treatments, often given just intravaginally. What are the implications of these findings for clinical practice and/or further research? Our report identifies a potentially significant new MC-focused direction, of relevance to millions of affected women worldwide, for clinical treatment as well as for basic and clinical research, which historically has yielded major advancements disappointingly disproportionate to the scope of the affected population.

Impact of fellowship training level on colonoscopy quality and efficiency metrics.

BACKGROUND AND AIMS: Previous studies have described variable effects of fellow involvement on the adenoma detection rate (ADR), but few have stratified this effect by level of training. We aimed to evaluate the "fellow effect" on multiple procedural metrics including a newly defined adenoma management efficiency index, which may have a role in documenting colonoscopy proficiency for trainees. We also describe the impact of level of training on moderate sedation use. METHODS: We performed a retrospective review of 2024 patients (mean age, 60.9 ± 10 years; 94% men) who underwent outpatient colonoscopy between June 2012 and December 2014 at our Veterans Affairs Medical Center. Colonoscopies were divided into 5 groups. The first 2 groups were first-year fellows in the first 6 months and last 6 months of the training year. Second- and third-year fellows and attending-only procedures accounted for 1 group each. We collected data on doses of sedatives used, frequency of adjunctive agent use, procedural times, and location, size, and histology of polyps. We defined the adenoma management efficiency index as average time required per adenoma resected during withdrawal. RESULTS: Of the colonoscopies performed, 1675 involved a fellow and 349 were performed by the attending alone. There was no difference in ADR between fellows according to level of training (P = .8) or between fellows compared with attending-only procedures (P = .67). Procedural times decreased consistently during training and declined further for attending-only procedures. This translated into improvement in the adenoma management efficiency index (fellow groups by ascending level of training: 23.5 minutes vs 18.3 minutes vs 13.7 minutes vs 13.4 minutes vs attending group 11.7 minutes; P < .001). There was no difference in the average doses of midazolam and fentanyl used among fellow groups (P = .16 and P = .1, respectively). Compared with attending-only procedures, fellow involvement was associated with higher doses of fentanyl and midazolam and more frequent use of diphenhydramine and glucagon (P < .0001, P = .0002, P < .0001, and P = .01, respectively). CONCLUSIONS: ADR was similar at different stages of fellowship training and comparable with the attending group. Efficiency of detecting and resecting polyps improved throughout training without reaching the attending level. Fellow involvement led to a greater use of moderate sedation, which may relate to a longer procedure duration and an evolving experience in endoscopic technique.

In Vivo Quantitative Understanding of PEGylated Liposome's Influence on Brain Delivery of Diphenhydramine.

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood-brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio ( Kp,uu) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of Kp,uu to 1.5 ( p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease ( Kp,uu 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.

Opioid-Induced "Likeability" and "Feeling Good" Are Not Associated With Return Visits to an ED Among Migraine Patients Administered IV Hydromorphone.

BACKGROUND: Parenteral opioids are used in more than 50% of emergency department (ED) visits for migraine. Use of opioids for migraine has been associated with subsequent ED visits, perhaps because of opioid-induced euphoria. In this study, we quantify the extent to which nontherapeutic effects of opioids influence migraine outcomes. We hypothesized that "feeling good" and medication likeability would in fact be associated with receipt of opioids (rather than relief of migraine pain) and that receipt of opioids (rather than relief of migraine pain) would be associated with return visits to the ED. METHODS: During an ED-based clinical trial, migraine patients were randomized to receive hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg IV. Thirty minutes after medication administration, we asked, (1) How much did you like the medication you received? and (2) How good did the medication make you feel? Participants were asked to provide answers on a 0-10 scale. We also determined 0-10 pain scores at baseline and 1 hour and number of return visits for headache during the subsequent month. RESULTS: Sixty-three patients received prochlorperazine and 64 hydromorphone. Prochlorperazine pain scores improved by 6.8 (SD: 2.6), hydromorphone by 4.7 (SD: 3.3) (95%CI for difference of 2.1: 1.0, 3.2). On the 0-10 likeability scale, prochlorperazine patients reported a mean of 7.2 (SD: 2.8), hydromorphone 6.9 (SD: 2.9) (95% CI for difference of 0.3: -0.7, 1.3). On the 0-10 feeling good scale, prochlorperazine patients reported a mean of 7.5 (SD: 2.3), hydromorphone 6.8 (SD: 2.8) (95%CI: for difference of 0.7: -0.2, 1.6). In the hydromorphone group, 8/57 (14%, 95%CI: 7, 26%) returned to the ED vs 5/63 (8%, 95%CI: 3,18%) in the prochlorperazine group. In regression modeling, feeling good was independently associated with pain relief (P < .01) but not with medication received (P = .67) or return visits (P = .12). Similarly, medication likeability was independently associated with pain relief (P < .01) but not medication received (P = .12) or return visits (P = .16). CONCLUSION: We did not detect an association between hydromorphone and medication likeability, feeling good, or return visits to the ED. Headache relief was associated with medication likeability and feeling good.

An exploratory study of IV metoclopramide+diphenhydramine for acute post-traumatic headache.

BACKGROUND: Headache is a frequent complaint among the 1.4 million patients who present to US emergency departments (ED) annually following trauma to the head. There are no evidence-based treatments of acute post-traumatic headache. METHODS: This was an ED-based, prospective study of intravenous (IV) metoclopramide 20mg+diphenhydramine 25mg for acute post-traumatic headache. Patients who presented to our EDs with a moderate or severe headache meeting international criteria were enrolled and followed by telephone 2 and 7days later. The primary outcome was "sustained headache relief" (headache level less than "moderate" in the ED, no additional headache medication, and no relapse to headache worse than "mild").We also gathered data on associated symptomotology using the validated Post Concussion Symptom Scale (PCSS). RESULTS: 21 patients were enrolled. Twelve of 20 (60%) patients with available follow-up data reported sustained headache relief. All but one of the 21 enrolled patients (95%) reported improvement of headache to no worse than mild. Seven of 19 (37%) patients with available data reported moderate or severe headache during the 48h after ED discharge. One week later, 5/19 patients reported experiencing headaches "frequently" or "always". The mean Post Concussion Symptom Score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at the time of ED discharge and 11.4 (SD 21.4) at one week after treatment. CONCLUSION: IV metoclopramide 20mg+diphenhydramine 25mg is an effective and well-tolerated medication regimen for patients presenting to the ED with acute post-traumatic headache, though 1/3 of patients report headache relapse after ED discharge and 1/4 of patients report persistent headaches one week later.

Metoclopramide and Diphenhydramine: A Randomized Controlled Trial of a Treatment for Headache in Pregnancy when Acetaminophen Alone Is Ineffective (MAD Headache Study).

OBJECTIVE: We investigated whether metoclopramide administered with diphenhydramine (MAD) relieves headache in pregnant women when acetaminophen alone is ineffective, using codeine for comparison. STUDY DESIGN: Normotensive pregnant women in the second or third trimester were randomized to MAD intravenously (10 mg and 25 mg, respectively) or codeine orally (30 mg) for headache after 650 to 1,000 mg of acetaminophen failed to relieve their headaches. Headache severity (pain score 0-10) was noted at intervals over 24 hours. The primary outcome was reduction in pain score 6 hours after medication administration. A sample size calculation of 35 patients per group was based on estimated reduction in headache pain score by at least two points, with an α of 0.05 and a power of 80%. RESULTS: No difference was seen in the primary outcome. MAD pain scores were lower at 30 minutes (3 ± 2.8 versus 5.8 ± 2.3, p < 0.001), 1 hour (2.2 ± 2.3 vs. 4.1 ± 3; p < 0.01), and 12 hours (1.3 ± 2.5 vs. 2.7 ± 3; p < 0.05), but not at 6 hours. Time to perceived headache relief was shorter for MAD than for codeine (20.2 ± 13.4 vs. 62.4 ± 62.2 minutes; p < 0.001). More patients in the MAD group reported full headache relief within 24 hours (76.5 vs. 37.5%; p < 0.01). CONCLUSION: MAD effectively relieves headaches in pregnant women when acetaminophen fails.