Successful and Rapid Reduction in Neurosedative and Analgesic Medications in Complex Infants with Severe Bronchopulmonary Dysplasia After Tracheostomy Placement: Experience with 24-hour Propofol Infusions.

Infants with severe bronchopulmonary dysplasia may require high doses of neurosedative medications to ensure pain control and stability following tracheostomy placement. Subsequent weaning of these medications safely and rapidly is a challenge. We describe a 24-hour propofol infusion to reduce neurosedative medications in 3 high-risk infants following tracheostomy placement.

Oral and topical analgesia in pediatric electrodiagnostic studies.

INTRODUCTION/AIMS: Electrodiagnostic examinations, such as nerve conduction studies (NCS) and needle electromyography (EMG), are perceived as painful by children and their parents/guardians. Methods to reduce peri-procedural pain improve compliance and have neurocognitive and neuropsychiatric benefits. This study aimed to assess the efficacy of combined oral and topical analgesics (COTA), oral analgesics (OA), and placebo in reducing pain during NCS/EMG in children. METHODS: We performed a double-blind, randomized, placebo-controlled trial on children presenting to our neurophysiology lab. Patients were stratified into two age groups (6M-6Y and 7Y-18Y) and randomized into three arms: COTA, OA, and placebo. Pain scores post-NCS/EMG were assessed using the Modified Behavioral Pain Scale (MBPS) and Faces Pain Scale-Revised (FPS-R). RESULTS: One hundred thirteen participants were enrolled. A comparison of participants from both age groups combined revealed no significant differences in guardian FPS-R scores across all arms for NCS and EMG. A significant difference in the distribution of post-NCS FPS-R score severities in children aged 7Y-18Y was noted between OA and placebo (p = .007). EMG was more painful than NCS across all arms (p < .05). In children aged 6M-6Y undergoing at least 10 muscle samplings during EMG, those receiving COTA had significantly lower pain scores (p = .014). DISCUSSION: This study reveals the complexity of pediatric pain perception during NCS/EMG and highlights that other methods to reduce experienced pain are required. Our findings suggest that procedural characteristics, such as number of muscles sampled, may influence the effectiveness of analgesia and serve as a foundation for future research aimed at optimizing pain management strategies.

The effectiveness of parenteral agents for pain reduction in patients with migraine presenting to emergency settings: A systematic review and network analysis.

OBJECTIVES: To assess the comparative effectiveness and safety of parenteral agents for pain reduction in patients with acute migraine. BACKGROUND: Parenteral agents have been shown to be effective in treating acute migraine pain; however, the comparative effectiveness of different approaches is unclear. METHODS: Nine electronic databases and gray literature sources were searched to identify randomized clinical trials assessing parenteral agents to treat acute migraine pain in emergency settings. Two independent reviewers completed study screening, data extraction, and Cochrane risk-of-bias assessment, with differences being resolved by adjudication. The protocol of the review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42018100096). RESULTS: A total of 97 unique studies were included, with most studies reporting a high or unclear risk of bias. Monotherapy, as well as combination therapy, successfully reduced pain scores prior to discharge. They also increased the proportion of patients reporting pain relief and being pain free. Across the pain outcomes assessed, combination therapy was one of the higher ranked approaches and provided robust improvements in pain outcomes, including lowering pain scores (mean difference -3.36, 95% confidence interval [CI] -4.64 to -2.08) and increasing the proportion of patients reporting pain relief (risk ratio [RR] 2.83, 95% CI 1.74-4.61). Neuroleptics and metoclopramide also ranked high in terms of the proportion of patients reporting pain relief (neuroleptics RR 2.76, 95% CI 2.12-3.60; metoclopramide RR 2.58, 95% CI 1.90-3.49) and being pain free before emergency department discharge (neuroleptics RR 4.8, 95% CI 3.61-6.49; metoclopramide RR 4.1, 95% CI 3.02-5.44). Most parenteral agents were associated with increased adverse events, particularly combination therapy and neuroleptics. CONCLUSIONS: Various parenteral agents were found to provide effective pain relief. Considering the consistent improvements across various outcomes, combination therapy, as well as monotherapy of either metoclopramide or neuroleptics are recommended as first-line options for managing acute migraine pain. There are risks of adverse events, especially akathisia, following treatment with these agents. We recommend that a shared decision-making model be considered to effectively identify the best treatment option based on the patient's needs.

Functional impairment of chronic migraine with medication overuse: Secondary analysis from the Medication Overuse Treatment Strategy (MOTS) trial.

BACKGROUND: Chronic migraine exerts substantial negative impacts on daily functioning. Efforts to manage impaired functioning may result in medication overuse, which contributes to the worsening profile and chronification of migraine. The Migraine Functional Impact Questionnaire (MFIQ) is a recently developed measure assessing the impact of migraine on physical, social, and emotional function. OBJECTIVE: The objective of this analysis was to assess changes in MFIQ scores following initiation or modification of migraine preventive medication and determine if changes in function are associated with changes in other aspects of migraine burden, such as headache frequency, headache intensity, and symptoms of anxiety and depression. METHODS: This is a secondary analysis of data from the Medication Overuse Treatment Strategy (MOTS) trial, a prospective pragmatic clinical trial that investigated two treatment strategies for those with chronic migraine and medication overuse. Data from both treatment arms were pooled and analyzed using a pre-post design. Prior to and 12 weeks following initiation or modification of migraine preventive medication, participants completed a series of questionnaires that captured migraine characteristics, medication use, migraine-related physical impairment (MFIQ), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire 9 [PHQ-9]) symptoms. Changes from baseline in all measures were assessed using the paired t-test. Relationships between changes in MFIQ scores and other measures were assessed using linear regression. Multivariable modeling was performed to determine which additional variables contributed to the change in MFIQ beyond that already explained by an individual variable. Model terms were selected by using elastic net regularization. Only those participants who completed the baseline and 12-week MFIQ were included in this analysis. RESULTS: Of the 537 patients, 88.2% were female, and the average age was 45 years (standard deviation 13). The mean frequency of days with moderate-to-severe headache improved 39.2% from 13.5 per 30 days at baseline to 8.1 per 30 days at week 12. The mean MFIQ Usual Activities Global score improved by 15.0 points (on a 100-point scale). All five domains (Usual Activities Global, Usual Activities, Social Function, Emotional Function, Physical Function) of the MFIQ improved by a mean of at least 13.0 points. Changes in PHQ-9 score, followed by changes in headache frequency, had the strongest associations with change in all domains of the MFIQ. CONCLUSIONS: The negative impact of chronic migraine with medication overuse on physical, social, and emotional functioning substantially lessened following initiation or modification of migraine preventive medication. Improved functioning, as measured by the MFIQ, was most strongly associated with reductions in depression scores and headache frequency, highlighting the importance of recognizing and monitoring changes in depressive symptoms, in addition to headache frequency and functional impairment, when evaluating response to preventive medications.

Use of electronic health record data to examine administrations of pro re nata analgesics during hip fracture post-acute care.

PURPOSE: Medications prescribed to older adults in US skilled nursing facilities (SNF) and administrations of pro re nata (PRN) "as needed" medications are unobservable in Medicare insurance claims. There is an ongoing deficit in our understanding of medication use during post-acute care. Using SNF electronic health record (EHR) datasets, including medication orders and barcode medication administration records, we described patterns of PRN analgesic prescribing and administrations among SNF residents with hip fracture. METHODS: Eligible participants resided in SNFs owned by 11 chains, had a diagnosis of hip fracture between January 1, 2018 to August 2, 2021, and received at least one administration of an analgesic medication in the 100 days after the hip fracture. We described the scheduling of analgesics, the proportion of available PRN doses administered, and the proportion of days with at least one PRN analgesic administration. RESULTS: Among 24 038 residents, 57.3% had orders for PRN acetaminophen, 67.4% PRN opioids, 4.2% PRN non-steroidal anti-inflammatory drugs, and 18.6% PRN combination products. The median proportion of available PRN doses administered per drug was 3%-50% and the median proportion of days where one or more doses of an ordered PRN analgesic was administered was 25%-75%. Results differed by analgesic class and the number of administrations ordered per day. CONCLUSIONS: EHRs can be leveraged to ascertain precise analgesic exposures during SNF stays. Future pharmacoepidemiology studies should consider linking SNF EHRs to insurance claims to construct a longitudinal history of medication use and healthcare utilization prior to and during episodes of SNF care.

Acupuncture Versus Oral Medications for Acute/Subacute Non-Specific Low Back Pain: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Pharmacologic intervention do not always achieve benefits in the treatment of acute/subacute non-specific low back pain (NSLBP). We assessed efficacy and safety of acupuncture for acute/subacute NSLBP as alternative treatment. RECENT FINDINGS: We searched PubMed, Web of Science, Embase, Cochrane Library, Scopus, Epistemonikos, CNKI, Wan Fang Database, VIP database, CBMLD, CSTJ, clinical trials, EUCTR, World WHO ICTRP, and ChiCTR for randomized controlled trials, cross-over studies, and cohort studies of NSLBP treated by acupuncture versus oral medication from inception to 23th April 2022. A total of 6 784 records were identified, and 14 studies were included 1 263 participants in this review. The results of the meta-analysis indicated that acupuncture therapy was slightly more effective than oral medication in improving pain (P < 0.00001, I2 = 92%, MD = -1.17, 95% CI [-1.61, -0.72]). According to the results of the meta-analysis, acupuncture therapy exhibited a significant advantage over oral medication with a substantial effect (P < 0.00001, I2 = 90%, SMD = -1.42, 95% CI [-2.22, -0.62]). Based on the results of the meta-analysis, acupuncture therapy was associated with a 12% improvement rate compared to oral medication in patients with acute/subacute NSLBP (P < 0.0001, I2 = 54%, RR = 1.11, 95% CI [1.05, 1.18]). Acupuncture is more effective and safer than oral medication in treating acute/subacute NSLBP. This systematic review is poised to offer valuable guidance to clinicians treating acute/subacute NSLBP and potentially benefit the afflicted patients. REGISTRATION: This review was registered in PROSPERO ( http://www.crd.york.ac.uk/prospero ) with registration number CRD42021278346.

High uptake of menstrual health information, products and analgesics within an integrated sexual reproductive health service for young people in Zimbabwe.

BACKGROUND: Despite being integral to women's well-being, achieving good menstrual health (MH) remains a challenge. This study examined MH services uptake (including information, analgesics, and a choice of MH products - the menstrual cup and reusable pads) and sustained use of MH products within an integrated sexual and reproductive health intervention for young people in Zimbabwe. METHODS: This mixed-methods study was nested within a cluster randomised trial of integrated sexual and reproductive health services (CHIEDZA) for youth in three provinces (Harare, Mashonaland East, and Bulawayo). The study collected qualitative and quantitative data from 27,725 female clients aged 16-24 years, who accessed CHIEDZA from April 2019 - March 2022. Using a biometric (fingerprint recognition) identification system, known as SIMPRINTS, uptake of MH information, products, and analgesics and other services was tracked for each client. Descriptive statistics and logistic regression were used to investigate MH service uptake and product choice and use over time, and the factors associated with these outcomes. Thematic analysis of focus group discussions and interviews were used to further explore providers' and participants' experiences of the MH service and CHIEDZA intervention. RESULTS: Overall, 36,991 clients accessed CHIEDZA of whom 27,725 (75%) were female. Almost all (n = 26,448; 95.4%) took up the MH service at least once: 25433 took up an MH product with the majority (23,346; 92.8%) choosing reusable pads. The uptake of cups varied across province with Bulawayo province having the highest uptake (13.4%). Clients aged 20-24 years old were more likely to choose cups than reusable pads compared with those aged 16-19 years (9.4% vs 6.0%; p < 0.001). Over the implementation period, 300/1819 (16.5%) of clients swapped from the menstrual cup to reusable pads and 83/23346 (0.4%) swapped from reusable pads to the menstrual cup. Provision of the MH service encouraged uptake of other important SRH services. Qualitative findings highlighted the provision of free integrated SRH and MH services that included a choice of MH products and analgesics in a youth-friendly environment were key to high uptake and overall female engagement with SRH services. CONCLUSIONS: High uptake demonstrates how the MH service provided much needed access to MH products and information. Integration of MH within an SRH intervention proved central to young women accessing other SRH services.

Low-dose short infusion ketamine as adjunct to morphine for acute long bone fracture in the emergency department: a randomized controlled trial.

BACKGROUND: Ketamine is recognized as an alternative for pain management; however, concerns about emergent adverse reactions have limited its widespread adoption. This study aimed to assess the efficacy of a short infusion of low-dose ketamine (LDK) compared to intravenous morphine (MOR) as adjunctive analgesia for acute long bone fracture pain. METHODS: This single-blinded, randomized controlled trial was conducted in a single emergency department. Patients with acute long bone fractures and numerical rating scale (NRS) pain scores ≥ 6 following an initial dose of intravenous morphine were assigned to receive either a LDK (0.3 mg/kg) over 15 min or intravenous MOR at a dose of 0.1 mg/kg administered over 5 min. Throughout a 120-min observation period, patients were regularly evaluated for pain level (0-10), side effects, and the need for additional rescue analgesia. RESULTS: A total of 58 subjects participated, with 27 in the MOR group and 31 in the LDK group. Demographic variables and baseline NRS scores were comparable between the MOR (8.3 ± 1.3) and LDK (8.9 ± 1.2) groups. At 30 min, the LDK group showed a significantly greater mean reduction in NRS scores (3.1 ± 2.03) compared to the MOR group (1.8 ± 1.59) (p = 0.009). Similarly, at 60 min, there were significant differences in mean NRS score reductions (LDK 3.5 ± 2.17; MOR mean reduction = 2.4, ± 1.84) with a p-value of 0.04. No significant differences were observed at other time intervals. The incidence of dizziness was higher in the LDK group at 19.4% (p = 0.026). CONCLUSION: Short infusion low-dose ketamine, as an adjunct to morphine, is effective in reducing pain during the initial 30 to 60 min and demonstrated comparability to intravenous morphine alone in reducing pain over the subsequent 60 min for acute long bone fractures. However, it was associated with a higher incidence of dizziness. TRIAL REGISTRATION: NMRR17318438970 (2 May 2018; www.nmrr.gov.my ).

Transdermal Delivery of Cannabidiol for the Management of Acute Inflammatory Pain: A Comprehensive Review of the Literature.

The emerging field of nanotechnology has paved the way for revolutionary advancements in drug delivery systems, with nanosystems emerging as a promising avenue for enhancing the therapeutic potential and the stability of various bioactive compounds. Among these, cannabidiol (CBD), the non-psychotropic compound of the Cannabis sativa plant, has gained attention for its therapeutic properties. Consequently, researchers have devoted significant efforts to unlock the full potential of CBD's clinical benefits, where various nanosystems and excipients have emerged to overcome challenges associated with its bioavailability, stability, and controlled release for its transdermal application. Therefore, this comprehensive review aims to explain CBD's role in managing acute inflammatory pain and offers an overview of the state of the art of existing delivery systems and excipients for CBD. To summarize this review, a summary of the cannabinoids and therapeutical targets of CBD will be discussed, followed by its conventional modes of administration. The transdermal route of administration and the current topical and transdermal delivery systems will also be reviewed. This review will conclude with an overview of in vivo techniques that allow the evaluation of the anti-inflammatory and analgesic potentials of these systems.

The effect of oral pregabalin on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To investigate the effect of three different doses of oral pregabalin on minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective, randomized, placebo-controlled, blinded, crossover trial. ANIMALS: A group of eight healthy adult cats aged 24-48 months. METHODS: Cats were randomly assigned to three oral doses of pregabalin (low dose: 2.5 mg kg-1, medium dose: 5 mg kg-1, high dose: 10 mg kg-1) or placebo 2 hours before MACISO determination, with the multiple treatments administered with a minimum 7 day washout period. Anesthesia was induced and maintained with isoflurane in oxygen until endotracheal intubation was achieved, and maintained with isoflurane with volume-controlled ventilation. MACISO was determined in triplicate using the bracketing technique and tail clamp method 120 minutes after pregabalin or placebo administration. Physiologic variables (including heart rate and blood pressure) recorded during MACISO determination were averaged and compared between the pregabalin and placebo treatments. One-way analysis of variance and the Friedman test were used to assess the difference for normally and non-normally distributed data, respectively. The Tukey test was used as a post hoc analysis. Values of p < 0.05 were considered significant. RESULTS: The MACISO with the medium- and high-dose pregabalin treatments were 1.33 ± 0.21% and 1.23 ± 0.17%, respectively. These were significantly lower than MACISO after placebo treatment (1.62 ± 0.13%; p = 0.014, p < 0.001, respectively), representing a decrease of 18 ± 9% and 24 ± 6%. The mean plasma pregabalin concentration was negatively correlated with MACISO values. Physiologic variables did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Doses of 5 or 10 mg kg-1 pregabalin, administered orally 2 hours before determining MACISO, had a significant isoflurane-sparing effect in cats.

Progress in the validation of nociception monitoring in guiding intraoperative analgesic therapy.

PURPOSE OF REVIEW: This article summarizes the current level of validation for several nociception monitors using a categorized validation process to facilitate the comparison of performance. RECENT FINDINGS: Nociception monitors improve the detection of a shift in the nociception and antinociception balance during anesthesia, guiding perioperative analgesic therapy. A clear overview and comparison of the validation process for these monitors is missing. RESULTS: Within a 2-year time-frame, we identified validation studies for four monitors [analgesia nociception index (ANI), nociception level monitor (NOL), surgical pleth index (SPI), and pupillometry]. We categorized these studies in one out of six mandatory validation steps: developmental studies, clinical validation studies, pharmacological validation studies, clinical utility studies, outcome improvement studies and economical evaluation studies. The current level of validation for most monitors is mainly focused on the first three categories, whereas ANI, NOL, and SPI advanced most in the availability of clinical utility studies and provide confirmation of a clinical outcome improvement. Analysis of economical value for public health effects is not yet publicly available for the studied monitors. SUMMARY: This review proposes a stepwise structure for validation of new monitoring technology, which facilitates comparison between the level of validation of different devices and identifies the need for future research questions.

Alleviating severity of limb trauma pain with coadministration of topical sesame oil and standard treatments: A GRADE-assessed systematic review and meta-analysis of randomised controlled trials.

Recent randomised controlled trials (RCTs) have investigated the analgesic activity of sesame oil among patients with limb trauma; nevertheless, their findings are inconsistent. Hence, this review aimed to clarify the impact of topical administration of sesame oil on acute pain of adult outpatients with minor limb trauma. The online databases (e.g., Scopus, PubMed, Web of Science) were searched up to 31 January 2024. The RCTs were included if they compared the effect of applying standard treatments plus topical sesame oil to administering standard treatments alone or with a placebo/sham treatment. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and the Cochrane Collaboration's risk of bias tool were applied to address the evidence quality and the study's methodological rigour, respectively. Four RCTs had the inclusion criteria, and their findings were pooled in a meta-analysis employing a random-effects approach. According to the pooled analysis, the reduction in mean change of the pain score from baseline to the second/third intervention day was significantly higher in favour of clients who received standard care plus daily massage of the trauma site with sesame oil compared to those who received a control condition (weighted mean difference: -1.10; 95% confidence interval [-1.62, -0.57]; p < 0.001). However, the evidence quality was moderate, and only two studies had good methodological rigour. Hence, more high-quality studies are needed to make a solid evidence-based conclusion about the favourable consequence of topical sesame oil on alleviating acute traumatic limb pain.

The Effect of Preprocedural Low-Dose Ketamine for Pain and Anxiety in Patients during Thoracic Epidural Catheterization.

Background and Objectives: Thoracic epidural catheterization (TEC) can be both uncomfortable and fearful for patients when performed awake with the thought that the procedure may be painful. The aim of this study was to assess the effect of low-dose intravenous ketamine administration on pain and anxiety during the TEC procedure. Materials and Methods: Sixty patients were randomly divided into two groups to receive intravenous (IV) placebo (Group P) and IV low-dose (0.15 mg/kg) ketamine (LDK) (Group K) 3 min before the procedure in a double-blind manner. A visual analog scale (VAS) was used to measure anxiety (VAS-A) and pain (VAS-P) scores. Vital parameters were monitored before premedication (T1), 20 min after premedication (T2), during skin anesthesia (T3), during TEC (T4), and 5 min after TEC (T5). VAS-A values were recorded at T1, T3, T4, and T5 periods, and VAS-P levels were noted at T3, T4, and T5 periods. Results: During TEC (T4), both VAS-P and VAS-A were significantly lower in Group K (p < 0.001). The mean VAS-A value was 10.6 mm lower, and the mean VAS-P value was 9 mm lower in Group K than in Group P at the T4 time point. Additionally, the mean VAS-P value was 7.7 mm lower in Group K compared to Group P at the T3 time point (p < 0.001). Both groups showed a statistically significant difference in VAS-A measurements when compared at their respective time points (p < 0.001). However, only Group P demonstrated a statistically significant difference in VAS-P measurements (p < 0.001). VAS-P values remained stable in Group K. The number of patients who did not recall the procedure was significantly higher in Group K (p < 0.001). Furthermore, the number of patients who would consent to the same procedure in the future was significantly higher in Group K (p = 0.007). Conclusions: A preprocedural LDK (0.15 mg/kg) can effectively prevent anxiety and pain experienced by patients during the TEC procedure. Administration of LDK may provide a more comfortable procedure process without causing ketamine-induced side effects (hemodynamic, respiratory, and psychological).

Characteristics and outcomes of peripheral neuropathic pain patients with repeated applications of high-concentration capsaicin cutaneous patch: Results of a retrospective chart review in Germany.

OBJECTIVE: The aim of this study was to evaluate patient characteristics, concomitant analgesic medication, and pain intensity in a real-world setting in Germany, focusing on the repeated application of high-concentration capsaicin patch (HCCP) for neuropathic pain. DESIGN: Data were collected from electronic medical records of patients who received at least two HCCP treatments between January 2011 and July 2022. Subgroup analyses were performed based on the number of HCCP treatments, age groups, and specific neuropathic pain conditions. SETTING: The study was conducted at an outpatient pain center in Wiesbaden, Germany. SUBJECTS: The study included 97 patients, primarily diagnosed with neuropathic back pain, postoperative or post-traumatic neuropathic pain, and postherpetic neuralgia. METHODS: The daily dose of concomitant medications (eg, opioids and anticonvulsants) at the start of capsaicin therapy was compared with the average within 2 years of capsaicin therapy. The last observation carried forward method was used if HCCP treatment was discontinued before the end of the 2-year period. RESULTS: The majority of patients received concomitant medications, with opioids, anticonvulsants, and antidepressants being the most common. The average daily morphine equivalent dose decreased significantly during HCCP treatment. Pain intensity at baseline was generally high, but substantial improvements were observed in patients who received at least three HCCP applications. CONCLUSIONS: This study provides evidence for the effectiveness of HCCP treatment in reducing pain intensity and concomitant opioid use in patients with neuropathic pain. Further research is needed to explore the long-term outcomes and optimal treatment regimens for different patient populations.

[Analgesics, chronic pain and musculoskeletal rehabilitation]. / Médicaments antalgiques, douleur chronique et réadaptation de l'appareil locomoteur.

The majority of patients following musculoskeletal rehabilitation are taking painkillers. However, apart from one recent observational study, there is a lack of data. The use of analgesics, particularly opioids, is associated with higher scores for pain, anxiety, depression, catastrophizing and disability, as well as poorer results in functional tests. Prescribing analgesic treatment with precise objectives (improving pain and function) should also include identifying psychosocial factors associated with a poor prognosis. Regular reassessment of the treatment should make it possible to limit side-effects and the risk of misuse and help patients to engage in an active rehabilitation programme and resume regular physical activity.

La majorité des patients effectuant une réadaptation musculosquelettique consomme des antalgiques. Cependant, en dehors d'une étude observationnelle récente, les données manquent. La prise d'antalgiques, en particulier les opioïdes, est associée à des scores de douleur, d'anxiété, de dépression, de catastrophisme et de handicap élevés, ainsi qu'à des résultats plus faibles aux tests fonctionnels. La prescription d'un traitement antalgique avec des objectifs précis (amélioration de la douleur et de la fonction) doit également comporter une détection des facteurs psychosociaux de mauvais pronostic. Une réévaluation régulière de la prescription devrait permettre de limiter les effets secondaires, les risques de mésusage et aider les patients à s'engager dans un programme de réadaptation actif et à reprendre une activité physique régulière.

Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.

Importance: In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014. Objective: To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate. Design, Setting, and Participants: This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG. Exposures: Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products. Main Outcomes and Measures: Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate. Results: In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings. Conclusions and Relevance: The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.

Trial of Galcanezumab in Prevention of Episodic Cluster Headache.

BACKGROUND: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. METHODS: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. RESULTS: Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).

Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age = 22 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC = flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p > 0.05). After 30 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, p = 0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16 ± 0.04 vs. 0.29 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, p = 0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p > 0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.

Perianal Application of Glyceryl Trinitrate Ointment Versus Tocopherol Acetate Ointment in the Treatment of Chronic Anal Fissure: A Randomized Clinical Trial.

BACKGROUND: Medical treatment, including glyceryl trinitrate ointment, represents the first step for the management of chronic anal fissure. However, glyceryl trinitrate ointment is associated with headache and, consequently, a high withdrawal rate of the treatment. OBJECTIVE: The aim of the present study was to evaluate the effect of the topical application of tocopherol acetate ointment on pain relief and chronic anal fissure epithelialization, comparing it with the effect of a standard treatment with glyceryl trinitrate ointment. DESIGN: This is a 2-parallel-group, single-center, randomized controlled, intent-to-treat clinical trial. SETTINGS: This study was conducted at the Garcilaso Clinic affiliated with Universidad Alfonso X (Madrid, Spain). PATIENTS: Patients with chronic anal fissure were selected. INTERVENTIONS: Patients were randomly assigned into 2 groups: patients receiving tocopherol acetate ointment and patients receiving glyceryl trinitrate ointment. MAIN OUTCOME MEASURES: The primary end point was quantification of anal pain 8 weeks after beginning the treatment as measured by a Visual Analogue Scale ranging from 0 to 100 mm. The secondary end points were the healing rate (during the treatment period of 8 weeks) and the recurrence rate. RESULTS: One hundred sixty consecutive patients were treated, 80 in each group. By 8 weeks after treatment, mean anal pain score declined by 56.2 mm in the glyceryl trinitrate ointment group compared with a mean anal pain score decline of 67.1 mm in the tocopherol acetate ointment group (mean difference, 10.9 mm (95% CI, 4.3-18.6); p = 0.018). Sixteen weeks after finishing the therapy, the recurrence rate was 13.2% in the glyceryl trinitrate ointment group vs 2.9 in the tocopherol acetate ointment group (p = 0.031). LIMITATIONS: Limitations of the study include the absence of manometric measurements of the internal anal sphincter before and after the treatments and the use of glyceryl trinitrate ointment as an active comparator, whereas calcium channel blockers are actually the standard treatment. CONCLUSIONS: Anal pain was significantly lower in the tocopherol acetate ointment group than in the glyceryl trinitrate ointment group at 8 weeks after treatment. Tocopherol acetate ointment achieved a greater healing rate and a lower recurrence rate 16 weeks after finishing the treatment. See Video Abstract at http://links.lww.com/DCR/B751. REGISTRATION: URL: https://www.clinicaltrials.gov; Identifier: NCT03787030.APLICACIÓN PERIANAL DE POMADA DE TRINITRATO DE GLICERILO FRENTE A LA POMADA DE ACETATO DE TOCOFEROL EN EL TRATAMIENTO DE LA FISURA ANAL CRÓNICA: UN ENSAYO CLÍNICO ALEATORIZADOANTECEDENTES:El tratamiento médico, incluida la pomada de trinitrato de glicerilo, representa el primer paso para el tratamiento de la fisura anal crónica. Sin embargo, la pomada de trinitrato de glicerilo se asocia con cefalea y, en consecuencia, una alta tasa de cancelación del tratamiento.OBJETIVO:El objetivo del presente estudio fue evaluar el efecto de la aplicación tópica de pomada de acetato de tocoferol en el alivio del dolor y la epitelización de la fisura anal crónica, comparándolo con el efecto de un tratamiento estándar con pomada de trinitrato de glicerilo.DISEÑO:Ensayo clínico con intención de tratar controlado, aleatorizado, de un solo centro, con dos grupos paralelos.ESCENARIO:Clínica Garcilaso adscrita a la Universidad Alfonso X (Madrid, España).PACIENTES:Pacientes con fisura anal crónica.INTERVENCIONES:Los pacientes fueron aleatorizados en 2 grupos: pacientes que recibieron pomada de acetato de tocoferol y pacientes que recibieron pomada de trinitrato de glicerilo.PRINCIPALES MEDIDAS DE RESULTADO:El criterio de valoración principal fue la cuantificación del dolor anal 8 semanas después de comenzar el tratamiento, medido por la escala analógica visual que varía de 0 a 100 mm. Los criterios de valoración secundarios fueron la tasa de curación (durante el período de tratamiento de 8 semanas) y la tasa de recurrencia.RESULTADOS:Se trataron ciento sesenta pacientes consecutivos, 80 en cada grupo. A las ocho semanas después del tratamiento, la puntuación media de dolor anal se redujo en 56.2 mm en el grupo de pomada de trinitrato de glicerilo en comparación con una disminución de la puntuación de dolor anal medio de 67.1 mm en el grupo de pomada de acetato de tocoferol (diferencia media: 10.9 mm (intervalo de confianza del 95%; 4.3 a 18.6; p = 0.018) Dieciséis semanas después de finalizar la terapia, la tasa de recurrencia fue del 13.2% en el grupo de pomada de trinitrato de glicerilo frente a 2.9 en el grupo de pomada de acetato de tocoferol (p = 0.031).LIMITACIONES:Ausencia de medidas manométricas del esfínter anal interno antes y después de los tratamientos. Ungüento de trinitrato de glicerilo como comparador activo, mientras que los bloqueadores de los canales de calcio son en realidad el tratamiento estándar de oro.CONCLUSIONES:El dolor anal fue significativamente menor en el grupo de ungüento de acetato de tocoferol que en el grupo de ungüento de trinitrato de glicerilo a las 8 semanas después del tratamiento. La pomada de acetato de tocoferol logró una mayor tasa de curación y una menor tasa de recurrencia 16 semanas después de finalizar el tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B751. (Traducción-Dr. Jorge Silva Velazco).

Intranasal ketamine for acute cluster headache attacks-Results from a proof-of-concept open-label trial.

OBJECTIVE: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. BACKGROUND: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack. METHODS: We conducted an open-label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in-hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment. RESULTS: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: -0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11-point NRS (mean difference: 4.3, 95% CI: 2.4-6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. CONCLUSION: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine.