Oral Transmucosal Research Articles

An Exploration of Analgesia Options for Australian Sheep.

During their lifetime, sheep undergo many painful husbandry and disease processes. Procedures undertaken on the farm, such as tail docking, castration, and mulesing, all cause considerable pain. In addition, sheep may experience painful diseases and injuries that require treatment by veterinary practitioners, and in biomedical research, sheep may undergo painful experimental procedures or conditions. It is important due to ethics, animal welfare, social licence, and, at times, legal requirements for farmers, veterinary practitioners, and researchers to provide pain relief for animals in their care. While there is a heightened awareness of and a greater interest in animal welfare, there remain few licensed and known analgesia options for sheep within Australia. A literature review was undertaken to identify currently known and potential future options for analgesic agents in sheep in farm and biomedical settings. Non-steroidal anti-inflammatories, opioids, local anaesthetics, α2 adrenoreceptor agonists, and NMDA receptor antagonists are some of the more common classes of analgesic drugs referred to in the literature, but few drugs are registered for use in sheep, with even fewer proven to be effective. Only six analgesic product formulations, namely, lignocaine (e.g., Numocaine®), Tri-Solfen®, ketamine, xylazine, and meloxicam (oral transmucosal and injectable formulations), are currently registered in Australia and known to be efficacious in some types of painful conditions in sheep. The gap in knowledge and availability of analgesia in sheep can pose risks to animal welfare, social licence, and research outcomes. This article presents a summary of analgesic agents that have been used in sheep on farms and in clinical veterinary and biomedical research settings along with details on whether their efficacy was assessed, doses, routes of administration, indication for use, and pain assessment techniques (if any) used. The outcome of this research highlights the challenges, gaps, and opportunities for better analgesia options in sheep.

New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Opioid analgesics for nociceptive cancer pain: Acomprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies.

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm2/h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4-5 cell layers with basal cells still undergoing mitosis. The optimum period at the air-liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca2+, retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes' differentiation and inflammatory conditions, etc.).

Oral transmucosal delivery of eletriptan for neurological diseases

Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

Rapid oral transmucosal delivery of zaleplon–lavender oil utilizing self-nanoemulsifying lyophilized tablets technology: development, optimization and pharmacokinetic evaluation

Based on the administration convenience, transmucosal buccal drug delivery allows special strength points over peroral routes for systemic delivery. It could achieve local or systemic effect and boost drugs’ bioavailability for agents with first pass metabolism. The current study aimed to manufacture and optimize a lavender oil–based nanoemulsion loaded with zaleplon and incorporate it into fast-disintegrating tablets to promote its dissolution and oral bioavailability via oral mucosa. Zaleplon-loaded nanoemulsions were devised with various levels of lavender oil (10% to 25%), the surfactant Sorbeth-20 (35% to 65%), and the co-surfactant HCO-60 (20% to 40%); the extreme vertices mixture statistical design was adopted. The droplet size and drug-loading efficiency were the evaluated. The optimal formulation was transformed into self-nanoemulsified lyophilized tablets (ZP-LV-SNELTs), which were tested for their uniformity of content, friability, and disintegration time with in-vitro release. Finally, the pharmacokinetic parameters of the ZP-LV-SNELTs were determined and compared with those of marketed formulations. The optimal nanoemulsion had a droplet size of 87 nm and drug-loading capacity of 185 mg/mL. ZP-LV-SNELTs exhibited acceptable friability and weight uniformity and a short disintegration time. The in-vitro release of ZP-LV-SNELTs was 17 times faster than that of the marketed tablet. Moreover, the optimal ZP-LV-SNELTs increased the bioavailability of zaleplon in rabbits by 1.6-fold compared with the commercial tablets. Hence, this investigation revealed that ZP-LV-SNELTs delivered zaleplon with enhanced solubility, a fast release, and boosted bioavailability thru oral mucosa which provided a favorable route for drug administration which is suggested to be clinically investigated in future studies

Composite dissolvable microneedle patch for therapy of oral mucosal diseases.

A composite microneedle patch (MN patch) is developed for oral transmucosal administration. To improve the oral transmucosal drug delivery efficiency, the composite MN patch is designed to consist of an array of 100 dissolvable microneedles (MNs) with drug-loaded tips and a backing layer. The MNs are composed of two parts, the hyaluronic acid (HA) tip part and the polyvinylpyrrolidone (PVP) base part. Due to the small size and sufficient mechanical strength, the HA-PVP MNs can painlessly penetrate the oral mucosa barrier and deliver drugs directly to the basal layer or submucosa. Betamethasone sodium phosphate (BSP), as the model drug, is concentrated in the HA tip parts to avoid the drug waste caused by mucosa elasticity. Considering the special moist environment and saliva flow in the mouth, a double-layer backing layer composed of a poly(vinyl alcohol) (PVA) adhesive layer and an ethyl cellulose (EC) waterproof layer is designed and constructed, which could reduce the saliva flow effects. The in vitro and in vivo results demonstrate that the MN patch could achieve rapid and efficient BSP release in oral mucosa due to the rapid dissolution of HA. The proposed MN patch provides a novel strategy for the therapy of oral mucosal diseases.

Pharmacokinetics of intravenous, oral transmucosal, and intranasal buprenorphine in healthy male dogs.

Effective management of pain in animals is of critical importance but options are limited for treating acute pain in dogs on an outpatient basis. The objective of this study was to compare the plasma concentrations and pharmacokinetics of a concentrated solution of buprenorphine, 1.8 mg/ml (Simbadol™) administered intravenously, intranasally, and via the oral transmucosal (OTM) route in healthy male dogs. Five healthy castrated adult male Beagle‐cross dogs were included in this randomized blocked crossover study. The dogs received 0.03 mg/kg body weight buprenorphine intravenously, intranasally, or via the OTM route, with a minimum 72‐h washout period between treatments. Blood samples were collected at multiple intervals up to 24 h post administration and buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. Non‐compartmental pharmacokinetic analysis revealed that the area under the curve of intravenous, intranasal, and OTM routes were 28.0 (15.1–41.3) h × ng/ml, 16.1 (3.4–28.7) h × ng/ml and 10.8 (8.8–11.8) h × ng/ml, respectively. The bioavailability of intranasal and OTM routes were 57.5 (22.7–93.7)% and 41.1 (25.5–69.4)%, respectively. Intranasal and OTM routes of administration of concentrated buprenorphine in dogs may allow for the provision of analgesic care at home.

An open-label clinical trial of oral transmucosal haloperidol and oral transmucosal olanzapine in the treatment of terminal delirium at home

BackgroundThe phenomenon of restlessness, agitation, or cognitive disturbances experienced by dying patients is well-known in palliative care; more than half of these patients will experience delirium symptoms at end-of-life. When not identified early and effectively managed, delirium symptoms could lead to caregiver and patient distress and harm.MethodsEighty patients with a prognosis of 7 days or less will be recruited for an open-label randomised control trial. The two arms compare oral-transmucosal haloperidol 2.5 mg vs olanzapine 5 mg over 72 h. The severity of agitation, delirium and toxicities of treatments will be compared at the 24th, 48th and 72nd hour after drug administration.DiscussionThis trial is the first to compare anti-psychotics in the management of delirium at the dying stage in the home hospice setting using the oral transmucosal route. Ethical considerations, as well as recruitment procedures, are discussed.Trial registrationThis study was registered in ClinicalTrials.gov – identifier NCT04750395

Nanocarriers-Assisted Needle-Free Vaccine Delivery Through Oral and Intranasal Transmucosal Routes: A Novel Therapeutic Conduit.

Drug delivery using oral route is the most popular, convenient, safest and least expensive approach. It includes oral transmucosal delivery of bioactive compounds as the mucosal cavity offers an intriguing approach for systemic drug distribution. Owing to the dense vascular architecture and high blood flow, oral mucosal layers are easily permeable and can be an ideal site for drug administration. Recently, the transmucosal route is being investigated for other therapeutic candidates such as vaccines for their efficient delivery. Vaccines have the potential to trigger immune reactions and can act as both prophylactic and therapeutic conduit to a variety of diseases. Administration of vaccines using transmucosal route offers multiple advantages, the most important one being the needle-free (non-invasive) delivery. Development of needle-free devices are the most recent and pioneering breakthrough in the delivery of drugs and vaccines, enabling patients to avoid needles, reducing anxiety, pain and fear as well as improving compliance. Oral, nasal and aerosol vaccination is a novel immunization approach that utilizes a nanocarrier to administer the vaccine. Nanocarriers improve the bioavailability and serve as adjuvants to elicit a stronger immune response, resulting in increased effectiveness of vaccination. Drugs and vaccines with lower penetration abilities can also be delivered transmucosally while maintaining their biological function. The development of micro/nanocarriers for transmucosal delivery of macromolecules, vaccines and other substances is currently drawing much attention and a number of studies were performed recently. This comprehensive review is aimed to summarize the most recent investigations on needle-free and non-invasive approaches for the delivery of vaccines using oral transmucosal route, their strengths and associated challenges. The oral transmucosal vaccine delivery by nanocarriers is the most upcoming advancement in efficient vaccine delivery and this review would help further research and trials in this field.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers.

Background For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug's high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

A pilot study investigating the pharmacokinetics of intravenous, oral transmucosal, and intranasal concentrated buprenorphine in dogs

A pilot study investigating the pharmacokinetics of intravenous, oral transmucosal, and intranasal concentrated buprenorphine in dogs

A novel versatile flow-donor chamber as biorelevant ex-vivo test assessing oral mucoadhesive formulations

Oral transmucosal drug delivery is a non-invasive administration route for rapid therapeutic onset and greater bioavailability avoiding the first-pass metabolism. Mucoadhesive formulations are advantageous as they may retain the drug at the administration site. Proper equipment to assess mucoadhesive properties and corresponding drug absorption is fundamental for the development of novel drug delivery systems. Here we developed a new flow-through donor chamber for well-established diffusion cells, and we tested the effects on drug and formulation retention in situ of adding mucoadhesive polymers or mesoporous silica particles to a reference formulation. Mesoporous silica particles are of particular interest as they may be used to encapsulate and retain drug molecules. Compared to other ex-vivo methods described in literature for assessing mucoadhesive performance and transmucosal drug delivery, this new donor chamber provides several advantages: i) it reflects physiological conditions better as a realistic saliva flow can be provided over the administration site, ii) it is versatile since it can be mounted on any kind of vertical diffusion cell allowing simultaneous detection of drug retention at the administration site and drug permeation through the tissue, and iii) it enables optical quantification of formulations residence time aided by image processing. This new flow-through donor diffusion cell set-up proved sensitive to differentiate a reference formulation from one where 20 %(w/w) Carbomer was added (to further improve the mucoadhesive properties), with respect to both drug and formulation residence times. We also found that mesoporous silica particles, investigated as particles only and mixed together with the reference formulation, gave very similar drug and formulation retention to what we observed with the mucoadhesive Carbomer. However, after some time (>30 min) it became obvious that the tablet excipients in the reference formulation promote particle retention on the mucosa. This work provides a new simple and versatile biorelevant test for the evaluation of oral mucoadhesive formulations and paves the way for further studies on mesoporous silica particles as valuable excipients for enhancing oral mucoadhesion.

Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery.

Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.

Evaluation of Oral Transmucosal Administration of Pentobarbital for Euthanasia of Conscious Wild Birds

ABSTRACT This prospective study evaluated oral transmucosal pentobarbital sodium at three doses in 110 wild-caught wild birds requiring euthanasia. Birds received transmucosal pentobarbital at five (430 mg/kg), six (516 mg/kg), and seven times (602 mg/kg) the intravenous dose for mammals. Time to first effects and loss of consciousness, presence of pupillary light and corneal reflexes, apnea, and asystole were recorded each minute. When asystole was not achieved at 5 minutes, IV pentobarbital was administered. Combining data for all doses, loss of consciousness occurred at a median (range) of 2 minutes (0–4.75 min), apnea at 3 minutes (0–6 min), and asystole at 4 minutes (0.5–5 min). Loss of consciousness and apnea occurred significantly faster in the 602 mg/kg dose group than in the 430 mg/kg group (p = 0.009, difference of 0.6 ± 0.2 min; p = 0.024, difference of 0.7 ± 0.3 min), respectively. Apnea and asystole were achieved in 80/110 birds within 5 minutes. Oral transmucosal pentobarbital results in rapid loss of consciousness and respiratory arrest and provides a reliable alternative euthanasia method compared to intravenous administration.

Current status and issues in clinical use of opioids

In Japan, 14 opioids with a variety of dosage forms, such as oral preparation, injection, transdermal patch, transmucosal and suppository are clinically available as analgesics, and their use properly depends on the type and degree of pain and patient condition. Fundamentally, strong opioids are restricted to only treatment of cancer pain, while the indication of fentanyl transdermal patch and oxycodone tamper resistant tablet has been expanded for the treatment of non-cancer chronic pain. In US, the additional indication of opioids to chronic pain has led to prolongation and generalization of opioid use, which may contribute to "opioid crisis" in which opioid-related death strikingly increased due to opioid abuse and overdose-induced respiratory depression. Currently, opioid-related abuse and death have not been evident in Japan, while abuse of antitussive opioids (codeine and dihydrocodeine) are recently seen as a problem, which may suggest the sense of guilt to abuse legally-uncontrolled drugs (ex. weak opioids, antitussives or hypnotics) may be low in Japanese. In this review, I will summarize current status and issues in clinical use of opioid analgesics, and will talk about the necessity and expectation for development of novel analgesics without serious adverse reactions such as addiction and respiratory depression.

Oral Transmucosal or Intramuscular Administration of Dexmedetomidine-Methadone Combination in Dogs: Sedative and Physiological Effects.

Simple SummaryDuring the last decade, new alternative non-invasive administration routes for drug delivery have gained interest in veterinary medicine. The administration of drugs via the oral transmucosal route is non-invasive, painless, easy to perform, and generally well tolerated. Furthermore, it avoids gastric acid degradation typical of oral administration. All these characteristics contribute to make this administration route very attractive, especially for veterinary patients who are difficult to inject, fearful, or anxious. In contrast, intramuscular injection is associated with pain and requires more invasive restraint, potentially incrementing patients’ discomfort. The aim of this study was to assess and compare the sedative and clinical effects of a dexmedetomidine–methadone combination following either oral transmucosal and intramuscular administration in healthy dogs and to record any possible adverse effects following each administration route. The present study suggests that oral transmucosal administration of dexmedetomidine and methadone combination provided a satisfactory level of sedation, allowing safe handling of the patients with less pronounced cardiorespiratory effects. Indeed, thanks to the lesser impact on the cardiac function, it could be considered as a useful option for those patients difficult to restrain in which cardiovascular stability should be preserved.The aim of this study was to compare the sedative and physiological effects following either oral transmucosal (OTM) or intramuscular administration of dexmedetomidine–methadone combination in healthy dogs. Thirty dogs were randomly assigned to receive a dexmedetomidine–methadone combination either by the OTM (n = 15) or intramuscular (n = 15) route. Sedation was scored 10, 20, and 30 min after drugs administration. Heart rate (HR), non-invasive blood pressure (NIBP), respiratory rate (fR), and body rectal temperature were recorded before drugs administration and then every 10 min for 30 min. Propofol dose required for orotracheal intubation was recorded. Sedation scores increased over time within both groups with higher values in intramuscular group (p < 0.05). Within each group, HR decreased significantly compared with baseline (p < 0.001) and was significantly lower in intramuscular group compared with the OTM group (p < 0.001). In both groups, NIBP increased significantly compared with baseline (p < 0.05). In the intramuscular group, fR was lower compared with the OTM group at all the observational time points (p < 0.001). Propofol dose was lower in the intramuscular group (p < 0.05). Compared to intramuscular dexmedetomidine–methadone, OTM combination produced lower but effective sedation in healthy dogs.

The Efficacy of Meperidine for Pain Management in Orthopedic, Dental, and General Surgery in Children: A Review Study

Background: The present study aimed to assess the efficacy of Meperidine for pain relief in children after orthopedic, abdominal surgery, and laceration repair. Materials and Methods: A systematic serch was performed using the following online databases: Medline, Cochrane, Web of Science, Scopus, and Embase to 2 June 2020, with keywords: (Meperidine OR Pethidine) AND (Pain) AND (Child OR Children) with no language restriction. Results: The Acetaminophen had slightly higher pain scores compared to Meperidine after dental restoration among children. There was better sedation along with more rapid onset and recovery in the combined regimens of Atropine/Midazolam/Ketamine compared to Meperidine/Midazolam. Two studies reported the superiority of Morphine over Meperidine for pain management. A study found a significant increase in the mean pediatric pain scores in the Tramadol group compared to the Meperidine group after 24 hours. There was no difference in the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) between MPC (Meperidine/Promethazine/Chlorpromazine), and OTFC (Oral Transmucosal Fentanyl Citrate) groups during the laceration repair. In the study on the incidence of sleep on the way home or shortly after arriving at home, there were differences in chloral hydrate, Meperidine, and Hydroxyzine regimen compared to Midazolam alone among children being sedated during endodontic procedures. Conclusion: Meperidine was effective for controlling pain in orthopedic, abdominal surgery, laceration repair, and dental restoration. However, it was only superior to the Tramadol group. Regarding dental surgery, a combination regimen were more effective compared to single Midazolam. The pain intensity during early recovery was slightly lower in Meperidine group. The regimen had better sedation with more rapid onset and recovery compared to Meperidine/Midazolam.

Efficacy of mifepristone – Prostaglandin analogue combination in medical termination of pregnancy up to and beyond 7 weeks of amenorrhea: The RYMMa study.

ObjectiveTo assess, in real-life conditions, the success rate of the protocol mifepristone 600 mg / prostaglandin analogue (PG) in women requesting medical termination of pregnancy (MToP) either up to or beyond 7 weeks of amenorrhea (WA). Study designThe study was performed between 2015 and 2016. This was a non-interventional prospective, multicentre, longitudinal study conducted in France, among a sample of public and/or private centres dealing with MToP. Characteristics of women, term of Mtop, modality of PG used were reported. The primary outcome was success of MToP, defined as complete abortion without surgical procedure. ResultsA total of 893 pregnant women with less than the legal term of 14 WA were included in this study: 490 (54.9 %) ≤7 WA and 403 (45.1 %) >7 WA comprising 29 > 9 WA. The mean age of women was 28.1 ± 6.8 years and the one of pregnancy was 7.0 WA ± 1.3 WA. The most frequently used PG combined to mifepristone 600 mg was misoprostol 400 μg (57.0 % ≤7 WA and 35.1 % >7 WA) or 800 μg per os (oral or oral transmucosal) (27.5 % ≤7 WA and 40.1 % >7 WA). Vaginal misoprostol (6.4 %, N = 48) and gemeprost (5.2 %, N = 39) were less used. In women ≤7 WA (N = 422) and women >7 WA (N = 354) for whom result of the MToP was collected, success rates were 94.5 % (95 %CI 91.9 %–96.5 %) and 92.4 % (95 %CI 89.1 %–94.9 %), respectively (p = 0.219). In multivariate regression analysis, three factors were significantly associated with a higher risk of MToP failure: increased number of previous pregnancies (OR = 1.233; 95 %CI 1.086–1.401 for one pregnancy), increased number of previous surgical ToPs (OR = 1.563; 95 %CI 1.036–2.359 for one ToP) and increased interval between mifepristone and PG intake (OR = 1.061; 95 %CI 1.012–1.112 for one hour). Term of pregnancy (OR = 1.497; 95 %CI 0.833–2.690 for ≤7 WA vs >7WA), administration route (OR = 1.553; 95 %CI 0.488–4.936 for oral vs oral transmucosal; and OR = 1.216; 95 %CI 0.625–2.366 for vaginal vs oral transmucosal), and dose of misoprostol (OR = 1.000; 95 %CI 0.999–1.001), were not associated with the risk of failure. Overall, tolerance was good. ConclusionThis study showed, in real-life settings, a high rate of success for MToP using mifepristone 600 mg, independent of the pregnancy term and the therapeutic protocol used. MToP was safe and well tolerated however only a small number of women beyond 9 WA have been included.

Oral Transmucosal Cannabidiol Oil Formulation as Part of a Multimodal Analgesic Regimen: Effects on Pain Relief and Quality of Life Improvement in Dogs Affected by Spontaneous Osteoarthritis.

Simple SummaryOsteoarthritis is a progressive and degenerative condition that affects dog populations, causing pain. The pain associated with osteoarthritis is considered to be chronic, owing to both active inflammation and to a maladaptive component caused by central sensitization. Chronic pain in dogs is being increasingly recognised as a significant problem, and finding successful treatments against canine osteoarthritis-related pain is challenging. The aim of this study was to assess the efficacy in pain management over a twelve-week period of oral transmucosal cannabidiol, in combination with a multimodal pharmacological protocol, in dogs affected by spontaneous osteoarthritis. Dogs receiving oral transmucosal cannabidiol in addition to an anti-inflammatory drug, gabapentin and amitriptyline showed a meaningful improvement in Canine Brief Pain Inventory scores, in comparison with dogs that did not receive cannabidiol. The present study suggests that the addition of oral transmucosal cannabidiol to a multimodal pharmacological treatment for canine osteoarthritis improves owner reported pain scores and quality of life of dogs, without severe adverse effects.The aim of this study was to evaluate the efficacy of oral transmucosal (OTM) cannabidiol (CBD), in addition to a multimodal pharmacological treatment for chronic osteoarthritis-related pain in dogs. Twenty-one dogs were randomly divided into two groups: in group CBD (n = 9), OTM CBD (2 mg kg−1 every 12 h) was included in the therapeutic protocol (anti-inflammatory drug, gabapentin, amitriptyline), while in group C (n = 12), CBD was not administered. Dogs were evaluated by owners based on the Canine Brief Pain Inventory scoring system before treatment initiation (T0), and one (T1), two (T2), four (T3) and twelve (T4) weeks thereafter. Pain Severity Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0043) and T3 (p = 0.016). Pain Interference Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0007) and T4 (p = 0.004). Quality of Life Index was significantly higher in CBD group at T1 (p = 0.003). The addition of OTM CBD showed promising results. Further pharmacokinetics and long-term studies in larger populations are needed to encourage its inclusion into a multimodal pharmacological approach for canine osteoarthritis-related pain.