Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children.

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day- 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats.

Opioid use disorder affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. The Food and Drug Administration-approved opioid receptor antagonist naloxone (e.g., Narcan) is used currently to treat overdose; however, a short duration of action limits its clinical utility. Methocinnamox (MCAM) is a long-lasting opioid receptor antagonist that may reverse and prevent the ventilatory-depressant effects of fentanyl. This study compared the ability of naloxone (0.0001-10 mg/kg) and MCAM (0.0001-10 mg/kg) to reverse and prevent ventilatory depression by fentanyl and compared the duration of action of MCAM intravenously and subcutaneously in two procedures: ventilation and warm-water tail withdrawal. In male Sprague-Dawley rats (N = 8), fentanyl (0.0032-0.178 mg/kg, i.v.) decreased minute volume in a dose- and time-dependent manner with a dose of 0.178 mg/kg decreasing VE to less than 40% of control. MCAM and naloxone reversed the ventilatory-depressant effects of 0.178 mg/kg fentanyl in a dose-related manner. The day after antagonist administration, MCAM but not naloxone attenuated the ventilatory-depressant effects of fentanyl. The duration of action of MCAM lasted up to 3 days and at least 2 weeks after intravenous and subcutaneous administration, respectively. MCAM attenuated the antinociceptive effects of fentanyl, with antagonism lasting up to 5 days and more than 2 weeks after intravenous and subcutaneous administration, respectively. Reversal and prolonged antagonism by MCAM might provide an effective treatment option for the opioid crisis, particularly toxicity from fentanyl and related highly potent analogs. SIGNIFICANCE STATEMENT: This study demonstrates that like naloxone, methocinnamox (MCAM) reverses the ventilatory-depressant effects of fentanyl in a time- and dose-related manner. However, unlike naloxone, the duration of action of MCAM was greater than 2 weeks when administered subcutaneously and up to 5 days when administered intravenously. These data suggest that MCAM might be particularly useful for rescuing individuals from opioid overdose, including fentanyl overdose, as well as protecting against the reemergence of ventilatory depression (renarconization).

Physiologically-Based Pharmacokinetic Model of Morphine and Morphine-3-Glucuronide in Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, is increasing in prevalence. NASH-related alterations in hepatic protein expression (e.g., transporters) and in overall physiology may affect drug exposure by altering drug disposition and elimination. The aim of this study was to build a physiologically-based pharmacokinetic (PBPK) model to predict drug exposure in NASH by incorporating NASH-related changes in hepatic transporters. Morphine and morphine-3-glucuronide (M3G) were used as model compounds. A PBPK model of morphine with permeability-limited hepatic disposition was extended to include M3G disposition and enterohepatic recycling (EHR). The model captured the area under the plasma concentration-time curve (AUC) of morphine and M3G after intravenous morphine administration within 0.82-fold and 1.94-fold of observed values from 3 independent clinical studies for healthy adult subjects (6, 10, and 14 individuals). When NASH-related changes in multidrug resistance-associated protein 2 (MRP2) and MRP3 were incorporated into the model, the predicted M3G mean AUC in NASH was 1.34-fold higher compared to healthy subjects, which is slightly lower than the observed value (1.63-fold). Exploratory simulations on other physiological changes occurring in NASH (e.g., moderate decreases in glomerular filtration rate and portal vein blood flow) revealed that the effect of transporter changes was most prominent. Additionally, NASH-related transporter changes resulted in decreased morphine EHR, which could be important for drugs with extensive EHR. This study is an important first step to predict drug disposition in complex diseases such as NASH using PBPK modeling.

Use of a Noninvasive Brain-Penetrating Peptide-Drug Conjugate Strategy to Improve the Delivery of Opioid Pain Relief Medications to the Brain.

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the angiopep-2 peptide (An2) that crosses the blood-brain barrier (BBB) by low-density lipoprotein receptor-related protein 1 receptor-mediated transcytosis with either morphine or M6G. We demonstrated improvement of BBB permeability of these new entities compared with that of unconjugated M6G and morphine. Intravenous or subcutaneous administration of the An2-M6G conjugate exerted greater and more sustained analgesic activity than equivalent doses of either morphine or M6G. Likewise, subcutaneous An2-morphine induced a delayed but prolonged antinociceptive effect. The effects of these conjugates on the gastrointestinal tract motility were also evaluated. An2-morphine significantly reduced the intestinal transit time, whereas An2-M6G exhibited a reduced constipation profile, as compared with an equimolar dose of morphine. In summary, we have developed new brain-penetrant opioid conjugates exhibiting improved analgesia to side effect ratios. These results thus support the use of An2-carrier peptides as an innovative BBB-targeting technology to deliver effective drugs, such as M6G, for pain management. SIGNIFICANCE STATEMENT: The metabolite morphine-6-glucuronide (M6G) does not efficiently cross the blood-brain barrier. The low-density lipoprotein receptor-related protein 1 peptide ligand angiopep-2 may serve as an effective drug delivery system to the brain. Here, we demonstrated that the coupling of M6G to angiopep-2 peptide (An2) improves its brain penetration and significantly increases its analgesic potency. The An2-M6G conjugate has a favorable side effect profile that includes reduction of developing constipation. An2-M6G exhibits a unique pharmacodynamic profile with a better therapeutic window than morphine.

The Reducing Opioid Use in Children with Clefts Protocol: A Multidisciplinary Quality Improvement Effort to Reduce Perioperative Opioid Use in Patients Undergoing Cleft Surgery.

BACKGROUND: Cleft repair requires multiple operations from infancy through adolescence, with repeated exposure to opioids and their associated risks. The authors implemented a quality improvement project to reduce perioperative opioid exposure in their cleft lip/palate population. METHODS: After identifying key drivers of perioperative opioid administration, quality improvement interventions were developed to address these key drivers and reduce postoperative opioid administration from 0.30 mg/kg of morphine equivalents to 0.20 mg/kg of morphine equivalents. Data were retrospectively collected from January 1, 2015, until initiation of the quality improvement project (May 1, 2017), tracked over the 6-month quality improvement study period, and the subsequent 14 months. Metrics included morphine equivalents of opioids received during admission, administration of intraoperative nerve blocks, adherence to revised electronic medical record order sets, length of stay, and pain scores. RESULTS: The final sample included 624 patients. Before implementation (n =354), children received an average of 0.30 mg/kg of morphine equivalents postoperatively. After implementation (n = 270), children received an average of 0.14 mg/kg of morphine equivalents postoperatively (p < 0.001) without increased length of stay (28.3 versus 28.7 hours; p = 0.719) or pain at less than 6 hours (1.78 versus 1.74; p = 0.626) or more than 6 hours postoperatively (1.50 versus 1.49; p = 0.924). CONCLUSIONS: Perioperative opioid administration after cleft repair can be reduced in a relatively short period by identifying key drivers and addressing perioperative education, standardization of intraoperative pain control, and postoperative prioritization of nonopioid medications and nonpharmacologic pain control. The authors' quality improvement framework has promise for adaptation in future efforts to reduce opioid use in other surgical patient populations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Nuevas estrategias en el control del dolor postoperatorio en la cirugía de amígdalas. ¿Es oro todo lo que reluce? / New strategies for postoperative pain control in tonsillectomy surgery. Is all that glitters gold?

Introducción: La amigdalectomía es un procedimiento quirúrgico cada vez más frecuente en pacientes adultos. El dolor postoperatorio puede ser intenso, y tiene una gran impronta sobre la calidad de vida de los enfermos. El paracetamol y los antinflamatorios no esteroideos (AINE) son, a menudo, insuficientes para tratar el dolor durante las primeras 48 horas postoperatorias. La analgesia controlada por el paciente (PCA) con cloruro mórfico es una alternativa eficaz y segura para el control del dolor agudo postoperatorio. Material y métodos: El objetivo principal fue comparar la calidad analgésica de una PCA con cloruro mórfico frente a la administración pautada de paracetamol y AINE para tratar el dolor postoperatorio de pacientes adultos intervenidos de amigdalectomía. Como objetivo secundario se estudió la frecuencia de efectos adversos y satisfacción en cada grupo. Se realizó un estudio de cohortes retrospectivo con los pacientes adultos intervenidos de amigdalectomía durante el año 2017. Se registró la escala verbal numérica (EVN) en las 24 horas y en las 48 horas del postoperatorio. Se recogió la aparición de efectos secundarios. Se realizó el estudio estadístico con el programa SPSS(R). Resultados: Se evaluaron un total de 46 pacientes, 20 del grupo de tratamiento de analgesia convencional y 26 tratados con PCA de cloruro mórfico. No hallamos diferencias significativas en las características demográficas de los grupos. El grupo de PCA tuvo una EVN menor que el grupo de analgesia convencional a las 24 horas y a las 48 horas. La diferencia fue estadísticamente significativa, tanto para el dolor en reposo como para el dolor en actividad. La incidencia de efectos secundarios fue mayor en el grupo PCA (46,15 %) frente al grupo de analgesia con paracetamol y AINE (15 %). Discusión: La analgesia con un PCA de cloruro mórfico es más eficaz que la administración de paracetamol y AINE para tratar el dolor postoperatorio de la amigdalectomía del paciente adulto. Los efectos adversos son más frecuentes con la PCA de morfina

Introduction: Tonsillectomy is surgical procedure which is being every time more often in adult patients. Postoperative pain may be very intense, and it has a very important mark in the quality of life of our patients. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) may not be enough for pain management during the first 48 hours post-surgery. Morphine patient-controlled analgesia (PCA) is an effective and safe alternative for postoperative acute pain management. Material and methods: Our main goal was to compare the quality of analgesia between morphine PCA and acetaminophen and NSAIDs use for acute pain control in adult patients who had tonsillectomy surgery. Our secondary goal was to study the frequency of side effects and the satisfaction level on each group. A retrospective cohort study was performed with those adult patients who underwent tonsillectomy during the year 2017. Pain was evaluated during the first 24 and 48 hours post-surgery with the numerical rating scale (NRS). Secondary side effects were reported. The statistical study was performed with SPSS(R) programme. Results: a total of 46 patients were evaluated, 20 patients belonged to the group for conventional analgesia and 26 belonged to the group of morphine PCA. We did not find significative differences in the demographic characteristics in both groups. PCA group had a smaller NRS compared to the other conventional analgesia group during the first 24 and the 48 hours. The difference was statistically significant for pain control during activity and resting. The incidence of secondary effects was greater for the PCA group (46,15 %) than for the acetaminophen and NSAIDs group (15 %). Discussion: Analgesia with morphine PCA is more effective than the administration of acetaminophen and NSAIDs for postoperative pain control in tonsillectomy procedure in the adult patient. The adverse effects are more frequent with morphine PCA

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats.

A novel µ-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1-10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund's adjuvant). Before MCAM, morphine, fentanyl, and the κ-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective µ-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT: The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by µ-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.

Intra-Articular Tranexamic Acid Mitigates Blood Loss and Morphine Use After Total Knee Arthroplasty. A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid (TXA) has been widely used in total knee arthroplasty (TKA) for blood loss reduction. Given limited evidence on potential relationship between the TXA and improvement of pain control and functional outcome after TKA, this study aimed at comparing the blood loss, pain scores, morphine consumption, and knee flexion across the TXA administration routes. METHODS: The 228 primary TKA were randomized into no TXA use (No-TXA), intra-articular TXA (15 mg/kg) use (IA-TXA), and intravenous TXA (10 mg/kg) use (IV-TXA). A multivariate regression analysis was used for comparing perioperative blood loss (PBL), drain output, average number of units of blood transfused (ANUBT), visual analogue scales (VAS) for pain, amount of morphine consumption, and knee flexion angle. RESULTS: The IA-TXA and IV-TXA group had 193.26 (P < .01) and 160.30 mL (P < .01) less PBL than No-TXA, respectively. No-TXA significantly required higher ANUBT than IA-TXA and IV-TXA (P = .03). The IA-TXA group had lower VAS at 6 (P = .04), 12 (P = .03), and 24 hours (P = .02) postoperative when compared to No-TXA, while IV-TXA had no effect. The IA-TXA required 18.26 mg less total morphine at 48 hours than No-TXA (P = .02), whereas IV-TXA used insignificantly (5.31 mg; P = .31) less total morphine at 48 hours than No-TXA. Both TXA routes tended to improve knee flexion, but not statistically significant. CONCLUSION: Both IA-TXA and IV-TXA could significantly reduce PBL and ANUBT. The IA-TXA could significantly mitigate VAS and morphine use after TKA. Hence, IA-TXA could minimize blood loss and may be considered as an adjunct to pain control following TKA.

The active heroin metabolite 6-acetylmorphine has robust reinforcing effects as assessed by self-administration in the rat.

Previous studies have suggested that at least some of the behavioral effects of heroin might be mediated by its active metabolite 6-acetylmorphine (6-AM). The aim of the present study was to investigate the reinforcing effects of 6-AM and its role in mediating those of heroin. We used an intravenous self-administration procedure in male Sprague-Dawley rats including four phases: acquisition, extinction, reinstatement of drug-seeking, and re-acquisition. Independent groups of rats readily learned to self-administer equimolar doses (0.135 µmol/kg) of either 6-AM (44.3 µg/kg) or heroin (50 µg/kg). Under a fixed ratio 1 (FR1) schedule of reinforcement, the rate of responding was the same for 6-AM and heroin, but it was significantly higher for 6-AM than for heroin under a FR2 schedule. A non-contingent infusion ('priming') of 0.068 µmol/kg of either 6-AM or heroin reinstated non-reinforced drug-seeking (relapse). The rats readily re-acquired self-administration behaviour when given access to one of two doses (0.068 and 0.135 µmol/kg) of 6-AM or heroin. Pretreatment with a specific monoclonal antibody (mAb) against 6-AM blocked the priming effect of 6-AM, and modified the rate of lever-pressing on re-acquisition of 6-AM self-administration in a manner compatible with a shift to the right of the dose-effect curve. The mAb did not affect heroin responding. The present results show that 6-AM possesses reinforcing effects similar to those of heroin. The lack of effect of 6-AM mAb on heroin priming and heroin self-administration calls for further studies to clarify the role of heroin and its metabolites in heroin reward. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

Liposomal bupivacaine efficacy for postoperative pain following posterior vaginal surgery: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Effective postoperative pain management is a crucial component of recovery following surgery. Narcotics are a cornerstone of postoperative analgesia, but can require a redosing requirement, encompass a lengthy list of side effects and adverse reaction risks, as well as carry a dependency potential. The national focus on decreasing opioid use has directly impacted postoperative pain management. Previous studies have reported the beneficial use of a single intraoperative injection of extended-release liposomal bupivacaine in postoperative pain management, however the same results have not been extensively studied in the urogynecology literature. OBJECTIVE: We sought to evaluate cumulative postoperative vaginal pain on days 1 and 3 after posterior vaginal wall surgery comparing study medication (extended-release liposomal bupivacaine) to placebo (saline). Secondary aims were to evaluate vaginal pain on postoperative day 7 and total morphine-equivalent narcotic usage on days 1, 3, and 7. STUDY DESIGN: This is a randomized, double-blinded, placebo-controlled trial with 100 subjects recruited from Walter Reed National Military Medical Center urogynecology clinic. All subjects were age >18 years and scheduled for surgery involving the posterior vaginal wall or muscularis (including posterior colporrhaphy, colpocleisis, sphincteroplasty, perineorrhaphy), excluding those with regular narcotic usage or concurrent pain management requiring the use of epidural anesthesia. A sample size of 96 patients was calculated. Subjects were randomized to receive either 20 mL of extended-release liposomal bupivacaine (Exparel) (Pacira Pharmaceuticals Inc, Parsippany, NJ) or 20 mL of placebo (saline) at the end of surgery. Concealed syringes were used and injected immediately postoperative into the lateral vaginal wall/levator muscle area and perineal body. In-house morphine-equivalent narcotic usage was recorded along with the postoperative day 1 pain scores. Patients were contacted by telephone on postoperative days 3 and 7. Vaginal pain scores were evaluated using the Defense and Veterans Pain Rating Scale, cumulatively and on days 1, 3, and 7. Overall morphine-equivalent narcotics were compared between the 2 groups. RESULTS: From October 2014 through August 2017, 100 patients were enrolled and completed the study; 49 (49%) of the patients were randomized to the study group and 51 (51%) were in the placebo group. There was no significant difference between vaginal pain scores between the study group and the placebo group (postoperative day 1: study medication median score 1 [interquartile range 0-3], placebo median score 1 [interquartile range 0-3] [P = .59]; postoperative day 3: study medication median score 2 [interquartile range 0-3], placebo median score 1 [interquartile range 0-3] [P = .20]; postoperative day 7: study medication median score 3 [interquartile range 1-4], placebo median score 1.5 [interquartile range 0-3] [P = .06]). Cumulative pain scores postoperative day 1-7 were also not significant (study medication median score 6 [interquartile range 1-10], placebo median score 4 [interquartile range 1-8] [P = .14]). Multivariate model for the presence of vaginal pain was calculated and after controlling for body mass index, age, and combined laparoscopy surgery, there was no significant difference between the study and the placebo groups (P = .62). There was no statistically significant difference in morphine equivalents for the 2 groups: study medication 112.5 (interquartile range 45-207) and placebo 101.5 (interquartile range 37.5-195), P = .81. CONCLUSION: The use of extended-release liposomal bupivacaine in posterior vaginal wall surgeries, injected into the lateral posterior vaginal wall and perineal body, does not provide a significant decrease in postoperative pain or decrease narcotic medication usage when compared to saline.

Characteristics of opioid-maintained clients smoking fentanyl patches: The importance of confirmatory drug analysis illustrated by a case series and mini-review.

The increase in opioid prescribing in many European countries over the last decade has raised concerns about associated diversion, overdose, and mortality. Fentanyl is one of these synthetic opioids that is typically prescribed as a transdermal patch for pain that requires continuous pain relief and has been the focus of investigation due to reports of overdose and death. We report a case series of 14 drug addiction treatment entrants, who entered treatment in a service located in the region of Southern Denmark from August 2015 to December 2015 for smoking fentanyl patches. Clients presented with difficulties breathing and pains in the lungs. The clients had a history of past opioid use, including heroin. Relapses resulted in treatment disengagement. Immunoassays for fentanyl were used in the service. In some cases, false negative results occurred. Clients' urine samples were subsequently analysed in a collaborating laboratory. Seven clients tested positive for fentanyl. One client was positive for both fentanyl and heroin. Analyses were also positive for other opioids and metabolites in 6 clients, predominantly codeine and oxycodone. Results from confirmatory analysis contributed to clearer insights into clients' drug histories, which facilitated personalised care plans consisting of opioid agonist therapy informed by confirmed drug use. In Denmark, prescription levels of fentanyl are high, which has been accompanied by observations of diversion and smoking in a smaller population. In addition to revision of inappropriate prescribing to reduce diversion, we recommend increased reliance upon confirmatory drug analysis in the addiction treatment sector in Denmark.

A one-pot multicomponent approach to a new series of morphine derivatives and their biological evaluation.

A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics.

Black Tar Heroin Skin Popping as a Cause of Wound Botulism.

BACKGROUND: Botulism is a rare potentially fatal and treatable disorder caused by a bacteria-produced toxin that affects the presynaptic synaptic membrane resulting in a characteristic neuromuscular dysfunction. It is caused by either the ingestion of the toxin or the bacteria, inhalation, or wound infection. We present our observations with a descriptive case series of wound botulism secondary to black tar heroin (BTH) injection. METHODS: We report a retrospective single-center case series of 15 consecutive cases of wound botulism presenting to University Medical Center of El Paso. Medical records where reviewed to obtain demographic information, clinical presentation, treatment, and outcome. RESULTS: We identified fifteen patients with mean age of 47 years: twelve men, and three women. All had administered BTH through skin popping and had abscesses in the administration areas. By history, the most common symptoms were dysphagia (66%), proximal muscle weakness of upper and lower extremity (60%), neck flexor muscle weakness (33%), ophthalmoplegia (53%), bilateral ptosis (46%), dysarthria (53%), double vision (40%), blurred vision (33%), and dry mouth (20%). During the examination, the most common features noted were: proximal muscle weakness of upper and lower extremities (73%), ophthalmoplegia (53%), ptosis (46%). In patients with documented wound botulism, the pupils were reactive in 46%. All patients required mechanical ventilation and were treated with the trivalent antitoxin. Eleven patients (73.3%) were discharged home, two were transferred to a skill nursing facility, and two were transferred to long-term acute care facility. CONCLUSION: In our patients, BTH injection, involving the action of injecting under the skin acetylated morphine derivatives (mostly 6-monoacetylmorphine and 3-monoacetylmorphine), was associated with the development of botulism. The availability of BTH at the US-Mexican border is not surprising since it is frequently produced in Latin America. Its association with the development of botulism should be recognized early to allow a prompt diagnosis and treatment with the antitoxin. A clinical feature worth noting is the presence of normal pupillary light reflex in nearly half of patients. Therefore, the presence of a normal pupillary response does not exclude the presence of wound botulism.

Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region.

Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared to be disrupted with cocaine. Unlike in the amygdala, methamphetamine-associated memory storage was not disrupted by NMIIi in the hippocampus, nucleus accumbens, or orbitofrontal cortex. NMIIi in the hippocampus did appear to disrupt reconsolidation. Identification of the unique mechanisms responsible for NMII-mediated, amygdala-dependent disruption of memory storage associated with the amphetamine class may enable induction of retrieval-independent vulnerability to other pathological memories.

[Arthrocentesis of the temporomandibular joint and intra-articular injections : An update]. / Arthrocentèse de l'articulation temporomandibulaire et injection(s) intra-articulaire(s) : un état des lieux.

INTRODUCTION: Arthocentesis of the temporomandibular joint combined with intra-articular washout and, more recently, intra-articular injection of pharmacological agents has been developed from the 1990s and is nowadays extensively in use for the treatment of temporomandibular dysfunctions (TMDs). The goal of our work was to answer 3 questions: 1. Is intra-articular washout effective for the treatment of TMDs ? 2. What kind of pharmacological agents may nowadays be injected in addition to washout and are these injections useful ? 3. What is the place of these treatments in the treatment strategies of TMDs ? MATERIAL AND METHODS: A bibliographic research has been carried out in the PubMed database using following keywords arthrocentesis, temporomandibular joint. The 27 articles published between 1991 and 2016, indicating patient's inclusion criterions and objectively evaluating the clinical results (mouth opening, intra-articular noises, pain) were selected. Pharmacological agents were noticed when used. RESULTS: 1. All authors concluded to the efficacy of intra-articular washout. No prognostic factor for arthrocentesis efficacy could be identified. 2. Main pharmacological agents used were steroids, hyaluronic acid, morphine-based drugs and platelet rich plasma. Superiority of ith-injection protocols failed to win unanimous support. All authors who compared with- and without-injection protocols concluded to the superiority of with-injection protocols, whatever the agent. DISCUSSION: Numerous studies have proven the efficacy of intra-articular washout for the treatment of TMDs resistant to noninvasive treatments. The advantage of any kind of pharmacological agent is not clear. Mechanisms of action are not all elucidated. No pharmacological agent showed any superiority over another. Study methodologies are often defective: imprecise inclusion criterions, short follow-up, confounding variables not taken into account, few comparison between pharmacological agents.

[Analysis of the accessibility of short acting oral opioids in Hungary]. / A rövid hatású, szájon át adható morfinszármazékok hazai elérhetoségének elemzése.

Short acting oral formulas make part of optimal opioid analgesia. The use of short acting oral morphine has not widely spread in Hungary, and these drugs completely lacked from the market for three years. Since December 2015 short acting morphine-sulphate has again been commercialised. The causes of the market failure are analysed in this article. The aim of the retrospective analysis is to help the accessibility of the medicine to every patient in need. Prescription morphine use depends on the harmonised cooperation of a number of actors. Besides regulating and financing authorities and professional organisations, patients and the opinion forming media are also responsible for building up the right routine.

[Study of Supplementary Analgesics Capable of Reducing the Dosage of Morphine].

Morphine with its potent analgesic property has been widely used for the treatment of various types of pain. However, the intrathecal (i.t.) administration of morphine at doses far higher than those required for antinociception exhibited nociceptive-related behaviors consisting of scratching, biting and licking, hyperalgesia, and allodynia in mice. Morphine-3-glucuronide (M3G), one of the major metabolites of morphine, has been found to evoke nociceptive behaviors similar to those after high-dose i.t. morphine. It is plausible that M3G may be responsible for nociception seen after high-dose i.t. morphine treatment. This article reviews the potential mechanism of spinally mediated nociceptive behaviors evoked by i.t. M3G in mice. We discuss the possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, dynorphin, and Leu-enkephalin in the primary afferent fibers following i.t. M3G administration. It is possible to speculate that i.t. M3G could indirectly activate NK1, NMDA, and δ2-opioid receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The major function of NO is the production of cGMP and the activation of protein kinase G (PKG). The NO-cGMP-PKG pathway plays an important role in M3G-induced nociceptive behavior. The phosphorylation of extracellular signal-related kinase (ERK) in the dorsal spinal cord was also evoked via the NO-cGMP-PKG pathway through the activation of δ2-opioid, NK1, and NMDA receptors, contributing to M3G-induced nociceptive behaviors. The demonstration of a neural mechanism underlying M3G-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.

Intrathecal morphine-3-glucuronide-induced nociceptive behavior via Delta-2 opioid receptors in the spinal cord.

Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces severe hindlimb scratching followed by biting and licking in mice. The M3G-induced behavioral response was inhibited dose-dependently by pretreatment with an antisera against dynorphin. However, the selective κ-opioid receptor antagonist, nor-BNI did not prevent the M3G-induced behavioral response. Dynorphin is rapidly degraded by a dynorphin-converting enzyme (cystein protease), to leucine-enkephalin (Leu-ENK). The M3G-induced behavioral response was inhibited dose-dependently by pretreatment with the antisera against Leu-ENK. We also showed that M3G co-administered with Leu-ENK-converting enzyme inhibitors, phosphoramidon and bestatin produced much stronger behavioral responses than M3G alone. Furthermore, the M3G-induced behavioral responses were inhibited dose-dependently by i.t. co-administration of the non-selective δ-opioid receptor antagonist, naltrindole or the selective δ2-opioid receptor antagonist, naltriben, whereas the selective δ1-opioid receptor antagonist, BNTX had no effect. An i.t. injection of M3G also produced a definite activation of ERK in the lumbar dorsal spinal cord. Western blotting analysis revealed that antisera against dynorphin, antisera against Leu-ENK, naltrindole or naltriben resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that M3G-induced nociceptive responses and ERK activation may be triggered via δ2-opioid receptors activated by Leu-ENK, which is formed from dynorphin in the spinal cord.

A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats.

BACKGROUND: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. METHODS: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.

[Cytokines level in patients with drug-induced jaw necrosis].

The study included 15 patients with purulent inflammatory diseases of maxillofacial area and 25 patients with facial bone necrosis induced by synthetic drugs. Pro- and anti-inflammatory cytokines levels in saliva and wound fluid were analyzed in two groups. The results proved cytokines to play important role in jaw necrosis induced by drugs containing red phosphorus.