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"Morphine"
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Morphine
\"Young Dr. Bromgard has come to a small country town to assume a new practice. No sooner has he arrived than he receives word that a colleague, Dr. Polyakov, has fallen gravely ill. Before Bromgard can go to his friend's aid, Polyakov is brought to his practice in the middle of the night with a self-inflicted gunshot wound, and, barely conscious, gives Bromgard his journal before dying\"--Amazon.com.
Book
P270 Blending the block: measuring baricity when morphine meets hyperbaric bupivacaine
Application for ESRA Abstract Prizes:Background and AimsIn spinal anesthesia, baricity determines intrathecal drug spread and block characteristics. Hyperbaric bupivacaine is widely used for lower limb arthroplasties. In our institution, it is routinely combined with preservative-free morphine to enhance postoperative analgesia. While this combination is common in clinical practice, its physicochemical effect on baricity has not been quantified. We aimed to evaluate the density - and hence baricity - of this custom-made intrathecal mixture.MethodsThe density of hyperbaric bupivacaine (Marcaine® Spinal 0.5% Heavy), morphine (100 µg/mL in saline), and their 2.2:1 mL and 2.4:1 mL (Marcaine®:morphine) mixtures were measured at room temperature using the Menarini Aution MAX AE-4030 system. Three samples of each solution were analyzed. Theoretical calculations were performed for validation.ResultsMean measured densities (standard deviation) in g/cm3 were: morphine 100 µg/mL: 1.004 (0.001); hyperbaric bupivacaine: 1.029 (0); mixture (2.2 + 1 mL): 1.021 (0.001); mixture (2.4 + 1 mL): 1.021 (confirmed in duplicate). Theoretically calculated densities for these mixtures were 1.0212 and 1.0216 g/cm3, respectively. Despite the dilution, the final mixture remains hyperbaric relative to CSF (~1.0003 g/cm3 at 37°C).ConclusionsThis is the first study to quantify the baricity of a commonly used morphine-bupivacaine spinal mixture. Although addition of the morphine solution lowers the density of hyperbaric bupivacaine, the mixture remains hyperbaric, supporting its continued clinical use with expected spread behavior. These findings reinforce the importance of physicochemical validation in custom-made intrathecal preparations.
Journal Article
Nightmare in Berlin
\"Late April, 1945. The war is over, yet Dr Doll, a loner and 'moderate pessimist,' lives in constant fear. By night, he is haunted by nightmarish images of the bombsite in which he is trapped--he, and the rest of Germany. More than anything, he wishes to vanquish the demon of collective guilt, but he is unable to right any wrongs, especially in his position as mayor of a small town in north-east Germany that has been occupied by the Red Army. Dr Doll flees for Berlin, where he finds escape in a morphine addiction: each dose is a 'small death'\"--Back cover.
Book
Co-Expression of GRK2 Reveals a Novel Conformational State of the micro-Opioid Receptor
Agonists at the [micro]-opioid receptor are known to produce potent analgesic responses in the clinical setting, therefore, an increased understanding of the molecular interactions of ligands at this receptor could lead to improved analgesics. As historically morphine has been shown to be a poor recruiter of [beta]-arrestin in recombinant cell systems and this can be overcome by the co-expression of GRK2, we investigated the effects of GRK2 co-expression, in a recombinant [micro]-opioid receptor cell line, on ligand affinity and intrinsic activity in both [beta]-arrestin recruitment and [.sup.35 S]GTP[gamma]S binding assays. We also investigated the effect of receptor depletion in the [beta]-arrestin assay. GRK2 co-expression increased both agonist Emax and potency in the [beta]-arrestin assay. The increase in agonist potency could not be reversed using receptor depletion, supporting that the effects were due to a novel receptor conformation not system amplification. We also observed a small but significant effect on agonist K.sub.L values. Potency values in the [.sup.35 S]GTP[gamma]S assay were unchanged; however, inverse agonist activity became evident with GRK2 co-expression. We conclude that this is direct evidence that the [micro]-opioid receptor is an allosteric protein and the co-expression of signalling molecules elicits changes in its conformation and thus ligand affinity. This has implications when describing how ligands interact with the receptor and how efficacy is determined.
Journal Article
EP093 Complete pericapsular hip block using combined PENG and deep posterior gluteal compartment (DPGC) blocks compared to LIA for postoperative analgesia in elective THA
Background and AimsCommon blocks for THA (total hip arthroplasty) mainly target pain originating from the anterior part of the hip, overlooking posterior capsule’s contribution to the overall pain. Our study aims to evaluate the benefit and safety of a complete pericapsular hip block compared with local infiltration analgesia (LIA).MethodsMedical files of patients scheduled for elective THA were retrospectively analysed. Over the past two months, 26 patients who received a preoperative ultrasound-guided complete pericapsular hip block were matched (for age, sex and BMI) with 26 patients receiving intra-operative LIA by surgeon. The type of hip local analgesia was left to the discretion of the anaesthesiologist. All THA were performed under general anaesthesia and postoperative analgesia was standardised. Time before first rescue analgesia and morphine dose in PACU, total morphine consumption at 48 h were noted.ResultsAge was 68±10 years, BMI was 28±5.5 and preoperative opioid intake was reported by 2/26 and 3/26 patients, respectively in complete hip block and LIA group. Results are detailed in table 1. No side effects related to any analgesic technique were noticed.ConclusionsThe findings suggest that an effective complete pericapsular hip block may offer superior prolonged postoperative analgesia and opioid-sparing effects compared to a surgical LIA.Abstract EP093 Table 1Comparison of postoperative morphine requirements between the pericapsular hip block group and the LIA matched group. Data include PACU rescue morphine parameters (time to first rescue, dose and proportion not requiring rescue) and cumulative morphine consumption on the ward over 48 hours.
Journal Article
The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence
Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut–brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence.
Journal Article
Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice
RationaleCorticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined.ObjectiveTo determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice.MethodsMice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator.ResultsPretreatment with TCAP-1 (10–250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250–500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases.ConclusionsThese findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal.
Journal Article
Evidence-Based Morphine Dosing for Postoperative Neonates and Infants
Background and Objectives
From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg
1.5
/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) <10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this model-derived dosing regimen yields significantly reduced doses in neonates aged <10 days.
Methods
Concentration predictions of the population model were prospectively evaluated in postoperative term neonates and infants up to the age of 1 year who received morphine doses according to the model-derived algorithm. The efficacy of this dosing algorithm was evaluated using morphine rescue medication and actual average infusion rates.
Results
Morphine and metabolite concentrations were accurately predicted by the paediatric pharmacokinetic morphine model. With regard to efficacy, 5 out of 18 neonates (27.8 %) with a PNA of <10 days needed rescue medication versus 18 of the 20 older patients (90 %) (
p
= 0.06). The median (interquartile range [IQR]) total morphine rescue dose was 0 (0–20) μg/kg in younger patients versus 193 (19–362) μg/kg in older patients (
p
= 0.003). The median (IQR) actual average morphine infusion rate was 4.4 (4.0–4.8) μg/kg/h in younger patients versus 14.4 (11.3–23.4) μg/kg/h in older patients (
p
< 0.001).
Conclusion
Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA <10 days. The fact that many neonates and infants with a PNA ≥10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.
Journal Article
Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide
Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the
Oprm1
gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.
Journal Article