Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children.

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.

MRGPRX2 and Adverse Drug Reactions.

Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.

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.

Sublingual Versus Swallowed Morphine: A Comparison.

BACKGROUND: The optimal route for immediate-release morphine administration is controversial. The known physical characteristics of morphine that allow absorption are counter to the unproven belief that sublingual morphine is absorbed more quickly. OBJECTIVE: The aim of this study was to compare swallowed and sublingual morphine for effects on plasma morphine concentrations (PMCs), pain relief, and taste. METHODS: Ten participants with cancer (mean age, 50 ± 12 years) received a 10-mg morphine tablet in a randomized crossover design with repeated premeasure and postmeasure for 60 minutes. Measures included PMC and visual analog scale (100 mm) scores for pain relief and taste. RESULTS: Interindividual variability in maximum PMC was 25-fold (2.2-55 ng/mL). At 60 minutes, sublingual and swallowed routes were not significantly different for mean area under the curve for PMC (swallowed, 329 ± 314 ng/mL; sublingual, 314 ± 299 ng/mL) or for mean pain relief scores (swallowed, 81 ± 32; sublingual, 78 ± 31). Taste scores at 5 (P < .05), 10 (P < .04), 15 (P < .02), and 20 (P < .04) minutes after swallowed doses were significantly less unpleasant than after sublingual doses. CONCLUSION: In this crossover design, between-group PMCs were similar for sublingual and swallowed morphine and resulted in a similar level of pain relief. Given the 25-fold across-participant differences in PMC after the same dose, additional research is warranted to identify the sources of this tremendous variability in PMC. IMPLICATIONS FOR PRACTICE: Because of unpleasant taste, which could influence adherence and subsequent analgesia, clinicians should encourage patients to swallow their morphine doses and restrict use of sublingual morphine to individuals who are unable to swallow.

Effect of the Combination of Ketorolac and Bupivacaine on Transversus Abdominis Plane Block for Postoperative Analgesia After Gynecological Laparoscopic Surgery.

BACKGROUND This study assessed the additional benefits of bupivacaine when combined with ketorolac for transversus abdominis plane (TAP) block after gynecological laparoscopic surgery. MATERIAL AND METHODS This randomized, observer-blind trial recruited 153 patients who underwent gynecological laparoscopic surgery. Patients were randomly assigned to receive bupivacaine combined with ketorolac 15 mg/side for TAP block (TK group), bupivacaine for TAP block and 30 mg postoperative intravenous ketorolac (T group), or 30 mg postoperative intravenous ketorolac alone (C group). The primary endpoints included consumption of sufentanil for 24 h postoperatively, actual press times of the patient-controlled analgesia (PCA) pump, and effective press times of the PCA pump, whereas the secondary endpoints included numerical rating scale (NRS) pain scores at rest and during activity, satisfaction with analgesia, episodes of nausea and vomiting and length of hospital stay. RESULTS Sufentanil consumption, actual press times of the PCA pump, and effective press times of the PCA pump were lower in the TK and T groups than in the C group. NRS scores at rest and during activity at 1, 2, 4, 6, and 24 hours were significantly lower in the TK and T groups than in the C group. The TK and T groups showed greater satisfaction with analgesia than the C group, while the TK group showed greater overall satisfaction than the C group. Lengths of stay, rates of nausea and vomiting, and venting times did not differ significantly among the three groups. CONCLUSIONS Combined ketorolac and bupivacaine as TAP block improved the effectiveness of analgesia without increasing adverse events. Trial registration number: ChiCTR1900022577.

Relationship between opiates and asthma in the determination of death.

Several studies have shown an association between asthma and opiate abuse. This retrospective study aims to analyse the demographic, toxicological, and seasonal differences in asthmatic and non-asthmatic subjects who died of opiates. In addition, the relationship between toxicological levels of opiates and histologic grade of lung inflammation is examined. Deaths from 2013 to 2018 involving opiates as the primary cause of death in Cook County, Illinois (USA) were reviewed. Twenty-six cases of opiate deaths of individuals with a history of asthma and lung histology slides available were identified. In comparison, 40 cases of deaths due to opiates only were analysed. A check-list system for the evaluation of the grade of microscopic inflammation in asthma was developed. We found statistically significant differences between the asthmatics and the non-asthmatics regarding demography (age and race) and toxicology (6-MAM presence). In particular, the "opiate and asthma group" was mainly composed of African-American subjects, in contrast with the "opiate group", consisting mostly of Caucasian. The mean age was significantly higher in the "opiate and asthma group" compared with the "opiate group". A greater presence of 6-MAM was detected in the "opiate group" compared with the "opiate and asthma group". While we expected to find that low opiate levels would lead to deaths in asthmatics and, in particular, that lower opiate concentrations would cause deaths in subjects with higher grades of histologic inflammation, our study suggests that the quantity of drug and the level of inflammation are not statistically significant in the determination of death. We, therefore, recommend histologic examination of the lungs to evaluate for asthma, particularly in suspected low-level opiate-related deaths, to help further clarify any relationship between asthma and opiate use.

Negative hair test result after long-term drug use. About a case involving morphine and literature review.

Although it has been accepted by most scientists that drugs circulating in blood are eligible to hair incorporation, this cannot be considered as a general statement. A 42-year old man was found dead in his swimming pool. He was living alone, and seen alive 2 days before by a neighbour. Femoral blood, cardiac blood and hair were collected during body examination. Free morphine was identified in femoral blood at 28 ng/mL, corresponding to his treatment for chronic pain (3 × 5 mg daily for 4 months). However, with a limit of quantitation (LOQ) at 10 pg/mg, segmental hair testing (3 × 1 cm) for morphine was negative. In this paper, the author has reviewed the different factors which can be responsible of this discrepancy. Several variables can influence the detection of a drug in hair and the author has listed reasons that can account for the absence of analytical response in hair after drug administration. The drug may not be incorporated in hair. That is the case for large bio-molecules, such as hormones, which cannot be transferred from the blood capillaries to growing cells of hair. Cosmetic treatments (perming, colouring, bleaching) or environmental aggressions (ultraviolet radiation, thermal application) will always reduce the concentrations. In this case, the lack of morphine detection was attributed to the effects of chlorinated water from the swimming pool. A negative hair result is also a result. However, this can be interpreted in three different ways: 1. the owner of the hair did not take or was not exposed to the specific drug, 2. the procedure is not sensitive enough to detect the drug, or 3. something happened after drug incorporation (cosmetic treatment, environmental influence).

Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery.

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50 , the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case-by-case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks.

Postmortem metabolomics: Correlating time-dependent concentration changes of xenobiotic and endogenous compounds.

Postmortem redistribution (PMR) describes the artificial postmortem concentration changes of xenobiotics that may pose major challenges in forensic toxicology. Only a few studies have systematically investigated time-dependent postmortem drug concentration changes so far and the a posteriori estimation of the occurrence of PMR is not yet possible. In this context, the general concept that postmortem biochemical changes in blood might parallel drug redistribution mechanisms seems promising. Thus, the current study investigated the possible correlations between time-dependent postmortem concentration changes of xenobiotic and endogenous compounds; exemplified for authentic morphine (n = 19) and methadone (n = 11) cases. Peripheral blood samples at two time-points postmortem were analyzed for morphine and methadone concentrations and an (un)targeted postmortem metabolomics approach was utilized to combine targeted quantitative analysis of 56 endogenous analytes and untargeted screening for endogenous compounds (characterizing 1174 features); liquid and gas chromatography-mass spectrometry was used respectively. Individual statistically significant correlations between morphine/methadone and endogenous compounds/features could be determined. Hence, the general applicability of the proposed concept could successfully be confirmed. To verify the reproducibility and robustness of the correlating behavior, a larger dataset must be analyzed next. Once a marker/set of markers is found (e.g. robust correlation with specific xenobiotic or xenobiotic class), these could be used as surrogates to further study the time-dependent PMR in a broader variety of cases (e.g. independent of a xenobiotic drug present). A crucial next step will also be the attempt to create a statistical model that allows a posteriori estimation of PMR occurrence of xenobiotics to assist forensic toxicologists in postmortem case interpretation.

Morphine plasmatic concentration in a pregnant mare and its foal after long term epidural administration.

BACKGROUND: Epidural administration of morphine has been shown to be an effective analgesic strategy in horses; however, the possible occurrence of side effects limits its usage. In order to decrease their frequency, it is important to target the minimal effective plasma concentration and avoid overdosing. As to date species-specific pharmacokinetics data are not available for epidural morphine, the dosing regimen is usually established on the basis of clinical reports and personal experience. In certain physiological conditions, like gestation, the outcome of an empirical dosing scheme can be unpredictable. The aim of this case report is to describe the pharmacological profile of morphine and its metabolites after prolonged epidural administration in a pregnant mare and her foal. CASE PRESENTATION: A 20 years old pregnant mare was presented to our hospital because of severe lameness, 2 months before delivery. Following an ineffective systemic pain treatment, an epidural catheter was inserted and morphine administered (initial dose 0.1 mg/kg every 8 h). Due to its efficacy in controlling pain, it was continued until end of gestation. Plasmatic concentration of morphine and its metabolites were assessed in the mare 6 weeks after starting the treatment, and in both the mare and foal during the first days after delivery. Plasmatic values similar to those previously reported in the literature following morphine short term administration through various routes and not accompanied by side effects were found in the mare, except during an excitatory period. Moreover, no evidence of dangerous drug accumulation or significant milk passage was noticed in the foal. Mild reduction of feces production with no signs of colic and two self-limiting episodes of excitement occurred during treatment in the mare. No side effects occurred during gestation and first phases of life in the foal. CONCLUSION: Prolonged epidural administration of morphine in a pregnant mare allowed good pain control in absence of clinically relevant side effects, in both the mare and her foal. Sudden increase in morphine plasmatic concentration can occur and side effects appear; careful treatment to the lowest effective dose and continuous monitoring of the clinical condition of the treated horse should be performed.

Effects of Obstructive Sleep Apnea and Obesity on Morphine Pharmacokinetics in Children.

BACKGROUND: Obesity increases susceptibility to chronic pain, increases metabolism, and is associated with obstructive sleep apnea syndrome (OSAS), all which can complicate perioperative pain management of patients. In addition, obesity and OSAS can cause elevation of the adipose-derived hormone leptin, which increases metabolism. We hypothesized that obesity along with sleep apnea and leptin independently enhance morphine pharmacokinetics. METHODS: Children 5-12 years of age who were presenting for surgery were administered a morphine dose of 0.05 mg/kg. Blood was collected at baseline and at subsequent preset times for pharmacokinetic analysis of morphine and its metabolites. Three groups were studied: a nonobese group with severe OSAS, an obese group with severe OSAS, and a control group. RESULTS: Thirty-four patients consisting of controls (n = 16), nonobese/OSAS (n = 8), and obese/OSAS (n = 10) underwent analysis. The obese/OSAS group had a higher dose-adjusted mean maximum morphine concentration (CMAX) over 540 minutes compared to the controls (P < .001) and those with only OSAS (P = .014). The obese/OSAS group also had lower volume of distribution (Vd) when compared to OSAS-only patients (P = .007). In addition, those in the obese/OSAS group had a higher morphine 3-glucuronide (M3G) maximum concentration (P = .012) and a higher ratio of M3G to morphine than did the control group (P = .011). Time to maximum morphine 6-glucuronide (M6G) concentration was significantly lower in both nonobese/OSAS and obese/OSAS groups than in the control group (P < .005). C-reactive protein (CRP), interleukin (IL)-10, and leptin were all higher in the obese/OSAS group than in controls (P = .004, 0.026, and <0.001, respectively), and compared to OSAS-only patients, CRP (P = .013) and leptin (P = .002) levels were higher in the obese/OSAS group. CONCLUSIONS: The combination of obesity and OSAS was associated with an increase in morphine metabolism compared with that in normal-weight controls. Our previous study in mice demonstrated that obesity from leptin deficiency decreased morphine metabolism, but that metabolism normalized after leptin replacement. Leptin may be a cause of the increased morphine metabolism observed in obese patients.

Pharmacokinetics of an intravenous constant rate infusion of a morphine-lidocaine-ketamine combination in Holstein calves undergoing umbilical herniorrhaphy.

OBJECTIVE: To describe the pharmacokinetics of morphine, lidocaine, and ketamine associated with IV administration of a constant rate infusion (CRI) of a morphine-lidocaine-ketamine (MLK) combination to calves undergoing umbilical herniorrhaphy. ANIMALS: 20 weaned Holstein calves with umbilical hernias. PROCEDURES: Calves were randomly assigned to receive a CRI of an MLK solution (0.11 mL/kg/h; morphine, 4.8 µg/kg/h; lidocaine, 2.1 mg/kg/h; and ketamine, 0.42 mg/kg/h) for 24 hours (MLK group) or 2 doses of flunixin meglumine (1.1 mg/kg, IV, q 24 h) and a CRI of saline (0.9% NaCl) solution (0.11 mL/kg/h) for 24 hours (control group). For all calves, the CRI was begun after anesthesia induction. Blood samples were obtained immediately before and at predetermined times for 120 hours after initiation of the assigned treatment. Noncompartmental analysis was used to estimate pharmacokinetic parameters for the MLK group. RESULTS: During the CRI, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine. Mean terminal half-life was 4.1, 0.98, and 1.55 hours and area under the concentration-time curve was 41, 14,494, and 7,426 h•µg/mL for morphine, lidocaine, and ketamine, respectively. After the CRI, the mean serum drug concentration at steady state was 6.3, 616.7, and 328 ng/mL for morphine, lidocaine, and ketamine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: During the CRI of the MLK solution, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine, likely owing to the fairly long half-life of morphine. Kinetic analyses of MLK infusions in cattle are necessary to establish optimal dosing protocols.

Roles of UGT2B7 C802T gene polymorphism on the efficacy of morphine treatment on cancer pain among the Chinese han population.

BACKGROUND: Morphine is a common analgesic often used to manage chronic pain, especially for patients with pain due to malignancies. Since UGT2B7 plays an important role in the metabolism of morphine, UGT2B7 gene mutation may influence the efficacy of morphine in patients with cancer being treated by this medication. AIMS: The aim of this study is to investigate the relationship between the polymorphisms of UGT2B7 and the efficacy of morphine treatment on cancer pain among the Chinese Han population. MATERIALS AND METHODS: A total of 120 patients with cancer pain were enrolled in this study. Morphine was administrated through patient-controlled analgesia infusion pump, and the visual analog score (VAS) was used for pain assessment at 0.5, 4, 6, 12, 24, 48, and 72-h post morphine treatment, respectively. The plasma concentration of morphine and genetic polymorphism of UGT2B7 C802T and G221T was analyzed, respectively. RESULTS: The frequencies of UGT2B7 C802T were CC: 13.33%, CT: 45% and TT: 41.67%, and the frequencies of UGT2B7 G221T were GG: 76.67%, GT: 22.5% and TT: 0.83%. Moreover, the VAS score of patients with either C802T CT or TT was significantly higher than that in patients with C802T CC. However, no difference of VAS scores was observed between patients carrying G221T GG and patients carrying G221T GT. The plasma concentration of morphine for patients with the C802T CC was significantly lower than that in patients carrying C802T CT or TT, while there was no significant difference in the level of morphine between patients with G221T GG and G221T GT. CONCLUSION: The polymorphism of UGT2B7 C802T, but not UGT2B7 G221T, has been associated with the efficacy of morphine treatment on cancer pain among Chinese Han population.

Correlation between interleukin-6 levels and methadone maintenance therapy outcomes.

BACKGROUND: The outcome of methadone maintenance therapy (MMT) varies in each patient with opioid use disorder (OUD). Opioid abuse activates proinflammatory processes by increasing cytokine production and impairing neurotrophic factor expression, and possibly leads to a vicious cycle that hinders recovery. Therefore, we investigated whether markers of inflammation and neurotrophic expression correlate with the MMT outcomes in OUD patients. METHOD: We investigated OUD patients undergoing MMT and followed them up for 12 weeks. We measured plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-1ß, transforming growth factor (TGF)-ß1, brain-derived neurotrophic factor (BDNF), urinary morphine tests, and plasma morphine levels at baseline and on weeks 1, 4, 8, and 12 during MMT. Multiple linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the cytokine and BDNF levels and MMT outcomes. RESULTS: We initially enrolled 104 patients, but only 78 patients completed end-of-study assessments. Plasma levels of CRP, TGF-ß1, and BDNF fell during MMT. Plasma IL-6 levels were significantly associated with plasma morphine levels (P = 0.005) and urinary morphine-positive (+) results (P = 0.04), and significantly associated with poor compliance (P = 0.009) and early dropout from MMT (P = 0.001). However, other cytokine and BDNF levels were not consistently associated with MMT outcomes. CONCLUSION: Higher IL-6 levels were associated with poor MMT outcomes. Additional studies on regulating IL-6 expression to improve treatment outcomes in OUD patients might be warranted.

A Randomized, Crossover Study on the Effect of Food on the Pharmacokinetic Characteristics of Morphine ARER (MorphaBond™ ER), an Abuse-Deterrent Formulation of Extended-Release Morphine.

INTRODUCTION: Food can alter the pharmacokinetics of certain abuse-deterrent formulations. Morphine ARER is an oral abuse-deterrent formulation of ER morphine sulfate tablets formulated with physical and chemical properties that contribute to the abuse-deterrent aspects of the drug. This study compared the relative bioavailability of Morphine ARER in the presence and absence of food. METHODS: This was a randomized, single-dose, two-treatment, crossover study in which healthy adults received Morphine ARER 100 mg under fasting and fed conditions. Subjects were given naltrexone 50 mg to limit opioid effects. Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide (M6G) were obtained up to 48 h post-dose; area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC0-∞), maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) were calculated. Safety was evaluated by observation or report of adverse events, which were monitored during the treatment periods. RESULTS: Of 28 enrolled subjects, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Under fed conditions, the Cmax for morphine was 33% higher (44.78 vs. 33.30 ng/ml for fed and fasted conditions, respectively) and the median Tmax was 30 min longer than under fasted conditions. The overall morphine exposure (AUC0-∞) was similar for fed (440.6 ng · h/ml) vs. fasted conditions (395.1 ng · h/ml). For M6G, the Cmax and AUC0-∞ were similar under both conditions, and the median Tmax for M6G was 60 min longer under fed conditions. Common adverse events were somnolence and nausea. CONCLUSION: Morphine ARER can be administered without regard to food. Plain language summary available for this article. FUNDING: Inspirion Delivery Sciences, LLC.

Food alters how the body processes some currently available opioids. How the opioid is formulated in the final commercial product can impact this effect. Morphine ARER is a new oral abuse-deterrent formulation of extended-release morphine created with properties to make it more difficult to abuse via the intranasal and intravenous routes. To better understand how food affects Morphine ARER bioavailability, we compared the amount of morphine in the blood when 100 mg of Morphine ARER was given with or without food, in random order, to 27 healthy volunteers. Plasma samples were collected up to 48 h after dosing to measure the concentrations of morphine and its active metabolite morphine-6-glucuronide. We measured the amount of drug absorbed by using the area under the plasma concentration-time curve (AUC) and the rate of drug absorption by looking at the highest amount of drug observed in the blood using the maximum observed plasma concentration (C_max) and time to C_max (T_max). When subjects were fed, the C_max for morphine was 33% higher (44.78 ng/ml) than when they fasted (33.30 ng/ml). The median T_max was 30 min longer when subjects were fed. Total morphine exposure (AUC_0­∞) was similar when subjects were fed (440.6 ng · h/ml) or when they fasted (395.1 ng · h/ml). Safety was evaluated throughout the treatment periods by adverse events, either observed by the clinician or reported by subjects. The most common adverse events noted were somnolence (e.g., sleepiness) and nausea. Our findings show that Morphine ARER has similar bioavailability when taken with or without food.

Rapid Discovery of Illuminating Peptides for Instant Detection of Opioids in Blood and Body Fluids.

The United States is currently experiencing an opioid crisis, with more than 47,000 deaths in 2017 due to opioid overdoses. Current approaches for opioid identification and quantification in body fluids include immunoassays and chromatographic methods (e.g., LC-MS, GC-MS), which require expensive instrumentation and extensive sample preparation. Our aim was to develop a portable point-of-care device that can be used for the instant detection of opioids in body fluids. Here, we reported the development of a morphine-sensitive fluorescence-based sensor chip to sensitively detect morphine in the blood using a homogeneous immunoassay without any washing steps. Morphine-sensitive illuminating peptides were identified using a high throughput one-bead one-compound (OBOC) combinatorial peptide library approach. The OBOC libraries contain a large number of random peptides with a molecular rotor dye, malachite green (MG), that are coupled to the amino group on the side chain of lysine at different positions of the peptides. The OBOC libraries were then screened for fluorescent activation under a confocal microscope, using an anti-morphine monoclonal antibody as the screening probe, in the presence and absence of free morphine. Using this novel three-step fluorescent screening assay, we were able to identify the peptide-beads that fluoresce in the presence of an anti-morphine antibody, but lost fluorescence when the free morphine was present. After the positive beads were decoded using automatic Edman microsequencing, the morphine-sensitive illuminating peptides were then synthesized in soluble form, functionalized with an azido group, and immobilized onto microfabricated PEG-array spots on a glass slide. The sensor chip was then evaluated for the detection of morphine in plasma. We demonstrated that this proof-of-concept platform can be used to develop fluorescence-based sensors against morphine. More importantly, this technology can also be applied to the discovery of other novel illuminating peptidic sensors for the detection of illicit drugs and cancer biomarkers in body fluids.

Morphine Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

OBJECTIVE: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions. INTERVENTIONS: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation. MEASUREMENTS AND MAIN RESULTS: Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified. CONCLUSIONS: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.

Integrated Model to Describe Morphine Pharmacokinetics in Humans.

The pharmacokinetics (PK) of morphine has been extensively investigated. Though different publications have focused on the various aspects of morphine PK, none have quantitatively interpreted morphine PK across different publications. The objective of this research is to summarize the current understanding of morphine PK in humans quantitatively. In this research, a parent-metabolite compartmental PK modeling approach was used to summarize the current understanding of morphine PK in humans. Plasma concentration-time profiles and cumulative urine recovery time profiles of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were digitized from the previous publications to develop the parent-metabolite PK model. The parent-metabolite PK model successfully described the plasma concentration-time profiles and cumulative urine recovery of morphine as well as its two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after intravenous and oral administration of morphine. This research separated out the first-pass effect on morphine metabolism after oral administration. By integrating these results with two mass balance studies of morphine, a clear picture of morphine absorption and disposition is given. Though the results are mainly based on data collected from healthy volunteers or patients whose disease is not expected to impact morphine PK, the parent-metabolite model sets a framework to further evaluate morphine PK in special populations, such as pediatrics and patients with renal impairment.

Stability studies in biological fluids during post-analysis custody. Opiate compounds derived from heroin consumption.

In Forensic Toxicology, the evidences have to be maintained under custody for, at least, one year. Depending on the conditions and duration of storage, drug concentrations might have changed considerably since the first analysis. The aim of this study is to evaluate in vitro stability of opiate compounds, derived from heroin consumption, 6-acetylmorphine (6-MAM), morphine (MOR) and codeine (COD), in blood and urine, during post-analysis custody. Parameters evaluated were: time of custody, temperature, addition of preservative (blood) and pH (urine). Blood and urine samples were spiked with the three analytes to give a final concentration of 1000 ng/mL. The prepared samples were divided into 2 groups and stored at two temperatures (4 °C and -20 °C). Each one of these groups was subsequently divided in other two groups: with and without preservative (1%NaF) for blood, and pH 4 and 8 in the case of urine. 6-MAM, MOR and COD were analyzed by GCMS after SPE and derivatization with BSTFA. Analyses were performed in triplicate every two weeks for a year. In blood samples 6-MAM is the only compound that degrades. The best storage conditions were at -20 °C with NaF, with 6-MAM recoveries, after one year of custody, of 47.1 ± 1.5%; while in the other conditions 6-MAM disappeared after 215 days (at 4 °C with NaF), 45 days (at -20 °C without NaF) and 15 days (at 4 °C without preservative). COD does not degrade, with recoveries higher than 90%, in all of the conditions. They ranged from 89.7 ± 3.6% in samples maintained at -20 °C without NaF to 95.9 ± 2.0% in those maintained at 4 °C with NaF. MOR recoveries were lower than those of COD. They ranged from 66.9 ± 3.6%, in frozen samples added with NaF, to 78.6 ± 0.5% in refrigerated samples without preservative. In urine samples the three compounds were stable in all the studied conditions, with the exception of 6-MAM in samples at pH 8 and stored at 4 °C. In these conditions, 6-MAM disappeared after 135 days of custody; while recoveries in the other conditions ranged from 93.7 ± 6.4%, at 4 °C and pH 4, to 85.1 ± 2.0% at -20 °C and pH 8. MOR and COD recoveries were similar in the four conditions. In the case of MOR, they ranged from 82.1 ± 1.2% at 4 °C and pH 4 to 89.5 ± 6.0% at -20 °C and pH 8. As far as COD is concerned, recoveries ranged from 111.6 ± 5.8% at 4 °C and pH 8 to 102.6 ± 1.2% at 4 °C and pH 4. In conclusion, the study showed that the most labile opiate compound is 6-MAM. Its stability mainly depends on urine pH or the addition of preservative, in blood samples. The best storage conditions for samples from heroin consumers are in the freezer, at -20 °C. In addition, blood samples must be added with 1%NaF and urine samples must be buffered at pH 4.

Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review.

BACKGROUND: Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings. METHODS: The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement. RESULTS: In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers. CONCLUSIONS: Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context. TRIAL REGISTRATION: Registration number: CRD42017057831 .