Pharmacodynamics Of Morphine Research Articles

PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans.

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

O5 | Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 30-30 ORAL PRESENTATIONS O5 | Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses First published: 11 June 2023 https://doi.org/10.1111/jvp.13171Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 30-30 RelatedInformation

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses.

The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2mg/kg morphine and oral doses of 0.2, 0.6, and 0.8mg/kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (Cmax : 11.6-37.8ng/mL (0.6mg/kg); 15.8-42.6ng/mL (0.8mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.

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.

Pharmacogenomics and Morphine.

Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu‐opioid receptors predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2 member B7 and encounters the transporter proteins organic cation transporter isoform 1 and P‐glycoprotein (adenosine triphosphate–binding cassette subfamily B member 1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations.

Postoperative breakthrough pain in paediatric cardiac surgery not reduced by increased morphine concentrations.

Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine. Data on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 μg kg-1) with continuous infusion (40 μg kg-1 h-1) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling. During the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml-1 (range 7-180 ng ml-1). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml-1) increased at higher morphine concentrations (P < 0.001). In this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children. In children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children.

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

Effects of periodic intake of drugs of abuse (morphine) on HIV dynamics: Mathematical model and analysis

Drugs of abuse, such as opiates, have been widely associated with diminishing host-immune responses, including suppression of HIV-specific antibody responses. In particular, periodic intake of the drugs of abuse can result in time-varying periodic antibody level within HIV-infected individuals, consequently altering the HIV dynamics. In this study, we develop a mathematical model to analyze the effects of periodic intake of morphine, a widely used opiate. We consider two routes of morphine intake, namely, intravenous morphine (IVM) and slow-release oral morphine (SROM), and integrate several morphine pharmacodynamic parameters into HIV dynamics model. Using our non-autonomous model system we formulate the infection threshold, Ri, for global stability of infection-free equilibrium, which provides a condition for avoiding viral infection in a host. We demonstrate that the infection threshold highly depends on the morphine pharmacodynamic parameters. Such information can be useful in the design of antibody-based vaccines. In addition, we also thoroughly evaluate how alteration of the antibody level due to periodic intake of morphine can affect the viral load and the CD4 count in HIV infected drug abusers.

Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses.

The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5mg/kg, or saline control. Blood samples were collected up to 72hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine-3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine-6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady-state and systemic clearance ranged from 9.40 to 16.9L/kg and 23.3 to 32.4mlmin-1 kg-1 , respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites.

Opioid-related genetic polymorphisms do not influence postoperative opioid requirement: A prospective observational study.

Among the various factors that may influence the pharmacological response to opioids, genetic polymorphisms [single nucleotide polymorphisms (SNP)] have generated some interest. To examine the influence on morphine dose requirements and adverse events in the postoperative period of four SNP [opioid receptor mu1 (OPRM1), ATP-binding cassette subfamily B, member 1 (ABCB1) ex-21 and ex-26, catechol-o-methyltransferase (COMT)] in candidate genes involved in morphine pharmacodynamics and pharmacokinetics. A single centre prospective study. University Hospital, Paris, France, from 2 January 2007 to 15 November 2011. A total of 438 white adults scheduled for major orthopaedic surgery (spine, hip and knee) under general anaesthesia. The main exclusion criteria were receiving opioids for chronic pain, nonopioid drugs within 2 days prior to surgery, pregnancy, renal insufficiency, sleep apnoea obstruction syndrome, morbid obesity, severe hepatic impairment, cognitive dysfunction. Assays of plasma concentrations of morphine and metabolites (morphine 3-glucuronide and morphine 6-glucuronide) were performed and common polymorphisms in four candidate genes [OPRM1 A118G rs1799971; P-glycoprotein (ABCB1) T3435C (rs1045642) and G2677T/A (rs2032582); COMT Val 158 Met (rs4680)] were analysed.Morphine was titrated by staff in the postanaesthesia care unit (PACU) and in the ward patient-controlled intravenous analgesia was used for 24 h. The dose of morphine required to achieve pain relief and the influence of SNP in genes involved in morphine pharmacodynamics and kinetics on morphine dose requirements. Secondary endpoints were the concentrations of morphine, morphine 6-glucuronide and morphine 3-gluguronide, the proportion of patients requiring a rescue analgesic and the proportion of morphine-related adverse events. A total of 404 patients completed the study to final analysis. The mean ± SD morphine dose to achieve pain relief was 15.8 ± 8.8 mg in the PACU and 22.7 ± 18.6 mg during patient-controlled intravenous administration. Morphine-related adverse events were observed in 37%. There was no relationship between any genetic polymorphisms and morphine dose, morphine 3-gluguronide and morphine 6-glucuronide concentration, morphine-related adverse events or pain level. In the PACU only, P-glycoprotein polymorphisms (ex-21; ex-26) were significantly associated with morphine concentration but the prediction of the model was poor (R = 0.04) CONCLUSION: No major relationship has been demonstrated between SNP of OPRM1, ABCB1, COMT and morphine requirement, pain level or adverse effects in the postoperative period. NCT00822549 (www.clinicaltrials.gov).

Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models

Drug–target binding kinetics (as determined by association and dissociation rate constants, kon and koff) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug–target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment–target binding kinetics (EC–TB) model were tested on either plasma (ECPL, TBPL and EC–TBPL) or brain extracellular fluid (ECF) (ECECF, TBECF and EC–TBECF) morphine concentrations and EEG amplitude in rats. It was also analyzed when a significant shift in the time to maximal target occupancy (TmaxTO) with increasing dose, the discriminating feature between the TB and EC model, occurs in the TB model. All TB models assumed a linear relationship between target occupancy and drug effect on the EEG amplitude. All three model types performed similarly in describing the morphine pharmacodynamics data, although the EC model provided the best statistical result. The analysis of the shift in TmaxTO (∆TmaxTO) as a result of increasing dose revealed that ∆TmaxTO is decreasing towards zero if the koff is much smaller than the elimination rate constant or if the target concentration is larger than the initial morphine concentration. The results for the morphine PKPD modelling and the analysis of ∆TmaxTO indicate that the EC and TB models do not necessarily lead to different drug effect versus time curves for different doses if a delay between drug concentrations and drug effect (hysteresis) is described. Drawing mechanistic conclusions from successfully fitting one of these two models should therefore be avoided. Since the TB model can be informed by in vitro measurements of kon and koff, a target binding model should be considered more often for mechanistic modelling purposes.

Pharmacokinetics of Morphine in Rats with Adjuvant-induced Arthritis.

We investigated the in vivo dynamics and analgesic effect of morphine using an adjuvant-induced arthritis (AA) rat as a model of chronic inflammation. Morphine generally binds to μ-opioid receptors in the brain to exert its effects. After several minutes, it is metabolized by glucuronidation via a UDP-glucuronosyltransferase (UGT). Here, we showed that in AA rats, UGT activity in liver microsomes was reduced. Morphine-free serum fractions in AA rats were also decreased (control, 84.9%; AA, 63.9%) and the expression of ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), which plays a crucial role in morphine bile excretion, decreased to 23.0% that of the control group. However, we observed no significant difference between the AA and control groups regarding blood concentrations of morphine and morphine-3-glucuronide. In contrast, the analgesic effect of morphine increased 4-fold in AA rats. Our results showed that the pharmacokinetics of morphine is not changed, but the pharmacodynamics of morphine is enhanced in chronic inflammation.

Pharmacokinetics and Pharmacodynamics of Morphine and its Major Metabolites Following Intravenous Administration of Four Doses to Horses

ObjectiveTo understand the pharmacokinetics of morphine and correlate the serum values of morphine and its metabolites to pharmacodynamic data.Materials and MethodsUsing a balanced randomized 5‐way crossover design; ten horses received an intravenous injection of saline and morphine at doses of 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, and 0.5 mg/kg. This was repeated until all horses received all treatments. A minimum washout period of 2 weeks was observed between treatments. Blood samples were collected at various time post drug administration, concentrations of morphine, M3G and M6G determined using liquid chromatography‐mass spectrometry and pharmacokinetic analysis performed. Horses were outfitted with step counters and Holter monitors. Gastrointestinal borborygmi, respiration, defecation, and overall demeanor were assessed. Concentrations of parent compound, M3G and M6G were correlated to pharmacodynamic data to better understand the effects of the active metabolites.ResultsMorphine is metabolized into two metabolites in the horse: morphine‐ 6 glucuronide (M6G) and morphine‐3 glucuronide (M3G). Both metabolites and parent compound were detected in the serum as soon as 5 minutes after administration. M3G was found in much higher concentrations than both M6G and parent compound. Concentrations of metabolites and parent compound were dose dependent with the highest concentrations seen in the 0.5 g/kg dose group. Plasma concentrations of morphine fit best in a three‐compartment model and were characterized by rapid distribution and slower elimination phases. Individual pharmacokinetic parameters for metabolites were obtained by noncompartmental analysis. Higher concentrations of M3G correlated with an increase in step count, increase in heart rate, and decrease in gastrointestinal borborygmi seen in the high dose group.Conclusions and Potential ImpactThis project delivers basic pharmacokinetic and pharmacodynamic knowledge of morphine administration to horses and provides valuable information regarding morphine metabolism in horses and the characteristics of these metabolites. The large amount of M3G may be contributing to the neuroexcitatory effects seen in horses after high doses of morphine. Further exploration of the individual effects of the metabolites would be helpful in potentially identifying a novel analgesic. This would be a large advance in veterinary medicine as the number of analgesics available to equine patients currently is limited an often come with severe side effects such as renal failure, gastrointestinal slowing, and increased CNS activity.Support or Funding InformationCalifornia Horse Racing Board Pharmacology Research FundsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning

To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i.e., COMFORT‐B, preterm infant pain profile [PIPP], Neonatal Infant Pain Scale (NIPS), and visual analogue scale (VAS)). The item response theory (IRT) was used to analyze the data in order for us to handle the data from multiple‐item pain scores. The analysis showed an intra‐individual relationship between morphine concentrations and pain reduction, as measured by COMFORT‐B and VAS. However, the small magnitude of the morphine effect was not considered clinically relevant for this intervention in preterm neonates.

Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

AimA high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers. MethodsPharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0–150min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation (“the cold pressor test” where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined. ResultsNeither AUC0–150min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05). ConclusionsIn this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

Modelling concentration–analgesia relationships for morphine to evaluate experimental pain models

The aim of this study was to develop population pharmacokinetic–pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics.In a randomised, double-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin and muscle.Baseline pain metrics varied between individuals and occasions, and were described with interindividual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model with interindividual variability on drug effect slope and linked to an effect compartment for muscle pressure. The models indicate that a steady-state morphine concentration of 21ng/ml causes 33% and 0.84% increases in stimulus intensity from baseline for muscle pressure and skin heat, respectively.The population pharmacokinetic–pharmacodynamic models developed in this study indicate that mechanical stimulation of muscle is a more clinically relevant pain stimulus for the assessment of morphine pharmacodynamics than thermal stimulation of skin.

The pharmacology of medieval sedatives: The “Great Rest” of the Antidotarium Nicolai

Ethnopharmacological relevancePast practices of compound drugs from different plant ingredients enjoyed remarkable longevity over centuries yet are largely dismissed by modern science as subtherapeutic, lethal or fanciful. Aim of the studyTo examine the phytochemical content of a popular medieval opiate drug called the “Great Rest” and gauge the bioavailability and combined effects of its alkaloid compounds (morphine, codeine, hyoscyamine, scopolamine) on the human body according to modern pharmacokinetic and pharmacodynamic parameters established for these compounds. Calculations and theoryWe reviewed the most recent studies on the pharmacodynamics of morphine, codeine, hyoscyamine and scopolamine to ascertain plasma concentrations required for different physiological effects and applied these findings to dosage of the Great Rest. ResultsGiven the proportional quantities of the alkaloid rich plants, we calculate the optimal dose of Great Rest to be 3.1±0.1–5.3±0.76g and reveal that the lethal dose of Great Rest is double the therapeutic concentration where all three alkaloid compounds are biologically active. ConclusionThis study helps establish the effective dose (ED50), toxic dose (TD50) and lethal dose (LD50) rates for the ingestion of raw opium, henbane and mandrake, and describes their probable combined effects, which may be applied to similar types of pre-modern pharmaceuticals to reveal the empirical logic behind past practices.

Cyclosporine-inhibitable Blood–Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Fourteen healthy volunteers received morphine (0.1 mg/kg, 1-h IV infusion) in a crossover study without (control) or with the infusion of validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2-h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml·h (P < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm·h), plasma effect-site transfer rate constant (k(e0), median 0.27 vs. 0.17 h(-1)), and maximum calculated effect-site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml; all P < 0.05). Analgesia testing was confounded by cyclosporine-related pain. Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Morphine is an important drug used to alleviate moderate to severe pain. This opiate is mainly metabolized by glucuronidation to a non-analgesic metabolite, morphine-3-glucuronide (M-3-G) and an active metabolite morphine-6-glucuronide (M-6-G). To understand the modulation of morphine glucuronidation activity by environmental factors, the effect of endogenous and food-derived compounds on morphine uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) in rat and human microsomes was evaluated examining the 50% inhibitory concentration (IC(50)). The liver microsomes from Sprague-Dawley rats (RLM) and humans (HLM, 150 donors, pooled microsomes) were used as enzyme sources. Of 27 compounds tested, monoterpenoid alcohols, such as borneol and iso-borneol, exhibited a strong inhibitory effect on morphine glucuronidation in rat liver microsomes (RLM), whereas we failed to detect any inhibitory effect of endogenous substances including amino acids and sugars. The substances which have the ability to inhibit the activity in RLM are also inhibitory toward morphine glucuronidation in HLM and UGT2B7 baculosomes. However, the difference was that while the strongest inhibitory effect was observed for iso-menthol in HLM, borneol was the strongest inhibitor of the activity mediated by RLM. Although zidovudine is a typical substrate of UGT2B7, the inhibition of morphine glucuronidation by zidovudine was far weaker than that of monoterpenoid alcohols. These results demonstrate that dietary and supplementary monoterpenoid alcohols modify the pharmacokinetics and pharmacodynamics of morphine through inhibition of UGT2B7.

Pilot Study Examining the Frequency of Several Gene Polymorphisms Involved in Morphine Pharmacodynamics and Pharmacokinetics in a Morbidly Obese Population

Morbidly obese patients are at significantly elevated risk of postsurgery complications and merit closer monitoring by health care professionals after bariatric surgery. It is now recognized that genetic factors influence individual patient's response to drug used in anesthesia and analgesia. Among the many drug administered by anesthetists, we focused in this pilot study on morphine, since morphine patient-controlled anesthesia in obese patients undergoing gastric bypass surgery is frequently prescribed. We examined the allelic frequency of three polymorphisms involved in morphine pharmacodynamics and pharmacokinetics in patients with body mass index (BMI) >40. One hundred and nine morbidly obese patients (BMI = 49.1 ± 7.7 kg/m²) were genotyped for three polymorphisms c.A118G of mu opioid receptor (OPRM1), c.C3435T of the P-glycoprotein gene (ABCB1), and p.Val158Met of catechol-O-methyltransferase gene (COMT). Allelic frequencies were 118G-0.22, C3435-0.55, and 158Met-0.5 in our whole population and 0.23, 0.5, and 0.47 in Caucasian population. Allelic frequencies did not differ according to gender. Mean BMI did no differ according to the allelic variant. OPRM1118G allele was more frequent in our population than in most previously described European populations. Since the concept of "personalized medicine" promises to individualize therapeutics and optimize medical treatment in term of efficacy and safety, especially when prescribing drugs with a narrow therapeutic index such as morphine, further clinical studies examining the clinical consequences of the OPRM1 c.A118G polymorphism in patients undergoing gastric bypass surgery are needed.