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Pharmacology Research & Perspectives Jun 2023The opioid epidemic has impacted over 10 million Americans in 2019. Opioids, like morphine, bind non-selectively in both peripheral tissue, leading to effective pain...
The opioid epidemic has impacted over 10 million Americans in 2019. Opioids, like morphine, bind non-selectively in both peripheral tissue, leading to effective pain relief, and central tissue, resulting in dangerous side effects and addiction. The inflamed conditions of injured tissues have a lower pH (pH = 6-6.5) environment than healthy tissue (pH = 7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using molecular extension and dissection techniques. Morphine binds to the μ-opioid receptor (MOR) when the biochemically active amine group is protonated. Fluorination of a β-carbon from the tertiary amine group led to a reduced pKa of the derivative through induction. Through a decrease in the pKa, protonation is still statistically favored in lower pH environments of inflamed tissue but primarily deprotonated in healthy tissue. The cyclohexenol and N-methyl-piperidine rings of morphine are removed to increase conformational flexibility when binding while still maintaining the interactions required for analgesia. Electronic structure calculations were performed with Gaussian16 using the Keck Computational Research Cluster at Chapman University to determine the pKa. The theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. Fluoromorphine β-C2 was designed computationally and modeled within the MOR using Maestro: Schrödinger. This derivative exhibits a pKa reduction and enhanced ligand-protein interactions within the MOR. β-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.83) relative to morphine, reducing binding within healthy, central tissue.
Topics: Humans; Morphine Derivatives; Analgesics, Opioid; Morphine; Pain; Analgesia
PubMed: 37078224
DOI: 10.1002/prp2.1075 -
Clinical Pharmacokinetics Jul 2017Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it... (Clinical Trial)
Clinical Trial
BACKGROUND
Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.
METHODS
Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.
RESULTS
A one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m. The clearance of morphine or its metabolites was not found to be correlated with treatment failure.
CONCLUSION
The influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Female; Glucuronosyltransferase; Humans; Infusions, Subcutaneous; Male; Middle Aged; Models, Biological; Morphine; Morphine Derivatives; Multidrug Resistance-Associated Proteins; Neoplasms; Organic Cation Transporter 1; Pain; Polymorphism, Genetic; Treatment Outcome
PubMed: 27815868
DOI: 10.1007/s40262-016-0471-7 -
British Journal of Anaesthesia May 1990The analgesic efficacy and CSF pharmacokinetics of intrathecal morphine sulphate and morphine-6-glucuronide (M6G) were compared in a single-blind crossover study. Lumbar... (Clinical Trial)
Clinical Trial Comparative Study
The analgesic efficacy and CSF pharmacokinetics of intrathecal morphine sulphate and morphine-6-glucuronide (M6G) were compared in a single-blind crossover study. Lumbar intrathecal catheters were sited in three patients with chronic cancer pain, and morphine sulphate 500 micrograms or M6G 500 micrograms given via the catheter on separate days. CSF was sampled for 24 h following drug administration and analysed for morphine and M6G by high pressure liquid chromatography. The mean (SD) requirement for patient controlled analgesia with pethidine was 393.3 (227.4) mg/24 h during the morphine limb of the trial and 226.7 (113.6) mg/24 h during the M6G limb. M6G was not detected in CSF following administration of morphine. Fitting of CSF concentrations to triexponential curves revealed mean (SD) alpha, beta and gamma half-lives of 13.2 (7.4), 54.9 (31.5) and 222.5 (100) min for morphine and 11.2 (2.4), 67.3 (49.9) and 619.3 (629.7) min for M6G.
Topics: Aged; Chronic Disease; Humans; Injections, Spinal; Male; Middle Aged; Morphine; Morphine Derivatives; Pain; Single-Blind Method
PubMed: 2354092
DOI: 10.1093/bja/64.5.547 -
Canadian Medical Association Journal Feb 1955
Topics: Anesthesia; Anesthesiology; Atropine; Atropine Derivatives; Humans; Morphine
PubMed: 14352090
DOI: No ID Found -
British Journal of Anaesthesia Feb 2004Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy.
METHODS
Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.
RESULTS
The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.
CONCLUSION
M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.
Topics: Aging; Analgesics, Opioid; Body Weight; Child, Preschool; Drug Administration Schedule; Female; Half-Life; Humans; Infant; Infant, Newborn; Male; Models, Biological; Morphine; Morphine Derivatives; Pain, Postoperative; Single-Blind Method
PubMed: 14722170
DOI: 10.1093/bja/aeh042 -
Biomedicine & Pharmacotherapy =... Sep 2022S-nitrosothiols exert multiple effects on neural processes in the central and peripheral nervous system. This study shows that intravenous infusion of...
S-nitrosothiols exert multiple effects on neural processes in the central and peripheral nervous system. This study shows that intravenous infusion of S-nitroso-L-cysteine (SNO-L-CYS, 1 μmol/kg/min) in anesthetized male Sprague Dawley rats elicits (a) sustained increases in minute ventilation, via increases in frequency of breathing and tidal volume, (b) a decrease in Alveolar-arterial (A-a) gradient, thus improving alveolar gas-exchange, (c) concomitant changes in arterial blood-gas chemistry, such as an increase in pO and a decrease in pCO, (d) a decrease in mean arterial blood pressure (MAP), and (e) an increase in tail-flick (TF) latency (antinociception). Infusion of S-nitroso-D-cysteine (SNO-D-CYS, 1 μmol/kg/min, IV), did not elicit similar responses, except for a sustained decrease in MAP equivalent to that elicited by SNO-L-CYS. A bolus injection of morphine (2 mg/kg, IV) in rats receiving an infusion of vehicle elicited (a) sustained decreases in frequency of breathing tidal volume, and therefore minute ventilation, (b) a sustained decrease in MAP, (c) sustained decreases in pH, pO and maximal sO with sustained increases in pCO and A-a gradient, and (d) a sustained increase in TF latency. In rats receiving SNO-L-CYS infusion, morphine elicited markedly smaller changes in minute ventilation, arterial blood gas chemistry, A-a gradient and MAP. In contrast, the antinociceptive effects of morphine were enhanced in rats receiving the infusion of SNO-L-CYS. The morphine-induced responses in rats receiving SNO-D-CYS infusion were similar to vehicle-infused rats. These data are the first to demonstrate that infusion of an S-nitrosothiol, such as SNO-L-CYS, can stereoselectively ameliorate the adverse effects of morphine on breathing and alveolar gas exchange while promoting antinociception.
Topics: Analgesia; Animals; Cysteine; Male; Morphine; Rats; Rats, Sprague-Dawley; S-Nitrosothiols
PubMed: 36076552
DOI: 10.1016/j.biopha.2022.113436 -
BMC Veterinary Research May 2022In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of...
BACKGROUND
In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency.
RESULTS
Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied.
CONCLUSIONS
The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.
Topics: Analgesics, Opioid; Animals; Codeine; Glucuronides; Horses; Morphine; Morphine Derivatives; Nociception
PubMed: 35614473
DOI: 10.1186/s12917-022-03299-0 -
Anesthesiology Jun 2009
Topics: Analgesics, Opioid; Animals; Hyperalgesia; Mice; Mice, Knockout; Morphine; Morphine Derivatives; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu
PubMed: 19417609
DOI: 10.1097/ALN.0b013e3181a1075b -
American Journal of Veterinary Research Jun 2012To compare the cardiorespiratory, gastrointestinal, analgesic, and behavioral effects between IV and IM administration of morphine in conscious horses with no signs of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the cardiorespiratory, gastrointestinal, analgesic, and behavioral effects between IV and IM administration of morphine in conscious horses with no signs of pain.
ANIMALS
6 healthy adult horses.
PROCEDURES
Horses received saline (0.9% NaCl) solution (IM or IV) or morphine sulfate (0.05 and 0.1 mg/kg, IM or IV) in a randomized, masked crossover study design. The following variables were measured before and for 360 minutes after drug administration: heart and respiratory rates; systolic, diastolic, and mean arterial blood pressures; rectal temperature; arterial pH and blood gas variables; intestinal motility; and response to thermal and electrical noxious stimuli. Adverse effects and horse behavior were also recorded. Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were measured via liquid chromatography-mass spectrometry.
RESULTS
No significant differences in any variable were evident after saline solution administration. Intravenous and IM administration of morphine resulted in minimal and short-term cardiorespiratory, intestinal motility, and behavioral changes. A decrease in gastrointestinal motility was detected 1 to 2 hours after IM administration of morphine at doses of 0.05 and 0.1 mg/kg and after IV administration of morphine at a dose of 0.1 mg/kg. Morphine administration yielded no change in any horse's response to noxious stimuli. Both morphine-3-glucuronide and morphine-6-glucuronide were detected in plasma after IV and IM administration of morphine.
CONCLUSIONS AND CLINICAL RELEVANCE
Clinically relevant doses of morphine sulfate yielded minimal and short-term behavioral and intestinal motility effects in healthy horses with no signs of pain. Neither dose of morphine affected their response to a noxious stimulus.
Topics: Analysis of Variance; Animals; Body Temperature; Cross-Over Studies; Gastrointestinal Motility; Heart Rate; Horses; Injections, Intramuscular; Injections, Intravenous; Morphine; Morphine Derivatives; Motor Activity; Pain Threshold; Respiratory Rate
PubMed: 22620693
DOI: 10.2460/ajvr.73.6.799 -
CPT: Pharmacometrics & Systems... May 2017Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate...
Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three- and one-compartment models, respectively. After accounting for the effect of total body weight on all clearance and volume of distribution parameters using an allometric scaling approach, NASH severity score (NASF; combination of fibrosis and nonalcoholic fatty liver disease activity scores) was the most significant predictor of differences in M3G exposure. The model predicted a linear decrease in the clearance of M3G with increasing NASF scores on a natural logarithmic scale. These results may provide some insight into the potential effect of NASH on the disposition of hepatic transporter substrates.
Topics: Adult; Analgesics, Opioid; Female; Healthy Volunteers; Humans; Male; Middle Aged; Models, Biological; Morphine; Morphine Derivatives; Non-alcoholic Fatty Liver Disease; Tissue Distribution; Young Adult
PubMed: 28417561
DOI: 10.1002/psp4.12185