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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin.

After injection, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and further to morphine. As morphine has been shown to increase striatal dopamine, whereas 6-MAM has not been studied in this respect, we gave i.v. injections of 3 µmol 6-MAM, morphine or heroin to rats. Opioids were measured in blood, and dopamine and opioids in microdialysate from brain striatal extracellular fluid (ECF), by UPLC-MS/MS. After 6-MAM injection, 6-MAM ECF concentrations increased rapidly, and reached Cmax of 4.4 µM after 8 min. After heroin injection, 6-MAM increased rapidly in blood and reached Cmax of 6.4 µM in ECF after 8 min, while ECF Cmax for heroin was 1.2 µM after 2 min. T max for morphine in ECF was 29 and 24 min following 6-MAM and heroin administration, respectively, with corresponding Cmax levels of 1 and 2 µM. Dopamine levels peaked after 8 and 14 min following 6-MAM and heroin administration, respectively. The dopamine responses were equal, indicating no dopamine release by heroin per se. Furthermore, 6-MAM, and not morphine, appeared to mediate the early dopamine response, whereas morphine administration, giving rise to morphine ECF concentrations similar to those observed shortly after 6-MAM injection, did not increase ECF dopamine. 6-MAM appeared accordingly to be the substance responsible for the early increase in dopamine observed after heroin injection. As 6-MAM was formed rapidly from heroin in blood, and was the major substance reaching the brain after heroin administration, this also indicates that factors influencing blood 6-MAM concentrations might change the behavioural effects of heroin.

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

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

Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide.

BACKGROUND: Morphine-6-glucuronide (M6G) is a strong µ-receptor agonist with higher affinity than morphine itself. It has been suggested that M6G contributes to the analgesic effect after administration of morphine, but the extent of its contribution remains unclear. METHODS: In order to elucidate the relative contribution of both drugs to the overall analgesic effect mediated by the µ-receptor, published data on µ-receptor binding, plasma protein binding, concentrations [preferably area under the concentration-time curve (AUC)] of morphine and M6G in blood or cerebrospinal fluid (CSF), or concentration ratios were used to calculate free CSF concentration corrected for receptor binding for each compound. To compare different routes of administration, free CSF concentrations of M and M6G corrected for potency were added and compared with oral administration. RESULTS: Based on AUC data, there is a major contribution of M6G to the overall analgesic effect; the mean contributions being estimated as 96.6%, 85.6%, 85.4%, and 91.3% after oral, s.c., i.v., and rectal administration of morphine, respectively. In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Owing to accumulation of M6G over time in these patients, morphine may be regarded as a prodrug. CONCLUSIONS: When administering morphine to patients, the analgesic effect is mainly caused by M6G instead of morphine itself, irrespective of the route of administration. Therefore, the patient's kidney function plays a key role in determining the optimal daily dose of morphine.

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

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

Non-linear blood-brain barrier transport and dosing strategies influence receptor occupancy ratios of morphine and its metabolites in pain matrix.

BACKGROUND AND PURPOSE: Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose-effect relationships of morphine, we investigated the effects of its non-linear blood-brain barrier (BBB) transport on µ-receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. EXPERIMENTAL APPROACH: CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate- and extended-release formulations were generated using a physiology-based pharmacokinetic model of the CNS, with non-linear BBB transport of morphine. The simulated CNS exposure profiles were then used to derive corresponding µ-receptor occupancies at multiple CNS pain matrix locations. KEY RESULTS: Simulated CNS exposure profiles for morphine, M3G and M6G, associated with non-linear BBB transport of morphine resulted in varying µ-receptor occupancies between different dose regimens, formulations and CNS locations. At lower doses, the µ-receptor occupancy of morphine was relatively higher than at higher doses of morphine, due to the relative contribution of M3G and M6G. At such higher doses, M6G showed higher occupancy than morphine, whereas M3G occupancy was low throughout the dose ranges. CONCLUSION AND IMPLICATIONS: Non-linear BBB transport of morphine affects the µ-receptor occupancy ratios of morphine with its metabolites, depending on dose and route of administration, and CNS location. These predictions need validation in animal or clinical experiments, to understand the clinical implications.

Morphine induces hyperalgesia without involvement of µ-opioid receptor or morphine-3-glucuronide.

Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia. In the first study, CD-1 mice injected with morphine (15 mg/kg subcutaneously) after pretreatment with the opioid receptor antagonist naltrexone (NTX) (15 mg/kg) showed tail withdrawal latency reductions indicative of hyperalgesia (2.5 ± 0.1 s at t = 30 min, P < 0.001 versus baseline). In these mice, the morphine/M3G concentration ratios versus effect showed a negative correlation (r(p) = -0.65, P < 0.001), indicating that higher morphine relative to M3G concentrations are associated with increased OIH. In the second study, similar hyperalgesic responses were observed in mice lacking the multidrug resistance protein 3 (MRP3) transporter protein (Mrp3(-/-) mice) in the liver and their wild-type controls (FVB mice; latency reductions: 3.1 ± 0.2 s at t = 30 min, P < 0.001 versus within-strain baseline). In the final study, the pharmacokinetics of morphine and M3G were measured in Mrp3(-/-) and FVB mice. Mrp3(-/-) mice displayed a significantly reduced capacity to export M3G into the systemic circulation, with plasma M3G concentrations just 7% of those observed in FVB controls. The data confirm previous literature that morphine causes hyperalgesia in the absence of opioid receptor activation but also indicate that this hyperalgesia may occur without a significant contribution of hepatic M3G. The relevance of these data to humans has yet to be demonstrated.

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain.

PURPOSE: Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days. METHODS: Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C(SS) on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3. RESULTS: Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350-2000) mg/day in the SAG group and 800 (range 90-3600) mg/day in the 3DS group (p = 0.43);42% reached C(SS) for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p = 0.032). One SAG patient suffered from respiratory depression on day 5. CONCLUSION: The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.

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

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

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

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

[Treatment of epidural morphine induced pruritus with butorphanol].

BACKGROUND: Epidural morphine has been used to provide postoperative analgesia. However, one of the most common side effects of epidural morphine is pruritus. The incidence may or may not be related to the dose of morphine administered. First, we examined whether epidural morphine induced a dose-related increase in pruritus or not. Secondly, the purpose of this study was to evaluate the relief of pruritus when a combination of epidural morphine (a mu-receptor agonist) and butorphanol (a mu-receptor antagonist and kappa-receptor agonist) was administered. METHODS: The incidence of pruritus, in 100 patients after abdominal surgery receiving continuous epidural analgesia with 0.2% ropivacaine + morphine, was retrospectively evaluated. Secondly, 60 adult patients undergoing abdominal surgery were randomly assigned to receive one of three epidural regimens; (1) continuous infusion of 0.2% ropivacaine with morphine 3.3 mg x day(-1) + butorphanol 2 mg x day(-1) (group MB), (2) morphine 3.3 mg x day(-1) alone (group M), or (3) butorphanol 2 mg x day(-1) alone (group B) at a rate of 4 ml x hr(-1), for 75 hours. RESULTS: Continuous epidural morphine at more than 3 mg x day(-1) caused a dose-related increase in pruritus. Pruritus was 0% in group B and group MB, but 55% in group M. CONCLUSIONS: Butorphanol 2 mg x day(-1) was effective in preventing pruritus associated with continuous epidural infusion of morphine 3.3 mg x day(-1).