Pharmacokinetics Of Morphine Research Articles

Short Stay Pyeloplasty: Variables Affecting Pain and Length of Stay

Pyeloplasty is increasingly performed on a short stay basis. We sought to determine what patient and treatment variables affect postoperative pain and length of stay, and whether an open approach could be considered "minimally invasive." We performed a retrospective review of patients younger than 10 years who underwent open pyeloplasty between 2001 and 2007. All patients received ketorolac every 6 hours and acetaminophen with codeine as needed. Data extracted from the medical records included morphine and codeine usage, patient age and gender, incision type, operative time, stent usage and outcome data (pain scores and length of stay). Multiple regression analyses were used to determine the association between variables and outcomes. A total of 51 patients met the inclusion criteria. Patient age and gender, operative time and stent usage had no significant correlation with mean or median pain scores. Children who received morphine had significantly higher mean, median and maximum pain scores and length of stay (33 vs 23 hours) than those who did not receive morphine. Multiple regression analyses revealed that morphine usage and dorsal lumbotomy incision were independently associated with higher mean, median and maximum pain scores, and a nephroureteral catheter was correlated with a higher maximum pain score. The only variable associated with length of stay was morphine usage. Morphine usage was the most significant variable associated with increased pain scores and increased length of stay. Ketorolac and acetaminophen/codeine provide better pain control, and allow children to return home within 24 hours. With mean pain scores less than 1 this series demonstrates that open pyeloplasty can be "minimally invasive."

Pharmacokinetics of morphine and its metabolites in freshwater rainbow trout (Oncorhynchus mykiss)

In this study, we injected morphine sulfate IP into rainbow trout and measured the concentration of morphine and all potential metabolites in plasma using LC-MS/MS at a series of times after the injection. The pharmacokinetics of morphine were similar to those previously reported for seawater-acclimated rainbow trout, i.e. they were about one order of magnitude slower than in similarly sized mammals. The only metabolite of morphine present in the plasma was morphine-3-beta-D-glucuronide (M3G); morphine-6-beta-D-glucuronide (M6G) was not detected. M3G gradually increased after the morphine injection, peaked about 2 days later, then gradually decreased. In mammals, M3G plasma levels exceed morphine levels extremely rapidly, i.e. in less than an hour, regardless of dose, route of administration, or species. In trout, it took 2 days for M3G levels to exceed morphine levels. This is the first study of the metabolites of morphine in any ectotherm. We conclude that trout can metabolize morphine, but at a rate much slower than in mammals.

Effect of Concomitant Ingestion of Alcohol on the In Vivo Pharmacokinetics of KADIAN (Morphine Sulfate Extended-Release) Capsules

The recent withdrawal of hydromorphone hydrochloride extended-release capsules (Palladone; Purdue Pharma L.P., Stamford, CT) from the market after pharmacokinetic data revealed a risk of alcohol-induced dose-dumping prompted a re-examination of the risk-benefit profiles of extended-release drugs. Although warnings on concomitant alcohol use are included on opioid product labels, further investigations of extended-release formulations to determine the risk of dose-dumping were recommended by the US Food and Drug Administration. The present study was undertaken to assess the single-dose relative bioavailability of polymer-coated, extended-release morphine sulfate capsules (KADIAN, 100 mg; Alpharma Pharmaceuticals LLC, Piscataway, NJ). This open-label, randomized, 3-way crossover study with an additional index arm, conducted among 32 healthy male volunteers, found no significant evidence of a formulation interaction between KADIAN and alcohol, in vivo. The pharmacokinetics of serum morphine did not differ significantly among subjects taking KADIAN with water (fasted) or with 240 mL 40% alcohol under fasted or fed conditions. Analysis of variance ratios of least-squares means for ln-transformed AUC(infinity) and C(max) satisfied the criteria (90% confidence intervals within 80%-125%) to declare no drug formulation interaction among the KADIAN regimens dosed with alcohol compared with KADIAN taken with water. There were no serious adverse events or deaths reported during the study. Because of the high rate of alcohol use in the United States, the potential for drug-alcohol interactions is an important clinical concern. Although it is recommended that alcohol not be used while the patient is taking opioids, results of this in vivo study indicate that the risk of alcohol-induced dose-dumping in connection with the use of KADIAN is negligible.

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial

Enhancement by Grapefruit Juice of Morphine Antinociception

The aim of this study was to investigate the effect of grapefruit juice intake on the antinociception of morphine in rats. The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat). Further, the effect of grapefruit juice was examined in morphine-tolerant rats. The repeated administration of morphine (100 mg/kg p.o.) for 5 d caused a marked decrease in the antinociception, indicating the development of morphine-tolerance. In the morphine-tolerant rats, oral administration of grapefruit juice potentiated significantly the antinociceptive effect of morphine. To examine the pharmacokinetics of morphine after the repeated treatment with morphine for 5 d, microdialysis probes were implanted into the jugular vein and spinal intrathecal space in rats. The morphine concentrations in the blood and intrathecal cerebrospinal fluid (CSF) were gradually decreased by the repeated treatment with morphine. The grapefruit juice treatment significantly increased the blood concentration of morphine in morphine-tolerant rats. These results suggest that oral administration of grapefruit juice enhances the morphine antinociception by increasing the intestinal absorption of this agent.

Pain following surgery: management, outcome, and prediction

Despite advances in the treatment of postoperative pain, nearly 30% of patients experience moderate to severe pain following major surgery. The present thesis includes four studies intended to evaluate important aspects of postoperative pain. In studies I and II, patient-controlled epidural analgesia (PCEA, n = 1,670), using local anesthetics and morphine, was associated with significantly lower pain ratings than intravenous patient-controlled analgesia (PCA, n = 1,026) using morphine following major surgery. Respiratory depression, sedation, confusion, hallucinations, and nightmares were more frequently observed in the PCA group, while technical difficulties leading to insufficient analgesia were more frequent in the PCEA group. In study III, morphine pharmacokinetics were studied in patients undergoing major liver resection (n = 15) in comparison with a group undergoing colon surgery (n = 15). Liver resection was associated with higher plasma concentrations of morphine indicating a decrease in morphine clearance, compared to controls. Sedation scores were higher in patients undergoing liver resection than in controls. In study IV, the predictive potential of psychometric variables and preoperative responses to experimental heat stimuli were evaluated in patients scheduled for a laparoscopic sterilization procedure (n = 59). Pre-surgical pain and preoperative heat pain sensitivity were important predictors of postoperative pain, while psychometric estimates of vulnerability, anxiety, and depression only contributed to a lesser degree. The prediction model accounted for 29-43% of the total variance in postoperative movement-related pain. Optimum pain management requires careful consideration regarding surgical procedure, analgesic technique, pharmacokinetics, and risk factors in the development of postoperative pain. (Less)

Morphine reduces spinal c-fos expression dose-dependently during experimental laparotomy in pigs: A combined pharmacokinetic and surgical study

The pharmacokinetics of intravenous morphine 2.5 mg/kg ( n = 4) and 10 mg/kg ( n = 4) in plasma and cerebrospinal fluid (CSF) of pigs was studied. Plasma half-life was 1.0 ± 0.1 h and the main metabolite was morphine-3-glucuronide, whereas morphine-6-glucuronide was negligible. CSF morphine concentration peaked after 20–30 min (2.5 mg/kg) and 60–120 min (10 mg/kg), and elimination half-life was 3.5 ± 0.3 h. Subsequently, the effect of morphine on surgery-induced spinal nociception in pigs subjected to unilateral laparotomy was evaluated by stereological quantification of the total number of Fos-like-immunoreactive (Fos-LI) spinal neurons of the dorsal horn. Surgery ( n = 4) induced 91,680 ± 14,974 Fos-LI neurons ipsilaterally and morphine reduced this number to 45,771 ± 8755 following the 2.5 mg/kg dose ( p < 0.01; n = 6) and 14,981 ± 2327 following the 10 mg/kg dose ( p < 0.001; n = 6). These results indicate that morphine dose-dependently reduces the number of surgery-induced Fos-LI neurons in the spinal cord. As even a high dose of morphine does not reduce spinal c-fos expression to basal level, it may be appropriate to use other analgesics simultaneously with morphine during surgery.

Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery

To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery. This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramuscularly (IM). Arterial blood and CSF samples (from a spinal catheter) were drawn simultaneously at 10, 30, 60, and 120 min after administration. Morphine and metabolites [morphine-3-glucuronide (M-3-G), morphine-6-glucuronide (M-6-G), and normorphine (NM)] were determined by a validated liquid chromatography-tandem mass spectrometry method. Thirty-eight patients were included: 13 men and 25 women, 20 in the IV, 18 in the IM group. Serum concentrations of M after 10 min were consistently higher after IM than IV, concentrations of M-3-G and M-6-G after IM surpassed those of IV after 45 min. NM was not found. None of the metabolites was found in CSF. CSF morphine concentrations and CSF/serum concentration ratios were consistently higher after IV compared to IM. The mean AUC(CSF)/AUC(serum) (0-120 min) concentration ratios were 0.18 and 0.09 after IV and IM, respectively. The uptake of morphine to the CSF was consistently higher after IV administration than after IM already after 10 min. The higher CSF concentration may be caused by an initially higher morphine blood/CSF gradient following IV morphine injection. The pharmacokinetic findings are compatible with a more rapid and extensive initial effect of IV morphine compared with IM.

Population pharmacokinetic modelling of non‐linear brain distribution of morphine: influence of active saturable influx and P‐glycoprotein mediated efflux

Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. Male rats received a 10-min infusion of 4 mg kg(-1) of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg(-1) morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min(-1). The active efflux rate constant decreased from 0.0195 min(-1) to 0.0113 min(-1) in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (N(max)/V(ecf)) of 0.66 ng min(-1) ml(-1) and was saturated at low concentrations of morphine (C(50)=9.9 ng ml(-1)). Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine.

Morphine Metabolism After Major Liver Surgery

Impaired metabolism of morphine may lead to an increase in sedation and respiratory depression. In the present study we investigated morphine pharmacokinetics in patients who had undergone liver resection (n = 15) compared to a control group undergoing colon resection (n = 15). Morphine was administered IV by patient-controlled analgesia. Plasma concentrations of morphine, morphine-6-glucuronide, and morphine-3-glucuronide were measured 2-3 times daily for the first two postoperative days. Pain intensity scores were assessed three times daily and respiratory rate and sedation scores every third hour. There were no differences in morphine requirements 1.1 (0.8-2.5 [median, interquartile range]) mg/h (liver resection) and 1.5 (1.1-1.7) mg/h (colon resection) [P = 0.84]) or in pain intensity scores (P > 0.3) between the groups. Plasma morphine concentrations were higher in patients undergoing liver resection than in the control group (P < 0.01) reflecting a lower rate of morphine metabolism. Plasma morphine concentrations were correlated with the volume of liver resection (P < 0.02). However, plasma concentrations of morphine-6-glucuronide and morphine-3-glucuronide did not differ between the groups (P = 0.62 and P = 0.48, respectively). There was a higher incidence of sedation (P = 0.02), but not respiratory depression (P = 0.48), after liver resection. The study demonstrates that plasma concentrations of morphine are higher in patients undergoing liver resection compared with patients undergoing colon resection. Sedation scores were higher in patients undergoing liver resection. Caution is therefore recommended when administering morphine to this patient group.

Pharmacokinetics and physiological effects of two intravenous infusion rates of morphine in conscious dogs

This study examined the pharmacokinetics and physiologic effects of two infusions rates of morphine in conscious dogs. Five adult dogs were randomly studied at weekly intervals. An initial dose of either 0.3 or 0.6 mg/kg were each followed by infusions of 0.17 and 0.34 mg/kg/h. Plasma morphine concentrations, physiological parameters, sedation and mechanical antinociception were evaluated during each infusion. Morphine was assayed by high pressure liquid chromatography (HPLC) with electrochemical coulometric detection and pharmacokinetic parameters were calculated. Data were fitted to a bi-compartment model with a rapid distribution (<1 min for both doses) and slower termination rate. For the high and low doses, respectively, mean+/-SD terminal half-life was 38+/-5 and 27+/-14 min, apparent volumes of distribution at steady-state were 1.9+/-0.5 and 1.3+/-0.8 L/kg, with clearances of 50+/-15 and 67+/-20 mL/kg/min. Steady-state plasma concentrations ranged from 93 to 180 ng/mL and 45 to 80 ng/mL in the high and low doses, respectively. Respiratory rate increased significantly, pulse oximetry remained>95% and body temperature decreased significantly during both infusions. No vomition or neuroexcitation occurred. Sedation and mechanical antinociception were both mild during the lower infusion rate, and mild to moderate during the higher infusion rate. In conclusion, morphine pharmacokinetics was not altered by increasing infusion rates, producing stable, long-lasting plasma concentrations.

(757): Morphine release profile in a formulation containing polymer-coated extended-release morphine sulfate plus sequestered naltrexone

Fear of government action against healthcare providers who prescribe opioids is a contributing factor to the under-treatment of chronic pain.1Jung Pain Med. 2006Google Scholar There is a demand for products with reduced abuse liability.2Wright Drug Alcohol Depend. 2006Google Scholar One such formulation under development includes polymer-coated extended-release morphine sulfate (P-ERMS) surrounding a sequestered core of naltrexone, an opioid antagonist that competes at the opioid receptor sites. The product is designed to release naltrexone if product tampering occurs by crushing, chewing, or dissolving. Morphine pharmacokinetics of this formulation were assessed in this single-dose, open-label, two-period crossover study (fasted and fed) in eight healthy subjects aged 21 to 45 years. After an overnight fast, subjects either received study drug (containing 60-mg morphine sulfate) or consumed a standard high-calorie, high-fat breakfast and took the dose 30 minutes later. Blood samples for morphine pharmacokinetic analysis were drawn prior to dosing and at intervals from 0.5 to 168.0 hours postdose. For the 60-mg morphine dose, Cmax was 10.70 ng/mL fasted and 9.18 ng/mL fed. AUCinf was 260.6 hr*ng/mL fasted and 246.0 hr*ng/mL fed. The Tmax for morphine was 7.50 hours fasted and 8.75 hours fed, consistent with a sustained-release profile and with current prescribing information for P-ERMS.3KADIAN® package insert, Alpharma Branded ProductsGoogle Scholar Adverse events, reported in five subjects, were either mild or moderate in intensity, and resolved. Study results demonstrated that the release characteristics of morphine in this formulation containing a sequestered naltrexone core were similar to characteristics demonstrated in previous studies of P-ERMS. The study formulation was well tolerated.

Recent developments in the pharmacological management of pain in children

This review explores progress in developmental pharmacokinetics, pharmacogenomics and formulations of analgesic agents, and discusses potential implications for pain therapy. Characterization of the developmental pharmacokinetics of morphine, tramadol, paracetamol and nonsteroidal anti-inflammatory drugs has improved dosing in children. Oral sugar solutions have replaced the brandy/sugar pacifier and are effective for single painful events in neonates. Intravenous paracetamol offers increased dosing accuracy, and avoids absorption and bioavailability variability. New nitric-oxide-releasing versions of paracetamol and nonsteroidal anti-inflammatory drugs offer safer alternatives to their parent drugs with enhanced potency. Ketamine has come under a cloud for its possible effects on the neonatal developing brain, but it is being used increasingly in children to supplement opioids for pain after major surgery. Hopes that morphine analgesia may improve neurological outcome in premature babies have not materialized. Reports concerning chronic pain are generally case series and controlled trials are rare and nearly nonexistent in children. Unlicensed drug use in the very young will increase as familiarity increases. Pharmacogenomic studies have the potential to tailor drug therapy to the individual and decrease between-patient variability. Unfortunately, the pharmacodynamic knowledge in children of analgesic agents remains neglected and is usually extrapolated from adult data.

Evaluation of the pharmacokinetic profile and analgesic efficacy of oral morphine after total hip arthroplasty

Oral morphine may be useful for postoperative pain relief, but few studies have tested its use after in-hospital surgery. We evaluated clinical efficacy and the pharmacokinetic parameters of oral morphine after total hip arthroplasty. We recruited 60 patients who had total hip arthroplasty under general anaesthesia. The patients were randomized to receive placebo, 10 mg morphine sulphate or 20 mg morphine sulphate orally every 4 h for 24 h. The oral administration was started 3 h after the morphine-loading dose in the Post Anaesthesia Care Unit and then patients used intravenous morphine patient-controlled analgesia for 24 h. Pain score at rest (scored by patients on a visual analogue scale), sedation, nausea, vomiting and urinary retention were monitored. In 11 additional total hip arthroplasty patients, we determined the pharmacokinetics of morphine and its metabolites after oral administration of 20 mg morphine sulphate every 4 h for 16 h. The amount of morphine administered via patient-controlled analgesia over 24 h was reduced in the 20-mg group compared with that in the placebo group (19.0 +/- 2.7 mg vs. 33.0 +/- 5.5 mg; P = 0.03). No significant morphine-sparing effect was observed in the 10-mg group. Pain scores and side-effects were similar in all groups. The pharmacokinetic study revealed a limited and slow absorption of morphine. Despite a limited absorption of oral morphine postoperatively, high doses of oral morphine have a significant analgesic effect after total hip arthroplasty.

SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES

Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20-0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 microM) and human liver microsomes (6.1+/-1.2 microM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335+/-128 microM and 186 microM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.

Pharmacokinetics of morphine and plasma concentrations of morphine‐6‐glucuronide following morphine administration to dogs

The purpose of this study was to evaluate the pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) following morphine administered intravenously and orally to dogs in a randomized crossover design. Six healthy 3-4-year-old Beagle dogs were administered morphine sulfate (0.5 mg/kg) as an i.v. bolus and extended release tablets were administered orally as whole tablets (1.6 +/- 0.1 mg/kg) in a randomized crossover design. Plasma concentrations of morphine and M-6-G were determined using high-pressure liquid chromatography and electrochemical coulometric detection. Following i.v. administration all dogs exhibited dysphoria and sedation, and four or six dogs vomited. Mean +/- SE values for half-life, apparent volume of distribution, and clearance after i.v. administration were 1.16 +/- 0.15 h, 4.55 +/- 0.17 L/kg, and 62.46 +/- 10.44 mL/min/kg, respectively. One dog vomited following oral administration and was excluded from the oral analysis. Oral bioavailability was 5% as determined from naïve-averaged analysis. The M-6-G was not detected in any plasma samples following oral or i.v. administration of morphine at a 25 ng/mL the limit of quantification. Computer simulations concluded morphine sulfate administered 0.5 mg/kg intravenously every 2 h would maintain morphine plasma concentrations consistent with analgesic plasma concentrations in humans. Oral morphine is poorly and erratically absorbed in dogs.

Pharmocokinetic and pharmacodynamic evaluation of intravenous morphine in dogs

Morphine is considered the prototypical opiate analgesic. Despite the common use of morphine in dogs, ideal dosing strategies have not been formulated due to the difficulty in assessing its analgesic effects. The purpose of this study was to: 1) evaluate a noninvasive mechanical threshold device (von Frey device) to measure antinociceptive responses (pharmacodynamics) of opiates in dogs and 2) evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous (IV) morphine in dogs. Six healthy Beagle dogs were used. The von Frey threshold (vFT) response was evaluated hourly for 8 hours in each dog to examine the effect of repeated testing (controls). PK and PD (vFT) measurements were then made following a 1 mg kg–1 IV bolus of morphine sulfate. A two way blinded crossover consisted of an 8 hour IV constant rate infusion of saline or morphine with hourly PD measurements. The individual CRI was based on individual PK data and adjusted every 2 hours to attain targeted plasma concentrations of morphine of 10, 20, 30, and 40 ng mL–1. Blood samples were taken hourly in all phases, except the controls. No significant (p > 0.05) intraindividual changes in vFT occurred in the controls over 8 hours. The morphine bolus produced increased vFT at 1, 2, 3, and 4 hours post injection (p 30 ng mL–1, when compared to saline controls (p < 0.05). Targeted plasma concentrations were inconsistent at higher infusion rates, suggesting the PK of morphine may change during CRI. The actual mean ± SD CRI plasma concentrations (ng ml–1) were 10.8 ± 3.0, 22.7 ± 7.4, 32.4 ± 13.9, 35.7 ± 16.9. Morphine dosing protocols should be re-evaluated, as sufficient analgesia may not be obtained from published dosages. Intravenous boluses may be more predictable than CRI.

A head-to-head, single-dose trial of KADIAN® vs AVINZA® 30mg in healthy, opioid-naïve subjects in the fed state: Comparison of pharmacokinetics

KADIAN® and AVINZA®, both indicated for treatment of moderate-to-severe chronic pain, are two different encapsulated pellet formulations of sustained-release morphine sulfate. Each is designed to deliver effective morphine plasma concentrations for up to 24 hours. KADIAN, indicated for either once-daily or q12h dosing, has 100% of its pellets in a sustained-release formulation, while AVINZA, indicated for once-daily dosing, has 10% of its pellets in an immediate-release (IR) formulation. This randomized, double-blind, crossover study compared the pharmacokinetics of morphine and its main metabolites in healthy, opioid-naïve subjects (n=36) and alternates (n=4) who were randomized to receive either KADIAN or AVINZA 30mg after a standard meal. Plasma samples were obtained hourly for the first 12 hours and at 14, 16, 20, 24, 30, 36, 48, and 60 hours. Adverse events were documented. After a single dose, KADIAN provided slightly higher mean plasma morphine levels than AVINZA at each time point from 8–60 hours, though differences were not statistically significant. As expected, AVINZA had an earlier Tmax than KADIAN (6.7h vs 12.9h); however, the two medications were bioequivalent based on Cmax and AUC per FDA guidelines. 1Available at: http://www.fda.gov/cder/guidance/3616fnl.htm The t1/2 data (14.5h for KADIAN, 15.6h for AVINZA) demonstrated that both products support once-daily dosing. Data on four patients who took AVINZA were replaced with data from the alternates because they had vomiting episodes 10–13 hours post-dose. The adverse event profile in this sample of subjects was similar between the two treatments. Although there are formulation differences between KADIAN and AVINZA, there appear to be few pharmacokinetic differences between the products, except for the earlier Tmaxseen with AVINZA, presumably due to its IR component. Additional trials are needed to assess whether the formulation differences produce clinically relevant differences, when used as indicated for long-term treatment of chronic pain. 1Available at: http://www.fda.gov/cder/guidance/3616fnl.htm

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. Observational study in a level III referral center. Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data. Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability. Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.

Blood free morphine levels vary with concomitant alcohol and benzodiazepine use

Aims: To record the concentration of morphine in post-mortem blood samples from fatalities arising directly from illicit drug abuse in Grampian, Scotland and to explore whether there is any difference in the morphine levels with co-existent drugs especially alcohol and benzodiazepines. Methods: Drug-related deaths that had positive blood toxicology for morphine from the beginning of January 1995 until the end of December 2001 were identified from the database of toxicological data held in the Department of Clinical Biochemistry, Aberdeen Royal Infirmary, and the data analysed in conjunction with the information in the files of the Forensic Medicine Unit, University of Aberdeen. Results: One hundred and twenty-six cases were identified and consisted of 106 males and 20 females with an age range 17–51 (Median 26 years). Morphine was the single isolate in only 21 cases giving a median blood free morphine (BFM) of 0.19 mg/L. When morphine and benzodiazepines were the primary isolates ( n=25) the median BFM was 0.37 mg/L, and when morphine was in combination with alcohol ( n=21) the median BFM was 0.18 mg/L. Statistical significance was noted between these groups ( p<0.05). The remaining 59 cases had morphine combined with other drugs. Conclusions: In the studied cases, the concentrations of BFM were statistically higher when morphine was only isolated in conjunction with benzodiazepines than when combined only with alcohol. These results may be multi-factorial; user error while under drug influence, the individuals drug tolerance, or related to the pharmacokinetics of morphine and its interactions with alcohol and benzodiazepines. Our understanding of the interactions of these substances appears to be far from clear.