Morphine Metabolites Research Articles

Co-Administration of Dextromethorphan and Morphine: Reduction of Post-Operative Pain and Lack of Influence on Morphine Metabolism

We investigated co-analgesic effect of dextromethorphan in adolescent post-operative patients with idiopathic scoliosis. In a double-blind study, 60 patients with ASA physical status I-II were randomised into two groups. Group dextromethorphan (n = 30; age: 15.9 +/- 2.4 years) was given oral dextromethorphan 30 or 45 mg 1 hr before surgery and 8, 20 and 32 hr after operation. Group placebo (n = 30; age: 16.5 +/- 2.7 years) received placebo at identical times. Post-operative analgesic requirements were assessed using nurse-controlled analgesia system. Pain was assessed using numeric rating scale before first administration of morphine and at 2, 3, 4, 6, 24 and 48 hr after operation. Blood samples were taken 20 min. after the first use of morphine (within 1 hr after operation). The total use of analgesics during surgery was lower in the dextromethorphan group. The dose of morphine providing relief immediately after surgery, as well as total analgesic requirements in the first and second day after surgery did not differ between groups. Subjectively evaluated pain intensity score (numeric rating scale) was lower for the dextromethorphan patients in the first 4 hr, but not later after surgery. Plasma levels of morphine, morphine-6-glucuronide and morphine-3-glucuronide did not differ between groups. Dextromethorphan did not influence morphine glucuronidation, in terms of promotion of formation of any morphine glucuronides. In conclusion, in young patients subjected to spine surgery, addition of dextromethorphan to morphine reduced pain only in early post-operative period. In such patients, co-analgesic action of dextromethorphan was not associated with significant changes in plasma levels of morphine metabolites.

Emphysematous pyelitis

CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacodynamic effects were determined over 6 h. Codeine-apparent clearance and partial metabolic clearance by O-demethylation were significantly greater in the Caucasian than in the Chinese subjects (1939 ± 175 ml/min versus 1301 ± 193 ml/min, <i>p</i> &lt; .03 and 162.7 ± 36.6 ml/min versus 52.7 ± 12.7 ml/min,<i>p</i> &lt; .02, respectively). Codeine’s respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chinese subjects (<i>p</i> &lt; .05), but no interethnic differences were noted in codeine’s effect on the digit symbol substitution test and pupillary ratio. No morphine or morphine metabolites were detected in plasma when codeine was coadministered with quinidine. Codeine O-demethylation was significantly reduced after quinidine in both ethnic groups; however, the absolute decrease was greater in Caucasians (115.8 ± 25.9 ml/min versus 46.8 ± 10.6 ml/min, respectively,<i>p</i> &lt; .03). The diminished production of morphine after quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine’s effects (<i>p</i> &lt; .01). In conclusion, Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine. In addition, quinidine induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in Caucasians.

Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: A pilot study

The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus. The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two. Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine's inpatient unit. A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without myoclonus. Analysis included demographic, metabolic and clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide. No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated. In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.

A Change in the Plasma Concentration of Morphine and Morphine Metabolites During Morphine Administration in Terminal Canser Patients with Renal Dysfunction

A Change in the Plasma Concentration of Morphine and Morphine Metabolites During Morphine Administration in Terminal Canser Patients with Renal Dysfunction

A Change of Plasma Concentration of Morphine and Morphine Metabolites During Long-term Administration of Slow-release Oral Morphine

A Change of Plasma Concentration of Morphine and Morphine Metabolites During Long-term Administration of Slow-release Oral Morphine

2009 in Review

2009 in Review

A randomized study of the serum pharmacokinetics of lower thoracic extended-release epidural morphine (DepoDur®) after lidocaine-epinephrine test dose administration in patients undergoing upper abdominal surgery

The primary objective was to evaluate the serum pharmacokinetic profile of a single 15-mg dose of extended-release epidural morphine (EREM) administered at the lower thoracic epidural space alone or following a lidocaine-epinephrine test dose in patients undergoing major upper abdominal surgery. This randomized, open-label study recruited men and women > or = 18 years of age scheduled for major upper abdominal surgery. Patients were randomly assigned to 1 of 5 treatment groups and were administered a single 15-mg dose of EREM or EREM preceded by a 3 ml lidocaine (1.5%)/epinephrine (1 : 200,000) test dose with or without a saline flush: EREM alone; test dose + flush + 3-minute wait + EREM; test dose + flush + 10-minute wait + EREM; test dose + flush + 15-minute wait + EREM; or test dose + 3-minute wait + EREM. EREM was administered at the lower thoracic epidural intervertebral space (T8 - T12) approximately 30 minutes before the surgical incision. Noncompartmental pharmacokinetic parameters were determined based on the serum concentration-time profiles of morphine and morphine metabolites. Effectiveness and safety were also assessed. The intent-to-treat and safety populations included 39 patients; the pharmacokinetic population included 37 patients. Administration of EREM 3 minutes after a lidocaine-epinephrine test dose, with or without a flush, resulted in an increased mean maximum serum concentration of morphine (Cmax; flush, 30.2 +/- 8.5 ng/ml; no flush, 25.6 +/- 10.1 ng/ml; EREM alone, 11.5 +/- 7.3 ng/ml) and a decreased median time to Cmax (tmax; flush, 0.2 h; no flush, 0.2 h; EREM alone, 2.0 h) compared with administration of EREM alone, without affecting relative morphine bioavailability. Flushing the catheter and waiting 15 minutes normalized the Cmax (11.4 +/- 6.4 ng/ml) but not the median tmax (0.5 h). There were no significant group differences in safety, tolerability, or analgesic effectiveness. The interaction between EREM and a lidocaine-epinephrine test dose administered at T8 - T12 can be minimized by waiting 15 minutes after test dose administration. The overall safety and effectiveness of 15 mg EREM administered at the lower thoracic epidural intervertebral space in patients undergoing major upper abdominal surgery appears similar to that observed in previous studies assessing lumbar administration. ClinicalTrials.gov Identifier: NCT00728832.

Different Effects on Dopamine Release in Nucleus Accumbens in Mice by the Morphine Metabolites Morphine‐6‐Glucuronide and Morphine‐3‐Glucuronide

Different Effects on Dopamine Release in Nucleus Accumbens in Mice by the Morphine Metabolites Morphine‐6‐Glucuronide and Morphine‐3‐Glucuronide

Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β

Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine. M3G has little-to-no affinity for opioid receptors and induces pain by unknown mechanisms. The pain-enhancing effects of M3G have been proposed to significantly and progressively oppose morphine analgesia as metabolism ensues. We have recently documented that morphine activates toll-like receptor 4 (TLR4), beyond its classical actions on μ-opioid receptors. This suggests that M3G may similarly activate TLR4. This activation could provide a novel mechanism for M3G-mediated pain enhancement, as (a) TLR4 is predominantly expressed by microglia in spinal cord and (b) TLR4 activation releases pain-enhancing substances, including interleukin-1 (IL-1). We present in vitro evidence that M3G activates TLR4, an effect blocked by TLR4 inhibitors, and that M3G activates microglia to produce IL-1. In vivo, intrathecal M3G (0.75 μg) induced potent allodynia and hyperalgesia, blocked or reversed by interleukin-1 receptor antagonist, minocycline (microglial inhibitor), and (+)-and (−)-naloxone. This latter study extends our prior demonstrations that TLR4 signaling is inhibited by naloxone nonstereoselectively. These results with (+)-and (−)-naloxone also demonstrate that the effects cannot be accounted for by actions at classical, stereoselective opioid receptors. Hyperalgesia (allodynia was not tested) and in vitro M3G-induced TLR4 signaling were both blocked by 17-DMAG, an inhibitor of heat shock protein 90 (HSP90) that can contribute to TLR4 signaling. Providing further evidence of proinflammatory activation, M3G upregulated TLR4 and CD11b (microglial/macrophage activation marker) mRNAs in dorsal spinal cord as well as IL-1 protein in the lumbosacral cerebrospinal fluid. Finally, in silico and in vivo data support that the glucuronic acid moiety is capable of inducing TLR4/MD-2 activation and enhanced pain. These data provide the first evidence for a TLR4 and IL-1 mediated component to M3G-induced effects, likely of at least microglial origin.

The INFUSE-Morphine IIB Study: Use of Recombinant Human Hyaluronidase (rHuPH20) to Enhance the Absorption of Subcutaneous Morphine in Healthy Volunteers

Morphine is usually given intravenously (IV) for the treatment of moderate-to-severe pain, but subcutaneous (SC) administration is a viable alternative for parenteral delivery. The pharmacokinetics of SC morphine may be enhanced by coadministration with a hyaluronidase product. In this Phase IV, double-blind, randomized, crossover study, 18 healthy adults received a single dose of 2 mg morphine SC with 150 U of recombinant human hyaluronidase (rHuPH20), SC with 0.9% normal saline, or IV on three consecutive days. The primary endpoint was time to maximum plasma morphine concentration ( T max) for SC injection with rHuPH20 vs. SC injection without rHuPH20. Safety and tolerability were assessed each study day, the day after the last injection, and 28 days after the last injection. After SC dosing, morphine mean T max was significantly shorter with rHuPH20 than without it. Mean maximum plasma morphine concentration ( C max) after SC dosing was 29% greater with rHuPH20 than without rHuPH20 ( P = 0.023), although the extent of exposure of morphine was similar. T max was shortest and C max was highest with IV administration. For the major active metabolite of morphine, morphine-6-glucuronide, mean T max after SC morphine was significantly shorter with rHuPH20 than without rHuPH20 (a difference of approximately 17.5 minutes; P = 0.0169). Coadministration of morphine with rHuPH20 appeared safe and well tolerated. Compared with SC morphine alone, rHuPH20 shortens morphine T max and raises C max in healthy adults, without changing the extent of exposure.

Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain*

In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury. Observational human pharmacokinetic study. Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center. Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters. We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin. Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed. Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.

Morphine Inhalation by Cancer Patients: A Comparison of Different Nebulization Techniques Using Pharmacokinetic, Spirometric, and Gasometric Parameters

Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System-Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2–5 μm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5–2 μm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6 ± 2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8 ± 8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20–40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs.

Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.

Spinal ERK activation via NO–cGMP pathway contributes to nociceptive behavior induced by morphine-3-glucuronide

Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces a severe hindlimb scratching followed by biting and licking in mice. The pain-related behavior evoked by M3G was inhibited dose-dependently by i.t. co-administration of tachykinin NK 1 receptor antagonists, sendide, [D-Phe 7, D-His 9] substance P(6-11), CP-99994 or RP-67580 and i.t. pretreatment with antiserum against substance P. The competitive NMDA receptor antagonists, D-APV and CPP, the NMDA ion-channel blocker, MK-801 or the competitive antagonist of the polyamine recognition site of NMDA receptor ion-channel complex, ifenprodil, produced inhibitory effects on i.t. M3G-evoked nociceptive response. The NO–cGMP–PKG pathway, which involves the extracellular signal-regulated kinase (ERK), has been implicated as mediators of plasticity in several pain models. Here, we investigated whether M3G could influence the ERK activation in the NO–cGMP–PKG pathway. The i.t. injection of M3G evoked a definite activation of ERK in the lumbar dorsal spinal cord, which was prevented dose-dependently by U0126, a MAP kinase-ERK inhibitor. The selective nNOS inhibitor N ω-propyl- l-arginine, the selective iNOS inhibitor W1400, the soluble guanylate cyclase inhibitor ODQ and the PKG inhibitor KT-5823 inhibited dose-dependently the nociceptive response to i.t. M3G. In western blotting analysis, inhibiting M3G-induced nociceptive response using these inhibitors resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that activation of the spinal ERK signaling in the NO–cGMP–PKG pathway contributes to i.t. M3G-evoked nociceptive response.

Extended-Release Epidural Morphine (DepoDur) Following Epidural Bupivacaine in Patients Undergoing Lower Abdominal Surgery

The primary objective was to compare the serum pharmacokinetic profile of a single dose of extended-release epidural morphine (EREM) administered alone versus 15 to 60 mins after an analgesic epidural dose of bupivacaine. This multicenter study enrolled 144 patients, 18 years or older, with scheduled lower abdominal surgery under general anesthesia. Patients were randomly assigned to a single 15-mg dose of EREM; the same dose administered 15, 30, or 60 mins after epidural bupivacaine (20 mL 0.25%); or epidural placebo (normal saline) administered 15, 30, or 60 mins after bupivacaine. Postoperatively, fentanyl patient-controlled analgesia was offered for breakthrough pain. Multiple serum samples were analyzed for morphine and morphine metabolites. Safety and efficacy were assessed. The mean maximum serum concentration and area under the concentration-time curve for morphine and metabolites were not significantly different when EREM was administered alone versus 15, 30, or 60 mins after bupivacaine. Median time to maximum serum concentration and median apparent terminal elimination half-life were also comparable. Total fentanyl patient-controlled analgesia consumption was comparable among all EREM groups (with/without prior bupivacaine) but significantly (P < 0.05) lower compared with the bupivacaine + placebo group. Nausea, vomiting, and dizziness were consistently more frequent in groups receiving EREM after bupivacaine versus EREM alone. The pharmacokinetic and efficacy profiles of a single 15-mg dose of EREM were not significantly altered when administered 15, 30, or 60 mins after an analgesic epidural dose of bupivacaine.

Morphine-6β-glucuronide Rapidly Increases Pain Sensitivity Independently of Opioid Receptor Activity in Mice and Humans

Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice. Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking mu-, kappa-, and delta-opioid receptors and their B6129F(1) controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion. Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F(1) control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-D-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion. These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T(1/2) = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C(max) = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C(max) = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C(max) = 6.74 microg/mL; T(max) = 0.85 h) and eliminated (T(1/2) = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after i.v. and oral administration.

Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity

After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 µmol/kg), administered together, and also in combination with with 200 µml/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 µmol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

OPIOID‐INDUCED HYPERALGESIA IN A PATIENT WITH DEMENTIA

OPIOID‐INDUCED HYPERALGESIA IN A PATIENT WITH DEMENTIA

Rapid simultaneous determination of codeine and morphine in plasma using LC‐ESI‐MS/MS: Application to a clinical pharmacokinetic study

A rapid and sensitive high-performance LC-MS/MS method was developed and validated for the simultaneous quantification of codeine and its metabolite morphine in human plasma using donepezil as an internal standard (IS). Following a single liquid-liquid extraction with ethyl acetate, the analytes were separated using an isocratic mobile phase on a C(18 )column and analyzed by MS/MS in the selected reaction monitoring mode using the respective [M+H](+ )ions, mass-to-charge ratio (m/z) 300/165 for codeine, m/z 286/165 for morphine and m/z 380/91 for IS. The method exhibited a linear dynamic range of 0.2-100/0.5-250 ng/mL for codeine/morphine in human plasma, respectively. The lower LOQs were 0.2 and 0.5 ng/mL for codeine and its metabolite morphine using 0.5 mL of human plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.0 min for each sample made it possible to analyze more than 300 human plasma samples per day. The validated LC-MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 30 mg codeine phosphate.