Metabolism and pharmacokinetics of morphine in neonates: A review

Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

Simultaneous determination of 11 opiates in hair by liquid chromatography-tandem mass spectrometry / 药学学报

The paper reports the establishment of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneous analysis of 11 opiates in hair samples, and the study of presence of opiates in the hair of active heroin addicts. About 20 mg of decontaminated and pulverized hair sample was hydrolyzed with buffer solution for 30 min, in the presence of morphine-d3 and acetylmorphine-d6 used as internal standards, and then extracted with the mixture of dichlormethane and isopropanol, separated by the Allure PFP propyl column with a mobile phase consisting of acetonitrile and 20 mmol L(-1) ammonium acetate buffer, and then analyzed by LC-MS/MS. Multiple reaction monitoring (MRM) mode was used to analyze 11 opiates. Eleven opiates showed a fairly good linearity over the corresponding range (r > 0.996 0). The detection limits were less than 0.05 ng mg(-1). The recoveries were between 47.2% and 110%, and the deviations of intra- and inter-day precision were less than 14%. Heroin, acetylmorphine, morphine, codeine, acetylcodeine and hydrocodone were detected in hair samples of 21 herion addicts. The developed method shows high sensitivity and selectivity, and is suitable for the simultaneous analysis of 11 opiates in hair samples and identify legal and illegal use of opiates.

[Effectiveness of grouped spiritual psychotherapy on patients with opium using disorder]

Introduction: Some scientists believe that the definition of Bio-psychosocial is not a comprehensive definition for humankind. They are willing to add the spirituality as a part of human being

Methods: This study aimed to assess the effectiveness of a spiritual group therapy among patients with opium using disorders in Tehran. This study was a clinical trial in which 61 opium users were selected using simple sampling from patient referred to the Iranian national center for addiction studies and two other private centers. Patients were divided into two equal intervention and control groups. The intervention group was treated by spiritual group therapy presented at Yale University, modified according to the Iranian/Islamic culture of the participants within eight sessions in eight weeks. Urine morphine test was done for each participant every week. The Beck depression test, Beck anxiety test and quality of life test [the short form Health survey SF36] were completed before, during and after the intervention

Results: The mean scores of the depression test [p>0.002], anxiety test [p>0.001], and the short form health survey SF 36 test [p>0.001] were improved in the intervention group after the intervention. Although urine morphine test showed a negative trend, the decline was not statistically significant [p<0.75]

Conclusion: This package showed to be effective in many dimensions of psycho-somatic, social and spiritual health of opium users. Subsequent interventions with more modified packages may be more influential

Simultaneous determination of opioid compounds in human urine by UPLC-MS/MS / 法医学杂志

OBJECTIVE@#To propose a method for simultaneous determination of codeine(COD), 6-monoacetyl-morphine (6-MAM), morphine (MOR), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in human urine by ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS).@*METHODS@#After precipitation of protein by acetonitrile, the urine samples, with added the morphine-d3 (MOR-d3) and morphine-3-Glucuronide-d3 (M3G-d3) as internal standards, were pre-treated by Sirocco protein precipitation plate, and then analyzed by UPLC-MS/MS.@*RESULTS@#The limit of detection was 0.2 ng/mL for both COD and MAM, the limit of quantitation was 0.5 ng/mL for both COD and MAM. The limit of detection was 0.5 ng/mL for MOR, M3G and M6G, the limit of quantitation was 1 ng/mL for them. The linear correlation coefficients were not less than 0.9997, both the inter-day and intra-day precisions were less than 10%, the recoveries were in the range of 70.0% to 98.3%, the matrix effects were about 50.5% to 99.0%.@*CONCLUSION@#This proposed method is simple, rapid and accurate, it could be applied in forensic toxicological analysis.

Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period

OBJECTIVE: To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug. METHOD: A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify®, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-After the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. RESULTS: The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r²=0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9 percent and 6.8 percent, and 0.1 percent and 0.8 percent systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98 percent) and relative (100.7 percent) recoveries. Morphine dose requirements and plasma levels are discussed. CONCLUSION: The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

Ensayo Clínico Boble Ciego, Controlado para Evaluar la Efectividad Analgésica de 100 Microgramos de Morfina Intratecal en el Control del Dolor Postoperatorio / Clinical trial Boble Blind, Controlled to Evaluate the Analgesic Effectiveness of 100 Microgramos of Morphine Intratecal in the Control of the Postoperative Pain

Antecedentes:La morfina intratecal constituye una excelente alternativa para el manejo del dolor post-operatorio, en cirugías con anestesia espinal. La efectividad analgésica post operatoria de 100 µg de morfina, adicionados al anestésico local en anestesia espinal, ha sido estudiada en cirugías de cesárea, resección transuretral de próstata y reemplazos articulares. El propósito de este estudio es valorar la efectividad analgésica de 100 µg de morfina intratecal en adultos jóvenes, sometidos a cirugía abdominal baja o de miembros inferiores.Métodos: Se realizó un ensayo clínico, multicéntrico, doble ciego, aleatorizado con 140 pacientes. Setenta pacientes recibieron 100 microgramos de clorhidrato de morfina, adicionados al anestésico local grupo experimental; 70 pacientes no recibieron morfina intratecal grupo control. La efectividad analgésica y los efectos secundarios fueron estudiados por un período de 36 horas después de cirugía.Resultados: La dosis de morfina fue efectiva para el control del dolor en el postquirúrgico. El efecto analgésico se extendió, en el grupo experimental, a las 35 horas de seguimiento, especialmente en el postoperatorio inmediato (NNT 2). La incidencia de efectos secundarios fue: prurito 60 (NNH 2), náusea y vómito 25 (NNH 11), retención urinaria 24.3 (NNH 5) y depresión respiratoria 0. No hubo diferencias en las características de la anestesia, ni en el comportamiento hemodinámico entre los dos grupos. Conclusiones: 100 microgramos de morfina son efectivos para aliviar el dolor postoperatorio en las primeras 12 horas. Los efectos secundarios que se presentaron fueron tolerables y no requirieron tratamiento. La muestra del estudio no fue suficiente para evaluar depresión respiratoria...

Fatal heroin intoxication in body packers in northern Thailand during the last decade: two case reports.

A body packer is an important means of drug trafficking. While drug packets are inside the body, they can leak or rupture causing acute substance toxicity. Most of the reports of body packer syndrome have come from Europe and North America, which are destination targets. In the present study, the authors reported two cases of fatal heroin body packers from the northern part of Thailand. Both cases were foreign tourists who came to Chiang Mai and stayed in a hotel or a guesthouse room in which the deaths occurred. The autopsy findings revealed rupturing of heroin packages in the stomach. The packaging used in both cases was not sophisticated. The powder was packed inside condoms without extra covering, as observed in some other professional packers. The amount of heroin transported was about 30-50 gm. The purity of heroin in this powder was about 50-90%. Their destinations were their home countries and not directly to Europe or North America. Deaths occurred just prior to their return. The cause of death was a heroin overdose. A significant level of heroin metabolites, 6-MAM and morphine were detected in the blood and urine.

Potentiation of Morphine's Antinociception by Group II and Group III Metabotropic Glutamate Receptors Agonists on a Rat Incisional Pain / 대한통증학회지

BACKGROUND: The aim of this study was to clarify the role of spinal groups II and III metabotropic glutamate receptors (mGluRs) with respect to postoperative pain at the spinal level. In addition, the nature of the pharmacological interaction between groups II and III mGluRs agonists and morphine was determined. METHODS: Catheters were inserted into the intrathecal space of male SD rats. To induce postoperative pain, an incision was made in the plantar surface of the hind paw. A pharmacological characteristic for the interaction between groups II and III mGluRs agonists and morphine was evaluated using a fixed-dose analysis. RESULTS: None of intrathecal group II and III mGluRs agonists modified the withdrawal threshold of the incisional pain. The administration of intrathecal morphine resulted in an increase of a dose dependent withdrawal threshold. A fixed-dose analysis revealed that the group III mGluRs agonist, ACPT-III, increased the antinociceptive action of morphine, while the group II mGluRs agonist, APDC, had no effect the antinociception of morphine. CONCLUSIONS: These results suggest that group II and III mGluRs may not play a direct modulatory role in the processing of postoperative pain at the spinal level. However, agonizing group III mGluRs may indirectly contributable to the potentiation of morphines antinociception in the spinal cord. Thus, the combination of morphine and a group III mGluRs agonist may be useful in the management of spinal postoperative pain.

The research of the heroin and its metabolites analysis in clinical samples / 法医学杂志

Heroin can be metabolized easily in body and the mail metabolites are 6-MAM, morphine and so on. At present, there are urine, blood, hair and so on as specimens for detection, while the analytical technology conclude TLC, GC, HPLC, GC/MS, LC/MS, IA, CE etc. In this paper, these technologies used for heroin's metabolites were viewed in order to provide some reference to the study in relative field.

Alkaloids from a Tibetan medicine Meconopsis quintuplinervia Regel / 药学学报

<p><b>AIM</b>To reinvestigate the chemical constituents of the ethanolic extract of Meconopsis quintuplinervia Regel which is a traditional Tibetan medicine used for treatments of hepatitis, tuberculosis etc..</p><p><b>METHODS</b>The compounds were enriched by column chromatography techniques over silica gel, macro porous resin and Sephadex LH-20 absorbents, and finally purified by reverse phase preparative HPLC methods with isocratic mobile phase systems of methanol-H2O-acetic acid (500:500:1) and acetonitrile-H2O-acetic acid (200:800:1). Structural determination of the pure compounds were based on extensive analyses of modern spectroscopic methods including IR, MS, HRMS, 1D- and 2D-NMR spectra.</p><p><b>RESULTS</b>Three alkaloids were obtained and their structures were elucidated as norsanguinarine (I), O-methylflavinantine (II) and 6-methoxy-17-methyl-2, 3-[methylenebis (oxy)]-morphin-5-en-7-one (III).</p><p><b>CONCLUSION</b>Norsanguinarine (I) was isolated from genus Meconopsis for the first time, and 6-methoxy-17-methyl-2,3-[methylenebis(oxy)]-morphin-5-en-7-one (III) is a new alkaloid named as meconoquintupline.</p>

Column-switching high-performance liquid chromatographic method for the determination of morphine and O6-monoacetylmorphine in urine / 法医学杂志

OBJECTIVE@#To develop a column-switching high-performance liquid chromatographic method for the determination of morphine and O6-monoacetylmorphine in urine.@*METHODS@#Urine samples (1.0 ml) were spiked with 1.0 ml borate buffer, after centrifugation, 1.0 ml of supernate were injected directly into an extraction column (YWG C18 33 mm x 5.0 mm, 10 microns). After a washing step with the extraction mobile phase, the retained morphine and O6-monoacetylmorphine were flushed into the analytical column (Lichrospher 100 CN 125 mm x 4.0 mm, 5 microns) with the mobile phase CH3OH-H2O (60:40). The analytical mobile phase is CH3OH-phosphate buffer (pH6.86) (22:78). The UV detector was set at lambda 286 nm.@*RESULTS@#The method shows excellent linearity from 50 to 1,600 ng/ml for morphine and from 100 to 1,600 ng/ml for O6-monoacetylmorphine. The linear correlation coefficients were > 0.999. The relative standard deviations were < 4%. The limits of detection were 40 ng/ml for both morphine and O6-monoacetylmorphine.@*CONCLUSION@#The method described is sensitive, rapid, reproducible, and simple.

Assessment of minidose intrathecal morphine for analgesia after haemorroidectomy

The efficacy of 0.5 kg intrethecal morphine was tested on 10 patients who had haemorrhoidectomy performed at the University College Hospital (UCH); Ibadan. In view of the excellent analgesia in the immediate post-operative period and absence of delayed respiratory depression usually associated with higher doses of spinal opiates it is recommanded that use of technique be encouraged in similar surgical patients for pain relief

Acute Pulmonary Edema During a Cesarian Section - A case report / 대한마취과학회지

Pulmonary edema may be defined broadly as excessive fluid accumulation in the interstitial and air spaces of the lung. We recently a previously healthy parturient with ritodrine treatment who suddenly developed severe pulmonary edema during a Cesarian Section under Genera) Anesthesia, For this presented cases, we believe that overloading, Ritodrine, oxytocin, ergot derivatives wi11 be the causative factors. We had good result with PEEP, diuretics, and morphines.

Acute Pulmonary Edema During a Cesarian Section - A case report / 대한마취과학회지

Pulmonary edema may be defined broadly as excessive fluid accumulation in the interstitial and air spaces of the lung. We recently a previously healthy parturient with ritodrine treatment who suddenly developed severe pulmonary edema during a Cesarian Section under Genera) Anesthesia, For this presented cases, we believe that overloading, Ritodrine, oxytocin, ergot derivatives wi11 be the causative factors. We had good result with PEEP, diuretics, and morphines.