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.

Uso de analgésicos no pós-operatóro para tratamento da dor em hospital no sul do Brasil / Use of analgesics in postoperative to pain relief in a hospital in south of Brazil

Justificativa e objetivo: O tratamento inadequado da dor pós-operatória resulta em aumento da morbimortalidade. A morfina é o analgésico opióide de primeira escolha no tratamento da dor aguda de grande intensidade, como é a dor pós-operatória. No Brasil, tem ocorridoa subutilização da morfina, que é substituída por analgésicos mais fracos ou com menor eficácia comprovada.Este estudo teve como objetivo avaliar a freqüência da utilização de analgésicos em pacientes submetidos a procedimentos cirúrgicos em um hospital do sul de Santa Catarina, analisando o grau de satisfação dos pacientes em relação à analgesia no manejo da dor pós-operatória. Métodos: Foi realizado um estudo epidemiológicodescritivo e transversal com 98 pacientes entrevistados no pós-operatório, após submeterem-se a cirurgias ortopédicas, cesarianas ou histerectomias no referido hospital,no período de março a agosto de 2006.Resultados: A média de idade dos entrevistados foi de 41,5 anos ± 21,7 anos. Dos pacientes selecionados,56,1% realizaram cirurgia ortopédica, 40,8% cesariana e 3,1% histerectomia. O medicamento prescrito com maiorfreqüência foi o cetoprofeno e a principal associação utilizadafoi tramadol e fármaco não-opióide em 28% dos casos. Nenhum paciente utilizou morfina. Na escala numéricade dor, a média constatada foi de 4,4 ± 2,6, sendo esta considerada dor de moderada intensidade. Conclusões: Para o tratamento da dor pós-operatória têm sido empregados analgésicos não-opióides, primordialmente antiinflamatórios não-esteroidais, queeventualmente são associados a opióides fracos como o tramadol. No entanto, o relato de dor de moderada intensidade e o surgimento de reações adversas indicam escolha inadequada e não racional dos analgésicos utilizadosno tratamento da dor pós-operatória.

Background and objective: The inadequate treatment of postoperative pain results in the increase of patientmorbimortality. Morphine is the first choice of opioid analgesics in the treatment of acute pain of greatintensity, such as postoperative pain. In Brazil morphine has been underutilized, being substituted by weaker or less effective analgesics. The objective of this study was to evaluate the frequency use of analgesics by patients submitted to surgical procedures in a hospital in South of Brazil, analyzing their degree of satisfaction with analgesia in handling postoperative pain. Methods: A descriptive, prospective and transversalepidemiological study was conducted with 98 patients interviewed in the postoperative phase, after beingsubmitted to orthopedic surgery, caesarean section or hysterectomy in the hospital, between March and August,2006. Results: The median age was 41.5 and standard deviation was ± 21.7. Of the selected patients, 56.1%had been submitted to orthopedic surgery, 40.8% to caesarian section and 3.1% to hysterectomy. The most frequently prescribed medicine was cetoprofen and tramadol was the main association used with non-opioid agentin 28% of the cases. In the numerical pain scale, the mean found was 4.4, standard deviation was 2.6, whichis considered moderate-intensity pain.Conclusions: Non-opioid analgesics, primarily nonsteroidal anti-inflammatory drugs, which are eventually associated with weak opioids such as tramadol, have been used for the treatment of postoperative pain. However, reports of moderate intensity pain and the emergence of adverse reactions indicate inappropriate choice and non-rational use of analgesics for the treatmentof postoperative pain.

Reflexiones sobre la Biosíntesis de la Morfina y el Parkinson Idiopático / Reflections on the biosynthesis of morphine and idiopathic Parkinson's disease

Con base en un caso personal estudiado en forma diaria y continua se deduce que la enfermedad de Parkinson idiopática es una autointoxicación endógena por alteraciones en la biosíntesis de la morfina, y se propone la determinación de los niveles de ésta en la sangre tanto en los parkinsonianos antes de cualquier tratamiento y, con el fin de establecer su diagnóstico preclínico, en los depresivos que constituyen el grupo mas afectado por la enfermedad de Parkinson.

Based on a day-by-day, in-depth study of a clinical case, it was deduced that Parkinson's disease results in autointoxication, due to damage to morphine biosynthesis. Blood morphine levels should be studied in patients suffering from Parkinson's disease before treatment as well as in depressive patients (being the group most affected by Parkinson´s disease) to achieve early preclinical diagnosis.

Effects of naltrexone and cross-tolerance to morphine in a learned helplessness paradigm

Opiates have been implicated in learned helplessness (LH), a phenomenon known to be related to opiate stress-induced analgesia (SIA). In the present study, we investigated the role of opiates in the induction of LH and SIA under different conditions. Adult female Wistar rats were trained either by receiving 60 inescapable 1-mA footshocks (IS group, N = 114) or by confinement in the shock box (control or NS group, N = 92). The pain threshold of some of the animals was immediately evaluated in a tail-flick test while the rest were used 24 h later in a shutttle box experiment to examine their escape performance. The opiate antagonist naltrexone (0 or 8 mg/kg, ip) and the previous induction of cross-tolerance to morphine by the chronic administration of morphine (0 or 10 mg/kg, sc, for 13 days) were used to identify opiate involvement. Analysis of variance revealed that only animals in the IS group demonstrated antinociception and an escape deficit, both of which were resistant to the procedures applied before the training session. However, the escape deficit could be reversed if the treatments were given before the test session. We conclude that, under our conditions, induction of the LH deficit in escape performance is not opiate-mediated although its expression is opiate-modulated.

Dynamics of Met5- and Leu5-enkephalin and their receptor binding activity in relation to morphine.

A complete normal coordinate analysis of Met5- and Leu5-enkephalins using Wilson's GF matrix method and Urey Bradley force field has been carried out to understand the dynamical behaviour of enkephalins. In addition, the charge distributions on different atoms of the two enkephalins and morphine using CNDO/2 method are also reported. The similarity in the charge distribution on the part of these two molecules is indicative of the possible interactions at the same receptor site as that of morphine and its derivatives. Apart from the topographical features and charge distribution, binding onto receptor site is not a static but a dynamic process and low frequency modes must play an important role in the recognition process. The significance of the out-of-plane amide VII band and other skeletal modes as characteristic of conformational states of Met5- and Leu5-enkephalins are discussed.

Morphine elimination and hepatic blood flow

To investigate the influence of changes in portal venous blood flow on the clearance of morphine, the elimination of a single intravenous dose of morphine sulphate was studied in twelve patients with periportal fibrosis undergoing distal splenorenal shunt for portal hypertension. All patients had almost normal preoperative liver function. Six patients [Group A] received morphine after induction of anesthesia but before surgery; a further six patients [Group B] received morphine after completion of the splenorenal shunt and removal of all vascular clamps. Blood was sampled for 24 hours after morphine administration and analysed for plasma morphine concentration using high performance liquid chromatography. The maximum concentration of morphine was significantly greater in those patients in Group B who received morphine after the shunt [P <.002]. Clearance of morphine during the operation was also significantly reduced in these patients compared with the initial clearance [before release of the clamps] in Group A [P <.004]. As a consequence of these changes the AUC was greater in this group [P < 0.004]. However, there were no differences with the elimination rates after surgery had finished. The results suggest that in individuals with normal liver function, the clearance of morphine is dependent on hepatic blood flow

Modulation of morphine induced antinociception by intracerebroventricularly administered captopril.

Captopril when administered intracerebroventricularly (icv) in doses of 100, 300, 500 and 1000 micrograms induced a dose dependent antinociceptive effect in rats. Naloxone pretreatment (10 mg/kg, ip) completely antagonised antinociceptive effect of captopril, suggesting thereby the involvement of brain enkephalinergic system. Captopril 300 micrograms, icv potentiated the antinociceptive effect of morphine in intact animals. The bilateral adrenalectomy did not have any effect on this potentiation as against the reported blockade of potentiation in adrenalectomized animals when captopril was administered by systemic route. Thus potentiation of morphine induced antinociception by icv captopril is unlikely to be exerted through an effect on adrenal function and is most likely due to increased brain enkephalin levels.