Comparison of a morphine and midazolam combination with morphine alone for paediatric displaced fractures: a randomized study

Aim: To compare the efficacy of sublingual midazolam with oral morphine versus that of oral morphine with placebo in a paediatric population attending an emergency department (ED) with acute long‐bone fractures. Methods: A sample of children aged 5–16 years with clinically deformed closed long‐bone fractures was randomized to groups receiving either oral morphine (0.5 mg/kg)/sublingual placebo or oral morphine (0.5 mg/kg)/sublingual midazolam (0.2 mg/kg). The main exclusion criteria were narcotic or benzodiazepine use, significant head injury, multiple organ failure, femoral fracture and allergy. Pain scores were rated on a 100‐mm visual analogue scale (VAS) at 0, 15, 30, 60, 90 and 120 min. Results: Fifty‐eight children were enrolled (mean age: 10.5 years, SD 2.7). Fractures concerned the radius or ulna in 43 cases (74.1%), the humerus (22.4%) and the tibia or fibula (3.5%). No significant difference in VAS scores was observed between the two treatment arms (p = 0.72). Drowsiness was significantly more frequent in the midazolam group (p = 0.007) during the first 2 h after administration. No serious adverse event was observed. Conclusion: The analgesic performances of morphine and the combination of morphine with midazolam assessed by VAS were similar in children presenting at the ED with a long‐bone fracture.     

The maturation of morphine clearance and metabolism.

OBJECTIVE--To determine how early in childhood the clearance of morphine sulfate reaches that in adults. DESIGN--Patient series. SETTING--Children's Hospital and Medical Center, Seattle, Wash. PARTICIPANTS--Forty-nine children aged 1 day to 2.5 years with normal renal and hepatic function. All children were receiving a constant rate intravenous infusion of morphine for postoperative analgesia for greater than 24 hours. INTERVENTIONS--Blood and urine samples were collected during infusion and immediately after discontinuation of the morphine infusion. MEASUREMENTS--Morphine concentrations were determined and clearance was calculated using the infusion data. Half-life and volume of distribution were calculated using the postinfusion data. The formation of metabolites was evaluated using the urine data. Morphine clearance increased with age, median clearances ranging from 5 mL/kg per minute in neonates aged 1 to 7 days to 21 mL/kg per minute in infants aged 6 months and older. This change in clearance correlated with age. The formation clearance of morphine glucuronide was correlated with age, whereas the formation clearance of morphine sulfate and the renal clearance of morphine were independent of age. CONCLUSIONS--Morphine clearance reaches adult values by age 6 months to 2.5 years. In contrast to previous reports on the maturation of sulfate conjugation, it does not appear that morphine sulfate clearance is enhanced relative to glucuronidation in early infancy.     

Urinary effects of morphine in preterm infants

AIM: To describe the association between morphine administration in preterm infants, hydronephrosis, and renal dysfunction. METHODS: The findings were based on serial ultrasound examinations and blood studies. RESULTS: Two preterm infants had bladder distension and hydronephrosis after they received intravenous morphine for analgesia. Morphine was used at a low dose. Each patient had a normal urine output and normal serum creatinine before the signs and symptoms of urinary retention were observed. Within 24 h of morphine administration, each infant concurrently developed oliguria and elevation of the serum creatinine. Cessation of morphine and urinary drainage resulted in rapid and complete resolution of the hydronephrosis and the elevated creatinine. CONCLUSION: Morphine, even at low dosages, can be associated with hydronephrosis in hospitalized preterm infants.     

Intrathecal morphine for pediatric renal transplant recipients

Many pediatric renal transplant recipients have significant discomfort in the early postoperative period despite opioid administration. Intrathecal morphine is safe and effective for pain control in children. We examined our results with the use of intrathecal morphine for postoperative analgesia in renal transplant recipients at our institution. The morphine was administered while the patients were under general anesthesia. Seventeen of 22 patients received excellent pain control and there were few minor and no major complications. Intrathecal morphine is beneficial for postoperative analgesia in pediatric renal transplant recipients.     

Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain.

OBJECTIVES: (1) To determine the pharmacokinetics of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) in children with cancer receiving morphine as immediate-release morphine liquid or sustained-release tablets. (2) To determine differences with age within the group and from adults. (3) To explore relationships between plasma concentration and pain measurements. STUDY DESIGN: Blood samples were collected and plasma analyzed by high-performance liquid chromatography with electrochemical and fluorescence detection. Population pharmacokinetic parameters were derived with the program P-PHARM. RESULTS: Forty children with a median age of 11.4 years (range 1.7 to 18.7 years) received a median dose of 1.4 mg/kg/d (range 0.4 to 24.6 mg/kg/d). A median of 4 blood samples per child was collected. Plasma clearance of morphine was 23.1 mL/min per kg body weight. The volume of distribution was 5.2 L/kg. Molar ratios of M3G/morphine, M6G/morphine, and M3G/M6G were 21.1, 4.7, and 4.2, respectively. Children <11 years had significantly higher clearance and larger volume of distribution for morphine and its glucuronides than older children and adults. Regression analysis indicated average plasma morphine concentration equal to dose (mg/kg/d) x 8.6 (95% confidence interval 7.4 to 9.9). Significant pain was present in 30% of the children. Higher pain scores were recorded in children with average morphine concentrations <12 ng/mL (P <.01 MW). CONCLUSION: Age differences in morphine pharmacokinetics exist within children and compared with adults. The study supports a starting dose of 1.5 to 2. 0 mg/kg/d to provide plasma morphine concentrations >12 ng/mL in children with cancer pain unrelieved by mild to moderate strength analgesia.     

内生吗啡对儿童脓毒症的诊断价值

目的 检测脓毒症患儿血浆内生吗啡浓度,探讨内生吗啡对脓毒症患儿发生休克、死亡及多器官功能障碍（MODS）的预测价值。方法 符合诊断标准的脓毒症患儿（n=31）,根据是否伴有休克分为脓毒症非休克组（n=19）和休克组（n=12）;根据结局分为存活组（n=22）和死亡组（n=9）;根据是否伴有MODS分为非MODS组（n=13）和MODS组（n=18）。另设普通感染患儿（n=16）和行健康体检儿童（n=31）作为对照。用高效液相质谱串联法检测各组血浆内生吗啡浓度。用受试者工作特征曲线（ROC）评估内生吗啡对脓毒症患儿发生休克、死亡及MODS的预测价值。结果 健康对照组儿童血浆未检测到内生吗啡,普通感染组仅3例患儿血浆检测到内生吗啡;脓毒症患儿血浆中均检测到内生吗啡。休克组患儿血浆内生吗啡浓度高于非休克组（P < 0.05）;死亡患儿血浆内生吗啡浓度高于存活患儿（P < 0.05）;MODS患儿血浆内生吗啡浓度高于非MODS患儿（P < 0.05）。ROC结果显示内生吗啡对脓毒症患儿休克、死亡和MODS均有预测价值（P < 0.05）。结论 脓毒症患儿血浆内生吗啡浓度明显升高,其对脓毒症患儿休克、死亡、MODS风险的发生有较好的预测价值。     

Effects of neonatal stress and morphine on murine hippocampal gene expression

Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to five treatment conditions between postnatal d 5 and 9: 1) control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline, and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of gene sets related to fear response, oxygen carrying capacity, and NMDA receptor synthesis. Morphine down-regulated gene sets related to immune function. Stress + morphine resulted in enrichment of mitochondrial electron transport gene sets and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, and morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress + morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment.     

Long-acting morphine for pain control in paediatric oncology

BACKGROUND: Guidelines for treatment of paediatric cancer pain recommend the usage of long-acting morphine. However, published paediatric experience with this drug is restricted to 147 children not systematically evaluated, and thus insufficient. We aimed to systematically analyse the age-dependent effects and adverse effects of long-acting morphine in paediatric cancer patients. PROCEDURE: Ninety-five children aged 1 to 19 years were enrolled in a collaborative retrospective study conducted over seven-and-a-half years. Pain was scored according to a numeric rating scale (NRS, range 0 to 5), and the corresponding medication was recorded. RESULTS: In 83 children documentation period started during morphine treatment (71, oral long-acting; 1, rectal; 11, IV). Mean oral/equivalent morphine starting dose was 1.3 mg/kgbw/d (SD 0.9). Mean end dose was 2.8 mg/kgbw/d (SD 2.7). Infants aged < 7 years received the highest average dose (2.6 mg/kgbw/d, SD 2.8), while patients > 12 years received the lowest dose (1.4 mg/kgbw/d, SD 1.1). Median pain intensity decreased from score 1.0 (mean 1.2) NRS at the beginning to 0 (mean 0.6) NRS at the end. The proportion of patients scoring > 2 NRS (severe or most severe pain) under morphine treatment decreased from 26 to 12% (P = 0.08). In children > 12 years pruritus was frequently observed (23% of patients). In all age groups, there were no severe adverse effects during the study period. CONCLUSIONS: In paediatric haematology/oncology, pain control by oral long-acting morphine proved to be safe and effective even in the very young patients. The pharmacological properties of long-acting morphine are ideally suited for paediatric use, combining efficacy and compatibility.     

Continuous subcutaneous infusion of morphine in children with cancer

Seventeen children with severe pain due to malignant neoplasm were successfully treated with a subcutaneous infusion of morphine sulfate using a syringe pump. Pain relief was adequate in every case without major side effects. The median dosage required was 0.06 mg/kg/hr (range, 0.025 to 1.79 mg/kg/hr). Three patients received the subcutaneous infusion at home. No patient required an intravenous line for pain control.     

Postoperative analgesia. Use of intrathecal morphine in children

The identification of opiate receptors in the spinal cord gave rise to the suggestion that the use of intrathecal and epidural narcotics may provide effective and safe postoperative analgesia. The authors retrospectively reviewed the records of ten children who received intrathecal morphine as part of their anesthetic care over the last 2 years. Preservative-free morphine (Duramorph) in a dose of 0.02 mg/kg was administered to all patients in the lumbar intrathecal space before the start of the surgical procedure. Adequate postoperative analgesia was achieved in the ten children. No patient required supplemental analgesic agents for the initial 15-hour postoperative period. Surgical procedures included exploratory laparotomy, laryngotracheoplasty, and craniofacial reconstruction. As with narcotics administered by any route, intrathecal morphine can cause respiratory depression, and such depression may be delayed for up to 24 hours after the dose. Therefore, the postoperative respiratory status of these children should be monitored for 24 hours after the dose, preferably in an intensive care unit. With this caveat, the use of intrathecal morphine provides safe and effective postoperative analgesia in children undergoing major surgery.     

Effect of morphine and pancuronium on the stress response in ventilated preterm infants

Nintey-five premature newborns who had hyaline membrane disease and were struggling against the ventilator were randomised to one of three treatment groups: morphine (group M), pancuronium (group P) or morphine with pancuronium (group M+P). The dose of morphine was 50 μg/kg per h but was increased to 100 μg/kg per h in group M infants if they continued to struggle. The dosage of pancuronium was 100 μg/kg given as required to inhibit spontaneous respiration. Plasma catecholamine levels were measured on entry and at 24 h. Blood pressure and ventilatory requirements were determined on entry and at 6 h. The clinical outcome of the infants was documented. Group M infants (n=29) showed a significant reduction in noradrenaline levels (median change −2.2 nmols/1 (range −47.2 to +7.2 nmols/1), although seven were withdrawn from this group because of failure to settle. Group P (n=28) and group M + P (n=38) showed no significant change in noradrenaline levels. Comparison between the groups showed that group M infants had a significant reduction in noradrenaline levels compared with group P. The immediate effects of treatment on blood pressure and ventilatory requirements were similar in the three groups. The clinical outcome did not differ for any of the measured parameters. When adequate sedation is achieved, morphine may reduce the stress of newborn intensive care.     

Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants

BACKGROUND: Midazolam sedation and morphine analgesia are commonly used in ventilated premature infants. OBJECTIVES: To evaluate the effects of midazolam versus morphine infusion on cerebral oxygenation and hemodynamics in ventilated premature infants. METHODS: 11 patients (GA 26.6-33.0 weeks, BW 780-2,335 g) were sedated with midazolam (loading dose 0.2 mg/kg, maintenance 0.2 mg/kg/h) and 10 patients (GA 26.4-33.3 weeks, BW 842-1,955 g) were sedated with morphine (loading dose 0.05 mg/kg, maintenance 0.01 mg/kg/h). Changes in oxyhemoglobin (Delta cO2Hb) and deoxyhemoglobin (Delta cHHb) were assessed using near infrared spectrophotometry. Changes in cHbD (= Delta cO(2)Hb - Delta cHHb) reflect changes in cerebral blood oxygenation and changes in concentration of total hemoglobin (Delta ctHb = Delta cO2Hb + Delta cHHb) represent changes in cerebral blood volume (DeltaCBV). Changes in cerebral blood flow velocity (DeltaCBFV) were intermittently measured using Doppler ultrasound. Heart rate (HR), mean arterial blood pressure (MABP), arterial oxygen saturation (saO2) and transcutaneous measured pO2 (tcpO2) and pCO2 (tcpCO2) were continuously registered. Statistical analyses were carried out using linear mixed models to account for the longitudinal character study design. RESULTS: Within 15 min after the loading dose of midazolam, a decrease in saO2, tcpO2 and cHbD was observed in 5/11 infants. In addition, a fall in MABP and CBFV was observed 15 min after midazolam administration. Immediately after morphine infusion a decrease in saO2, tcpO2 and cHbD was observed in 6/10 infants. Furthermore, morphine infusion resulted in a persistent increase in CBV. CONCLUSIONS: Administration of midazolam and morphine in ventilated premature infants causes significant changes in cerebral oxygenation and hemodynamics, which might be harmful.     

Postoperative morphine infusion in newborn infants: assessment of disposition characteristics and safety

Twelve newborn infants were given morphine intravenously for postoperative analgesia. They received a continuous infusion of 6.2 to 40 micrograms/kg/hr for 9 to 105 hours (mean +/- SEM 59.5 +/- 10.2 hours); in four the infusion was preceded by a loading dose of 50 to 100 micrograms/kg. Morphine plasma concentrations correlated with the rate of infusion, but with large variability. There was a tendency for plasma morphine concentrations to decrease in some patients receiving a constant infusion rate, suggesting improvement in morphine clearance rate. Elimination half-life of morphine (13.9 +/- 6.4 hours) was significantly longer than in older children and adults (about 2 hours). Similarly, morphine concentrations in neonates receiving 20 micrograms/kg/hr for 24 hours were three times higher (52 +/- 31 ng/ml) than in older children receiving the same schedule. Two infants who received 32 and 40 micrograms/kg/hr, respectively, developed generalized seizures. Because of the apparently greater sensitivity to morphine and the lower elimination rate in newborn infants, the infused dose should not exceed 15 micrograms/kg/hr.     

Analgosedation with low-dose morphine for preterm infants with CPAP: risks and benefits

BACKGROUND: CPAP is widely used in preterm infants on NICUs but it poses a stressful stimulus to the patient, sometimes requiring the use of analgosedative drugs. AIM: The aim of this study is to evaluate the risks and benefits associated with the use of low-dose morphine in preterm infants with CPAP, especially apnea. METHODS: Sixty-four CPAP-treated preterm infants, who received a low single dose of morphine (recommended 0.01 mg/kg), were included in this prospective study. Observation-time was 4 h prior to injection, directly before injecting, until 15 min and 15-30 min, 30 min-1 h, 1-2 h, 2-3 h, 3-4 h, 4-5 h and 5-6 h after injection. For all observation periods incidence of apnea, heart rate, respiratory rate and a score for analgesia and for sedation were recorded. RESULTS: Sixty-four preterm infants (29.6+/-3.3 weeks gestational age (GA), birth weight 1401+/-735 g) received 0.025+/-0.012 mg/kg morphine i.v. on the day 10-13 of life. The decrease in heart and respiratory rate, scores for analgesia and sedation were significant. The overall incidence of apnea did not increase compared to the 4 h pre-morphine period. Six patients (9.3%) experienced considerable delayed apnea. This group was significantly younger in GA (p<0.001) and lighter in birth weight (p=0.002). CONCLUSION: Morphine in dosage less than half of recommended dosage has a high analgetic and sedative potential. The danger of delayed severe apnea has to be taken into consideration in the clinical situation, especially in patients<28 weeks.     

Gallbladder sludge and lithiasis in an infant born to a morphine user mother

We report a 3-month-old boy with gallbladder sludge formation and lithiasis. The known associated factors causing cholelithiasis in infancy were not present. We postulate that maternal chronic use of morphine during pregnancy may result in biliary sludge formation in utero in the fetus with progression and manifestation of cholelithiasis at 3-months of age.