Duration Of Morphine Treatment Research Articles

Phenobarbital and Clonidine as Secondary Medications for Neonatal Opioid Withdrawal Syndrome.

Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS. We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders. Of 563 infants with NOWS treated with morphine, 32% (n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001). Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings.

Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL). We conducted this study to evaluate the added value of determining some genetic and non-genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP), as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively). The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine.

Subdural haemorrhage is associated with recent morphine treatment in patients with cancer: A retrospective population-based nested case-control study

Background: This study investigated the relationship between recent morphine use and risk of subdural haemorrhage (SDH) in patients with cancer.Methods: This study identified a malignancy cohort of 25 322 patients who had never received morphine treatment. In this malignancy cohort, 200 patients who subsequently developed SDH were designated as the SDH group. Control-group patients without SDH were selected from the malignancy cohort and were matched ∼4:1 to each SDH case for age, sex, year of cancer diagnosis and index year. Morphine use was designated as ‘recent’ if the prescription duration covered the index date or ended within 6 months before the index date. Logistic regression was used to estimate odds ratios and 95% confidence intervals and a multivariable model was applied to control for age, sex and cerebrovascular disease.Results: Compared with non-morphine users, patients with cancer who received morphine within 6 months of the index date exhibited a 2.58-fold (95% CI = 1.23–5.39) increase in the risk of developing SDH. The risk of SDH development increased as the duration of morphine treatment increased.Conclusion: The incidence of SDH in patients with cancer in Taiwan is associated with recent morphine treatment (≤6 months) and is dependent on the duration of morphine use.

560 Effects of Morphine on General Movements of Preterm Infants

Background: The influence of morphine on the developing central nervous system (CNS) of preterm infants is not fully known. Concern for neurological side effects has lead to hesitancy in using morphine within NICUs. Analysis of general movements (GMs) is a method to evaluate the influence of medication on cerebral function. Objective: To investigate the influence of morphine treatment on cerebral function of preterm infants by analyzing the quality of their GMs. Method: Prospective cohort study on preterm infants receiving continuous morphine (10 µg/ kg/h) for at least 24h. We assessed GM-quality before, during and after morphine treatment. To evaluate subtle differences in movement quality, we also determined a motor optimality score (OS, range 8-18) of the GMs. Finally, we determined the relationship between GMs and various clinical factors that might confound our findings. Results: Twenty-nine preterm infants (GA 31 [25.6- 35.7] weeks, birthweight 1525 [630-3000] grams, median[range]) were studied. After morphine was started, GM-quality and OS did not change. During morphine treatment OS improved, with median OS increasing from 9 to 10 (p< 0.05). After morphine therapy GM-quality and OS improved further, median OS increasing to 12 (p < 0.01). Duration of morphine treatment did not influence GM-quality or OS. GM-quality correlated positively to postnatal age (r=0.444, p< 0.01) and negatively to respiratory support (r= -0.490, p< 0.01). Conclusion: Morphine treatment did not impair quality of movements in preterm infants. This study indicates that morphine treatment has no direct adverse influence on the CNS and can be used safely in preterm infants.

Neonatal outcome of 58 infants exposed to maternal buprenorphine in utero

To study the neonatal outcome of infants exposed to buprenorphine in utero. We prospectively followed 54 buprenorphine-using pregnant women and their 58 infants. Urinary buprenorphine and norbuprenorphine concentrations in the mothers were measured prior to delivery, and in the infants during the first 3 days of life. The Finnegan score was used to evaluate neonatal abstinence syndrome. Other medical problems as well as social outcomes were recorded. All infants had buprenorphine in their urine. A total of 38 infants required 20 +/- 10 days (range 7-48 days) of morphine treatment for neonatal abstinence syndrome. The length of hospital stay for all infants was 25 +/- 19 days (range 3-125 days). The infants' highest urinary norbuprenorphine concentrations across their first 3 days of life correlated with the length of hospital stay and duration of morphine treatment (both p < 0.05). The mean birth weight and mean head circumference (n = 58) were below average (mean -0.7 standard deviation [SD] and mean -0.5 SD, respectively). Eleven infants were discharged home, 19 infants were placed in foster care and 28 infants were discharged with their mothers to Mother and Child homes or to other institutions. Maternal buprenorphine use at the time of birth may cause neonatal abstinence syndrome, requiring long-term hospitalization. Multiple social problems require a multidisciplinary team approach.

The Val158Met polymorphism of the human catechol -O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients

Catechol- O-methyltransferase (COMT) inactivates dopamine, epinephrine and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three- to-four-fold variation in the COMT enzyme activity, the Met form displaying lower enzymatic activity. The Val158Met polymorphism affects pain perception, and subjects with the Met/Met genotype have the most pronounced response to experimental pain. Based on this information we analyzed the influence from the COMT Val158Met polymorphism on the efficacy of morphine in a cohort of patients suffering from cancer pain. We genotyped 207 Caucasian cancer patients on morphine treatment with respect to the Val158Met polymorphism and compared the morphine doses, serum concentrations of morphine and morphine metabolites between the genotype groups. Patients with the Val/Val genotype ( n=44) needed more morphine (155±160 mg/24 h) when compared to the Val/Met (117±100 mg/24 h; n=96) and the Met/Met genotype (95±99 mg/24 h; n=67) groups ( P=0.025). This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, perceived pain intensity, adverse symptoms, or time until death. These results suggest that genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.

The 118 A &gt; G polymorphism in the human µ‐opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease

Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients. We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms. No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms. Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.

Opiate withdrawal in the neonatal rat: relationship to duration of treatment and naloxone dose.

Treatment of developing rat pups with morphine (MOR) causes the development of physical dependence, but the relationship of the withdrawal syndrome to the duration/intensity of treatment has not been described. The purpose of the present study was to characterize the emergence of various behavioral components of withdrawal in neonatal rats, and to develop a useful measure of overall intensity of withdrawal (OIW). Rat pups were treated with morphine (MOR) (20 mg/kg, SC, b.i.d.) for 0-5 days. On postnatal day 10 (P10), animals received saline (SAL) or a challenge dose of MOR (25 mg/kg). Withdrawal was precipitated with naloxone HCl (NAL) (0.1, 0.5 or 2.5 mg/kg) 2 h after the MOR injection, and behaviors were quantitated for 10 min. To investigate the ability of clonidine HCl (CLON) to suppress withdrawal, pups were treated for 0 or 5 days with MOR, given a MOR challenge and either SAL or CLON (0.2 mg/kg), followed by SAL or NAL (2.5 mg/kg, SC). To evaluate endocrine components of withdrawal, growth hormone responses to withdrawal were examined. The OIW and NAL-induced GH suppression increased with increasing NAL dose and duration of morphine treatment. However, individual behaviors showed differing patterns of expression. Clonidine decreased the severity of tremor and reduced the OIW. These results demonstrate that the intensity of neonatal opiate withdrawal is related to the duration and intensity of treatment. The profile of observed withdrawal behaviors may reflect the involvement of the noradrenergic system.

Possible role of cyclic AMP and dopamine in morphine tolerance and physical dependence

In chronically morphinized rats undergoing naloxone induced withdrawal the cerebellar Cyclic 3′, 5′ adenosine monophosphate (Cyclic AMP) was significantly higher than the controls. The cerebellar dopamine (DA) and norepinephrine (NE) were decreased, elevated or unchanged depending on the duration of morphine treatment. The corpus striatal DA levels during withdrawal were markedly elevated and the striatal cyclic AMP levels were unchanged. The NE levels in the striatal tissue were either elevated or unchanged depending upon the duration of morphine administration. In sharp contrast to the chronically morphinized rats undergoing naloxone induced withdrawal, the rats made morphine dependent over a period of eight weeks showed quite moderate changes in the striatal and cerebellar cyclic AMP and DA levels. Thus alterations in the DA and the cyclic AMP levels in the central nervous system (CNS) may play an important role in the naloxone induced stereotyped morphine withdrawal behavior.