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JAMA Nov 2022Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness,... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed.
OBJECTIVE
To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019.
INTERVENTIONS
People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week's dose, or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days -3 to -1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day -1) to the mean step count from week 3 (from days 19 to 21).
RESULTS
Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -0.3 [95% CI, -0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, -0.3 [95%, CI, -1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -1453 [95% CI, -3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, -1312 [95% CI, -3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, -692 [95% CI, -2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, -1924 [95% CI, -47 699 to 921]).
CONCLUSIONS AND RELEVANCE
Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02720822.
Topics: Aged; Female; Humans; Male; Delayed-Action Preparations; Double-Blind Method; Dyspnea; Morphine; Pulmonary Disease, Chronic Obstructive; Respiratory System Agents; Chronic Disease; Treatment Outcome
PubMed: 36413230
DOI: 10.1001/jama.2022.20206 -
European Journal of Heart Failure Oct 2022Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute cardiogenic pulmonary oedema (ACPE). We compared the efficacy and safety of midazolam and morphine in patients with ACPE.
METHODS AND RESULTS
A randomized, multicentre, open-label, blinded endpoint clinical trial was performed in seven Spanish emergency departments (EDs). Patients >18 years old clinically diagnosed with ACPE and with dyspnoea and anxiety were randomized (1:1) at ED arrival to receive either intravenous midazolam or morphine. Efficacy was assessed by in-hospital all-cause mortality (primary endpoint). Safety was assessed through serious adverse event (SAE) reporting, and the composite endpoint included 30-day mortality and SAE. Analyses were made on an intention-to-treat basis. The trial was stopped early after a planned interim analysis by the safety monitoring committee. At that time, 111 patients had been randomized: 55 to midazolam and 56 to morphine. There were no significant differences in the primary endpoint (in-hospital mortality for midazolam vs. morphine 12.7% vs. 17.9%; risk ratio[RR] 0.71, 95% confidence interval [CI] 0.29-1.74; p = 0.60). SAE were less common with midazolam versus morphine (18.2% vs. 42.9%; RR 0.42, 95% CI 0.22-0.80; p = 0.007), as were the composite endpoint (23.6% vs. 44.6%; RR 0.53, 95% CI 0.30-0.92; p = 0.03).
CONCLUSION
Although the number of patients was too small to draw final conclusions and there were no significant differences in mortality between midazolam and morphine, a significantly higher rate of SAEs was found in the morphine group.
Topics: Humans; Adolescent; Midazolam; Morphine; Pulmonary Edema; Heart Failure; Hospital Mortality
PubMed: 35780488
DOI: 10.1002/ejhf.2602 -
Anesthesiology Jun 2020Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery.
METHODS
In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded.
RESULTS
There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan-Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200).
CONCLUSIONS
Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen.
Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Analgesics, Opioid; Cesarean Section; Double-Blind Method; Female; Humans; Hydromorphone; Male; Morphine; Pain, Postoperative; Treatment Outcome
PubMed: 32251031
DOI: 10.1097/ALN.0000000000003283 -
JAMA Pediatrics Aug 2018Although opioids are used to treat neonatal abstinence syndrome (NAS), the best pharmacologic treatment has not been established. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Although opioids are used to treat neonatal abstinence syndrome (NAS), the best pharmacologic treatment has not been established.
OBJECTIVE
To compare the safety and efficacy of methadone and morphine in NAS.
DESIGN, SETTING, AND PARTICIPANTS
In this randomized, double-blind, intention-to-treat trial, term infants from 8 US newborn units whose mothers received buprenorphine, methadone, or opioids for pain control during pregnancy were eligible. A total of 117 infants were randomized to receive methadone or morphine from February 9, 2014, to March 6, 2017. Mothers who declined randomization could consent to data collection and standard institutional treatment.
INTERVENTIONS
Infants were assessed with the Finnegan Neonatal Abstinence Scoring System every 4 hours and treated with methadone or placebo every 4 hours or morphine every 4 hours. Infants with persistently elevated Finnegan scores received dose increases. Infants who exceeded a predetermined opioid dose received phenobarbital. Dose reductions occurred every 12 to 48 hours when signs of NAS were controlled with therapy, stopping at 20% of the original dose.
MAIN OUTCOMES AND MEASURES
The primary end point was length of hospital stay (LOS). The secondary end points were LOS attributable to NAS and length of drug treatment (LOT).
RESULTS
A total of 183 mothers consented to have their infants in the study; 117 infants required treatment. Because 1 parent withdrew consent, data were analyzed on 116 infants (mean [SD] gestational age, 39.1 [1.1] weeks; mean [SD] birth weight, 3157 [486] g; 58 [50%] male). Demographic variables and risk factors were similar except for more prenatal cigarette exposure in infants who received methadone. Adjusting for study site and maternal opioid type, methadone was associated with decreased mean number of days for LOS by 14% (relative number of days, 0.86; 95% CI, 0.74-1.00; P = .046), corresponding to a difference of 2.9 days; 14% reduction in LOS attributable to NAS (relative number of days, 0.86; 95% CI, 0.77-0.96; P = .01), corresponding to a difference of 2.7 days; and 16% reduction in LOT (relative number of days, 0.84; 95% CI, 0.73-0.97; P = .02), corresponding to a difference of 2.3 days. Methadone was also associated with reduced median LOS (16 vs 20 days, P = .005), LOS attributable to NAS (16 vs 19 days, P = .005), and LOT (11.5 vs 15 days, P = .009). Study infants had better short-term outcomes than 170 nonrandomized infants treated with morphine per standard institutional protocols.
CONCLUSIONS AND RELEVANCE
With use of weight- and sign-based treatment for NAS, short-term outcomes were better in infants receiving methadone compared with morphine. Assessment of longer-term outcomes is ongoing.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01958476.
Topics: Analgesics, Opioid; Double-Blind Method; Female; Humans; Infant, Newborn; Intention to Treat Analysis; Male; Methadone; Morphine; Neonatal Abstinence Syndrome; Treatment Outcome
PubMed: 29913015
DOI: 10.1001/jamapediatrics.2018.1307 -
Ugeskrift For Laeger Jan 2024Chronic malignant pain is a common and feared condition. Especially, since many patients do not achieve proper pain relief from conventional peroral medication regimes... (Review)
Review
Chronic malignant pain is a common and feared condition. Especially, since many patients do not achieve proper pain relief from conventional peroral medication regimes and possible unacceptable side effects of high dosing. As argued in this review, in these patients, continuous intrathecal infusion of pain medicine by a programmable subcutaneously placed pump enables good pain relief, less systemic side effects, and better life quality. Intrathecal pain treatment should therefore be considered in patients with a proper performance score and suitable estimated life expectancy.
Topics: Humans; Morphine; Analgesics; Palliative Care; Pain Management; Pain; Chronic Pain
PubMed: 38305326
DOI: 10.61409/V08230541 -
Pain Research & Management 2019Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms... (Review)
Review
Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.
Topics: Analgesics, Opioid; Animals; Drug Tolerance; Humans; MicroRNAs; Morphine
PubMed: 31182985
DOI: 10.1155/2019/9432965 -
Science Advances Jun 2023The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain...
The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTA) to the IPAC lateral region GABAergic neurons (IPACL) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1-expressing neurons (NAcSh) to the IPAC medial region GABAergic neurons (IPACM) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTAIPACL and NAcShIPACM were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.
Topics: Morphine; Ventral Tegmental Area; Reward; GABAergic Neurons; gamma-Aminobutyric Acid
PubMed: 37352353
DOI: 10.1126/sciadv.adg5849 -
Acta Medica Portuguesa Mar 2016
Topics: Analgesics, Opioid; Humans; Morphine; Practice Guidelines as Topic
PubMed: 27285090
DOI: 10.20344/amp.7663 -
Neurologia (Barcelona, Spain) Apr 2015Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are... (Review)
Review
INTRODUCTION
Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning.
OBJECTIVE
In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults.
DEVELOPMENT
Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas.
CONCLUSIONS
The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction.
Topics: Amygdala; Animals; Brain; Dendritic Spines; Hippocampus; Humans; Morphine; Neuronal Plasticity; Receptors, Opioid
PubMed: 25444409
DOI: 10.1016/j.nrl.2014.08.004 -
Neuroscience Sep 2023Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which... (Review)
Review
Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which limits its clinical application. The complex mechanisms underlying the development of morphine analgesia into tolerance involve multiple nuclei in the brain. Recent studies reveal the signaling at the cellular and molecular levels as well as neural circuits contributing to morphine analgesia and tolerance in the ventral tegmental area (VTA), which is traditionally considered a critical center of opioid reward and addiction. Existing studies show that dopamine receptors and μ-opioid receptors participate in morphine tolerance through the altered activities of dopaminergic and/or non-dopaminergic neurons in the VTA. Several neural circuits related to the VTA are also involved in the regulation of morphine analgesia and the development of drug tolerance. Reviewing specific cellular and molecular targets and related neural circuits may provide novel precautionary strategies for morphine tolerance.
Topics: Humans; Morphine; Ventral Tegmental Area; Analgesics, Opioid; Pain; Analgesia
PubMed: 37286162
DOI: 10.1016/j.neuroscience.2023.05.026