Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice.

Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as a life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6 J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD.

Low dose of morphine to relieve dyspnea in acute respiratory failure (OpiDys): protocol for a double-blind randomized controlled study.

BACKGROUND: Dyspnea is common and severe in intensive care unit (ICU) patients managed for acute respiratory failure. Dyspnea appears to be associated with impaired prognosis and neuropsychological sequels. Pain and dyspnea share many similarities and previous studies have shown the benefit of morphine on dyspnea in patients with end-stage onco-hematological disease and severe heart or respiratory disease. In these populations, morphine administration was safe. Here, we hypothesize that low-dose opioids may help to reduce dyspnea in patients admitted to the ICU for acute respiratory failure. The primary objective of the trial is to determine whether the administration of low-dose titrated opioids, compared to placebo, in patients admitted to the ICU for acute respiratory failure with severe dyspnea decreases the mean 24-h intensity of dyspnea score. METHODS: In this single-center double-blind randomized controlled trial with 2 parallel arms, we plan to include 22 patients (aged 18-75 years) on spontaneous ventilation with either non-invasive ventilation, high flow oxygen therapy or standard oxygen therapy admitted to the ICU for acute respiratory failure with severe dyspnea. They will be assigned after randomization with a 1:1 allocation ratio to receive in experimental arm administration of low-dose titrated morphine hydrochloride for 24 h consisting in an intravenous titration relayed subcutaneously according to a predefined protocol, or a placebo (0.9% NaCl) administered according to the same protocol in the control arm. The primary endpoint is the mean 24-h dyspnea score assessed by a visual analog scale of dyspnea. DISCUSSION: To our knowledge, this study is the first to evaluate the benefit of opioids on dyspnea in ICU patients admitted for acute respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT04358133 . Registered on 24 April 2020.

Epidural morphine in COVID ARDS patients with high respiratory drive: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: We aim to study the effect of epidural morphine as a means to reduce high respiratory drive in COVID 19 patients on non-invasive ventilation (NIV)-primary end point-and to study its effect on respiratory parameters, subjective patient comfort, rates of endotracheal intubation, duration of mechanical ventilation and mortality. TRIAL DESIGN: Parallel group, randomised, double blind, single centre placebo control trial. Allocation ratio 1:1, superiority trial PARTICIPANTS: Trial site and population-COVID ICU patients in the All India Institute of Medical Sciences (AIIMS) Bhubaneswar, Odisha, India Inclusion and exclusion criteria Inclusion criteria Adult patients on NIV with COVID-19 Exclusion criteria Metabolic acidosis HCO3-< 16 and pH < 7.2. Severe hypoxemia warranting cessation of NIV and intubation, non-acceptance of NIV and proven sepsis. Technical difficulty for epidural catheterization, coagulation abnormalities, low respiratory drive and EOL orders. Sources or methods of recruitment-daily discussion at 8 am of new admissions to COVID ICU on NIV-consenting adult patients with COVID19 on NIV and high respiratory drive; not meeting exclusion criteria will be recruited for the trial and randomised. INTERVENTION AND COMPARATOR: Patients of both groups will be turned to a lateral or sitting position (as comfortable), and an injection of local anaesthetic be given at lumbar 2-3/3-4 space. In the intervention group, an epidural catheter will be inserted using aseptic technique and fixed to the skin. The control group will have a sham catheter fixed exactly like in the intervention group, but not entering the epidural space. The intervention group will be administered injection morphine sulphate once every 18-24 h into the epidural space. The doses will be escalated daily (5-10 mg), titrated to effect: escalation limited by hypoventilation resulting in respiratory acidosis (pH < 7.2). The intervention will continue for a minimum of 2 doses and a maximum of 5 doses (96 h) of morphine. It will be stopped if the epidural catheter gets dislodged before the second dose or the patient is weaned off non-invasive ventilation to high flow mask for a continuous period of 24 h or requires endotracheal intubation. The patient will be followed up till death or 28 days after ICU discharge. MAIN OUTCOMES: Primary outcome-diaphragm thickening index fraction (average of minimum 3 readings) Secondary outcomes-ventilator parameters, sedation and pain scores, subjective comfort and dyspnoea scores, time to intubation, length of stay on NIV and 28-day mortality Timing of outcome assessment-every 8th hour assessment for 24 h after the last dose of epidural morphine or 120 h whichever is greater RANDOMISATION: A central random number list will be kept with the study research assistant. She will randomise according to the numbers available in the list using an allocation ratio of 1:1. An opaque sealed envelope concealing the allotted randomisation code will be dispatched to the ICU team. BLINDING (MASKING): The assessor, patient, nurses and physicians will be blind to group allocation. One member of the team not involved in research will administer the intervention. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Twenty-five patients per group; 50 patients total TRIAL STATUS: Protocol version 1. Not recruiting yet. Recruitment to begin by 24 July 2021 and end by 31 August 2022 TRIAL REGISTRATION: Central Trials Registry India CTRI CTRI/2021/07/035093 . Registered on 23 July 2021. Prospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Consideration of immunomodulatory actions of morphine in COVID-19 - Short report.

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.