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Nebulized versus intravenous morphine titration for the initial treatment of severe acute pain in the emergency department: study protocol for a multicenter, prospective randomized and controlled trial, CLIN-AEROMORPH.

ABSTRACT: BACKGROUND:Intravenous morphine titration (IVMT) is the French gold standard for opioid treatment in the emergency department (ED). Nebulized morphine titration (NMT) may represent an alternative without venous access, but it has not been adequately studied in adults. We test the hypothesis that NMT is at least as effective as IVMT to initially manage severe acute pain in the ED. METHODS/DESIGN:We designed a multicenter (10 French EDs), single-blind, randomized and controlled trial. Adults between 18 and 75?years with visual analog scale (VAS)???70/100 or numeric rating scale (NRS)???7/10 will be enrolled. We will randomize 850 patients into two groups to compare two routes of MT as long as VAS?>? 30 or NRS?>? 3. In group A (425), patients will receive an initial NMT for 5-25?min associated with titration of an intravenously (IV) administered placebo of physiologic serum (PS). In group B (425), patients will receive IVMT plus nebulized PS placebo. NMT is defined as a minimum of 1 and a maximum of 3 5-min nebulized boluses of 10?mg or 15?mg (weight???60?kg), at 10-min fixed intervals. IVMT is defined as a minimum of 1 and a maximum of 6 boluses of 2?mg or 3?mg (weight???60?kg), at 5-min fixed intervals. Nebulized placebo titration will be performed every 10?min. IV titration of PS will be performed every 5?min. In both groups, after 25?min, if VAS >?30/100 or NRS?>?3/10, routine IVMT will be continued until pain relief. Pain severity, vital signs, bronchospasm, and Ramsay score will be recorded every 5?min. The primary outcome is the rate of relief obtained 1?h from the start of drug administration. Complete pain relief in both groups will be compared with a non-inferiority design. Secondary outcomes are pain relief at 30?min (the end of NMT) and at 2?h and median pain relief. We will compare final doses, and study the feasibility and tolerance of NMT (protocol deviations, respiratory or hemodynamic depression, sedation, and minor vegetative side effects). Co-analgesia will be recorded. Discharge criteria from the ED and hospital are defined. DISCUSSION:This trial is the first multicenter randomized and controlled NMT protocol for severe pain in the ED using the titration concept. We propose an original approach of combined titration with an endpoint at 1?h and a non-inferiority design. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03257319 . Registered on 22 August 2017.

SUBMITTER: Lvovschi VE

PROVIDER: S-EPMC6458825 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Nebulized versus intravenous morphine titration for the initial treatment of severe acute pain in the emergency department: study protocol for a multicenter, prospective randomized and controlled trial, CLIN-AEROMORPH.

Lvovschi Virginie Eve VE Joly Justine J Lemaire Nicolas N Maignan Maxime M Canavaggio Pauline P Leroi Anne-Marie AM Tavolacci Marie-Pierre MP Joly Luc-Marie LM

Trials 20190411 1

<h4>Background</h4>Intravenous morphine titration (IVMT) is the French gold standard for opioid treatment in the emergency department (ED). Nebulized morphine titration (NMT) may represent an alternative without venous access, but it has not been adequately studied in adults. We test the hypothesis that NMT is at least as effective as IVMT to initially manage severe acute pain in the ED.<h4>Methods/design</h4>We designed a multicenter (10 French EDs), single-blind, randomized and controlled tria ...[more]

PMID: 30975187

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Project description:BackgroundPain is one of the main reasons to present to emergency departments (EDs). Opioids are indispensable for acute pain management but are associated with side effects, misuse, and dependence. The aim of this study was to test whether a single dose of intravenous (IV) acetaminophen (paracetamol) can reduce the use of morphine for pain relief and/or morphine-related adverse events (AEs).MethodsED patients >18 years with acute pain (i.e., Numeric Rating Scale [NRS] > 4) were screened for eligibility. Patients with analgesia in the past 6 h, chronic pain, or clinical instability were excluded. Patients were randomized in a 1:1 ratio to receive either morphine 0.1 mg/kg and 1 g acetaminophen IV or morphine 0.1 mg/kg and placebo IV. The intervention was double-blinded. Additional morphine 0.05 mg/kg IV was administered every 15 minutes until pain relief (defined as NRS < 4) and whether the pain recurred. The primary outcome was the mean morphine dose for pain relief. Secondary outcomes were the total amount of morphine given, time to achieve pain relief, and AEs.ResultsA total of 220 patients were randomized and 202 evaluated for the primary outcome. The mean morphine dose for pain relief was similar in both groups (acetaminophen 0.15 mg ± 0.07 mg/kg, placebo 0.16 ± 0.07 mg/kg). There were no differences in the total amount of morphine given (acetaminophen 0.19 ± 0.09 mg/kg, placebo 0.19 ± 0.1 mg/kg), the time to achieve pain relief (acetaminophen 30 min [95% CI 17-31 min], placebo 30 min [95% CI 30-35 min]), and the frequency of AEs (overall 27.4%). Time to pain recurrence did not differ significantly between the groups (hazard ratio 1.23 [0.76-1.98], p = 0.40).ConclusionsIn ED patients, acetaminophen had no additional effect on pain control or morphine-sparing effect at the time of first morphine administration. Titrated morphine with the algorithm used was highly effective, with 80% of all patients reporting pain relief within 60 min of starting therapy.

Project description:Opioid titration is an effective strategy for treating pain; however, titration is generally impractical in the busy emergency department (ED) setting. Our objective was to test a rapid, two-step, hydromorphone titration protocol against usual care in older patients presenting to the ED with acute severe pain.This was a prospective, randomized clinical trial of patients 65 years of age and older presenting to an adult, urban, academic ED with acute severe pain. The study was registered at http://www.clinicaltrials.gov (NCT01429285). Patients randomized to the hydromorphone titration protocol initially received 0.5 mg intravenous hydromorphone. Patients randomized to usual care received any dose of any intravenous opioid. At 15 min, patients in both groups were asked, 'Do you want more pain medication?' Patients in the hydromorphone titration group who answered 'yes' received a second dose of 0.5 mg intravenous hydromorphone. Patients in the usual care group who answered 'yes' had their ED attending physician notified, who then could administer any (or no) additional medication. The primary efficacy outcome was satisfactory analgesia defined a priori as the patient declining additional analgesia at least once when asked at 15 or 60 min after administration of the initial opioid. Dose was calculated in morphine equivalent units (MEU: 1 mg hydromorphone = 7 mg morphine). The need for naloxone to reverse adverse opioid effects was the primary safety outcome.83.0 % of 153 patients in the hydromorphone titration group achieved satisfactory analgesia compared with 82.5 % of 166 patients in the usual care group (p = 0.91). Patients in the hydromorphone titration group received lower mean initial doses of opioids at baseline than patients in the usual care group (3.5 MEU vs. 4.7 MEU, respectively; p ? 0.001) and lower total opioids through 60 min (5.3 MEU vs. 6.0 MEU; p = 0.03). No patient needed naloxone.Low-dose titration of intravenous hydromorphone in increments of 0.5 mg provides comparable analgesia to usual care with less opioid over 60 min.

Project description:Purpose:Opioid analgesics remain the cornerstone of treatment for severe trauma pain in the emergency setting, but there are barriers to their use. This post hoc analysis of a previously reported trial (MEDITA) investigated the efficacy and safety of low-dose methoxyflurane versus intravenous (IV) morphine for severe trauma pain. Patients and Methods:MEDITA was a Phase IIIb, randomized, active-controlled, parallel-group, open-label study in Italian pre-hospital units and emergency departments (EudraCT: 2017-001565-25; NCT03585374). Adult patients (N=272) with moderate-to-severe trauma pain (score ?4 on the Numerical Rating Scale [NRS]) were randomized 1:1 to inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1g or ketoprofen 100mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ?7]). Analyses were performed for the severe pain subgroup. The primary efficacy variable was the overall change from baseline in visual analog scale (VAS) pain intensity at 3, 5 and 10min post-randomization. Non-inferiority of methoxyflurane versus morphine was concluded if the upper 95% confidence interval (CI) for the treatment difference was <1; superiority was concluded if the upper 95% CI was <0. Results:Ninety-three patients (methoxyflurane: 49; SAT: 44) were included in the severe pain intention-to-treat population. The reduction in VAS pain intensity over the first 10min was superior for methoxyflurane versus morphine (adjusted mean treatment difference: -5.54mm; 95% CI: -10.49, -0.59mm; p=0.029). Median time to onset of pain relief was 9min for methoxyflurane and 15min for morphine. Patients rated treatment efficacy and physicians rated treatment practicality "Excellent" or "Very good" for more methoxyflurane-treated patients (42.8% and 67.3%) than morphine-treated patients (18.1% and 22.8%). Adverse events, all non-serious, were reported in 20.4% of methoxyflurane-treated patients and in 4.8% of morphine-treated patients. Conclusion:Methoxyflurane provided superior short-term pain relief to IV morphine in patients with severe trauma pain and offers an effective non-narcotic treatment option.

Project description:STUDY OBJECTIVE:We compare the efficacy and safety of intravenous lidocaine with that of hydromorphone for the treatment of acute abdominal pain in the emergency department (ED). METHODS:This was a randomized, double-blind, clinical trial conducted in 2 EDs in the Bronx, NY. Adults weighing 60 to 120 kg were randomized to receive 120 mg of intravenous lidocaine or 1 mg of intravenous hydromorphone. Thirty minutes after administration of the first dose of the study drug, participants were asked whether they needed a second dose of the investigational medication to which they were randomized. Patients were also stratified according to clinical suspicion of nephrolithiasis. The primary outcome was improvement in pain scores of 0 to 10 between baseline and 90 minutes. An important secondary outcome was need for "off-protocol" parenteral analgesics, including opioids and nonsteroidal anti-inflammatory drugs. RESULTS:We enrolled 154 patients, of whom 77 received lidocaine and 77 received hydromorphone. By 90 minutes, patients randomized to lidocaine improved by a mean of 3.8 points on the 0-to-10 scale, whereas those randomized to hydromorphone improved by a mean of 5.0 points (mean difference 1.2; 95% confidence interval 0.3 to 2.2). Need for off-protocol "rescue" analgesics occurred for 39 of 77 lidocaine patients (51%) and 20 of 77 hydromorphone patients (26%) (difference 25%; 95% confidence interval 10% to 40%). Adverse events were comparable between groups. Among the subset of 22 patients with nephrolithiasis, lidocaine patients reported a mean improvement of 3.4 points on the pain scale, whereas hydromorphone patients reported a mean improvement of 6.4 points (mean difference 3.0; 95% confidence interval 0.5 to 5.5). CONCLUSION:Intravenous hydromorphone was superior to intravenous lidocaine both for general abdominal pain and a subset of patients with nephrolithiasis. A majority of patients randomly allocated to lidocaine required additional analgesics.

Dataset Information

Nebulized versus intravenous morphine titration for the initial treatment of severe acute pain in the emergency department: study protocol for a multicenter, prospective randomized and controlled trial, CLIN-AEROMORPH.

Publications

Nebulized versus intravenous morphine titration for the initial treatment of severe acute pain in the emergency department: study protocol for a multicenter, prospective randomized and controlled trial, CLIN-AEROMORPH.

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