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.

Keywords: Analgesia; Morphine; Nebulized; Pain; Randomised controlled trial; Single blind.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol and patient-informed consent procedures received Ethics Committee approval (SUD-MEDITERRANEE1 approval number 17 32) on 17 May 2017 prior to registration (reference number 2014/009/HP).

Authorization for this protocol has also been granted by the ANSM (French Competent Authority) (art. L 1123-8 of French Public Health Code). Thanks to these two centralized procedures, this study has gained ethical approval at both central and local levels for all centers participating in the study. Any modifications to the protocol that may impact the conduct of the study, potential benefit to the patient, or that may affect patient safety will require a formal amendment to the protocol and new approval from the Ethics Committee according to local regulations and a request for authorization by the ANSM (art. L 1123-9). Approval by these two institutional committees is also required for new center recruiting.

Information has been provided to the directors and pharmacists of centers participating in the study before the research began (art. L 1123-13 of French Public Health Code).

Competing interests

The authors declare that they have no competing interests.

However, the authors VEL and NL disclose that they have individually received occasional travel grants for participation in national and international congresses from Mundipharma.

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Figures

Fig. 1

CLIN-AEROMORPH study flow chart

Fig. 2

Study design

Fig. 3

Monitoring sheet

Fig. 4

Schedule of enrollment, interventions, and assessments