Inhaled vs IV Opioid Dosing for the Initial Treatment of Severe Acute Pain in the Emergency Department

Study Overview
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Brief Summary
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Prospective single-blind, multicenter, national, randomized, controlled trial in 15 Emergency Department to compare two ways of morphine titration. The eligible patient is included immediately after his arrival in the Emergency Department, after being questioned by the triage nurse about the presence and the intensity of pain, when the VAS is greater than 70 (or EN>7) and after written consent. After installation into the examination room, patient is randomized in one of two parallel groups (stratified by sex and center using software) and receives one of the two treatments, either inhaled morphine + IV placebo or IV morphine+ inhaled placebo (control group). In both groups, titration is defined by a dose of repeated boluses as long as the relief is not achieved (VAS> 30 or EN >3) and the criteria to stop titration are not met. A 5 minutes time interval between the boluses is chosen. Each aerosol takes 5 minutes at a constant air flow, aerosol mask, plastic tubing and PVC transparent tank are used. Thus patient receives a maximum of 3 aerosol (one aerosol every 10 minutes) and a maximum of 6 IV injections (one injection every 5 minutes) The stopping criteria, except pain relief, are linked to the occurrence of side effects and specific cares are described into the protocol (in case of severe ventilatory depression naloxone titration is provided). Exit criteria from the emergency room and from the hospital are defined. An information sheet is delivered.

Official Title
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Inhaled Versus Intravenous Opioid Dosing for the Initial Treatment of Severe Acute Pain in the Emergency Department

Conditions
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Pain, Acute, Emergencies, Morphine

Intervention / Treatment
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* Drug: inhaled titration of morphine chlorhydrate
* Drug: IV placebo
* Device: Inhaled placebo
* Drug: IV titration of morphine chlorhydrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and <75 years old; EVA ≥ 70/100 or EN ≥ 7/10; Patient who received clear information from the investigator and read and signed the consent form; Patient affiliated with, or beneficiary of a social security category; For women: O of childbearing age: effective contraception (oral contraception, intrauterine device or use of condoms) O menopausal status (amenorrhoea less than 12 months before the inclusion visit) O objectivized sterility (diagnosis or surgically) Exclusion Criteria: Chronic pain (> 3 months) Taking opioids longer than 10 days (including weak opioids tramadol and / or codeine); Taking Rifampicin; Impaired ability to discern, cognitive impairment; Morphine-related contraindications: O Obstructive chronic obstructive or restrictive respiratory failure known or suspected compensated or not, O Hypersensitivity to the active substance or to any of the excipients, O Severe hepatocellular insufficiency (known or suspected), O Chronic renal failure known or suspected, O Uncontrolled epilepsy, O Cranial trauma (intracranial hypertension), O Associations with buprenorphine, nalbuphine, pentazocine and naltrexone Active drug history or practice (s); Evidence of reduced fracture or dislocation in emergency rooms; Suspected occlusive syndrome SaO2 <95%; FR <12 / min; Glasgow <15 or other alertness disorders; HR heart rate <50 bpm and / or Auriculo-Ventricular block (PR XML File Identifier: zR6XOYKSEQ9GjQHghP8c465EwF0= Page 15/30 interval> 200 ms); Arterial hypotension with systolic blood pressure TA syst <100 mm Hg; Pregnant or nursing Persons deprived of their liberty by an administrative or judicial decision, a person placed under the safeguard of justice, guardianship; Patients with poor comprehension of spoken or written French; Patients participating in another interventional clinical study; Contra-indication related to the use of saline solution Contra-indications related to the use of aerosol: O Necessity to access the face O Allergy known to plastic

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: inhaled morphine + IV placebo<br>Arm A: inhaled titration of morphine chlorhydrate+ IV placebo | Drug: inhaled titration of morphine chlorhydrate<br>* Patient in arm A will receive 1 to 3 titration<br>* Other names: IV placebo;Drug: IV placebo<br>* Patient in arm A will receive 1 to 6 injection<br>* Other names: inhaled titration of morphine chlorhydrate;|
| Placebo Comparator: IV morphine +inhaled placebo<br>Arm B:IV titration of morphine chlorhydrate + inhaled placebo | Device: Inhaled placebo<br>* Patient in arm B will receive 1 to 3 titration<br>* Other names: IV titration of morphine chlorhydrate;Drug: IV titration of morphine chlorhydrate<br>* Patient in arm BA will receive 1 to 6 injection<br>* Other names: Inhaled placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of relief obtained or success rate at 1 hour from the start of drug administration, and not at the end of titration, such as EVA1 ≤ 30/100 (or EN1 ≤ 3/10). | Rate of relief obtained or success rate at 1 hour from the start of drug administration, and not at the end of titration, such as EVA1 ≤ 30/100 (or EN1 ≤ 3/10). | 1 hour after the initiation of the titration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate antalgic efficacy criteria | Quantity of morphine administered from the beginning of the titration until the end of the titration | From the beginning of the titration until the end of the titration- assessed within one day | 
| Evaluate antalgic efficacy criteria | Delay between first administration of Morphine and EVA ≤ 30 or EN ≤ 3 obtained | From the beginning of the titration until the end of the titration- assessed up to one day | 
| Evaluate antalgic efficacy criteria | Delay between first administration of Morphine and EVA ≤ 30 or EN ≤ 3 obtained for patient treated only with morphine IV | From the beginning of the titration until the end of the titration- assessed up to one day | 
| Evaluate antalgic efficacy criteria | Number of patients with EVA ≤ 30 or EN ≤ 3 at the end of titration | From the beginning of the titration until the end of the titration- assessed up to one day | 
| Evaluate antalgic efficacy criteria | Number of patients with EVA ≤ 30 or EN ≤ 3 at 30 minutes | 30 minutes after the initiation of the titration | 
| Evaluate antalgic efficacy criteria | Number of patients treated only by exclusive inhalation titration with EVA ≤ 30 or EN ≤ 3 | From the beginning of the titration until the end of the titration- assessed up to one day | 
| Evaluate antalgic efficacy criteria | Quantity of of co-analgesia administered from the beginning of the titration | From the beginning of the titration until the end of the titration- assessed up to one day | 
| Evaluate antalgic efficacy criteria | Number of patients with EVA ≤ 30 or EN ≤ 3 after 60 minutes | 1hour after the initiation of the titration | 
| Evaluate antalgic efficacy criteria | Number of patients with EVA ≤ 30 or EN ≤ 3 after 120 minutes | 2hours after the initiation of the titration | 
| Assess the feasibility of an aerosol titration (compliance to the protocol) | Number of deviations from protocol | From the beginning of the titration until the end of the aerosol titration- within one hour after the start of the titration | 
| Safety-Proportion of Sleepy patients (Ramsay score = 3) (adverse events) | Proportion of Sleepy patients (Ramsay score = 3) | Until 3hours after the end of the titration | 
| Safety- incidence of minor side effects in each arm of which neurovegetative usually known and related to opiates (nausea, vomiting, urine retention, ...) | incidence of minor side effects in each arm of which neurovegetative usually known and related to opiates (nausea, vomiting, urine retention, ...) | Until 3hours after the end of the titration | 
| Safety- Proportion of serious adverse events in each arm | Proportion of serious adverse events in each arm | Until 3hours after the end of the titration |