First Evaluation of Morphine Hydrochloride by Nebulisation in Healthy Volunteers

Acute pain relief in emergency setting is still a public health priority. Pain is the primary reason for emergency room use, but the situation of "oligo-analgesia" persists in all countries. Intravenous morphine titration has become the standard method for severe acute pain management in the emergency department, but it is still insufficiently implemented. Deviations from the recommended protocol are common: initial additional loading doses, unusually extended intervals between bolus, premature discontinuation. Several factors contribute to these difficulties: heaviness of its setting up, especially in overcrowding case, procedure rigidity, high consumption of nursing time. This method requires a systematic intravenously route, which has several inconvenients: algogenic procedures, coupled initial diagnostic venous sampling (delay for analgesia), excessive "medicalization" of ambulatory patients (risk of infection and less mobility in the emergency department). An alternative to reduce the analgesic latency in emergency department, without losing the benefits of tolerance and safety should be welcome. The inhaled route looks promising, but has yet not been enough evaluated in adults, and even less in the emergency room. Aerosol techniques change from one study to another (molecules, materials, doses, painful intensities included, judgment criteria and assessment times). A morphine titration by aerosol therapy could be an interesting alternative to the standard method disadvantages, using faster, painless and easier procedures, leading to "demedicalization".

To the need for stronger fundamentals, an additional study was designed in healthy volunteers. The objective is to compare the titration of intravenous morphine titration aerosol in moderate acute pain caused by electrostimulation.

To purchase this aim, we first need to determine accurately the smallest dose of effective and well tolerated inhaled morphine, to provide the "bolus" dose we have to repeat by titration, which is still currently unknown. This dose is called ED50, it's the effective dose for at least 50% of healthy volunteers relieved. ED50 for intravenous morphine is also needed to be established, unknown in this indication. The determination of these two parallel ED50 would allow a reliable conversion factor between the two routes of administration for morphine "bolus", which can then be tested in comparative titrations. To validate our induced pain model in healthy volunteers, we also have chosen to fix in these conditions the ED50 of fentanyl that the effective dose by nebulization is better known. This study would also describe the pharmacokinetics of inhaled morphine and its derivatives after a single spray.


Eligibility Criteria:
Inclusion Criteria:

* Sex: We choose to include 50% of men and 50% women (this covariate will be included in the parameters to balance the randomization list).
* Age: Healthy volunteers will be between 18 to 60 years
* Body mass index (BMI) between 19 and 29 kg / m²
* effective contraception methods in women of childbearing age
* Signature of informed consent
* Affiliation to a social security scheme

Exclusion Criteria:

* Taking painkillers long-term
* Taking psychotropic drugs long-term
* Healthy volunteers with chronic pain
* Drug addiction
* Chronic neuropsychiatric pathology which may alter the pain threshold
* Active Smoking
* Chronic obstructive or restrictive respiratory pathology
* Progressive known pathology (hypertension, kidney failure, heart, liver ...)
* Chronic treatments are prohibited except oral contraception
* Delirium or dementia, people who did not understand the pain scales
* Lack of understanding of the French language
* pregnancy and lactation
* Poor venous capital
* History of abnormal reaction at a local / regional anesthesia
* Heart rate : HR \<50 bpm
* Hypotension TAsyst with systolic blood pressure \<100 mm Hg
* Atrioventricular block (PR interval\> 200 ms)
* Period exclusion of another biomedical research
* Nobody placed under judicial protection, guardianship