Opioid Effects on Swallowing and Esophageal Sphincter Pressure

Can Opioid Induced Effects on Esophageal Motility and Lower Esophageal Sphincter be Counteracted by a Dopamine Receptor Antagonist?

The purpose of this study is to determine whether a dopamine receptor antagonist metoclopramide can counteract opioid induced effects on esophageal motility and lower esophageal sphincter. The aim of this study is also to evaluate if the opioid antagonist naloxone reduces the opioid induced pharyngeal and esophageal dysfunction.

Opioids induce pharyngeal and esophageal dysfunction and reduce the lower esophageal sphincter (LES) pressure, and thereby decreases the barrier pressure between the stomach and esophagus. This contributes to an increased risk of regurgitation and aspiration during anaesthesia induction and in the postoperative period, when the patient is treated with opioids for pain relief. The effect of opioid antagonists on the opioid induced pharyngeal dysfunction and lower esophageal sphincter pressure are unknown. In a recently performed clinical trial we found that the peripheral opioid antagonist methylnaltrexone didn't have effect on the pharyngeal induced pharyngeal and esophageal dysfunction.This indicates that the negative opioid induced effects are not peripherally induced or mediated via peripheral opioid receptors. In previously performed studies most of the volunteers reported swallowing problems when receiving infusion of the opioid remifentanil, we have also found that remifentanil abolished spontaneous esophageal motility. The purpose of the study is to evaluate if opioid induced effects on the lower esophageal sphincter can be counteracted by a dopamine receptor antagonist, metoclopramide. It is previously known that dopamine, a catecholamine neurotransmitter, decreases the lower esophageal sphincter pressure and that a dopamine antagonist has the ability to increase the pressure. Further in this study we want to evaluate if the opioid antagonist naloxone, which affects both peripheral and central opioid receptors, reduces the opioid induced pharyngeal and esophageal dysfunction. A third aim of the study is to evaluate if the previously reported swallowing difficulties during infusion of opioid remifentanil are dose related, consequently does a higher concentration of opioids increase the swallowing difficulties. The pharyngeal and esophageal motility/function can be registered in an easy and objective way with the high resolution manometry, ManoScan 360. ManoScan 360 is an equipment with 36 sensors at 1 cm spacing with 12 tip transducers at every sensor. The 36 closely spaced sensors automatically capture all relevant motor function from the pharynx to the stomach. The system collects reliable and consistent data records with improved diagnostic accuracy, and the data are analyzed using ManoView analyzes software. ManoScan 360 has a CE mark approval and has been used at Örebro University Hospital during the last three years.

Lower esophageal sphincter pressure, Esophageal motility, Remifentanil, Metoclopramide, Naloxone, High resolution solid state manometry

Injection fluid, solution 0,4 mg/kg Bolus infusion 6ug/kg at one occasion Continuous infusion 0,1 ug/kg/minute during 50 min

Powder for injection/ infusion fluid solution, 2 mg Infusion TCI 1ng/kg 10 min ( 0,05 ug/kg/min) Infusion TCI 2ng/kg 10 min ( 0.10 ug/kg/min) Infusion TCI 3ng/kg 20 min ( 0,15 ug/kg/min)

The volunteers will be asked to do dry swallowing and assess the swallowing difficulty on the basis of following criteria: no difficulties, mild, moderate or severe difficulties.

Inclusion Criteria: 18 - 40 year old healthy volunteers from both sexes. Have signed and dated Informed Consent. Willing and able to comply with the protocol for the duration of the trial. Exclusion Criteria: Anamnesis of pharyngoesophageal dysfunction Known history of cardiac, pulmonary or neurological disease Ongoing medication Allergies to or history of reaction to naloxone, remifentanil, fentanyl analogues or metoclopramide Pregnancy or breast feeding BMI > 30 Previous participation in a medical clinical trial where opioid has been used or have during last 30 days participated in any other medicinal clinical trial or in a trial where follow-up in not completed.