Opioid-Induced Swallowing Dysfunction - The Impact of Bolus Volume

Opioid-Induced Swallowing Dysfunction - The Impact of Bolus Volume: a Randomized, Double-Blind Study in Healthy Volunteers

The purpose of the study is to evaluate the impact of different bolus volumes and viscosity on remifentanil-induced swallowing dysfunction in healthy volunteers.Hence, whether swallowing tasks can be done safer during sedation by altering bolus volumes and viscosities will be revealed. Furthermore, the study will clarify underlying mechanisms (central vs. peripheral effects) of remifentanil-induced swallowing dysfunction. If methylnaltrexone reverses the remifentanil-induced effects on swallowing, this would suggest a dominant peripherally mediated mechanism.

Study Overview

• Status: Unknown
• Conditions: Pharyngeal Dysfunction; Pharyngeal Swallowing
• Intervention / Treatment: Drug: RemifentanilMNTX; Drug: PlaceboMNTX

Detailed Description

Monitored anesthesia care (MAC) is commonly applied in modern perioperative care and means that minor surgical procedures are accomplished in awake patients using local anesthesia and light sedation. MAC has many advantages compared to general anesthesia; the recovery time after anesthesia is shorter and risk for postoperative nausea is lower to mention some. However, the patient is spontaneously breathing and the airway is not protected by an endotracheal tube which potentially increases risk of pulmonary aspiration. Pulmonary aspiration, that is inhalation of stomach and/or pharyngeal contents into the lungs, is a severe anesthesia-related complication and can in worst case lead to pneumonia and even death. Intact swallowing function is crucial in avoiding aspiration and how sedatives and analgesic agents used during MAC influence swallowing function is not fully understood.

Pharyngeal function during bolus swallowing is measured by combined high resolution impedance manometry (HRIM). The HRIM catheter is inserted through the nose in such a way that sensors straddle the entire pharynx and esophagus with the distal catheter tip in the stomach. Dynamic pressure changes and flow can be detected during swallowing and data registered by HRIM are analysed using purpose-designed software, AIM analysis (automated impedance manometry analysis). AIM analysis derives pressure flow variables which describe different physiological events like bolus timing and bolus distension in the pharynx and the esophagus during swallowing. A Swallow Risk Index value, quantifying risk of deglutitive aspiration, can also be defined.

The aim of the study is to evaluate impact of different bolus volumes on remifentanil-induced swallowing dysfunction in healthy volunteers. The study will clarify underlying mechanisms (central vs. peripheral effects) of remifentanil-induced swallowing dysfunction. Furthermore, whether swallowing tasks can be done safer during sedation by altering bolus volumes will be revealed. In addition to bolus volume, different bolus viscosities will be tested. It is shown that higher bolus viscosity diminishes misdirected swallows in dysphagic patients and higher bolus viscosity may possibly counteracts the swallowing dysfunction induced by remifentanil. Moreover, if MNTX reverses the remifentanil-induced effects on swallowing, then this would suggest a dominant peripherally mediated mechanism. Our aim is also to evaluate impact of remifentanil exposure on esophageal motility and impact of methylnaltrexone alone on swallowing function.

20 healthy volunteers will be studied on two different occasions approximately one week apart. In a randomized order volunteers will receive intravenous infusion of remifentanil and an intravenous injection of MNTX on one occasion, and placebo (normal saline) infusion and an intravenous injection of MNTX on the other occasion. Blood samples are obtained for plasma concentration determination of the study drug and sedation levels are assessed during study drug exposure.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Johanna Savilampi, MD, PhD; Phone Number: +46196020266; Email: johanna.savilampi@regionorebrolan.se

Study Locations

• Sweden
  • Örebro, Sweden, 70185
    • Recruiting
    • Department of Anaesthesiology and Intensive Care, Örebro University Hospital
    • Contact: Johanna Savilampi, Phd; Email: johanna.savilampi@regionorebrolan.se
    • Contact: Per Cajander, MD; Email: per.cajander@regionorebrolan.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ≥ 18 - ≤ 40 year old healthy volunteers from both sexes.
2. Have signed and dated Informed Consent.
3. Willing and able to comply with the protocol for the duration of the trial.

Exclusion Criteria:

1. Anamnesis of pharyngoesophageal dysfunction.
2. Known or history of gastrointestinal, severe cardiac, pulmonary or neurological disease
3. Ongoing medication that may affect upper gastrointestinal tract, larynx or lower airway.
4. Allergies to or history of reaction to remifentanil, fentanyl analogues or dexmedetomidine.
5. Pregnancy or breast feeding
6. BMI > 30
7. Smoking
8. Previous participation in a medicinal clinical trial during the last year where an opioid has been used or have during the last 30 days participated in any other medicinal clinical trial or in a trial where follow-up is not completed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RemifentanilMNTX; Volunteers are given an intravenous infusion with remifentanil, with an effect-site target concentration of 3 ng/ml via a target-controlled infusion (TCI) pump. After a series of swallowing tests an intravenous injection of methylnaltrexone of 0,3 mg/kg is given.	Drug: RemifentanilMNTX; Remifentanil infusion TCI 3 ng/ml, Methylnaltrexone injection 0.3 mg/kg; Other Names: Ultiva; Relistor; Remifentanil; Methylnaltrexone
Active Comparator: PlaceboMNTX; Volunteers are given an intravenous infusion with saline 0,9%. After a series of swallowing tests an intravenous injection of methylnaltrexone of 0,3 mg/kg is given.	Drug: PlaceboMNTX; Placebo (NaCl 0.9%) TCI infusion, Methylnaltrexone injection 0.3 mg/kg; Other Names: Sodium Chloride 0.9%; Relistor; Methylnaltrexone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pressure Flow pharyngeal variables, 10 ml vs 20 ml bolus	Difference in pharyngeal pressure flow variables during remifentanil exposure between bolus volumes of 10 ml and 20 ml compared to placebo.	Up to 60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pressure Flow pharyngeal variables, liquid vs semisolid bolus	Difference in pharyngeal pressure flow variables during remifentanil exposure between liquid and semisolid boluses compared to placebo	Up to 60 minutes
Pressure Flow pharyngeal variables, remifentanil before vs after methylnaltrexone	Difference in pharyngeal pressure flow variables during remifentanil exposure before and after methylnaltrexone administration compared to placebo.	Up to 60 minutes
Pressure Flow pharyngeal variables, placebo before vs after methylnaltrexone	Difference in pharyngeal pressure flow variables during placebo infusion before and after methylnaltrexone administration.	Up to 60 minutes
Pressure Flow esophageal motility variables, 10 ml vs 20 ml bolus	Difference in variables of esophageal motility between different bolus volumes during remifentanil exposure compared to placebo.	Up to 60 minutes
Pressure Flow esophageal motility variables, liquid vs semisolid bolus	Difference in variables of esophageal motility between liquid and semisolid boluses during remifentanil exposure compared to placebo.	Up to 60 minutes
Pressure Flow esophageal motility variables, remifentanil before vs after methylnaltrexone	Difference in variables of esophageal motility during remifentanil exposure before and after methylnaltrexone administration compared to placebo.	Up to 60 minutes
Pressure Flow esophageal motility variables, placebo before vs after methylnaltrexone	Difference in variables of esophageal motility during placebo infusion before and after methylnaltrexone administration.	Up to 60 minutes

Collaborators and Investigators

• Sponsor: Region Örebro County
• Investigators: Principal Investigator: Johanna Savilampi, MD, PhD, University Hospital in Örebro

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2017
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2018

Study Registration Dates

• First Submitted: September 12, 2017
• First Submitted That Met QC Criteria: September 12, 2017
• First Posted (Actual): September 14, 2017

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: December 11, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Remifentanil; Methylnaltrexone; Pharyngeal dysfunction; Anesthetic sedation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Alcohol Deterrents; Remifentanil; Naltrexone; Methylnaltrexone
• Other Study ID Numbers: JS006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No