Remifentanil in Adults With OSA (AROSA)

Opioid Sensitivity in Adults With Treated and Untreated Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) is the most common problem that affects sleep. People with this problem have their airway blocked or minimized, causing snoring or gasping while sleeping. It can also reduce the amount of oxygen that circulates in the blood of people affected by it. Millions of Americans have OSA; 10% of adults have diagnosed OSA, an estimated 25% have undiagnosed OSA. There is concern in the medical community about how to manage pain in patients with OSA because of the risk of decreased or slower breathing associated with certain pain medications called opioids. Giving OSA patients opioids could cause them to have even lower oxygen amounts in their blood stream. It is conceivable that patients with OSA may require lower doses of opioids to cause decreased breathing as compared to patients without OSA, however this has not been proven. In this study, we are using a very short acting and easily reversible opioid pain medication called remifentanil in patients with OSA in order to find out if treated and untreated OSA patients respond to opioid differently than patients without OSA.

Study Overview

• Status: Completed
• Conditions: Apnea, Sleep
• Intervention / Treatment: Drug: Targeted infusion of remifentanil

Detailed Description

Open-label, parallel group study. Twenty adults each with untreated OSA, CPAP-treated OSA, and no OSA will undergo a stepped-dose target-controlled opioid (remifentanil) infusion, measurement of opioid effects (miosis, respiratory rate, end-expired CO2, thermal analgesia) and plasma drug concentrations. Remifentanil clinical effects, pharmacodynamics (concentration-effect relationships), and pharmacokinetics will be compared between the three groups, as will relationships between effects and nighttime hypoxemia (assessed by home PSG).

The ultimate long-term goal for this research is to improve the perioperative care and pain management of patients with obstructive sleep apnea (OSA). While patients with OSA are believed to be more sensitive to the analgesic and adverse effects of opioids, there are no studies that assess the effects of the OSA gold-standard treatment, namely CPAP, on this purported sensitivity. Furthermore, OSA is a heterogeneous disease and not all patients who carry an OSA diagnosis are likely to have the same opioid sensitivity. At present no easily administered test is able to determine the degree of opioid sensitivity of an individual patient.

The specific goal of this research is to validate or refute, the untested yet "conventional wisdom" that adults with untreated OSA have increased sensitivity to the clinical effects of opioids, especially ventilatory depression. We will test the presumptive hypotheses that a) untreated OSA increases ventilatory, miotic, and analgesic effects of opioids, b) the magnitude of increase is proportional to the degree of nighttime hypoxia, and c) CPAP treatment of OSA normalizes altered opioid responses.

These hypotheses will be tested by evaluating the pharmacodynamics (concentration-effect relationship) of the prototype opioid remifentanil in patients with and without OSA using objective opioid sensitivity markers to determine if patients with OSA have increased sensitivity to opioids and to determine if treatment with CPAP alters this purported sensitivity. Our study drug, remifentanil, is an ultra-short acting μ-selective opioid agonist, which is the same receptor at which longer acting opioids such as morphine act. Since the site of action of remifentanil is the same as other opioids, the results of this study will be able to be generalized to other opioids, improving our clinical understanding and practice in this patient population. Opioid effects will be determined by the decrease in pupil diameter, which is the most sensitive measure of opioid effects at the drug concentrations and subanesthetic doses to be used. The degree to which changes in pupil diameter correlate with changes in respiratory rate will be compared.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University St Louis School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. 18 to 70 year-old males or non-pregnant females
2. Provide informed consent

Exclusion Criteria

1. History of liver disease
2. pregnant or nursing females
3. known history of addiction to drugs or alcohol
4. craniofacial anomalies that preclude proper fit of pupillometry goggles
5. eye abnormalities that preclude the measurement of pupil diameter
6. use of home oxygen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: targeted infusion of remifentanil untreated OSA; Stepped-dose, targeted infusion of remifentanil with measurement of miosis, respiratory rate, end-expired CO2, and thermal analgesia and plasma drug concentrations. Remifentanil dose will be based on ideal body weight.	Drug: Targeted infusion of remifentanil; Remifentanil dosing will be calculated using ideal body weight and infused to achieve brain concentrations of 0.5, 1, 2, 3, and 4 ng/ml; approximately 10 minutes at each concentration.; Other Names: Ultiva
Experimental: targeted infusion of remifentanil CPAP treated OSA; Stepped-dose, targeted infusion of remifentanil with measurement of miosis, respiratory rate, end-expired CO2, and thermal analgesia and plasma drug concentrations. Remifentanil dose will be based on ideal body weight.	Drug: Targeted infusion of remifentanil; Remifentanil dosing will be calculated using ideal body weight and infused to achieve brain concentrations of 0.5, 1, 2, 3, and 4 ng/ml; approximately 10 minutes at each concentration.; Other Names: Ultiva
Experimental: targeted infusion of remifentanil No OSA; Stepped-dose, targeted infusion of remifentanil with measurement of miosis, respiratory rate, end-expired CO2, and thermal analgesia and plasma drug concentrations. Remifentanil dose will be based on ideal body weight.	Drug: Targeted infusion of remifentanil; Remifentanil dosing will be calculated using ideal body weight and infused to achieve brain concentrations of 0.5, 1, 2, 3, and 4 ng/ml; approximately 10 minutes at each concentration.; Other Names: Ultiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The relationship between remifentanil concentration and miotic effect	Baseline, 10, 20, 30, 40, and 50 minutes for each concentration

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Evan Kharasch, MD, PhD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2016
• Primary Completion (Actual): May 2, 2018
• Study Completion (Actual): May 2, 2018

Study Registration Dates

• First Submitted: September 8, 2016
• First Submitted That Met QC Criteria: September 12, 2016
• First Posted (Estimate): September 13, 2016

Study Record Updates

• Last Update Posted (Actual): October 4, 2018
• Last Update Submitted That Met QC Criteria: October 2, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: sensitivity, opioid
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Remifentanil
• Other Study ID Numbers: 201605158

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO