Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing (POLO)
Primary Purpose
Opioid-induced Respiratory Depression
Status
Recruiting
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Pregabalin 150mg
Oxycodone 10mg
Lacosamide 150 mg
Sponsored by
About this trial
This is an interventional prevention trial for Opioid-induced Respiratory Depression focused on measuring Oxycodone, Pregabalin, Lacosamide
Eligibility Criteria
Inclusion Criteria:
- aged 18-45 years,
- body mass index < 30 kg.m-2,
- able to understand the written informed consent form,
- able to communicate with the staff,
- able and willing to complete the study procedures,
- signed the informed consent form.
Exclusion Criteria:
- Presence or history of any medical or psychiatric disease (incl. a history of substance abuse, anxiety, or the presence of a painful syndrome such as fibromyalgia);
- Use of any medication in the three months prior to the study which may influence the outcome of the study as judged by the investigator;
- Use of more than 21 alcohol units per week;
- A positive urinary drug test or a breath alcohol test at screening or on the morning of the experiment;
- Pregnancy, lactating or a positive pregnancy test on the morning of the experiment;
- Participation in another drug trial in the 60 days prior to dosing.
Sites / Locations
- Leiden University Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Other
Arm Label
Oxycodone + Pregabalin
Oxycodone + Lacosamide
Oxycodone
Arm Description
Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg pregabaline capsule.
Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg Lacosamide capsule.
Amendment: one open label arm. In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone as a visit 3 was added.
Outcomes
Primary Outcome Measures
Ventilation
The primary endpoint of the study is the change in ventilation at an increased level of CO2
Ventilation
The primary endpoint of the study is the change in ventilation at an increased level of CO2
Secondary Outcome Measures
Level of sedation
The subjects will be queried using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect), every hour after dosing up to 8h
Pain relief
The relief of pain is measured using a painful stimulus (eg pressure pain)
Occurence of nausea/vomiting
The subjects will be queried using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect).
pupil diameter
Measurement of pupil diameter following drug intake.
Baseline ventilation
Minute ventilation in L/min prior to increasing inhaled CO2.
Full Information
NCT ID
NCT05598905
First Posted
October 13, 2022
Last Updated
August 9, 2023
Sponsor
Leiden University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT05598905
Brief Title
Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing
Acronym
POLO
Official Title
Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing: an Exploratory Study in Healthy Volunteers (The Polo Study)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 10, 2022 (Actual)
Primary Completion Date
October 3, 2023 (Anticipated)
Study Completion Date
December 3, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Opioids are commonly prescribed for moderate to severe pain. While initially intended for moderate to severe acute and cancer pain, opioids are currently frequently considered and prescribed in chronic noncancer pain. Due to the large increase in opioid prescription rate, the number of unintentional drug overdoses is rapidly increasing, not only in the Unites States but also in the Netherlands. A potential lethal consequence of an opioid overdose is opioid-induced respiratory depression. Additionally, it is well known that opioids are often used (and abused) in combination with other legal or illicit substances, for example alcohol, benzodiazepines, cannabis, neuropathic pain medication including the anticonvulsant pregabaline. There are no high-quality data on the interaction between oxycodone and (neuropathic pain) medication on the ventilatory control system. Case reports and randomized studies show that pregabalin induces respiratory depression when combined with opioids. Some alternatives to pregabalin may have a better safety profile. One such alternative is lacosamide, an antiepileptic with a different mode of action than pregabalin, and effective in the treatment of neuropathic pain. The hypothesis is that in contrast to lacosamide, pregabalin will increase the respiratory depressant effect of low-dose oxycodone.
The objective of the study is to quantify the effect of pregabalin and lacosamide on oxycodone-induced respiratory depression.
24 participants will be screened beforehand if subjects meet the inclusion and exclusion criteria. If so, the subjects will visit the hospital twice. On both occasions, participants will take a 10 mg oxycodone tablet and 90 minutes after a capsule of pregabalin or lacosamide. The order of visits will be randomized. During the visits, at set time points the hypercapnic ventilatory response will be measured, relief of nociception, pupil diameter and several side effects other than respiratory depression. There will be a washout period of 7 days between study visits with the study ending after 2 visits.
Amendment:
In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone was added as a visit 3. Since the procedures in this third arm will be identical to the two blinded arms, no changes will be made to any of the procedures apart from not administering any lacosamide or pregabalin.
Detailed Description
Opioids are commonly prescribed for moderate to severe pain. While initially intended for moderate to severe acute and cancer pain, opioids are currently frequently considered and prescribed in chronic noncancer pain. Due to the large increase in opioid prescription rate, the number of unintentional drug overdoses is rapidly increasing, not only in the Unites States but also in the Netherlands. A potential lethal consequence of an opioid overdose is opioid-induced respiratory depression. Additionally, it is well known that opioids are often used (and abused) in combination with other legal or illicit substances, for example alcohol, benzodiazepines, cannabis, neuropathic pain medication including the anticonvulsant pregabalin. There are no high-quality data on the interaction between oxycodone and (neuropathic pain) medication on the ventilatory control system. Case reports and randomized studies show that pregabalin induces respiratory depression when combined with opioids. Some alternatives to pregabalin may have a better safety profile. One such alternative is lacosamide, an antiepileptic with a different mode of action than pregabalin, and effective in the treatment of neuropathic pain. The hypothesis is that in contrast to lacosamide, pregabalin will increase the respiratory depressant effect of low-dose oxycodone.
The objective of the study is to quantify the effect of pregabalin and lacosamide on oxycodone-induced respiratory depression.
24 participants will be screened beforehand if the subject meets the inclusion and exclusion criteria. If so, the subjects will visit the hospital twice. On both occasions, participants will be sober and take a 10 mg oxycodone tablet and 90 minutes after a capsule of pregabalin or lacosamide. The order of visits will be randomized using a randomisation list made in R by an independent investigator not involved in data acquisition. Upon arrival in the laboratory, a urinary drug test and breath alcohol test will be performed. When these tests are positive, the subject is excluded from further participation. An intravenous access line will be placed in the left or right arm/hand for fluid administration (NaCl/Glucose 50-100 ml/h). Next, the first hypercapnic ventilatory responses (HCVR) will be obtained (t = -30 min). This is the pre-dug baseline measurement. At t = 0, the subjects will next receive a 10 mg oxycodone immediate release tablet that the subjects will swallow with 100 mL water. Next, the HCVRs at 1-hour intervals will be obtained until 8 hours after oxycodone intake. At t = 90 min the subject will ingest a pregabalin or lacosamide tablet (150 mg). At set time points the hypercapnic ventilatory response will be measured, relief of nociception, pupil diameter and several side effects other than respiratory depression such as sedation, nausea and vomiting. There will be a washout period of 7 days between study visits with the study ending after 2 visits.
Breathing tests: Breathing tests are so-called rebreathing tests in which subjects inhale 7% CO2 in oxygen from a 4-6 L rebreathing bag. By rebreathing carbon dioxide for 3-5 minutes the hypercapnic ventilatory response will be obtained. Ventilation will be measured via the pneumotachograph system.
Electrical pain test: A locally designed and manufactured transcutaneous electrical stimulation device is used to create a constant current electrical stimulus train (stimulation at 20 Hz, pulse duration 0.2 ms). The device is attached to two surface electrodes that are applied on the skin over the tibial bone of the non-dominant side. The current over the electrodes is increased from 0 mA at a rate of 0.5 mA/s, to a maximum of 128 mA. The subjects are instructed to indicate when the stimulation becomes painful (electrical pain threshold, EPTh) by pressing a button on a control box. By pressing a second button, the subjects will end the stimulus train when the pain is perceived as intolerable (electrical pain tolerance, EPTol).
Pressure pain test: a pressure pain stimulus will be applied on the skin area (1 cm2) between thumb and index finger, by using the Wagner Instruments FDN 200 Algometer. Subjects will indicate when the pressure stimulus becomes painful (pain threshold) after which the stimulus is stopped. The pressure necessary to induce pain will be recorded. The pressure pain test will follow the electrical pain test by 5-10 min.
Questionnaires: the subjects will be queried using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect), for sedation, nausea and vomiting. Additionally, the occurrences of vomiting will be counted.
Pupil diameter: At 30-min intervals, the pupil diameter will be measured using a handheld pupillometer (Neuroptics PLR-3000 pupillometer).
Amendment:
In the study, the effect of two drugs are compared, lacosamide and pregabalin, on top of 10 mg oxycodone, on the ventilatory control system. In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone was added. The reason for this is many-fold:
It will give an indication of the effect of 10 mg oxycodone on the hypercapnic ventilatory response;
It will allow an indication of any difference in effect relative to oxycodone + lacosamide and oxycodone + pregabalin. Note that a formal statistical analysis between just oxycodone and oxycodone + lacosamide or oxycodone + pregabalin will not be performed. The just oxycodone data will be presented as mean ± 95% confidence interval and there will be visually determined whether the mean data from oxycodone + lacosamide and oxycodone + pregabalin fall out of the confidence interval of just oxycodone;
Since the procedures in this third arm will be identical to the two blinded arms, there will be no change to any of the procedures apart from not administering any lacosamide or pregabalin. Hence, there are no other changes to the protocol than the addition of one additional open label arm.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Opioid-induced Respiratory Depression
Keywords
Oxycodone, Pregabalin, Lacosamide
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Double-blind, randomized cross-over design.
Amendment:
In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone as a visit 3 was added.
Masking
ParticipantInvestigator
Masking Description
Double-blind cross-over trial in which the order of visits is randomized.
Amendment:
In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone as a visit 3 was added.
Allocation
Randomized
Enrollment
24 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Oxycodone + Pregabalin
Arm Type
Experimental
Arm Description
Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg pregabaline capsule.
Arm Title
Oxycodone + Lacosamide
Arm Type
Experimental
Arm Description
Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg Lacosamide capsule.
Arm Title
Oxycodone
Arm Type
Other
Arm Description
Amendment:
one open label arm.
In order to get an impression of the effect of 10 mg oxycodone per se, one open label arm of just 10 mg oxycodone as a visit 3 was added.
Intervention Type
Drug
Intervention Name(s)
Pregabalin 150mg
Other Intervention Name(s)
Lyrica capsule 150 mg
Intervention Description
one capsule of 150mg 90 minutes after 10mg of oxycodone
Intervention Type
Drug
Intervention Name(s)
Oxycodone 10mg
Other Intervention Name(s)
Oxycodone tablet 10 mg
Intervention Description
one 10mg tablet
Intervention Type
Drug
Intervention Name(s)
Lacosamide 150 mg
Other Intervention Name(s)
Vimpat 150 mg capsule
Intervention Description
one capsule of 150mg 90 minutes after 10mg of oxycodone
Primary Outcome Measure Information:
Title
Ventilation
Description
The primary endpoint of the study is the change in ventilation at an increased level of CO2
Time Frame
Study day 1
Title
Ventilation
Description
The primary endpoint of the study is the change in ventilation at an increased level of CO2
Time Frame
Study day 2
Secondary Outcome Measure Information:
Title
Level of sedation
Description
The subjects will be queried using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect), every hour after dosing up to 8h
Time Frame
Study day 1
Title
Pain relief
Description
The relief of pain is measured using a painful stimulus (eg pressure pain)
Time Frame
Study day 1
Title
Occurence of nausea/vomiting
Description
The subjects will be queried using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect).
Time Frame
Study day 1
Title
pupil diameter
Description
Measurement of pupil diameter following drug intake.
Time Frame
Study day 1
Title
Baseline ventilation
Description
Minute ventilation in L/min prior to increasing inhaled CO2.
Time Frame
Study day 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
aged 18-45 years,
body mass index < 30 kg.m-2,
able to understand the written informed consent form,
able to communicate with the staff,
able and willing to complete the study procedures,
signed the informed consent form.
Exclusion Criteria:
Presence or history of any medical or psychiatric disease (incl. a history of substance abuse, anxiety, or the presence of a painful syndrome such as fibromyalgia);
Use of any medication in the three months prior to the study which may influence the outcome of the study as judged by the investigator;
Use of more than 21 alcohol units per week;
A positive urinary drug test or a breath alcohol test at screening or on the morning of the experiment;
Pregnancy, lactating or a positive pregnancy test on the morning of the experiment;
Participation in another drug trial in the 60 days prior to dosing.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tom Van Dasselaar, MD
Phone
+31 (0)715298151
Email
T.m.van_dasselaar@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Albert Dahan, MD PhD
Phone
+31715269111
Email
a.dahan@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marieke Niesters, MD, PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
State/Province
ZH
ZIP/Postal Code
2333 ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Albert Dahan, MD PhD
Phone
+31715269111
Email
a.dahan@lumc.nl
First Name & Middle Initial & Last Name & Degree
Monique van Velzen, PhD
Phone
+31715262301
Email
m.van_velzen@lumc.nl
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing
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