Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing (POLO)

Combined Effect of Pregabalin and Oxycodone, and Lacosamide and Oxycodone, on Breathing: an Exploratory Study in Healthy Volunteers (The Polo Study)

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.

Study Overview

• Status: Completed
• Conditions: Opioid-induced Respiratory Depression
• Intervention / Treatment: Drug: Pregabalin 150mg; Drug: Oxycodone 10mg; Drug: Lacosamide 150 mg

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:

1. It will give an indication of the effect of 10 mg oxycodone on the hypercapnic ventilatory response;
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • ZH
    • Leiden, ZH, Netherlands, 2333 ZA
      • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxycodone + Pregabalin; Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg pregabaline capsule.	Drug: Pregabalin 150mg; one capsule of 150mg 90 minutes after 10mg of oxycodone; Other Names: Lyrica capsule 150 mg; Drug: Oxycodone 10mg; one 10mg tablet; Other Names: Oxycodone tablet 10 mg
Experimental: Oxycodone + Lacosamide; Participants will visit twice. On one visit they will take a 10mg oxycodone tablet and 90 minutes later a 150mg Lacosamide capsule.	Drug: Oxycodone 10mg; one 10mg tablet; Other Names: Oxycodone tablet 10 mg; Drug: Lacosamide 150 mg; one capsule of 150mg 90 minutes after 10mg of oxycodone; Other Names: Vimpat 150 mg capsule
Other: Oxycodone; 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.	Drug: Oxycodone 10mg; one 10mg tablet; Other Names: Oxycodone tablet 10 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilation	The primary endpoint of the study is the change in ventilation at an increased level of CO2	Study day 1
Ventilation	The primary endpoint of the study is the change in ventilation at an increased level of CO2	Study day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain relief	The relief of pain is measured using a painful stimulus (eg pressure pain)	Study day 1
pupil diameter	Measurement of pupil diameter following drug intake.	Study day 1
Baseline ventilation	Minute ventilation in L/min prior to increasing inhaled CO2.	Study day 1
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	Study day 1
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).	Study day 1

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Marieke Niesters, MD, PhD, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2022
• Primary Completion (Actual): January 12, 2024
• Study Completion (Actual): January 12, 2024

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 27, 2022
• First Posted (Actual): October 28, 2022

Study Record Updates

• Last Update Posted (Actual): June 4, 2024
• Last Update Submitted That Met QC Criteria: June 3, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Pregabalin; Lacosamide; Oxycodone
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pregabalin; Lacosamide; Oxycodone
• Other Study ID Numbers: P22.044

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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