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 investigators hypothesize 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, the investigators will perform a urinary drug test and breath alcohol test. 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 investigators will obtain HCVRs at 1-hour intervals 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: the investigators will apply a pressure pain stimulus 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 investigators will query the subjects using Visual Analogue Scales from 0-10 cm (range from no effect to most severe effect), for sedation, nausea and vomiting. Additionally, the investigators will count the occurrences of vomiting.~Pupil diameter: At 30-min intervals, the pupil diameter will be measured using a handheld pupillometer (Neuroptics PLR-3000 pupillometer).
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. We hypothesize 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.