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.