Study: NCT04742790

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Cognitive auditory-evoked potentials (P300)
Description: Cognitive auditory-evoked potentials will be recorded before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. Short-lasting auditory tones will be delivered using a three-stimulus oddball paradigm combining standard tones (90% of stimuli), slightly different target tones that the subject must attend and detect (10% of stimuli), and strongly different distractor non-target tones (10% of stimuli). The stimuli will be delivered binaurally using headphones. Participants will be instructed to press a button when they detect a target tone, and to ignore the standard and distractor non-target tones. The EEG recordings will be used to measure the amplitude and latency of the cognitive P3a and P3b potentials (Komerchero \& Polich 1999). Changes in P3a/P3b amplitude will be used as a measure of drug-induced effects on cognition (expressed as percentage of change).

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Cervical somatosensory-evoked potentials
Description: Cervical spinal-cord evoked potentials will be recorded before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. The responses will be elicited by transcutaneous electrical stimulation of the median nerve. The N13 component of this response is mediated by large myelinated non-nociceptive fibers and reflects a segmental postsynaptic response of dorsal horn interneurons at the level of lumbar spinal cord (Cruccu et al., 2008). Changes in magnitude of the N13 will be used as a measure of drug-induced effects on spinal cord function (expressed as percentage of change).

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Pupillometry
Description: Pupillometry measurements will be performed before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. Pupillometry has been proposed as a method to assess opioid pharmacodynamics. The extent of pupil dilatation can provide an index of nociceptive input via autonomic innervation of the iris muscles, while the extent of the attenuation of this pupillary response during exposure to opioid analgesics could provide an index of pharmacological effects reflecting the extent of opioid receptor occupancy in the CNS. Pupillometry (static pupil diameter, variability of pupil diameter \[variation coefficient of pupillary dilation, VCPD, Charier et al. 2017\]), light-evoked speed of pupil constriction \[maximum pupil constriction velocity, PCV, Connely et al., 2014\]) will be measured using a handheld pupillometry device routinely used for clinical evaluations.

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Saccadic Peak Velocity
Description: The saccadic peak velocity (SPV; m/s) will be measured before before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. Saccadic peak velocity is one of the most sensitive parameters for sedation. Recording of eye movements will be performed in a quiet room with dimmed lightning. Average values of saccadic peak velocity (expressed as degrees/second) of all correct saccades will be measured.

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Adaptive tracking test
Description: The test will be performed before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. Adaptive tracking is a pursuit-tracking task sensitive to impairment of eye-hand coordination by drugs. It has been proven useful for measuring CNS effects of alcohol, various other psychoactive drugs, and sleep deprivation.

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: Body Sway Test
Description: Body sway will be assessed before (visit 1) and 7-10 after (visit 2) initiating the combination treatment, using a body sway meter and with eyes closed. The body sway meter allows measurement of body movements in a single plane, providing a measure of postural stability. The method has been used to demonstrate effects of sleep deprivation, ethanol and psychoactive drugs. All body movements over a 2-min period are integrated and expressed as millimeters of sway.

Intervention type: DIAGNOSTIC_TEST
Group type: EXPERIMENTAL
Intervention: N-back working memory test
Description: Working memory performance will be assessed before (visit 1) and 7-10 after (visit 2) initiating the combination treatment. In this test, a series of letters are shown to the participant on a computer screen. The test includes three conditions with increased working memory load. The 0-back condition simply requires to indicate whether the presented letter is the letter X or another letter. In the 1-back condition, participants are requested to indicate whether the displayed letter is identical to the preceding letter. In the 2-back condition, participants are required indicate whether the letter is repeated with one other letter in between (e.g., B ... C ... B).

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Patient-reported outcomes
Description: Before (visit 1) and 7-10 after (visit 2) initiating the combination treatment, but also daily between the two visits, 14 days, 1 month, 3 months and 6 months after treatment initiation, patient-reported outcomes will be collected to assess clinical effects and side-effects of the combination treatmen These include the short form of the Brief Pain Inventory (BPI), the PROMIS PQ-NEURO score for neuropathic pain, the Stanford Sleepiness Scale (SSS), and the PROMIS Neuro-QOL self-assessment of cognitive functioning.