Table 2 Exclusion criteria at screening visit

01

Presence of any medical devices (e.g., cardiac pacemaker), implants, or prothesis unless it is beyond discussion that these will not put the subject’s safety during the study at risk and will not interfere with the results of the study.

To avoid interference with the purpose of the study and to ascertain the subject’s good health

02

Known or suspected allergic reactions or hypersensitivity to components of lacosamide (Vimpat®). Second- or third-degree atrioventricular (AV) block.

Contraindications for lacosamide

03

Known or suspected allergic reactions or hypersensitivity to components of pregabalin (Lyrica®).

Contraindications for pregabalin

04

Known or suspected allergic reactions or hypersensitivity to components of tapentadol (Palexia®). Known contraindication for drugs with μ-opioid agonist activity, i.e., significant respiratory depression, acute or severe bronchial asthma or hypercapnia. Present or suspected paralytic ileus. Acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic drugs.

Contraindications for tapentadol

05

Not willing or able to abstain from changes in physical exercise activities during the study.

To avoid interference with the purpose of the study

06

Any chronic pain condition or recent (i.e., within the preceding 2 years) history thereof.

To avoid interference with the purpose of the study

07

Migraine (at least 1 attack in the last 24 months).

To avoid interference with the purpose of the study

08

Recurrent headache or back pain on more than 5 days/month in the last 3 months.

To avoid interference with the purpose of the study

09

Caffeine consumption of more than 8 servings of coffee, tea, or other caffeinated drinks per day. Each serving is approximately 120 mg of caffeine.

To avoid interference with the purpose of the study

10

Any relevant symptom of neurological dysfunction of the motor and sensory system that may interfere with the conduct of the study.

To avoid interference with the purpose of the study

11

Clinically evident psychiatric diseases (e.g., depression, anxiety).

To avoid interference with the purpose of the study

12

History or symptoms of central nervous system disease or peripheral nerve lesions or dysfunction with sequelae that may impact the study assessments or that may deteriorate by one dose of a drug with antiepileptic, noradrenergic or opioid activity.

To avoid interference with the purpose of the study

Subject safety

13

Focused neurological examination showing signs of abnormality.

To avoid interference with the purpose of the study

14

Active internal disease or sequelae of internal disease (e.g., diabetes mellitus, liver diseases, kidney diseases, cardiovascular diseases, hypo- or hyperthyroidism, hypertension).

To ascertain the subject’s good health

15

Diseases or conditions known to interfere with the distribution, metabolism, or excretion of drugs.

To avoid artifacts

16

Clinically significant disease (e.g., medical history of infection with human immunodeficiency virus (HIV) type 1 or type 2, hepatitis B, or hepatitis C) or condition that may affect efficacy or safety assessments, or any other reasons which, in investigator’s opinion, may preclude the subject’s participation in the trial.

Safety of investigator and their staff

Standardization of the trial population

17

Not willing or able to abstain from alcohol from 48 h prior to any study period and until the end of the study period.

To ascertain and protect the subject’s good health and suitability for the study

18

Consumption of cannabis in the last 4 weeks prior to the study.

To ascertain and protect the subject’s good health and suitability for the study

19

Evidence or history of alcohol or drug (opioids, amphetamines, benzodiazepines cannabinoids) abuse (as defined by ICD-10 or DSM IV) including positive or missing drugs of abuse screen (urine drugs of abuse test). Consumption of more than 21 alcohol units per week for male subjects and more than 14 units per week for female subjects (1 alcohol unit = 1 beer [12 oz./355 mL] = 1 wine [5 oz./150 mL] = 1 liquor [1.5 oz./40 mL] = 0.75 oz./20 mL alcohol).

To ascertain and protect the subject’s good health and suitability for the study

20

Habitually smoking more than 10 cigarettes, 2 cigars, or 2 pipes of tobacco per day within the last 6 months before enrollment in this trial.

To ascertain the subject’s good health

21

Known or suspected of not being willing or able to comply with the requirements of the trial protocol or the instructions.

To ascertain the subject’s suitability for the study

22

Inability to communicate meaningfully with the trial site staff (e.g., insufficient language skills).

To ascertain the subject’s safety

23

Any person with direct involvement in the trial conduct; any person under the direct supervision of the investigator or dependent on the investigator.

Ethical requirement

24

Blood loss of 500 mL or more (e.g., owing to blood donation) within 3 months before enrollment in this trial.

To ascertain the subject’s suitability for the study

25

Pregnancy, planned pregnancy or lactation.

Ethical requirement to protect the unborn or newborn child

26

Presence of dermatological conditions in the test areas of the study that would prevent the proper application of study procedures, such as electrodes for HFS, pinprick (dermatitis, psoriasis, contact eczema, local changes of the skin due to regularly playing volleyball etc.).

To avoid interference with the purpose of the study

27

Any other reason to exclude the subject according to judgment by the investigator

To avoid interference with the purpose of the study

28

Any drug intake in the past 2 weeks including antibiotics, herbal medicines, and other remedies except the following allowed drugs: oral paracetamol or ibuprofen for a self-limiting condition (e.g., toothache, bruise) for up to 3 days in total within the past 2 weeks; oral antihistaminics and nasal aerosol and topical treatments for seasonal allergy up to 1 week before screening; contraceptives are allowed without time limit.

To ascertain the subject’s good health and to avoid interference with the purpose of the study

29

Any transient illness within 2 weeks before screening.

To ensure the subject’s good health

30

Changes in physical exercise activities, e.g., starting workout/training within 1 week before screening.

To avoid interference with the purpose of the study

31

Current or recent (during the preceding 2 weeks) acute pain lasting more than 4 h.

To avoid interference with the purpose of the study

32

Jet lag / irregular working hours / sleep restriction in the last 3 days before the screening period.

To avoid interference with the purpose of the study