Translational trial to explore the pharmacodynamic effects of multiple oral dose
administrations of tapentadol PR, pregabalin, and combinations of
both in an intradermal capsaicin hypersensitization model in healthy
subjects.

Tapentadol and pregabalin are approved drugs for the treatment of neuropathic
pain and are typically administered as separate treatments. It is expected that
when these drugs are given together in 1 formulation (in 1 capsule, for
example), lower doses of both drugs may be needed to obtain the same clinical
efficacy but then with less side effects for the patients.

The purpose of the study is to investigate the optimal dose combination of both
drugs in healthy volunteers who will undergo a pain test.

The study will be performed in 2 parts, Parts A and B. Part A will consist of 2
groups of 18 male subjects each and Part B will consist of 2 groups of 24
healthy male subjects each.

For all groups, there will be 3 treatment periods in which the study drug is
administered on 3 consecutive days. On Days 1 and 2, the study drug is
administered twice in the morning (2 hours apart) and twice in the evening (2
hours apart). On Day 3, the study drug is administered twice in the morning
only (2 hours apart). The pain tests will be performed after the last dose on
Day 3 of each period.

Tapentadol (Palexia Retard)
Pregabalin (Lyrica)
Capsaicin

Both tapentadol and pregabalin have been marketed for many years. The adverse
effect profiles of both drugs are well-known, and the drugs will be
administered in this study at doses that are known to be well tolerated. The
most common adverse effects (more than 10% of the people) with tapentadol are
nausea, constipation, dizziness, drowsiness, and headache; and with pregabalin
these are are dizziness, somnolence, peripheral edema, ataxia, fatigue,
xerostomia, weight gain, tremor, blurred vision, and diplopia. When the 2 drugs
are combined, the chance of adverse effects occurring may increase. You should
be aware that the aforementioned adverse effects and possibly other, still
unknown adverse effects, may occur during the study. However, with the doses
used in this study no serious adverse effects are expected.

Capsaicin, the *hot* substance in chili peppers, is commonly used in
experimental pain models in healthy volunteers and is generally regarded as
safe. Administration of capsaicin gives a transient, intense pain at the site
of injection, which is often described as intense burning, aching or stinging.
Shortly after the injection an area of sensitization develops with allodynia (a
painful response to a usually non-painful stimulus) and hyperalgesia (an
increased pain sensation to mildly painful stimuli) around the injection site.
In addition, there will be redness of the skin. The painfulness and redness is
only short lasting and will disappear within 2 hours. The sensitization
symptoms may last up to 12 to 24 hours.

The cold pain assessment as used in this study has been used extensively in
studies with healthy volunteers. Even though it is painful, it is generally
well-tolerated and of sufficiently short duration to avoid any risk to the
health or well-being of healthy volunteers.