VALIDATION STUDY: NOCICEPTIVE PAIN MODEL AND PHARMACOLOGICAL INTERVENTION

Pain is divided into 2 main categories: acute and chronic pain. Acute or
nociceptive pain is part of a rapid warning relay instructing the motor neurons
of the central nervous system to minimize detected physical harm. Chronic pain
encompasses neuropathic pain, pain as a direct consequence of a lesion or
dysfunction affecting the somatosensory system.

In early clinical development, pain models, including different pain tests, in
healthy volunteers can play an important role in the study of pain mechanisms
and in the testing of new analgesic drugs. The pain tests provide a useful tool
for obtaining an early insight into the analgesic potential. In addition, the
pain tests may provide information on dose selection for later phase studies
and on the time course of the analgesia.

Pain detection threshold tests attempt to identify the point at which a painful
experience becomes distinguishable from a non-painful one by using a stimulus
of increasing intensity. Pain detection thresholds have been found to be
sensitive to a number of different analgesic compounds and are a fast and
reliable indicator of sensory changes.1,2,3,4 Besides, they are useful in
determining the effect of analgesics on the perception of painful stimuli over
a period of time in the same subject. In addition, a visual analog scale (VAS)
consisting of a vertical bar on a screen anchored with the descriptors *no
pain* (numeric value = 0) and *worst possible pain* (numeric value = 100) is
often used for the detection of pain.

The aim of the present study is to demonstrate that the nociceptive pain model
can be used in the clinic of PRA International-Early Development Services
(PRA-EDS) for showing the effect of the analgesic remifentanil and therefore
for testing the effect of novel analgesic compounds in the future.

Randomized, double-blind, placebo-controlled, two-way crossover study with a
washout of at least 7 days

Ultiva (remifentanil) and inducing light pain sensations

Ultiva (remifentanil): nausea, vomiting, low blood pressure, slow heart rate,
high blood pressure after surgery, itch, muscle rigidity, low respiratory
frequency, respiratory disturbances, shivering after surgery.