Influence of Tapentadol on endogenous modulation of pain in chronic neuropathic pain patients and healthy volunteers

Endogenous modulation of pain. Pain perception is modulated via facilitatory
and inhibitory control systems. Inhibitory control is most important to chronic
pain patients as there are strong indications that failed inhibition
constitutes a predisposition to acquired chronic pain. Various systems involved
in inhibitory control have been demonstrated over the years. Two systems seem
important: (1) top-down inhibition of afferent noxious information by
endogenous analgesia originating in the periaquaductal grey (PAG) and affecting
pain perception via descending pathways; (2) bottom-up activation of pain
modulatory systems via activation of spino-bulbo-spinal loops originating in
the dorsal horn of the spinal cord. The effect that the latter system has on
pain perception is called Diffuse Noxious Inhibitory Control (DNIC). The two
systems are interconnected and DNIC is considered a bottom-up activation of the
pain modulatory mechanism, as part of the descending endogenous analgesia
system. DNIC dysfunctions or is less efficacious in various complex chronic
pain states, such as irritable bowel syndrome, chronic headache, fibromyalgia
and temporomandibular disorder.

Offset analgesia (OA) is another expression of the endogenous analgesia system
and is evoked by noxious stimulation, in order to reduce (or control) the
perception of the noxious event. Offset analgesia becomes apart when an even
more painful stimulus occurs briefly during prolonged painful stimulation. Due
to activation of the endogenous opioid system the prolonged stimulation is
perceived less painful after the intense noxious stimulus than therefore. In a
current study (P09.107) we observed that patients with neuropathic pain have a
delayed OA or sometimes even absent OA, suggesting a crucial role of pain
pathways involved in OA in the development of chronic pain.

Neuropathic pain. Neuropathic pain is a form of chronic pain due to an evident
nerve lesion from trauma (incl. surgical trauma), diabetes (small fiber
neuropathy), infection (incl. HIV), chemotherapy, etc. The primary sensation is
a burning pain coinciding with areas of hyperalgesia and allodynia. In the
current study we will focus on patients with chronic neuropathic pain caused by
diabetes.

Tapentadol and endogenous modulation of pain. Tapentadol is a centrally acting
analgesic with two mechanisms of action: a µ-opioid receptor agonism and
noradrenaline (NA) reuptake inhibition. Although the binding of tapentadol to
the µ-opioid receptor is weaker than that of morphine its analgesic action is
similar to that of morphine due to the (synergistic) effect of the second
mechanism (i.e., NA reuptake inhibition). NA plays a role in the endogenous
descending pain inhibitory system. Especially at descending pathways NA
reuptake inhibition plays a crucial role at the spinal level to reduce chronic
neuropathic pain. Hence it is to be expected that tapentadol has a modulatory
role on DNIC and OA and consequently will ameliorate pain in chronic
neuropathic pain patients.

1. Measure DNIC and offset analgesia in neuropathic pain patients;

2. Compare DNIC and offset analgesia in chronic pain patients with DNIC and
offset analgesia in healthy volunteers;

3. Assess the effect of oral tapentadol on DNIC and offset analgesia relative
to placebo and morphine.

Randomized double blind

Ingestion of pain killer

Limited: nausea, sedation, respiratory depression