Pain Clinical Trial
Official title:
Analgesic Effect of Oxytocin Receptor Modulation in Healthy Volunteers
Carbetocin is a synthetic analogue of the hormone Oxytocin and is routinely used in
obstetric anesthesiology to control uterine bleeding after cesarean section. As an
incidental finding, women who received carbetocin had less pain after cesarean section than
women who had received Oxytocin. Carbetocin may therefore have an analgesic effect.
The present study examines this analgesic effect using different sensory tests, e.g.
pressure, heat, cold and electrical pain before and after administration of carbetocin in
healthy male volunteers. Any changes in these sensory tests might be indicative of an
analgesic property of carbetocin.
Background
Chronic pain is still a largely unresolved issue, causing suffering, disability and high
social costs. The search for novel pharmacological targets is therefore a priority. A recent
study on postpartal bleeding came to the accidental finding of a possible analgesic action
of the oxytocin agonists carbetocin.
Oxytocin is a well known nonapeptide synthesized in the hypothalamus, acting as neurohormone
during parturition and the milk ejection reflex. Animal studies have found that descending
pathways for oxytocin synthetizing neurons project to the lamina I-II of the spinal cord,
where they activate a subpopulation of glutamatergic and GABAergic interneurons. In addition
to GABAergic hyperpolarisation, models of oxytocin selectively blocking A-delta and C-fibers
have been published. Intrathecal administration of oxytocin prevents long-term potentiation
in the dorsal horn, which is thought to be an important mechanism of enhanced central pain
processing.
Antagonism to GABAergic and glycinergic neurotransmission mimics many symptoms of
inflammatory and neuropathic pain. A loss of synaptic inhibition in the dorsal horn occurs
in animal models of experimental pain.
Inhibitory synaptic transmission in the spinal cord dorsal horn use GABA and glycine as
their principal fast neurotransmitters. Both of them open the Cl- -channels, which induce
postsynaptic hyperpolarisation and impairs the propagation of excitatory potentials on
dendrites of neurons. Immunofluorescence studies have revealed abundant glycinergic
innervations in the dorsal horn. According to this model, inhibitory GABAergic and
glycinergic interneurons in the superficial spinal dorsal horn are key components in the
control of pain transmission from the periphery to the brain. The model states that a
non-painful stimulation is felt as non painful as long as the synaptic GABAergic and
glycinergic inhibition remains intact. A human study on GABAergic modulation of pain by
benzodiazepines has been recently performed by our group and was suggestive for an analgesic
action. However, these drugs cause sedation and addiction, which strongly limit their
clinical usefulness. A pharmacological GABA modulation via the oxytocin receptor may be an
attractive alternative, since oxytocin agonists are devoid of these side effects.
Quantitative sensory tests (QST) are used to explore the central processing of painful
stimuli in healthy volunteers and patients. They are based on a multimodal and multi-tissue
approach, combining different pain modalities applied to different tissues in order to
gather sufficient and differentiated information about the human nociceptive system under
normal and pathological conditions. QST will be our tool to characterize analgesic efficacy
of carbetocin.
Objective
We will test the hypothesis that carbetocin produces analgesia in healthy volunteers, as
assessed by multimodal experimental pain testing.
Methods
Intradermal capsaicin injection in the volar forearm is used to create experimental pain an
hyperalgesia. The area of hyperalgesia to pinprick and brush allodynia is quantified, and
pressure, heat, cold and electrical pain thresholds as well as nociceptive withdrawal reflex
thresholds are assessed 30 minutes after capsaicin injection (baseline assessments).
Carbetocin 0.1 mg is injected intravenously and the above measurements repeated after 10, 60
and 120 minutes. Blood samples are taken in order to investigate plasma carbetocin levels at
10, 60 and 120 minutes and genetic variants of the oxytocin receptor gene.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science
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