Analgesic Effect of Oxytocin Receptor Modulation
Condition: Pain; Hyperalgesia; Central Sensitization
MeSH terms: Hyperalgesia
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Carbetocin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Carbetocin 0.1 mg single dose is intravenously administered; 1ml of NaCl 0.9% is administered intravenously
Intervention MeSH terms: Carbetocin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: randomized controlled trial; placebo controlled trial; cross over trial