- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01918475
Analgesic Effect of Oxytocin Receptor Modulation
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.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
-
Bern, Switzerland, 3010 Bern
- University Department of Anesthesiology and Pain Therapy, Bern University Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- male
- pain-free
- written informed consent
Exclusion Criteria
- chronic pain
- acute pain at time of testing
- sign or suspicion of neurological dysfunction at the tested sites
- intake of opioids
- intake of benzodiazepines
- intake of antidepressants
- intake of anticonvulsants
- intake of any analgesic drug 48h prior to test
- known allergy to carbetocin
- allergy to capsaicin
- cardiovascular disease
- asthma bronchiale
- migraine
- epilepsy
- history of liver disease
- history of renal disease
Study Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: TRIPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Carbetocin first
Subjects receive carbetocin 0.1 mg intravenously in the first session and placebo (NaCl 0.9%) in the second session
|
Carbetocin 0.1 mg single dose is intravenously administered
1ml of NaCl 0.9% is administered intravenously
|
ACTIVE_COMPARATOR: Placebo first
Subjects receive placebo (NaCl 0.9%) intravenously in the first session and carbetocin 0.1 mg in the second session
|
Carbetocin 0.1 mg single dose is intravenously administered
1ml of NaCl 0.9% is administered intravenously
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Change in intramuscular electrical pain threshold compared to baseline
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Capsaicin-induced area of hyperalgesia and allodynia
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Nociceptive withdrawal reflex thresholds of the foot
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Single cutaneous electrical pain thresholds
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Repeated cutaneous electrical pain thresholds
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Single intramuscular electrical pain threshold
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Heat pain detection threshold
Time Frame: 10, 60 and 120 minutes after carbeoticin administration
|
10, 60 and 120 minutes after carbeoticin administration
|
Heat pain tolerance threshold
Time Frame: 10, 60 and 120 minutes after carbetocin administration
|
10, 60 and 120 minutes after carbetocin administration
|
Collaborators and Investigators
Investigators
- Study Chair: Michele Curatolo, M.D., Ph.D., University Department of Anesthesiology and Pain Therapy, Inselspital Bern, Switzerland
Publications and helpful links
General Publications
- De Bonis M, Torricelli M, Leoni L, Berti P, Ciani V, Puzzutiello R, Severi FM, Petraglia F. Carbetocin versus oxytocin after caesarean section: similar efficacy but reduced pain perception in women with high risk of postpartum haemorrhage. J Matern Fetal Neonatal Med. 2012 Jun;25(6):732-5. doi: 10.3109/14767058.2011.587920. Epub 2011 Jul 15.
- Rousselot P, Papadopoulos G, Merighi A, Poulain DA, Theodosis DT. Oxytocinergic innervation of the rat spinal cord. An electron microscopic study. Brain Res. 1990 Oct 8;529(1-2):178-84. doi: 10.1016/0006-8993(90)90825-v.
- Breton JD, Veinante P, Uhl-Bronner S, Vergnano AM, Freund-Mercier MJ, Schlichter R, Poisbeau P. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition. Mol Pain. 2008 May 29;4:19. doi: 10.1186/1744-8069-4-19.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 140/12
- 2013DR1021 (OTHER: Swissmedic)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Pain
-
Flowonix MedicalApproved for marketingBack Pain | Leg Pain | Trunk Pain | Intractable Pain | Arm Pain
-
University Hospital Schleswig-HolsteinZealand University Hospital; European Regional Development Fund; Design School...CompletedPain, Acute | Pain, Chronic | Pain Measurement | Pain, CancerGermany
-
Dr. Negrin University HospitalCompletedPostoperative Pain, Acute | Postoperative Pain, ChronicSpain
-
George Washington UniversityRecruitingCervical Fusion | Pain, Back | Pain, Neck | Myofacial PainUnited States
-
Dow University of Health SciencesRecruitingLow Back Pain | Chronic Low-back Pain | Low Back Pain, Mechanical | Mechanical Low Back Pain | Pain, Chronic | Pain, Back | Lower Back Pain Chronic | CLBP - Chronic Low Back PainPakistan
-
Atatürk Chest Diseases and Chest Surgery Training...RecruitingPostoperative Pain | Postoperative Pain, Acute | Postoperative Pain, Chronic | VATSTurkey
-
Universitat Jaume ICompletedPain, Acute | Pain, Chronic | OncologySpain
-
Janssen Research & Development, LLCCompletedPain, Radiating | Pain, Burning | Pain, Crushing | Pain, Migratory | Pain, SplittingUnited States, France, Spain, Poland, Portugal
-
susanne beckerSNSFCompletedLow Back Pain | Pain, Acute | Pain, ChronicSwitzerland
-
University of Campinas, BrazilCompletedPREGNANCY | LUMBAR BACK PAIN | PELVIC PAIN
Clinical Trials on Carbetocin
-
Ciusss de L'Est de l'Île de MontréalCompletedCesarean Section Complications | Hemodynamic InstabilityCanada
-
University Hospital, Basel, SwitzerlandObstetric Anaesthetists' Association United KingdomCompletedAnesthesia; Reaction | Complications; Cesarean SectionSwitzerland
-
Levo Therapeutics, Inc.CompletedPrader-Willi SyndromeUnited States, Canada, Australia
-
University of British ColumbiaEdwards LifesciencesCompletedPregnancy | Effect of Carbetocin on Cardiovascular SystemCanada
-
Bezmialem Vakif UniversityCompleted
-
Cairo UniversityCompletedAbdominal MyomectomyEgypt
-
Cairo UniversityRecruitingPostpartum HemorrhageEgypt
-
Sohag UniversityAl-Azhar UniversityUnknownPostpartum HemorrhageEgypt
-
National University Hospital, SingaporeNational Healthcare Group, SingaporeCompleted
-
Cairo UniversityCompletedPost Partum Hemorrhage | Obesity, MaternalEgypt