Acute Pain
Conditions
Keywords
healthy volunteers, pain control, oxytocin
Brief summary
The goal of this clinical trial is to learn if oxytocin reduces pain in a small area of skin after pulses of non-burning heat by changing how nerves in the heated area react to pressing a thin, bendable plastic bristle and a thick, non-bending plastic bristle in adult, healthy participants. The man questions it aims to answer are: Does oxytocin increase the number of times a fiber which normally responds only to the thin bristle fires (sends a signal) after the heat pulses. Does oxytocin raise the number of times a fiber which normally responds only to the thick bristle fires (sends a signal) after the heat pulses. Researchers will compare oxytocin to a placebo (a look-alike substance that contains no drug) to see if oxytocin ABC works to change how nerves react to light touch and painful pressing in an area of sensitized skin. Participants will: Receive an intravenous injection of oxytocin or placebo on one occasion On the same day, a needle will be put near nerve fibers to record their firing before and after a few cycles of short heating of the skin.
Detailed description
This protocol will utilize a randomized, triple-masked study design to compare intravenous (IV) oxytocin to placebo on peripheral nerve response to acute pain sensitization in healthy volunteers. Equal numbers of adult men and women; ages 18-65 will be recruited. Participants, recruited from the regional community will report to the Linköping University Neurophysiologic Research Laboratory (Linköping, Sweden) for a 2-hour visit to complete eligibility screening, informed consent, pregnancy and drug use laboratory tests, and questionnaires regarding drug and alcohol use, and receive training in the tests to be used on the study day. On a subsequent study day, participants will come initially to the Linköping University Medical Center where an IV catheter will be inserted and they will receive either IV oxytocin (20 IU) or an equal volume of placebo. Study drug will be randomized and administered in two 30-minute infusions separated by the minutes. Rapid rates of oxytocin infusion can cause acute adverse events in the first minutes of infusion. Although these adverse events rapidly resolve despite continuing the infusion, one event (facial flushing) could negate the blind of study personnel. For that reason, the first infusion will be given at 2 rates, a very slow rate for the first 5 minutes and a greater rate for the remaining 25 minutes. This has been demonstrated to reduce the incidence of facial flushing with oxytocin to a rate similar to placebo. Participants will be continuously monitored for vital signs and intermittently queried for any subjective sensations or adverse events during infusion. After study drug infusion is complete, the IV catheter will be removed and the participant accompanied to the Linköping University Neurophysiologic Research Laboratory, adjacent to the Medical Center, where they will complete psychologic questionnaires and cognitive tests and undergo sensory testing of the skin on the arm of brushing using a computer controlled, robotic system. Then, a 200 micrometer tungsten electrode will be inserted in the radial or peroneal nerve under real-time ultrasound guidance and manipulated until a single nerve fiber and its area of skin innervation (receptive field) are identified. The nerve fiber will be categorized by its speed of conduction and firing pattern to a variety of non-noxious and noxious sensory stimuli to the receptive field. A temperature controlled thermode will be placed on the skin adjacent to and overlapping with the receptive field and acute inflammation induced by 10-second cycles of heating the probe to 50°C with 10 seconds at a non-noxious temperature (30°C) between each heat pulse for a total of 2 minutes. The response of the nerve fiber to noxious and non-noxious stimuli will be repeated. The primary analysis will compare fiber firing in response to a fixed intensity punctate stimulus in the fiber's receptive field between oxytocin and placebo and will be performed separately on touch-sensitive fibers (fast conducting, low threshold mechanoreceptors (A-LTMRs)) and pain-sensitive fibers (fast conducting, low threshold mechanoreceptors (A-HTMRs)). Based on numerous studies performed in rodents at Wake Forest University School of Medicine, we hypothesize that acute heat-induced inflammation will render A-LTMRs less responsive to a touch punctate stimulus and A-HTMRs more responsive to a noxious punctate stimulus and that both of these effects will be reduced by at least 50% in participants who receive IV oxytocin. If such results are obtained, they will challenge the existing paradigm that reduction in pain threshold (allodynia) after sensitization from peripheral injury is driven by increased A-LTMR input and support further exploration for the mechanisms by which oxytocin returns changes in touch and pain fibers towards normal to treat pain.
Interventions
Intravenous oxytocin, 20 IU will be administered via two 30-minute infusions separated by 30 minutes
DRUGIntravenous Placebo
Intravenous placebo will be infused in the same volume and timing as the intravenous oxytocin intervention
Sponsors
Wake Forest University Health Sciences
National Institute of Neurological Disorders and Stroke (NINDS)
Linkoeping University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The Linkoeping University (Linkoeping, Sweden) research pharmacy will prepare solutions and dispense them on the day of each study using a randomization stratified by sex that will be concealed until the end of the clinical trial.
Intervention model description
Each participant will be randomized to receive an intravenous (IV) infusion of study drug, either IV saline (placebo) or IV oxytocin (20 IU).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* In good health as determined by the Principal Investigator (PI) or co-investigators based on prior medical history, current psychiatric assessment, and clinical assessment of lab tests. * Female participants of child-bearing potential including those \< 1 year post-menopausal, must be practicing highly effective methods of birth control such as hormonal methods (e.g., combined oral, implantable, injectable, or transdermal contraceptives), double barrier methods (e.g., condoms, sponge, diaphragm, or vaginal ring plus spermicidal jellies or cream), or abstinence from heterosexual intercourse for a minimum of 1 full cycle before study drug administration. * Normal blood pressure (systolic 90-140 mmHg; diastolic 50-90 mmHg) resting heart rate 45-100 beats per minute) without medication. * Proficient in Swedish or English
Exclusion criteria
* Hypersensitivity, allergy, or a history of significant reaction to any ingredients of the active drug (Oxytocin Grindeks® 8.7 microgram/ml solution) or the placebo (Sodium Chloride , ATC code: V07AB). * Any disease, diagnosis, or condition (medical or surgical) that, in the opinion of the PI, would place the participant at increased risk (active gynecologic disease in which increased uterine tone would be detrimental e.g., uterine fibroids with ongoing bleeding), compromise the participant's compliance with study procedures, or compromise the quality of the data. * Women who are pregnant (positive result for urine pregnancy test at screening visit), women who are currently nursing or lactating, women that have been pregnant within 2 years. * Body Mass Index (BMI) \> 30 * Participants with neuropathy, chronic pain, diabetes mellitus, or taking benzodiazepines or pain medications on a daily basis. * Participants with current or history of ventricular tachycardia, atrial fibrillation or prolonged QT interval. * Participants with past or current history of hyponatremia or at risk for hyponatremia; anyone taking thiazide diuretics, loop diuretics, combination diuretics, lithium, carbamazepine, enalapril, ramipril, celecoxib, temazepam, gliclazide, glimepiride, glibenclamide, glipizide, omeprazole, pantoprazole, desmopressin, antidepressants (SSRI's or MAOI), or the recreational drug ecstasy. * Participants with a known latex allergy. * Participants with substances use disorders or any other psychiatric disorder(s). * Participant with high risk of fainting episodes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of nerve fiber discharges with von Frey filament application | 2-8 hours after start of the first IV infusion | The number of nerve fiber discharges in response to a 5 second application of a 20 mN force von Frey filament and to a 1000 mN force von Frey filament to the area of skin responding to sensory stimulation. These are measured twice, once before and once after skin inflammation induced by heat pulses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Verbal pain intensity score with von Frey filament application | 2-8 hours after start of the first IV infusion | Verbal pain intensity score in response to a 5 second application of a 20 mN force von Frey filament and to a 1000 mN force von Frey filament to the area of skin responding to sensory stimulation. Pain scores are obtained twice, once before and once after skin inflammation induced by heat pulses. Pain intensity is rated on a 0-10 scale with 0 being no pain at all and 10 being the worst imaginable pain. |
| Pattern of nerve fiber discharges with von Frey filament application | 2-8 hours after start of the first IV infusion | The pattern of spikes in response to a 5 second application of 20 mN force von Frey filament and to a 1000 mN force von Frey filament to the area of skin responding to sensory stimulation. Pattern is categorized as one of 4 choices (rapidly adapting, slow adapting, continuous, or on-off) according to standard neurophysiological definitions. These will be measured twice, once before and once after heat-induced inflammation |
| Number of nerve fiber burst discharges with tuning fork application | 2-8 hours after start of the first IV infusion | The number of spike bursts in response to a 2 second application of a 128 Hz tuning fork to the receptive field. If there are any bursts to 128 Hz, then the test will be repeated with, separately, a 75 Hz tuning fork and a 512 Hz tuning fork to the area of skin responding to sensory stimulation. Spike bursts are defined as multiple spikes coinciding with each vibration of the tuning fork. These will be measured twice, once before and once after heat-induced inflammation |
| Number of nerve fiber discharges with warming and cooling | 2-8 hours after start of the first IV infusion | The number of discharges in response to slow warming to 50 degrees C and slow cooling to 0 degrees C by application of a Peltier-controlled thermode to the area of skin responding to sensory stimulation. Spike bursts are defined as multiple spikes coinciding with each vibration of the tuning fork. These will be measured twice, once before and once after heat-induced inflammation |
| Number of nerve fiber discharges with soft brushing | 2-8 hours after start of the first IV infusion | The number of discharges in response to brushing in the receptive field using a computer controlled robotic device at various pressures and speeds. Total discharges with each brush will be measured. The brushing tests will be performed twice, once before and once after heat-induced inflammation |
| Number of nerve fiber discharges with von Frey filament application: stimulus response relationship | 2-8 hours after start of the first IV infusion | The number of discharges in response to 5 sec application of von Frey filaments of 8 different forces from 4-3000 mN, presented in random order to the area of skin responding to sensory stimulation. Threshold will be determined as the lowest force resulting in any discharge. A stimulus response curve will be created using number of discharges to 5 second von Frey application at each of the 8 forces. This stimulus response is measured twice, once before and once after skin inflammation induced by heat pulses. |
| Inflammation response to skin heating | 2-8 hours after start of the first IV infusion | The area of erythema immediately after skin heating to 6 cycles of 50 degrees C for 10 sec over a total of 2 minutes will be calculated by measurement of height and width in mm, with values expressed in mm squared. |
Countries
Sweden
Contacts
CONTACTHakan Olausson, MD, PhD
CONTACTSaad Nagi, PhD
STUDY_CHAIRJames Eisenach, MD
Atrium Health Wake Forest University School of Medicine
Outcome results
None listed