Clinical trial NCT04903002: Evaluating the Efficacy of Intranasal Oxytocin on Chronic Pain
Official title: Evaluating the Efficacy of Intranasal Oxytocin on Pain and Function Among Individuals Who Experience Chronic Pain: a Multisite, Placebo-controlled, Blinded, Sequential, Within-subjects Crossover Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Chronic Pain
Lead sponsor: Memorial University of Newfoundland
Sponsor class: OTHER
Collaborators: name: University of Calgary
name: University of British Columbia
First posted: 2021-05-26
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: One in five Canadians live with chronic pain, defined as pain that lasts longer than 3-months. Living with chronic pain has a detrimental impact on physical health, emotional health, and quality of life. Current treatments rarely result in pain relief and often do not meaningfully improve physical or emotional function. Further, medication used to treat pain often causes unwanted symptoms. There is a need to develop new treatments to help manage chronic pain. The use of a nasal spray containing manufactured oxytocin may improve pain management. Oxytocin is produced in the human body and has been shown to impact the pain pathway in animals. Our project tests whether the use of a nasal spray containing oxytocin will improve pain and function in men and women who live with chronic pain. Men and women with chronic nerve, muscle, or pelvic pain will be recruited in Vancouver, Calgary, and St. John's. Each person will be assigned to complete three interventions in a random order. Each intervention involves using a nasal spray twice per day over a 2-week period. The nasal spray will contain a small dose of oxytocin during one intervention and a medium dose during the second intervention. The nasal spray during the final intervention will have no oxytocin. This final intervention is a control intervention that will allow us to measure the effect of simply taking a nasal spray (i.e., the impact of expectation). Participants and researchers will not know which interventions involve the use of oxytocin. Participants will rate their pain and function each day throughout each task. The investigators will calculate each person's score on pain and function. The investigators will test whether participants report less pain and better function when they use oxytocin compared to the control. The results of this project may improve pain, function, and quality of life among those who live with chronic pain.

Detailed description: Background and Importance: Chronic pain affects 1 in 5 Canadians and is associated with considerable burden, both individual (disability, reduced physical and emotional function) and economic ($43 billion annual cost to the economy). Available treatments for chronic pain rarely resolve symptoms, may be associated with addiction and often do not improve function. There is a need for analgesics that are non-addictive, have low adverse effect profiles, and offer effective relief.

Our work suggests that oxytocin (OT), a neuropeptide produced in the hypothalamus, may be a safe and effective adjuvant analgesic for a broad patient population. There are three mechanisms through which OT may decrease pain sensitivity: 1) a direct hypothalamo-spinal projection transports OT to the dorsal horn, reducing pain signaling from the periphery to the brain; 2) binding to opioid receptors and stimulating endogenous opioid release in the brain; and 3) improving mood, anxiety, and stress. Our team published a systematic review of the effect of OT on pain showing that 29/33 animal investigations report that OT decreases pain. It is difficult to draw firm conclusions about the effect of OT on pain in humans due to a paucity of methodologically rigorous trials.

Goals / Research Aim: To evaluate the efficacy of intranasal OT as an adjuvant treatment to improve pain and function among men and women with chronic pain.

Methods:

Design: Multi-site, dose-response, placebo-controlled, blinded, sequential, within-subjects crossover trial.

Outcomes: As recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, the primary outcome is change in pain-intensity assessed using the Brief Pain Inventory obtained from daily diaries.

Conditions: Experimental 1: 2-week course of 24-IU intranasal OT administered twice daily. Experimental 2: 2-week course of 48-IU intranasal OT administered twice daily. Control: 2-week course of intranasal placebo. Wash-Out: 2-week period occurring between each condition to allow OT to clear the system.

Recruitment: Patients with chronic neuropathic, musculoskeletal and pelvic pain will be recruited from 3 sites: Vancouver, Calgary, and St. John's. Patients will be randomized to one of 2 sequences (24-IU OT, placebo, 48-IU OT; placebo, 24-IU OT; 48-IU OT). Randomization will be centralized and stratified by site.

Blinding: Patients, researchers, and outcome assessors will be blind to condition.

Sample Size: 336 patients (112 per site) are required to detect a clinically significant (1-point; d = .50) change in pain using covariate adjusted repeated measures design with alpha = .05, power = .80, and one cluster (site).

Expected Outcomes: Provide a definitive answer regarding the efficacy of OT to improve pain and function in chronic pain in humans. An efficacy trial of this nature is a necessary prerequisite to conducting a translation trial which is aimed at improving the uptake and utilization of proven therapies in clinical practice and community settings.

Eligibility criteria: Inter-Site Inclusion Criteria:

1. Adult (\> 18 years) men and premenopausal women;
2. On stable medication for pain management for 3 months or more with no anticipated changes during the 10-weeks of this trial;
3. Moderate pain at baseline (i.e., a score of 4-8 on a 10-point numeric rating scale) to prevent floor and ceiling effects.
4. Can commit the use of two forms of effective contraception (e.g., barrier methods), or one highly effective method, including abstinence, intrauterine device, intrauterine system (IUS), vasectomy, tubal ligation, or hormonal contraceptive (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants)

Intra-Site Inclusion Criteria:

1. Surrey, BC: Men and women with primary neuropathic pain - pain arising as a direct consequence of a lesion or disease affecting the central or peripheral nervous system - will be eligible. Neuropathic pain will be screened for using a score of 3+ on the Douleur Neuropathique 4 Interview, and confirmed through investigation (e.g., electromyography).
2. Calgary, AB: Women with chronic (intermittent or constant) pelvic musculoskeletal pain (i.e., located primarily in the pelvic region and reproducible on palpation of the pelvic floor) who have not received a hysterectomy will be eligible. Women with a primary diagnosis of endometriosis, dysmenorrhea, functional bowel disorder, interstitial cystitis, fibromyalgia or sacroiliac instability as defined by European Guidelines, will be excluded.
3. Carbonear NL: Men and women with primary musculoskeletal pain of back, neck, or shoulder origin will be eligible. Pain will be assessed using the BPI-SF and confirmed through physical examination.

Exclusion Criteria:

1. Positive urine pregnancy test or contemplating pregnancy;
2. Concurrent use of another nasal spray;
3. Nasal pathology (e.g., ears, nose, and throat diagnosis);
4. Diabetes insipidus;
5. Current diagnosis or history of cancer
6. Significant unmanaged psychopathology (e.g., severe depression as indicated by a score ≥ 15 on the Patient Health Questionnaire -9) due to its inverse association with patient adherence to procedures; and
7. Receiving hormone treatment for gender-related motivations.
8. documented cardiovascular event (e.g., myocardial infarction)
9. known prolongation of the QTc interval; 10) known hypersensitivity to oxytocin
10. known latex allergy
11. known or suspected renal impairment.

Primary outcomes:
measure: Pain intensity
timeFrame: Change from Day 1 to Day 14 of nasal spray administration.
measure: Pain-related interference
timeFrame: Change from Day 1 to Day 14 of nasal spray administration.
Secondary outcomes:
measure: Emotional function
timeFrame: Change from Day 1 to Day 14 of nasal spray administration.
measure: Sleep Disturbance
timeFrame: Change from Day 1 to Day 14 of nasal spray administration.
measure: Global Impression of Change
timeFrame: Rated at Day 14 of nasal spray administration
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Calgary Chronic Pain Centre
state: Alberta
city: Surrey
country: Canada
facility: Jim Pattison Outpatient Care & Surgical Centre Pain Clinic (JPOCSC-PC)
state: British Columbia
city: Carbonear
country: Canada
facility: Carbonear General Hospital
state: Newfoundland and Labrador
Study officials:
affiliation: Memorial University of Newfoundland
name: Joshua Rash, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rash JA, Campbell TS, Cooper L, Flusk D, MacInnes A, Nasr-Esfahani M, Mekhael AA, Poulin PA, Robert M, Yi Y. Evaluating the efficacy of intranasal oxytocin on pain and function among individuals who experience chronic pain: a protocol for a multisite, placebo-controlled, blinded, sequential, within-subjects crossover trial. BMJ Open. 2021 Sep 23;11(9):e055039. doi: 10.1136/bmjopen-2021-055039.