Evaluating the Efficacy of Intranasal Oxytocin on Chronic Pain

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: 24-IU oxytocin
* Drug: 48-IU oxytocin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inter-Site Inclusion Criteria: Adult (> 18 years) men and premenopausal women; On stable medication for pain management for 3 months or more with no anticipated changes during the 10-weeks of this trial; Moderate pain at baseline (i.e., a score of 4-8 on a 10-point numeric rating scale) to prevent floor and ceiling effects. 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: 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). 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. 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: Positive urine pregnancy test or contemplating pregnancy; Concurrent use of another nasal spray; Nasal pathology (e.g., ears, nose, and throat diagnosis); Diabetes insipidus; Current diagnosis or history of cancer 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 Receiving hormone treatment for gender-related motivations. documented cardiovascular event (e.g., myocardial infarction) known prolongation of the QTc interval; 10) known hypersensitivity to oxytocin known latex allergy known or suspected renal impairment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Crossover sequence 1: Oxytocin first<br>Patients receive 2-weeks courses of 24-IU oxytocin, placebo, 48-IU oxytocin. | Drug: 24-IU oxytocin<br>* Patients will self-administer a 2-week course of 24-IU intranasal oxytocin [4-IU per puff (12-IU delivered to each nostril); Syntocinon, Novartis, Switzerland], twice per day (once in the morning and once in the evening).<br>Drug: 48-IU oxytocin<br>* Patients will self-administer a 2-week course of 48-IU intranasal oxytocin [4-IU per puff (24-IU delivered to each nostril); Syntocinon, Novartis, Switzerland], twice per day (once in the morning and once in the evening).<br>Drug: Placebo<br>* Patients will receive an intranasal placebo containing the same ingredients as the oxytocin nasal spray with the exception of active oxytocin. Administration schedule and procedure will be identical to that described in 24-IU oxytocin.<br>|
| Other: Crossover sequence 2: placebo first<br>Patients receive 2-weeks courses of placebo, 24-IU oxytocin, 48-IU oxytocin. | Drug: 24-IU oxytocin<br>* Patients will self-administer a 2-week course of 24-IU intranasal oxytocin [4-IU per puff (12-IU delivered to each nostril); Syntocinon, Novartis, Switzerland], twice per day (once in the morning and once in the evening).<br>Drug: 48-IU oxytocin<br>* Patients will self-administer a 2-week course of 48-IU intranasal oxytocin [4-IU per puff (24-IU delivered to each nostril); Syntocinon, Novartis, Switzerland], twice per day (once in the morning and once in the evening).<br>Drug: Placebo<br>* Patients will receive an intranasal placebo containing the same ingredients as the oxytocin nasal spray with the exception of active oxytocin. Administration schedule and procedure will be identical to that described in 24-IU oxytocin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity | Pain severity index on the Brief Pain Inventory - Short Form (BPI-SF). Mean scores range from 0 to 10 with higher scores indicating greater pain. | Change from Day 1 to Day 14 of nasal spray administration. | 
| Pain-related interference | Pain interference index on the Brief Pain Inventory - Short Form (BPI-SF). Mean scores range from 0 to 10 with higher scores indicating greater pain-related interference. | Change from Day 1 to Day 14 of nasal spray administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emotional function | Depression, Anxiety and Stress scale (DASS). Scores are calculated for 3 subscales that are each composed of 7-items (Depression, Anxiety and Stress). Scores on subscales range between 0 and 21 with higher scores reflecting greater reports of Depression, Anxiety or Stress. | Change from Day 1 to Day 14 of nasal spray administration. | 
| Sleep Disturbance | Sleep problems index on the Medical Outcomes Study Sleep Scale | Change from Day 1 to Day 14 of nasal spray administration. | 
| Global Impression of Change | Patient Global Impression of Change Scale (PGIC). Scores on this single item measure range between 1 and 7 with higher scores reflecting greater impression of beneficial change. | Rated at Day 14 of nasal spray administration |