Inclusion criteria

Non-menopausal women with chronic (intermittent or constant) pelvic musculoskeletal pain (ie, pain exceeding 6 months in duration, ie, located primarily in the pelvic region and reproducible on palpation to the muscles spanning the pelvic floor) will be eligible to participate if they: (1) have regular menstrual periods (monthly within a 21–35 day range), given that pain varies across the menstrual cycle31 ,32 and nasal spray administration will occur during the luteal phase; (2) use a permanent, hormonal, or barrier form of contraception, or abstinence in order to minimise the risk of pregnancy during the trial, given that oxytocin is a potent uterogenic agent; (3) can commit to not change their medication during the 6 weeks of this study; and (4) have a moderate amount of pain at baseline (ie, a pain score of 4–7 out of 10 on a numeric rating scale). A baseline pain score of 4–7 out of 10 was selected to prevent floor and ceiling effects and ensure that participants have room to change throughout the course of the study.

Exclusion criteria

Exclusion criteria include: muscle pain as a result of systemic disease, scoring positive on a urine pregnancy test or contemplating pregnancy, concurrent use of another nasal spray, nasal pathology (eg, ears, nose and throat diagnosis), diabetes insipidus, previous or concurrent use of narcotics delivered intranasally (eg, cocaine) or sacroiliac instability as defined by the European Guidelines.33 Women will also be excluded if they have a primary diagnosis of endometriosis, dysmenorrhoea, interstitial cystitis, functional bowel disorder, fibromyalgia or neuropathic pain. Given that the heart contains oxytocin receptors,34 that, when bound to, result in inhibitory effects on cardiovascular activity,35 a review of medical chart will be performed and women prescribed antihypertensive medication and those with heart problems (eg, cardiomyopathy, history of myocardial infarction, arrhythmias, prolonged QT interval) will be excluded.

Patient screening, recruitment and enrolment

Fifty women with chronic pelvic musculoskeletal pain will be recruited from the Calgary CPC and directly from the gynaecology clinics of MR and MN-E. Women will be examined by a study gynaecologist (JFJ, MN-E, MR) trained to examine sacroiliac instability and myofascial pain. Chronic pelvic musculoskeletal pain will be confirmed through a physical examination. Any concerns of sacroiliac instability on physical examination will be further assessed by a pelvic physiotherapist. It is estimated that 15 women per month could meet inclusion criteria.

Women will visit the laboratory four times (baseline, 2, 4, 6 weeks). Vital signs (heart rate (HR) and blood pressure (BP)) and self-reported pelvic pain will be monitored at all visits. The first dose of each nasal spray (baseline and 4-week visits) will be supervised and vitals taken every 10 min for 30 min. Women whose HR and BP decrease by 15% within this period will be identified as sensitive to the effect of intranasal oxytocin and withdrawn from the trial due to safety concerns. Patient symptoms and side effects will be monitored during the 2-week, 4-week and 6-week laboratory visits and again over the phone 2 weeks after trial completion.

Baseline assessment

Testing will occur during the luteal phase of the menstrual cycle (ie, days 14–28) as this is the phase during which women report the highest pain.32 At ∼day 14 of their menstrual cycle, participants will attend a baseline session at the Calgary CPC. The objectives of the trial will be explained by a study gynaecologist (JFJ, MN-E, MR) who will also obtain consent to participate. Women will then complete a urine drug and pregnancy test, be randomised to study condition and fill out baseline study questionnaires (refer to table 1 for a schedule of assessments).

Randomisation and blinding

A research assistant (RA) not involved in study recruitment will use Research Randomizer (http://www.randomizer.org/) to generate lists of randomly sequenced numbers, stratified by recruiter (MR, MN-E), for assigning patients to condition in a manner consistent with CONSORT.28 ,29 Central randomisation will be performed using a 1:1 allocation schedule with random block sizes of 4, 6 and 8. The allocation sequence will be concealed from the researcher using sequentially numbered, opaque and sealed envelopes. In order to protect against expectation effects and biases, the RA completing baseline assessment and providing participants with their nasal spray will be unaware of condition or nasal spray (oxytocin or placebo), participants will not know what condition they have been assigned to and an RA not affiliated with this study will complete the outcome assessment without being aware of nasal spray that participants are assigned to. Adequacy of blinding will not be formally evaluated, given the lack of evidence for, and concern against conducting such an assessment.29

Experimental condition

During the experimental condition, participants will receive a 2-week course of intranasal oxytocin. Participants will self-administer 24 IU intranasal oxytocin (12 IU delivered to each nostril; Syntocinon, Novartis, Switzerland), two times per day (once in the morning and once in the evening). In order to ensure standardisation of nasal spray administration, participants will be trained in the self-administration of intranasal oxytocin in accordance with published recommendations for the standardisation of oxytocin nasal administration.36 Two times per day dosing will ensure elevated central concentration of oxytocin throughout the day, given that salivary concentration of oxytocin was elevated for 7 hours following intranasal administration of 24 IU oxytocin.37 Further, a 24 IU dose represents a safe and effective concentration for two times per day dosing (see Rash and Campbell38). Oxytocin nasal spray is well tolerated and doses ranging from 10 to 60 IU have produced no reliable side effects in humans relative to placebo.7 Moreover, a recent study of 14 women with fibromyalgia reported that an 80 IU dose of intranasal oxytocin was well tolerated and had no differential side effects from placebo when delivered daily over a 3-week period.23 Participants will be instructed to store nasal spray at room temperature (between 15°C and 25°C) and outside of range of children.

Control condition

During the control condition, participants will receive a 2-week course of intranasal placebo (containing the same ingredients as the oxytocin nasal spray except for the active oxytocin) self-administered on the same schedule as the experimental condition. The bottles containing oxytocin and placebo will be identical in appearance, smell, texture and taste. Different coloured stickers will be applied to the bottles in order to distinguish oxytocin from placebo. Only the study coordinator will be aware of what colour signifies which nasal spray and blinding will only be broken should an adverse event occur.

Washout period

The experimental and control conditions will be separated by a washout period of ∼2 weeks to ensure that intransal administration coincides with the same phase of the menstrual cycle. If women have regular menstrual cycles (by definition ≤35 days, and the luteal phase is the fixed component of the menstrual cycle), the washout phase may be extended by up to 7 days to ensure that all women receive treatment in the same menstrual cycle phase. This time frame will be sufficient, given that the half-life of oxytocin administered centrally using nasal spray is 2–7 hours and 7 half-lives will be achieved for full clearance in 14–49 hours.

Daily diaries

Participants will be provided with daily diaries to record their menstrual cycle, time of nasal spray administration, study assessments and side effects (refer to table 1 for a schedule of assessments).

Participant engagement

A multipronged approach will be used to encourage participant engagement in our trial. First, the timeline and demands of the trial will be explicitly discussed at the outset with participants, who will be asked to sign a behavioural contract to commit to trying to meet the requirements. Second, women will receive telephone reminders prior to each laboratory visit and again if they miss one visit. Third, expectations will be developed for participant attendance. We will ensure that participants know our research staff by name and will be made aware that their research associate has an appointment scheduled with them and will be awaiting their arrival. Fourth, participants who have difficulties attending sessions will be provided with a telephone-based motivational conversation during which ambivalence towards attending sessions will be openly discussed with the goal of securing commitment to attend a session at a time that is convenient for them. Many of these strategies have been identified by Cochrane reviews as methods for improving patient recruitment39 and retention.40

Primary outcome

As recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT),41 pain and functional impairment will be measured at baseline and daily using the Brief Pain Inventory-Short Form (BPI-SF42). The BPI-SF measures pain intensity, the impact of pain on seven daily activities (eg, activity, work, sleep) and analgesic use. The BPI was originally designed to measure cancer pain, but has been shown to be a reliable and valid instrument for measuring non-cancer pain.43–46 Test–retest values for pain and interference typically range between 0.72 and 0.98, and data from studies in many countries have supported a two-factor solution of pain severity and interference.47

Secondary outcomes

As recommended by the IMMPACT,41 secondary outcomes include emotional function, sleep disturbance and global impression of change.

Mood will be measured daily using the Positive and Negative Affect Scale (PANAS48). The PANAS comprises 10 positive affect words (eg, excited, proud) and 10 negative affect words (eg, distressed, upset). Participants are asked to rate how they feel ‘today’ using a 5-point Likert scale ranging from 1 ‘slightly or not at all’ to 5 ‘extremely’. The PANAS has excellent internal consistency (Cronbach α=0.87–0.90), moderate 8-week test–retest reliability (r=0.39–0.47) and correlates strongly and in the expected directions with measures of mood, well-being, distress and psychopathology.48

Emotional function will be measured weekly using the Depression Anxiety Stress Scale (DASS-2149). The DASS is a 21-item measure consisting of 3 scales that each comprise 7 items—Depression, Anxiety and Stress. Items refer to the past week and scores range from 0 ‘did not apply to me at all’ to 4 ‘applied to me very much, or most of the time’. The scales are considered to approximate facets of diagnostic categories, including Depression scale for mood disorders, Anxiety scale for panic disorder and Stress scale for generalised anxiety disorder.50 Numerous studies have reported favourable psychometric properties of the DASS in clinical samples50 and older patients in primary care.51 In patients with chronic pain specifically, the DASS has shown construct validity (ie, was related to other measures of similar constructs) and strong internal consistency (Cronbach α=0.68–0.96).52 ,53 The DASS has also shown moderate to strong 3-month test–retest reliability (rs=0.59–0.77) in a sample of older adults.54

Sleep disturbance will be assessed weekly with the Medical Outcomes Study Sleep Scale (MOS-S55). The MOS-S is a 12-item self-report measure designed to assess the important dimensions of sleep, including initiation, maintenance, respiratory problems, quantity, perceived adequacy and somnolence. Preliminary support for the MOS-S was provided in the developmental sample of 3445 individuals with chronic illness.56 Further support for the reliability and validity of the MOS-S was reported in a nationally representative sample of 1011 US adults and in a sample of 173 adults with neuropathic pain (eg, moderate to strong internal consistency among different subscales; Cronbach α=0.63–0.83).57 Another large study of people with neuropathic pain (n=603) reported a similar Cronbach α (0.64–0.87) as well as good test–retest reliability (r=0.67–0.87).58

Global change across the course of study will be assessed at the end of each 2-week course of nasal spray using the Patients' Global Impression of Change scale (PGIC59). This measure is a single-item rating by participants of their improvement with treatment during a clinical trial on a seven-point scale ranging from ‘very much improved’, to ‘very much worse’ with ‘no change’ as the midpoint. There has been wide use of the PGIC in chronic pain trials,60 ,61 and data provide a responsive and readily interpretable measure of participants' assessment of clinical importance of treatment.

Demographics and covariates

Demographic information will be assessed using a demographic questionnaire, including age, ethnicity, medical comorbidities, medications taken, employment status, marital status, obstetrical history, menstrual history, urinary symptoms, headaches, substance use and smoking status.

Subjective social status is highly correlated with socioeconomic status and will be measured to characterise the sample using the MacArthur Ladder, an image of a ladder meant to represent ranks of social status, on which people mark an ‘x’ on the rung they think best represents their rank.62

Concern over pain will be assessed using the Pain Catastrophizing Scale (PCS63). The PCS is a 13-item questionnaire that instructs participants to reflect on past painful experiences (eg, ‘I worry all the time about whether the pain will end’) and indicate the degree to which they experienced each of 13 thoughts or feelings when experiencing pain, on 5-point scales with the anchors of (0) ‘not at all’ and (4) ‘all the time’. The PCS yields a total score and three subscale scores assessing rumination, magnification and helplessness. Internal consistency of the PCS total score is excellent (Cronbach α=0.93–0.95 in undergraduate, community and outpatient pain populations) and good for subscale scores (Cronbach α=0.75–0.95) in undergraduate63 ,64 and outpatient pain samples.65 Scores on the PCS are positively correlated (r=0.42) with a measure of negative thoughts in response to pain64 offering support for convergent validity, and have been used to discriminate community and outpatient pain populations.65 Finally, total PCS scores have demonstrated adequate test–retest reliability over a mean period of 52 days in a sample of chronic pain patients.66

Social support will be measured using the Multidimensional Scale of Perceived Social Support (MSPSS67). The MSPSS is a 12-item scale that measures the perceived availability and adequacy of emotional and instrumental social support offered by family, friends and significant others (eg, ‘There is a special person who is around when I am in need’). Participants respond using a 7-point Likert scale ranging between 1 ‘very strongly disagree’ and 7 ‘very strongly agree’. Empirical evidence suggests that intranasal oxytocin and social support interact to reduce stress15 and social support and oxytocin may also interact to reduce pain. The MSPSS has demonstrated strong internal consistency and test–retest reliability among older adults.68

Treatment expectations will be measured using the Credibility/Expectancy Questionnaire (CEQ69). The CEQ is a six-item questionnaire that measures two factors—cognitively based credibility of treatment and affective-based expectancy of treatment effectiveness. The scale has a strong internal consistency (Cronbach α=0.84–0.85) and good test–retest reliability (r=0.75–0.82).69

Side effects and safety monitoring. As recommended for trials of chronic pain,70 side effects will be assessed using open-ended prompts (ie, have you experienced any unwanted symptoms in the past 24 hours) and the Symptom Assessment Schedule (SAS71) supplemented with additional symptoms (eg, euphoria, nasal irritation, dizziness) identified in a recent trial evaluating the effect of intranasal oxytocin on pain in a sample of 14 women with fibromyalgia.23 Further, all participants will be provided with a number for Health Link (#811) in order to ensure participant safety. Health Link is a free service in Alberta, Canada, that participants can call 24 hours/day to receive health advice from a registered nurse.

Risk management and discontinuation criteria. Rescue medication is not required with intranasal oxytocin. The best method to resolve side effects is to discontinue use of the drug, which is our recommended course of action. Participants may voluntarily withdraw from the study at any point in time by informing the researcher that they wish to discontinue their participation. Participants are explicitly informed, verbally and in writing, that their decision to discontinue will not impact their future treatment by their physician. Given the limited drug interaction and rare, but non-fatal side effects, we have no a priori defined discontinuation criteria. In accordance with recommendations of the European Medicines Agency, a data monitoring committee is not needed, given that: (1) chronic pelvic musculoskeletal pain is not a life-threatening condition; (2) study duration is brief; and (3) intranasal oxytocin has been extensively studied and side effects are rare and benign.7

Sample size calculation

We powered this study and based our sample size calculation on the number of patients needed to assess our primary outcome: change in self-reported pain between oxytocin and placebo nasal spray. In our previous work, intranasal oxytocin resulted in significant reductions in the report of acute pain (10–15% reduction in pain), with moderate to large effect sizes (η_p²=0.11–0.13).72 This equated to a minimally clinically significant reduction in pain of 1 cm on a 10 cm visual analogue scale.73 Given that our previous trial utilised a healthy sample, we powered this trial using a conservative estimate of a medium effect size. Setting power at 90%, α=0.05 and 2-tailed hypothesis testing, 44 patients would need to be recruited to detect a covariate adjusted medium effect (d=0.50). Calculations were performed using GPower.74 Fifty patients will be recruited in order to preserve power and account for potential attrition of 15%.

Data management

Data from this study will be stored and protected in two ways: (1) electronic files will be password-protected and accessed only by the research team; (2) paper files will be stored in a locked filing cabinet within the study site, and will be accessible only to the research team. Data will be deidentified to protect participant confidentiality. An RA blind to study condition will perform data entry and a second RA will randomly sample 25% of entry values to ensure accuracy. Members of the investigative team will have access to the final trial data set.

Statistical analysis plan

An intention-to-treat analysis will be performed,75 in accordance with CONSORT guidelines,28 ,29 to provide an assessment of the practical impact of a treatment. Primary analysis: Improvement in pain following oxytocin nasal spray relative to placebo nasal spray will be assessed using the BPI-SF. Using the linear mixed model function in SPSS, the analytic strategy is a mixed models analysis of covariance with time (baseline, 14 days) as the within-participant factor and treatment condition (oxytocin, placebo) as the condition factor after adjusting for relevant covariates. Given that randomisation is expected to eliminate selection bias and equate groups on relevant baseline characteristics,29 an a priori decision was made to include only covariates with a strong empirically established association with the dependent variable, rather than include all possible covariates. Any missing data will be handled using multiple imputation in accordance with Harrell's guidelines.76 Secondary analyses: The effects of the oxytocin nasal spray on change in mood, emotional function and sleep will be evaluated in a manner analogous to that described above.