Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000532404
Ethics application status
Approved
Date submitted
20/04/2016
Date registered
26/04/2016
Date last updated
15/08/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Oxytocin in Chronic Neck and Shoulder Pain
Scientific title
Efficacy and Safety of Oxytocin in Chronic Neck and Shoulder Pain
Secondary ID [1] 289047 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Musculoskeletal neck and/or shoulder pain that has lasted for a minimum of 12 months 298472 0
Condition category
Condition code
Musculoskeletal 298567 298567 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oxytocin (24 International Units) administered via nasal spray. Participants will self administer the intranasal spray under verbal instructions from the researcher. Participants will be instructed to keep the bottle in an upright position during the puffing. Before
puffing commences, four pre-puffs will squirted from the spray bottle by the
researcher to ensure normal distribution of each spray before use. The order of
administration was always as follow: insert spray-head, exhale,  puff, inhale nasally. Administration will alternate between the nostrils after each spray, with 45-second break between each administration, until 3 puffs (4 IU each) per nostril is reached (total dose 24 IU). Participants were allowed to blow their noses before puffing commenced and will be asked to avoid this until the end of the testing sessions. They will be allowed to dab off any leaking fluid from their noses with a tissue. A stopwatch will be used to time the 45-second breaks, and again after the last puff to keep time until the expected peak levels of oxytocin within the central nervous system (approximately 45 minutes after the administration of the last spray).

As this is a randomised crossover trial, participants will receive the oxytocin nasal spray in one session, and the placebo spray in the other. The two sessions are separated by a minimum of 14 days. Following the administration of the sprays and waiting for the sprays to become active within the central nervous system, the researcher will guide participants through a series of experimental tasks, which are described below.

Task 1: Oxytocin, heart rate variability, and stress
When the participant is comfortable, heart rate will be recorded while participants are prompted to inhale and exhale at regular intervals of 15 cycles per minute for two minutes. Spectral analysis with Fast Fourier Transformation will compute variability in low and high frequency heart periods (HRV). Respiratory sinus arrhythmia (RSA) will be analysed with the peak-to-valley method, calculating the mean difference between the shortest heart R-R period during inspiration and the longest R-R period during expiration. Following the paced breathing task, participants will be asked to complete a cognitive stressor task, the Serial Sevens (SS) task to induce a state of stress. Participants will be instructed to count backwards by sevens (e.g., 1,000, 993, 986, 979 etc.) while the experimenter pressures them to “hurry up” and “go faster” over a period of two minutes.

Task 2: Effect of oxytocin on physical functioning
Hand strength will be assessed in a standardised way using an isometric hydraulic hand dynamometer “Jamar” (Sammons Preston, Inc, Bolingbrook, IL) in the sitting position with a straight back, shoulder adducted and in a relaxed position, elbow flexed to 90 degrees, and the lower arm and wrist in a neutral position. This test will examine hand strength in the dominant hand of the participant. A single handgrip position will be used and adapted to the hand size of the participants. After maximal squeeze duration of 8 seconds, the peak value will be recorded in kilograms. Recordings will be taken in triplicate, with the mean of the final two trials to be used for statistical and analytic purposes.

Lifting ability will be assessed via a modification of the progressive isoinertial lifting evaluation (PILE) protocol, utilised to explore the maximal lifting capacity of the participant. All lifting tests will be executed with a plastic crate and 2.5 kg weight plates which will be added to the crate until the maximum amount of weight is reached. The maximum performance will be recorded in kg.

The PILE involves lifting the weights in 1) a lumbar test from floor to waist, and 2) a cervical test evaluating shoulder girdle and upper extremity lift capacity from waist to shoulder height. Participants will begin with a light load (i.e. the weight of the crate and one free weight). Weight is incremented upwards at a rate of the initial free weight following the completion of two repetitions of a lift. A “lifting movement” is defined as a single transfer from one level to the next i.e. from the floor to the waist, or the waist to the shoulder. Both lifts will continue until the participant reaches an end point (see below). The lumbar and cervical PILE tests are done separately, as the norms and biomechanics differ for varying lifting heights. The test will be terminated when the first of the following end-points is achieved:
1) Safety end point: the participant can safely and correctly complete two repetitions of the lift at the highest possible weight load, 25 kg (i.e. the weight of the wooden/plastic crate plus the additional weight plates); or
2) Biomechanical end point: the participant fails to adhere to the correct lifting technique in order to be able to lift the box during the repetitions; or
3) Fear of pain end point: the participant does not want to continue the task because they report they fear they will hurt themselves if they continue the task; or
4) Pain end point: the participant reports that they are in pain

At the completion of each paradigm (lifting, handgrip strength), participants will be required to indicate the amount of effort they exerted during the completion of the task on an 11-point numerical rating scale (NRS), with anchors of 0 (no effort at all) and 10 (maximum possible effort).

Task 3: Oxytocin and the perception of thermal pain
Threshold testing will first be conducted to determine the participant’s individual heat pain threshold on the anterior surface of the dominant arm of the participant. The thermode will be attached to the arm of the participant with the minimum pressure required to ensure that the whole surface of the thermode remains in contact with the skin via a Velcro strap. Three trials will be performed: the first of which will be discarded, and the average threshold from the final two trials will be used in the proposed analyses. All trials will begin with the thermode at a baseline temperature of 32 degrees C, with the thermode increasing in temperature at a rate of 1 degree/second. Each individual trial will end when the participant indicates when they first perceive the thermal stimulation as painful, by pressing a button on the Pathway Response Unit. The thermode then returns to the baseline temperature at a rate of 8 degrees C/second. There will be an interval of 60 seconds between trials. If on any trial the thermode reaches the upper ceiling limit (set at 50 degrees C for safety purposes), the trial will be discontinued and thermal pain tolerance set at 50 degrees C.

A total of 9 (3 x 39 degrees C, 3 x 42 degrees C, 3 x 45 degrees C) thermal stimulations will be delivered to each of the target sites (described below) for all participants. The temperatures will be presented in pseudorandomised order. Each trial will begin at a baseline temperature of 32 degrees C and participants will fixate on a crosshair for 2 seconds. The thermode will then increase in temperature so that the target temperature is delivered within 1 second. The target temperature will be maintained for 2 seconds before returning to the baseline temperature over a period of 1 second. Participants will then have 8 seconds to rate the intensity and unpleasantness of the thermal stimulus using a computerised 11-point NRS, with anchors of 0 (no pain/not unpleasant) to 10 (extreme pain/extremely unpleasant). Participants will be asked to select the number on the scale that best represents the intensity and unpleasantness of the pain experience.

Site 1: Cervical spine - over the back of the neck, between the hairline and the collar of a t-shirt.
Site 2: Deltoid - The point at which the deltoid muscle inserts into the deltoid tuberosity of the humerus
Site 3: Tibialis anterior - two thirds of the way up the muscle that runs alongside your shin

Task 4: Influence of oxytocin on anxiety and arousal during the anticipation and experience of thermal pain
This paradigm employs various anticipatory visual cues that are paired with specific stimulus intensities. There are four stimulus conditions (cue to anticipate either high pain, low pain, no pain or unknown pain) with three stimulus intensities (high pain (45 degrees C), low pain (42 degrees C) and no pain (32 degrees C)). The stimuli will be delivered for 2 seconds to produce intense pain, low pain and innocuous sensations, respectively. These stimuli will be delivered in a pseudorandom and counterbalanced order by the CHEPS thermode, which will be securely attached to the anterior surface of the dominant forearm of the participant.

In the experiment, participants will be presented with a black crosshair on a 14 inch laptop screen for 4 seconds before being presented with a cue for 4 seconds, followed by the application of the stimulus over a 4 second period. Heart rate and skin conductance will be recorded throughout the periods of fixation, cue presentation, and stimulus delivery. To verify that both groups of participants have a similar experience with the task and to assess how participants perceived the thermal heat stimuli; all participants will complete ratings after the delivery of each stimulus, using an 11 point NRS ranging from 0 (not at all anxious/no pain/not unpleasant) to 10 (extremely anxious/worst pain/extremely unpleasant) via the following questions:

1) How anxious were you?
2) How intense was it?
3) How unpleasant was it?

Instructions
Before the commencement of this task participants will receive the following instructions:

“In this experiment you will be presented with a series of cues, with painful thermal stimuli following the presentation of each cue. Following each stimulus you will be asked a series of questions relating to how you experienced and perceived the cue and its paired stimulus.”

Association between the visual cue and the stimulus delivered
As participants are tested twice, different types of cue will be used in each session in an attempt to reduce the carryover/learning effect between the two sessions. Half of the participants recruited will be exposed to the coloured cues in their first session and half of the participants will be exposed to the shape cues in their first session, determined in a pseudorandomised manner.

Timing list for experimental tasks:
Written informed consent and completion of questionnaires (session 1 only) - 30 minutes
Administration of intranasal oxytocin or placebo - 45 minutes
Task 1 - 10 minutes
Task 2 - 10 minutes
Task 3 - 20 minutes
Task 4 - 25 minutes
Participant debrief - 5 minutes
TOTAL Time - 155 minutes
Intervention code [1] 294534 0
Treatment: Drugs
Comparator / control treatment
Placebo nasal spray that contains the same ingredients as the intervention, minus the active ingredient.
A group of healthy, pain-free controls will also be enrolled in this study as a control group.
Control group
Placebo

Outcomes
Primary outcome [1] 298056 0
Maximum change in heart rate measured by a 5 lead electrocardiograph system between anticipation and stimulus delivery periods of pain anxiety paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [1] 298056 0
Heart rate is monitored continuously during the completion of Task 1 and Task 4 in both testing sessions.
Primary outcome [2] 298057 0
Maximum change in skin conductance measured by skin conductance finger electrodes between anticipation and stimulus delivery periods of pain anxiety paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [2] 298057 0
Skin conductance is monitored continuously during the completion of Task 1 and Task 4 in both testing sessions.
Primary outcome [3] 298058 0
Subjective ratings of anticipatory anxiety using an 11-point numerical rating scale (NRS) in response to the presentation of a visual cue in pain anxiety paradigm.
Timepoint [3] 298058 0
Measured in 12 seconds following stimulus delivery.
Secondary outcome [1] 323069 0
Subjective ratings of pain intensity using an 11-point numerical rating scale (NRS) in response to the delivery of thermal heat stimuli during a pain anxiety paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [1] 323069 0
Measured in 12 seconds following stimulus delivery.
Secondary outcome [2] 323070 0
Subjective ratings of pain intensity using an 11-point numerical rating scale (NRS) in response to the delivery of thermal heat stimuli during a pain sensitivity paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [2] 323070 0
Measured in 8 seconds following stimulus delivery.
Secondary outcome [3] 323071 0
Musculoskeletal neck and shoulder pain assessed using a 100mm Visual Analogue Scale (VAS)
Timepoint [3] 323071 0
Prior to administration of nasal sprays, prior to commencement of experimental paradigms, and following conclusion of experimental paradigms in first and second testing sessions separated by approximately two weeks.
Secondary outcome [4] 323072 0
Pain threshold level assessed using a device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [4] 323072 0
Pain threshold level is measured 65 minutes post study drug administration in both testing sessions.
Secondary outcome [5] 323073 0
Dominant hand grip strength (measured in kilograms) assessed by a digital dynamometer.
Timepoint [5] 323073 0
Hand grip strength is measured 55 minutes post nasal spray administration (Task 2) in both testing sessions.
Secondary outcome [6] 323074 0
Weight able to safely lift from the floor to waist height, and then from waist height to shoulder height as part of the Progressive Isoinertial Lifting Evaluation (PILE) task.
Timepoint [6] 323074 0
Lifting ability is measured 60 minutes post nasal spray administration (Task 2) in both testing sessions.
Secondary outcome [7] 323075 0
Heart rate variability as measured by a 5 lead electrocardiograph system at rest and during a counting task.
Timepoint [7] 323075 0
Heart rate is recorded continuously throughout Task 1 in both testing sessions, 45 minutes post nasal spray administration.
Secondary outcome [8] 323143 0
Subjective ratings of pain unpleasantness using an 11-point numerical rating scale (NRS) in response to the delivery of thermal heat stimuli during a pain anxiety paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [8] 323143 0
Measured in 12 seconds following stimulus delivery (Task 4).
Secondary outcome [9] 323144 0
Subjective ratings of pain intensity using an 11-point numerical rating scale (NRS) in response to the delivery of thermal heat stimuli during a pain sensitivity paradigm. The heat stimuli are delivered by device that can deliver a controlled amount of heat to the skin to cause a burning sensation.
Timepoint [9] 323144 0
Measured in 8 seconds following stimulus delivery (Task 3).

Eligibility
Key inclusion criteria
Chronic pain participants: English speaking patients aged 18-60 living with musculoskeletal neck and/or shoulder pain that has lasted for at least twelve months and who have been constant in their pain and symptoms for the last 6 months.

Healthy volunteers will be recruited as control participants and will be subject to the same inclusion/exclusion criteria as the chronic pain participants, with the exception of the presence of the neck and/or shoulder pain.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Any form of current active treatment (e.g. physiotherapy, manual therapy); past or current history of medical conditions known to affect autonomic functioning (e.g. diabetes, dysthyroidism); past or current history of cancer or other malignancies, asthma or any other chronic respiratory condition, psychological or psychiatric conditions (identified as “at risk” of moderate depression, anxiety, or suicidal ideation (as indicated by scores higher than 20 on the Beck Depression Inventory II (BDI-II), scores greater than 15 on the Beck Anxiety Inventory (BAI), or a score of 2 or more on item 9 of the BDI-II)) , alcohol or substance abuse disorders, hypertension or heart disease, neurodegenerative diseases, colour blindness, moderate-severe traumatic brain injury; medications known to affect the autonomic nervous system (e.g. beta blockers, selective serotonin reuptake inhibitors, opioids, benzodiazepines, tricyclic antidepressants, anticholinergics, antiarrhythmics); pregnancy or breastfeeding; any known allergies; incapable of walking; bedridden.

Healthy volunteers will be recruited as control participants and will be subject to the same inclusion/exclusion criteria as the chronic pain participants, with the exception of the presence of the neck and/or shoulder pain.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Nasal sprays will be labelled with a code specific for participants as they are recruited. The compounding chemist will provide a randomisation schedule to ensure the study follows a double-blind cross-over randomised controlled trial experimental design. This randomisation schedule will be kept by an individual not involved in the recruitment or screening of participants, the administration of the sprays, or data collection.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation of the drugs will be conducted by the clinical trials pharmacist by means of a computerised method using Microsoft Windows Excel.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
23/09/2015
Date of last participant enrolment
Anticipated
30/06/2017
Actual
25/11/2016
Date of last data collection
Anticipated
31/01/2017
Actual
16/12/2016
Sample size
Target
50
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 293426 0
Government body
Name [1] 293426 0
Australian Research Council
Country [1] 293426 0
Australia
Funding source category [2] 293427 0
University
Name [2] 293427 0
Monash University
Country [2] 293427 0
Australia
Primary sponsor type
Individual
Name
Dr Melita Giummarra
Address
School of Public Health and Preventive Medicine
Monash University
99 Commercial Road
MELBOURNE VIC 3000
Country
Australia
Secondary sponsor category [1] 292245 0
University
Name [1] 292245 0
Monash University
Address [1] 292245 0
Wellington Road
Clayton
Victoria
3800
Country [1] 292245 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294869 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 294869 0
Ethics committee country [1] 294869 0
Australia
Date submitted for ethics approval [1] 294869 0
27/02/2015
Approval date [1] 294869 0
20/04/2015
Ethics approval number [1] 294869 0
CF15/659 - 2015000303
Ethics committee name [2] 294870 0
Alfred Health Human Ethics Committee
Ethics committee address [2] 294870 0
Ethics committee country [2] 294870 0
Australia
Date submitted for ethics approval [2] 294870 0
29/02/2016
Approval date [2] 294870 0
Ethics approval number [2] 294870 0
Approved

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65294 0
Dr Melita Giummarra
Address 65294 0
School of Public Health and Preventive Medicine
Monash University
99 Commercial Road
MELBOURNE VIC 3000
Country 65294 0
Australia
Phone 65294 0
+61 3 9903 0365
Fax 65294 0
Email 65294 0
[email protected]
Contact person for public queries
Name 65295 0
Lincoln Tracy
Address 65295 0
C/O ENRU
School of Psychological Sciences
18 Innovation Walk
Monash University
Clayton VIC 3800
Country 65295 0
Australia
Phone 65295 0
+61 400 692 375
Fax 65295 0
Email 65295 0
[email protected]
Contact person for scientific queries
Name 65296 0
Lincoln Tracy
Address 65296 0
C/O ENRU
School of Psychological Sciences
18 Innovation Walk
Monash University
Clayton VIC 3800
Country 65296 0
Australia
Phone 65296 0
+61 400 692 375
Fax 65296 0
Email 65296 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSex-specific effects of intranasal oxytocin on thermal pain perception: A randomised, double-blind, placebo-controlled cross-over study.2017https://dx.doi.org/10.1016/j.psyneuen.2017.05.028
EmbaseIntranasal oxytocin reduces heart rate variability during a mental arithmetic task: A randomised, double-blind, placebo-controlled cross-over study.2018https://dx.doi.org/10.1016/j.pnpbp.2017.08.016
N.B. These documents automatically identified may not have been verified by the study sponsor.