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Trial registered on ANZCTR


Registration number
ACTRN12619000418178p
Ethics application status
Submitted, not yet approved
Date submitted
18/02/2019
Date registered
14/03/2019
Date last updated
26/03/2019
Date data sharing statement initially provided
14/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Palmitoylethanolamide for the treatment of centralised chronic pain
Scientific title
Palmitoylethanolamide for the treatment of chronic nociplastic pain: a randomised double-blind placebo-controlled trial.
Secondary ID [1] 297436 0
Nil known
Universal Trial Number (UTN)
U1111-1228-7941
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Pain 311616 0
Condition category
Condition code
Anaesthesiology 310242 310242 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Palmitoylethanolamide 300mg capsules. 300mg orally twice daily for 2 weeks then 600mg orally twice daily for further 24 weeks.

Patients will be reviewed at 3 months and 6 months and asked to bring in medications to monitor adherence.
Intervention code [1] 313691 0
Treatment: Drugs
Comparator / control treatment
Placebo capsule containing lacose. one capsule orally twice daily for 2 weeks then two capsules orally twice daily for further 24 weeks.
Control group
Placebo

Outcomes
Primary outcome [1] 319127 0
Mean pain interference as assessed by the Brief Pain Inventory (BPI)
Timepoint [1] 319127 0
6 months post baseline
Secondary outcome [1] 367039 0
Mean Pain Interference as measured by BPI
Timepoint [1] 367039 0
3 months post baseline
Secondary outcome [2] 367040 0
Average pain as measure by BPI
Timepoint [2] 367040 0
3 months post baseline
Secondary outcome [3] 367041 0
Average pain as measure by BPI
Timepoint [3] 367041 0
6 months post baseline
Secondary outcome [4] 367042 0
DASS21 score
Timepoint [4] 367042 0
3 months post baseline
Secondary outcome [5] 367043 0
DASS21 score
Timepoint [5] 367043 0
6 months post baseline
Secondary outcome [6] 367044 0
Pain Catastrophising Scale (PCS) score
Timepoint [6] 367044 0
3 months post baseline
Secondary outcome [7] 367045 0
PCS score
Timepoint [7] 367045 0
6 months post baseline
Secondary outcome [8] 367046 0
Patient Self Efficacy Questionnaire (PSEQ) score
Timepoint [8] 367046 0
3 months post baseline
Secondary outcome [9] 367047 0
PSEQ score
Timepoint [9] 367047 0
6 months post baseline
Secondary outcome [10] 367048 0
Global assessment of change
Timepoint [10] 367048 0
3 months post baseline
Secondary outcome [11] 367049 0
Global assessment of change
Timepoint [11] 367049 0
6 months post baseline
Secondary outcome [12] 367050 0
Change in daily opioid dose in oral morphine equivalents. The patients use of opioid medications be ascertained from a medication list. Dosing of opioid medications will converted to oral morphine equivalents (OME) using the Australian and New Zealand Collage of Anaesthetists Faculty of Pain Medicine Opioid Calculator . The change (increase or reduction) between baseline and 3 months time point.
Timepoint [12] 367050 0
Baseline to 3 months post baseline
Secondary outcome [13] 367051 0
Change in daily opioid dose in oral morphine equivalents. The patients use of opioid medications be ascertained from a medication list. Dosing of opioid medications will converted to oral morphine equivalents (OME) using the Australian and New Zealand Collage of Anaesthetists Faculty of Pain Medicine Opioid Calculator . The change (increase or reduction) between baseline and 6 months time point.
Timepoint [13] 367051 0
Baseline to 6 months post baseline
Secondary outcome [14] 367052 0
Symptom Severity Score (SSS) from 2011 ACR Fibromyalgia Survey questionnaire
Timepoint [14] 367052 0
3 months post baseline
Secondary outcome [15] 367053 0
Symptom Severity Score (SSS) from 2011 ACR Fibromyalgia Survey questionnaire
Timepoint [15] 367053 0
6 months post baseline

Eligibility
Key inclusion criteria
• Chronic pain at least 3 months duration AND
• Evidence of centralised pain/ neuroinflammatory response as evidenced by Symptom Severity Score (from Fibromyalgia Survey Score) greater than or equal to 7/12 AND
• Average pain intensity as measured by modified BPI greater than or equal to 5/10 (moderate or severe) AND
• Pain interference as measure by BPI greater than or equal to 5/10 (moderate or severe)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Daily opioids > 120 OME
• Planned procedural intervention within 6 months
• Pre-study use of PEA
• Workers compensation or other ongoing compensation claim
• Major psychiatric disease (BPAD, Psychosis, PTSD)
• Pregnancy or breastfeeding
• Non-English speaking
• Cognitive impairment significant enough to impair informed consent

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)
numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical analysis
Continuous outcomes will be assessed for normality using the SK test. Normal data will be presented as mean (SD) and analysed by Student T-test. Non-normal data will be presented as median (IQR) and assessed by Mann-Whitney U-test. Categorical data will be assessed by Chi-Squared test or Fisher’s exact test as appropriate.

Patients will be requested to complete the full 6 months of study drug therapy, and will be requested to complete follow up questionnaires regardless of compliance with use of study drug. Missing data will be filled using last data carried forward. Outcomes will be analysed in an intention to treat analysis, and an alpha of 0.01 will be used to determine statistical significance.

Sample size calculation.
Given a mean baseline pain interference of 7.0, and reductions in pain interference of 30% and 50% in the placebo and PEA groups respectively and an expected SD of 2.0, 100 patients will give 82.4% power with an alpha of 0.01.



Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 13171 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 25726 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 302005 0
Charities/Societies/Foundations
Name [1] 302005 0
ANZCA Research Foundation
Address [1] 302005 0
630 St Kilda Rd, Melbourne VIC 3004
Country [1] 302005 0
Australia
Funding source category [2] 302007 0
Hospital
Name [2] 302007 0
Sir Charles Gairdner Hospital
Address [2] 302007 0
Hospital Ave Nedlands WA 6009
Country [2] 302007 0
Australia
Primary sponsor type
Individual
Name
Daniel Ellyard
Address
Department of Pain Medicine
Sir Charles Gairdner Hospital
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 301789 0
None
Name [1] 301789 0
Address [1] 301789 0
Country [1] 301789 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 302681 0
Sir Charles Gairdner Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 302681 0
Hospital Ave, Nedlands WA 6009
Ethics committee country [1] 302681 0
Australia
Date submitted for ethics approval [1] 302681 0
14/02/2019
Approval date [1] 302681 0
Ethics approval number [1] 302681 0

Summary
Brief summary
Chronic low level inflammation within the central nervous system (CNS) is increasingly being recognised as a potential contributor to many types of persistent pain. Through the activation of glia, especially microglia and astrocytes, it is thought that alterations in synaptic function lead to changes in the way that pain is processed within the CNS. It is believed that these changes play a significant part in the development of central sensitisation. There is also evidence that this glial activation may also account for many of the neuro-vegetative features common in persistent pain such as anxiety, depression, fatigue, poor sleep and cognitive problems. It is hoped that medicines that are able to suppress CNS inflammation might help relieve pain, improve function and associated psychiatric symptoms in patients with chronic pain.

Palmitoylethanolamide (PEA) is a naturally occurring fatty acid involved with known anti-inflammatory properties and has been suggested to be involved in the regulation and termination of inflammatory responses within the CNS. It is currently classed as a nutraceutical and available from compounding chemists without prescription. There is some evidence that administration of PEA has analgesic benefits in a variety of causes of persistent pain, although evidence is limited by significant industry support. It does have anecdotal evidence of positive effects and appears to be very well tolerated, with a low risk of serious adverse effects. Given the limitations in current pharmacologic options in the management of persistent pain, it represents a potential useful addition to the current therapeutic options.

The aim of this study is to assess the ability of daily oral administration of PEA to achieve long lasting improvements pain and function in patients being treated in a tertiary hospital pain clinic. Patients will be selected based on evidence of neuro- vegetative features as assessed by the Symptom Severity Score (SSS ) from the 2011 revised ACR Fibromyalgia Criteria regardless of primary pain diagnosis. The study aims to have high external validity. Patients will be randomised to PEA or placebo in addition to their current therapy for a period of 6 months.

Outcomes will be assessed via the electronic Persistent Pain Outcomes Collaborative (ePPOC) questionnaires, with a primary outcome of Pain Interference as assessed by the Brief Pain Inventory (BPI) at 6 months.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91046 0
Dr Daniel Ellyard
Address 91046 0
Department of Pain Medicine
Sir Charles Gairdner Hospital
Hospital Ave, Nedlands WA 6009
Country 91046 0
Australia
Phone 91046 0
+61 8 6457 3333
Fax 91046 0
Email 91046 0
daniel.ellyard@health.wa.gov.au
Contact person for public queries
Name 91047 0
Dr Daniel Ellyard
Address 91047 0
Department of Pain Medicine
Sir Charles Gairdner Hospital
Hospital Ave, Nedlands WA 6009
Country 91047 0
Australia
Phone 91047 0
+61 8 6457 3333
Fax 91047 0
Email 91047 0
daniel.ellyard@health.wa.gov.au
Contact person for scientific queries
Name 91048 0
Dr Daniel Ellyard
Address 91048 0
Department of Pain Medicine
Sir Charles Gairdner Hospital
Hospital Ave, Nedlands WA 6009
Country 91048 0
Australia
Phone 91048 0
+61 8 6457 3333
Fax 91048 0
Email 91048 0
daniel.ellyard@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual scores for each of the primary and secondary outcomes.
When will data be available (start and end dates)?
Following publications of results, no end date
Available to whom?
Journal editors, Researches conducting systemic reviews/meta-analysis
Available for what types of analyses?
systemic reviews/meta-analysis
How or where can data be obtained?
Following written request - de-identified data spread sheets will be supplied
What supporting documents are/will be available?
Study protocol
Ethical approval
Summary results
No Results