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Low Dose Naltrexone for Chronic Pain From Arthritis (LDN-VA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03008590
Recruitment Status : Completed
First Posted : January 2, 2017
Last Update Posted : January 29, 2020
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE December 22, 2016
First Posted Date  ICMJE January 2, 2017
Last Update Posted Date January 29, 2020
Actual Study Start Date  ICMJE May 1, 2018
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 29, 2016)
Brief Pain Inventory - Pain Interference [ Time Frame: 16 weeks ]
Average of 7 questions on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2018)
  • Brief Pain Inventory - Pain Severity [ Time Frame: 16 weeks ]
    Average severity of pain in the past 7 days (0-10)
  • painDETECT [ Time Frame: 16 weeks ]
    Measure of neuropathic pain (0-38)
  • Brief Fatigue Inventory [ Time Frame: 16 weeks ]
    Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales).
  • PROMIS-29 [ Time Frame: 16 weeks ]
    Questionnaire, survey of health-related quality of life across 8 domains.
  • Beck Depression Inventory-II [ Time Frame: 16 weeks ]
    Questionnaire measuring severity of depression. Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study.
  • Clinical Global Impression of Severity (CGI-S) [ Time Frame: 16 weeks ]
    7-point scale of patients' self-reporting of severity during the study.
  • C reactive protein [ Time Frame: 16 weeks ]
    Biomarker of inflammation
  • DAS-28 [ Time Frame: 16 weeks ]
    Assessment of disease activity in rheumatoid arthritis (only for patients with rheumatoid arthritis)
  • BASDAI [ Time Frame: 16 weeks ]
    Assessment of disease activity by MD in spondyloarthritis (to be used only for patients with spondyloarthritis)
  • Clinical Global Impression of Improvement (CGI-I) [ Time Frame: 16 weeks ]
    7-point scale of patients' self-reporting of improvement or worsening during the study
Original Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2016)
  • Brief Pain Inventory - Pain Severity [ Time Frame: 16 weeks ]
    Average severity of pain in the past 7 days (0-10)
  • painDETECT [ Time Frame: 16 weeks ]
    Measure of neuropathic pain (0-38)
  • Pressure Pain Threshold Testing [ Time Frame: 16 weeks ]
    Measurement of the minimum amount of pressure applied to the kneecap produces pain, using an algometer. A low PPT is regarded as a measure of sensitization to painful stimuli.
  • Brief Fatigue Inventory [ Time Frame: 16 weeks ]
    Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales).
  • PROMIS-29 [ Time Frame: 16 weeks ]
    Questionnaire, survey of health-related quality of life across 8 domains.
  • Beck Depression Inventory-II [ Time Frame: 16 weeks ]
    Questionnaire measuring severity of depression. Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study.
  • Clinical Global Impression of Severity (CGI-S) [ Time Frame: 16 weeks ]
    7-point scale of patients' self-reporting of severity during the study.
  • C reactive protein [ Time Frame: 16 weeks ]
    Biomarker of inflammation
  • DAS-28 [ Time Frame: 16 weeks ]
    Assessment of disease activity in rheumatoid arthritis (only for patients with rheumatoid arthritis)
  • BASDAI [ Time Frame: 16 weeks ]
    Assessment of disease activity by MD in spondyloarthritis (to be used only for patients with spondyloarthritis)
  • Clinical Global Impression of Improvement (CGI-I) [ Time Frame: 16 weeks ]
    7-point scale of patients' self-reporting of improvement or worsening during the study
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low Dose Naltrexone for Chronic Pain From Arthritis
Official Title  ICMJE Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis
Brief Summary Over 100 million Americans report chronic pain. Veterans are disproportionately affected for multiple reasons, including injuries and post-traumatic stress disorder. Treatment for chronic pain is a priority research area for the VA. One of the most common causes of chronic pain is osteoarthritis (OA). OA is attributable to "wear and tear," but reasons for pain are complex. Inflammatory arthritis (IA) includes multiple severe diseases that affect 2-3% of persons and require treatment with immune-suppressive drugs to prevent joint destruction. Pain often persists despite effective treatment. Pain in arthritis results from multiple sources: inflammation, perception of pain in the joint, and interpretation of pain by the brain. Unfortunately, management of pain in arthritis remains a challenge. Low dose naltrexone is a widely used but unproven "alternative" approach to chronic pain. It is attractive for study because it is safe and is proposed to work on all three pathways that contribute to pain. A small but high-quality clinical trial is needed to determine whether to invest in definitive studies.
Detailed Description

Chronic pain affects over 100 million Americans, and arthritis is the most common cause. Existing treatments for chronic arthritic pain are only mildly effective, and risks of medications used to treat pain are numerous and continue to be discovered. Treatment of chronic is a high priority research area for VA CSR&D.

Naltrexone is an opioid antagonist that is FDA approved in an oral daily dose of 50 mg to prevent recidivism in alcoholics. At much lower doses of 4 - 4.5 mg daily, however, it has been shown in small, blinded, randomized trials to improve pain in fibromyalgia, gastrointestinal symptoms in Crohn's disease, and quality of life in multiple sclerosis. The only other published data are case reports in complex regional pain syndrome, low back pain, and scleroderma. However, advocacy of low-dose naltrexone (LDN) by internet-based MDs and patients is high, and since LDN can be prescribed off-label, its use greatly exceeds what is justified by evidence. The drug can be prescribed only via compounding pharmacies, so its use costs a patient ~$40/month.

Among the many unproven treatments that are widely used, LDN is of particular interest because results of surveys of patients are particularly impressive, because it is quite safe, and because its benefit is plausible pharmacologically. There is evidence both for modulation of central pain-processing pathways and for down-regulation of inflammatory pathways in microglia. Considering the diversity of conditions proposed to benefit from LDN and the unequivocal need for better approaches to pain relief in chronic conditions, high-quality clinical trials are needed in both inflammatory and non-inflammatory conditions. This small but placebo-controlled study, powered to detect an effect size as small as that seen with NSAIDs or the most beneficial non-pharmacologic approaches, is proposed as a prerequisite for considering a pivotal trial through the VA Cooperative Studies Program.

The proposed study is a randomized, double-blinded, cross-over, placebo-controlled trial in adults with osteoarthritis or inflammatory arthritis and persistent pain. Sixty patients will be enrolled for 16 weeks, during which they will receive LDN for 8 weeks and placebo for 8 weeks. Widely accepted patient-reported outcome measures will be used. The co-primary endpoints are reduction in pain severity or pain's interference with function during 8 weeks of LDN compared to 8 weeks placebo, using the Brief Pain Inventory. Other patient-reported data will be used both as secondary outcomes and as covariates in analyzing determinants of response to treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Osteoarthritis
  • Arthritis, Rheumatoid
  • Arthritis, Psoriatic
Intervention  ICMJE
  • Drug: Naltrexone
    One 4.5 mg capsule each evening
  • Drug: Placebo
    One capsule each evening
Study Arms  ICMJE
  • Naltrexone first then placebo
    Naltrexone for 8 weeks, then placebo for 8 weeks, blinded cross-over design
    Interventions:
    • Drug: Naltrexone
    • Drug: Placebo
  • Placebo first then naltrexone
    Placebo for 8 weeks, then naltrexone for 8 weeks, blinded cross-over design
    Interventions:
    • Drug: Naltrexone
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 27, 2020)
23
Original Estimated Enrollment  ICMJE
 (submitted: December 29, 2016)
60
Actual Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Patients must meet all of the following criteria in order to be eligible for enrollment:

  • Veteran or otherwise eligible for VA benefits, able to travel to VA Boston
  • One or more of the following chronic conditions:

    • osteoarthritis
    • rheumatoid arthritis
    • non-axial spondyloarthritis
  • Average daily pain interference with function (average of the 7 parts of question 9 on the Brief Pain Inventory) rated at least 4 on a scale of 0-10, and no higher than 9
  • No change in medication in the past 8 weeks made with the expectation of improving pain
  • No plan to start another medication or a non-pharmacologic treatment regimen likely to affect pain during the next 16 weeks
  • Age at least 18
  • Registered for medical care in the VA Boston Healthcare System
  • Capable of informed consent, and willingness to comply with study procedures, including receipt of weekly phone calls from the study coordinator

Exclusion Criteria:

Any of the following requires exclusion from participation:

  • Current use of opioids including tramadol
  • Pregnant, breast feeding, or unwilling to engage in contraceptive practices if sexually active and capable of conceiving
  • Schizophrenia, bipolar disorder, or poorly controlled depression or anxiety
  • Previous use of low-dose naltrexone
  • Back pain described by the patient as greater in severity than arthritic pain in a non-axial location
  • Significant kidney disease, defined as glomerular filtration rate < 30 ml/min
  • Liver cirrhosis. There is no specific screening procedure to exclude cirrhosis.
  • Painful peripheral neuropathy. There is no specific screening procedure.
  • Plan to have surgery during the next 16 weeks
  • Inconsistency in self-reporting at the screening visit. BPI, PainDETECT, WOMAC, and PROMIS-29 all contain 0-10 scales of average pain intensity, although the times listed vary from 1-4 weeks. The severity reported on these three scales cannot differ by more than 1.
  • Other qualitative circumstances that the investigator feels would make the patient a poor candidate for this clinical trial, such as an unstable social situation or unreliable transportation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03008590
Other Study ID Numbers  ICMJE NURB-008-16S
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: A de-identified, anonymized dataset containing all the primary study data will be created and shared per VA policies. This dataset will be included as a supplementary file attached to the published manuscript, which in turn will be available through PubMed Central per VA rules. In the event that the study has not been published, the dataset will be made available by other means within 3 years of study completion. The publicly available dataset will not include any identifiers, e.g. age will be included but not birthdate.
Supporting Materials: Informed Consent Form (ICF)
Time Frame: ICF to be posted within 3 months per VA policy. De-identified dataset to be included as supplementary material with publication, anticipated to be within 12 months of study completion.
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul A. Monach, MD PhD VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
PRS Account VA Office of Research and Development
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP