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

February 10, 2021 updated by: VA Office of Research and Development

Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
29

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: Naltrexone first then placebo
Naltrexone for 8 weeks, then placebo for 8 weeks, blinded cross-over design
Drug: Naltrexone
One 4.5 mg capsule each evening
Drug: Placebo
One capsule each evening
Other: Placebo first then naltrexone
Placebo for 8 weeks, then naltrexone for 8 weeks, blinded cross-over design
Drug: Naltrexone
One 4.5 mg capsule each evening
Drug: Placebo
One capsule each evening

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Brief Pain Inventory - Pain Interference
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo
Sum of 7 questions (each on a 0-10 scale, therefore 0-70 total) on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo.
8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Brief Pain Inventory - Pain Severity
Time Frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Average severity of pain in the past 7 days (0-10). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, and after 8 weeks placebo.
8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
painDETECT
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Measure of neuropathic pain (0-38). Lower score indicates nociceptive pain, higher score indicates neuropathic pain. Results are reported as change from baseline: after 8 weeks of naltrexone or after 8 weeks placebo.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Brief Fatigue Inventory
Time Frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone or after 8 weeks placebo.
8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Beck Depression Inventory-II
Time Frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Questionnaire measuring severity of depression (0-69). Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo
8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Clinical Global Impression of Severity (CGI-S)
Time Frame: 8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo
7-point scale (1-7) of patients' self-reporting of severity during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.
8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo
Clinical Global Impression of Improvement (CGI-I)
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
7-point scale (1-7) of patients' self-reporting of improvement or worsening during the study. A higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Questionnaire, survey of 29 questions assessing health-related quality of life across 8 domains. The subscores are not added to give a single score. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
C Reactive Protein (CRP)
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Blood test for inflammation. Plan was to reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Disease Activity Score (DAS28)
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Measure of disease activity in rheumatoid arthritis. Plan was to reported report results as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Bath Ankylosing Spondylitis Activity Index (BASDAI)
Time Frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Patient-reported index of disease activity for ankylosing spondylitis. Higher is more severe. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo) but data were not collected.
8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
VA Office of Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Paul A. Monach, MD PhD, VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 1, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2019

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 22, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 29, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 2, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 3, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 10, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NURB-008-16S

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • Informed Consent Form (ICF)

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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