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

• ClinicalTrials.gov Identifier: NCT03008590
• Recruitment Status: Completed
• First Posted: January 2, 2017
• Results First Posted: March 3, 2021
• Last Update Posted: March 3, 2021
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Osteoarthritis; Arthritis, Rheumatoid; Arthritis, Psoriatic	Drug: Naltrexone; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis
• Actual Study Start Date: May 1, 2018
• Actual Primary Completion Date: December 31, 2019
• Actual Study Completion Date: December 31, 2019

Arms and Interventions

Arm	Intervention/treatment
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
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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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
5. 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.
6. 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.
7. 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. 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.
9. 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.
10. 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.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, United States, 02130

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: Paul A. Monach, MD PhD; VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:

Informed Consent Form  [PDF] March 25, 2019

Study Protocol and Statistical Analysis Plan  [PDF] September 9, 2019

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT03008590
• Other Study ID Numbers: NURB-008-16S
• First Posted: January 2, 2017
• Results First Posted: March 3, 2021
• Last Update Posted: March 3, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• 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.

• 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

Keywords provided by VA Office of Research and Development:

Pain management; Naltrexone; Controlled clinical trials, randomized

Additional relevant MeSH terms:

Arthritis; Osteoarthritis; Arthritis, Rheumatoid; Arthritis, Psoriatic; Chronic Pain; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Pain; Neurologic Manifestations; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Spondylarthropathies; Spondylarthritis; Spondylitis; Spinal Diseases; Bone Diseases; Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Naltrexone; Alcohol Deterrents; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents