Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis
Project Number5I01CX001513-02
Contact PI/Project LeaderMONACH, PAUL A
Awardee OrganizationVA BOSTON HEALTH CARE SYSTEM
Description
Abstract Text
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 12 weeks, during
which they will receive LDN for 8 weeks and placebo for 4 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 4 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. Key inclusion criteria include diagnosis of OA or IA and pain rated at least 4 on a scale
of 0-10, a widely accepted criterion. Key exclusion criteria, chosen conservatively for the purposes of safety,
include opioid use or severe liver, kidney, or psychiatric disease. OA, IA, and inadequate control of pain are
sufficiently common that the study can be completed in two years at a single center.
Public Health Relevance Statement
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.
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