Arthritis, Psoriatic, Arthritis, Rheumatoid, Osteoarthritis
Conditions
Keywords
Pain management, Naltrexone, Controlled clinical trials, randomized
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.
Interventions
DRUGNaltrexone
One 4.5 mg capsule each evening
DRUGPlacebo
One capsule each evening
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Pain Inventory - Pain Interference | 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
| Measure | Time frame | Description |
|---|---|---|
| painDETECT | 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. |
| Brief Fatigue Inventory | 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. |
| Beck Depression Inventory-II | 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 |
| Clinical Global Impression of Severity (CGI-S) | 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. |
| Brief Pain Inventory - Pain Severity | 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. |
| Patient Reported Outcomes Measurement Information System Profile (PROMIS-29) | 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. |
| C Reactive Protein (CRP) | 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. |
| Disease Activity Score (DAS28) | 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. |
| Bath Ankylosing Spondylitis Activity Index (BASDAI) | 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. |
| Clinical Global Impression of Improvement (CGI-I) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Naltrexone First Received naltrexone first, then placebo | 11 |
| Placebo First Received placebo first, then naltrexone | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | Naltrexone First | Total | Placebo First |
|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 8.2 | 63 years STANDARD_DEVIATION 10 | 64 years STANDARD_DEVIATION 11.9 |
| Body mass index | 33 kg/m^2 STANDARD_DEVIATION 7.9 | 34 kg/m^2 STANDARD_DEVIATION 7.3 | 35 kg/m^2 STANDARD_DEVIATION 6.9 |
| Brief Pain Inventory - Pain interference (sum of 7 subscales, each 0-10) | 39 units on a 0-70 scale (higher is worse) STANDARD_DEVIATION 9.5 | 41 units on a 0-70 scale (higher is worse) STANDARD_DEVIATION 10.5 | 42 units on a 0-70 scale (higher is worse) STANDARD_DEVIATION 11.5 |
| Brief Pain Inventory - Pain severity | 5.9 units on a 0-10 scale (higher is worse) STANDARD_DEVIATION 1.2 | 5.9 units on a 0-10 scale (higher is worse) STANDARD_DEVIATION 1.2 | 5.9 units on a 0-10 scale (higher is worse) STANDARD_DEVIATION 1.3 |
| Diagnosis, OA or IA Inflammatory arthritis | 4 Participants | 6 Participants | 2 Participants |
| Diagnosis, OA or IA Osteoarthritis | 7 Participants | 17 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 22 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 20 Participants | 11 Participants |
| Region of Enrollment United States | 11 Participants | 23 Participants | 12 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 7 / 29 | 12 / 29 |
| serious Total, serious adverse events | 0 / 29 | 2 / 29 |
Outcome results
Primary
Brief Pain Inventory - Pain Interference
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Brief Pain Inventory - Pain Interference | -23 units on a scale | Standard Deviation 19.4 |
| At End of 8 Weeks Placebo Treatment | Brief Pain Inventory - Pain Interference | -22 units on a scale | Standard Deviation 19.2 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.9Mixed Models Analysis
Secondary
Bath Ankylosing Spondylitis Activity Index (BASDAI)
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Population: Data not collected
Secondary
Beck Depression Inventory-II
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
Time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Beck Depression Inventory-II | -1.0 units on a scale | Standard Deviation 4.29 |
| At End of 8 Weeks Placebo Treatment | Beck Depression Inventory-II | -1.7 units on a scale | Standard Deviation 6.04 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.04Mixed Models Analysis
Secondary
Brief Fatigue Inventory
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.
Time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Brief Fatigue Inventory | -1.8 units on a scale | Standard Deviation 1.61 |
| At End of 8 Weeks Placebo Treatment | Brief Fatigue Inventory | -1.8 units on a scale | Standard Deviation 2.71 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.3Mixed Models Analysis
Secondary
Brief Pain Inventory - Pain Severity
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.
Time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Brief Pain Inventory - Pain Severity | -1.7 units on a scale | Standard Deviation 1.87 |
| At End of 8 Weeks Placebo Treatment | Brief Pain Inventory - Pain Severity | -2.0 units on a scale | Standard Deviation 2.17 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.22Mixed Models Analysis
Secondary
Clinical Global Impression of Improvement (CGI-I)
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Clinical Global Impression of Improvement (CGI-I) | -0.3 units on a scale | Standard Deviation 1.2 |
| At End of 8 Weeks Placebo Treatment | Clinical Global Impression of Improvement (CGI-I) | -0.2 units on a scale | Standard Deviation 1.71 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.92Mixed Models Analysis
Secondary
Clinical Global Impression of Severity (CGI-S)
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.
Time frame: 8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | Clinical Global Impression of Severity (CGI-S) | -1.1 units on a scale | Standard Deviation 1.59 |
| At End of 8 Weeks Placebo Treatment | Clinical Global Impression of Severity (CGI-S) | -1.1 units on a scale | Standard Deviation 1.83 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.78Mixed Models Analysis
Secondary
C Reactive Protein (CRP)
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Population: Data were not collected
Secondary
Disease Activity Score (DAS28)
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Population: Data not collected.
Secondary
painDETECT
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| At End of 8 Weeks Naltrexone Treatment | painDETECT | -4.0 units on a scale | Standard Deviation 6.26 |
| At End of 8 Weeks Placebo Treatment | painDETECT | -5.6 units on a scale | Standard Deviation 5.73 |
Comparison: Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).p-value: 0.02Mixed Models Analysis
Secondary
Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)
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.
Time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
Population: Data not collected