Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis
Phase: PHASE2
Conditions: Osteoarthritis, Arthritis, Rheumatoid, Arthritis, Psoriatic
Sponsor: VA Office of Research and Development

1 
 
Clinical Trial Protocol 
 
Title: 
Low dose naltrexone for chronic pain in osteoarthritis and 
inflammatory arthritis 
Protocol Number: 
 
IRB #3062 (VA Boston Healthcare System) 
ClinicalTrials.gov: 
 
NCT03008590 
Investigational Product:   
Naltrexone 4.5 mg 
Protocol Version: 
 
5 (September 9, 2019) 
 
Principal Investigator 
 
Paul Monach, MD, PhD 
PI Address: 
 
Rheumatology Section, VA Boston Healthcare System 
 
 
150 South Huntington Ave. 
 
 
Jamaica Plain, MA  02130 
 
PI Telephone: 
 
857-364-5552 
 
PI email: 
 
paul.monach@va.gov 
 
Trial Sponsor: 
 
VA ORD 
AE Reporting: 
 
Paul Monach 
 
 
Study coordinator, Britte Beaudette-Zlatanova 
 
Protocol and AE Review:  
IRB of VA Boston Healthcare System, DMC (VA Central Office) 
Funding: 
 
CSR&D Merit Review Award 
 
 

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Table of Contents  
1. Synopsis ………………………………………………………………………………………………………….. 4  
2. Study abstract ……………………………………………………………………………………………………. 8  
3. Study endpoints ………………………………………………………………………………………………….. 8   
a. Primary outcome ……………………………………………………………………………………….. 8  
b. Secondary outcomes …………………………………………………………………………………... 8   
4. Background and Rationale ……………………………………………………………………………………… 9 
a. Background ……………………………………………………………………………………………… 9   
b. Rationale for the Clinical Trial Design ……………………………………………………………….. 13  
5. Study Design and Methods …………………………………………………………………………………….. 14  
a. Overview ………………………………………………………………………………………………… 14   
b. Identification of Patients ……………………………………………………………………………….. 15   
i. Inclusion Criteria ………………………………………………………………………………. 15  
ii. Exclusion Criteria ………………………………………………………………………………15 
iii. Notes on inclusion and exclusion criteria ………………………………………………….. 16   
c. Study Medication ……………………………………………………………………………………….. 16   
i. Randomized Treatment Period: Methods and Doses ……………………………………... 17   
ii. Prohibited Medications ……………………………………………………………………….. 17   
d. Study Procedures ………………………………………………………………………………………. 18 
i. Recruitment ……………………………………………………………………………………. 18 
ii. Screening ……………………………………………………………………………………… 19 
iii. Enrollment …………………………………………………………………………………….. 19 
iv. Visit Frequency/ Visit Schedule …………………………………………………………….. 19 
v. Study Assessments …………………………………………………………………………... 19 
1). Study Assessment …………………………………………………………………. 19 
2). Study Schedule Table …………………………………………………………….. 21 
e. Common Closing Date - Study Duration …………………………………………………………….  22 
f. Criteria for Withdrawal of Study Medication – Early Termination …………………………………. 22 
g. Outcome Definitions …………………………………………………………………………………… 22 
6. Safety Monitoring and Adverse Event Reporting …………………………………………………………….  22 
a. Nature of Study ………………………………………………………………………………………… 22 
b. Study Oversight ……………………………………………………………………………………….. 23 
c. Definitions ………………………………………………………………………………………………. 23 
d. Toxicity Grading of Adverse Events ………………………………………………………………….  24 
e. Relation to Study Therapy ……………………………………………………………………………. 24 
f. Standard Elements …………………………………………………………………………………….. 25 
g. Expected/Known Risks/Adverse Events Associated with Study Intervention and Procedures .. 25 
h. Reporting Timeline …………………………………………………………………………………….. 25 
i. Investigational New Drug Application (IND) …………………………………………………………. 25 
j. Planned Interim Analysis ………………………………………………………………………………. 25 
k. Criteria to Suspend Enrollment ………………………………………………………………………. 26 
7. Data Analysis and Statistical Considerations ………………………………………………………………… 26 
a. Primary Outcome …….………………………………………………………………………………… 26 
 
i. Primary Analytical Approach to the Primary Outcome ……………………………………. 26 
 
ii. Secondary Analytical Approaches to the Primary Outcome …………………………….. 26 
 
iii. Sample Size Calculations …………………………………………………………………… 27 
b. Secondary Outcomes …………………………………………………………………………………. 28 
8. Data Management ………………………………………………………………………………………………. 28 
a. Registration …………………………………………………………………………………………….. 28 

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b. Randomization …………………………………………………………………………………………. 29 
c. Data Entry ………………………………………………………………………………………………. 29 
d. Data Quality Control …………………………………………………………………………………… 30 
9. Protection of Human Subjects …………………………………………………………………………………. 30 
a. GCP Statement ………………………………………………………………………………………… 30 
b. Benefits and Risks …………………………………………………………………………………….. 30 
i. Risks of Low-Dose Naltrexone ……………………………………………………………… 31 
ii. Other Risks ………………………………………………………………………………….… 31 
10. References ……………………………………………………………………………………………………… 32 
 
 

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1. Synopsis 
 
 
Title 
 
Low dose naltrexone for chronic pain in osteoarthritis and inflammatory arthritis 
 
 
Clinical Phase 
II 
 
Investigators 
 
Principal Investigator:  Paul A. Monach, MD, PhD 
 
 
Study Principal 
Investigator 
 
Paul A. Monach, MD, PhD 
 
 
Co-Investigators 
 
Eugene Bacorro, MD 
Maureen Dubreuil, MD 
Maneet Kaur, MD 
Antonio Lazzari, MD 
Caryn Libbey, MD 
John Otis, PhD 
 
 
IND Holder / Sponsor 
 
Not applicable (exempt) 
 
 
Funding 
 
VA CSR&D Merit Review Award 
 
 
Accrual Objective 
 
60 enrolled subjects, to achieve 54 subjects completing protocol. Patients with 
osteoarthritis (minimum 30) or inflammatory arthritis (rheumatoid arthritis or 
non-axial spondyloarthritis, minimum 10) will be enrolled. 
 
 
Accrual Period 
 
18 months 
 
 
Study Duration 
 
24 months 
 
 
 
Study Design 
 
 
Randomized, double-blind, cross-over, placebo-controlled trial to evaluate the 
efficacy of naltrexone 4.5 mg daily in reducing chronic pain in patients with 
persistent pain from arthritis.  Additional medical problems and medications 
given to control pain must be stable for 8 weeks.   
 
At study enrollment, each patient will be randomized to receive either oral 
naltrexone for 8 weeks followed by oral placebo for 8 weeks, or placebo for 8 
weeks followed by naltrexone for 8 weeks.  The patient will be blinded to the 
cross-over time. The primary outcome measures and most secondary outcome 
measures are patient-reported and will be recorded weekly by patients.  Other 
outcome measures will be collected at 3 in-person visits. 
 
 
Primary Objective 
 
Reduction in interference of pain with activities, with naltrexone compared to 
placebo 
 
 
Primary Outcome 
Measures 
 
 
Brief Pain Inventory (BPI) (pain interference) 
 
 
Secondary Objectives 
 
Reduction in severity of pain with naltrexone 
Reduction in fatigue with naltrexone. 
Improvement in quality of life with naltrexone 
Monitoring of mood during naltrexone treatment 
Assessment of changes in disease activity during naltrexone treatment 
Assessment of factors associated with improvement: neuropathic pain, type of 
arthritis, biomarkers of inflammation 

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Safety of naltrexone in patients with rheumatic diseases 
 
 
Secondary Outcome  
Measures 
 
Brief Pain Inventory (all other sub-scales than pain interference) 
painDETECT (neuropathic pain) 
Brief Fatigue Inventory 
PROMIS-29 (HRQoL survey) 
Beck Depression Inventory-II 
Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) Scale 
Use of “as-needed” analgesic medications 
Disease activity: DAS28, BASDAI 
Biomarkers associated with inflammation 
Adverse events, including grade 1 neuropsychiatric events 
 
Inclusion Criteria 
 
Patients must meet all of the following criteria in order to be eligible for 
enrollment: 
 
• 
One or more of the following chronic conditions: osteoarthritis, 
rheumatoid arthritis, peripheral spondyloarthritis 
• 
Average daily pain interference with function (average of the 7 parts of 
question 9 on the BPI) rated at least 4 on a scale of 0-10, and no 
higher than 9 
• 
No increase 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 
• 
Capable of informed consent, and willingness to comply with study 
procedures, including receipt of weekly phone calls from the study 
coordinator 
 
 
Exclusion Criteria 
 
• 
Use of opioids including tramadol, in the past 7 days  
• 
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 for more than 8 weeks or in the 
past 2 weeks 
• 
Back pain described by the patient as greater in severity than arthritic 
pain in all peripheral locations 
• 
Significant kidney disease, defined as glomerular filtration rate < 30 
ml/min 
• 
Liver cirrhosis. There is no specific screening procedure to exclude 
cirrhosis. 
• 
Peripheral neuropathy described by the patient as greater in severity 
than arthritic pain.  There is no specific screening procedure. 
• 
Plan to have surgery during the next 16 weeks 
• 
Other qualitative circumstances that the investigator feels would make 

6 
 
the patient a poor candidate for this clinical trial, such as an unstable 
social situation or unreliable transportation 
 
 
 
Study Treatment 
 
 
Patients will undergo a blinded randomization to receive naltrexone or placebo 
during the first treatment period, and will receive the opposite during the 
second treatment period: 
Group 
Weeks 1-8 
Weeks 9-16 
1 
Low-Dose Naltrexone 
Placebo 
2 
Placebo 
Low-Dose Naltrexone 
 
Naltrexone will be provided at 4.5 mg in a capsule, to be taken daily. Placebo 
capsules will be made to be indistinguishable from naltrexone. 
Use of any opioid agonist, including tramadol, is an exclusion criterion for 
enrollment, and these drugs must also be avoided during the trial.  
  
 
Data Collection 
Schedule 
 
The primary outcome measure and most secondary outcome measures will be 
reported by patients weekly using paper forms. 
 
In-person study visits:  screening/baseline and weeks 8 and 16.  Adverse 
events and disease activity will be assessed at the in-person visits. 
 
 
Statistical Analysis 
 
Pain interference on the Brief Pain Inventory, an average of scores of 7 
questions, each measured on a scale of 0-10, will be analyzed as the primary 
outcome measure.   
 
The summary of each patient’s response to LDN compared to placebo will be 
made using linear contrasts.  Thus, for each patient: 
          d = an1xn1 + an2xn2 … + an8xn8 – ap1xp1 – ap2xp2 … – ap8xp8 
where each “a” indicates a weight assigned to that observation on the basis of 
fitting the pre-post crossover data from all patients with a cubic spline or two 
linear splines; n indicates treatment with naltrexone; p indicates treatment with 
placebo; x indicates magnitude of pain interference; and numbers indicate 
weeks on the treatment.  The first two observations following cross-over will be 
dropped in each patient.  Thus, in group 1, weights of ap1 and ap2 will be 0, and 
in group 2, weights an1 and an2 will be 0.  Weights will be adjusted in individual 
patients in the event of missing data; the weight given to the summary value of 
each patient’s data (d) in the full analysis, however, will be equal.  In each 
patient, the sum of all weights will be set to 0. The distribution of d among all 
patients will then be compared to a null distribution by t-test.  
 
The minimum effect size (ES) that characterizes treatments that are regarded 
as being effective for reducing pain in OA is about 0.3 compared to oral 
placebo.  Estimating that the response during placebo will have a standard 
deviation  = 2.0 on a scale of 0-10, the minimum absolute mean difference 
between LDN and placebo that we wish to detect is  = ES *  = 0.3 * 2 = 0.6. 
The design has 80% power to detect a mean difference between treatments of 
0.6 or larger with a two-sided type I error of 5%.   This allows for up to 4 of 30 
patients in each group to drop out before 12 weeks. 
 
The primary analysis will include osteoarthritis and inflammatory arthritides 
together to maximize power.  Osteoarthritis and inflammatory arthritis will also 
be analyzed separately because they have different pathophysiologies. 
 
Effects of covariates on response to treatment will be analyzed in two ways: 
 
1. Linear regression, where response (d) is the dependent variable, and 

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independent variables include age, sex, diagnosis of OA or IA, group 
assignment (1 or 2), baseline pain severity, baseline CRP (with or without an 
interaction term to limit this variable to patients with IA), and baseline scores 
on painDETECT (total score), Brief Fatigue Inventory (total score), and Beck 
Depression Inventory-II (total score) 
 
2. Mixed model, where the raw score (x) at any time is the dependent variable, 
and independent fixed effect variables include current treatment, time since 
enrollment, all of the covariates listed above for linear regression, and the 
random effect is the patient 
 
The primary and secondary analytical approaches for the secondary outcomes 
will be the same as for the co-primary outcome measures for all continuous 
variables.  Outcomes based on classification will use analysis of proportions of 
patients transitioning from one class to another. 
 
 
Safety and Monitoring 
 
Standardized definitions and timelines will be used for the reporting of serious 
and non-serious adverse events. 
 
A VA-assigned Data Monitoring Committee (DMC) and the Institutional Review 
Board of the VA Boston Healthcare System will monitor safety and all other 
aspects of the study. 
 
 
 
 

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2. Study Abstract  (summary for lay-persons) 
 
Naltrexone is an FDA approved drug (for alcoholism) that has found widespread use “off-label” 
to treat pain and fatigue at much lower doses than are used for the approved indication.  There 
are a few scientific studies in three conditions (fibromyalgia, Crohn's disease, and multiple 
sclerosis) that suggest that this drug has benefit and is safe.  However, considering the extent of 
use in other conditions, and uncertainty about the mechanism of action (purely a pain 
reliever?  other benefits on brain chemistry?  anti-inflammatory?), study is needed in diverse 
diseases.  The current study is intended to generate preliminary data in several rheumatologic 
conditions (osteoarthritis and multiple forms of inflammatory arthritis) in order to select such 
conditions for future study in larger clinical trials.  Although it is a pilot study, a placebo-
controlled component is used because of the prominent placebo group effect seen in studies in 
which self-reported pain is the main outcome.  A "blinded cross-over" design is used so that 
patients will not know when they might be transitioning between placebo and naltrexone. 
 
 
 
3. Study Endpoints 
 
a. Primary Outcome 
• Average interference of pain with general activity (question 9 on the Brief Pain 
Inventory, an average of 7 sub-questions, each 0-10) will be compared during 
naltrexone treatment and during placebo treatment. 
 
 
b. Secondary Outcomes 
The secondary outcome measures include: 
• Brief Pain Inventory [other individual questions than those used for the primary 
outcome, particularly question 5 (average pain severity)] 
• painDETECT (continuous measure 0-38, or classified as 
nociceptive/unclear/neuropathic per the questionnaire guidelines) 
• Brief Fatigue Inventory, specifically question 2 (usual level in past 24 hours, 0-10) and 
question 4 (interference in the past 24 hours, average of 6 questions 0-10 each) 
• PROMIS-29 (total score, continuous measure, 28-150) 
• Beck Depression Inventory-II (continuous measure 0-63, or classified as 
minimal/mild/moderate/severe per the questionnaire guidelines) 
• Use of “as-needed” analgesic medications (weekly, expressed as % of maximum 
prescription dose) 
• Patient global assessment of improvement or worsening on a 7-point scale [Clinical 
Global Impression of Severity (CGI-S) and Improvement (CGI-I) Scales] 
• CRP 
• Adverse events, collected using the IRB’s and DMC’s standard forms 
 
 

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Secondary outcome measures for specific diseases: 
• Rheumatoid arthritis:  DAS28, as a continuous measure or classified as 
good/moderate/no response per EULAR criteria 
• Spondyloarthritis:  BASDAI, as a continuous measure 
 
4. Background and Rationale  
 
a. Background 
 
Chronic Pain and Arthritis 
According to an Institute of Medicine report, 116 million Americans are affected by chronic 
pain, at an overall annual cost of $635 billion (1).  Veterans are expected to be 
disproportionately affected for multiple reasons, including service-related injuries and 
psychiatric comorbidities such as post-traumatic stress disorder and depression.  Treatment 
for chronic pain has been and continues to be a priority research area for VA CSR&D.   
 
The two most common causes of chronic pain are osteoarthritis (OA) and back pain (2).  OA 
is defined by cartilage loss that is usually attributable in large part to mechanical causes, but 
abnormalities are numerous and the relationships between them are complex (3, 4).  OA is 
estimated to affect 12.1 million Americans, at an annual cost of $89 billion in medical 
expenses and additional costs related to reduced productivity (2).  Important risk factors for 
OA in different locations include obesity, advancing age, and prior injury, all of which are 
highly relevant to the population served by the VA. 
 
Inflammatory arthritis (IA) includes multiple diseases, but the most common and destructive 
are rheumatoid arthritis (RA) and spondyloarthritis (SpA), a term that encompasses psoriatic 
arthritis, ankylosing spondylitis, reactive arthritis, and arthritis associated with inflammatory 
bowel disease.  Together, RA and SpA affect 2-3% of persons and usually require treatment 
with immune-suppressive drugs in order to prevent severe joint damage.  Most patients 
achieve good control of disease, but there is often evidence of some ongoing inflammation; 
e.g. in one large cohort, only 25% met criteria for remission one year after enrollment, and 
72% of those patients had already been in remission at enrollment (5).  SpA is the one form 
of arthritis that is more common in men than women and often has onset in early adulthood, 
thus is enriched in the VA population; an important registry in SpA (Program to Understand 
the Long-term Outcomes in Spondyloarthritis, PULSAR) was established in the VA in 2007 
and is ongoing. 
 
Mechanisms of Pain in Arthritis 
Mechanisms of pain include peripheral and central sources (2, 6).  In turn, although the 
neurons that conduct painful sensations are the same regardless of the stimulus, peripheral 
sources can be subdivided into those that are purely nociceptive and those that include an 
inflammatory component.  In all persons experiencing pain, central nervous system 
mechanisms are involved, and these mechanisms are variably active in different persons.  

10 
 
“Central sensitization” is a characteristic of chronic pain of various origins, and in 
fibromyalgia – the quintessential syndrome of chronic widespread pain – central 
sensitization may explain the entire syndrome, since there is no evidence of damage in most 
areas where pain is experienced. 
 
Pain in arthritis results from a combination of these sources.  Although one might expect that 
pain in OA would be attributable to purely non-inflammatory, peripheral, nociceptive input, 
the other sources play a role.  Inflammation is apparent in OA both pathologically and by 
measurement of inflammatory cytokines, and the degree of synovial inflammation seen on 
MRI is one factor associated with pain in persons with OA (4, 7).  Self-reported pain 
attributable to OA is more severe in persons with evidence of central sensitization (8).  In 
turn, pain in the inflammatory arthritides is not entirely attributable to inflammation.  Joint 
damage leads to non-inflammatory peripheral pain, and patients with RA and fibromyalgia 
report higher levels of joint pain than patients with RA who do not also have fibromyalgia (1, 
9).  For unclear reasons, the prevalence of fibromyalgia is higher in persons with RA (10) 
and in several other autoimmune diseases than in the general population.  Despite great 
advances in treatment of inflammation in RA, 40-65% of all RA patients have reported 
inadequate control of pain despite modern therapies (6), and 12% of patients meeting 
criteria for remission reported chronic pain of clinically significant severity in one study (5). 
 
1 
Thus, approaches to pain management in the arthritides could include reduction of 
inflammation, nociception, and central sensitization. 
 
Treatment of Arthritic Pain 
Unfortunately, management of pain in OA, as in management of chronic pain more 
generally, remains a challenge despite great effort.  Acetaminophen produces little if any 
benefit above placebo (11).  Non-steroidal anti-inflammatory drugs (NSAIDs) are clearly 
superior to placebo or acetaminophen, with effect sizes 0.3 – 0.5 (“small” in common 
interpretation (12)) in meta-analyses of multiple trials (11, 13), but this benefit corresponds 
to median absolute reductions in pain, relative to placebo, of less than 20%, a common 
standard for the minimum clinically significant difference (12, 14, 15).  However, excess 
cardiovascular risk has now been attributed to NSAIDs as an entire class (16), not just to 
Cox-2 selective drugs, and NSAIDs were already known to confer important risks of peptic 
ulcer disease and kidney damage.  Tramadol, stronger opioids, and a variety of non-
pharmacologic interventions perform no better than NSAIDs based on effect sizes and 
improvement in pain reduction versus placebo (13) (and see numerous Cochrane reviews), 
and an “epidemic” of abuse of prescription opioids has received great attention in both the 
medical literature and popular media.  FDA approval of duloxetine to treat pain in OA, on the 
basis of an absolute difference in pain relief of 10% compared to placebo (17), is arguably 
the biggest advance in pain management in OA in the past decade.  Intra-articular injections 
of corticosteroids (CS) or hyaluronic acid (HA) derivatives have higher absolute 
improvements than oral drugs, but since the placebo effect of intra-articular injection is also 
high, the improvement after CS or HA injection relative to placebo remains modest (18).  
Combination pharmacologic therapy also has been disappointing (19).  Total joint 

11 
 
replacement (TJR) is the only treatment with gratifying improvements in pain in most 
patients, but many patients are not good surgical candidates due to young age, old age, or 
comorbidities, and TJR brings multiple short-term risks plus the long-term risk of prosthesis 
failure particularly in young persons. 
 
Pain management per se has not been studied as extensively in the inflammatory 
arthritides, since the focus has been on control of inflammation and prevention of structural 
damage.  However, persistent pain despite apparent control of inflammation is common, as 
noted above, and use of NSAIDs and opioids has the same problems with effectiveness and 
safety in IA as in OA. 
 
Considering the mediocre benefit of individual modalities in controlling chronic pain, 
combination therapies involving collaboration across disciplines have been studied – 
including VA-based studies published in high-profile journals (20-22) – and are widely 
advocated, as evident in the National Pain Strategy (23).  However, the benefit of such 
approaches is still less than clinically significant in many patients, likely not even additive for 
the benefits of individual interventions.  The pharmacologic component of multi-modality 
pain management is clearly a weak point in such interventions and arguably the most 
amenable to improvement. 
 
Low-Dose Naltrexone 
Naltrexone is an opioid antagonist that is used in high doses for emergency treatment of 
opioid overdose and is FDA approved in an oral daily dose of 50 mg to prevent recidivism in 
alcoholics (see Prescribing Information).  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 (24), 
gastrointestinal symptoms in Crohn’s disease (25, 26), and quality of life in multiple sclerosis 
(27).  In addition, case reports indicating considerable benefit in patients with complex 
regional pain syndrome (28), low back pain (29), and scleroderma (30) have been 
published, although publication bias for case reports is presumed to be high.  The 
mechanism/s is/are unclear, with proposals including not only modulation of central pain-
processing pathways but also mitigation of inflammatory roles of microglia (31).  In addition 
to blocking opioid receptors, naltrexone blocks TLR-4, and some studies suggest that the 
anti-inflammatory effects of low dose naltrexone are independent of opioid receptors (31).  
Even if effects are mediated entirely by mu, kappa, and delta opioid receptors, the 
relationship of pharmacokinetics to downstream effects is likely to be complex, by analogy to 
the finding that opioid agonists can produce analgesia or hyperalgesia at different doses 
(31). 
  
There is also a lot of enthusiastic discussion about low-dose naltrexone (LDN) on the 
internet (see results of a Google search of “low dose naltrexone arthritis”), based mostly on 
testimonials from patients and the recommendations of web-based MDs and other self-
appointed experts, most of whom recommend a range of other unproven remedies as 
well.  The testimonials are essentially case reports using patient-reported outcomes (as a 
class, the type of outcome used in all studies of pain management), but of course they must 

12 
 
be viewed with skepticism because of massive selection bias and uncertainty about the 
patients’ diagnoses.  Considering the modest benefit of other options, use of LDN will 
continue or increase in the absence of studies that support its effectiveness and 
systematically gather data on safety.  Since the drug can be prescribed but only via 
compounding pharmacies, its use produces significant cost to patients (~$40/month). 
 
What makes LDN of greater interest than most unproven treatments for arthritic pain is a 
combination of pharmacologic plausibility, the afore mentioned trials in other painful 
conditions, and striking results of an internet-based survey 
(http://curetogether.com/Arthritis/ig/treatment-effectiveness-vs-popularity).  The survey itself 
was unbiased in asking persons to rate a large number of approaches they might have used 
for arthritic pain, but there was no way to validate what type of arthritis the participants had, 
and the population of responders (who sign up as members based on self-reported 
conditions) was undoubtedly biased in multiple ways.  That being acknowledged, LDN was 
ranked as high as any therapy, and most notably, the other therapies that did as well are 
known to be highly effective in IA or OA (Enbrel, oral or injectable corticosteroids, TJR), 
whereas the numerous approaches that did not perform as well include all of the 
pharmacologic and non-pharmacologic approaches known to provide mediocre benefit 
based on randomized trials (Fig. 1).  On closer inspection, the survey is not nearly as large 
as it appears:  although the group has 1554 members, fewer than 200 produced the 2127 
total evaluations of all therapies, and only 17 persons commented on LDN.  
 
 
 
Intriguingly, 23 members of a group reporting RA (presumably overlapping with the “arthritis” 
group) also placed LDN with TJR and corticosteroids and seemingly above DMARDs, 
biologics, and non-pharmacologic therapies.  In a group of patients reporting OA, only 5 
commented on LDN, and only 2 of those reported benefit.  In fibromyalgia, 72 respondents 
again gave LDN the highest rating among pharmacologic therapies, with the only 
approaches giving comparable relief being rest/sleep, application of heat, and stress 
Figure 1.  Results of an online survey about 
effectiveness of 33 treatments for arthritis pain. 
X-axis = fraction of respondents who tried a 
given treatment. Y-axis = average rated 
effectiveness of a given treatment. Vertical line = 
average fraction of respondents who had tried 
each treatment. Horizontal line = average rated 
effectiveness of all treatments. LDN = low dose 
naltrexone.  
From http://blog.23andme .com/23andme-
research/ what-patients-say-works-for-arthritis/ 

13 
 
reduction.  Scanning across other disease states was both encouraging and concerning for 
the survey reaching a biased population: LDN was at or near the top of therapies reported in 
patients with multiple sclerosis (n=128), fatigue (n=112), Crohn’s disease (n=33), 
neuropathy (v=22), Sjogren’s syndrome (v=9), Hashimoto’s (v=9), psoriasis (v=7), hepatitis 
C (v=6), sarcoidosis (v=4), symptom relief in breast cancer (v=4) or non-small-cell lung 
cancer (v=4), psoriatic arthritis (v=3), ankylosing spondylitis (v=3), polymyositis (v=3), 
scleroderma (v=3), HIV (v=2), lupus (v=1), and complex partial seizures (v=1).  Reassuringly 
with regard to bias based on belief systems, LDN was not reported as being reliably helpful 
in 4-20 patients each with irritable bowel syndrome, anxiety, depression, asthma, dandruff, 
Raynaud’s, night cramps, Lyme disease, low back pain, or prostate cancer.  Reassuringly 
with regard to possible bias by the survey designers, LDN was not suggested as an option 
for diabetes, COPD, gout, eczema, congestive heart failure, or many other conditions.  
 
These data provide further support that LDN may provide an important advance in 
management of pain and other symptoms – particularly in inflammatory diseases – but do 
little to alleviate the concern that hype has exceeded evidence.  
 
Other attractive features of LDN are its safety and tolerability, based on the known risks at 
the much higher FDA-approved doses and the side effects reported in clinical trials (see 
Section 9). 
  
Considering the diversity of conditions proposed to benefit from LDN; mechanism(s) of 
action that may or may not include modulation of inflammatory, nociceptive, and central pain 
pathways; and the unequivocal need for better therapies in these conditions; high-quality 
trials are needed in both inflammatory and non-inflammatory conditions in which central 
pathways play variable roles. However, funding agencies appropriately expect high-quality 
preliminary data before investing in definitive trials. This study is designed to obtain such 
data in a 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. 
 
b. Rationale for the Clinical Trial Design 
 
The relatively rapid onset of action of naltrexone means that cross-over designs are 
feasible, increasing power to detect significant benefit.  Indeed, the afore mentioned studies 
in fibromyalgia and Crohn’s used cross-over designs.  One disadvantage of a cross-over 
design using subjective outcomes is that placebo/nocebo effects are likely to be amplified 
during the second treatment period if the cross-over time is unblinded, because the patient’s 
experience during the first period will change his/her expectation for the second period.  
Therefore, the cross-over time will be blinded.  The PI has been advised by an expert in the 
field to design the study so that each patient is taking LDN for at least 8 weeks and ideally 
longer (J. Younger, personal communication), and to keep the placebo period at least 6 
weeks in the LDN-first group so as to minimize carry-over of benefit. 
 

14 
 
The most important outcomes will be patient-reported.  The number of in-person visits is 
moderate, chosen to ensure collection of sufficient patient-reported data and distribution of 
study drug without being a strong disincentive to participation.  
 
 
5. Study Design and Methods  
 
a. Overview  
 
This randomized, double-blinded, placebo-controlled, cross-over trial will enroll 60 patients 
(a minimum of 30 with osteoarthritis and a minimum of 10 with inflammatory arthritis) with 
persistent pain despite standard management approaches.  Patients will receive low-dose 
naltrexone for 8 weeks and placebo for 8 weeks, according to either of two schedules in 
which the patient is blinded to the durations of treatment and the possible cross-over times.  
Medical conditions and treatment (pharmacologic and non-pharmacologic) relevant to pain 
must be stable for at least 8 weeks prior to enrollment, and patients will only be enrolled if 
they and the investigator do not plan to make other treatment changes (pharmacologic or 
non-pharmacologic) over the next 16 weeks. 
 
Assessments for the primary outcome and most of the secondary outcomes will be by 
patient-reported outcomes on a weekly basis.  In patients with IA, assessment of disease 
activity will also occur at the 3 study visits over the course of 16 weeks.   
 
The conditions to be studied are common. We anticipate seeing at least 4 eligible patients 
per week and enrolling 25% of them, thus completing enrollment within 18 months.  The 
only eligibility criteria that are likely to limit enrollment are pain severity and absence of 
recent change in other medications. 
 
The study design meets the great majority of the 25 recommendations for design of clinical 
trials in knee OA made by the Osteoarthritis Research Society International (OARSI)(14):  
effective randomization strategy; pre-specified stratification and subset analyses; adequate 
blinding procedures; specification of who is blinded; indistinguishable drug and placebo; 
minimization of confounding by changes in concomitant medications; assessment of 
potential participants’ consistency in reporting; explicit exclusion based on specific 
comorbidities; characterization of pain subphenotypes; minimum baseline pain ≥ 4 on a 0-10 
scale; use of validated patient-reported outcome measures; definition of primary and 
secondary outcome measures a priori; and assessment of three core clinical measures 
(pain, physical function, and patient global assessment).  Seven additional 
recommendations apply only to studies that are unblinded or assess structural changes in 
OA, and three others relate to registering and reporting (and will also be followed).  This 
study only falls short of these recommendations on two counts: by including a 
heterogeneous group of conditions (deliberately), and by not including a set of objective 
measures of physical function. 

15 
 
 
The study also includes the four outcome domains identified by consensus in the Initiative 
on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT):  pain 
intensity, physical functioning, emotional functioning, and global rating of improvement (12). 
 
b. Identification of Patients  
 
i. Inclusion Criteria  
 
Patients must meet all of the following criteria in order to be eligible for enrollment: 
• 
One or more of the following chronic conditions: osteoarthritis, rheumatoid arthritis, 
peripheral spondyloarthritis (which may include shoulder or hip involvement) 
• 
Average daily pain interference with function (average of the 7 parts of question 9 on 
the BPI) rated at least 4 on a scale of 0-10, and no higher than 9 
• 
No increase in medication in the past 8 weeks made with the expectation of 
improving pain, including acetaminophen, any NSAID, any opioid, tramadol, 
gabapentin, pregabalin, cyclobenzaprine, any tricyclic antidepressant, duloxetine, 
systemic or injectable corticosteroids, or injectable viscosupplements 
• 
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 
• 
Capable of informed consent, and willingness to comply with study procedures, 
including receipt of weekly phone calls from the study coordinator 
 
 
ii. Exclusion Criteria  
 
• 
Use of opioids, including tramadol, in the past 7 days (determined by asking 
participant if they have used any opioid containing medications in the past 7 days or 
plan to use any opioid containing medications) 
• 
Pregnant, breast feeding, or unwilling to engage in contraceptive practices if sexually 
active and capable of conceiving (determined by asking participant if they are 
pregnant or breast feeding or plan to become pregnant during the duration of the 
study) 
• 
Schizophrenia, bipolar disorder, or poorly controlled depression or anxiety 
• 
Previous use of naltrexone for more than 8 weeks or in the past 2 weeks, at a low 
dose or FDA approved dose 
• 
Back pain described by the patient as greater in severity than arthritic pain in all 
peripheral locations 
• 
Significant kidney disease, defined as glomerular filtration rate < 30 ml/min 
• 
Liver cirrhosis. There is no specific screening procedure to exclude cirrhosis. 
• 
Peripheral neuropathy described by the patient as greater in severity than arthritic 
pain.  There is no specific screening procedure. 
• 
Plan to have surgery during the next 16 weeks 

16 
 
• 
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 
 
 
iii.  Notes on Inclusion and Exclusion Criteria 
 
Patients will be regarded as having rheumatoid arthritis or spondyloarthritis based on 
their assessment by a rheumatologist (including the PI) in the VA Boston Healthcare 
System.  Although criteria exist for diagnosis of RA and psoriatic arthritis, these criteria 
were created primarily to have high specificity for enrollment of patients in clinical trials in 
which disease activity and structural damage (rather than pain) are the outcomes of 
interest.  Applying such criteria in the current study may be too restrictive. 
 
Average daily pain of at least 4 on a scale of 0-10 is widely recommended and used in 
trials in OA (14, 32), since lower levels of pain may not induce a patient to seek 
treatment (i.e. are not clinically significant), and inclusion of patients with lower levels of 
pain may make it more difficult to see differences between treatment arms.   
 
Patients with severe psychiatric illnesses will be excluded in part because of uncertain 
safety of the treatment and in part because of concerns about reliability of data. Current 
DSM-5 diagnoses of bipolar and related disorders or schizophrenia spectrum and other 
psychotic disorders (APA, 2013) will be grounds for exclusion.  Patients with severe 
depression will be identified and excluded on the basis of a total score ≥ 29, or a score 
of 2 or 3 on the question of suicidality, on the Beck Depression Inventory-II administered 
at screening. 
 
Previous extended use of naltrexone is an exclusion so as to avoid enrolling patients 
who have previously reported benefit at a low dose, or who had side effects at the FDA-
approved dose. 
 
Patients with moderate to severe chronic kidney or liver disease are excluded due to 
delayed drug elimination and metabolism, in accordance with the Prescribing Information 
for the (much larger) FDA-approved 50 mg dose.  
 
Patients with peripheral neuropathy as the major source of pain are excluded only in 
order to prevent sources of pain from being too heterogeneous, not for safety reasons. 
 
c. Study Medications  
 
An investigational product, also known as investigational medicinal product in some regions, 
is defined as a pharmaceutical form of an active substance or placebo being tested or used 
as a reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) differently than the authorized form, or 

17 
 
used for an unauthorized indication, or when used to gain further information about the 
authorized form. The investigational product will be stored in a secure area according to 
local regulations. It is the responsibility of the investigator to ensure that investigational 
product is only dispensed to study participants. The investigational product will be dispensed 
only from official study sites by authorized personnel according to local regulations. 
 
In this protocol, the investigational products are: 
• 
Naltrexone for oral use, 4.5 mg per capsule, to be taken daily 
• 
Placebo to match naltrexone for oral use 
 
These products will be manufactured as capsules by the VA Boston Investigational Drug 
Service.  Naltrexone powder will be purchased from Letco Medical (Decatur, AL): 
 
Naltrexone HCL, USP (Dihydrate), NDC No. 62991-1243-02 
 
Capsules will be colored so that naltrexone and placebo are indistinguishable in 
appearance.  They will be stored in the pharmacy until the day of distribution and will be 
distributed in bottles sufficient for 28 days of use.  Patients will be instructed to use the 
bottles in the numbered order.  Bottles 1 and 2 will be distributed at enrollment or mailed to 
the participant.  Bottles 3 and 4 will be distributed at the in-person visit at week 8 or mailed 
to the participant.  Bottles 1 and 3 will each contain 28 capsules, and bottles 2 and 4 will 
each contain 10 extra capsules in case the patient has a delay in an in-person visit beyond 
exactly 8 weeks.  It will therefore be evident to the patient that s/he will be receiving the 
same drug for a given 4-week period, but it will not be evident to the patient that treatment 
will not change in the transitions from bottle 1 and 2 and bottle 3 to 4, and will always 
change in the transition from bottle 2 to 3. 
 
i. Randomized Treatment Periods: Methods and Doses  
 
At enrollment, eligible patients will undergo randomization to receive oral naltrexone and 
placebo according to one of two schemes (Table 1). Randomization will be performed by 
the research pharmacy.  Patients will be informed that they will receive naltrexone for 8 
weeks and placebo for 8 weeks but will not be given the details of the possible treatment 
timelines.   
 
Table 1.  Treatment groups. 
Group 
Weeks 1-8 
Weeks 9-16 
1 
Low-Dose Naltrexone 
Placebo 
2 
Placebo 
Low-Dose Naltrexone 
Low-dose naltrexone = 4.5 mg 
 
To ensure that equal numbers of patients with OA and IA are incorporated into the two 
groups, stratification by these two diagnostic groups will be used.   
 
ii.  Prohibited Medications  

18 
 
 
Use of any opioid agonist, including tramadol, is an exclusion criterion for enrollment, 
and these drugs must also be avoided during the trial.  If a patient must use an opioid 
agonist for more than 2 days during the trial, that patient must be removed from the trial, 
and data will be censored at the time of that treatment. 
 
Medications to treat pain must not have been increased for 8 weeks prior to enrollment.  
Opioids, including tramadol, may not have been used for at least 7 days prior to 
enrollment.  If a patient must have a change in treatment (pharmacologic or non-
pharmacologic) related to pain or arthritis, that patient must be removed from the trial, 
and data will be censored at the time of that treatment change.  Stable treatment with IV 
medications that require pre-treatment with other medications to prevent infusion 
reactions (e.g., rituximab, infliximab, IVIG) will not be regarded as a change in treatment.  
Corticosteroid or viscosupplementation injection intended to improve musculoskeletal 
pain must have been given at least 8 weeks prior to enrollment. 
 
It is expected that many patients will be using acetaminophen or NSAIDs as needed 
before enrollment.  Rather than requiring patients to move to a fixed schedule, data on 
use of such drugs will be collected and used in analyses. 
 
 
d. Study Procedures  
 
i. Recruitment  
 
Recruitment will occur through the clinical practices of the rheumatologists at the three 
main campuses of the VA Boston Healthcare System.  Primary care providers will be 
notified about the trial and will be encouraged to contact the PI about potential 
participants.  Pre-screening by discussion with the referring physician and review of 
medical records will greatly reduce the number of screening failures.  Referring 
physicians will be asked to ask prospective enrollees to rate their average daily pain 
severity and pain interference (0-10) for the past two weeks, but will be asked not to tell 
patients that the criterion for eligibility is ≥4.  In this way, the time between identification 
of a potential enrollee and the screening/baseline visit will serve as a run-in period for 
the purposes of severity and stability of daily pain.  An IRB-approved brochure will be 
available to inform potential patients about the study.  If permitted by the staff in the 
primary care clinics or pain clinic, the brochure will be displayed in common areas 
(waiting rooms or hallways) for patients to pick up themselves.  Providers who are not 
investigators will not be asked to distribute brochures.  Brochures will not be mailed.  
This recruitment technique will not require additional study staff. 
 
The PI plans to include five other rheumatologists in the VA Boston Healthcare System 
as co-investigators.  However, other colleagues may become credentialed for research.  
If necessary and practical, these rheumatologists will be added as co-investigators for 

19 
 
the current study.  The assessment of disease activity in RA and SpA is easily derived 
from standard clinical practice. 
 
ii. Screening  
 
Screening will be performed by the PI or co-investigator at an in-person visit.  Patients 
who meet eligibility criteria may enroll at the same visit.  They may receive study drug 
either at enrollment or later by mail or in-person, but they must begin study drug within 
14 days of screening. 
 
iii. Enrollment  
 
Details of the goals of the research and the risks and benefits of the protocol will be 
reviewed with each patient who meets eligibility criteria. Consent will be obtained by the 
investigator, a sub-investigator, a research assistant, or a study coordinator.  Patients 
who choose to enroll will be randomized to one of two treatment groups as above, in a 
double-blinded manner.  Study drug (sufficient for 66 days, in case a visit cannot be 
scheduled at exactly 56 days) will be distributed in person or by mail. The IRB of the VA 
Boston Healthcare System will approve the protocol and the consent document prior to 
enrollment of any patient.   
 
iv. Visit Frequency/ Visit Schedule  
 
There will be 3 in-person study visits:  screening / enrollment and 8 and 16 weeks after 
enrollment.  Study drug will be distributed at (in person) or shortly after (by mail or in 
person) the first two of these visits.  Patients who are unable to attend the second and/or 
third in-person visits may remain in the study if completed questionnaires, new 
questionnaires, and study drug are delivered by mail. 
 
v. Study Assessments  
 
1). Study Assessment  
 
Patient-reported outcomes will be reported weekly on paper forms.  Subjects may 
receive reminders by phone.  The outcome measures used will be: 
 
Primary outcome measure (all patients): 
• 
Brief Pain Inventory-short form (BPI) (33): The BPI is a 9-item self-report 
questionnaire that allows patients to rate the severity of their pain and the degree 
to which their pain interferes with common dimensions of feeling and function. 
For the purpose of the proposed study, we will be particularly interested in pain 
“interference”. A recent consensus panel recommended that the two domains 
measured by the BPI – pain intensity (severity) and the impact of pain on 
functioning (interference) – be included as outcomes in all chronic-pain clinical 

20 
 
trials (IMMPACT, (34)). The IMMPACT panel (www.immpact.org) specifically 
identified the interference items of the BPI, rated on a 0–10 scale, as one of the 
two scales recommended for assessment of pain-related functional impairment 
(35). It has excellent reliability and validity and it has been used widely in OA 
research (36). (weekly questionnaire)  
Secondary outcome measures: 
• 
Brief Pain Inventory short form, other questions than those used for the primary 
outcome, particularly question 5, average pain severity (weekly) 
• 
painDETECT (for neuropathic component of pain) (37, 38) (only at weeks 0, 4, 8, 
12, and 16)  
• 
PROMIS-29 (survey of quality of life in multiple domains) (40) (only at weeks 0, 
4, 8, 12, and 16) 
• 
Brief Fatigue Inventory, specifically question 2 (usual level in past 24 hours, 0-10)   
and question 4 (interference in the past 24 hours, average of 6 questions 0-10 
each) 
• 
Beck Depression Inventory-II (purchase pending), a widely used 21-question 
assessment of the severity of depression (only at weeks 0, 4, 8, 12, 16) 
• 
Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) Scale.  
The CGI-S/I is the most widely used clinician-rated measure of treatment related 
functioning and response. The CGI-S score rates severity of illness on a 7-point 
scale, ranging from 1 (“normal”) to 7 (“among the most severely ill patients”).  
The CGI-I score rates clinical improvement on a 7-point scale ranging from 1 
(“very much improved” to 7 (“very much worse”) (weekly) 
• 
Use of “as-needed” analgesic medications, using a form that will contain the 
names of the specific medications (only at weeks 0, 4, 8, 12, 16) 
• 
C reactive protein (CRP), a widely used clinical measure of inflammation.  
• 
Rheumatoid arthritis:  DAS28 (only at in-person visits) 
• 
Spondyloarthritis:  BASDAI (only at in-person visits) 
  
Assessment of blinding (all patients): 
• 
Question asking whether the patient thinks s/he is taking LDN, or placebo, or is 
not sure (weekly) 
 
 
The investigator and coordinator will also inquire about adverse events and 
medication use, including whether there has been interruption in use of study drug, 
at the 2 in-person visits following enrollment.  At the weekly phone-calls to remind 
patients to complete questionnaires, they will also be asked if they have experienced 
adverse events and will be reminded to inform the study team of serious adverse 
events as soon as possible after they occur. 
 
Although efforts will be made to schedule patients exactly 8 weeks and 16 weeks after 
they start study drug, the in-person cross-over day may occur up to 7 days before or up 

21 
 
to 10 days after week 8, i.e., between days 49 and 66.  If the “week 8” cross-over visit 
does not occur at day 56, the clock will be re-set for weeks 9-16.  Thus, the final “week 
16” visit may occur any time between 49 and 66 days after the actual “week 8” cross-
over date.  Sufficient drug is distributed at enrollment and week 8 to allow 66 days of 
treatment.  If a participant is not able to come to an in-person visit within the window, an 
out of window visit may occur and will be noted as a protocol deviation.  The study 
consists of two consecutive 8-week treatment periods.  An interruption in use of the 
study drug may occur for up to 4 weeks when it occurs between the first and second 
study periods. Allowing this extended time frame off study drug between treatment 
periods is appropriate; inclusion of a protocolized “wash-out” period is a common design 
in cross-over studies. Because there is no defined wash-out period in this study, the 
analysis plan already included omission of data from the first two weeks after cross-over 
(see Section 7). 
 
 
 
2). Study Schedule Table  
 
 
Screen / 
Enroll 
Wk 
0 
Wks 
1-3 
Wk 
4 
Wks 
5-7 
Wk 
8 
Wks 
9-11 
Wk 
12 
Wks 
13-15 
Wk 
16 
Consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
Phone reminders 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Complete weekly 
questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete every-4-
week 
questionnaires 
X 
 
 
X 
 
X 
 
X 
 
X 
Return 
questionnaires 
 
 
 
 
 
X 
 
 
 
X 
Distribute 
questionnaires 
X 
 
 
 
 
X 
 
 
 
 
Distribute 
study drug 
X 
 
 
 
 
X 
 
 
 
 
Collect unused 
study drug 
 
 
 
 
 
X 
 
 
 
X 
Report AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Assess 
disease activity 
X 
 
 
 
 
X 
 
 
 
X 
Assess 
medication use 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests * 
X 
 
 
 
 
X 
 
 
 
X 

22 
 
In-person visits are at screening / enrollment and weeks (Wks) 8 and 16.  Wk 0 (Baseline) may 
occur in-person at enrollment or within 14 days at home.  Phone reminders to complete 
questionnaires weekly may occur but are not essential to the protocol.  Non-serious adverse 
events (AEs) will be collected at in-person visits; subjects will be instructed to report potential 
serious adverse events (SAEs) as soon as possible and will be asked about non-serious AEs 
during the weekly phone conversations when those occur. 
* Complete blood count with differential, electrolytes, BUN, creatinine, liver function tests, ESR, 
CRP. Inability to provide these samples will be regarded simply as missing data (as with an 
incomplete questionnaire) rather than as a protocol deviation. 
 
e. Common Closing Date - Study Duration  
 
The study will close 16 weeks after enrollment of the last subject.  Data will not be collected 
from subjects after they have completed the 16 weeks of the study. 
 
 
f. Criteria for Withdrawal of Study Medication – Early Termination  
 
• 
Use of any opioid agonist, including tramadol, for more than two days 
• 
Rise in AST or ALT to a level 3-fold above the upper limit of normal, or more than 2-fold 
above the patient’s level at baseline if that baseline was abnormal. 
• 
Decline in kidney function (drop in GFR to < 30 ml/min) 
• 
Pregnancy or nursing 
• 
Addition or discontinuation of any medication given on a scheduled basis to treat pain.  
For medications taken as-needed, changes in frequency will not be grounds for 
withdrawal; rather, patients will be asked how frequently they have been using such 
medications. 
 
g. Outcome Definitions  
 
See Section 7, Data Analysis 
 
6. Safety Monitoring and Adverse Event Reporting 
 
a. Nature of Study 
 
In determining what type of adverse events will be reported, several facts about the drug 
being tested and the nature of the underlying disease need to be considered.   
 
Naltrexone is an FDA approved drug at 50 mg, a dose 11-fold higher than is to be used in 
this study. The side effects with this higher dose – as well as a 300 mg dose that is no 
longer used – are described in the Prescribing Information. Side effects of low-dose 

23 
 
naltrexone have been described in several published trials, but those encompass only about 
170 patients followed for a few months. 
 
b. Study Oversight 
 
The Principal Investigator has primary oversight responsibility of this clinical trial. The IRB of 
the VA Boston Healthcare System has oversight responsibility for this clinical trial. A Data 
Monitoring Committee (DMC) will be assigned by VA Central Office.  The DMC and IRB will 
review accrual, patterns and frequencies of all adverse events and protocol compliance 
every 4 months. The DMC and IRB make recommendations to the Principal Investigator 
regarding the continuation status of the protocol. 
 
The Principal Investigator and the research team are responsible for identifying adverse 
events. Adverse events and protocol compliance will be reviewed once a month by the 
Principal Investigator.  
 
c. Definitions 
 
This section defines the types of adverse events and outlines a process for the appropriate 
collecting, grading, and reporting procedures. The information in this section complies with 
ICH Guidelines E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting of the International Conference of Harmonization (ICH) Guideline for 
Good Clinical Practice and applies the Standards set forth in the National Cancer Institute 
(NCI), Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
Adverse event is defined as: “…an unfavorable and unintended sign, symptom or disease 
associated with a patient’s participation in a study.” 
 
Serious adverse events (SAE) will be defined according to 21CFR 312.32. 
 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalization or prolongs an existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
An important medical event may be considered an SAE when, based upon appropriate 
medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
In addition, other events that will be reported as SAEs in conjunction with this trial include: 
• 
Pregnancy 
• 
Cancer 

24 
 
• 
Overdose of the study drug 
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug 
 
An unexpected adverse event is defined as any adverse experience, the specificity or 
severity of which is not consistent with the risks of information described in the protocol. 
Therefore, expected adverse events are those that are identified in the research protocol, 
package insert, or investigational brochure as having been previously associated with the 
study agents or are known consequences of a person’s medical condition and thus having 
the potential to arise as a consequence of participation in the study. 
 
 
d. Toxicity Grading of Adverse Events 
 
Toxicity grades will be assessed according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) (http://ctep.cancer.gov/reporting/ctc.html). The purpose of using 
the CTCAE system is to provide a standard language to describe toxicities, to facilitate 
tabulation and analysis of the data and to facilitate the assessment of the clinical 
significance of all adverse events. The CTCAE provides the following grades and 
descriptions in the CTCAE manual (v4.0). Adverse events should be recorded and graded 1 
to 5 according to the CTCAE grade provided below: 
 
• 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living 
• 
Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
activities of daily living 
• 
Grade 4 = Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 = Death related to adverse event 
 
As only naltrexone and placebo will be considered to be study drugs in this trial, only 
adverse events possibly, probably, or definitely related to naltrexone will be considered 
reportable for this study. 
 
e. Relation to Study Therapy 
 
The relation or attribution of an adverse event to an investigational product is determined by 
the investigator and then recorded on the appropriate case report form and/or SAE reporting 
form. The CTCAE provides the following descriptors and definitions for assigning an 
attribution to each adverse event. 
 
Code   Descriptor     Definition 

25 
 
“Unrelated” Category Code 
1        Unrelated       The adverse event is clearly not related to the investigational product 
“Related” Category Codes 
2        Unlikely  
     The adverse event is doubtfully related to the investigational product 
3        Possible       The adverse event may be related to the investigational product 
4        Probable       The adverse event is likely related to the investigational product 
5        Definite  
     The adverse event is clearly related to the investigational product 
 
f. Standard Elements 
 
A set of standard elements for adverse event data will be collected. These elements include: 
patient ID, dates for event/event reported/date resolved, the event itself, event severity, 
whether it was expected and/or serious (as defined above), patient status, place of adverse 
event treatment (to further determine serious events), causality, and subsequent changes to 
protocol or consent form. Additionally, the reporter may write a more detailed description of 
the event and any other pertinent information. 
 
g. Expected / Known Risks and Adverse Events Associated with Study 
Intervention and Procedures 
 
i.  Study Drug/Intervention: For known risks of study intervention, see Section 9. 
ii. Study Procedures: For risks of study procedures, see Section 9. 
 
h. Reporting Timeline 
 
• 
The investigator will fulfill all reporting requirements of the IRB of the VA Boston 
Healthcare System. 
• 
Within 24 hours (of learning of the event), co-investigators must report to the PI any 
SAE whether related or unrelated to study drug.  The PI in turn must review and report 
the SAE to the IRB within 24 hours of learning of the event, and to the DMC within 2 
working days of learning of the event. 
• 
Expected or unexpected adverse events that are grade 1 will only be collected or 
reported at the discretion of the PI, for example, neuropsychiatric side effects that have 
been reported in previous studies 
• 
All other expected or unexpected reportable adverse events must be reported within 20 
working days of the notification of the event or of the site becoming aware of the event. 
 
i. Investigational New Drug Application (IND) 
 
The FDA has made a formal ruling that this study is exempt from needing an IND. 
 
j. Planned Interim Analysis 
 

26 
 
There is no plan for an interim analysis.  Progress reports will be submitted to the DMC 
every 4 months. 
 
k. Criteria to Suspend Enrollment 
 
There are no pre-specified criteria to suspend enrollment. 
 
 
7. Data Analysis and Statistical Considerations 
 
a.  Primary Outcome 
 
Interference of pain with general activity (question 9 on the Brief Pain Inventory, an average 
of 7 sub-questions, each 0-10) is the primary outcome measure.  Pain severity is the primary 
outcome reported in studies of pain in OA.  However, some patients will choose to increase 
activity at the expense of a level of pain that they have learned to tolerate, so “pain 
interference” is of at least equal interest (12, 23). 
 
i.  Primary Analytic Approach to the Primary Outcome 
 
The goal is to determine the difference in pain interference during treatment with LDN 
versus placebo.  We will take advantage of the multiple data points obtained from each 
patient to improve the precision of that estimate, reducing the risk of type II error.  The 
summary of each patient’s response to LDN compared to placebo will be made using 
linear contrasts.  Thus, for each patient: 
 
d = an1xn1 + an2xn2 … + an8xn8 – ap1xp1 – ap2xp2 … – ap8xp8 
 
where each “a” indicates a weight assigned to that observation on the basis of fitting the 
pre-post crossover data from all patients with a cubic spline or two linear splines; n 
indicates treatment with naltrexone; p indicates treatment with placebo; x indicates pain 
severity or pain interference; and numbers indicate weeks on the treatment.  The first 
observation following cross-over will be dropped in each patient.  Thus, in group 1, 
weights ap1 and ap2 will be 0, and in group 2, weights an1 and an2 will be 0.  Weights will 
be adjusted in individual patients in the event of missing data, and data obtained during 
an active adverse event will not be included; the weight given to the summary value of 
each patient’s data (d) in the full analysis, however, will be equal.  In each patient, the 
sum of all weights will be set to 0. 
 
The distribution of d among all patients will then be compared to a null distribution by t-
test.   
 
ii.  Secondary Analytic Approaches to the Primary Outcome 

27 
 
 
Effects of covariates on response to treatment will be analyzed in two ways: 
 
1. Linear regression, where response (d) is the dependent variable, and independent 
variables include age, sex, diagnosis of OA or IA, group assignment (1 or 2), baseline 
pain severity, baseline CRP (with or without an interaction term to limit this variable to 
patients with IA), and baseline scores on painDETECT (total score), Brief Fatigue 
Inventory (total score), and Beck Depression Inventory-II (total score) 
 
2. Mixed model, where the raw score (x) at any time is the dependent variable, and 
independent fixed effect variables include current treatment, time since enrollment, all of 
the covariates listed above for linear regression, and the random effect is the patient. 
 
The ability to detect a clinically significant difference is also considered essential for trials 
of pain in OA and other conditions. The proportions of patients experiencing 
improvement or worsening of at least 2 (on 0-10 scales) on pain interference and/or pain 
severity relative to the scores at enrollment after 8 weeks on LDN or placebo will be 
compared.  This standard meets or exceeds standards proposed by various 
organizations (11, 12, 14).  This analysis will be between-patient and limited to the first 8 
weeks in the study, since carry-over and time-dependent effects will make data after 
cross-over difficult to interpret. An overall assessment of significant improvement will be 
made on the basis of improvement of at least 2 points in either pain severity or pain 
interference, without worsening of 2 or more on the other scale.   
 
iii.  Sample Size Calculations 
 
The primary study end point will be the ability of LDN (denoted as ‘n’ below) to reduce 
pain interference to a greater extent than placebo (p).   
 
The minimum effect size (ES) that characterizes treatments that are regarded as being 
effective for reducing pain in OA is about 0.3 compared to oral placebo (18).  Estimating 
that the response during placebo will have a standard deviation  = 2.0 on a scale of 0-
10 (32), the minimum absolute mean difference between LDN and placebo that we wish 
to detect is  = ES *  = 0.3 * 2 = 0.6. 
 
The two crossover patterns are [pppppppp_nnnnnnnn] and [nnnnnnnn_pppppppp].   
Removing the two observations just after cross-over, the patterns are either [8p and 6n] 
or [8n and 6p].   With 30 subjects per pattern the overall mean difference, d =  [D(8p, 6n) 
+ D(8n,6p)]/60 where D denotes the sum of the 30 ‘n-p’ differences in each pattern.   We 
assume an autocorrelation model, that r is the correlation for adjacent times, and that 𝑟𝑗 
is the correlation between times j units apart.  Then, the variance of d roughly doubles, 
compared to assuming that r = 0.   Exact calculations show that with 26 to 30 subjects 
per pattern group and 0.5 ≤𝑟≤0.7 that the variance of d ranges from 0.014 to 0.018.   
Hence, we assume Var(d) = 0.016.  For this form of the t-test, it follows that: 

28 
 
 
The design has 80% power to detect a mean difference between treatments of 0.6 or 
larger with a two-sided type I error of 5%.   This allows for up to 4 of 30 patients in each 
group to drop out before 12 weeks.   
 
 
  
b.  Secondary Outcomes 
 
The secondary outcome measures include: 
• 
Brief Pain Inventory (other individual questions than those used for the primary outcome, 
especially average pain severity = question 5) 
• 
painDETECT (continuous measure 0-38, or classified as 
nociceptive/unclear/neuropathic per the questionnaire guidelines) 
• 
Brief Fatigue Inventory, specifically question 2 (usual level in past 24 hours, 0-10) and 
question 4 (interference in the past 24 hours, average of 6 questions 0-10 each) 
• 
PROMIS-29 (total score, continuous measure, 28-150) 
• 
Beck Depression Inventory-II (continuous measure 0-63, or classified as 
minimal/mild/moderate/severe per the questionnaire guidelines) 
• 
Use of “as-needed” analgesic medications (expressed as % of maximum prescription 
dose) 
• 
Patient global assessment of improvement or worsening on a 7-point scale [Clinical 
Global Impression of Severity (CGI-S) and Improvement (CGI-I) Scales] 
• 
CRP 
• 
Adverse events, including pre-specified minor adverse events (vivid dreams, headache, 
dizziness, insomnia, fatigue, nausea) and categories of severe adverse events 
(cardiovascular, neuropsychiatric, malignancy, serious infection)  
 
Secondary outcome measures for specific diseases: 
• 
Rheumatoid arthritis:  DAS28, as a continuous measure or classified as 
good/moderate/no response per EULAR criteria 
• 
Spondyloarthritis:  BASDAI, as a continuous measure 
 
The primary and secondary analytical approaches for the secondary outcomes will be the 
same as for the primary outcome measures for all continuous variables.  Weightings will 
change for outcomes measured every 4 or 8 weeks rather than weekly.  Outcomes based 
on classification will use analysis of proportions of patients transitioning from one class to 
another.  Proportions of patients experiencing categories of adverse events while receiving 
LDN or placebo will be compared by Fisher’s exact tests. 
 
8. Data Management 
 
a. Registration 

29 
 
 
At enrollment, each patient will be assigned an ID number beginning with the type of arthritis 
(OA or IA) followed by order of enrollment among patients with OA or IA (01-60).  This ID 
number will be seen by the investigator and study participant and used on all questionnaires 
as well as the case report forms used for the additional data obtained at in-person visits.  A 
file that links the patient’s name and chronological ID number to the random study ID 
number will be maintained by the study coordinator on a VA network drive.  This process will 
minimize the chance that the PI will be able to identify individual subjects if he is 
participating in data analysis, particularly important for any exploratory analyses beyond 
those that are pre-specified. 
 
b. Randomization 
 
The research pharmacy will perform the randomization using a varying block design 
provided by the statistician, and the study staff will remain blinded to group assignment.  
The pharmacist will log treatment assignments. The patient and investigator will remain 
blinded to the treatment assignments until completion of the last visit of the last patient 
enrolled. At that time, the blind will be broken and the PI will be informed about treatment 
assignments and will notify the patients and their MDs which treatments they received.  
Patients will be notified of their treatment assignments by the sending of an IRB approved 
letter within one month after the last patient’s last visit or within one month after IRB 
approval of the letter, whichever is later.  The participants’ PCPs and/or rheumatologists will 
be notified by being copied on a CPRS note containing the approximate dates of study 
treatment and the treatment assignments within one month after the last patient’s last visit.  
Unblinding of the treatment assignment during the study will be performed only in rare 
instances where knowledge of the treatment assignment is felt to be necessary to protect 
patient safety, as determined by the IRB of the VA Boston Healthcare System.  The two 
research pharmacists will be unblinded to treatment and can be reached 24/7 by phone and 
are able to access pharmacy records off-site.  Request for unblinding will be made 
simultaneously in writing.  The IRB and DMC will be notified of the treatment assignment 
revealed by unblinding according to the timeline of SAE reporting, since it is expected that 
any unblinding will be associated with an SAE. 
 
c. Data Entry 
 
All study data will be recorded on paper forms by the patient or transcribed from the 
patient’s oral report by the investigator or study coordinator, then collected and copied into 
electronic files by the coordinator or a research assistant.  Although direct electronic data 
entry by patients would be preferred by some patients and would avoid the problem of 
questionnaires being lost, it is felt that relying on electronic forms would exclude many 
potential participants.  Data will be copied from paper forms to similarly formatted electronic 
versions. 
 

30 
 
Paper forms produced by this study including signed consent forms will be stored in a 
locked office or other secure facility for a minimum defined time period per VA and FDA 
regulations.  Electronic files including study data, the file linking patient identifiers to coded 
data, IRB communications, and other regulatory documents will be stored on a secure 
SharePoint site set up specifically for this study behind the VA firewall.  Electronic copying of 
study data from paper forms will occur directly on the SharePoint site.  Research records will 
be kept indefinitely or until the law allows their destruction in accordance with the VA Record 
Control Schedule.  Paper records will be shredded, and electronic records will be destroyed 
in a manner in which they cannot be retrieved.   
 
 
d. Data Quality Control 
 
As an assessment of compliance with treatment, patients will be asked to return the 
previous containers of study drug at the next in-person visit, and asked not to throw out any 
extra doses that might remain because they forgot to take them. 
 
At the second and third in-person study visits, it will be clear to the study coordinator which 
patients are completing study questionnaires and which are not.  One of the reasons for 
planning to average the results of patient-reported outcome measures at multiple time points 
in a weighted manner is so that data will still be usable if a patient only completes the forms 
at in-person visits.  At in-person visits, patients will complete questionnaires without the 
participation of the investigator of coordinator, since their presence might influence reporting 
compared to data recorded when alone. 
 
Two steps will be taken to maximize the numbers of patients who complete all 3 in-person 
visits.  First, they will be given a financial incentive at a level that is not expected to raise 
concerns about coercion:  $20 for the screening visit, $20 for visit 2, $20 for visit 3, and an 
additional $20 at visit 3 if all 3 visits were completed.  Second, the study coordinator and PI 
will arrange schedules such that patients can be seen at at least 2 of the 3 campuses of the 
VA Boston Healthcare System. 
 
9. Protection of Human Subjects 
 
a. GCP Statement 
 
This clinical trial will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and 
all applicable regulatory requirements. 
 
b. Benefits and Risks 
 
The potential benefits of participating in this study are improvement in pain and/or 
improvement in function as limited by pain. The potential risks of this study are side effects 

31 
 
of naltrexone, delay in seeking other approaches to pain management, and potential loss of 
confidentiality. 
 
i. Risks of Low-Dose Naltrexone (LDN) 
 
In studies of low-dose naltrexone (LDN) that included about 170 patients, no liver toxicity 
or severe depression has been reported.  No other dangerous side effects have been 
reported, either, but the number of patients in these studies is too small to be confident 
that there are no dangers that might occur rarely (24-27).  The only common side effect 
repeatedly reported for LDN has been vivid dreams (sometimes but not usually 
described as nightmares).  Headaches, dizziness, insomnia, fatigue and nausea have 
been reported in some studies but not others (24-27). 
 
At doses 11 times higher than those used in this study (50 mg rather than 4.5 mg), 
naltrexone use has been associated with the following: 
• Liver toxicity:  usually this was mild, only apparent on blood testing, and without 
symptoms, but some cases of hepatitis (abdominal pain, loss of appetite, and 
jaundice) have been reported.  Serious liver injury has only been reported with much 
higher doses (300 mg daily) that are no longer used. 
• Depression and suicidal thoughts 
• Symptoms of opioid withdrawal in patients also taking opioid pain relievers 
 
All of these risks have been used to create exclusion criteria for this study. 
The 50 mg dose has only been used to treat patients with alcoholism or opioid abuse 
problems, who are already at high risk for liver disease, depression, suicide, and use of 
opioid medications without telling their physicians.  The full package insert is available 
on-line and is considered to be the Investigator’s Brochure for this study. 
 
Even in the event that a patient is using opioids surreptitiously or via prescription outside 
the VA, naltrexone is unlikely to cause severe opioid withdrawal symptoms at the low 
dose used in this study.  However, it is possible that it would make such drugs less 
effective as pain relievers.  Opioid agonists have been formulated with low-dose 
antagonists in an effort to reduce risk of addiction or development of tolerance, so there 
is substantial evidence of safety of such combinations.  
 
ii. Other Risks 
 
The main procedures being performed for research purposes are questionnaires.  
Additional physical examination and laboratory testing will be performed at the 4 in-
person visits but the disease activity scales generated by including such information are 
advocated for routine clinical use and therefore are consistent with standard of care 
practice.  All non-medication study procedures therefore confer minimal risk. 
 

32 
 
The risk associated with potential delay in seeking other approaches to pain 
management is also considered to be minimal.  Only patients who report stable pain for 
the previous 2 months and stable use of medications to control pain, and who report no 
intention of making other efforts to control pain during the coming 16 weeks, will be 
approached for participation in this study.  Standard approaches to preserving 
confidentiality of research data are noted in Section 8. 
 
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