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14 Articles in Volume 21, Issue #5
Analgesics of the Future: Interleukin-17 Inhibitors for Treating Psoriatic Arthritis
Ask the PharmD: What evidence exists for metformin in treating rheumatoid arthritis pain?
Case Chat: Spasms vs. Spasticity and Muscle Relaxant Options
CDC Opioid Prescribing Guideline Updates Are in the Works: Will the Changes be Enough?
Chronic Pain Management in Marginalized Populations: How to Rebalance the Provider-Patient Relationship
Dantrolene: The Forgotten Molecule for Outpatient Spasticity
Forgotten Analgesics: The Drugs Pain Practitioners Need to Reconsider
Machine Learning Predicts Patient Response to Rheumatoid Arthritis Therapy
Perspective: Where Have All the Rheumatologists Gone?
Rheumatoid Arthritis and Bridge Therapy: Primary Care Considerations
Root Cause of Plantar Fasciitis: Three-Step Exercise Protocol
Shoulder Pain and Rotator Cuff Injuries: Emerging Treatments
Special Report: The Evolution of Rheumatoid Arthritis Treatment, from Gold to Gene Therapy
Transfer of Care: Barriers and Solutions in Chronic Pain Management

Ask the PharmD: What evidence exists for metformin in treating rheumatoid arthritis pain?

The anti-inflammatory effects of metformin suggest a novel and exciting pathway for pain relief in those with rheumatoid arthritis, including its possibility as an adjunct treatment to methotrexate.

Metformin is a commonly used as a first-line agent for the treatment of type 2 diabetes mellitus. The agent acts through various mechanisms to accomplish blood glucose lowering. These mechanisms are broadly linked to effects on the cell cycle as well as signaling pathways, including m-TOR and AMPK.

Metformin’s Anti-Inflammatory Effects

A 2019 study by Chen et al investigated the mechanistic possibilities of metformin for rheumatoid arthritis (RA) centered on the effect of synovial fibroblast-like cells (FLS) on RA progression, which was described as a key cell type contributing to joint destruction.1,2 Metformin inhibits FLS proliferation through cell cycle induction as well as regulation of the m-TOR pathway and activation of AMPK.1 This inhibition suggests anti-inflammatory effects that may be beneficial in managing symptoms of RA. In 2020, Salvatore et al further demonstrated the possible benefits of metformin through the m-TOR and AMPK pathways by focusing on the pro-inflammatory cytokine interleukin IL-17, which is produced by Th17 cells, among other mechanisms. Salvatore’s team asserted that AMPK and m-TOR may be associated with Th17 cell suppression, resulting in anti-inflammatory effects.3

American College of Rheumatology (ACR) guidelines on treating rheumatoid arthritis recommend a treat-to-target approach. (Image: iStock)


ACR Guidelines on Treating Rheumatoid Arthritis

The American College of Rheumatology (ACR) guidelines on treating rheumatoid arthritis recommend a treat-to-target approach, essentially recommending that clinical decisions be personalized to the patient case. Currently, even in individuals with low disease severity who have never taken a disease-modifying anti-rheumatic drug (DMARD) for RA, the recommendation is to prescribe DMARD monotherapy, preferably methotrexate. (See also, the ACR's reproductive care guidelines for people with rheumatic disease.)

As alternative or later-line options, the ACR guidelines recommend combining traditional DMARDs, tumor necrosis factor (TNF) inhibitors, or non-TNF biologics. Last-line approaches target the utilization of different combinations of these mechanisms. No drug mechanisms are currently available that specifically use the m-TOR or AMPK pathways to target FLS.4

The public health and quality of life impact of RA supports the importance of discovery and development of new treatments. Fifteen million US adults report severe joint pain due to arthritis. Rheumatic conditions and arthritis are a leading cause of missed work with 2.5 times increased risk of falls and arthritis-related healthcare costs of $304 billion.5 Thus, a novel mechanism for treating RA would be valuable.

Metformin as an Adjunct Therapy to Methotrexate: The Data

A 2021 randomized, double-blind, placebo-controlled trial by Abdallah et al attempted to determine whether metformin as an adjunct to methotrexate therapy was superior to methotrexate alone. The primary outcome was ACR 20% improvement criteria (ACR20) response rate, which is a composite including a count of swollen or tender joints, pain assessment, functional ability score, patient and physician global assessment of arthritis, and the C-reactive protein level after 12 weeks. Secondary outcomes included ACR 50% improvement (ACR50) and ACR 70% improvement (ACR70) in addition to disease activity score at 28 joints (DAS). The DAS indicates RA disease activity, considering swollen or tender joint number and inflammatory markers.

Subjects participating in Abdallah’s research had to be between 24- and 58-years-old with active RA for any disease duration. Individuals receiving methotrexate, NSAIDs, acetaminophen, selective COX-2 inhibitors, and low-dose oral corticosteroids were allowed to enroll. Those taking biological DMARDs, with severe anemia or active infection, pregnant or lactating, congestive heart failure, high-dose steroids, or clinically significant renal or hepatic disease were excluded. Sixty patients (60) received the intervention of methotrexate 7.5 mg IM once weekly plus metformin extended-release 1,000 mg once daily with food for 12 weeks. Another 60 patients received the placebo tablet plus methotrexate 7.5 mg IM once weekly.6

Results indicated that the intervention group had a total of 80.8% of patients meeting ACR20 response at 12 weeks while the placebo group had a total of 54.7% of patients (P = 0.001; NNT = 4). The ACR50 response at 12 weeks was also significantly higher in the intervention group (32.1% vs 13.5%; P = 0.0047). The ACR70 response at 12 weeks was significantly higher in the intervention group as well (16.4% vs 6.8%; P = 0.0038). Subjects showing high disease activity at baseline (DAS > 5.1) also demonstrated an increase in DAS remission in the intervention group at 12 weeks (50.7% vs 21.5%; P = 0.004). Individuals with low disease activity also had significant results (80.0% vs 50.0%; P = 0.015). Additionally, the intervention group showed a significant reduction in the serum level of TNF-α, IL-1β, IL-6, IL-17A, NF-κB, TGG- β1, MDA, anti-CCP, and IGF-IR expression as compared with the placebo group at 12 weeks.

Further, the intervention group showed a significant increase in IL-10 and AMPK upregulation as compared with placebo at 12 weeks. Adverse events included nausea, stomatitis, bloating, insomnia, headache, hair loss, decreased white blood cells, pharyngitis, increased liver enzymes (ALT and AST), increased blood cholesterol and triglycerides, and increased LDL. The rates of these events varied between 5% and 15%.6

Metformin for Rheumatoid Arthritis Management: Practical Takeaways

Despite the promising findings of Abdallah’s study, limitations exist regarding generalizability of the findings. It is early to consider metformin as an adjunct for management of RA due to the small sample size, single region studied, and short 12-week study duration. The demographic data was balanced between groups regarding disease severity, sex, age, weight, disease duration, duration of prior methotrexate therapy, and concomitant glucocorticoid and NSAID use. This increases internal validity and the strength of the results. The researchers did not, however, show the rates of other DMARDs such as hydroxychloroquine. Additionally, only middle-aged patients were included with those older than 58 years excluded. Future studies with longer follow-up, larger sample sizes, greater diversity, and stratification for confounders are warranted.

Other clinical trials of metformin for pain syndromes are ongoing. A trial iregistered in clinicaltrials.gov is evaluating the use of metformin for chronic pain after thoracic surgery in patients with diabetes. The two arms are metformin versus insulin as a placebo to control blood glucose. The primary outcome investigated will be the incidence of chronic pain three months after the surgery. Completion was expected in December 2020; however, no additional information is available within the registry.7

One trial, currently recruiting patients, aims to assess the use of metformin for lower back pain in patients without diabetes. This trial has 4 comparator arms: high- and low-dose metformin, placebo, and wait-list control that will be randomized to one of the other treatment arms. The primary outcomes investigated are change in the numeric pain scale and change in the Oswestry Disability Index, both over 15 months.8 An earlier 2019 study, which is also currently recruiting patients, aims to discover the effect of metformin for RA. This trial will compare standard-of-care DMARDs with adjunctive metformin against these same DMARDs plus placebo. The primary outcome will be the change in DAS scores at 6 months. January 2020 was the estimated date of study completion. No additional information is available within the registry.9

Other conditions have been studied but RA holds the best data for metformin use in the literature to date. Other studied disorders include osteoarthritis,10,11 chemotherapy-induced peripheral neuropathy12, statin-associated muscle pain,13 and PCOS-related pain.14  The other pain syndromes studied lack sufficient evidence to support the use of metformin. (See also, cognition and RA.)

Overall, metformin signifies a novel and exciting pathway for pain relief in rheumatoid arthritis due to its mechanism in the m-TOR and AMPK signaling pathways. Although limited evidence suggests benefit for metformin as an adjunct to methotrexate in patients with active RA, more research is needed to clarify its role in treatment. Metformin use is currently being studied in multiple clinical trials that may shed more light on its place in therapy for people with rheumatoid arthritis.


Last updated on: September 8, 2021
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Special Report: The Evolution of Rheumatoid Arthritis Treatment, from Gold to Gene Therapy
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