There is no single best prescription medication for osteoarthritis. The right choice depends on which joint is affected, your other health conditions, and how severe your pain is. That said, oral NSAIDs (nonsteroidal anti-inflammatory drugs) remain the most widely prescribed and effective class of medication for osteoarthritis pain, with celecoxib and diclofenac leading the pack for most patients.
Oral NSAIDs: The Primary Option
Prescription-strength NSAIDs are the backbone of osteoarthritis treatment because they address both pain and the low-grade inflammation that drives joint damage. The most commonly prescribed options include celecoxib, diclofenac, naproxen, and meloxicam. All of them reduce pain effectively, but they differ in important ways when it comes to side effects and who can safely take them.
Celecoxib stands out in head-to-head comparisons. A meta-analysis published in Pain Medicine found that celecoxib provided significantly better pain relief than diclofenac for knee osteoarthritis, while also producing roughly 66% fewer complications overall. The reason: celecoxib is a selective COX-2 inhibitor, meaning it targets inflammation without disrupting the protective enzyme (COX-1) that shields your stomach lining. Traditional NSAIDs like naproxen and ibuprofen inhibit both enzymes, which is why stomach ulcers, bleeding, and gastrointestinal irritation are more common with those drugs.
That selectivity comes with a trade-off. COX-2 inhibitors like celecoxib carry a known concern for increased cardiovascular risk. For someone with a history of heart disease or stroke, this is a serious consideration. Your prescriber will weigh your gut risk against your heart risk when choosing which NSAID to recommend.
Why Your Heart Medications Matter
If you take low-dose aspirin to protect your heart, your choice of NSAID becomes more complicated. Research published in the American Journal of Epidemiology found that ibuprofen and naproxen can interfere with aspirin’s ability to prevent blood clots, effectively canceling out its heart-protective benefit. Other NSAIDs, including celecoxib, diclofenac, and meloxicam, did not show this interaction. For patients on daily aspirin therapy, those alternatives are generally safer choices.
Topical NSAIDs: Lower Risk, Targeted Relief
Prescription topical diclofenac (applied as a gel or solution directly to the skin over the affected joint) offers a way to get anti-inflammatory medication where you need it while dramatically reducing the systemic side effects. A systematic review and meta-analysis in Medicine found that gastrointestinal reactions were about 70% less common with topical NSAIDs compared to oral versions. The trade-off is mild: topical formulations can cause local skin irritation like redness or dryness at the application site.
Topical NSAIDs work best for joints close to the skin’s surface, particularly the knee and hand. They are less effective for deep joints like the hip, where the medication can’t penetrate well enough. For knee osteoarthritis specifically, a topical NSAID is often worth trying before committing to a daily oral pill, especially if you have a sensitive stomach or kidney concerns.
Duloxetine: When Pain Has a Central Component
Duloxetine is not an anti-inflammatory. It works in the brain and spinal cord by increasing levels of serotonin and norepinephrine, two chemical messengers that help your nervous system regulate pain signals. It is prescribed at 60 mg per day for osteoarthritis and has shown moderate but meaningful improvements in pain, physical function, and quality of life over 13 weeks of treatment.
This medication is particularly useful for two groups of patients. The first is people who cannot tolerate NSAIDs due to stomach, kidney, or heart problems. The second is people whose osteoarthritis pain coexists with depression, which affects roughly 1 in 5 adults with the condition. Depression amplifies pain perception and makes people less likely to stay consistent with exercise and other treatments, so addressing both problems with one medication can be a practical advantage.
Joint Injections for Targeted Relief
When oral or topical medications aren’t enough, injections directly into the joint offer another layer of treatment. The two main options are corticosteroid injections and hyaluronic acid injections, and they work on different timelines.
Corticosteroid injections deliver fast, potent anti-inflammatory relief. Pain improvement typically peaks within the first month but fades relatively quickly. These injections are best used for flare-ups or short-term relief rather than ongoing management, and most guidelines recommend limiting them to three or four per joint per year because repeated use may accelerate cartilage breakdown.
Hyaluronic acid injections take longer to kick in but tend to provide longer-lasting benefits. Hyaluronic acid is a natural component of joint fluid that acts as a lubricant and shock absorber. Injected versions supplement what osteoarthritis has worn away. Studies show that while corticosteroids win in the first month, hyaluronic acid produces better results at later follow-ups, though the overall effect at six months is moderate. These injections are most commonly used in the knee and are typically considered when other treatments have provided incomplete relief.
Tramadol: A Last Resort With Limited Benefit
Tramadol, a weak opioid-like pain reliever, is sometimes prescribed when other medications have failed. However, the evidence supporting its use is underwhelming. A 2025 systematic review in BMJ Evidence-Based Medicine concluded that tramadol provides only modest short-term pain reduction for chronic pain conditions, while increasing the risk of both serious and non-serious side effects, including cardiac events. The current consensus frames tramadol as a cautious, short-term, second-line option at best, not a foundation for ongoing osteoarthritis management. Stronger opioids are generally discouraged for osteoarthritis entirely due to the risks of dependence and the availability of safer alternatives.
Monitoring During Long-Term Use
Any prescription NSAID taken regularly requires periodic blood work. Kidney function should be checked within the first few weeks of starting therapy and at regular intervals afterward, since NSAIDs can reduce blood flow to the kidneys. Liver enzyme levels should also be tested occasionally, as liver toxicity is an uncommon but real possibility. Your provider may also recommend periodic stool tests or blood counts to catch hidden gastrointestinal bleeding early, particularly if you are on a traditional (non-selective) NSAID.
People at highest risk for NSAID complications include those over 65, anyone with a history of stomach ulcers, and those with existing kidney disease or heart failure. For these patients, the lowest effective dose for the shortest possible duration remains the guiding principle, and topical formulations or duloxetine may be preferable alternatives to daily oral NSAIDs.