There is no single best prescription medication for osteoarthritis. The right choice depends on which joints are affected, how severe your pain is, what other health conditions you have, and how your body tolerates different drugs. That said, clinical guidelines consistently point to one starting place: topical anti-inflammatory gels applied directly to the joint, which offer meaningful pain relief with far fewer side effects than pills.
From there, treatment typically moves through oral anti-inflammatories, injections, and other options depending on what works and what your body can handle. Here’s how the main prescription options compare.
Topical Anti-Inflammatories: The Recommended First Step
The American College of Rheumatology recommends topical anti-inflammatory gels, specifically prescription-strength diclofenac, before oral medications for osteoarthritis in accessible joints like knees and hands. The reasoning is straightforward: the drug goes where the pain is, and very little enters your bloodstream.
Three large randomized trials tested 1% diclofenac gel on knee osteoarthritis over 12 weeks. Patients 65 and older saw their pain scores drop significantly more than placebo (a reduction of 5.3 points versus 4.1 on a 20-point scale), and physical function improved nearly 40% more than placebo. Pain during movement also dropped substantially. Across a broader meta-analysis, topical anti-inflammatories as a class were consistently superior to placebo.
The main limitation is location. Topical gels work well for knees, hands, and other joints close to the skin surface. They’re less practical for hips or the spine, where deeper tissue makes absorption unreliable. Older adults should also be aware that thinner skin absorbs more of the drug into the bloodstream, and applying heat to the area before or after increases absorption further, which can raise the risk of the same side effects you’d get from a pill.
Oral Anti-Inflammatories: Stronger but Riskier
When topical treatment isn’t enough or the affected joint is too deep for a gel to reach, oral prescription anti-inflammatories are the next tier. These fall into two categories: non-selective types (like naproxen and prescription-strength ibuprofen) and selective types (like celecoxib) that target inflammation more narrowly.
Celecoxib has a notable advantage for your stomach. In a head-to-head trial published in The Lancet, patients taking celecoxib had a recurrent stomach bleeding rate of 5.6% over 18 months, compared to 12.3% for naproxen. That’s roughly half the risk. Celecoxib caused 14 cases of upper gastrointestinal bleeding versus 31 for naproxen in the same study. For anyone with a history of stomach ulcers or bleeding, that difference matters.
The tradeoff is cardiovascular risk. All oral anti-inflammatories can raise blood pressure and increase the chance of heart attack or stroke with long-term use, and celecoxib is no exception. Your doctor will weigh your stomach risk against your heart risk when choosing between these options. Neither is risk-free for extended use.
What Long-Term Use Requires
If you take oral anti-inflammatories regularly, expect blood work. Before starting, you’ll typically have your kidney function, blood counts, and blood pressure checked. Within the first two weeks, kidney function and blood counts are rechecked. Blood pressure gets measured within four weeks. Once you’re stable, periodic monitoring continues, with kidney and liver function tests and blood counts repeated on an ongoing basis. This isn’t optional caution. These drugs can quietly damage kidneys and the stomach lining without producing obvious symptoms until the problem is advanced.
Joint Injections: Targeted but Temporary
For a single severely painful joint, especially the knee, injections can deliver relief that pills can’t match. Two types are commonly used, and they work on very different timelines.
Corticosteroid injections reduce inflammation quickly and can provide relief within days. The catch is that they’re strictly short-term treatment. Guidelines recommend waiting at least 12 weeks between injections, and repeated steroid shots into the same joint may accelerate cartilage loss over time. They’re best suited for flare-ups rather than ongoing management.
Hyaluronic acid injections take a different approach. Rather than reducing inflammation, they supplement the joint’s natural lubricating fluid. The process involves one injection per week for three to six weeks, with at least six months between series. Relief tends to build gradually and, for some people, lasts several months. The evidence on hyaluronic acid is more mixed than for steroids. Some patients get substantial benefit, others notice little difference, and guidelines vary on how strongly they recommend it.
Options When You Can’t Take Anti-Inflammatories
Many people with osteoarthritis also have kidney disease, heart failure, or a history of stomach bleeding that makes oral anti-inflammatories unsafe. If your kidney filtration rate (eGFR) is below 60, the National Kidney Foundation advises avoiding oral anti-inflammatories entirely. This rules out the most effective drug class for a large portion of the osteoarthritis population, since both conditions become more common with age.
Topical diclofenac gel can still be an option even with reduced kidney function, because so little of the drug reaches the bloodstream. Acetaminophen is also considered safe for the kidneys at recommended doses, though its effect on osteoarthritis pain is modest compared to anti-inflammatories.
Tramadol, a mild opioid-like pain reliever, is sometimes prescribed when other options fail. It doesn’t cause stomach bleeding or kidney damage, and it doesn’t harm joint cartilage. But the benefits are small. A systematic review found that tramadol produces only modest improvements in pain and function. One in five people who take it experiences side effects like nausea, dizziness, or constipation, and one in eight stops the medication because of them. It’s generally considered a last resort rather than a frontline treatment.
A newer category of non-opioid pain signal blockers became available in early 2025. These work by interrupting pain signals in the body without affecting the brain, which means they carry no addiction risk. Early guidance suggests they don’t require dose adjustments for most levels of kidney impairment, though people on dialysis or with very low kidney function (eGFR of 15 or less) should not use them.
How Doctors Typically Sequence Treatment
In practice, osteoarthritis treatment follows a ladder. You start with the safest effective option and step up only when needed. For a painful knee or hand, that means topical diclofenac first. If that’s insufficient, an oral anti-inflammatory gets added or substituted, with the specific choice depending on your stomach and heart risk profile. Injections come in for joints that aren’t responding to medication or during painful flares. Tramadol and newer pain blockers fill the gap for people who can’t tolerate anything else.
The “best” medication is really the one that gives you enough pain relief to stay active without creating new health problems. Physical activity, even when it seems counterintuitive with joint pain, remains one of the most effective treatments for osteoarthritis. Most prescribers combine medication with physical therapy, strengthening exercises, or movement practices like tai chi or yoga. Medication manages the pain; movement protects the joint long-term.
What works at 55 may not work at 70, and what works for your knee may not work for your hip. Expect your treatment plan to evolve, and don’t assume that a medication that stopped working needs to be replaced with something stronger. Sometimes switching to a different delivery method, like moving from a pill to a gel or adding an injection during a flare, is more effective than escalating to a riskier drug.