There’s no single best medicine for arthritis pain. The right choice depends on which type of arthritis you have, which joints are affected, and how severe your symptoms are. For the most common form, osteoarthritis, the American College of Rheumatology recommends topical anti-inflammatory drugs as a strong first choice for knee pain, and oral anti-inflammatories for hand pain. For rheumatoid arthritis, the goal shifts from just relieving pain to stopping the immune system from damaging your joints.
Osteoarthritis vs. Rheumatoid Arthritis
These two conditions look similar on the surface but work very differently inside your body, and that difference changes which medications help. Osteoarthritis is wear-and-tear damage to the cartilage cushioning your joints. It develops gradually, usually in the knees, hips, hands, or spine, and the pain tends to worsen with activity and improve with rest.
Rheumatoid arthritis is an autoimmune disease where your immune system attacks the lining of your joints, causing inflammation, swelling, and eventually joint destruction. It often affects both sides of the body symmetrically and can come with fatigue and stiffness that lasts for hours in the morning. Pain relievers alone won’t stop rheumatoid arthritis from progressing. You need medications that calm the immune response itself.
Over-the-Counter Options for Osteoarthritis
Most people start with what’s available at the pharmacy, and for osteoarthritis, anti-inflammatory drugs (NSAIDs) consistently outperform acetaminophen (Tylenol). A large network meta-analysis of 122 randomized controlled trials covering more than 47,000 participants found that both topical and oral NSAIDs were meaningfully better than acetaminophen at improving joint function in knee osteoarthritis. Acetaminophen can take the edge off mild pain, but it doesn’t reduce inflammation, which is a key driver of arthritis discomfort.
Common over-the-counter NSAIDs include ibuprofen (Advil, Motrin) and naproxen (Aleve). Both reduce pain and swelling. The practical difference comes down to dosing schedule and safety profile. Naproxen lasts longer, so you take it less often. It also appears safer for your heart: a major study from Oxford found that high doses of ibuprofen and diclofenac increased the risk of a major cardiovascular event (heart attack, stroke, or cardiovascular death) by about one-third, while high-dose naproxen did not carry the same heart risk.
That said, all oral NSAIDs raise the risk of stomach ulcers and gastrointestinal bleeding by two to four times, depending on the specific drug and dose. The general rule is to use the lowest effective dose for the shortest time you can manage.
Why Topical NSAIDs Deserve a Closer Look
For knee osteoarthritis specifically, topical anti-inflammatory gels and creams are now recommended as a first step, even before oral versions. The ACR/Arthritis Foundation guidelines strongly recommend trying topical NSAIDs before moving to pills. Diclofenac gel (sold over the counter as Voltaren) is the most widely available option.
The appeal is straightforward: topical NSAIDs deliver similar concentrations of medication to the muscle and joint tissue underneath the skin, but with much lower levels circulating in your bloodstream. That means far less exposure to your stomach, kidneys, and cardiovascular system. For joints close to the surface, like knees, hands, and wrists, this works well. For deeper joints like hips, topical options are less effective and oral medications are usually the better route.
One caveat: in a randomized trial comparing topical diclofenac to oral ibuprofen for acute musculoskeletal pain, the oral version provided somewhat better relief. Topical NSAIDs are a strong option for managing chronic, day-to-day arthritis pain with fewer side effects, but they may not match the punch of oral NSAIDs during a significant flare.
Prescription Medications for Osteoarthritis
When over-the-counter options aren’t enough, your doctor has several tools to escalate treatment. Prescription-strength oral NSAIDs offer higher doses than what’s available on the shelf, sometimes paired with a stomach-protecting medication to reduce the risk of ulcers.
A less obvious option is duloxetine, a medication originally developed as an antidepressant. It works by boosting two brain chemicals (serotonin and norepinephrine) that activate your body’s built-in pain suppression system. This effect is independent of its mood benefits. A meta-analysis of nine randomized controlled trials found that duloxetine provided modest to moderate pain relief, improved physical function, and boosted quality of life in people with osteoarthritis. It’s particularly useful when pain has become chronic and centralized, meaning your nervous system has become oversensitized and is amplifying pain signals beyond what the joint damage alone would explain.
Joint Injections
Corticosteroid injections deliver a powerful anti-inflammatory directly into the joint. They can provide significant relief within days, making them useful for managing painful flares. The downside is that the benefit is temporary, typically lasting weeks to a few months, and repeated injections may accelerate cartilage loss over time. Most doctors limit these to three or four per year in any single joint.
Hyaluronic acid injections (sometimes called viscosupplementation) aim to restore the lubricating fluid in the joint. In a head-to-head comparison, pain and function improved similarly with both corticosteroid and hyaluronic acid injections at three and six months, with no significant difference between the two. Hyaluronic acid injections are more controversial. Some patients report lasting relief, but clinical guidelines vary on whether the evidence supports routine use.
Rheumatoid Arthritis Requires Different Medications
If you have rheumatoid arthritis, pain relief alone isn’t enough. The priority is stopping your immune system from destroying your joints, and the medications that do this are called disease-modifying antirheumatic drugs, or DMARDs. Methotrexate is the cornerstone of RA treatment. It’s typically the first prescription you’ll receive after diagnosis, taken once a week as a pill or injection. It suppresses the overactive immune response that drives joint inflammation and damage.
These medications take patience. You won’t feel a dramatic improvement the first week. It generally takes three to four months to see a significant change, and for some people, it can take six months or longer. During that ramp-up period, your doctor may prescribe NSAIDs or short courses of corticosteroids to manage pain while you wait for the DMARD to reach full effect.
If methotrexate alone isn’t controlling your disease, the next step is usually adding a biologic medication. Biologics are lab-engineered proteins that block specific parts of the immune system driving your inflammation. Some target a protein called TNF-alpha, others block interleukin-6, and others interfere with immune cell activation. These are given as injections or infusions. If you receive weekly injections, you may notice improvement within a few weeks. Less frequent dosing schedules can take longer. If your symptoms haven’t improved within three to four months on a biologic, switching to a different one is standard practice.
A newer class of RA medications, called JAK inhibitors, works as a pill rather than an injection. They block signals inside immune cells that trigger inflammation. However, safety concerns have narrowed their use. They’ve been linked to cardiovascular events, blood clots, and certain cancers in some patients, and current guidelines generally reserve them for people who haven’t responded to other treatments, particularly those without existing heart disease risk factors.
Matching the Medicine to Your Situation
For mild to moderate osteoarthritis in a knee or hand, start with a topical NSAID like diclofenac gel. It offers real relief with minimal systemic risk. If that’s not enough, oral naproxen is a reasonable next step given its relatively favorable cardiovascular profile compared to ibuprofen. Keep acetaminophen in your toolkit for days when you need something gentler on your stomach, but don’t expect it to match the anti-inflammatory effect of NSAIDs.
For osteoarthritis that hasn’t responded well to anti-inflammatories, or when chronic pain has taken on a life of its own, duloxetine is worth discussing with your doctor. For periodic flares that make it hard to function, a corticosteroid injection can buy you weeks of significant relief.
For rheumatoid arthritis, the conversation is fundamentally different. Early, aggressive treatment with methotrexate or another DMARD is what protects your joints long-term. Pain management matters, but it’s secondary to disease control. The sooner you start a DMARD after diagnosis, the better your outcomes tend to be over the following years.