Paracetamol matched anti-inflammatories for arthritis pain

Two everyday tablets are offered for arthritis pain, and they are not interchangeable. One upsets stomachs; the other is limited by what a liver can take. Which an older adult should reach for first has been argued over for years.

A trial in Osteoarthritis and Cartilage Open, named RETHINK, put the question to 400 adults aged 65 and over with hip or knee osteoarthritis, randomized, double-blind, over eight weeks.

The two drugs relieved pain almost identically. The trial nonetheless failed to prove what it set out to prove, and the gap between those two sentences is worth understanding.

What osteoarthritis is and how it is treated

Osteoarthritis, sometimes called OA, is a type of arthritis that only affects the joints, usually in the hands, knees, hips, neck, and lower back. It’s the most common type of arthritis.

The symptoms are mechanical: pain when you move, which often gets better with rest, and stiffness, especially for the first 30 minutes after you get up from resting.

Treatment starts before any tablet. Exercises to improve strength, flexibility and balance come first, then braces or shoe inserts (orthotics), and you can buy some pain relievers and arthritis creams without a prescription.

The tablet question matters because the two options carry different risks. An NSAID, meaning a non-steroidal anti-inflammatory drug, can cause stomach upset or even ulcers in some people. The longer you take them, the greater the chance of these side effects. Acetaminophen is often recommended for arthritis pain because it has fewer side effects than many other pain medicines when used as directed.

How the RETHINK arthritis trial was built

This multicenter, randomized, double-blind, parallel-group study enrolled patients aged 65 years or older with osteoarthritis-related pain.

Participants were randomly assigned to receive acetaminophen (1800 mg/day) or NSAIDs (loxoprofen 180 mg/day or celecoxib 200 mg/day). Loxoprofen is widely used in Japan; celecoxib is the anti-inflammatory designed to be gentler on the stomach.

The primary endpoint was the change in Brief Pain Inventory (BPI) item 3 (worst pain) score from baseline to week 8. That item asks how bad the pain has been at its worst, on a scale from nought to ten.

Of the 400 patients enrolled, 191 and 197 were in the acetaminophen (mean age 73.6 years; 83.2% female) and NSAID groups (mean age 73.3 years; 74.6% female), respectively.

What the pain scores actually did

The least-squares mean change in BPI item 3 scores at 8 weeks was -1.79 in the acetaminophen group and -1.94 in the NSAIDs group.

Both groups improved by nearly two points on a ten-point scale, which is a real change for a person living with it. The between-group difference in BPI item 3 scores change was 0.14.

Fourteen hundredths of a point. On a scale where clinicians look for a change of one to two points before calling it meaningful, that is a difference nobody could feel.

Safety separated them where the pharmacology predicts. No major safety concerns were identified; however, gastrointestinal disorders occurred more frequently with NSAIDs and were the most common cause of treatment discontinuation.

Why a tiny pain difference still failed the test

Here is where the arithmetic and the headline diverge. Acetaminophen achieved a similar reduction in osteoarthritis-related pain to NSAIDs in older adults after eight weeks; however, non-inferiority was not demonstrated.

A non-inferiority trial does not ask whether two results look alike. It asks a stricter question: is the worst plausible performance of the new option still acceptable?

The measured difference was 0.14, and the uncertainty around it ran to 0.61 at the unfavorable end. Because that upper bound crossed the margin the researchers had set in advance, the formal conclusion is that the trial did not prove acetaminophen non-inferior, even with 400 people and a near-identical result.

That is a statement about the trial’s size, not about the drugs. A bigger study with the same average difference would have narrowed the range and probably passed.

What this arthritis trial cannot settle

Eight weeks is short for a condition measured in decades, and osteoarthritis pain fluctuates enough that two months tells you little about two years.

The comparison is also to specific drugs at specific doses. Loxoprofen at 180 mg and celecoxib at 200 mg are not every anti-inflammatory at every dose, and the acetaminophen dose was modest: adults should not take more than 4 grams in a single day, and this trial used less than half of that.

The participants were Japanese, older and mostly female, and both body size and drug metabolism vary across populations.

The trial also cannot say anything about the people who stopped taking the anti-inflammatory because of their stomach, beyond noting that this was the most common reason for stopping.

What to do about arthritis pain in a knee

The authors land where the evidence does: these findings suggest that treatment choice may depend on the balance between analgesic efficacy and safety considerations.

For an older adult with knee or hip pain, that translates into a real conversation rather than a default. The anti-inflammatory relieved pain a fraction more and upset more stomachs. Acetaminophen did nearly as well with fewer of those problems, at a dose well under the daily limit.

Neither is the first thing to try. Exercise to improve strength, flexibility and balance still sits ahead of both, and it is the part of the treatment nobody can prescribe on your behalf.