A few additional steps may help prevent or relieve GI and oral problems:

  • Split the dose. Most RA patients take methotrexate orally, in a dose consisting of several pills. Some find that splitting the dose eases GI side effects; take half the pills in the morning and the other half 12 hours later, preferably with food.
  • Ask about medication. For very severe stomach queasiness, your doctor can prescribe an anti-nausea drug such as ondansetron (Zofran), says pharmacist James Bennett of Children’s Hospital in Boston.
  • Swap your pills. When nothing else helps, switching from oral methotrexate to the injectable version can eliminate GI distress.
  • Try a rinse. To relieve painful mouth sores, a salt-water rinse or special mouthwash containing lidocaine (a pain reliever) may help, says Bennett.

Protecting the Liver

Since methotrexate blocks folate, taking folic acid — the manmade version of the vitamin — might seem like it would be counterproductive. However, methotrexate appears to relieve pain and other RA symptoms through actions that are largely unrelated to folate, explains Edwin Chan, MD, a rheumatologist and researcher at the New York University School of Medicine. Dr. Chan and other investigators discovered that methotrexate causes cells to release a molecule called adenosine, which blocks other chemicals that promote inflammation.

Fighting inflammation helps relieve painful, swollen joints. But Dr. Chan notes that adenosine also causes fibrosis, or buildup of scar tissue, in the liver; over time, that could result in liver disease. Your doctor will run routine blood tests to monitor your liver function, but it’s worth noting that only about one in 1,000 RA patients taking methotrexate experience serious liver damage. Yet it’s important to note that alcohol also releases adenosine in the liver, says Dr. Chan. That’s why your physician may advise you to avoid booze while taking methotrexate in order to limit your risk for liver problems. In rare cases, methotrexate users may develop fibrosis and inflammation in the lungs, though this is unlikely to be related to adenosine release, says Dr. Chan. Report a dry cough, shortness of breath, or any other respiratory problem to your doctor.

Regular blood tests are also necessary to detect signs of other problems that can arise in methotrexate users, including a drop in white blood cells, which normally guard against infections. Also, some people experience a dip in production of blood platelets, which could cause abnormal bleeding. However, these changes in the blood often go away if you stop taking the drug temporarily (which should only be done under a doctor’s supervision).

Fear of side effects causes some primary care physicians who treat RA to prescribe methotrexate in doses too small to provide adequate pain relief, says Yusuf Yazici, MD, an assistant professor of medicine and colleague of Chan’s at the New York University School of Medicine. But most people tolerate the drug quite well, especially if they take folic acid and practice other good habits.

Says Dr. Yazici: “There’s no reason to be afraid of methotrexate.”