Arthritis Medication and Nausea

Medication is almost always a fact of life when you’ve got a condition like rheumatoid arthritis (RA) or other type of inflammatory arthritis — and for many people, so are nausea and other GI issues that are a frequent side effect of these drugs. While taking the disease-modifying drug sulfasalazine, Anita Marie P. went through “horrendous GI pain and symptoms like diarrhea and reflux,” she told us on Facebook. Methotrexate was no better: “I was nauseous all the time and had no appetite,” she added.

“Some degree of nausea is quite common, unfortunately,” says Vinicius Domingues, MD, CreakyJoints medical advisor and a rheumatologist who practices in Daytona Beach, Florida. Nausea tends to be common in disease-modifying antirheumatic drugs (DMARDs), as well as other types. These medications modulate the immune system to help reduce pain, swelling, and damage to your joints and are considered a first-line treatment for patients diagnosed with rheumatoid arthritis and other inflammatory diseases, especially methotrexate.

But it’s hard to predict who may feel queasy and who won’t while taking these medications. “It’s not necessarily even correlated in patients with gastroenteritis or patients with reflux,” says Dr. Domingues. “I think potentially those patients are at a higher risk, but it’s hard to say.” Dosage also does not necessarily matter. Patients who take three pills a week of methotrexate can have bad GI symptoms and others who take 10 pills a week can feel fine, he adds.

Some people may just be prone to gastrointestinal issues from arthritis medications because their GI system “is their weak spot,” explains Rochelle Rosian, MD, a staff member of Cleveland Clinic’s department of rheumatic and immunologic diseases in Cleveland, Ohio.

The important thing is not to get discouraged, says Dr. Domingues. “Sometimes the nausea or GI issues go away over time as your body adapts to the medications.” Or doctors can prescribe anti-nausea drugs and recommend proven stomach soothers (more on this below).

And if those don’t work, you can keep try different medications until you find a good combination that treats your arthritis symptoms without causing GI issues. “In this day and age, there are so many different medication options that your doctor can choose from. It might be better to try a different medication than have to take a nausea pill, a patch, or something on top of the medicine, just to power through the nausea,” says Dr. Rosian.

Why Arthritis Medications Can Upset Your Stomach

There are many different reasons drugs can make you feel nauseous or have other GI issues. Common ones include the way different medications work in your body (called their mechanism of action), interactions from taking multiple meds at the same time, or issues with how people digest medication. For example, non-steroidal anti-inflammatory drugs (NSAIDs) can irritate the stomach lining, causing nausea.

Many people with arthritis take multiple medications, so it’s important to learn more about which drugs may be the biggest culprits for GI issues while at the same time keeping an open mind. After all, you may be one of the luckier ones that escapes this particular side effect.

Medications that tend to be most problematic in terms of GI symptoms include conventional DMARDs and NSAIDs. Traditional DMARDs act on your immune system, which may also make you more prone to infections. But why most of them cause nausea, diarrhea, and gas isn’t fully understood.

Methotrexate and Nausea

Methotrexate was first used in very high doses as a cancer drug before it became widely used to treat many rheumatologic diseases, when it is given in much smaller doses. In cancer treatment, methotrexate works by attacking malignant cells that are dividing rapidly by depriving them of folate, a form of vitamin B that these cells need to survive. Methotrexate is classified as a folate antagonist — it blocks folate from malignant cells as well as healthy ones.

Patients with inflammatory arthritis take methotrexate in much, much lower doses than do cancer patients — typically somewhere between 10 milligrams to 25 milligrams one day a week. Still, that is enough to interfere with healthy cells that rapidly divide, like the mucus membrane in your mouth and the lining of your GI tract. These areas are more sensitive to methotrexate, which can explain the nausea and mouth sores, another potential side effect, Dr. Rosian explains.

Other DMARDs and Nausea

Leflunomide

If methotrexate alone isn’t controlling your RA symptoms, doctors will often prescribe leflunomide (Arava). Leflunomide is usually given alone as a once-daily pill. It can cause nausea, though it’s usually not as bad as with methotrexate, Dr. Rosian notes. There’s another side effect that might be even more challenging for patients. “While queasiness is up there, the biggest reason that people can’t tolerate leflunomide, GI-wise, is diarrhea,” says Dr. Rosian. It’s still treatable, but not as easily as nausea is.

Hydroxychloroquine

Hydroxychloroquine (Plaquenil) is usually given to patients with mild forms of RA or in combination with other medications for more severe cases. It is also widely used to treat lupus. It can upset your stomach, giving you a queasy feeling. “Generally if people can hang in there, even on one a day, they tend to be able after the first month to manage the nausea. I don’t know if their body adjusts to it, but it rarely continues to give them problems,” says Dr. Rosian.

Sulfasalazine

Most patients can take sulfasalazine (Azulfidine) with few side effects, according to the American College of Rheumatology, though the most commonly reported are nausea and abdominal discomfort. They tend to occur early in the course of treatment, usually improve over time, and may be avoided or minimized by increasing slowly from a low starting dose.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

For many different kinds of inflammatory arthritis — including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, gout, and others — NSAIDs are commonly prescribed to reduce inflammation and pain, especially during a flare. In some conditions, such as axSpA, NSAIDs are considered a first-line treatment and may be the primary medication patients take to relieve symptoms.

NSAIDs prevent the enzyme cyclooxygenase (COX) from making prostaglandins, hormone-like chemicals that produce inflammation. Because there is a type of COX that also protects the stomach lining (COX-1), NSAIDs can also irritate this gastric lining, producing a low-grade inflammation in the stomach too, says Dr. Rosian. The result: upset stomach, nausea, and heartburn.

Other Arthritis Drugs and Nausea

Beyond conventional DMARDs, other classes of medications for inflammatory arthritis include targeted oral medications and injectable or infused biologics.

Apremilast (Otezla)

People who take apremilast (Otezla), a targeted DMARD, for psoriatic arthritis may feel queasy or have other gastrointestinal issues like diarrhea, Dr. Rosian notes. Otezla works by suppressing an enzyme known as PDE4 that causes inflammation at the cellular level, but whether that mechanism is responsible for the resulting GI issues is unknown, she explains. Indian researchers found that diarrhea tended to be short-lived, starting within two weeks of taking Otezla and ending after the fourth week without any other intervention.

Biologics

Tabitha W. told us that she feels nauseous for two days after she takes her adalimumab (Humira) injection. But this side effect isn’t as common in biologic medications — advanced, targeted therapies that act on the immune system to reduce inflammation — as it is for conventional DMARDs, says Dr. Rosian, though she has heard of people having GI issues with infliximab (Remicade) and the other TNF inhibitors that block inflammation. Biologics are injected or infused. There are many different kinds of biologics that act on different immune system pathways and each can cause different combinations of side effects. You may feel generally “off” after a biologic treatment, including fatigue, headache, dizziness, irritation at the injection site, and more. Nausea or stomach upset can occur as well.

JAK Inhibitors

Janus kinase inhibitors are another kind of targeted immune system medication used to treat certain inflammatory conditions, including rheumatoid arthritis and psoriatic arthritis. Unlike biologics, they are taken orally as pills. Nausea is a reported side effect in some patients on these medications.

How to Minimize Nausea and GI Upset

1. Take folic acid with methotrexate

Because methotrexate suppresses folate, doctors typically prescribe folic acid supplements, usually taken daily, to boost folate stores and protect healthy cells. These supplements can often help minimize the queasies, but if they don’t, Dr. Rosian recommends patients take a prescription-strength version called leucovorin (a related vitamin called folinic acid) to counteract methotrexate’s nausea-inducing side effects. Elizabeth F. told us on Facebook that her daily folic acid helped her methotrexate-induced GI issues. And Pippa C. swore that folinic acid had decreased her mouth sores.

2. Try anti-nausea drugs

“I sometimes recommend that patients take Zofran, an anti-nausea medication, two or three hours before the methotrexate dose and then another the following day. It typically works pretty well in most patients,” says Dr. Domingues.

But as Tammy G. told us on Facebook, she turned down her doctor’s offer to prescribe an anti-nausea med. “So tired of taking handfuls of meds…. yuck,” she wrote. Dr. Rosian says her patients frequently have that reaction. “People don’t want to take one medicine, let alone take one and have to take folic acid and then something else for the side effect. It’s a pretty hard sale,” she notes.

Luckily, there are still other tactics that can help mitigate those queasy feelings.

3. Try a different form or dosing

Several people told us that switching to the injectable form of methotrexate seemed to help with nausea. For example, Matt B. told us on Instagram that taking 25 milligrams of methotrexate tablets for more than six years “destroyed my stomach and bowels.” After he switched to an injectable form of methotrexate, “my stomach is back to normal after about a year. I have had nausea on both tablets and injection, but the injection is a little easier to handle.”

Another strategy, which may apply only to certain medications, is to split the dose or increase the dose slowly. Dr. Domingues recommends splitting his patients’ leflunomide dose to relieve diarrhea, and he does this sometimes with methotrexate. “So as opposed to taking your six methotrexate pills at the same time, we do three in the morning and three at night. This has not necessarily been shown to be efficacious for nausea, though,” he notes.

4. Take your meds with your largest meal

Dr. Domingues advises his patients to take their DMARD medications with their biggest meal. “If your thing is breakfast, do it on breakfast. If your thing is lunch or dinner, do whatever fits your own schedule,” he says.

“I usually tell people I would much rather you take your medicine with a meal,” agrees Dr. Rosian. “Don’t eat extra to take this pill — in other words, don’t take your pill at 8 PM with three crackers. Just take your pill at 6:30 with your dinner.”

5. Sleep it off

A few CreakyJoints members told us on Facebook that they take their methotrexate at bedtime to avoid feeling nauseous during the day. And a few recommended taking it over the weekend. “I take methotrexate at night right before bed so I am sleeping during the nausea. I also take it on Saturday so I can rest during the brain fog and fatigue it gives me,” Jenny K. told us.

6. Soothe your stomach with peppermint or ginger

There is some data that peppermint can help minimize an upset stomach, though most of the research has been done on people with irritable bowel syndrome (IBS). Still, researchers from Baylor College of Medicine in Houston found studies that showed peppermint’s beneficial effects on a queasy stomach. And several patients told us on Facebook and Instagram that along with other strategies like taking their meds at night, they ate peppermints, drank peppermint tea, or sniffed peppermint oils, which seemed to help their nausea.

There’s science behind the claims that ginger can quell nausea too. An Australian study in 2017 found that the root helped chemotherapy patients with treatment-induced nausea. An Iranian study found that eating ginger could help post-operative patients with their upset stomachs. But no one has done clinical studies that show what dose or type of ginger is most effective.

Shaz S. told us on Facebook that methotrexate made her really gassy, but now she drinks several cups of lemon and ginger every day and “it’s no longer an issue.” Another potential stomach soother: drinking ginger ale.

As always, even with something as benign as ginger or peppermint tea, be sure to mention it to your rheumatologist.

7. Consider cannabis

Eileen D. told us on Facebook that she uses medical marijuana for nausea and it seems to help. And Melanie R., who’s had RA since she was a teenager, swears that medical cannabis saved her from serious issues with her GI tract. Talk to your doctor about medical marijuana or CBD if you’ve tried everything else and still suffer from GI distress.

Your Rheumatologist Can Help With Nausea

Even though many people may have to deal with nausea when taking various arthritis medications, don’t automatically presume that you will. Simply anticipating that a medication can make you quesy can make such side effects more likely. “What I tell patients is, reset the system and let’s make this work together,” says Dr. Domingues. And above all be honest about any and all side effects with your provider. “If my patients don’t report issues, I can’t help,” he adds.

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Keep Reading

Antimalarial drugs in the treatment of rheumatic disease. UpToDate. https://www.uptodate.com/contents/antimalarial-drugs-in-the-treatment-of-rheumatic-disease.

Calasan M, et al. Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Research & Therapy. December 2013. doi: http://dx.doi.org/10.1186/ar4413.

Chumpitazi BP, et al. Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Alimentary Pharmacology & Therapeutics. March 2018. doi: http://dx.doi.org/10.1111/apt.14519.

Interview with Vinicius Domingues, MD, CreakyJoints Medical Advisor

Interview with Rochelle Rosian, MD, Cleveland Clinic, Rheumatologic and Immunologic Disease

Major side effects of low-dose methotrexate. UpToDate. https://www.uptodate.com/contents/major-side-effects-of-low-dose-methotrexate.

Marx W, et al. Ginger-Mechanism of action in chemotherapy-induced nausea and vomiting: A review. Critical Reviews in Food Science & Nutrition. January 2017. doi: http://dx.doi.org/10.1080/10408398.2013.865590.

Methotrexate and Nausea. Johns Hopkins Arthritis Center. https://www.hopkinsarthritis.org/ask-the-expert/methotrexate-and-nausea.

Patient Fact Sheet: Hydroxychloroquine. American College of Rheumatology. https://www.rheumatology.org/Portals/0/Files/Hydroxychloroquine-Plaquenil-Fact-Sheet.pdf.

Patient Fact Sheet: Leflunomide. American College of Rheumatology. https://www.rheumatology.org/Portals/0/Files/Methotrexate-Fact-Sheet.pdf.

Patient Fact Sheet: Methotrexate. American College of Rheumatology. https://www.rheumatology.org/Portals/0/Files/Leflunomide-Arava-Fact-Sheet.pdf.

Patient Fact Sheet: Sulfasalazine. American College of Rheumatology. https://www.rheumatology.org/Portals/0/Files/Sulfasalazine-Azulfidine-Fact-Sheet.pdf.

Patient Fact Sheet: TNF Inhibitors. American College of Rheumatology. https://www.rheumatology.org/Portals/0/Files/TNF-Inhibitors-Fact-Sheet.pdf.

Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis. UpToDate. https://www.uptodate.com/contents/pharmacology-dosing-and-adverse-effects-of-leflunomide-in-the-treatment-of-rheumatoid-arthritis.

Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis. UpToDate. https://www.uptodate.com/contents/sulfasalazine-pharmacology-administration-and-adverse-effects-in-the-treatment-of-rheumatoid-arthritis.

Virtanen AT, et al. Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases. BioDrugs. January 2019. doi: https://doi.org/10.1007/s40259-019-00333-w.

What to do when your medication causes nausea. Harvard Health Publishing. https://www.health.harvard.edu/staying-healthy/what-to-do-when-your-medication-causes-nausea.