Indomethacin is one of the oldest and strongest NSAIDs available. It can help bring a normal life back to those that have debilitating joint pain and headaches. However, it causes more side effects than other similar drugs. Read on to learn more about its uses, possible side effects, and the best natural alternatives for safe pain and inflammation relief.

What is Indomethacin?

Indomethacin belongs to a group of drugs called NSAIDs, which also includes aspirin, Advil, and Aleve. Like other NSAIDs, indomethacin is used to relieve pain and reduce inflammation.

Brand names for indomethacin include Indocin, Indocid, and Tivorbex. Outside of the US, the generic name is indometacin.

Indomethacin is approved for the treatment of several joint diseases including rheumatoid arthritis, osteoarthritis, gout, as well as inflammation of the spine and tendons.

Off-label uses in the US include treating headaches, chronic back pain, menstrual cramps, heart defects in infants, and delaying premature births.

Mechanism of Action

Pain and Inflammation

Indomethacin works similar to other NSAID drugs.

It blocks the two inflammatory enzymes called COX-1 and COX-2, which create prostaglandins in the body. Prostaglandins are hormone-like compounds that play a role in inflammation, affect blood flow, stomach acidity, pain sensitivity, and more.

Indomethacin reduces pain and inflammation by lowering prostaglandins.

Headaches and Migraines

Indomethacin may help with several rare types of headaches, although its mechanism is still unclear.

Excessively increased blood flow in parts of the brain can trigger migraines and heachaches. Researchers think that indomethacin might work by narrowing brain blood vessels, reducing their swelling [R+].

Heart Defects in Infants

Indomethacin is sometimes used to treat a heart defect called patent ductus arteriosus that can inflict premature babies.

In healthy newborns, a blood vessel called the ductus arteriosus closes off once it is exposed to oxygen in the blood. Premature birth can disrupt this process and leave the blood vessel open, due to the action of certain prostaglandins. By decreasing prostaglandin levels, indomethacin helps close the blood vessel [R].

Delaying Premature Birth

Prostaglandins are also responsible for inducing labor in pregnant women. They cause  changes in the cervix and activate contractions [R+].

Indomethacin can delay birth by at least 48 hours and up to 7 days by suppressing prostaglandins [R].

How Does Indomethacin Compare to Other NSAIDs?

Indomethacin is one of the strongest nonselective NSAIDs. Being nonselective, it affects both COX-1 and COX-2. In comparison, Celebrex is a selective NSAID that only blocks COX-2. Overall, indomethacin is effective, but it tends to have more side effects compared to other NSAIDs.

According to large review, most NSAIDs were equally effective at lowering chronic spine inflammation (axial spondyloarthritis). However, indomethacin was associated with significantly more side effects [R].

For osteoarthritis, indomethacin was as effective as some and less effective than other NSAIDs in various clinical trials. However, people reported twice as many side effects when using indomethacin [R, R].

In a review of 13 different NSAIDs used for relieving menstrual cramps, indomethacin was the worst choice when it came to number of side effects [R].

Indomethacin is also not the ideal drug for treating heart defects in newborns. In a review of almost 5k newborns, high dose ibuprofen (Advil) achieved better results and had less side effects than indomethacin [R].

Indomethacin has the unique ability to improve rare forms of headaches and migraines. The reason why other NSAIDs are ineffective remains a mystery, while indomethacin provides good symptom relief [R].

Uses of Indomethacin

1) Indomethacin Reduces Pain and Inflammation in Joint Disease

NSAIDs are a commonly used for many different joint diseases. They can reduce pain and swelling with relatively mild side effects.

Indomethacin is clinically used to treat joint diseases like:

  • Gout
  • Autoimmune inflammation of the spine (Axial Spondyloarthritis)
  • Rheumatoid arthritis
  • Osteoarthritis
  • Tendon inflammation (Tendinitis)
  • Bursitis

Gout

Gout is a form of arthritis that can lead to recurring attacks of sharp pain, swelling, and redness,  which usually affect the feet. Inflammation is caused by tiny crystals that form on the joints and tendons when uric acid levels in the blood are too high. Persistently high uric acid levels can deform the joints, damage the kidneys, and cause kidney stones [R].

Diet and lifestyle play a large role in gout development. Eating meat or seafood, drinking beer, or being overweight can all increase your risk. Although gout is most common in older men, it can affect anyone.

NSAIDs have long been the preferred treatment for gout as they are effective and relatively cheap. Various NSAIDs were equally effective in clinical trials. For example, both indomethacin with ketoprofen relieved pain in 90% of the cases in a study of 59 people [R, R].

However, selective NSAIDs may be safer than nonselective ones, like indomethacin. One clinical trial found that the selective NSAID etoricoxib worked just as well as indomethacin but had ~24% fewer side effects [R].

Inflammation of the Spine

Ankylosing spondylitis is a form of chronic arthritis that causes long-term autoimmune inflammation of the joints inside the spine and pelvis. This can lead to back pain and stiffness that becomes worse over time.

This joint disease has no cure, but different strategies like surgery, physical therapy, and medication can relieve the pain and delay disease progression [R].

NSAIDs have long been a first-line treatment for this disease. Researchers recently conducted a large analysis of 39 clinical trials and over 4k people to uncover which NSAIDs have the best safety and effectiveness profile. They found the following [R]:

  • Indomethacin provides much greater pain relief than placebo
  • Indomethacin is as effective as other NSAIDs
  • More people experience side effects on indomethacin than on other NSAIDs

To sum it up, although indomethacin can relieve pain and damage in chronic spine arthritis, other NSAIDs may be an equally effective but safer alternative.

Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disorder that causes your immune system to mistakenly attack your own joints. This results in pain, inflammation, and stiffness. Treatment can be complex, involving multiple medications, physical therapy, or possibly surgery.

Indomethacin is sometimes used to relieve the symptoms of rheumatoid arthritis, as it can lower pain while improving grip strength and reducing stiffness [R, R].

Osteoarthritis

Osteoarthritis develops as the protective cartilage of the joints gradually breaks down. This can cause joint pain and stiffness.

Indomethacin was equally effective (or sometimes less effective) as other NSAIDs for osteoarthritis in clinical trials. However, it caused twice as many side effects [R, R, R].

Tendinitis

Tendinitis, sometimes called tennis elbow, is inflammation of the tendons usually caused by injury or repetitive movements. Although recovery can take months, the symptoms are temporary and treated with medications and rest.

Indomethacin is effective at relieving short-term pain in tendinitis. Special gel and spray forms can provide pain relief while causing fewer side effects than the pill forms [R, R, R, R].

Bursitis

Bursitis refers to inflammation of the fluid-filled sacs that cushion muscles, tendons, and bones.

Indomethacin is effective for short-term pain relief in bursitis. When compared to other NSAIDs, indomethacin works just as well but is more likely to cause side effects [R, R, R].

2) Indomethacin Relieves Migraines and Headaches

NSAIDs are frequently used to relieve headaches and migraines. Headaches are usually  classified based on the severity of the pain, location of the pain, additional symptoms, and other factors.

Some headaches belong to a group called “indomethacin-responsive headaches”. This unique set of headaches responds very well to indomethacin, while other NSAIDs have little to no effect.

Indomethacin-responsive headaches include [R+]:

  • Cough headaches
  • Exercise headaches
  • Cluster headaches, which are rare and severely painful
  • Headaches from sexual activity
  • Stabbing headaches
  • Coin-shaped (nummular) headaches
  • Hypnic headaches, which wake people from sleep
  • Several rare types of headache disorders

Although indomethacin is very effective for these specific headache types, a small number of people don’t respond to it (analysis of 81 clinical studies) [R].

Interestingly, indomethacin can actually trigger or worsen headaches in some people. This unwanted effect becomes more likely with higher drug doses [R].

According to new findings, indomethacin also helps relieve cluster heachaches and other very rare headache disorders in both adults and children [R, R].

Combination drugs like Difmetrè (indomethacin, prochlorperazine, and caffeine) can provide powerful migraine relief. In a clinical trial of over 100 people, this combination relieved 15% more people from painful migraine attacks than the anti-migraine drug sumatriptan [R].

NSAIDs are sometimes used to prevent migraines as well, but the evidence to support it is conflicting. There is not enough evidence that indomethacin can prevent migraines (analysis of 49 clinical trials) [R].

3) Indomethacin Relieves Chronic Back Pain

About 80% of adults experience lower back pain at some point in their lives. Back pain that lasts for 12 weeks or longer becomes a chronic condition. NSAIDs are commonly used for back pain, especially to help with short-term flare-ups [R].

Indomethacin was slightly more effective than placebo at reducing back pain and improving disability, according to an analysis of 13 clinical trials and over 1.3k people. All NSAIDs were equally effective, though, which means that indomethacin will work just as well as any other NSAID [R].

Although the placebo and effect is very strong when it comes to pain relief, these results don’t look too promising for indomethacin or NSAID drugs in general  [R].

4) Indomethacin Helps With Menstrual Cramps

NSAIDs are usually the first medications used for painful periods.

An analysis of 72 clinical trials compared 13 drugs to find the best one for painful periods. Indomethacin was much better than aspirin for menstrual cramps but caused more stomach discomfort. Other common NSAIDs like naproxen and ibuprofen outperformed indomethacin [R].

Heavy bleeding and pain are the most common reasons women stop using IUDs (intrauterine devices) as birth control. A review of 15 clinical trials found that indomethacin is effective at reducing both heavy bleeding and pain caused by IUDs [R].

5) Indomethacin for Heart Defects in Infants

Patent Ductus Arteriosus (PDA) is a heart condition that commonly affects premature infants. It occurs when a blood vessel in the heart does not close off properly, which allows blood to leak into unwanted areas like the lungs and cause blood flow distrurbances [R].

This condition can be treated surgically or by using NSAID medications. Prostaglandins are responsible for keeping this blood vessel open. By blocking prostaglandin production, NSAIDs can help seal off the open vessel [R].

Commonly used NSAIDs for PDA include indomethacin and ibuprofen. NSAIDs can successfully cure this defect in ~67% of infants. High dose ibuprofen was more effective and safer than indomethacin, according to a large review of trials with 4.8k infants. Indomethacin was more likely to cause gut injury infants  [R].

6) Indomethacin Delays Premature Birth

Premature birth is when a woman gives birth before reaching 37 weeks of pregnancy, which happens in about 5-18% of the cases. It is the leading cause of death in infants. Multiple risk factors can contribute to it, including the mother’s blood pressure, stress, weight, and race [R].

Many drugs can be used to delay labor and birth. The choice of medication depends on factors like how far along the pregnancy is, the mother’s medical history, and side effects.

Indomethacin is sometimes used to reduce contractions, which can delay birth for at least 48 hours [R].

However, a review of 20 trials and over 1.5k women concluded that indomethacin had doesn’t offer any clear benefit to the baby or the mother, compared to placebo or other medications. Indomethacin was able to delay birth, but it didn’t decrease the risk of infant death [R].

Indomethacin Safety

Indomethacin is relatively safe and reports of serious side effects are rare.

The risk of negative effects increases with long-term use, old age, and interactions with other conditions or medications.

The lowest effective dose for the shortest duration possible should be used to minimize risks.

The FDA highlights several warnings about indomethacin [R]:

  • NSAIDs can increase the risk of potentially fatal heart attacks and strokes
  • Indomethacin should not be used to treat pain during heart surgery
  • NSAIDs increase the risk of stomach injury, including ulcers, bleeding, and potentially fatal perforation

A serious allergic reaction may occur. Indomethacin should not be taken by anyone who has had an allergic reaction to other NSAIDs.

Indomethacin can make certain conditions worse. It should be used with caution in those that have [R+]:

  • High blood pressure
  • Heart failure
  • A history of stomach ulcers or bleeding
  • Kidney disease
  • Asthma

Pregnancy and Breastfeeding

During the first 30 weeks of pregnancy, Indomethacin is Pregnancy Category C, meaning [R]:

  • It had negative effects on the fetus in animal studies
  • There are no adequate and well-controlled human studies
  • The potential benefits can sometimes outweigh the possible side effects

Pregnant women should avoid taking indomethacin during the third trimester. It may cause a premature closure of an important blood vessel in the baby. However, indomethacin is sometimes used during labor to prevent premature birth [R, R+].

Indomethacin is generally considered safe when breastfeeding. Only very small amounts of indomethacin (that won’t affect the baby) can be transferred through the milk, according to cell-based studies [R].

Side-Effects

About 30-60% of people who take indomethacin experience side effects. Most side effects are dose-dependent. Indomethacin tends to cause more side effects than other NSAIDs [R+].

Some common side effects include [R+]:

  • Stomach discomfort
  • Headaches
  • Drowsiness
  • Dizziness
  • Heartburn
  • Indigestion
  • Diarrhea
  • Vomiting

Some rare but serious side effects include [R+]:

  • Hearing changes
  • Mental changes
  • Difficulty swallowing
  • Trouble breathing
  • Visual changes
  • Seizures

Long-term Effects

Indomethacin is harmful to the kidneys. Long-term use of NSAIDs can lead to chronic kidney disease [R].

Chronic use of NSAIDs is harmful to the heart. Indomethacin use can lead to increased and decreased blood pressure, as well as heart failure [R].

NSAIDs have long been known to cause gut issues and damage. Long-term use of indomethacin can lead to stomach bleeding and ulcers [R].

There are case reports of prolonged indomethacin use causing visual changes and deposits in the eyes [R, R+].

Can Indomethacin Get You “High”?

NSAIDs as a class are generally considered safe and non-addictive. Some common NSAIDs like aspirin and ibuprofen are over-the-counter medications that can be purchased by anyone.

Stronger pain medications like opioids are well-known to cause “highs” and can be very addictive. However, NSAIDs do not have the physical and psychological effects that usually cause a high.

Indomethacin does provide pain relief that some people may become reliant on. There are rare reports of certain people becoming addicted to NSAIDs [R].

Known rare side effects of indomethacin include a false sense of well-being, dissociation, and mental changes. These could all give a sense of being high, although quite rarely.

Recent research suggests that indomethacin might actually decrease the high experienced from other drugs. In mice, indomethacin decreased the rewarding effects of cocaine. In another small human study, marijuana smokers who were given indomethacin experienced a much milder high [R, R].

Indomethacin Overdose

If you or someone you are with might be experiencing an overdose, call an emergency number (911) or the National Poison Control Center hotline at 1-800-222-1222.

Because NSAIDs are commonly used, overdoses are frequent in both adults and children. Most cases result in little to no harm. One study found that only 0.26% out of over 50k NSAID overdose cases resulted in serious harm, while 0.02% resulted in death [R, R].

The usual signs of an indomethacin overdose are headaches, nausea, vomiting, blurred vision, dizziness, tiredness, and possibly seizures. Symptoms usually occur within 4 hours of taking the drug [R].

The toxic level of indomethacin has not been well established. Other NSAIDs like ibuprofen are not life-threatening until more than 400 mg/kg is taken (which would be ~50 pills for a person of 110 lbs) [R].

There is no antidote for NSAID poisoning. However, the symptoms are usually temporary and mild. Treatment may consist of restoring fluids lost from vomiting, anti-seizure medication if seizures occur, or using charcoal to help bind the drug from the stomach [R].

Drug Interactions

The most common drug interaction is with medications that also cause side effects to the stomach. It is important not to take any other NSAIDs while taking indomethacin, unless specifically directed by a doctor. This includes medications like aspirin, ibuprofen, naproxen, and others [R+].

Other medications with potential interactions are [R+]:

  • Blood thinners
  • Blood pressure medication
  • Diuretics
  • Digoxin
  • Lithium
  • Methotrexate
  • Cyclosporine
  • Probenecid

Dosage

Indomethacin comes in a number of strengths and forms:

  • Capsules – 20 mg, 25 mg, 40 mg, 50 mg
  • Extended-release Capsules – 75 mg
  • Powder for Injection – 1 mg (Not available in the US)
  • Liquid – 25 mg/5 mL
  • Suppositories – 50 mg

Generally, both the effectiveness and side effects depend on the dose. Indomethacin is quickly and completely absorbed in the stomach.  It should be taken with food if upset stomach occurs [R+].

Dosage can vary depending on the reason for treatment. In general, the lowest effective dose for the shortest duration possible should be used to minimize side effects.

The typical dosage for capsules is 25-50 mg 2-3 times per day with a maximum of 200 mg per day [R+].

The extended-release capsule is dosed at 75-150 mg per day with a maximum of 150 mg per day [R+].

In premature infants with heart defects, the dose is normally 0.2 mg/kg through IV (with additional doses based on age) [R].

When used to delay premature birth, a 50 mg initial dose is given plus 25-50 mg every 6 hours for up to 48 hours [R].

Genes / Genetic Interactions

The enzyme CYP2C9 is responsible for metabolizing many medications, including indomethacin. Your genes influence how well your CYP2C9 works, which greatly varies from person to person.

People who carry certain genetic variations of CYP2C9 can clear indomethacin from their body more quickly. They may require higher drug doses to see the same effect as people who don’t have this genetic variation [R].

CYP2C9 activity increases in pregnant women. This is complicated by the fact that indomethacin is sometimes used during pregnancy to delay premature births. A pregnant woman with genetic variations in CYP2C9 may require very different doses than women with a normal gene [R].

An observational study of premature infants found that genetic variations can also increase infant response to indomethacin. Two specific changes in the CYP2C9 gene increased the success rate of indomethacin for treating heart defects in infants (the G allele of rs2153628 and the T allele of rs1799853)  [R].

User Experiences

For the most part, users give indomethacin positive reviews, as it usually reduces pain and swelling.

Some users even call indomethacin a “miracle drug”, as it’s quick-acting and can help with joint problems. Especially in acute gout, where the pain can be unbearable, users report indomethacin provides near total relief within hours.

Many claim that indomethacin is a lifesaver for headaches as well. For some people, this is the only medication that works to relieve cluster headaches, which can be debilitating.

The number one complaint against indomethacin goes back to its side effects. Some users stop taking the medication because of the headaches, nausea, stomach aches, and other side effects they experience.

Also, indomethacin doesn’t work for everyone. A few users report no pain relief from gout and other types of joint pain. Some also report better results with other NSAIDs such as ibuprofen.

Natural Alternatives

Many herbs, nutrients, and natural substances can reduce pain and inflammation with very few side effects. In fact, some natural compounds have a very similar mechanism of action as indomethacin, working to block the inflammatory COX enzyme or lower prostaglandins. Most also have the added benefit of being antioxidants and supporting general wellness.

We break down the best alternatives that may provide you with natural inflammation- and pain-relief. These are gentle products that can have a powerful effect in the long run, especially when combined with lifestyle and dietary changes.

Most are safe to use alongside OTC painkillers, but be sure to consult your doctor to rule out any potential interactions with your medications.

1) Fish Oil

The omega 3 fatty acids in fish oil are effective natural anti-inflammatory compounds. Fish oil blocks the production of inflammatory substances and reduce their effects [R, R].

In a study of 250 people, 60% of those who used fish oil reported improved pain relief. In addition, 88% of people said they would continue taking fish oil while 59% stopped taking prescription NSAIDs [R].

In a cell study, omega 3 fatty acids from fish oil reduced the breakdown and inflammation of human cartilage affected by osteoarthritis [R].

The side effects of fish oil are much milder and less frequent than indomethacin. Aside from the unpleasant taste, fish oil may only cause an upset stomach and occasional belching [R].

Adults should get at least two servings of oily fish per week, which is equivalent to about 500 mg of omega-3 fats [R].

The recommended dose of fish oil supplements is a total of 1.5-5 g of EPA and DHA per day, to be taken with meals [R].

2) Ginger

Ginger contains over 100 active ingredients that give it many potential benefits. Research suggests that it may be an effective antioxidant, anti-inflammatory, antibacterial, and cancer-fighting herb [R].

In an analysis of 9 clinical trials, ginger reduced the inflammatory marker CRP, while also improving cholesterol and blood sugar [R].

A clinical trial of 43 people compared ginger with diclofenac, a popular NSAID, for osteoarthritis. Ginger was as effective as diclofenac at reducing pain but cause fewer side effects [R].

Ginger was effective at reducing menstrual cramps in a review of 6 clinical trials. It showed similar effectiveness to synthetic drugs typically used to relieve painful periods [R].

The side effects of ginger are minimal. It may reduce blood clotting and may interact with blood thinning medications [R].

3) White Willow Bark

White willow bark has long been used as an herbal remedy for pain and inflammation. The active ingredient found in white willow bark is very similar to the structure of aspirin. It blocks prostaglandins through the same mechanism as NSAIDs [R].

Clinical studies of white willow bark confirmed its back pain-relieving benefits. It is more effective than placebo and as effective as rofecoxib, a selective NSAID [R, R].

White willow bark has few side effects. Because of its similarity to aspirin, white willow bark should not be used in children or in other conditions where aspirin cannot be used [R].

4) Capsaicin

Capsaicin is the active ingredient in chili peppers and is responsible for their burning sensation. Capsaicin can reduce the sensitivity of pain cells and block some inflammatory compounds, which has made it a popular choice for topical pain relief [R].

According to a recent analysis of 5 clinical trials, capsaicin cream reduced moderate pain in osteoarthritis [R].

Side effects of topical capsaicin are minimal, aside from the burning sensation felt upon application.

5) Resveratrol

Resveratrol is a powerful antioxidant compound found in red wine (in the skin of red grapes).

Resveratrol research focused on its protective effects on the heart and brain, but this antioxidant may also help fight arthritis. In rabbits, resveratrol knee injections protected the cartilage against inflammatory arthritis [R].

6) Boswellia

Boswellia is a tree that produces a well-known resin called frankincense. This resin may have strong anti-inflammatory and pain relieving properties.

In a small clinical trial of 30 people with osteoarthritis in the knee, boswellia safely improved knee movement, walking distance, and knee pain. Findings from cell studies add to boswellia’s powerful anti-inflammatory potential [R, R].

Other Alternatives

Aside from the ones listed in this article, several other natural alternatives have the potential to relieve pain and reduce inflammation. Some act similar to indomethacin, by blocking COX-2. Read this article to learn about all of them and find the one that will offer you the desired benefits based on your health concerns.

Limitations & Caveats

For some conditions, the evidence to support indomethacin is strong. For other conditions, the research is lacking.

The role of indomethacin in joint diseases, headaches, and menstrual cramps is supported by strong clinical trials and reviews.

The benefits of delaying premature birth with indomethacin are unclear. A large analysis looking at 20 clinical trials and 1509 women found that all the available research is low quality. There is also insufficient data on safety and long-term effects. The researchers concluded there was not enough evidence to decide if NSAIDs had a place in premature birth therapy [R].

Reviews examining indomethacin and patent ductus arteriosus have also been performed. Many of the clinical trials suffer from small sample sizes and little data on long-term effects. Researchers state that longer studies are needed to truly evaluate effectiveness [R, R].

Take-Away:

Indomethacin can reduce severe pain from inflammatory and autoimmune conditions, such as rheumatoid arthritis, back pain, and chronic spine inflammation. It also helps relieve specific types of headaches that rarely respond to other similar NSAID drugs.
However, indomethacin has several drawbacks. It causes more side effects than similar drugs like Advil (ibuprofen) that work just as well. It can also interfere with labor and should not be used by pregnant women in the third trimester. Some people are allergic to this drug, while others may not respond to it at all.
Various natural alternatives can provide safe and effective pain relief in the long run, especially if you have mild symptoms or are looking for an additional remedy with few side effects. Fish oil, Boswellia, and ginger are just a couple of powerful supplements that may provide you with dual action: pain reduction and enhanced antioxidant defense, especially when combined with lifestyle changes and a healthy diet.

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