Is There Any Difference Between OTC Pain Relievers?

The differences between Tylenol, Aleve, Advil, and Aspirin

Most people have one or more over-the-counter (OTC) pain relievers in the house, but do you know which ones are best for certain kinds of pain? Or do you just reach for whatever is convenient? By and large, most people tend to stick with the brand they recognize or believe is "better" than others.

You may wonder whether there are really any differences between them. The fact is—they are all different in significant ways. When you're buying them, taking them, and especially combining them with each other or other medications, you need to know a few crucial pieces of information.

A photo illustration of aleve vs. tylenol

Verywell / Photo Illustration by Michela Buttignol / Getty Images

Properties of OTC Pain Relievers

The four main OTC pain drugs on the market are:

Each one has both benefits and risks. While their general function is more or less the same—to alleviate pain—their mechanism of action and how they're best used does vary. The reasons for using them can include some or all of the following:

  • To relieve a headache
  • To reduce pain, swelling, and stiffness in joints or muscles
  • To relieve pain from injury or nerve damage
  • To lower a fever
  • To lessen some of the symptoms—such as sinus pain—of allergies, colds, or the flu

The choice of drug depends largely on the condition(s) you need to treat and the potential problems that may prevent you from using a particular product.

Cox Enzymes and Inflammation

All of these OTC pain relievers have an impact on proteins called COX enzymes, but one of these medications works differently from the others.


Ibuprofen, naproxen sodium, and aspirin are all non-steroidal anti-inflammatory drugs (NSAIDs) with a similar mechanism of action. Because of this, you shouldn't combine more than one type of NSAID as that can increase the likelihood of side effects. Serious risks of NSAIDs—with the exception of aspirin—include an increased risk of heart attack or stroke.

NSAIDs work by blocking COX-1 and COX-2 enzymes outside of the central nervous system (CNS) and at the site of damaged tissues. COX enzymes are involved in the inflammatory process, so blocking them counters inflammation and the pain it can cause.


Meanwhile, acetaminophen's mechanism of action isn't fully understood, but it seems to increase your body's pain threshold (the point at which sensation is perceived as painful). It's thought to do this by targeting a protein sometimes called COX-3 that's actually a COX-1 variant.

However, a key difference is that acetaminophen blocks this protein inside the CNS (brain and spinal cord), not outside of it like NSAIDs. This crucial difference means that acetaminophen isn't effective for inflammation-related problems, such as sprains or rheumatoid arthritis.


Acetaminophen is one of the most-used drugs in the U.S., and it's in several hundred OTC products as well as numerous prescription medications. Brand names of OTC products containing acetaminophen include:

  • Tylenol
  • Actamin
  • Feverall
  • Panadol
  • Tempra Quicklets
  • Dayquil (combined with dextromethorphan and pseudoephedrine)
  • NyQuil Cold/Flu Relief (combined with dextromethorphan and doxylamine)

You'll also find acetaminophen in most drugs that say they relieve sinus pain, such as multi-symptom cold and flu products.

Acetaminophen is also used in combination opioid painkillers such as:

Best for Combining

Acetaminophen is used so widely because it's not only effective, it also has fewer side effects than other OTC pain medications and doesn't interact negatively with most common drugs. That's why it turns up in a lot of combination products. Also, because it has a different mechanism of action, acetaminophen can safely be combined with NSAIDs.

Some studies say it's just as good as NSAIDs for headaches, while others have found it to be less effective. However, studies have shown that drugs combining acetaminophen, aspirin, and caffeine are superior for some types of migraine disorders. Much of it depends on the type of headache and your individual response to the medications.

However, because acetaminophen doesn't reduce inflammation, it may be less effective for inflammatory causes of pain, like arthritis or certain injuries.


Acetaminophen is often combined with opioid pain medication to treat serious pain following surgery, from injuries, or from chronic pain. It is generally safe at the recommended dose, although some people may develop a serious skin rash.

An overdose of acetaminophen can cause serious, sometimes fatal, damage to your liver. It's important that you stay within the recommended dose. Because acetaminophen is in so many products, be sure to check the labels of all medications you're taking. It also helps to involve your healthcare provider and pharmacist in your treatment decisions.

Unlike NSAIDs, however, acetaminophen is not associated with an increased heart attack or stroke risk. The American Heart Association recommends acetaminophen as the first painkiller to try for people who've had a heart attack.

Acetaminophen Warnings

Acetaminophen liver toxicity is a serious problem in the U.S. due to the epidemic of opioid abuse and overdose. Many overdose deaths are caused by the acetaminophen, not the opioid. Liver damage is also more likely if acetaminophen is combined with alcohol.


Aspirin, also known as acetylsalicylic acid (ASA), is an NSAID used to treat pain, fever, and inflammation. It's in a host of products, both alone and in combination with other drugs. Brand names include:

  • Anacin Aspirin Regimen
  • Bayer
  • Bufferin
  • Empirin
  • Genacote
  • Miniprin
  • Uni-Buff

Some combination products containing aspirin are:

  • Alka-Selzer (with citric acid and sodium bicarbonate)
  • Anacin Advanced Headache Formula (with acetaminophen and caffeine)
  • Excedrin (with acetaminophen and caffeine)

It's also an ingredient in some combination prescription opioids, including:

  • Soma Compound with codeine
  • Alor, Lortab ASA, Panasal (with hydrocodone)
  • Endodan, Percodan, Roxiprin (with oxycodone)

Best for Heart Health

You've probably heard about taking daily low-dose aspirin for heart health, especially if you've had a heart attack or currently have heart disease. It's useful because it prevents your blood from clotting. In people whose arteries are narrowed, a clot can block blood flow to your heart or brain and cause a heart attack or stroke.

However, aspirin isn't safe for everyone, and as with any drug, you and your healthcare provider need to weigh the potential benefits and risks before deciding whether a daily aspirin regimen is right for you, and what dosage is appropriate.


Excess bleeding and upset stomach are common side effects of aspirin. Stomach ulcers and gastrointestinal bleeding can occur. This happens most often in people who:

If taken during a heart attack, aspirin can significantly reduce the chance of death. On the other hand, it should not be taken if you are having a stroke as strokes may be caused by the rupture of a vein (rather than by blockage). As such, aspirin can make a stroke worse by promoting bleeding.

Aspirin Warnings

Aspirin should be avoided in children with fever due to the risk of Reye's syndrome, which is a form of encephalopathy (a brain disease).


Ibuprofen is an NSAID used to treat pain, fever, and inflammation, and is commonly used to alleviate the symptoms of a migraine, menstrual cramps, or rheumatoid arthritis. As with all NSAIDs, ibuprofen is better than acetaminophen for inflammatory injury or disease. Brand names include:

Combination opioid products containing ibuprofen include:

  • Ibudone, Reprexain, Vicoprofen (with hydrocodone)
  • Combunox (with oxycodone)

Best for Quick Action

Ibuprofen is a short-acting NSAID that starts working faster than naproxen. This may be better for acute pain, like a new injury. The downside is that ibuprofen has to be taken more often than naproxen.


Ibuprofen has fewer side effects than some NSAIDs but can cause heartburn and a rash. It should be avoided in people with kidney or liver problems and may increase the risk of hypertension (high blood pressure) and heart attack if taken excessively.

Ibuprofen Warnings

Ibuprofen (and all NSAIDs except aspirin) may increase your risk of heart attack or stroke, which can happen suddenly and be fatal. Ibuprofen may also cause serious damage to the stomach or intestines, including bleeding, ulcers, or holes.

Naproxen Sodium

Naproxen sodium is an NSAID used to treat the same symptoms and conditions as ibuprofen (pain, fever, inflammation, migraine, menstrual cramps, rheumatoid arthritis). It's also sometimes used for the painful chronic conditions Paget's disease and Bartter syndrome.

Again, as an NSAID, naproxen is a better choice than acetaminophen for pain involving inflammation. Brand names include:

  • Aleve
  • Anaprex
  • Naprosyn
  • Aleve PM (with diphenhydramine)

Prescription products containing naproxen include:

  • Vimovo (with esomeprazole)
  • Treximet (with sumatriptan)

Best for Chronic Pain, Fewer Side Effects

Naproxen is a long-acting NSAID, meaning it takes longer to relieve your pain but remains in effect for longer than a short-acting NSAID like ibuprofen. You also don't have to take it as often. This can make it a better choice if you need to take it regularly for pain from a chronic condition.

Another real advantage is that naproxen sodium is associated with fewer side effects than ibuprofen, meaning it's safer overall and you may be able to tolerate it if ibuprofen bothers you.


Compared to ibuprofen, naproxen has a far higher risk of stomach ulcers. As such, it should be taken with food or avoided if you have a history of ulcers or inflammatory bowel disease (IBD).

Naproxen Sodium Warnings

As with most NSAIDs, naproxen may increase your risk of heart attack or stroke.

Mixing OTC Pain Relievers

You need to be careful when taking more than one OTC pain relievers. You shouldn't take more than one drug from a class at a time because it increases your risk of side effects or overdose. That means it's NOT safe to combine NSAIDs—aspirin, ibuprofen, naproxen, or prescription NSAIDs. Because acetaminophen has a different mechanism of action, it can be safely taken with NSAIDs.

  Acetaminophen  Aspirin Ibuprofen Naproxen
Acetaminophen -
Aspirin  -
Ibuprofen  - ⛔ 
Naproxen  ⛔  -
Source: ASHP SafeMedication

A Word From Verywell

When choosing the right pain reliever, it's important to look at the side effects and any potential drug interactions. Get advice from your healthcare provider as to which may be the best for you.

If you're in the drugstore and need some last-minute advice, particularly if you have medical conditions or take medications of any kind, you can also ask the pharmacist.

Frequently Asked Questions

  • What OTC pain relievers are easiest on kidneys?

    Acetaminophen is the OTC pain reliever of choice for people with kidney disease because ibuprofen and naproxen can decrease kidney function and aspirin is associated with bleeding complications. Even so, if your kidney function is impaired, use acetaminophen sparingly and under the care and supervision of your healthcare provider.

  • What OTC pain relievers are not NSAIDs?

    Acetaminophen is the only oral OTC pain reliever that's not an NSAID. Many OTC topical pain relievers don't contain NSAIDs.

  • Are any OTC pain relievers safe to take during pregnancy?

    Acetaminophen is considered the safest OTC pain reliever to take while you're pregnant, but it still should be used only short-term. 

    According to a study by the Centers for Disease Control and Prevention, birth defects were less common when acetaminophen was used during pregnancy than when NSAIDs or opioids were taken.

    As with anything you take during pregnancy, be sure to talk to your obstetrician before using it.

  • What OTC pain relievers can you take with blood thinners?

    Acetaminophen is the OTC pain reliever recommended for people taking blood thinners, but even it should only be taken with the knowledge and oversight of your healthcare provider. NSAIDs—and especially aspirin—can prevent clotting, so combining it with blood-thinning medications like Coumadin (warfarin) can increase your risk of severe and even fatal bleeding.

28 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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Additional Reading

By Kristina Duda, RN
Kristina Duda, BSN, RN, CPN, has been working in healthcare since 2002. She specializes in pediatrics and disease and infection prevention.