Evidence based

Best Pain Reliever: How to Pick the Right One?

Last updated: 
July 23, 2020
Gerrie Lim
Researcher and author
Dr. Juliana Bruner, DPT
Researcher and author, Physical Therapist

You’re probably familiar with Tylenol, Advil, Aspirin, and other pain relievers, but do you know the difference between all of them? Do you know what to be careful of when taking certain ones? How should you decide which one is appropriate for your pain?

In this guide, we’ll cover different classes of pain relievers, how they work, how to determine if your condition requires pain relievers, how to decide which pain reliever to use, and what to do when pain relievers don’t work.

Classes of Pain Relievers

Researchers classify pain relievers based on the types of chemical reactions they cause. Here are the most common classes. 

  • NSAIDs: Non-steroidal anti-inflammatory drugs, reduce inflammation and lower fevers by preventing blood from clotting. NSAIDs can lead to stomach ulcers, nausea, or, in severe cases, kidney problems.
  • COX-2 inhibitors: A subclass of NSAIDs that selectively block only one enzyme, reducing the risk of ulcers and bleeding
  • Acetaminophen: An active ingredient in many pain relievers, acetaminophen does not reduce inflammation like its NSAID counterparts, but also has fewer of the side effects. It’s classified as a “miscellaneous analgesic.” 
  • Muscle relaxants: Medications used to treat muscle spasms, spasticity, and pain
  • Antidepressants: Traditionally used to recenter chemical imbalances in the brain, antidepressants can also target the neurotransmitters involved in conditions like arthritis, migraines, and low back pain
  • Opioids: A class of drugs that are especially potent; they block pain signals and are often used to treat moderate to severe pain. The human body can build tolerance on opioids, while also growing dependent, which leads to higher and more frequent doses. It’s important to work with a health care provider to be safe in using these to manage your pain.


Pain relievers vary in potency and in mechanism of action. Some, like NSAIDs, are relatively low risk and often available over the counter, while others, like opioids, carry significant risks and can only be prescribed by doctors.

Non-steroidal Anti-inflammatory Drugs

While "non-steroidal anti-inflammatory drug" sounds complicated, you're probably already familiar with some common NSAIDs -- for example, ibuprofen (Advil, Motrin), aspirin (Bayer), or naproxen (Aleve). Research shows that NSAIDS are the most popular class of analgesic prescribed by primary care physicians when it comes to musculoskeletal pain (1).

When you get hurt, your body releases prostaglandins, a set of chemicals your cells produce to promote inflammation. Although inflammation promotes clotting, it also results in pain and sometimes fever. NSAIDs inhibit prostaglandin production by blocking the enzyme cyclooxygenase (COX), reducing inflammation and consequently pain. While they have cardiovascular effects, NSAIDS are not blood thinners.

However, prostaglandins also protect the stomach from acid and promote blood clotting, so taking too many NSAIDs over a brief period of time can result in stomach pain, ulcers, and increased bruising. In severe cases, NSAIDs can also increase a person’s risk of heart attack or stroke, due to the cardiovascular nature of its inhibition (2). Prolonged, chronic use can lead to kidney failure, liver failure, and prolonged bleeding after an injury or surgery. Additionally, some people may be allergic to NSAIDs, especially those with asthma.

Despite these risks, researchers have found that NSAIDs are “at least as effective as other oral analgesics” when it comes to treating an acute musculoskeletal injury and relieving pain (3). Providers suggest using NSAIDs as a first-line treatment for headaches, arthritis, lower back pain, and menstrual cramps.

Topical vs. Oral, Gel vs. Tablet

NSAIDs come in two forms: oral and topical. Oral medications come in the form of a tablet, capsule, or liquid, while topical forms come as creams, gels, or liquids applied to the skin.

Oral medications come in many different subtypes. Some pills are solid, comprised of compact dust, while others are a liquid gel. Liquid gel pills cost slightly more than the traditional tablets, as they theoretically dissolve faster and should relieve pain more rapidly. However, several studies have indicated that solid pills actually work at similar speeds to liquid gel pills (4, 5).

Topical NSAIDs can take some time to take effect, since they must penetrate several layers of your skin. However, topicals have the advantage of stronger drug delivery to a specific, localized site. Topicals can also cause less stomach damage and are a great option for patients who can’t tolerate the adverse effects of oral NSAIDs or may suffer from a history of gastrointestinal bleeding. Studies show that topical NSAIDs “are an effective alternative” for pain relief in patients with acute musculoskeletal injuries (6). Some topical NSAIDs to consider include diclofenac (Voltaren), ibuprofen (Nurofen) and piroxicam (Feldene).


NSAIDs are generally the first-line medications for pain management. They're relatively safe, although they do have gastrointestinal and cardiovascular side effects.

COX-2 Inhibitors

COX-2 inhibitors are a class of NSAIDs that selectively block just the COX-2 protein, as opposed to blocking both the COX-1 and COX-2 proteins like other NSAIDSs. As a result, COX-2 inhibitors generally carry fewer gastrointestinal side effects than other NSAIDs, although they still carry cardiovascular side effects.

Certain COX-2 inhibitors carry elevated risks for cardiovascular complications, and as a result of this the FDA applies stringent standards in its assessments of COX-2 inhibitors (7). Some examples of COX-2 inhibitors that have won Food and Drug Administration (FDA) approval include celecoxib (Celebrex), rofecoxib (Vioxx), and amlodipine (Consensi). It should be noted that COX-2 inhibitors can cause bloating, diarrhea, constipation, nausea or vomiting. Prolonged, chronic use can also lead to effects on kidney function.

Research shows that overall, COX-2 inhibitors and other NSAIDs have similar therapeutic profiles (8). COX-2 inhibitors are particularly effective for treating osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, menstruation pains, and acute musculoskeletal pain.


Unlike other NSAIDs, COX-2 inhibitors only block the COX-2 protein and thus carry fewer gastrointestinal side effects.


Acetaminophen is the active ingredient in many common over-the-counter analgesics as well as heavier pain relievers, but it doesn't fall within the NSAID category and as a result is only applicable for pain relief (not inflammation). Acetaminophen has many names, including paracetamol and APAP. Interestingly, scientists still don’t understand its mechanism of action (9). While acetaminophen is usually taken orally, it can also be administered intravenously.

Although acetaminophen doesn’t reduce inflammation, it also doesn’t irritate the stomach or intestinal lining. This makes it especially effective for controlling chronic pain in people who can’t tolerate NSAIDs.

That being said, it’s extremely important to be wary of your acetaminophen dosage, as adverse effects can occur much more easily with smaller doses of acetaminophen than of NSAIDs. A typical adult should not take more than 4,000 milligrams of acetaminophen in 24 hours, the equivalent of eight Extra Strength pills. Acetaminophen has an especially significant impact on the liver, and can cause liver failure when taken in high doses. It should also never be mixed with alcohol (10).

Over-the-counter acetaminophen is readily available as a generic, but some brand OTCs include Tylenol, Midol, Nyquil, Robitussin, Dayquil/Nyquil, and Sudafed. Many pain-relieving prescription medications contain APAP, such as Percocet, Vicodin, and Codeine.


Acetaminophen is one of the most widely used pain relievers, although the mechanism of action behind it still isn't fully understood. It has adverse effects on the liver and should not be used with alcohol.

Muscle Relaxants

Skeletal muscle relaxants reduce tension in muscles. These drugs are available by prescription and generally work by dulling or inhibiting nerve pathways that are excessively stimulated. Examples of muscle relaxants include Onabotulinumtoxin-A (Botox), methocarbamol (Robaxin), and cyclobenzaprine (Flexeril). This group of pain relievers are used to treat rigid and stiff muscles, muscle spasms, and some musculoskeletal disorders. Rigidity and stiffness in muscles is sometimes referred to as “spasticity.”

Skeletal muscle relaxants reduce tension in muscles, and they’re especially effective for treating acute low back pain (11). It’s important to keep in mind that muscle relaxants are typically intended for temporary relief. Muscle relaxant courses need to be tapered off and not abruptly halted in order to control withdrawals and nerve pain response.

Because of the strength of prescription-level muscle relaxants, many of them come with unavoidable side effects. These side effects include drowsiness, fatigue, dizziness, and dry mouth. Muscle relaxants act quickly and last for hours, and so they should never be taken before drinking or driving. In severe cases, muscle relaxants can cause liver damage. Some people may find muscle relaxants habit-forming, so it's important to take them only as directed by a doctor. If you find yourself using them over longer periods of time to manage pain, it may be time to talk to your doctor about an alternative. Excessive use of muscle relaxants can mask the real underlying cause of back pain (12).


Muscle relaxants are strong medications that can be useful for pain that doesn't respond to first-line treatments like NSAIDs. They're especially effective for treating acute pain.


Antidepressants are typically applicable in for mental health treatment. But did you know that they can be used for treating musculoskeletal conditions too?

Antidepressants can be used to treat chronic pain conditions, even if a patient doesn’t have depression. They’re used to manage arthritis, migraines, tension headaches, fibromyalgia, low back pain, pelvic pain, and multiple sclerosis. However, they’re not used to treat acute pain.

While scientists aren’t quite sure about the mechanism by which antidepressants relieve pain, they suspect it has to do with how antidepressants target neurotransmitters, the kind that send pain signals to your brain. Research suggests that antidepressants deal with pain by bringing more norepinephrine or serotonin (two specific neurotransmitters) to the dorsal horns, a part of the spinal cord that houses sensory neurons (13, 14). Antidepressants take up to a week to act but can provide significant pain relief.

There are several types of antidepressants:

  • Tricyclics antidepressants (TACs), or tricyclics, are the most commonly used type for pain management. They target both serotonin and norepinephrine. Some side effects of tricyclics include drowsiness, constipation, weight change, and changes to your sex life. Examples of tricyclics include desipramine (Norpramin), imipramine (Tofranil), and trimipramine (Surmontil). 
  • Another type of antidepressant that deals with the same neurotransmitters are serotonin and norepinephrine reuptake inhibitors (SNRIs). They’re particularly handy when it comes to anxiety disorders, long-term chronic pain, and nerve pain. Side effects include elevated blood pressure, nausea, excessive sweating, insomnia, and dizziness. Venlafaxine (Effexor), milnacipran (Savella), and duloxetine (Cymbalta) are all examples of SNRIs. 

Selective serotonin reuptake inhibitors (SSRIs) are a third class of antidepressants. While more research is needed, a study found that SSRI “seems to have an effect on most of chronic pain conditions.” Side effects are similar to other antidepressants, but researchers found that SSRIs are “better tolerated” and cause fewer side effects than other antidepressants (15). Sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac) and paroxetine (Paxil) are examples of SSRIs.


Antidepressants aren't just useful for treating depression – they can also help with cases of persistent chronic musculoskeletal pain, including nerve-related pain.


Opioids are the man-made version of opiates, natural pain-numbing substances found in poppy flowers. Opioids are narcotics, a medicine class that includes any psychoactive compounds with sleep-inducing properties. You may be familiar with the more common opioids, like oxycodone (OxyContin), hydrocodone (Vicodin), codeine, and morphine. They’re used to treat severe pain, such as the kind left resulting from surgery, broken bones, or other traumatic injuries, or persistent pain. However, milder forms are used to suppress cough or ease severe diarrhea.

Opioids relieve pain by attaching to specific proteins on the brain and consequently blocking pain messages. While immediate side effects include sleepiness, constipation, and nausea, the most serious risk of opioids is the risk of long-term addiction. The human body develops tolerance to opioids, so larger and more frequent doses are required to achieve the same relief. Because of this, it’s very easy to overdose on opioids. Symptoms of an overdose include shallow breathing, slowed heart rate, and loss of consciousness. If you see or experience any of these signs, seek medical help immediately.

It’s imperative to work with your physician to reduce the risk of addiction when using opioids. Be sure to use them only as directed. Opioids might be an option for moderate and severe short-term pain, but long-term use comes with risks. According to the American Society of Anesthesiologists, here are some questions you should ask your provider:

  • Why was I prescribed opioids? 
  • Are there other effective pain management options? 
  • If opioids are the best option to treat my moderate to severe pain, how long should I treat them?

Public Health Crisis

While opioids can be useful for pain management, they’re easily misused. In the 1990s, the medical community didn’t fully understand the risks entailed by opioid treatment. Today, the National Institute of Health (NIH) estimates that every day more than 130 people die in the United States because of opioids (16). More than 70,000 deaths resulted from drug overdoses in 2017, and over half of those deaths involved a prescription opioid (17).

The FDA has approved a naloxone spray to help combat the opioid epidemic. Naloxone is a life-saving medication that can partially or even completely reverse an opioid overdose and buy precious time to get someone to medical services. Often known by its brand name, Narcan, it can be purchased over the counter at most major pharmacies and it’s often covered by insurance with a co-pay of less than $20. The NIH has provided a list of where to find free Naloxone, bystander response training, and other resources. GetNaloxoneNow.org offers opioid overdose prevention training that can be completed in 20 minutes. The Substance Abuse and Mental Health Services Administration (SAMHSA) published a toolkit on how to deal with opioid overdoses. If you or someone you know suffers from substance abuse, you can call 1-800-662-4357 for SAMHSA’s free, confidential, 24/7 treatment and referral helpline.


Opioids are one of the strongest classes of pain relievers. While opioids can be useful, special care should be taken in designing opioid treatment plans given the risks and addiction potential of these drugs.

How to Determine If Your Condition Requires Pain Relievers

It may be tempting to use strong medications to deal with your pain. However, in addition to carrying risks and side effects, these medications can be costly. Here, we’ll provide you with a toolkit on how to assess your pain so you can respond with the proper pain management approach.

First, take not of a few important details about your pain. What body part is the pain coming from? Is it dull or sharp? Is it aching? How long have you been hurting?

Start by considering treatments that don’t require medication. The first-line treatment is always rest, whether it’s sleeping or taking it easy. Next, try using a hot or cold compress on where it hurts. If these first-line treatments don’t work, consider over-the-counter medications such as acetaminophen or NSAIDs.

If your pain persists longer than two weeks, causes stress, prevents sleep, or disrupts your daily activities, seek care from a healthcare professional. Your provider may prescribe stronger NSAIDs, muscle relaxants, antidepressants, or, in particularly serious cases, opioids. Complement your prescription pain management with non-pharmacologic treatments such as massages, physical therapy, or stretching exercises. Record any observations of your pain and the effects of the pain relievers. If you notice the pain doesn’t get better or it gets worse, your doctor may prescribe steroid injections or surgery.


The conservative care approach to pain management is the best approach. In general, it's good to start with rest and over the counter medications, and to only consider stronger drugs if your pain persists or is particularly severe.

Final Recommendations

The different classes of pain relievers each come with their pros and cons:

  • NSAIDs like Advil, Aleve, and Bayer are great for mild to moderate pain. Many are over-the-counter, and they can reduce inflammation, pain, and fever. Overuse can lead to gastrointestinal problems. 
  • COX-2 inhibitors like Celebrex, Vioxx, and Consensi are great for mild to moderate pain and have milder side effects than other NSAIDs. Overuse can lead to kidney problems. If you have heart problems, talk to your doctor before taking them.
  • Acetaminophen comes in many forms. OTC types like Tylenol are great for people with gastrointestinal and cardiovascular problems. Do not consume alcohol with acetaminophen, as it could affect your liver.
  • Muscle relaxants are great for stiff muscles, muscle spasms, and some musculoskeletal disorders. They should only be used for short-term temporary relief, as they can be addictive or hide an underlying condition.
  • Antidepressants can be used for chronic pain conditions. There are three types: tricyclics, serotonin and norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs). They don’t work within twenty-four hours but can be used to provide long-term moderate pain relief for conditions like arthritis, low back pain, and multiple sclerosis.
  • Opioids are a powerful class of pain relievers that should only be used for moderate to severe pain that comes after a traumatic event. They are easily addictive and easy to build tolerance to. They should not be used on a long-term basis. 

Pain relief should begin with the most conservative treatment possible – rest, physical therapy, hot or cold compresses, and OTC pain relievers. You may not even need medication. For more persistent cases, consider talking to your provider about prescription-strength NSAIDs, muscle relaxants, and antidepressants. Opioids should be avoided as much as possible given their addictive properties. Additionally, you should complement your drug regimen with physical therapy, as most medications have side effects that render them insufficient for long-term care by themselves. If pain relievers and physical therapy don’t work, then talk to your doctor about steroid injections or, in the most severe cases, surgery.

Musculoskeletal pain is extremely widespread, but with modern medicine, there are many options to choose from that can help manage your pain.

The information provided in this article is not a substitute for professional medical advice, diagnosis, or treatment. You should not rely upon the content provided in this article for specific medical advice. If you have any questions or concerns, please talk to your doctor.

Research Citations

Researched, written, and reviewed by:
Gerrie Lim
Researcher and author
Gerrie holds a Master's in Public Health from Columbia University and has worked with a number of healthcare organizations in the past. She's especially passionate about using media and technology to improve healthcare for marginalized populations.
Read full bio
Dr. Juliana Bruner, DPT
Researcher and author, Physical Therapist
Dr. Bruner is a physical therapist who is highly trained and skilled in helping people overcome their physical ailments to live the best life they can. She is also a writer who enjoys spreading knowledge about various topics in the PT and healthcare industry.
Read full bio
Is pain holding you back?
We offer online doctor visits, at-home physical therapy regimens, and safe medications delivered to your door
Get Started

Related Articles

This article is based on scientific evidence, written by experts and fact checked by experts.

Our team of board-certified physical therapists, physicians, and surgeons strive to be objective, unbiased, honest and to present both sides of the argument.

This article contains scientific references. The numbers in the parentheses (1, 2, 3) are clickable links to peer-reviewed scientific papers.