The Science of Pain-Killers
A user’s guide to over-the-counter analgesics like acetaminophen, ibuprofen, and more
Ordinary pain-killers like ibuprofen and acetaminophen are fairly safe and somewhat effective in moderation and work in different ways, so cautious experimentation is justified for many people. They are all roughly equally effective for acute pain,1 but relief is usually minor and varies with people and issues. They all suffer from a ceiling effect: they can only produce so much pain relief, no matter how much you take.2
And for chronic pain, the familiar pain-killers are just a crapshoot: for instance, headaches, arthritis, fibromyalgia, neuropathy, and runner’s knee are all extremely different kinds of pain, and many of them can be impervious to any kind of pain medication.
And all the conventional analgesics have risks! Anything that has the power to help also has the power to harm. “With great power, comes great responsibility.” It’s important to always minimize dosage and avoid chronic use. This user’s guide explains some science-based basics, mainly for chronic pain patients and athletes and other professionals who are frequently recovering from injuries.
Three important safety rules for common pain-killers
The one safety rule (“to rule them all”) is always minimize dosage and avoid chronic use, but that’s very general. Some pain killers are more of a problem than others, so specifically how can you “minimize dosage” while still getting as much benefit as possible? Here are three more specific rules:
- First choice! Prefer topical pain-killers (e.g. Voltaren) where applicable — usually superficially injured tissue. The limited, targeted dosing is a great feature!
- Second choice! Try acetaminophen (Tylenol, Panadol etc) if it’s helpful. Acetaminophen is one of the safest drugs in existence at recommended dosages, but quite dangerous in overdose.
- Third choice! Use ibuprofen and other NSAIDs last — they tends to be the most effective for the widest range of complaints, but also have significant side effects at any dose (though more is worse, of course).
Acetaminophen is one of the safest drugs in existence at recommended dosages… but often accidentally & dangerously overdosed due to its presence in cold medications.
The major properties of the common non-prescription pain drugs
|Generic name||Brand names|
|Non-steroidal anti-inflammatory drugs (NSAIDs):|
|diclofenac (topical)||Voltaren, Flector…|
There are four main kinds of over-the-counter (OTC) or non-prescription analgesic drugs: acetaminophen, plus the four major non-steroidal anti-inflammatories (NSAIDs): aspirin (Bayer, Bufferin), ibuprofen (Advil, Motrin), naproxen (Aleve), and diclofenac (Voltaren). The NSAIDs are also typically available in “prescription-strength” doses.3
Acetaminophen — also called paracetamol, just a confusing name difference for the same thing4 — is good for both fever and pain, and is one of the safest of all drugs at recommended dosages. However, overdose can badly hurt livers!5 Unfortunately, overdose is quite common because of “hidden” doses in cold meds and other drugs. Even if you know better than take too much of the stuff, you might not realize that you are! How much is too much? 3000mg (6 pills) per day for adults.6
Acetaminophen may also be dangerous during pregnancy, harming fetuses. Incredibly, this side effect was barely known until relatively recently; it remains unproven, but experts are concerned abut it, and recommend caution.7
Acetaminophen may not work well for musculoskeletal pain specifically.8
The four major NSAIDs all reduce inflammation as well as pain and fever, and are particularly useful for menstrual cramps. Unfortunately, at any dose they can cause some heart attacks and strokes9 and they are all “gut burners” — that is, they all irritate the GI tract, even taken with food.10 So they are a terrible idea for people with ulcers or irritable bowel syndrome.
NSAIDs also particularly stress the kidneys, so people with any kind of kidney trouble (e.g. diabetics) can’t use them at all. And they are incompatible with blood-thinners.
Aspirin may be the best of the NSAIDs for joint and muscle pain, but it’s also the most gut-burning of them all.
Arcoxia (etoricoxib) is widely used globally, and noteworthy because it was well rated for efficacy by a huge review of pain meds for arthritis (without regard to safety issues, which are significant).11 It is barely known in the US because the FDA refused to approve it back in 2007, pending extra safety data that it still doesn’t have (and may never get, because it may not be safe enough for their standards).
Oral diclofenac was also a big winner for arthritis, basically tied with etoricoxib, and continues to be prescribed frequently despite major safety concerns in recent history. Long term and/or large oral doses of any of the NSAIDs can be extremely dangerous, even lethal, but oral diclofenac is a special kind of awful — it’s linked to serious cardiovascular risks.12 Topical diclofenac (e.g. Voltaren) is a different animal…
Topical diclofenac medications (e.g. Voltaren, Flector, Pennsaid) are particularly effective and safe, the best of the OTC pain killers in many ways. These are anti-inflammatory creams, patches, and sprays that can be applied only where you need it, instead of soaking your entire system with a medication. They are much safer than any oral pain killer,13 because dramatically less medication reaches the bloodstream14 and “solely the dose determines that a thing is not a poison” (Paracelsus, the father of toxicology).
In the US, this drug is FDA-approved to treat osteoarthritis in “joints amenable to topical treatment, such as the knees and those of the hands,” but it probably also works for some other painful problems, such as some repetitive strain injuries and back pain. The evidence shows that it “provides clinically meaningful analgesia,” quite safely, and that claim has stood the test of time in trial after trial.151617 For much more information, see my article on topical pain-killers, which also looks at salicylates creams and rubefaciants.
One of the best uses of NSAIDs: treating menstrual cramps
Menstrual cramps are powered by prostaglandin, a molecule produced by the womb during menstruation. Prostaglandins are everywhere in physiology, and are also found in inflamed tissues. All of the non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin production, which is a big part of what makes them “anti-inflammatory.” And so NSAIDs are particularly effective for menstrual cramps, especially compared to the other common pain-killer, acetaminophen.
Think of the NSAIDs as truly effective muscle relaxants for one specific muscle. 😉
My wife credits me with teaching her about this, and she was quite impressed by the upgrade. She had been taking whatever medication was handy, oblivious to any difference — a good example of why people need a guide like this. It was a revelation to discover that one type of pain medication is truly superior for this purpose. But, amusingly, she never remembers which one, just that there is a better choice. And so, for well over a decade now, we have the same conversation regularly:
“Which one is it again for the cramps? Ibuprofen, right? But I always get this backwards, so it must be acetaminophen?”
“Rewind! Back to your first impression. You want me to write it on the bottle? Or make a chart?”
“Don’t you dare make a chart.”
Medication-overuse headaches: a special kind of side effect
Pain-killers taken for headaches may be a surprisingly common and ironic cause of headaches (though maybe less of a plague than some headlines have led us to fear; see Scher).
Formerly known as “rebound” headaches, this side effect is probably mostly caused by dependence-and-withdrawal physiology — like getting a headache when you quit drinking coffee (although it might be more complicated). This topic is obviously of special interest to patients with unexplained headaches, and so I discuss it a lot in my headaches guide, but it’s also just a major side effect for anyone treating anything with pain-killers long-term.
“Vitamin I” — the widespread athletic habit of taking ibuprofen to prevent soreness
Athletes, puh-lease don’t take “Vitamin I” to prevent the soreness that follows intense exertion (delayed-onset muscle soreness) It does not do that!18 Taking NSAIDs once the pain starts is actually the only known effective treatment for that kind of pain — but it doesn’t work when taken pre-emptively.
Worse still? NSAIDs may actually impair tendon19 and bone healing!20 😬
Athletes are very enthusiastic about ibuprofen, and there may be reasons for that. For instance, a 2021 study showed that it did reduce fatigue and increase power in powerlifters. However, importantly, it did not reduce oxidative stress, which is what you’d expect if it was effective at preventing soreness and other unpleasant biological consequences of intense exercise.21
Why aren’t pain-killers more effective in general?
Potent analgesia without unconsciousness is like fusion power or a phone battery that charges in five minutes and lasts for a month, a technology that’s always on the horizon: a pain-free future has been 10 years away for 50 years. Why? There is no such thing as a “broad spectrum” pain killer — and there never will be, because it’s impossible in principle. Pain is a beast with many heads, and it is impossible to slay them all with one sword — a point this website goes on and on about. Pain is weird!
The elephant in the room: OTC pain-killers for back pain
Physical therapist Adam Meakins, while suffering from an episode of acute back pain:
“Why are painkillers called painkillers when they rarely ‘kill’ pain? Surely they would be better called pain calmers, or pain dampeners, or pain reducers?”
Back pain is by far the most common and debilitating type of musculoskeletal pain. The majority of OTC analgesics are probably purchased for back pain, with the remainder being divided up between everything else.
So it’s a shame that they barely work.
Your typical sugar pill placebo is going to net you a drop in back pain of about 10%, which is also about where “minimum clinical significance” is usually defined. That is, less than a 10% reduction in pain just doesn’t matter — it’s too small. Guess how much pain relief people get from over-the-counter pain killers on average? Just that much. In a 2017 review of 35 studies, both placebos and common anti-inflammatories for back pain had a “smallest worthwhile effect” of about 10%.22 The authors think that “there are no simple analgesics that provide clinically important effects for spinal pain over placebo.”
Naproxen might be the best of the over-the-counter drugs for most back pain (without significant sciatica, which tends to be tougher to tame).23 The evidence isn’t exactly conclusive, but it’s enough to justify prioritizing naproxen when experimenting with back pain treatment. For more information about medicating back pain, see the (huge, book-length) back pain guide.
Most drugs work on only about a third of the population, they do no damage to another third, and the final third can have negative consequences.
Craig Venter, extremely famous and spooky smart geneticist (public lecture, Vancouver, May 3, 2011)
Muscle relaxants: an odd special case
Non-prescription muscle relaxants (methocarbamol, as found in Robaxin, Robaxacet, etc) are also available and often used (and abused) like pain-killers — mostly ineffectively, for two main reasons:
- Strangely, muscle relaxants aren’t very good at actually relaxing muscles.
- Also strangely, muscle spasm is actually a much less common cause of pain (especially back pain) than people think it is.
This topic is explored throughout in Cramps, Spasms, Tremors & Twitches: The biology and treatment of unwanted muscle contractions.
Thumbnail sketches of several other major types of pain-killing drugs
- Cannabis — Marijuana is allegedly medicine, widely believed to have many health benefits, but especially pain relief. As legalization spreads like a wildfire, so does the hype, racing well ahead of the science, which is genuinely incomplete and contradictory, and there are legitimate concerns. Despite its reputation for being completely safe, it’s not entirely. It is probably more of a pain-coping drug than a pain-killing drug.
- Supplements — Many nutritional supplements, vitamins, and minerals, are taken like drugs as a treatment for aches and pains (e.g. glucosamine, curcumin, protein, vitamin D). Most are considered either anti-inflammatory or a healing stimulant. The science is either negative or barely there, and contamination of these unregulated substances is common. Despite a few rays of hope, not a single one that is clearly useful for pain.
- Arnica — Homeopathic (diluted) arnica creams for pain, such as Traumeel, are quite popular. They contain only trace amounts of the best-known ingredient, arnica. They may contain other herbs as well, some of them less extremely diluted. Scientific evidence so far strongly suggests that effects of such creams are minor at best.
Ripening seed head of an opium poppy.
- Homeopathy — Homeopathy is the use of extremely diluted substances as medicine — not an “herbal” or “natural” remedy, but a “magical” one, based on flaky physics. Homeopathy has been harshly criticized by nearly all doctors and scientists for at least a century.
- Corticosteroids (injected) — A potent anti-inflammatory option that is clearly effective in the short term, but notoriously ineffective in the long-term, and too potent to be used more than a handful of times without degenerating connective tissue, sometimes disastrously.24 At best, these injections are a useful short-term tactic in rehab.
- Corticosteroids (oral) — Extremely effective for severe widespread inflammatory conditions (e.g. rheumatoid arthritis), but they are extreme overkill for almost any painful “hot spot,” like trying to put out a frying-pan fire by turning on the sprinkler system.
- Epsom salts — Epsom salt in your bath makes bath water feel “silkier,” but that’s probably all: it’s unlikely to be biologically relevant to aches and pains, and it may not even make it through the skin (osmosis is not even relevant, and it cannot “detox” anything).
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About Paul Ingraham
I am a science writer in Vancouver, Canada. I was a Registered Massage Therapist for a decade and the assistant editor of ScienceBasedMedicine.org for several years. I’ve had many injuries as a runner and ultimate player, and I’ve been a chronic pain patient myself since 2015. Full bio. See you on Facebook or Twitter., or subscribe:
- Does Epsom Salt Work? — The science and mythology of Epsom salt bathing for recovery from muscle pain, soreness, or injury
- Icing for Injuries, Tendinitis, and Inflammation — Become a cryotherapy master
- Do Nerve Blocks Work for Neck Pain and Low Back Pain? — Analysis of the science of stopping the pain of facet joint syndrome with nerve blocks, joint injections, and nerve ablation
- Placebo Power Hype — The placebo effect is fascinating, but its “power” isn’t all it’s cracked up to be
- Quite a Stretch — Stretching science has shown that this extremely popular form of exercise has almost no measurable benefits
- How risky are NSAIDS? — A good general discussion of OTC pain-killer risks and side effects, by pharmacist Scott Gavura.l
What’s new in this article?
Six updates have been logged for this article since publication (2021). All PainScience.com updates are logged to show a long term commitment to quality, accuracy, and currency. more
Like good footnotes, update logging sets PainScience.com apart from most other health websites and blogs. It’s fine print, but important fine print, in the same spirit of transparency as the editing history available for Wikipedia pages.
I log any change to articles that might be of interest to a keen reader. Complete update logging started in 2016. Prior to that, I only logged major updates for the most popular and controversial articles.
See the What’s New? page for updates to all recent site updates.
Mar 30, 2022 — Added brief summary of Arcoxia (etoricoxib).
2022 — Minor science update, added a citation to Aidar about the effect of ibuprofen on recovery from intense exercise.
2021 — Minor science update, new citation for the safety and efficacy of topical diclofenac.
2021 — Science and safety update about acetaminophen safety during pregnancy. See Bauer.
2021 — Added minor clarifications about the upper limits of efficacy, and contraindications for NSAIDs.
2021 — New section, “One of the best uses of NSAIDs: treating menstrual cramps.” I am embarrassed that this wasn’t in the first version! A major oversight.
2021 — Publication.
- Hung KK, Graham CA, Lo RS, et al. Oral paracetamol and/or ibuprofen for treating pain after soft tissue injuries: Single centre double-blind, randomised controlled clinical trial. PLoS One. 2018;13(2):e0192043. PubMed 29408866 ❐
- This is contrast to the narcotic pain-killers, which have unlimited analgesic potential in principle, but in practice you can only take so much of them before they suppress not just pain, but also consciousness, and life itself.
- The prescription-strength dosages are literally just more of the same drug. Different countries requiring prescription at different dosages. For instance, Naproxen isn’t available over-the-counter in the United Kingdom at all.
- Both names are extracted from the same syllabel salad of the chemical name: para-acetylaminophenol. Acetaminophen is used in the United States, Japan, Canada, Venezuela, Colombia, and Iran. Paracetamol dominates everywhere else.
- FDA.gov [Internet]. Acetaminophen and Liver Injury: Q & A for Consumers; 2009 Jun 4 [cited 16 Aug 31]. PainSci Bibliography 53431 ❐
“This drug is generally considered safe when used according to the directions on its labeling. But taking more than the recommended amount can cause liver damage, ranging from abnormalities in liver function blood tests, to acute liver failure, and even death.”
- From the horse’s mouth (Tylenol): “To help encourage the safe use of acetaminophen, the makers of TYLENOL® have lowered the maximum daily dose for single-ingredient Extra Strength TYLENOL® (acetaminophen) products sold in the U.S. from 8 pills per day (4,000 mg) to 6 pills per day (3,000 mg). The dosing interval has also changed from 2 pills every 4 – 6 hours to 2 pills every 6 hours.”
- Bauer AZ, Swan SH, Kriebel D, et al. Paracetamol use during pregnancy - a call for precautionary action. Nat Rev Endocrinol. 2021 Sep. PubMed 34556849 ❐
Wait, what? We’re just now figuring out that acetaminophen might cause birth defects?
Serious side effects, previously unknown, in one of the most widely consumed drugs on the planet?! That’s awful. And catnip for the medicine-is-evil crowd.
It remains uncertain, but this statement in the journal Nature is “currently supported by 91 scientists, clinicians and public health professionals from across the globe.” It is of course possible for a bunch of fancy people to put their names to complete garbage, but I doubt that’s the case here. At worst the concern might be somewhat overstated, but it does seem appropriate to apply the precautionary principle.
- Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225. PubMed 25828856 ❐ PainSci Bibliography 54220 ❐
- Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017 May;357:j1909. PubMed 28487435 ❐ PainSci Bibliography 53592 ❐
Taking any dose of common pain killers for as little as a week is associated with greater risk of heart attack, according to this meta-analysis, and the risk is greatest in the first month of use. This is probably primarily of concern for people already at risk for heart attack, but this data doesn’t address that question, and it’s a lot of people regardless.
- The effect of NSAIDs on the GI tract is actually indirect: it’s not because the medicine comes into direct contact with the walls of the GI tract, but because the medication, once it is in the bloodstream, affects the behaviour of cells in the lining of the gut. So it’s actually just a matter of dosage, regardless of the route of administration. If you were to smear a diclofenac gel all over your body, you would absorb enough of it that it would be a “gut burner” too!
- da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021 10;375:n2321. PubMed 34642179 ❐ PainSci Bibliography 52213 ❐
- McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013 Feb;10(2):e1001388. PubMed 23424288 ❐ PainSci Bibliography 54748 ❐
Diclofenac is an extremely popular painkiller associated with serious cardiovascular risks, as with other NSAIDs: “There is increasing regulatory concern about diclofenac. … Diclofenac has no advantage in terms of gastrointestinal safety and it has a clear cardiovascular disadvantage.”
- Pontes C, Marsal JR, Elorza JM, et al. Analgesic Use and Risk for Acute Coronary Events in Patients With Osteoarthritis: A Population-based, Nested Case-control Study. Clin Ther. 2018 Feb;40(2):270–283. PubMed 29398161 ❐
- PharmacyTimes.com [Internet]. Fudin J. Should Topical NSAIDs Have Strict Heart Risk Warnings?; 2018 March 10 [cited 18 Jun 12]. PainSci Bibliography 53132 ❐ Although this article’s title implies concerns about topical NSAID safety, it ends up answering that concern with very reassuring data, and it turns into a piece suggesting that the FDA needs to make it clearer that only oral NSAIDs are of concern, while topical is an extremely safe alternative! “ … all topical vehicles of diclofenac delivery result in only a small fraction of the diclofenac that actually reaches the systemic circulation compared with the oral route.”
- Altman R, Barkin RL. Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. Postgrad Med J. 2009 Mar;121(2):139–47. PubMed 19332972 ❐
- Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst Rev. 2015;6:CD007402. PubMed 26068955 ❐
- da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021 10;375:n2321. PubMed 34642179 ❐ PainSci Bibliography 52213 ❐
- Nieman DC, Henson DA, Dumke CL, et al. Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. Brain Behav Immun. 2006 Nov;20(6):578–84. PubMed 16554145 ❐
This experiment tested the effect of ibuprofen on hard-core marathoners. There were 29 ultra-marathoners on high doses of ibuprofen and 25 controls that completed the race without meds. There was no measurable difference in muscle damage or soreness between the two groups. Lead researcher David Niemen: “There is absolutely no reason for runners to be using ibuprofen.”
For some good mainstream journalism about this research see Convincing the Public to Accept New Medical Guidelines, by Aschwanden. For a good plain language tour of the topic in a major medical journal, see Warden.
- Bittermann A, Gao S, Rezvani S, et al. Oral Ibuprofen Interferes with Cellular Healing Responses in a Murine Model of Achilles Tendinopathy. J Musculoskelet Disord Treat. 2018;4(2). PubMed 30687812 ❐ PainSci Bibliography 52446 ❐
- Wheatley BM, Nappo KE, Christensen DL, et al. Effect of NSAIDs on Bone Healing Rates: A Meta-analysis. J Am Acad Orthop Surg. 2019 Apr;27(7):e330–e336. PubMed 30260913 ❐
This is a meta-analysis of 16 trials, showing that common over-the-counter pain-killers interfere with bone healing. Chronic overuse roughly doubles the risk that a fracture will heal slowly or not at all (“non-union,” a very serious complication).
The effect was not evident in children or in lower doses or temporary usage — this bad news applies only to adults taking too much of the stuff for too long. Unfortunately, a lot of people do that! The pain-killers in question are the non-steroidal anti-inflammatory drugs or NSAIDs like aspirin, ibuprofen, and naproxen — already notorious for several other significant side effects, and yet still widely overused.
- Aidar FJ, Fraga GS, Getirana-Mota M, et al. Effects of Ibuprofen Use on Lymphocyte Count and Oxidative Stress in Elite Paralympic Powerlifting. Biology (Basel). 2021 Sep;10(10). PubMed 34681085 ❐ PainSci Bibliography 51979 ❐
Ten national-level paralympic powerlifting athletes were assessed for post-training fatigue and oxidative stress with ibuprofen versus a placebo. (“Oxidative stress” is a general biological signature of a body under strain, measurable after bouts of intense exercise.) There were no differences in oxidative stress… but, surprisingly, the athletes with ibuprofen in their veins were stronger and had less fatigue.
- Machado GC, Maher CG, Ferreira PH, et al. Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. Ann Rheum Dis. 2017 Jul;76(7):1269–1278. PubMed 28153830 ❐
- Ashbrook J, Rogdakis N, Callaghan MJ, Yeowell G, Goodwin PC. The therapeutic management of back pain with and without sciatica in the emergency department: a systematic review. Physiotherapy. 2020 Jul;109:13–32. PubMed 32846282 ❐
- Okike K, King RK, Merchant JC, et al. Rapidly Destructive Hip Disease Following Intra-Articular Corticosteroid Injection of the Hip. J Bone Joint Surg Am. 2021 11;103(22):2070–2079. PubMed 34550909 ❐
This study identified a low risk of “rapid hip destruction disease” with one low-dose steroid injection, and “higher” risk with larger and multiple injections. This is hardly the only evidence of harm from steroid injections, but I think it is the most dramatic I have ever seen. RHDD is what it sounds like: premature and accelerated arthritis. Best avoided! This risk is remote, but also as serious as an amputation.