How Do Painkillers Actually Kill Pain? From Ibuprofen to Fentanyl, It’s About Meeting the Pain Where It’s At

Yves here. I have to admit to a selfish interest in the topic of pain and painkillers. I have a high pain threshold, which in most ways is good but it means I seldom get pain feedback when I am doing something stupid at the gym. So two days later I’ll be swollen and wonder what exactly I did to myself. My hips similarly were “terrible” before I  got new ones (my surgeon said in the bottom 1%) . I was able to put the procedure off because I had hardly any pain. The worst it got to be was the occasional 4 on a scale of 10.

I don’t know if that tendency is linked to one that some other readers have: not getting pain relief from opioids (I’m sure a high enough dose would knock me out) and feeling terrible when on them. High doses of NSAIDs work much better and are less disagreeable.

By Rebecca Seal, Associate Professor of Neurobiology, University of Pittsburgh Health Sciences and Benedict Alter, Assistant Professor of Anesthesiology and Perioperative Medicine, University of Pittsburgh Health Sciences. Originally published at The Conversation

Without the ability to feel pain, life is more dangerous. To avoid injury, pain tells us to use a hammer more gently, wait for the soup to cool or put on gloves in a snowball fight. Those with rare inherited disordersthat leave them without the ability to feel pain are unable to protect themselves from environmental threats, leading to broken bones, damaged skin, infections and ultimately a shorter life span.

In these contexts, pain is much more than a sensation: It is a protective call to action. But pain that is too intense or long-lasting can be debilitating. So how does modern medicine soften the call?

As a neurobiologistand an anesthesiologistwho study pain, this is a question we and other researchers have tried to answer. Science’s understanding of how the body senses tissue damage and perceives it as pain has progressed tremendously over the past several years. It has become clear that there are multiple pathwaysthat signal tissue damage to the brain and sound the pain alarm bell.

Interestingly, while the brain uses different pain signaling pathways depending on the type of damage, there is also redundancy to these pathways. Even more intriguing, these neural pathways morph and amplify signals in the case of chronic painand pain caused by conditions affecting nerves themselves, even though the protective function of pain is no longer needed.

Painkillers work by tackling different parts of these pathways. Not every painkiller works for every type of pain, however. Because of the multitude and redundancy of pain pathways, a perfect painkiller is elusive. But in the meantime, understanding how existing painkillers work helps medical providers and patients use them for the best results.

Anti-Inflammatory Painkillers

A bruise, sprain or broken bone from an injury all lead to tissue inflammation, an immune response that can lead to swelling and redness as the body tries to heal. Specialized nerve cells in the area of the injury called nociceptorssense the inflammatory chemicals the body produces and send pain signals to the brain.

Common over-the-counter anti-inflammatory painkillerswork by decreasing inflammation in the injured area. These are particularly useful for musculoskeletal injuries or other pain problems caused by inflammation such as arthritis.

Nonsteroidal anti-inflammatories like ibuprofen (Advil, Motrin), naproxen (Aleve) and aspirin do this by blocking an enzyme called COXthat plays a key role in a biochemical cascade that produces inflammatory chemicals. Blocking the cascade decreases the amount of inflammatory chemicals, and thereby reduces the pain signals sent to the brain. While acetaminophen (Tylenol), also known as paracetamol, doesn’t reduce inflammation as NSAIDs do, it also inhibits COX enzymes and has similar pain-reducing effects.

Prescription anti-inflammatory painkillers include other COX inhibitors, corticosteroids and, more recently, drugs that target and inactivate the inflammatory chemicalsthemselves.

Aspirin and ibuprofen work by blocking the COX enzymes that play a key role in pain-causing processes.

Because inflammatory chemicals are involved in other important physiological functions beyond just sounding the pain alarm, medications that block them will have side effects and potential health risks, including irritating the stomach lining and affecting kidney function. Over-the-counter medicationsare generally safe if the directions on the bottle are followed strictly.

Corticosteroidslike prednisone block the inflammatory cascade early on in the process, which is probably why they are so potent in reducing inflammation. However, because all the chemicals in the cascade are present in nearly every organ system, long-term use of steroids can pose many health risks that need to be discussed with a physician before starting a treatment plan.

Topical Medications

Many topical medicationstarget nociceptors, the specialized nerves that detect tissue damage. Local anesthetics, like lidocaine, prevent these nerves from sending electrical signals to the brain.

The protein sensors on the tips of other sensory neurons in the skin are also targets for topical painkillers. Activating these proteins can elicit particular sensations that can lessen the pain by reducing the activity of the damage-sensing nerves, like the cooling sensation of menthol or the burning sensation of capsaicin.

Because these topical medications work on the tiny nerves in the skin, they are best used for pain directly affecting the skin. For example, a shingles infectioncan damage the nerves in the skin, causing them to become overactive and send persistent pain signals to the brain. Silencing those nerves with topical lidocaine or an overwhelming dose of capsaicin can reduce these pain signals.

Nerve Injury Medications

Nerve injuries, most commonly from arthritis and diabetes, can cause the pain-sensing part of the nervous system to become overactive. These injuries sound the pain alarm even in the absence of tissue damage. The best painkillers in these conditions are those that dampen that alarm.

Antiepileptic drugs, such as gabapentin (Neurontin), suppress the pain-sensing system by blocking electrical signaling in the nerves. However, gabapentin can also reduce nerve activity in other parts of the nervous system, potentially leading to sleepiness and confusion.

Antidepressants, such as duloxetine and nortriptyline, are thought to work by increasing certain neurotransmitters in the spinal cord and brain involved in regulating pain pathways. But they may also alter chemical signaling in the gastrointestinal tract, leading to an upset stomach.

All these medications are prescribed by doctors.


Opioidsare chemicals found or derived from the opium poppy. One of the earliest opioids, morphine, was purified in the 1800s. Since then, medical use of opioids has expanded to include many natural and synthetic derivatives of morphine with varying potency and duration. Some common examples include codeine, tramadol, hydrocodone, oxycodone, buprenorphine and fentanyl.

Opioids decrease pain by activating the body’s endorphin system. Endorphinsare a type of opioid your body naturally produces that decreases incoming signals of injury and produces feelings of euphoria – the so-called “runner’s high.” Opioids simulate the effects of endorphins by acting on similar targets in the body.

While opioids can provide strong pain relief, they are not meant for long-term use because they are addictive.

Although opioids can decrease some types of acute pain, such as after surgery, musculoskeletal injuries like a broken leg or cancer pain, they are often ineffective for neuropathic injuries and chronic pain.

Because the body uses opioid receptors in other organ systems like the gastrointestinal tract and the lungs, side effects and risks include constipation and potentially fatal suppression of breathing. Prolonged use of opioids may also lead to tolerance, where more drug is required to get the same painkilling effect. This is why opioids can be addictive and are not intended for long-term use. All opioids are controlled substances and are carefully prescribed by doctors because of these side effects and risks.


Although cannabis has received a lot of attention for its potential medical uses, there isn’t sufficient evidence availableto conclude that it can effectively treat pain. Since the use of cannabis is illegal at the federal levelin the U.S., high-quality clinical research funded by the federal government has been lacking.

Researchers do know that the body naturally produces endocannabinoids, a form of the chemicals in cannabis, to decrease pain perception. Cannabinoids may also reduce inflammation. Given the lack of strong clinical evidence, physicians typically don’t recommend them over FDA-approved medications.

Matching Pain to Drug

While sounding the pain alarm is important for survival, dampening the klaxon when it’s too loud or unhelpful is sometimes necessary.

No existing medication can perfectly treat pain. Matching specific types of pain to drugs that target specific pathways can improve pain relief, but even then, medications can fail to work even for people with the same condition. More research that deepens the medical field’s understanding of the pain pathways and targets in the body can help lead to more effective treatments and improved pain management.

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  1. Terry Flynn

    Painkillers are something close to me both personally and professionally. Anybody who doesn’t know the Cox2 familyblogshow should look up Professor Paul Dieppe. He was my boss for 9 years. He was publicly thrown out of the (US based) international society which was anchored in rheumatology which wholeheartedly endorsed COX2. He was part of the (UK Bristol based – where I was) team that blew the whistle. He went up against the PMC and lost.

    Then he won when enough evidence emerged. He was reinstated and given their medal of honour. He found that funny ever since (though he wasn’t well disposed to the authorities because he was a member of Flight BA149 – google it if the first Iraq War is not indelibly printed upon your mind – and yes he WAS a human shield. His comments are too bad and personal to repeat here.)

    Painkillers are CRIMINALLY misunderstood. What started as a suspected STI on my part led – only due to the fact I Worked in medicine and knew my consultant who explained it – to the use of amitriptylline (an antidepressant) as a painkiller. What most docs don’t know is that this drug, at a LOW, clinically “irrelevant” dose, works wonders at non-specific pain relief, insomnia etc. It’s like aspirin – a drug used for one thing at first but which subsequently was found to be incredible for a bunch of other things (provided you adjust the dosage).

    Pregabalin is another good/awful drug. You can look up the prescribing in my county (Nottinghamshire, England) and you’d immediately see there’s very weird patterns. How come all the prescribing is done in former mining areas? Cause those poor men suffered years of awful physical work that messed up their backs. Prescribing for its “new use” (chronic anxiety) has plummetted – why? Because it turns out it is even worse than benzodiazepines (valium etc) for inducing tolerance and addiction. BUT they can’t preduct who will fall victim to this. Turns out you can’t make decisions based on previous tendency to get addicted etc. I have NO problem with benzos but I took a year to get off Pregabalin, prescribed initially in Sydney as a “two for one” to solve my slipped disc pain and anxiety. Nope. Won’t touch it now.

    My overall conclusion matches that of the post. There are NO easy answers and matching the patient to the kind of pain relief is often difficult and frustrating.

  2. dougie

    I started taking 50 mg of a high quality CBD product about 3 months ago. I had to shop around some, because the first product I purchased would occasionally leave me feeling a bit stoned. I wasn’t looking for that.

    I began taking it to see if it would help alleviate some mild to medium arthritis pain in my hands. It has helped enough that I no longer need to take Tylenol for the discomfort. I am considering raising the dosage to observe any further benefit.

    I found it much more effective over a longer period of time than a CBD topical cream I used briefly.

    As for claims made by some CBD proponents that it sharpens mental acuity? For me, not so much. I noticed no discernable effect in that area. I will stick with my morning cup of strong Italian roast coffee, thank you very much.

    1. JAC

      Cannibinoids and COX2 are connected. Let me explain.

      COX2 metabolizes Arachidonic Acid (AA), an Omega 6 Fatty Acid, into inflammatory proteins, one is PGE2.

      COX2 also metabolizes EPA, an Omega 3 Fatty Acid from fish, into inflammatory proteins as well, one is PGE3.

      These two prostoglandins have extremely different effects on the body and inflammation, with PGE3 seemingly less reactionary than PGE2.

      So lowering your Omega 6 fats and increasing Omega 3 will lower inflammatory pain. This is shown over and over ins studies but no one talks about it. This is also the link betwen Omega 3 and heart diseease.

      What else is not talked about is that our endogenous CBD, endocannabiniods (eCBs), are made from Omega 3 fats by this same COX enzyme.

      You see, no need for weed, just eat more fish.

      It seems logical to reason that you have a sensitivity to this fatty acid imbalance because genetics. Or you just eat way too much short chain omega 6 fatty acids.

      1. Susan the other

        I’m all for Omega-3 but you really can’t rub fish on your knees! I use a veterinary grade CBD that my bro-in-law sent me. It does work quite well for knee pain. The other thing that works almost magic for me is an aspirin in the morning with my coffee. The two in combination. As far as opioids and codeine, etc. go – they only make me groggy and slightly nauseous. Another thing I used to use was a little roll-on from the health food store called Sting-eaze – on mosquito bites (I’m super allergic) and it worked really well; another homeopathic item was called “Head-on” and just one roll across my forehead and it precluded the onset of a migraine. Like magic. Most recently I’ve been prescribed a super steroid cream called Triamcinolone, a cream for a super-itchy rash that I have no clue about. I thought it was monkeypox – but no – just an ordinary mysterious rash. And since I was hesitant to dose myself with steroids for too long I stopped, and every time my leg started to itch I simply put my hand over the itch and kept it warm. And the itch went away. Really. Maybe logically, because scratching also increases the heat in your skin and relieves the itch. It’s poss that a good itch/sting reliever is a heat pad. Or maybe it’s just me – my body pain/misery almost always responds to a heat pad.

        1. JAC

          Omega-3 will cause a systematic change and a systematic healing. That’s the trouble with CBD or anything topical, it doesn’t cure any systematic problem.

          I don’t know if you can afford this but there’s a few places that check red blood cell omega-3 levels.

          But I guess you didn’t bother to read or understand a single word I said so I don’t know why I bother sometimes.

          1. Janice

            JAC, I would like to know more about Omegas and where to test blood levels. Can you please provide some links?

  3. Howard

    All bodies are different and react differently to drugs. I have serve Neuropathy in both legs and feet. The doctors prescribed all the ” normal ” Neuropathy drugs for the pain. All those drugs made me a zombie unable to enjoy life.
    The one thing that has worked is opioids. I do not know how they reduce my pain I only know the make it bearable and I am able to have a life without being a zombie. I know that right now doctors and general public have been made to think opioids are a scourge.
    My experience tells me that properly taken for the right individual they can be a god send. I realize also from experience that those other drugs can be effective you just dont know for who until they are tried. The real issue is one size does not fit all.

    1. Lee

      Completely agree that opioids have their place. I took them for a decade only as prescribed (see my comment below) and they worked well, allowing me to function to a degree that otherwise would not have been possible. Depending on the nature of your pain, you might consider looking into low dose Naltrexone.

  4. Lee

    For some types of pain, in my case it’s chronic lower back pain associated with mild spondylolistheses exacerbated by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), low-dose Naltrexone works. The spinal malformation that I have would in most people cause mild to no discomfort. However ME/CFS, which is assumed to involve chronic inflammation of the central nervous system as the result of post acute sequalae following an illness such as influenza, can leave one with hypersensitivity to pain. I had previously being using opioids as prescribed, which were quite successfully replaced by low dose Naltrexone.

    Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review PubMed

  5. Wukchumni

    In Canada* they sell aspirin with codeine which is 1/3rd as much as prescription pills in the USA, over the counter.

    My sister gets nasty migraine headaches and its the one thing that really helps out, and I like em’ on the odd occasion when feeling beat after a long hike.

    * they used to be called ‘222’s’

    1. cresty

      Honestly the availability of this in the us would make a dent in the opioid problem.

      People in pain that doctors refuse to treat, which happens often especially with women, can have something that works, totally avoiding the street pain pill to fake heroin full if fent pipeline

      1. Sue inSoCal

        Wuk and Cresty, you both makes sense. I don’t believe one size fits all for pain relief or any condition. (The newer “sleep meds” make me agitated! When I was working, a bit of Restoril was a blessing if I had to get sleep before appearances. But, hands off benzodiazepines now.) I’ve been on a small bit of pain meds for a while, and I thankfully have a life. Cannabis whacks my central nervous system, and gabapentin is zombifying. I recall thinking Vioxx (Cox inhibitor) was a bloody miracle, until I had two giant ulcers I couldn’t feel. Iirc in the 90s/00s, there was a push for stronger medications. I had a liquid tincture of pain medication (lortab?) that I could titrate up or down, quite benign and very effective. But then came the push for the “contins”. I was made to switch to tablets (not a contin type) but I truly did not need anything stronger. Now, the pendulum has swung completely in the opposite direction and we have pain suicides from many Americans enduring intractable pain.

  6. Antagonist Muscles

    Every time I leave a comment here, the subject tends to be about my rare medical problems and super-sensory ability because my entire life revolves these medical problems. I have neuropathic pain in different body parts, and this pain is linked to my apparently augmented sensory ability. Let me assure you that super senses is on rare occasions an advantage but frequently a disability, particularly for me because once certain sensory thresholds are exceeded I feel pain. Considering how innocuous odors like perfume can cause me pain and fatigue, I had to resist trolling in the thread in yesterday’s links about perfume. Allodynia is the phenomenon of innocuous sensations causing pain. In addition, what I experience is similar to synesthesia (a sensory modality causing activation of another sense) since my central nervous system and brain have linked relatively low sensory stimuli with pain.

    However, my biggest problem is not pain caused by sensory stimulation. I certainly do have hyperacusis (ordinary sounds perceived as extremely loud) and mild pain, but far more troubling is fatigue and cognitive deficits. For example, the constant rumbling of air conditioning will cause mild pain, exhaustion, and concentration difficulty. Let me make an analogy if this is foreign to you. Suppose you need to do some deep thinking, and I blast music at rock concert levels, cranking up the amplifiers to eleven. You might think, “Wow, it’s so loud in here. I can’t even concentrate. Maybe I’ll leave.” Or if you can’t leave, you can put in some earplugs. But what do you do if the earplugs are inserted, and the music is still too loud? Welcome to my world.

    Nevertheless, the above post is about painkillers, and the important point about my above experiences is that I have thus far declined to take any systemic medication indicated for neuropathic pain even though my neurologist will prescribe gabapentin, pregabalin, nortriptyline, duloxetine, carbamazepine, etc. Some of my doctors have even floated the idea of cannabinoids and mu opioid antagonists. The pain I feel is a level one amount of pain. Are we really going to risk the numerous side effects – some of which are permanent – to lower my pain from one to zero? I feel the risk is too high, yet the two neurologists I have seen disagree.

  7. Antagonist Muscles

    I have a high pain threshold, which in most ways is good but it means I seldom get pain feedback when I am doing something stupid at the gym.

    I have an exquisite ability to sense minute amounts of pain. (See my super senses comment above.) This is often useful. I really can feel the pain in my shoulder has increased from 1.0 to 1.4 because I slept too long on my right side. This is a clear message to not do any strength training for the upper body. If my shoulder pain exceeds 3.0, the amount of time it takes me to nurse my shoulder pain below 1.0 will drastically increase.

    Most of us can distinguish between good pain and bad pain, as seen in exercising and acute injuries, respectively. The handful of people I know who never exercise associate increased heart rate, heavy breathing, and sweating with intense pain and suffering. They are all unhealthy because of lack of exercise and will never overcome the painful (good pain) hurdles necessary for good health. The pain signals generated by your body are complex and nuanced. One would be wise to interpret this pain.

  8. Tom Stone

    I have had all but Tramadol prescribed to me from time to time in the past, Vicodin made me stupid and did little for pain, Codeine 3 and 4 worked pretty well, as did oxycodone and hydrocodone.
    I was also prescribed with a fentanyl patch for my lower back when they first came out.
    It worked pretty well, but made me a little slow,as did Oxy
    And an adverse reaction to Bupren.
    I functioned well with both Codeine and Hydro, neither slowed me much mentally or physically.
    And quitting was 3 days of the shits and twitches.
    I’m glad they were there when I needed them and I was very happy to be done with them.

  9. roxan

    It’s Tylenol 1, I think. Used to go to Canada and buy it for my migraines.I don’t know, now–do you get searched at the border?You can probably get it prescribed here, although Tylenol 3 is more common, and Tylenol 4 is better yet–good luck getting anything. These are far too weak to help addicts. There is no high, whatsoever, with these pills, either.

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