I've noticed some pain killers working great for me, while others have no effect.

Works for me

Doesn't work for me

I doubt there is much of a placebo effect at work, since most of these either did or did not work when I first took them, without having expectations either way.

Whenever I have a head ache, I take an APC. I suspect it's actually the aspirin in there that does the job, since when I take just paracetamol, it doesn't do squat. As a kid I got children's aspirin, which worked.

I once had a severe back ache. I was prescribed diclofenac (a heavier variant than the over the counter one), which didn't work. I was then prescribed tramadol — same results. I then tried naproxen, which worked rightaway.

Why do some pain killers work while others don't?

Is there an underlying mechanism, that explains why some of these work while others don't? Does that predict if pain killers that I haven't used yet will work?

Please note that I'm not looking for medical advice on which pain killers to take; I'm just curious about how my body interacts with the various ones.

†: the one consisting of aspirin, paracetamol, and caffeine, not the one containing phenaticin. Think Excedrin.

  • 3
    $\begingroup$ Related: biology.stackexchange.com/questions/2922/… $\endgroup$
    – jonsca
    Sep 25, 2014 at 20:44
  • $\begingroup$ @jonsca That's interesting. The weird thing is that diclofenac is an NSAID as well, but doesn't work for me. So it's not just a case of NSAID vs non-NSAID. $\endgroup$
    – SQB
    Sep 26, 2014 at 6:03
  • $\begingroup$ NSAIDs are a pretty diverse group of drugs. You might find en.wikipedia.org/wiki/Diclofenac#Mechanism_of_action interesting. $\endgroup$ Sep 26, 2014 at 14:38
  • $\begingroup$ I've read that, and more, but I still don't have a clue. I don't even have a clue where to look. $\endgroup$
    – SQB
    Sep 26, 2014 at 20:24
  • 2
    $\begingroup$ Even if you're not looking for medical advice, I can't help but see this as a personal medical question. If you wanted to re-write it as a general question, I would be more inclined to answer. Right now I'm questioning why it shouldn't be voted to close. $\endgroup$
    – Atl LED
    Oct 7, 2014 at 15:01

2 Answers 2


Short answer: different people have different amount of active receptors. In treatment, combination scores of Pharmacodynamics and Pharmacokinetics determine the final effect of the drug. Receptors determine many effects of the drug in many pathways. Different people also sense pains differently (Psychology).

Review answer

The purpose of treatment is to relieve pain and maintain function. Your question is biased. You cannot only concentrate on painkilling in maintaining health. These both are the reasons for the complains of the patient, not only the pain.

For instance, in rheumatoid arthritis, response to therapy can be quantitated using many measures including American College of Rheumatology system values ACR20, ACR50 and ACR70, which denotes the percentage of patients showing an improvement of 20%, 50% or 70% in a global assessment of signs (maintaining function) and symptoms (pains).

Each patient has own health, different from one another. Our body adapts to the environment and individual conditions of the body to maintain homeostasis. Receptors adapt for instance. They can be active or inactive - in short-run and long-run - again depending on the conditions at hand.

Painkillers i.e. analgesics have different properties:

  • anti-inflammatory effect - acute and chronic conditions (inflammation is the major mechanism under many pathologies) e.g. nonsteiroidal anti-inflammatory drugs (NSAIDs, please, see this answer about the particular mechanisms and how different people have different effects from NSAID painkillers) and glucocorticoids (most)
  • symptoms relieving specific drugs e.g. disease-modifying antirheumatic drugs (DMARDs)
  • anti-platelet effect - e.g. the older you get, the more platelets stick together.
  • anti-pyretic effect
  • ...

which all can be toxic. Note that many drugs alone or/and as combination can work as painkillers i.e. pain relievers. Aspirin for instance has both anti-inflammatory and anti-platelet properties. However, it is rarely anymore used as anti-inflammatory. The anti-platelet property is dependent on the exact dosage of the administration. Aspirin's mechanism of action is to inhibit platelet COX which antiplatelet effect lasts 8-10 days (life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of 6-12 hours. Please, review any Pharmacology -textbook for more info about aspirin.

Each these drug has own Pharmacodynamics and Pharmacokinetics

  • Pharmacodynamics answers to the question What drug does to the body? It stimulates some receptors, activates some pathways, ...
  • Pharmacokinetics - What does body do to the drug? It metabolises it (enzymes, receptors). It distributes it. It excretes it (kidneys, feaces).

In treatment, you consider what is the target organ. You need to think what is causing the dysfunction and the pain. You try to restore the function and relieve pain. The component of drug needs to reach the target tissue e.g. your pancreas' beta cells do no produce insulin so your blood glucose is high. Complications of this are polyuria and eventually exodus if untreated. Insulin is injected into the fatty tissue. We do not have long-term acting insulin administered orally - our metabolism start to break the drug so it does not have wanted treatment. If insulin administered to the muscle, the time of action is too times less, again because muscle is metabolising the insulin i.e. a chain of peptides (protein).

No all symptoms and diseases have painkillers. For instance, prehemorrhoid and some types of itching related to posthemorrhoids. However, for both, there are some special salvas for proplylaxis but they are not complete.

Now, you can start to read something in SuperBest's answer about host's physiological variables and addiction/tolerance which alters the mechanisms (receptors) of pathways in Pharmacodynamics and Pharmacokinetics.


  1. Basic and Clinical Pharmacology, 11th edition, 2009, Bertram Katzung.
  2. My notes in Pharmacology classes during 2014.

I don't know of any interesting mechanism that is specific to pain killers, so I will instead answer for drugs in general.

Drug action is a complex process consisting of many steps. Let's take a simple example: A systemic direct inhibitor of a kinase. This drug would need to*:

  1. Be absorbed into your bloodstream
  2. Remain in your bloodstream for sufficient time
  3. Be absorbed into the tissue
  4. Be able to bind the target protein

1 can fail due to interaction with other concurrently taken drugs or food, or simply genetic factors affecting the particular functioning of the gut mucosa. 2 can fail because the kidneys are too good at eliminating it, or the liver is metabolizing it too agressively (both also subject to modulation by other drugs, foods and genetic factors). 3 can fail because the transports in the cells aren't working as rapidly, or represent an allele less likely to take in the drug, or are modulated by other drugs/foods. The tissue can also have efflux pumps or enzymes that break down the drug. 4 can fail because the drug was designed for a specific allele of that kinase, but you happen to have a different allele, which has a slightly different structure that is no longer targeted by this drug.

Then you have a host of physiological variables, and addiction/tolerance.

Apparently the most common genetic reason by far for variable drug sensitivity is the specific set of CYP genes you have. CYP enzymes are abundant in the liver and chemically process various molecules (including drugs).

Besides this, an interesting set of specific examples used to be available from 23andme. I'm not sure if they still provide this after the FDA ban on health information.

  • Clopidogrel sensitivity - CYP2C19 variation
  • Proton Pump Inhibitor (stomach acid reduction) - CYP2C19 variation
  • Abacavir (HIV drug) - HLA-B*5701 SNP
  • Acetaldehyde (alcohol flush) - ALDH2 mutation
  • 5-fluorouracil (chemotherapy) - DPYD mutation
  • PEG-IFN-alpha/RBV combination (Hepatitis C medicine) - IL28B SNP
  • Phenytoin (epilepsy drug) - CYP2C9 variants
  • Choline esters (class of muscle relaxants) - BCHE (CE degrader) variants
  • Sulfonylurea (used for type 2 diabetes) - CYP2C9 variants
  • Thiopurine (immune suppressant) - TPMT (enzyme that degrades thiopurine) variation
  • Warfarin (anticoagulant) - CYP2C9 variants
  • Caffeine - CYP1A2 SNP
  • Metformin (diabetes drug) - SNP rs11212617, near the ATM gene
  • Antidepressant - SNPs in ABCB1 affect likelihood of sexual dysfunction (common side effect)
  • Beta-Blocker (heart disease) - Mutations in ADRB1 which is normally blocked by the drug
  • Floxacillin (drug for staphylococcal infections) - SNPs in the MHC region affect liver toxicity of this drug
  • Heroin - OPRM1 receptor (target of heroin) SNPs affect efficacy
  • Lumiracoxib (used to treat pain and symptoms of osteoarthritis) - SNPs in the MHC region affect liver toxicity
  • Naltrexone (alcohol and narcotic addiction drug) - SNPs in OPRM1 affect how much it can reduce pleasurable feeling from narcotics
  • Statins (cardiovascular disease) - SNPs in COQ2 (mitochondrial component) affect risk of myopathy

As you can see, our friends the CYP family enzymes come up frequently, and some are even repeat offenders like CYP2C9. Besides that, there is a fair number of cases where variation in the specific target of the drug are relevant.

Note that this list is not comprehensive: Many drugs have not been studied in sufficient detail, and some may have complicated mechanisms instead of just "bind and inhibit protein X".

I have omitted many details and links to literature, I am sure you can easily find them by searching on Google Scholar with the keywords I already gave. Let me know if that doesn't work, though.

*: Note that these aren't necessarily required for all drugs. For example, some drugs can be applied directly to the skin and hence do not need to pass through blood.

  • $\begingroup$ Drugs, even for the direct inhibition of a kinase, don't have to enter the blood. Many do, but one could also, just as a quick example, apply a drug in a cream/skin permeable solution (to a skin tumor for the sake of argument for a kinase inhibitor). This is what defines a "local" treatment. $\endgroup$
    – Atl LED
    Oct 9, 2014 at 2:21
  • $\begingroup$ Out of curiosity: Are there any cancer treatments which are not systemic? Besides the tumor cells at the actual tumor site you always want to hit metastatic cells as well. At least for melanoma all kinase inhibitors (like vemurafenib) are given systemically as far as I know. $\endgroup$
    – Chris
    Oct 9, 2014 at 7:53
  • $\begingroup$ @Chris off the top of my head imiquimod, but when discussing pain management, there are far more. I find the phrasing "must: ..." to be incorect/misleading in this awnser. $\endgroup$
    – Atl LED
    Oct 9, 2014 at 11:56
  • $\begingroup$ Also, if you open yourself up to treatment and not drug, you had better hope your radiation treatment isn't systemic. $\endgroup$
    – Atl LED
    Oct 9, 2014 at 12:03
  • $\begingroup$ @AtlLED You definitely have a point with local treatment, but I can't figure out how to work it into my answer. To be sure, I was only giving an example of an inhibitor which happens to be delivered by blood, in order to illustrate how there may be several distinct families of factors at play. $\endgroup$
    – Superbest
    Oct 10, 2014 at 2:46

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