Why do different pain killers have different effects on people?

Question

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

Works for me

• Aspirin
• APC ^†
• Naproxen

Doesn't work for me

• Paracetamol
• Diclofenac
• Tramadol

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 larger dose than the over the counter version), which didn't work. I was then prescribed tramadol — same results. I then tried naproxen, which worked rightaway.

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

Is there an underlying mechanism, that explains why some of these work for some people while others don't? Does that predict if pain killers that I haven't had to use 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.

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

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I have asked this question before, over on the Biology Stack, but I haven't received a satisfying answer yet, just the general observation that different drugs affect different people differently.

Answer 1

I viewed your question in the Biology Stack and I think the answers you received are quite good. I´ll try sum up those long answers in the Biology Stack and present them more clearly.

Major factor influencing to the presumed effects of any drug is the first pass effect (Wikipedia). That means that every substance taken orally must absorb from intestine to the surrounding blood stream. All this blood with all absorbed substance (incl. sugar, fat, protein from food) are transported to liver. Liver then processes all the substances in the blood.

There are dozen of enzymes in the liver which processes the substances in the blood. One enzyme family particularly processes all the foreign substances (inc. drugs) (Wikipedia). Liver aims to remove all foreign substances from the blood, but some of the absorbed substance always escapes the liver to the systemic circulation. Only those molecules which escape liver without processing are transported to the tissues and afterwards can bind to their receptors in the tissue thus eliciting the proposed actions (ie. reducing pain).

Enzymes in the liver processes the foreign molecules in a way that they are secreted to bile and eventually to feces. For example enzyme CYP2E1 processes paracetamol (Wikipedia). There are three different CYP-enzymes which processes diclofenac molecules (PubMed). And for naproxen two CYP-enzymes exist (PubMed).

One major reason why diclofenac does not help you but naproxen does, is the different action of these enzymes. DNA in our cell nucleus defines how each protein is expressed in our body. These enzymes are these proteins. In your case it seems that enzymes responsible for processing diclofenac are expressed in large number in your liver, resulting to very low concentration of diclofenac molecules in your bloodstream. In other word the level of diclofenac in your blood stream is out of therapeutic window to elicit any responses in the body (Wikipedia). In contrary, your liver may express enzymes responsible for the processing of naproxen very little and thus many naproxen molecules may escape liver to the systematic circulation resulting the therapeutic level to elicit tissue responses.

This only one player in this topic, although very important and influential. There are also factor influencing after the first pass effect (receptor, expression of genes responsible for receptors, binding affinity ec.)

Answer 2

At first I want to note arkiaamu's answer is very good. If you also need a shorter answer take this:

Naproxene and Aspirine do not only 'directly' relieve pain, they also work antiinflammatory. In many cases the inflammation itself causes pain, so these drugs have different targets to work. See this

Tramadol is not antiinflammatory, neither is paracetamol.

You are not the only on feeling a difference between naproxene and diclofenac. Read the answer from arkiaamu for some ideas why. Reasons are multi-factorial including some personal things like genetics and gene-expression.

Please note that naproxene and aspirine have dangerous adverse effects (gastrointestinal bleeding). Aspirine should not be given to children, as it has some rare but very severe adverse effects that others do not have. (1)