Algorithm Finds Thousands of Unknown Drug Interaction Side Effects

ananyo writes "An algorithm designed by U.S. scientists to trawl through a plethora of drug interactions has yielded thousands of previously unknown side effects caused by taking drugs in combination (abstract). The work provides a way to sort through the hundreds of thousands of 'adverse events' reported to the U.S. Food and Drug Administration each year. The researchers developed an algorithm that would match data from each drug-exposed patient to a nonexposed control patient with the same condition. The approach automatically corrected for several known sources of bias, including those linked to gender, age and disease. The team then used this method to compile a database of 1,332 drugs and possible side effects that were not listed on the labels for those drugs. The algorithm came up with an average of 329 previously unknown adverse events for each drug — far surpassing the average of 69 side effects listed on most drug labels."

Comments

I was wondered about something

[zero.kalvin]

What kind of statistical analysis methods they use in these studies? For example we use a lot of Likelihood functions, BDT, and neural networks to get the maximum number of information out of our data. Do they use these kind of methods in there analysis ? ps, my field is astrophysics and astroparticles.

Re:I was wondered about something

[whydavid]

In Biomedicine you tend to see a heavy reliance on T-Tests, Chi-Square variants, Fisher's Exact, regression, McNemar's and Cox Proportional Hazards when temporally rich data is being tested. I don't have access to this article yet, but I would be surprised if they weren't performing a paired T-test in situations where outcome variables were measured on a ratio scale, McNemar's for binary outcomes where temporal data is not provided (maybe rare or nonexistent in this study), and Cox Proportional Hazards if there are any cases where we have a long temporal history of the data. Based on the sheer number of hypotheses tested we would expect to see some sort of correction for multiple testing here, too.

Re:I was wondered about something

[buchner.johannes]

As usual, Science&Nature only provide high-level info, so you'll have to dig deeper than the article ( http://stm.sciencemag.org/content/4/125/125ra31.full )
On the authors website, http://www.tatonetti.com/cv.html there is a paper that describes the machine-learning algorithms used:
Tatonetti, N.P., Fernald, G.H. & Altman, R.B. A novel signal detection algorithm for identifying hidden drug-drug interactions in adverse event reports. J Am Med Inform Assoc (2011) DOI:10.1136/amiajnl-2011-000214

Re:I was wondered about something

[ColdWetDog]

From the fine (real article)

Our new method (i) accomplishes the goals of stratification, dampening or removing the effect of covariates, without the need to divide drug-exposed reports into strata; (ii) is both adaptive (it removes different covariates for different drugs) and appropriate for systematic application and routine analysis; and (iii) is designed to complement modern signal detection approaches and thus extends the applicability and power of existing methods. Our model is inspired by the case-control approach to cohort selection in observational clinical studies. Each drug-exposed patient is matched to one (or more) nonexposed patients (controls). The nonexposed patients are selected on the basis of how well they match an exposed patient on a set of predefined covariates. Propensity score matching (PSM)—a statistical method designed to yield an unbiased estimate of treatment effects—has emerged as the preferred method of matching exposed and nonexposed patients in observational cohort studies and has yielded similar estimates of effects when compared to the results of randomized control trials (9–11). However, like other confounder controlling methods, PSM requires the covariates to be both known and measured; neither parameter is guaranteed to be present in spontaneous reporting systems. Instead, to match patients, we adapted PSM to use only the co-reported drugs and co-reported indications. We hypothesize that many confounders correlate with these key variables and do not need to be modeled.

As usual with these sorts of studies, my head asplode.

Re:I was wondered about something

[Frank T. Lofaro Jr.]

They call it novel so they can justify patenting it.

Like if I wanted to re-invent the wheel:

"A novel transportation facilitation device consisting of a round object on an axle to reduce friction and optionally provide a driving force to move the object the axle is attached to."

You'd need the word "novel" to get it past the patent office.

Re:I was wondered about something

[johanwanderer]

This article on pharmacovigilance probably has what you're looking for.

Re:not surprising

[Pieroxy]

Now instead of 60 warnings inside the bow we'll have 329 ? Sounds pretty futile to me. Nobody's going to read that.

Why not just writing: In addition to cure you, this drug might kill you or otherwise trigger another disease of allergy. Be warned.

Re:not surprising

[Anonymous Coward]

Presumably so doctors can better select functionally similar drugs to minimise these interactions...

For example, TFA says that the high-blood-pressure medication class thiazides and SSRIs can interact. Neither of these is available without prescription therefore a doctor could use such data to make better treatment decisions...

Re:not surprising

[zero.kalvin]

You can go even further, by using advanced techiniques, you can even combine several drugs to best treat certain conditions without giving the patient one larger dose of one medicine. For example if medicine X was found to react in a certain way with the insulin, and Y the fat cells in the body, while Z can catalyse the reaction of some hormone in the blood that will help. Instead of giving this person one large does of medicine A, he can be given small doses of these 4 things, and keep the harm at a minimum.

Re:not surprising

[aaaaaaargh!]

There are databases and search applications that can be made more accurate with the new data. For example, Denmark has an online system where citizens can enter the name of two drugs and get a list of possible side effects and warnings. There are also big US and European databases of this kind, although less open to the public (I believe).

I can imagine the commercials already..

[screff]

Does this mean those commercials on TV for prescription drugs will now take up an entire commercial break just reading the side effects? With some of the potential side effects being far worse than the condition that the drug intends to treat, it's going to be pretty intimidating for anyone who might have been interested in trying the newest drugs. It may help if the risk were quantified, but with frivolous lawsuits running rampant these days, the drug company legal team probably can't let them skip over the rarer ones for fear of getting sued.

Re:I can imagine the commercials already..

[WillAdams]

A better solution would be to just ban the placement of ads for prescription drugs anywhere other than medical literature.

Re:I can imagine the commercials already..

[__aaltlg1547]

Instead of consult your doctor they'll say consult our computer.

Re:I can imagine the commercials already..

[nbauman]

No, instead of reciting 69 side effects in ten seconds at the end of the commercial they'll recite 359 side effects in ten seconds.

Re:I can imagine the commercials already..

[nbauman]

Not with this Supreme Court.

Re:I can imagine the commercials already..

[ColdWetDog]

Commercial break?

Chucko, they're going to take up the entire program.

Re:I can imagine the commercials already..

[jd]

They'd only overturn the ban for companies donating to political campaigns, surely.

Re:I can imagine the commercials already..

[oreiasecaman]

Yeah, something like that... http://en.wikipedia.org/wiki/Clinical_decision_support_system

Re:I can imagine the commercials already..

[__aaltlg1547]

Yeah, something like that... http://en.wikipedia.org/wiki/Clinical_decision_support_system

Obviously you missed my use of the word "our."

Re:I can imagine the commercials already..

[oreiasecaman]

oh, sorry :)

Say!

[sixtyeight]

Say! Are there any new prescription drugs out there that I'm not taking, but should be? Those seem pretty safe.

Perhaps they'll soon come out with glossy color catalogs for the new ones each season. They'll be full of loads of bikini-clad women draped over cars, popping pills.

Re:Say!

[Chemisor]

Just say NO to drugs!

Multiple testing problem?

[FhnuZoag]

I am a statistician.

I've only done a light skim of the paper, but it seems to me that the OP (but not the paper itself) is being way too positive here. Their methodology seems to be very vulnerable to false positives - with a massive database of drugs and potential adverse effects, you'd expect a *lot* of apparent side effects occuring solely by chance. For example:

"We constructed a database of 438,801 off-label side effects for 1332 drugs and 10,097 adverse events."

Supposing you are doing a hypothesis test at the standard 0.05 significance level, for each of the 1332*10097 drug-side effect combinations. Then, with naive assumptions, on a null hypothesis, you'd be picking up an average of 666k+ 'side effects' anyway, purely by chance. With the drug interactions case, this multiple testing problem gets even worse.

Now, there are ways to correct for multiple testing, but for things as large and complicated as this problem, I'm not sure the standard methods are going to cut it. At best, this study should be considered more a *filter* on the set of potential side effects, than really an enumeration of effects that are actually there. This is ignoring other issues like the placebo effect.

Re:Multiple testing problem?

[whydavid]

I don't know why standard methods wouldn't cut it. Testing half a million SNPs and several combinations of those SNPs in a GWAS study is far more convoluted and controlling FDR through permutation is still relatively straightforward (though maybe computationally expensive...thought I doubt that is a huge problem for Stanford researchers). And your numbers are inflated by probably an order of magnitude even if no correction was done. They would not be testing all drug/ADE combinations because the vast majority of ADEs would not be present for a given drug and therefore wouldn't be tested.

Re:Multiple testing problem?

[Anne_Nonymous]

>> vulnerable to false positives

I don't know crap about the two tailed t-test, but I do know that if I ask for side effects in my drugs I better damn well get them!

Re:Multiple testing problem?

[Veetox]

"Their methodology seems to be very vulnerable to false positives..."

I would agree, and go on to suggest that this is intentional. Even after applying "corrective" measures, one has to pick a preference: false negative or false positive, and then show your work (just like in math class). When it comes to drugs, the control methods are never *really* enough. If you're doing an in silico screen, depending on the algorithms used, you may want false positives, because you're just going to throw everything into a high-throughput screen and let the robots do the rest of the work.

But further on down the pipeline, you want to bias towards false negatives, because you're looking for chemicals that have a strong interaction with their target and a week interaction with other targets. The statistics become a tool for making a decision, but never provide 100% assurance.

This study apparently seeks to show the possibilities of side effects, and then let patients/doctors decide if they apply. It's better than not saying anything at all. ...and serotonin reuptake inhibitors? You really want to know even the false positives for those!

Finally, it's likely that the methods of Tatonetti et al. require further refinement, but the rush to publish is an ugly spectre we all have to deal with in science.

Re:Multiple testing problem?

[Anonymous Coward]

IANAStatistician.

Is your computation of 1332*10097 correct? I think it's wrong.

Isn't the combinatorial function without repetition ((n+1)!) / (r!(n-r)! )?

Re:Multiple testing problem?

[FhnuZoag]

I both agree and disagree. In principle people really should stop using frequentist methods. In practice, though... There's still substantial disadvantages with Bayesian methodologies. For example, off the top of my head:

1. Relative slowness of computational algorithms for large datasets
2. Difficulty of presenting results to people with different prior beliefs. (Strictly speaking, in Bayesian terms, the answer you give must always be relative to *someone*.)
3. Ease of 'cheating', even unintentionally, by choosing priors to favour a certain result.
4. Proliferation of methods that pretend to be Bayesian but are in fact probably not. (e.g. Empirical bayes methods)

I'm saying this because this always comes up, but people don't realise the bayesian approach is necessarily a magic bullet either.

Re:Multiple testing problem?

[FhnuZoag]

GWAS done in the traditional hypothesis testing way have a *massive* multiple testing problem, which is only partially solved by imposing *extremely* stringent requirements on significance. That's why things like the Group Lasso and so on are being devised to work on them. It's definitely a non-trivial problem.

I agree that my calculations are very naive. But in my reading of the paper, I'm not really satisfied that they've done enough to deal with the multiple testing issue. (There is a mention of corrections for multiple testing, but that's in an unrelated section to the headline 'thousands of drug side effects' claim.) In the authors' defense, they don't claim that the effects they found are necessarily actually there. But the /. OP seems misleading.

Re:Multiple testing problem?

[FhnuZoag]

No, that would be the right calculation for arbitary combinations of a certain length. We're looking for the number of pairs (drug, side effect), of which there are #drugs*#sideeffects total.

Re:Multiple testing problem?

[Bromskloss]

• 2. Difficulty of presenting results to people with different prior beliefs. (Strictly speaking, in Bayesian terms, the answer you give must always be relative to *someone*.)
• 3. Ease of 'cheating', even unintentionally, by choosing priors to favour a certain result.

Why not just report likelihoods instead and let the reader multiply it with any prior they want? In many cases, the prior won't make much of a difference anyway, I suppose.

• 4. Proliferation of methods that pretend to be Bayesian but are in fact probably not. (e.g. Empirical bayes methods)

Sure, do away with empirical Bayes. Anyway, I don't think "When using Bayesian methods, you run the risk of using non-Bayesian methods." is an argument for not using Bayesian methods.

I'm saying this because this always comes up, but people don't realise the bayesian approach is necessarily a magic bullet either.

Regardless of what practical obstacles there might be for using Bayesian inference, using something else would be wrong, leading to results that make you take the wrong actions!

Re:Multiple testing problem?

[FhnuZoag]

"Why not just report likelihoods instead and let the reader multiply it with any prior they want? In many cases, the prior won't make much of a difference anyway, I suppose."

Reporting likelihoods (or rather summary statistics of likelihoods, because generally likelihoods are functions, not single spot values) is precisely what frequentist statistics is. The use of significance tests, p values and so on can be simply considered a standardised representation of the likelihood.

In the case of multiplying with any prior they want, in many (even most...) cases, the reader simply does not know what their prior is. And often, they do not even know, without a lot of work and some experience in statistical theory, what a 'sensible prior' is. For example, setting a flat prior for x (all values are equally likely a priori) can be actually *very* informative if later calculations make use of 1/x.

In most interesting cases, I'm afraid that the choice of prior *does* make a great difference. This is even more complicated if the prior is in the form of hyperparameters, in which case your prior choice can have a dramatic and non-linear effect on your result.

"Sure, do away with empirical Bayes. Anyway, I don't think "When using Bayesian methods, you run the risk of using non-Bayesian methods." is an argument for not using Bayesian methods."

But Empirical Bayes represents a huge chunk of how 'bayesian stats' is done in practice. The point here is that speakers don't define or understand clearly what is, or is not bayesian in the way that is proposed.

"Regardless of what practical obstacles there might be for using Bayesian inference, using something else would be wrong, leading to results that make you take the wrong actions!"

It depends on how the results are represented. Frequentist results are not 'wrong'. They represent a real value of the data. They may simply be irrelevant. And on the flip side, merely switching to Bayesian inference *does not prevent you from taking wrong actions*. What Bayesian inference accomplishes is that it shifts and makes explicit the mistake you are making.

For example, the false positive results I stated can be *exactly duplicated* by using a prior that is excessively permissive of finding positives, and that prior can look extremely reasonable. The real solution to these problems is to *understand what you are doing*, and this can be done in both a bayesian and frequentist way.

Re:Multiple testing problem?

[martas]

I agree with your cautionary point about the need to understand what one is doing when applying any statistical tool, however I find it hard to imagine any problem (at least in the hard sciences) where a Bayesian method is really called for. The notion of "prior beliefs" can be philosophically seductive, I admit, but in practice it is mathematically waaay too dangerous in my opinion. Yes, I know, there is a lot of work on things such as non-informative priors and such, but why go through all that trouble when you already have a whole theory developed under worst-case loss called frequentist statistics?

Yes, if everyone using statistical tools understood the implications of what they are doing fully then perhaps some people would correctly choose to use Bayesian methods. But given the impracticality of that proposition (seriously, how many biologists or physicists have the time to gain a deep understanding of statistics?), I would personally feel much safer if, when it comes to establishing some kind of scientific "truth" (such as the existence of the Higgs boson, or whether a drug interacts with another or not), people just stuck to frequentist methods. Of course there are many ways to screw that up too, but not nearly as many as for Bayesian tools (in my opinion).

Re:Multiple testing problem?

[martas]

Uh huh, and you can completely get rid of that problem by using Bayesian methods and getting nice clean wrong answers, and then stick your fingers in your ears and go "LALALALALA it's true according to my PRIOR BELIEFS, LALALALA"...

Re:Multiple testing problem?

[martas]

"false positives" come out by chance, there is nothing that can be done to prevent that. Now, underestimating the chance of false positives comes from a poor understanding of statistical tools, and there's a lot that can be done to prevent that. Sadly many scientists don't seem to be interested. (And no, I don't think Bayesian methods are the answer to that; if anything they give much more room for incorrect conclusions than frequentist methods do.)

Re:Multiple testing problem?

[FhnuZoag]

There's a placebo (strictly speaking, nocebo) effect in that people may report (and to be fair, often genuinely feel) side effects solely because of the fact they've been given medication, instead of any chemical or biological reason.

Re:Multiple testing problem?

[FhnuZoag]

'Factoring out your prior belief' in Bayesian statistics is like asking for water without the wetness. The best you can do is a prior sensitivity analysis that tells you what you have to believe in a priori to conclude a certain way, but the risk here is that you don't know if you are disbelieving in something because you are being reasonably skeptical, or just being stubborn.

Are these really the result of drug interactions?

[Attila Dimedici]

I definitely see this type of data mining as a useful tool, but to what degree of surety are they that the adverse effects are caused by the drugs in question? What percentage of people taking the drugs in question have to exhibit the effect before they consider it a product of drug interaction? It appears that they consider even one occurrence of the effect that does not appear in someone with the same condition not taking the drug to be an effect of the drug. If that is true, that would reduce the usability of this analysis. However, even with that flaw, this is a very valuable study. My stepfather struggled with a respiratory problem this winter that was caused by one of the medications he was on. His doctor never admitted that the medication was the problem, but it only started to clear up after he was taken off of it and that only happened when my mom insisted. She had found information that said the drug sometimes resulted in the respiratory problem he was experiencing.

Looks like...

[Shazback]

They're going to need bigger boxes.

Simple

[ledow]

All drugs have side-effects. In some those side-effects can be serious and even deadly, but it's pretty unpredictable what the side-effects will be and/or their severity in a particular patient, let alone one that takes other drugs. In others, the side-effects will never appear.

For instance, I'm one of those annoying people who doesn't take drugs unless absolutely necessary - not because I distrust the medical establishment (because I don't) but because if I don't need a drug, I won't take it - and even then, I never experience side-effects or, if I'm honest, much of the drug's effect anyway).

About the only thing I "take" is caffeine, and that only in drinks that happen to contain it - I don't deliberately seek it out or have a drink BECAUSE I need caffeine or because it's caffeinated (i.e. I've never said "Oh, I need a coffee" or had one to "perk me up").

People keep telling me to take headache tablets, cold/flu "remedies", painkillers, etc. etc. etc. and I avoid them like the plague. The people who use them use them CONSTANTLY and still get headaches, flu and pain worse than I ever have. If you have a pack of pills in your bag "just in case" of headache, cold, etc. then you should be made to throw them away - they are purely placebo. In any group of people, you'll find one who has pills for things like that. I *will* give you migraine relief, but that's a different thing entirely.

When I have had surgical work, I take the antibiotics and never get the painkillers. I don't see the point in them if I'm not hurting, but the antibiotics might *actually* be doing something (but I doubt it very much, to be honest).

But, literally ANYTHING I pop into my mouth that I haven't had before could kill me the instant it touches my stomach. You have no way to know. The question is now, and has only ever been, does the risk of the thing that the drug "fixes" overcome the risk of the drug itself? Hell, even paracetamol comes with a huge list of very-dangerous effects it can produce in some people. You can't read them all or not expect them to happen.

All this does is help doctors avoid risk-factors. Maybe they might spot a slightly increased risk that one drug has over a nearly-identical drug. But you're really playing tiny odds anyway. Any serious interactions that weren't down to just plain intolerance of the drug anyway have almost certainly already been found. That's why you do large-scale, long-term medical trials. Any new side-effects discovered will just go into a list of "possibles" but eventually every drug will list every side-effect as a "possible" effect, it's just a question of time and sufficient numbers.

Unless there is a known, dangerous interaction (in which case your doctor won't prescribe them to you simultaneously), nothing has changed, and you cannot begin to second-guess the drug itself. Hell, some people still only find out they are allergic to something in their 40's when they first try it. You can't account for that, and the majority of drug side-effects are minor and rare.

Look for them, by all means, but you might as well just write "There is always a risk of side-effects with any medication" on everything and have done with it, unless you know about a particularly dangerous interaction. Listing them only helps medical databases, not the average guy.

Re:Simple

[Anonymous Coward]

People keep telling me to take headache tablets, cold/flu "remedies", painkillers, etc. etc. etc. and I avoid them like the plague. The people who use them use them CONSTANTLY and still get headaches, flu and pain worse than I ever have. If you have a pack of pills in your bag "just in case" of headache, cold, etc. then you should be made to throw them away - they are purely placebo.

Look, somebody should hit your head with a hammer to make sure you know what you're talking about.

You ignore the fact that we are all different from each other. Headaches are a good example: I practically never get headaches.Other people I'm close to get absolutely terrible headaches from time to time that are so bad that they keep them awake and only the strongest Paracetamol can give some remedy for a short time. You either lack empathy (working in management?) or have really no idea how bad headaches or migraine can be.

Re:Simple

[ledow]

Migraines are a different matter that I covered separately in that same post BECAUSE they are nothing to do with headaches and because they have unique drugs that can combat them quite effectively if taken at the onset.

Anybody that confuses or merges migraine and headaches is lacking in understanding themselves. My current and previous partners both suffer severe migraine (up to and including visual effects such as not being able to cross a road because they see cars on the road and/or "seeing" people as headless when the migraine attacks).

And of course some things are subjective but you said it yourself - in a case where "only the strongest paracetamol can give some remedy for a short time", they need to be on the proper drug to deal with that (and/or find the cause of the headaches in the first place) or not at all. It's a case of "mild-drug, quite safe, let's take to help ease a serious warning sign because I always have".

It's not a question of lacking empathy. It's a question of being required to show displaced sympathy. Everyone has headaches, everyone has different severity, but if you are ROUTINELY taking paracetamol when they hit and they have little to NO effect, you're trying to self-medicate where medical advice should be sought.

My previous partner has a severe genetic condition which results in the joint's "safety barriers" being worn away because the collagen in her body is faulty. It's incredibly painful, all over the body, and has any number of weird side effects (immune to some anaesthetics, etc.). Their technique to cope was to take some paracetamol occasionally.

Their doctor advised them to take some more later. Once the doctor was given clear statements on the VOLUME of the chronic pain and my partner realised (in her own words) "that other people DON'T hurt all the time", they actually gave a medication which they themselves called "one step away from morphine". AND you could still take 8 paracetamol a day with it (which, again, we weren't told until we said that even on the drug given, there was still some pain). And that actually had some effect whereas the paracetamol, from day one, was next-to-useless.

If you have a headache that a headache tablet gets rid of, or helps, you don't have a need for the tablet, it's just convenience. If you have a headache that *isn't* affected enough by paracetamol, you need to get your doctor to give you something stronger. I'm *not* against prescription drugs. I'm against people thinking that "mild", over-the-counter drugs are harmless and effective for everything. They aren't.

Re:Simple

[zippthorne]

Have the people you're close to tried the other over-the counters, Aspirin or ibuprofen, etc?

I've personally found paracetamol to be pretty ineffective in just about any dosage, for pretty much every type of pain I've ever had (however, I've known people who found it effective for their own pain). This sucked growing up when I used to get terrible headaches and my parents were afraid of reye's syndrome and assumed all NSAIDS were aspirin for some reason (tylenol marketing dept, I assume...), so that's all I got....

Looking at the wikipedia page, I now find it pretty ironic that I was taking liver poison in an effort to avoid getting a liver disease...

Re:Simple

[mutube]

Migraines are a different matter that I covered separately in that same post BECAUSE they are nothing to do with headaches and because they have unique drugs that can combat them quite effectively if taken at the onset.

I understand what you're getting at - I myself won't take painkillers for mild headaches (drinking water usually does the trick - whether it's dehydration or placebo). However, in my early 20s I suffered from quite bad migraines (blindness aura, skin crawling insect feeling, crushing pain, and then a 'hangover' for 24 hours where I could barely get out of bed). After experimenting with a few variations of painkillers I found that the one thing that worked consistently for me was to take low dose paracetamol at the first onset of the aura - no headache and reduced 'hangover'.

The point is people respond differently to medication - and I'm very responsive to paracetamol (this extends to wisdom tooth pain - ibuprofen does nothing, paracetamol almost completely gone). Some people can manage quite horrendous pain with over the counter medication. Maybe your just not one of those people?

Interesting aside - for a long time I had difficulty sleeping and took to drinking Chamomile tea to help (which it did). After a while, making the tea was enough - I would make it, put it beside the bed, and promptly drop off to sleep. After a bit longer all I had to do was *think* about making it, and off I'd pop.

The 'placebo effect' (or, if it worked to begin with, Pavlov's dog) is often presented as a negative - but it's also an opportunity to programme yourself with something harmless. I saved a fortune on tea.

Re:Simple

[mcmonkey]

If you have a headache that a headache tablet gets rid of, or helps, you don't have a need for the tablet, it's just convenience.

WTF does that mean? If a drug helps, then you didn't really need the drug? Yeah, and if you don't feel hungry after eating, then you don't really need food. And if you can see after turning on a light, then it wasn't really dark.

As for "it's just convenience," are there any recorded cases of terminal migraines or headaches? Anything anyone does to alleviate headache pain is a convenience.

If you have a headache that *isn't* affected enough by paracetamol, you need to get your doctor to give you something stronger.

Well doctor, I get headaches that paracetamol has no effect on, but will go away if I take ibuprofen early enough. The only alternatives I've found for my headaches are taking oxycodone (or stronger) or just letting the pain get worse for usually 3 or 4 hours until I throw up and then almost immediately feel better.

As much as I'd love a steady supply of opiates, my brick-and-mortar doctor won't prescribe them. Instead he tells me to not try and be a tough guy (since I try not to take unnecessary, non-recreational drugs) and just take the ibuprofen before it gets too late.

But as an internet doctor, perhaps you can email me a prescription?

Re:Simple

[DragonWriter]

Migraines are a different matter that I covered separately in that same post BECAUSE they are nothing to do with headaches and because they have unique drugs that can combat them quite effectively if taken at the onset.

"Headache" is a vague symptom. Migraine is one of many conditions which produces a (very distinct kind of) headache as a symptom.Yes, it has distinct drugs which are effective at treating the condition or mitigating the symptom.

Fevers also cause headaches (which are very different than those produced by migraines), and there are drugs (many of which are over the counter) that relieve fevers (and drugs that treat the underlying conditions that produce some fevers, but many fevers that produce headaches don't require treatment of the underlying cause of the fever.)

Allergies also can produce headaches. There are medications which effectively treat allergies, both in the short and longer term, and many of these are over-the-counter.

One could go on in this vein for quite a while.

but if you are ROUTINELY taking paracetamol when they hit and they have little to NO effect, you're trying to self-medicate where medical advice should be sought.

Most OTC drugs have labels indicating that if they fail to relieve the symptoms are must be continuously used for a long time, medical advice can be sought (the exact phrasing varies considerably from OTC drug to OTC drug, because the conditions which indicate something other than the situations the OTC drug is meant to address are different.)

So, if your contention is that you should use OTC drugs according to their labels, then, yeah, that's pretty obvious. But that seems pretty different than your earlier suggestion that if you have OTC drugs kept handy "just in case", you ought to throw them out.

If you have a headache that a headache tablet gets rid of, or helps, you don't have a need for the tablet, it's just convenience.

Many common headache tablets are (among other things) fever reducers, and that's one of the key mechanisms by which they reduce common headaches. Reducing a dangerously-high fever is often more than a convenience.

But, yes, most OTC drugs aren't for treating conditions that are immediately life threatening, which appears to be the distinction you are making between "need" and "convenience". So what?

Re:Simple

[Anonymous Coward]

Have the people you're close to tried the other over-the counters, Aspirin or ibuprofen, etc? I've personally found paracetamol to be pretty ineffective in just about any dosage

Paracetamol (aka acetaminophen, aka Tylenol) is a troubling drug. It's therapeutic dose and toxic dose are very close. In some individuals, there's no safe effective does. There are times it's called for, but ibuprofen and aspirin are safer. That said, the anti-over-the-counter drug rant was just crazy. Those things are amazing when use correctly, sadly, most people take the wrong drugs and never read the labels.

Re:Simple

[Fwipp]

But, literally ANYTHING I pop into my mouth that I haven't had before could kill me the instant it touches my stomach. You have no way to know.

You've convinced me. I am switching to a zero-food diet.

Re:Simple

[zippthorne]

My personal experience is that they're pretty variable in pain relief. I assume that different causes of pain are more susceptible to different drugs, and sometimes I happen to pick the right one, but I'm not aware of any way to tell which kind of pain I'm having or how it matches with which kind of OTC pain reliever. Is there such a resource for determining it? I don't think the labels are very helpful in this regard.

Need an app to prioritize

[OutputLogic]

So there is a short list of drugs a person is taking, medium list of person's medical conditions, and a long list of drug interaction side effects. All a person needs to do is to prioritize that interaction list according to severity: from "will kill you" at the top down to "skin reddening" or "facial swelling" at the bottom, and pick the least damaging drugs. This calls for a smartphone app.

Re:not surprising

[whydavid]

Not to plug my profession or anything, but this is exactly why the entire field of biomedical informatics exists. If you think this is bad, consider the fact that there are currently over 20 million abstracts in PubMed....do you think even 10% of that has actually been properly synthesized into operational knowledge and applied to patient care? And we won't even go into genomic data, or even the amount of records that one patient might accumulate in their EMR over the span of a lifetime, or the fact that a 320 slice CT generates so many layers of images that they can't all be carefully reviewed (and an abnormality may be so small it only appears in a couple of them), or the overwhelming breadth and depth of surveillance data collected from ERs/pharmacies/drugstores/monitoring stations/schools/etc... by public health practitioners. There is a critical challenge in biomedicine to distill useful knowledge from all of this data...and it's akin to drinking from a firehose. No one is going to read the 329 warnings for the drug, but in an ideal world we'll be able to identify genetic indicators that make you more or less susceptible to certain side effects (pharmacogenomics) and present this information to you/your doctor (and no one has to read the booklet that comes with the prescription).

Re:not surprising

[Anonymous Coward]

Now instead of 60 warnings inside the bow we'll have 329 ? Sounds pretty futile to me. Nobody's going to read that.

Medical doctors are going to read that, it's their job.

Actually, think of the upsides

[twisteddk]

This algorithm may be able to idenify sideeffects when combining medicines.

However, sideeffects are by definition only negative. Once "results" rather than side effects are put through the same algorithm, we may be able to identify better and cheaper ways to combat disease. And we may even be able to find cures for known diseases with combinations of drugs that have never been tested before.

It's all about the data.

Re:Actually, think of the upsides

[Forty Two Tenfold]

However, sideeffects are by definition only negative.

Your geek card, please.

Re:Actually, think of the upsides

[Brian Feldman]

Why? He's right. He meant "de facto" and not "by definition," but he's right.

Re:Actually, think of the upsides

[fast turtle]

Whap!! Drink your coffee as he's completely correct. The Medical defination of Side-Effect is negative only as in detrimental. Otherwise it's classified as synergesic if beneficial.

Re:Actually, think of the upsides

[Forty Two Tenfold]

The side effect of aspirin is inhibited clotting. Now, in some cases this is unwanted (hemorrhage) but there is a whole group of... patients who take aspirin solely for that effect.

The Infancy of Medicine

[iliketrash]

OMG. I really do hope medicine outgrows its infancy during my lifetime.

Re:Algorithm tested?

[ananyo]

So the algorithm found 329 adverse effects which were not known previously. Has someone spent the time in checking the validity of the algorithm by doing studies to check these claims? If not, this is mostly paranoia.

RTFS. They've looked at electronic medical records and confirmed the prediction in the case of thiazides and SSRIs. They're planning more tests - eg a clinical trial.

A video comment on drugs.

[AG the other]

A nice song from Consumers Union about drug side effects to enrich your day.
http://youtu.be/mYodDH4qZQo

Re:Are these really the result of drug interaction

[Troyusrex]

Good points. I wish I had a moderator point left to give you. While this study's results should be taken with a grain of salt it's an innovative idea of how to better quantify side effects and better information for consumers.

Side effects

[jonpublic]

Ive had some pretty nasty side effects from a drug that weren't on the label. It really sucked. I'm still dealing with them.

Let me tell you that if you goto a doctor and say that you think that side effects are related to the drug he put you on and those side effects aren't yet on the label they will treat you like you are crazy. It was really eye openning to see how doctors can talk down to patients. The drug I was taking for example can cause tendons to snap. That was known. The doctor flat out didn't believe that incrediblely painful tendinitis could be related to taking the drug.

It really sucks. I got lucky though because a month later the FDA released a new list of side effects that for this drug that included my ones. Then I got a doctor to pay attention and help me out.

I knew the side effects were related to the drug thanks to a quick google search that showed thousands of other people had experienced the same things that I had. There were literally 100,000 posts in a forum discussing what I had experienced in the previous weeks.

I can't even imagine the complexity when combining two drugs and what havoc that could cause.

Re:not surprising

[schwit1]

Lawyers will love this. It's additional things they can use against doctors if a patient has an adverse side effect.

Re:not surprising

[rrossman2]

You can gget a drug interaction app for android and I assume others. You can also download the full blown deal on your PC... or go to a bookstore (maybe more so one on a campus) and purchase the "official" book off of the shelf....

You know what this means?

[KurtisKiesel]

That doctors will now have to consult a computer program before giving an Rx.... ABOUT DARN TIME.

Re:not surprising

[Phrogman]

While I go to my doctor to get treatment and any required prescriptions, I *always* double-check with my pharmacist to ensure there are no likely conflicts between the drugs I have been prescribed, my allergies to certain drugs etc. I trust my pharmacist will have read this stuff in detail, even if my doctor missed something.

Where is the database?

[Bromskloss]

I'd like to have a go at the database myself. Is it included in the article (which I don't have access to)? (It should be, IMHO, because how do you otherwise replicate their results?) Can it be found elsewhere?

Re:Where is the database?

[Bromskloss]

Thank you. I realise I shall need the article itself as well to be sure I understand what some of the numbers in the database mean.

This is not directed at side effects!

[kaws]

To be more precise it's directed at the interaction between drugs. So by itself, this study doesn't have any impact on a singular drug

cool results from data mining

[__aaltlg1547]

But it's not science yet. The more important findings need to be verified in controlled experiments.

Live as clean and natural as possible

[erroneus]

I think it goes without saying that we should all live as clean and natural as possible. I'm not saying we shouldn't use drugs to improve our health, to fight disease or to manage pain and discomfort. We should. It's very useful to do so. But I am saying we should actively seek to AVOID using drugs and to seek out the most healthy foods and to live the most healthy lifestyles available to us.

But you know what? I'm fat. I'm definitely overweight. I have been better than I am today but I ate too much of the wrong stuff for too long. I ride my bicycle a lot ... or I did until it got too cold and the mornings too dark. (damned DST... I was starting to ride in again but they shifted it an hour so I ride the bus in with the bike on front and ride home.) Anyway, excuses, excuses... I've got a million of them, but it doesn't stop the results which I have to face and deal with. 'Reality' doesn't accept excuses or offer exceptions.

So I'm not pointing fingers at anyone but if you think I am, then I'm pointing a finger at myself too. I know I should do better and I plan to. I'm back my my bike again riding home from work (freaking 5 miles of up-hill the whole way, with my clothes, laptop, shoes, water and a few tools adding about 35 to 40 lbs of weight on top of my 190+lbs and my mountain bike fitted with big side-bags and that's no joke!) and it's helping... my strength returning, the bounce in my step, my general feeling of lightness and I think there's a slight lowering of my blood pressure too though I think that has more to do with my dietary adjustments than added exercise.

Anyway, I think we should all seek to prevent rather than try to medicate after the fact.

Re:not surprising

[artfulshrapnel]

>> Medical doctors are going to read that, it's their job.

I think you mean "Medical doctors SHOULD read that...", or under the best cases "Medical doctors are going to TRY to read that..."

Realistically? They won't have the time to do it properly. Doctors are massively overworked, trying to see far too many patients and dealing with a field that is too broad and grows way too rapidly to keep up with even if they *didn't* have the inconvenience of actually applying their knowledge. I mean, this study alone claims to have discovered 438,228 new drug interactions and side effects. (329 side effects per drug x 1332 drugs) You try to do a thorough read-through and analysis of that kind of data without taking any time off from work; and work quick, you probably only have a week at most until something new you need to learn comes along....

Why not

[Dunbal]

Yes, let's bury the signal under even more noise.

This is going to make those drug commercials...

[gestalt_n_pepper]

a *lot* longer. Maybe, we can just turn them into the whole darn show. I see sitcoms developing around viagra. (Stay tuned for "What's up, Doc?!)

Re:not surprising

[Anonymous Coward]

You forgot to escape the space in "monitoring stations":

ERs/pharmacies/drugstores/monitoring\ stations/schools/etc

Re:not surprising

[ColdWetDog]

Epocrates will do that. It's free. BUT it has the same problem that every other adverse drug effect database has - it is sensitive, but not specific. Most entries basically imply that you will explode, dissolve or get turned into a Newt if you take the drug.

What's needed are accurate statistics on how many people get Newted and whether you are more likely to get into trouble if you take other medications or have other conditions. This paper says you can do some data mining to get at new insights to the problem but you still need to go out and see if your model is real. And that's the problem - it's hard to get a representative sample of people taking SSRIs and thiazide diuretics. Now, smaller countries, especially the Scandinavian countries (God baiting evil socialists that they are) have databases that might help answer those questions, but it's still lots of work.

Re:Are these really the result of drug interaction

[dgatwood]

What percentage of people taking the drugs in question have to exhibit the effect before they consider it a product of drug interaction?

Forty-two.

Just kidding. There is no single percentage. You need to know what percentage of people with the same disorders would exhibit that particular symptom while taking one or zero of those drugs, and compare the various percentages using a T-test or similar.

The minimum statistically significant difference in those percentages further depends on the sample size, and whether you report it or not depends on the margin of error you're willing to tolerate. If you're willing to tolerate a 20% probability that the adverse reaction was due to chance, you're going to get a lot more "hits" than if you are only willing to tolerate a 1% false hit rate. This is particularly problematic if your sample size is small, which when a large number of genetic factors are factored in, it almost always will be.

Re:not surprising

[djdanlib]

I love Slashdot.

Re:not surprising

[RenderSeven]

What's this 'bookstore' thing you mentioned?

Re:not surprising

[Frank T. Lofaro Jr.]

I believe Walgreens automatically checks.

They also have an online interaction checker on the web.

Re:not surprising

[jd]

A newt or a Newt? The former, I can live with.

Re:not surprising

[Anonymous Coward]

Not to burst your bubble but that is the reason pharmacists exist. Read all the comments. People think doctors know the interactions. They don't. Pharmacists have a doctorate in pharmacy, yes just as many years of training(school:intern/residency) as a "doctor" but specialize in drug interactions not treatment(using your data). (Meta: Pharmacists earn a Pharm.D degree, a doctorate of pharmacy, they are "doctors" but the uppity M.D.s think they have a stranglehold on "Dr." unless it's in another field like engineering) Pharmacists are the people that call the doctor after a patient is trying to fill a prescription and tell them, "No you can't prescribe X, your patient is already taking Y". They do that more often than you think. Sure biomedical informatics collects the the data but the doctor/pharmacist relationship is what keeps people from dieing on the front line. Without pharmacists in today's over-prescribed world you would have huge numbers of deaths. The bioinfo people like yourself would only have more data concerning the deaths but would be unable to stop it. I'm not degrading your profession, biomedical informatics is just one cog of the wheel though.

Re:not surprising

[jd]

No-one is going to read 329 warnings, but no-one is going to read sine tables either. Biomedical Informatics - and indeed any form of information clearing - is useful to the extent that we can avoid information saturation and filter down to what is actually important in some specific case.

There, of course, is the crunch. Services like PubMed are highly restricted, so the number of people with the skills to write data digestion software AND who have access to the data AND who have an interest (even a contractual one) to write such software is also going to be highly restricted. This limits the number of algorithms out there for analyzing the data and, in turn, limits the capacity of medical experts to make use of what is out there.

Has the full table of drug interactions been publicly published, in a machine-processable format? My suspicion is no. Given that repeat studies don't get published, as a matter of policy by journals, refutations of this analysis won't get documented and therefore any errors will be perpetuated. It doesn't help that medical journals are expensive to publish in and are biased in favour of sponsors. Further, because this is a meta-study, it is subject to the problem that 2% of scientists are guilty of misconduct and that patients are now so hyped up about side-effects that mis-reporting as a form of hypochondria may distort the results. It's not like doctors conduct tests to analyze these reports. There may not be any errors in this study, but if there are then neither we nor any doctor will know of it. The only obvious way to avoid that is to make analysis of the analysis a public affair.

And what if the table is fully accurate? Given that a tiny fraction of the publications ever get read, how many doctors will have a copy of that table? In paper or electronic form? Given the current economic climate and the tight budgetary constraints, it might take months if not years for the smaller doctor's offices to have databases containing the information. And longer for those databases to be usable in any practical fashion.

or the fact that a 320 slice CT generates so many layers of images that they can't all be carefully reviewed (and an abnormality may be so small it only appears in a couple of them)

That is so very, very true. And the problem is getting worse, not better. Scanners are improving all the time, the human brain is not, and the software used to convey data from the scanners to the brain is all that stands between the doctor and information overload. MRI scanners are up to 13T* - it's not altogether clear why as the 9.1T ones could see individual neurons, but there ya go - but since the bulk of hospitals use 2.5-3T MRIs and software is invariably written for the market, informatics on the BIG systems is primitive in comparison to the volume of data involved. Not that it's terribly good even for the smaller units.

*Yes, I know, 7.3T is the maximum that is authorized in the US for non-research purposes, but research scanners for living patients are much more powerful than that. And research is where you want the BEST informatics, particularly in this case because repeatability is going to be a serious problem.

Re:not surprising

[jd]

Sherlock Holmes always recommended a 7% solution.

More Side Effects?

[LifesABeach]

Time to invest in stocks that manufacture pill bottle labels.

It will not.

[bussdriver]

Doctors and nurses are still resisting checklists! SIMPLE CHECKLISTS!!? a proven method to drastically cut down errors to which there is no decent counter argument but here we are STILL - no checklists.

You think the human ego will not drastically hold back progress more than the other humans contribute towards progress? I don't.

Health for profit is not ultimately beneficial; it could be removed and replaced with something better but the culture is so brainwashed we'll continue down in the wrong direction -- we are already to the point where patents are harming scientific progress and corporate grants to research institutions influence the work being done. (I knew a few people, they wasted a lot of time twisting words to trick people into funding their real research and doing the minimum to appease the corporatist bent interests.)

Re:not surprising

[timeOday]

Now instead of 60 warnings inside the bow we'll have 329 ? Sounds pretty futile to me. Nobody's going to read that.

Surely you jest? That's like asking why somebody would bother to write a phonebook when nobody will read the whole thing. The big table of drug interactions is easily remembered by a computer. You enter a set of medications and it tells you what conflicts exist (and with what probability, hopefully) in that set.

My favorite side effect:

[FiloEleven]

"May result in increased desire for gambling or sexual activity."

I almost swore it was a joke the first time I saw the commercial, especially given that it was to treat restless leg syndrome.

they do the same thing the pharmacists do:

[pepty]

check the computer that has your prescription history and a drug interaction database.