However, I am pleased to see that the Stanford researchers are interested in how much of this extra cost is due to costly new medications that may or may not be worth their price — a topic too rarely discussed in the Ivory Towers of academia. They cite Januvia and Byetta as potential cost centers, but I can't help but think that they're missing the mark just a little bit. In outpatient diabetes management — and I'm going to assume that institutions and hospitals are similar — Byetta and Januvia, while successful, aren't what I would consider blockbusters. They aren't super mainstream yet.

In terms of quantity and price, the TZDs — particularly Actos, since Avandia got thrown under the bus — are far more costly. Yeah, incretins, whether direct or indirect are the new CME hotness with the associated mindshare, but compared to your TZDs, biguanides, and sulfonylureas, they're a distant a second/third/fourth fiddle in volume, if not cost.

Drug companies market these new drugs with claims of greater convenience and better control of blood sugar levels, and physicians have increasingly used them as alternatives to injected insulin, Alexander said. Insulin use has correspondingly dropped from 38 percent of treatment visits in 1994 to 28 percent in 2007.

This particular sentence bugs me because the implication is that insulin is cheaper than most oral medications. This just isn't true, particularly with the modified human insulins that can be very costly indeed. At the very least, they're on par with the cost of oral meds, and let's not forget that most people with T2DM would prefer not to stick themselves with a needle, no matter how small.

Talk of direct costs aside, it is obvious that $1 spent in the name of public health has a greater marginal utility than $1 spent on a medical intervention — be that drug therapy, a procedure, or whatever. Ben Franklin was right, after all. Unfortunately, the long-run cost savings of public health programs are notoriously difficult to measure, and certainly nowhere near as sexy as a medical intervention. Perhaps that's why public health gets shortchanged? I've spent some idle moments wondering how much money we could save if we spent a third or even a quarter as much combating things like poor nutrition and obesity as we do on direct healthcare itself.

It seems like the bulk of the money spent on prescription drugs is spent to offset the poor lifestyle choices that we Americans like to make. Unfortunately we pay dearly for that privilege. Any sort of nationalized healthcare will have to take this God-given right tendency into account.

"Prescribing this medicine is like trial and error in finding the right dosage that works best for you," says Krynetskiy. "Five milligrams is a typical dose, but a little less or a little more could have dramatic consequences or no benefit at all."

Doctors call this optimal dosage the therapeutic window, and Krynetskiy is trying to find it through pharmacogenomics, the study of a person's response to drugs based on their genetic makeup. It's a collaboration that crosses campuses and includes Krynetskiy and fellow clinical faculty at the School of Pharmacy, clinicians at Temple University Hospital and Jeannes Hospital. The researchers are studying why people process the same drug differently. In this case, they're trying to find the correlation between genotypes, or a person's inner code of DNA, and the correct dosage of Warfarin. By collecting saliva samples and extracting DNA from 77 participants already on the drug, the researchers can look for variances, genetic clues, which make people metabolize the same drug in very different ways.

Sounds more like a fun lab experiment than something that'll be clinically valuable for something as cheap as warfarin. This might be more interesting in terms of cost-benefit by choosing a drug that's both expensive and has a narrow therapeutic index. Aminoglycosides, some cancer drugs, and then there's always the iatrogenic narrowing of therapeutic windows — especially via the P450 isoenzyme — that might benefit from this kind of relatively blunt pharmacogenomic hashing. At the very least, some interesting and possibly useful trends might be established.

Warfarin, as cheap as it is, probably isn't a bad place to start. At the very least, I bet it makes for an awesome lab — we never did anything nearly as cool when I was in school…

Update from Eric:

It's not the cost of the drug – it's the cost of the 29% of Warfarin users that are hospitalized in the first year due to a drug-related adverse event.

If this is indeed the case, then preventing just one hospitalization could pay for dozens, and possibly hundreds of these tests, not to mention the impact on human and opportunity costs associated with hospitalization and ADEs.

This week's topic is panic disorder and relapse in patients with and without a history of substance abuse. Fun topic, really, and one close to my heart.

Case study:

[You are] working with a 32 year old man who comes to you for an evaluation of panic in August in Lowell. He meets the diagnostic criteria for panic disorder and has been experiencing untriggered episodes for the last 2 months. Name three factors that would guide your selection of medication and then discuss your pharmacologic plan for this unfortunate man.

One of the responses — by a prescriber in my area — was to encourage deep breathing, progressive relaxation, identifying triggers and avoiding the situation, CBT, and starting an SSRI. If panic continues, start a benzo.

This strikes me as fairly typical approach for a primary care provider in dealing with someone who presents during an acute panic attack, but I think that it's doing the patient a disservice. Perhaps it's also a typical response for a psychiatrist who is afraid to use benzodiazepines.

I'll post my response here, verbatim, because I think there's a deep (and common) misunderstanding of what panic is, and what having a panic attack is like.

It seems like you're thinking of panic as something that can be gotten out of, as though it's a normal fight-or-flight type response where removal from a stressful stimulus means no more panic.

This is dangerous thinking, and forgive me if I've read you wrong.

It can be harder than perhaps some practitioners think to identify a trigger. While triggers can often be identified, I think it's important to note that when a patient first presents, and you make a diagnosis of panic disorder, discovering these triggers will be more complex than simply avoiding a stressful situation, or simplifying and eliminating stressors from one's life. (Which is a very time-consuming process.)

You can't turn the ship on a dime.

Please don't fall victim to the idea that because you've been scared out of your wits a few times and your heartrate went up and your BP went through the roof that that is a panic attack. It's not. Panic attacks usually appear in a completely idiopathic manner, particularly the first time they hit. It's not an "Oh Gee, you scared me," type of thing, it's more of a "DEAR GOD I'M DYING, SOMEONE PLEASE DIAL 911" type of thing.* (The caps are appropriate there. )

Panic attacks can, and do hit without any warning in an otherwise comfortable, relaxed setting. Watching a movie in your living room, for example.

It's not like [situation] -> panic attack a few minutes or an hour later with a clear antagonist. It can come days after the stressors. It can also take a few weeks and lots of practice to build up an arsenal of effective coping mechanisms to return oneself to a calming state in the middle of an active attack.

Re: Deep breathing. This can also be problematic as at the point where one's lungs are fully inflated one can experience a PVC or PAC, which is VERY disconcerting to someone who's already acutely aware of what their heart is doing. I can actually trigger PVCs in myself by doing this.

–

I don't mean to lecture. I'm not the professor, and perhaps I've read too much between the lines of what you've written. As someone who didn't get out of bed for 3 weeks the first time I had a panic attack, I feel very strongly about the issue, and combatting it aggressively rather than taking a more laid back, it'll-fix-itself approach. Particularly this: "deep breathing, progressive relaxation, identifying triggers and avoiding the situation, CBT, [etc.]"

Those are all great long-term approaches, but the short-term is what someone with panic disorder in an active phase cares about most. Long term stuff can come after, just get me through right now.

And I am keenly aware that my personal experience should never cloud my clinical judgement inasmuch as that is humanly possible.

* I tried to dial 911 my first time, in the middle of a biochemistry lecture, no less. But I couldn't see well enough to dial the number. In retrospect, knowing what I know now, I'm glad I couldn't because that would have been a misuse of medical resources. :p

Early in panic, people are usually not capable of accessing the skills to use behavioral coping mechanisms. You usually need to halt the panic quickly and this is where BZDs are needed. Panic is such an uncomfortable and painful experience, the BZD's are in a way like pain medications in the early stages of treatment.

This is going to be quick and dirty because I've got some other things to do, but I've been putting it off far longer than I've meant to. (No time like the present, right?) In the January 2008 issue, CR ran a feature on how people could save money on prescriptions meds. Generally speaking, I am in favor of this kind of thing. I like people to know the alternatives, and how they can save money.

Generally-speaking, it's not a good idea to have word-choice errors in a piece that's supposed to be professional. (See image.) Maybe they should get a medically-trained copy editor and add them to the list of peer-reviewers. Ridiculous.

I've re-created the table they have:

I'll go through it quickly:

Zyrtec is now available OTC, and is comparable to the cost of Claritin. Claritin doesn't work for a goodly number of folks, so Zyrtec is a better option. Zyrtec went OTC the month after this was published — and it wasn't a big secret that it was going to happen.

For ADHD, Strattera is not a popular option. It doesn't work for many people, and ADHD people have a hard time remembering to take their meds consistently, which makes this option less desirable, particularly where it takes a little while for Strattera to begin working. I'm surprised this drug was listed at all, as it's rarely a first-line choice for ADHD spectrum disorders. Even comparing atomoxetine (an NRI) to methylphenidate (a stimulant) is a bit… off, and IMO, does the consumer no favors. Strattera is usually used where someone is at risk for drug abuse or has comorbidities like hypertension or anxiety (iatrogenic or otherwise) and so cannot tolerate stimulants.

Depression… don't have much to say there. Fluoxetine tends to be more stimulating than Lexapro, and there are other subtle differences (half-life, solubility, etc.), but for most people, switching from one to the other is probably not impossible.

As for Diabetes… well. Using a biguanide is usually the first step in treating metabolic syndrome, and then you add other meds on top of that. I'd be skeptical of any doctor who used Actos before using metformin without a given reason. Diabetes treatment tends to go in stepwise fashion like most other chronic illnesses. Removing a TZD from a pre-existing diabetic regimen can be done, but it's not as simple (or desirable) as this little blurb makes it seem. And a TZD isn't normally used as monotherapy. Frankly, I think suggesting Glucotrol rather than metformin would have made more therapeutic sense. And in terms of good use of space, I think think they would have been better going after the ARBs and hypertension in general here.

Heartburn and GERD? Nexium 20mg? Who even uses the 20mg strength Nexium? I see it maybe 3 times a year. They should have done 40mg Nexium and suggested 40mg of Prilosec. (Hilarious sidenote: 40mg Prilosec caps (the one without a generic) cost ~$60 more than 40mg Nexium caps.) Generally, though, this one wasn't too bad.

Insomnia: Eh, probably okay I guess. Insomnia is a poorly-treated condition in this country, and frankly, I'd rather see other methods explored before reaching for the BZRAs at all. But the BZRAs are the easiest, and they keep patients happy. Unfortunately, not enough time is spent diagnosing the underlying causes of insomnia, resulting in a poorly quality of life. There are differences in the polysomnograms of patients on eszopiclone and zolpidem, too, which are not talked about. I'd rather see ramelteon tried before any BZRA, and also see a psychologist about diagnosing an underlying cause for the insomnia in the first place, if a primary care provider cannot take the time (due to financial considerations) to do it themselves. And 5mg of Ambien might help with sleep induction, but the relatively short half-life will do next to nothing for those with sleep maintenance problems.

I'd rather have seen trazodone suggested, since insomnia is usually secondary to some kind of other psychiatric disturbance — a type of uni- or bipolar depression.

Not much to say about arthritis, but I hardly ever see Celebrex used anymore. Now that it stands alone as a COX-2 inhibitor, it's also the most expensive anti-inflammatory in the book and insurers are loathe to use it. I'd rather see diclofenac recommended over ibuprofen, and suggesting that 400mg of ibuprofen daily is anywhere near equivalent to 200mg of celecoxib is laughable.

Schizophrenia. SCHIZO-FREAKIN-PHRENIA? CR is going to tackle SCHIZOPHRENIA in an article about how to save money?!?! I am having difficulty wrapping my brain around that one.

But okay, here goes. Schizophreniform disorders should be managed by a psychiatrist or psychiatric NP, IMNSHO. Diagnosis is tricky, and management is always tricky. All that said… while first generation antipsychotics are often as effective as their second gen counterparts, I am extremely leery of merely saying that Y could be substituted for X. At least CR has the good grace to state "The antipsychotics have major side effects and response to them is highly variable" — AKA "Take our advice with a monster grain of salt." Not the least of the worries are akathisia, tardive dyskinesia, other extrapyramidal symptoms, weight gain, and about a bazillion other possible side effects. My mind is still boggled that they even went there.

Curiously, however, discontinuation rates of perphenazine in schizophrenic patients are lower than with any second gen antipsychotic save olanzapine (Zyprexa) — though people tended to d/c Zyprexa due to its metabolic effects and weight gain, and perphenazine for its extrapyramidal symptoms. Something to consider, I suppose.

–

All things considered, it's nice to see the mainstream media promoting saving money on drugs, but it bugs me that they did it in the way that they did.

$594 per year.

I asked Jane if she'd ever taken anything before the Nexium, because it looked to me like she started it in early 2006, and she told me that she hadn't. The doctor had given her samples, and then a prescription, and she'd been taking it ever since.

Here's the thing: Nexium isn't better than Prilosec. Yes, we all know it's the isolated, active enantiomer of omeprazole, and its time to acid drop is a bit better, and "studies" (paid for by AstraZeneca) have shown that Nexium beats Prilosec in squashing acid production.

Except that it doesn't, because if you look at the fine print, you'll see that those glossy, purty brochures that the big-titted drug reps bring you compare 40mg Nexium to 20mg Prilosec. In fact, when AZ did studies comparing 40mg to 40mg, they discovered that the difference was inconsequential, so they didn't include those results in their marketing materials. (My source for this is a former sales manager for AZ who used to have Nexium as a drug, and then went on to be a regional drug rep manager. He's with Forest now.)

Pretty slick. And underhanded.

Oh, and time to acid drop isn't a particularly important metric, by the way, because PPIs are maintenance meds, not Tums. And Nexium was only something like 2% better than Prilosec for the 8% of the study participants that even showed a difference. Whoopty-do. Clinically significant? Not especially.

Back to saving money. By changing from Nexium to Prilosec, Jane is able to pick a different Part D plan that has a lower premium, not to mention that when she comes to the pharmacy, her copayment will be lower, too. So Jane will be switching. And she could probably eke out a few more dollars in savings if she tried just 20mg omeprazole daily, but I thought I'd be generous by allowing for a non-standard dose in my calculations so her doctor would feel better about switching.

There is a tiny, tiny percentage of people — less than 1 in 100 — that do not respond to omeprazole that do respond to esomeprazole. No one knows why this is, and simply changing from one to the other results in marked improvement. That is no excuse for reaching right for the Nexium over the omeprazole, because sometimes the reverse is true: omeprazole works when esomeprazole does not. Sometimes neither of them work and you need to pick a different drug altogether. This phenomenon is true across all drug classes, and is another reason that having an inflexible, national formulary is a BAD idea.

[tags]healthcare, inefficiency[/tags]

I can speak for pharmacists, technicians, and patients when I say that its really, really nice to see a doctor doing the research to find out how much drugs actually cost. I see so much healthcare inefficiency on a daily basis just as it relates to drug therapy, it makes me want to start knocking heads together. Prescribers going right for the Nexium or Prevacid without EVER trying omeprazole; Lipitor when simvastatin is just as effective and has never been tried; Lescol XL, when pravastatin has never been tried; Avodart when finasteride has never been tried. Right for the ARB when an ACEi has never been tried.

Look, I don't give a fuck what your pet drug is. I don't give a damn what the drug rep shoves under your nose on a weekly basis. I don't care that you're unaware of the top-of-mind marketing that's being used on you without your knowledge or consent.

If it's going to cost an elderly person on a fixed income an extra $594/year because you "like it better", you need an ass-kicking.

And so on. I'm all for moving from one drug to another if a less expensive drug has been tried and has failed. That makes sense. But the absolute waste of money because less expensive alternatives have never been tried boggles my mind. I can truly understand why prior authorizations were invented, even if I curse them daily for wasting minutes of my precious time.

Back to the topic at hand: this time of year, people make appointments to see me, where we sit down(!), chat, review medications, and then we talk about what can be done for 2008. Most people that see me are happy with their drug therapy, except for one thing: it costs too much. The goal of their visit is to reduce the cost of their drug therapy for 2008, every single time. Without fail.

I have seen 7 people across two days. (An average appointment lasts about 45 minutes.) In that time, I have saved patients $11,831. That's an average inefficiency of ~$1700 per person. And these are people with drug coverage. The single highest total for one person was ~$3600/year.

In the next couple of days, I'll try to share some scenarios so you can see how much just one simple switch can save an average person.

Keep up the good work, Jay. Seriously. Pharmacists, technicians, and patients everywhere applaud your good sense and efforts.

[tags]healthcare, inefficiency[/tags]

7 years ago:
WTF is lisinopril?
Time: instantaneous

6 years ago:
I know how to spell lisinopril!
Time: ~0.5 seconds

5 years ago:
Lisinopril is for blood pressure!
Time: ~1-2 seconds

4 years ago:
Have I seen this before? Yes… I have because Aleve is naproxen sodium, and I've seen people take Naprosyn with lisinopril.
Time: ~2-3 seconds

3 years ago:
Lisinopril is an ACE inhibitor, and I see this combination every day.
"Sure, that's fine."
Time: ~0.75 seconds

2 years ago:
*Visual, mental review of systems, picturing the RAAS pathway and envisioning how naproxen is metabolized to see where and how the two intersect.*
"Sure, that's fine."
Time: ~0.5 seconds or so

Most recently:
How old is she? What's her creatinine clearance? Might she be better off with diclofenac or celecoxib? Eh, it's probably okay on a short-term basis, and it's not a terrible choice, but it's probably not the best choice, either.
"Sure, that's fine."
Time: ~1-2 seconds

What's the next step, I wonder? Quicker processing? Maybe. Deeper comprehension? Hopefully.

This development of thought processes is the difference between these two residents. The ability to take in a situation in its entirety, process it efficiently, while remaining calm and friendly takes time and exposure, and has very little to do with intelligence or any other innate quality.

* Naproxen is considered an unacceptable agent in geriatric patients even though it is used in the elderly pretty regularly. (My grandmother, for instance.) Probably because most internists, orthopods, and others are often not terribly familiar with geropharmacology, which is why geriatrics is its own specialty both in Medicine and Pharmacy.

My blood pressure went up a few points — at least they didn't say it to a patient.

Bacteriostatic doesn't mean that it doesn't work. It also doesn't mean that you'd be just as well off taking sugar pills. In fact, there are relatively few bactericidal drugs out there, and most of them are the nuclear bombs of the antibacterials: fluouroquinolones, vanco, rifampin, linezolid, and so on. The majority of oral antibiotics that are filled on a daily basis are, in fact, bacteriostatic.

And guess what? It doesn't matter. Bacteriostatic drugs hold the infection in check while the immune system clears it out. I thought this was common knowledge; I guess I was wrong. Of course there are instances when this isn't good enough. Those are the minority of circumstances, however. Infections don't usually need to be killed. That's why we have an immune system.

"Heresy!" you shout. Well, hear me out…

You see, there's almost no data to support the assertion that alcohol and metronidazole combine to create a disulfiram-like reaction. It's crazy, I know. How could this age-old advice be wrong? The reason this is drilled into pharmacy and med students' heads is because the conventional wisdom is old. It got here because "everyone knows" that ethanol + metronidazole = A Bad Time. Even though there's no meaningful evidence to support this conclusion.

Regular readers know my distaste (hah!) for metronidazole. In fact, I missed out on my best friend's 21st birthday drunkfestcelebration because of it. As it turns out, I missed out for naught. Alas.

Exhibit A is a meta-analysis of published anecdotes, "Do Ethanol and Metronidazole Interact to Produce a Disulfiram-Like Reaction" published in The Annals of Pharmacotherapy. Exhibit B is a double-blind, placebo-controlled study out of Finland, also published in TAOP entitled "Lack of Disulfiram-Like Reaction with Metronidazole and Ethanol" which is a bit more science-y and a little less meta-analysis-y.

This is a long entry, so here's a ToC.

1. Bits and bobs from Exhibit A
2. Bits and bobs from Exhibit B
3. Final thoughts

Bits and bobs from Exhibit A (Back to top)

The first account of a metronidazole-ethanol interaction was noted in 1964. At that time, folks wondered if Flagyl could be used to curb alcohol abuse. A sort of proto-Antabuse, if you will. 8 of 17 studies found it to be marginally effective. But only marginally, and only 2 of the 8 positive studies were double-blind, and these 2 studies were statistically significant only when dropouts had been excluded.

My commentary after each quote.

revealed six case reports involving a total of eight patients. Tunguy-Desmerais reported on a two-year-old child taking acetaminophen and amoxicillin for pharyngitis. After a febrile seizure, ulcerative gingivostomatitis was diagnosed, phenobarbital–vitamin B6 syrup was added, and oral metronidazole was started. The next evening, the child was flushed but not febrile and, because both the analgesic and phenobarbital–vitamin B6 syrup contained ethanol, a metronidazole–ethanol reaction was considered likely.

I'm not an expert in pediatric liver function, but I do know that it takes longer for children to metabolize EtOH than it does for an adult. And the flushing is certainly a side effect of plain old alcohol consumption. Going right for the metronidazole-ethanol "reaction" seems a little too convenient, and more than a little irresponsible.

Another report involved three patients: a woman prescribed rectal metronidazole following hysterectomy, who became nauseous, pale, and dyspneic 36 and 60 hours postoperatively and was discovered to have taken a large amount of whiskey just prior to each episode; an 18-year old patient being treated with amoxicillin and metronidazole for pelvic inflammatory disease who experienced nausea, flushing, and headaches each evening after drinking ethanol; and a man who, after a 1g dose of metronidazole and a shared bottle of wine at his evening meal, vomited violently.

1. Taking whiskey in a post-operative state is probably not advisable regardless of the circumstance. Hysterectomy, while relatively common, isn't a walk in the park.
2. Metronidazole can nausea and even vomiting all by itself. It doesn't need any help from alcohol.
3. See #2. 1g is a lot of metronidazole all at once, especially if you're unused its GI effects. Would the man have vomited even if he'd not had a bottle of wine? We can't be sure, but you can bet that it wouldn't have been mentioned in the literature if it hadn't. It would have been chalked up to a bad reaction to the medication.

Plosker reported a reaction following intravaginal use of metronidazole. This case involved a female pharmacist who, after two or three cocktails (each contained ~1 oz of (vodka), inserted a single vaginal suppository of metronidazole 500 mg and went to sleep. She awakened an hour later with a burning sensation in her stomach, nausea, and a severe headache accompanied by a cold sweat, which she believed was a metronidazole–ethanol reaction.

I could go for the easy ad hominem attack here, but it doesn't serve any real purpose — and in any case, I am on my way towards showing that EtOH and metronidazole is not necessarily the End of the World. That said, the burning sensation and nausea could have been from the medication itself. Flagyl can cause this type of reaction, even when it's not administered orally.

A potentially serious reaction involved a 16-year-old male who, nine days after resection of an hepatic echinococcal cyst, developed a staphylococcal infection. He was treated initially with intravenous vancomycin, followed by a combination of intravenous nafcillin, clindamycin, and gentamicin. This regimen was then changed to intravenous trimethoprim/sulfamethoxazole (TMP/SMX) and intravenous metronidazole, in addition to his chronic therapy with albendazole, docusate sodium, and ferrous sulfate. After 12 hours and for the following 60 hours until the TMP/SMX was switched to oral therapy, he vomited and experienced flushing, which was attributed to a metronidazole interaction with the alcohol in intravenous TMP/SMX.

Attributing these side effects to the EtOH in the TMP/SMX is easy. It's also irresponsible, because a mechanism of action had been proposed by this point in time, but not substantiated. (Exhibit B will cover this more.) This reaction is not completely out of the question — metronidazole can indeed increase the levels of intracolonic alcohol dehydrogenase — but it's still irresponsible to put down, for certain, that this was the cause of the boy's distress. I wonder if the heavy antibiotics he was on could have contributed to this. It seems possible that by mowing down his normal intestinal flora, he's in a position to experience these effects anyway.

Another potentially serious reaction reported by Harries et al. also involved intravenous metronidazole, this time combined with cefotaxime and papaveretum in a patient who had been drinking heavily and stabbed in the chest and abdomen. A chest drain was inserted and 500 mL of blood was drained; peritoneal lavage produced clear fluid only and the patient was admitted for observation. Four hours after an initial improvement, he became short of breath and nauseous; he vomited, had a headache, and was profoundly acidotic. This metabolic disturbance was attributed to a metronidazole–ethanol interaction.

Drunken guy stabbed in the chest and abdomen. Chest drain removes half a liter of fluid, and four hours later the patient complains of nausea, vomits, has a headache, and is acidotic. And then it's attributed to a metronidazole-ethanol interaction.

I could think of a few things that're more likely to have caused this. Can you? He's been stabbed and he's probably developing a hangover spring readily to mind.

This last one is a real doozy:

Toxicity due to an ethanol–metronidazole interaction appeared on the death certificate of a 31-year-old woman. Cina et al. described the case of an alcohol abuser who had been in frail health for four years following a serious car accident involving severe chest, abdominal, and closed head injuries. After being assaulted by a man, the patient had collapsed and died. Medications found at the scene included propoxyphene, acetaminophen, naproxen, metaxalone, carisoprodol, amitriptyline, hydroxyzine, vitamins, and cough syrup. No metronidazole or empty metronidazole container was found and she had not recently been prescribed metronidazole by her doctor. Because high concentrations of ethanol and acetaldehyde were found, assays were performed for disulfiram and metronidazole. There was no discussion of the methodology that reportedly found metronidazole in her serum, despite the fact that this was not one of the drugs found at the scene. In addition, there was no discussion about whether any of the other drugs in her possession, for which she was apparently not tested, may have cross-reacted in the metronidazole assay. It was concluded that she had probably ingested metronidazole without the knowledge of her physician and had discarded the bottle before she died.

I think the idiocy here speaks for itself. "It was concluded that she had probably ingested metronidazole without the knowledge of her physician and had discarded the bottle" my ass. Flagyl ain't a drug people are likely to abuse.

Indeed the common thread throughout these cases has been the assumption that metronidazole and ethanol are the culprits without any real testing to verify whether or not this is the case. This study was published in 2000, and while there was a proposed mechanism of action for this EtOH-metronidazole reaction, there was no real evidence yet to support the proposed mechanism. There are also possible — and I would be so bold as to suggest more probable — causes for each of these adverse events, and I have done my best to explain them.

Now on to Exhibit B which talks about the science of the proposed alcohol-metronidazole interaction.

Bits and Bobs from Exhibit B (Back to top)

Disulfiram works its magic by inhibiting the hepatic low aldehyde dehydrogenase (ALDH) which increases blood acetaldehyde concentrations after alcohol is consumed. This is exactly like "Asian flush" — a common, genetic condition wherein those affected are unable to effectively metabolize alcohol completely leading to flushing, nausea, and a quickened pulse.

It was theorized that metronidazole may have a similar effect on ALDH. However, studies have shown that this is not true in rats. So, what about people?

Well, it doesn't do it in humans, either. In fact, it had the opposite effect. Metronidazole caused a reduction in acetaldehyde production, opposite to the effect of disulfiram(!). Indeed, in Exhibit B, the graphs show (probably clinically insignificant) that the participants in the double-blind, placebo-controlled, alcohol-metronidazole study that the blood alcohol levels for the participants taking metronidazole were slightly lower than their placebo-controlled counterparts between the 40 and 80 minute marks:

None of the participants noted any dyspnea, flushing, vertigo, or headache during the test. Interestingly, the heart rates for the metronidazole group tended to be about 10bpm lower than the control group throughout the test. I don't know that this is clinically significant, but it is interesting:

Final thoughts (Back to top)

So we've got some age-old advice that doesn't stand up when tested properly, and we have a proposed mechanism of action that doesn't hold up to closer scrutiny, either. Where does that leave us?

It leaves us with a couple things… Some people experience GI distress while on Flagyl. Sometimes they vomit. Sometimes they drink alcohol and vomit. Sometimes they drink alcohol and don't vomit. That tells us that:

1. Flagyl is hard on the stomach. It's a difficult medication to tolerate for a good percentage of folks, regardless of its effect on blood acetaldehyde levels.
2. Flagyl is not a disulfiram-like drug, and should not be referred to as such.
3. Flagyl will not absolutely cause the vomiting associated with Antabuse when consumed in conjunction with alcohol. Pharmacists should stop counseling that it will.
4. Adverse events are too often attributed to metronidazole because it is convenient, and "everyone knows" that alcohol and Flagyl are a recipe for disaster.
5. Flagyl remains an unpleasant drug to take; its side effects are real and often severe, and should not be downplayed.
6. Patients should be educated about these side effects, and how to minimize them. Avoiding alcohol is one way to do this. Taking it with food is probably more effective. Doing both is obviously better than doing just one of the two.

It is my suspicion that early researchers thought there was a link between metronidazole and alcoholism due to the medication's side effects. Taste perversion. Smell perversion. These things will cause folks to avoid certain foods for the duration of the drug therapy. Alcohol is one of those things. It's coincidental, and its usefulness in the real world is questionable.

But she couldn't remember which type of Robitussin her friend told get, and needed our help.

The pharmacist pulled an answer out of his ass and made it sound really good. Turns out it was the right one. Guaifenesin, of course, thins mucus and he suggested that it might also thin the cervical mucus, allowing sperm to more easily penetrate. Seems this is, in fact, the idea behind using it to aid in fertility.

There is a small body of published literature that supports its use. One article (PDF) from Fertility and Sterility, published in 1982 stands out:

Couples with infertility should not use vaginal lubricants, which can impair sperm motility and activity. Twenty-three out of 40 females taking guaifenesin (200 mg orally three times a day) from day 5 to the day of BBT rise demonstrated improved cervical mucus quality, and 15 out of 23 couples conceived.

A second study published in 1991 (PDF). These findings are only relevant in the case where cervical mucus is abnormal, and can't be applied outside of this context. I'm not a fan of taking OTC or prescription meds willy-nilly, even if it is "only" Robitussin. Especially if the reason is because a friend told you so, or you "read it on the Internet".

Talk to your doctor, naturally. But I thought it was pretty interesting. But talk about off-label usage!

Exenatide (Byetta) is a glucagon-like peptide analog that responds to glucose by stimulating insulin release and inhibiting glucagon release. It also slows gastric emptying, inhibits synthesis of glucagon, and stimulates beta cell neogenesis by preventing beta cell death. It only responds in the presence of glucose, which means there's low risk for hypoglycemia.

Unfortunately, GLP-1 is broken down by DPP-IV, which limits native GLP-1 half-life to about 90 seconds. GLP-1 is also efficiently cleared by the kidneys. The other downside to Byetta is the fact that it's injected.

Sitagliptin (Januvia) prevents the breakdown of the body's own GLP-1 (and other incretin hormones) by inhibiting DPP-IV. As an oral tablet, patient compliance is likely to be higher, or at the very least, it's more convenient than poking oneself.

Despite having entirely different mechanisms of action, the net effect is the same: higher levels of GLP-1 in the body, with low risk of hypoglycemia. Both Byetta and Januvia are likely to help patients lose weight as well. There's been some talk about possibly getting Byetta approved as a weight-loss drug — I don't know how far along this idea is, however.

It's only a matter of time before we start getting insurance rejections for prior authorizations telling us that the doctor needs to try Januvia before they'll approve Byetta. This is good news for those seniors on Medicare Part D plans as well — Januvia can save them a pile of money because it's just so much cheaper than Byetta.

So to recap:

• Easier to store (no refrigeration)
• Oral tablet vs injection
• Once a day dosing instead of twice a day poking
• Cheaper

I think all the pieces are in place for Merck is going to eat Eli Lilly and Amylin's lunch here. It seems one investment house is also predicting something similar. (PDF)