How Nexium took down Prilosec and how Pharma changed our stomachs forever

Once upon a time, during the height of acid wash, shoulder pads, and the side pony tail, there was a great plague tormenting the people of the developed world. It started as a burning sensation in the solar plexus--right below the sternum--then churned its way up the esophagus, often leaving behind a sour taste in the mouth. It was born of over-sized meals, greasy fast food, and acidic ingredients (e.g. tomato sauce, orange juice, onions), fed by alcohol, cigarettes, and anti-inflammatory medications (e.g. ibuprofen, naproxen and aspirin), and showed up most often during post-meal naps and late-night bouts of insomnia. It seemed  to get worse with stress.

It was heartburn.

Other terms often used interchangeably for heartburn include acid reflux, dyspepsia, and indigestion. We doctors call it "gastro-esophageal reflux disease" or GERD,

(Okay, the term "heartburn" is derived from the Ancient Greek kardialgia (heart-pain), having first appeared in English literature in the 13th century, so to be perfectly honest, heartburn was a recognized plague long before acid wash. BUT what came next did actually happen in the '80s. . .).

http://www.adelle.com.au/wp-content/

How Pharma changed our stomachs
In  1989-- the very year of the peak of Paula Abdul and the fall of the Berlin Wall-- a most remarkable event occurred: Prilosec came on the market.

Prilosec was the first of a new drug class--a proton pump inhibitor-- designed to change the way our stomachs digest food forever. Its generic name was omeprazole. It has since been joined by brothers Prevacid (lansoprazole), Protonix (pantoprazole), Nexium (esomeprazole) and a gang of other inbred siblings whose generic names all end in -prazole. Prilosec was also the first to go over the counter in 2003.

Though Prilosec was the first of its kind, its little bro Nexium, released in 2001, has become the superstar. Between 2001 and 2012, Nexium (known to anyone who watches TV as "the purple pill") has grossed $48 billion. Yes, that's $48,000,000,000. That makes it #2 in all time drug sales (see here for more drug details). Oh, health care costs, where art thou going?

You should know that Prilosec and Nexium are made by the same pharmaceutical company (AstraZeneca), AND they are almost the same exact chemical compound. (Think identical twins with different haircuts). For those of you with any interest in organic chemistry, esomeprazole (Nexium) is simply the s-isomer of omeprazole. Who says o-chem isn't worth anything?!

The big differences between the two medications are the following: Nexium is always purple (Prilosec is sometimes pink), Nexium is still on patent (but generic will be available mid-2014) and Nexium costs five to ten times as much as Prilosec.


Okay, enough tangent.

How do proton pump inhibitors work?
Proton pump inhibitors (PPIs) decrease acid production in our stomachs, thereby lessening the discomfort caused by said acid. They accomplish this by blocking the proton pump in the parietal cells of the stomach lining (hence the name). Details on the nitty gritty mechanism can be found here.

Interestingly, these pumps are constantly being turned on, off, and over, so there is never complete inhibition of acid.  We need acid, in fact, to digest our food and absorb many nutrients, including iron, calcium, magnesium and Vitamin B12. PPIs are considered stronger than any other family of acid-blocking medicines on the market, and studies show they bring relief to 85-90% of people.

PPIs work best in the fasting (not-eating) state, so people are usually instructed to take them  first thing in the morning before breakfast. A single dose may bring some relief but tends to leave too many acid pumps around to do their thing, which is why taking a PPI on occasion ("as needed") doesn't often do the trick.  PPIs reach  maximum efficacy around day 5-7 of continuous use. Most over-the-counter formulations instruct patients to take the med for a total of 14 days before consulting a physician. The FDA recommends that PPIs be taken in the lowest dose for the shortest duration possible-- in most cases 4-8 weeks is probably sufficient.

Heartburn is a common and uncomfortable health condition, and for people experiencing acute discomfort, PPIs work remarkably well. I prescribe them with some regularity to a range of patients including the elderly, pregnant women and even children (for all these groups I have some serious reservations and a few caveats). When I personally had a bout of severe esophagitis during my Peace Corps years, I took a PPI for several months. It was miraculous.

PPIs serve an important purpose: they do what is asked of them, and they make people feel better.

The challenge comes when trying to get patients OFF of them.
You see, PPIs are pretty darn addictive. Addictive, you say, no way. How could anyone get addicted to a medicine that suppresses acid?!  If you object to the word addiction (see a prior post for discussion of chemical addiction versus chemical dependence), then you must at least concede that PPIs lead to a level of dependence. This is likely because our brilliant bodies try to circumvent the acid blockage by creating new acid pumps.

If you take a PPI for a short time (let's say 1-2 weeks for a bout of really bad heartburn), you probably won't have a problem, but if you take a PPI for longer than a few months, there is a good chance you will have a hard time stopping cold turkey. This is because, when you stop, your solar plexus will burn, your stomach will churn, and your heartburn comes back with such a vengeance that you find yourself popping another PPI just to get through the night. For all intents and purposes, you are now hooked.

PPIs also do nothing to encourage you to address why you might have GERD in the first place.
I have a large number of patients who are extremely attached to their PPIs-- so attached that they refuse to discontinue or taper, even as an experiment.  In sharing this, I am airing my own dirty doctor laundry-- it is with more than a touch of shame that I continue to refill medications for people when I know that in doing so, I may not be fulfilling my solemn promise to "do them no harm".

As you might have guessed, PPIs don't actually do anything to correct the underlying problem of acid reflux. They are a temporary fix-- a band-aid of sorts for your GERD-- making you feel better tonight or this week without helping you recover for the long-haul. There are some exceptions: in patients with known ulcer disease, PPIs promote actual healing of the gastric lining. And in specific combinations with other medications (e.g. for treatment of helicobacter pylori), they can be used to help eradicate disease.

It was thought for some time that PPIs were pretty harmless even if taken over long periods of time. Doctors and patients alike dismissed the dependence issue as unimportant. After all, you could always taper and eventually get off them. But the longer the PPIs have been out on the market, the more concerns have been raised about potential long-term effects on many other organ systems.

Here is a partial list of PPI-associated problems:

PPIs:

• inhibit absorption of important nutrients
• magnesium: taking PPIs for prolonged time (over a year) can deplete magnesium levels, leading to muscle spasms, irregular heartbeats, and convulsions (reference)
• vitamin B 12: people on PPI have a 65% increased risk of B12 deficiency compared to people not on a PPI. B12 is important vitamin that is involved our red blood cell production, which is important to get oxygen to all our tissues.  (reference)
• iron (reference)
• increase risk of osteoporosis and osteoporotic fractures: increased risk of fractures of the wrist, hip and spine. 25% increase in overall fractures, 47% increase in spinal fractures in postmenopausal women (reference)
• increase risk of clostridium difficile infection (antibiotic associated diarrhea) likely because decreased acid leads the bacteria to have a better environment to party (reference)
• increased risk of pneumonia: 30% increased risk for developing pneumonia (reference)
• drug interactions
• increased risk of atrophic gastritis, which could theoretically lead to increased risk for gastric cancer

As you can see, PPIs are clearly associated with serious harm--  especially when taken long term. While PPIs might enable us to keep on chug chug chugging on, eating like crap, drinking like fish, being lazy lumps, smoking cigarettes, and ignoring our own bodies' attempts to communicate with us, we will pay at some point. Are you willing to pay with your bones? Or your blood cells? What about your pocket book? We should not disregard potential long-term health effects because we are so tied to relief from our momentary discomfort.

We know better, don't we?


I would challenge you to consider simple ways in which you could change your life that will actually make you feel better now and for the duration.  Here are a few lifestyle modifications to consider to treat and/or prevent GERD:

1. Slow down your eating
2. Lose weight (only if you are overweight or obese)
3. Eat small frequent meals
4. Stop smoking
5. Decrease your alcohol intake
6. Avoid trigger foods ( trigger foods are different for different folks but consider cutting back on the following to see if you feel better: chocolate, coffee, cow's milk, orange juice, spicy foods, tea, tomato sauce/juice. Maybe even try one at a time.)
7. Exercise (Exercise actually helps the sphincter between your stomach and your esophagus work better! How cool is that?!)
8. If you have predominantly night-time symptoms, elevate the head of your bed 4-6 inches 
9. Herbal remedies: If you are considering herbal treatments, try licorice, slippery elm, marshmallow (the herb, not the white sugary puff) or chamomile 

And please don't misunderstand me-- if you need a PPI for a few weeks, go for it. It will probably help. Just remember that you have some more work to do than continuously pop the purple pill. If you do the work, you will feel better.  This I can attest to both personally and professionally.

May your solar plexus be healthy.

A

http://graphics8.nytimes.com/images/2007/02/08/fashion/08fitness.1.600.jpg

Additional References:
http://www.healthandwelfare.idaho.gov/Portals/0/Medical/PrescriptionDrugs/PPI%20Educational%20Information.pdf
http://www.fammed.wisc.edu/sites/default/files//webfm-uploads/documents/outreach/im/module_gerd_clinician.pdf
http://well.blogs.nytimes.com/2012/06/25/combating-acid-reflux-may-bring-host-of-ills/?_php=true&_type=blogs&_r=0

Maggie will not die without her Xanax

I am often a little behind on television. This is due, in large part, to the fact that we don't actually own a television. I share this to clarify why my husband and I are currently watching the very beginning of Season 1 of HBO's acclaimed drama The Newsroom, while the rest of you are watching the end of Season 2.

Back here in Season 1, during a very sweet scene, my attention was drawn to an awkward piece of dialogue--it first caught my ear because the writing was oddly stilted and then held me because the content was downright infuriating.

http://buzzhub.files.wordpress.com/2012/08/newsroom-hbo.jpg

It went something like this:
The smart young protagonist runs outside to the back patio in the midst of a full-blown panic attack. Her unrequited love bends down to comfort her. In between a series of witty and tender words in which he skillfully calms her anxiety, he manages to say, "Maggie, where's your Xanax?" She tells him she forgot it at home, and he responds with a furrowed brow, "You must always have your Xanax with you for moments like this. You need it. Don't ever leave home without your Xanax."

Uh oh. Red flag. Big red flag. GIANT red flag.

First, Xanax (and its generic equal alprazolam) is one of the most addictive and, frankly, troublesome medicines I prescribe. Sure it has its place, but it is not the equivalent-- as implied in this scene--to an epinephrine pen, which would be essential in the case of an allergic reaction. Maggie might very well feel like she may die, she might even call 9-1-1, but a panic attack, though frightening, is not actually life-threatening. I assure you, Maggie will not die without her Xanax.

Second, Xanax is a brand name drug that is actually now available in generic form. There is no reason for the screenwriters to use the brand name unless they are advertising the brand.  Hmmm. . .is drug-brand name-dropping on TV legal? Should it be? Is it ethical?

Third, are you agitated? Because I am. I think I need a Xanax.

Xanax for president?
Xanax (pronounced ZAN-ax) is the number one prescribed psychiatric medication in our country and has been in the number one position since 1988. In 2012, there were more than 47 million Xanax prescriptions written in the US. Forty-seven million! Most experts believe it to be the most successful anti-anxiety medicine on the market because of aggressive marketing by its maker, Upjohn. Upjohn has convinced patients and physicians alike that Xanax is the most effective treatment for panic attacks and panic disorder. That's why Maggie is taking it.

Xanax is a member of the benzodiazepine family (affectionately called "benzos" in the medical world). The benzos are a class of medicines used to treat anxiety that also includes lorazepam (aka Ativan, ranked #4 on the list of top psychiatric medications), diazepam (aka Valium, #9 on the list) and clonazepam (aka Klonipin). All of the benzos work on the brain's GABA receptors, which essentially are our "downer" or "quieting" neurons. Xanax activates our "downer" neurons, thereby turning down and quieting our anxious selves. Got that?

Even though you and I are supposed to believe Xanax is better than the other benzos for panic, a 2011 review of studies comparing Xanax to the other benzodiazepines found that Xanax was not, in fact, superior to any of the other benzos for panic disorder (see this link, if you are interested in the actual analysis). Xanax has also been shown to be notably inferior to two better treatment choices for panic: Cognitive Behavioral Therapy (CBT) and antidepressants (specifically, selective serotonin reuptake inhibitors, like Prozac and Zoloft, as well as tricyclic antidepressants, like Elavil).

CBT is a specific type of therapy that has been shown to be particularly effective in panic disorder--73% of patients are panic free after three to four months of CBT (I'll write about CBT in a future post). Studies of anti-depressants also show them to be effective (61% of patients are panic-attack free after 12 weeks of one of these medications). Okay, so admittedly neither of these treatment choices are foolproof (I, too, would like to see the results closer to 100%), but they do help a lot of people.

http://cdn1.tauntr.com/sites/default/files/BOSH-Xanax.jpg

The reason people like Xanax for panic is similar to the reason my husband likes his albuterol inhaler for his asthma: it works fast. Unfortunately, however, both Xanax and albuterol do little, if anything to prevent the next attacks. And Xanax does worse than doing nothing; in fact, Xanax leads to a triple whammy of benzo-badness: 1) It is addictive, 2) It causes rebound anxiety, and 3) It turns your brain into mush.
Sound enticing?

Just to be clear, my issue with Xanax is not specific to Xanax, it's just that Xanax is the incumbent benzodiazepine and has held that office for much longer than two presidential terms-- Xanax has been top dog since George Bush Senior was elected President.

Addiction
Okay, so there is a lot of tiptoeing around in the world of addiction medicine around semantics. Care is often taken to distinguish "dependence" from "addiction". "Dependence" is a term used to describe "physical dependence"-- that is, bodily adaptations that result in withdrawal when drugs are discontinued (e.g. If you stop drinking your two cups of coffee cold turkey, you'll probably get a really bad headache). "Addiction" is a term used to refer to "the loss of control over the intense urges to take the drug even at the expense of adverse consequences" (e.g. You lost your home and got divorced as a direct consequence of your gambling addiction).

Scientists all agree that Xanax leads to physical dependence. It changes the brain, at least during the time you take it, and perhaps forever. In fact, withdrawal  from any benzodiazepine can kill (unlike withdrawing from Prozac or morphine, both of which can make people miserable but won't actually kill them). Almost everyone who takes a daily or twice daily dose of Xanax develops dependence; not everyone gets addicted. There is a certain subset of people who can take Xanax on a regular basis without it having adverse consequences on their lives, but the risk of physical dependence leading to addiction is high.

Xanax is also a known drug of abuse. National rates of hospitalizations due to all benzodiazepines actually tripled between 1998 and 2008 (see national data). Benzodiazepines are often abused in combination with alcohol or other drugs (like opiates). In fact, benzos were recorded as contributing causes in 30% of prescription painkiller overdose deaths in 2011. Large numbers of high school students admit to having tried a benzodiazepine, most commonly Xanax. Some clinic systems have even stopped prescribing Xanax altogether because of drug-seeking behaviors (see story in NY Times from 2011).

Please remember that benzodiazepine withdrawal can be deadly. If you have been taking regular benzos for any length of time and you decide you want to stop taking them, you should work closely with your physician to do so. Don't stop them on a whim.

Rebound Anxiety and Rebound Insomnia
We have known since the benzodiazepines came on the market that they cause what we call "rebound anxiety" and "rebound insomnia". This basically means the more benzos you take, the more anxiety you have. Bummer. And not exactly what you were hoping for.

Brain Mush
Known effects of the benzodiazepines include sedation, decreased attention, and anterograde amnesia. In simpler terms, benzos make you sleepy (which is why they are used by anesthesiologists to put you  to sleep for surgery); they make you a little less "tuned in" (which is excellent for panic, not so excellent for driving your kiddos to school); and they make you lose your ability to create new memories during the time the medication is working (looking to forget what is just about to happen to you?).  Another bummer.

It's also pretty clear that some combination of those effects lead you to be a little less cognitively sharp. Brain mush is a very technical term for the dulling effects of benzodiazepine use; there is convincing evidence that long-term use of benzodiazepines causes people to score lower on neuropsychological tests. The longer you are on them, the worse you score (see here for study). Same is true in elderly people (here is that study).

Is there an appropriate time for benzos?

Yes, I think there is a time and a place for benzos, but they must be both prescribed and taken with care. You should work closely with your provider to discuss the risks and benefits and really take benzos only when absolutely needed. And, please, don't share them with your neighbors-- this is not a neighborly good deed.

Examples, in my opinion, of appropriate uses of benzos:

• I had a patient recently flying back East to her 50th high school reunion. She is terrified of flying and even more terrified of seeing her former classmates. I gave her a few tablets for the flight, both ways. I'm stingy, I think I gave her 6 pills.
• I have a patient with advanced dementia who gets super anxious before coming to any dentist or doctor's appointments. Her son gives her a baby dose of lorazepam before the visits, and we avert hours of drama for her and him.
• I had a patient recently assaulted at the transit center. He is having some flashbacks and panic when getting on the bus in the evening to go home. He is working closely with a therapist and considering starting an antidepressant, but he really needs to keep riding the bus to work in spite of his current symptoms. This is a temporary and urgent fix.

What about Maggie?
Well, let's be clear here. I am not Maggie's doctor. I don't have a relationship with her, nor do I know her well enough to know why she is taking Xanax and whether or not it is an appropriate choice. I have not probed her psychiatric history, I don't know her substance abuse history, and I don't know what other prescription or recreational drugs she uses. I can make an educated guess, from this scene, that she experiences panic attacks. In this context, it's hard for me to make a therapeutic decision for her.

I would say, if she has simple panic attacks that are random and infrequent, then yes, Xanax (or any of its equivalents) is probably an okay medicine for her. For very occasional use and only in combination with an adequate trial of cognitive behavioral therapy. I would also like to know what she is doing for her own self care (she has a super stressful job) and how she intends to manage stress going forward. I'd be worried she may have some underlying anxiety disorder that isn't be addressed. If she gets panic attacks any more often than infrequently, she should probably consider a trial of an anti-depressant.

I'd also say that Maggie shouldn't be advertising her Xanax to you. Decisions about your diagnosis and which medications are appropriate for you should be a matter of discussion with your primary care provider, not some pharmaceutical advertisement. Or some cute smart girl you see on TV.

Now let's talk about product placement (aka 'name dropping') of pharmaceuticals
I am not that media savvy. I'm forever missing references to pop culture, and I can never confirm or deny a particular star's presence in a film. So maybe it is not shocking that I had no idea that pharmaceutical product placement was "a thing" until I watched the Xanax scene. When I started researching material for this post, I found that others have been talking about the topic for years; the earliest policy research dates back to 2005. Have you ever noticed a drug-name being dropped on your favorite show?

I could take this opportunity to launch into a diatribe about direct-to-consumer advertising to patients (Cut to commercial: music plays, previously incontinent grandma cured by the magic medicine runs through an open field and hoists her grandchild above her head, huge smile on both faces, music fades.). But direct-to-consumer advertising is a big topic for another day. For today, I want to consider specifically the issue of pharmaceutical product placement in TV and movies. Should it be allowed?

According to Nielson Media, product placement is defined as "any verbal or visual integration of a brand into a plot line". Examples of common products intentionally placed in the way of TV and movie cameras include Mercedes-Benz vehicles (the 2012 winner for making the most big screen appearances), Apple computers (a close #2), Budweiser beer, and the classic example of E.T.'s Reeses Pieces.

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Turns out one of the first pharmaceutical product placements was in 2005 by the pharmaceutical company, Organon, which placed posters for Nuvaring, a birth control method, in the background of episodes of Scrubs and King of Queens. Soon after, analysts started noting Zoloft (an antidepressant) and Lap-Band (a patented procedure for gastric bypass surgery) being dropped into certain daytime soap operas. Even though I love birth control, I want people to know about anti-depressants and gastric bypass surgery, this still seems wrong.

Marketers are banking on our emotional relationships to some fictional character in some fantasy world to subtly persuade us that the medication our favorite character is taking is what we need too. This doesn't seem like a good way to get educated. 

In contrast to the examples mentioned above, some viewers might assume that the inclusion of medication brand-names in screenwriting is unavoidable. Some might argue that using brand names captures "how doctor's speak" or literally "how patients talk about their medications." What do you think?  If a scene is going to realistically cover a health issue, must the writer specifically mention a medication by name? Does it make the dialogue more real? Does it lend credibility? Or is it merely advertising?

I can share with you that, as a physician who cares about the undo influence of pharmaceutical companies on my practice, I very consciously try not to use brand names when speaking with patients or other providers about medications. In fact, writing "Xanax" over and over for this story is killing me. I do firmly believe that the more I see, write, read, and say a name, the more likely I am to prescribe and use that drug (rather than generic or equivalents that may be less expensive and just as good). I also know that I am human, my patients are human, and marketing works on humans.

There is no way to confirm that the name dropping is actually funded by the pharmaceutical companies because transactions between private companies and the media outlets are not privy to public information. So we won't really know. But we can guess. And my guess is that the makers of Xanax paid for Maggie's scene.


The practice of pharmaceutical product placement is also questionable from a legal perspective. The FDA has strict guidelines about what information needs to be included in pharmaceutical advertising (that's why we always hear that raspy voice at the end of the TV commercial reminding us that, "in rare circumstances we could die or lose our fourth digit on our left foot by taking such-and-such medication"). But, does the FDA consider this advertising? As far as I can uncover, the FDA, FCC and FTC currently do not have specific guidelines to address the use of prescription drug references in fictional entertainment. This gap clearly leaves some space for abuse-- and puts us at risk for some serious manipulation.

After all, if the cute smart girl is taking Xanax, why wouldn't I want it too?
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Additional  references on benzodiazepines:
http://www.psychologytoday.com/blog/how-everyone-became-depressed/201306/benzo-hysteria
http://psychcentral.com/lib/top-25-psychiatric-medication-prescriptions-for-2011/00012586

Additional references on product placement
http://www.pharmalive.com/sites/default/files/blogs/attachments/product-placement.pdf
http://www.marketingpower.com/AboutAMA/Pages/AMA%20Publications/AMA%20Journals/Journal%20of%20Public%20Policy%20Marketing/TOCS/summary%20spring%2008/Pharmaceuticaljppmmay08.aspx
http://www.rxentertainmentinc.com/what-we-do/product-placement/