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Thursday, May 28, 2015

Actinic Keratoses and Carac (fluorouracil) cream: why is this so expensive?

First, a disclaimer: I don't know why Carac (0.5% flourouracil cream) is so expensive. I will speculate, though, at the very end of this blog.

Sun and the skin: what happens
If a person reaches a certain age, has very little pigment in her skin, and has spent lots of time in the sun, bad stuff happens. The ultraviolet radiation of the sun does all kinds of great things: it makes us happy, causes us to synthesize vitamin D which strengthens our bones and it gives us this healthy glow until we get old and wrinkled and leathery. And even that can be charming. The skin cells put up with this remarkably well for a long time, partly aided by melanin pigment which absorbs the radiation, which is why we tan and freckle, if we are fair skinned. Eventually, though, we absorb enough radiation that it injures the skin and produces cells which multiply oddly. It also damages the skin's elasticity which creates wrinkles.

The cells which reproduce in odd ways peel, creating dry skin or dry spots, or warty growths or even small hard horns. The scaly spots are called "actinic keratoses" which just means sun induced scaly spots. Sometimes the skin cells become cancerous and lump up and create non-healing sores. This is when we regret going out without a hat or sunscreen, but, of course, it is too late.

Topical chemotherapy: good idea or great idea?
In 1957 scientists published a paper showing that flourouracil, a flourine attached to a nucleotide (RNA building block), inhibited liver cancer cells. This became one of our early chemotherapy drugs, and is still an important drug in treating colon cancer. When mixed up in a skin cream, it can kill the abnormal skin cells which grow on our sun exposed skin, allowing the normal ones to take their place.

The way fluorouracil cream was initially used was awesome and terrible. It was applied daily for 4-6 weeks to the affected area and the skin became a war zone. The abnormal cells died, leaving red swollen places where sun damage was most severe. Generally people using it looked pretty bad for weeks or longer. Eventually they healed and got rid of their scaly spots. Many people still use it this way, to good effect. We also found that we could treat just small areas at a time, and even just the scaly spots themselves, and that we could use the cream for shorter courses and avoid the intense inflammation. This was a major advance in therapy since our other main option was to freeze the spots with liquid nitrogen, which was a painful, expensive and seemingly never ending process, and which left little white scars.

A slight catch was that the fluorouracil cream was expensive. It was over $100 for a 30 gram tube. Maybe insurance would pay, but it was top tier, and at least some of the cost made its way to the consumer.

Several years ago my husband was prescribed Carac, one of the first fluorouracil creams. It was expensive, so we have made it last, far longer than the expiration date. It is a prized possession, that tube. We have both spent far too much time in the sun without protection, loving every minute of it, and regretting it now in hindsight. When the scaly spots become too annoying, we use the cream until they go away. But the tube is almost empty. Time to buy some more.

Pretty pricey
I looked online to find out how much it would cost if I bought it internationally. I found a product from India that was not too expensive. It was 5% flourouracil rather than the 0.5%, but that is the percentage in the brand name Efudex which is one of the alternatives in the US, so it seemed reasonable. I got the cream in the mail and tried it and it was slightly granular and didn't work. The effect of the Carac was dramatic. The effect of the Indian cream was essentially nothing. "You get what you pay for," I thought. I asked a compounding pharmacist acquaintance to make me some. I respect this pharmacist. He mixed up flourouracil in a skin cream base at a concentration of 5%. The cream was also grainy and didn't work. It seemed to do a little better than the Indian cream, but nothing like the Carac. Finally I decided to just get the Carac. I asked my friendly neighborhood pharmacist what it would cost. She told me that a tube of Carac, 30 grams, costs around $2000. NO! I will not do that! The amount of active chemical in that little tube, the fluorouracil that is used as intravenous chemotherapy, would cost about $40 retail. It is possible to get generic or brand name 5% fluororuacil creams for prices ranging from $170-$500 for a tube, but that is still horribly expensive, and if they didn't work, that would be an annoying next chapter in this tale of woe. Looking a bit harder I found that there is now a 2% solution which is a little less pricey, though there is nothing that I've read that tells me how or if this works. Maybe I should just make some, but playing around with chemotherapy drugs sounds like a bad idea.

Other options
What, then, should someone do with their actinic keratoses? It is just not reasonable to pay $2000 for a tube of cream. Uptodate, which is an online resource used by many physicians to keep abreast of expert management of diseases, says that the treatment of actinic keratoses, besides 0.5% fluorouracil cream, includes use of sunscreen to prevent further appearances of the little spots, dermabrasion to remove the affected skin (ouch)and that the use of topical retinoids (vitamin A derivatives) can help. They also mention that ingenol mebutate and imiquimod creams (both horribly expensive) are better than placebo as is chemical sensitization plus light therapy (I can only imagine what that costs.)

I have decided to use a retinol preparation which is pretty darn cheap and calls itself "wrinkle cream." It is in the cosmetic section of my local drugstore. Retinol is one of several retinoids that are approved for use on the skin, and also treat acne. I will also wear sunscreen and a hat. So far the retinol, when applied to the whole sun-damaged area (for me, the forehead) is helping reduce my sun induced roughness and scaling. Retinoids appear also to reduce the risk of developing squamous cell cancer, a common malignancy in sun exposed skin. For now, at least, my path is clear.

Mysteries persist
But there remain mysteries which I have been unable to solve using books and the interwebs. Why is 0.5% flurouracil 10 times more expensive than 5% fluorouracil, even though the latter is theoretically 10 times stronger? Why do they even make 5% flourouracil cream if the 0.5% stuff works just as well? Is it in some way very difficult to mix flourouracil into a cream? Why does Uptodate recommend 0.5% flourouracil and not 5%? I have no idea. I can speculate a bit about the costs, though.  It's possible that the cost of the 0.5% flourouracil is made to be as high as the newer creams, like imiquimod, which were priced that high because they were relatively new, and are still not generic. All of these creams are still financially viable because they were cheaper and more acceptable than going in to the doctor every few weeks to have him or her freeze a bunch of spots, resulting in what looked like a mild case of chicken pox which healed to make white scars. It's still really hard to believe that anyone would pay $2000 for a little tube of skin cream and that we, as physicians would regularly recommend that they do so.

Addendum 10/26/2015:
There is another treatment for skin aging and actinic keratoses, which also works for acne! Apparently Nicotinamide, vitamin B3, reduces signs of skin aging when used topically and reduces AK's significantly when taken orally at a dose of 500 mg twice daily. This article, out of Australia, also showed some reduction in non-melanoma skin cancers with it. Both topical and oral versions of Nicotinamide are available without a prescription.

Wednesday, May 27, 2015

More on the epidemic of prescription opiate use and abuse

 Facts (from the Centers for Disease Control Health report, 2013) :
  1. The consumption of opioid pain medications (like morphine, hydrocodone an oxycodone) increased 300% between 1999 and 2010.
  2. The death rates from poisoning by opioid pain medications more than tripled during that time.
  3. The greatest increases in deaths from opioids were seen in non-Hispanic whites and American Indian/Alaskan native populations, who showed a 4 fold increase in deaths.
I have written several blogs on this, most recently talking about the experience of working with a large group of outpatients who are habituated to these drugs and are experiencing side effects, including addiction, along with small improvements in pain that are clearly not worth the devastating consequences of taking these drugs long term.

"What is so devastating?" you may ask.

Here are some stories* (names and details changed for privacy):

  • Crystal is 43 years old. She was diagnosed with fibromyalgia, a painful condition of muscles without a clear cause, 20 years ago. She was started on pain pills 15 years ago and has been on them ever since. The doses have gradually increased and she is no longer able to work because of the sleepiness and confusion that goes along with the pain pills. She has been started on laxatives to treat the constipation and muscle relaxants which make her mouth drier than it already was with the pain pills, and takes an anti-anxiety pill to sleep and to calm down during the day. She still feels terrible and can barely get out of bed, so she has gained 40 pounds. She lives on disability. People ask her if she will sell them her drugs when she comes out of the pharmacy. She has had her car broken into on several occasions by people looking for pills. She can barely afford rent and food and doctor bills on her disability check.
  • John is 50 years old. He hurt both of his shoulders doing drywall installation 10 years ago. He found it difficult to sleep and so they gave him pain pills to take at night. He had his right shoulder operated on by an orthopedic surgeon but it still hurts, as does the left one. He now takes the pain pills all the time so he can do a little work around home. He has been disabled for work for several years. He has gained a lot of weight from being inactive and he feels useless and depressed. His weight has caused him to have knee arthritis and so it hurts when he tries to go out for a walk. He's hoping he can get a knee replacement so maybe he can be more active and lose the weight. His chronic opiate use means that his chance of a successful outcome from knee replacement is substantially poorer.
  • Bill fell off a horse when he was young and has had a tricky back ever since. He used to get prescriptions for pain pills every so often when it acted up, but since it was acting up so often he has started to get a prescription every month, for 240 hydrocodone pills, so he can take 2 of them 4 times a day. He tells the doctor he has to take them all the time or else the back is so bad he can hardly stand it. He has been selling or bartering most of his hydrocodone for several years. Sometimes he takes it for pain, sometimes recreationally and with his girlfriend. If he gets caught, this is a felony. It is also his main income.
  • Nancy has multiple sclerosis. She uses crutches and has back and arm pain. She is on muscle relaxants and pain pills. It is clear to any doctor why she would need these medications, so they are refilled monthly. She lives with her boyfriend and his grown kids. She doesn't take the pills herself. Her boyfriend and his kids use them or sell them. She is vulnerable due to her disability and they threaten to kick her out if she doesn't bring home the pills.
What seems to be happening here is that people get injured or sick, physicians put them on controlled substances in the mistaken thought that it will make them better, and because of the addictive potential and side effects of the medications, they continue to take them and become progressively poor and marginalized. They find relief only in the drugs and end up unable to perform at work, which results in either job loss or being unable to excel and rise in status and income. They get depressed and anxious, often, and are put on more medications. The pain pills can actually make them depressed, but this is rarely obvious to the patient because of the little bit of euphoria that often comes with each dose. They are hassled for their pills. Sometimes they sell them because they are poor, and then they are outside of the law and have a secret that further separates them from people who might help them, such as their doctors. They often smoke, and sometimes drink. The smoking gives them lung disease which puts them at increased risk of death from the respiratory depressant effects of their pain medications. Combining their medications with alcohol can kill them. They get put on medications which lead to obesity and this increases their pain, disability and lack of self confidence.

Turning this process around is going to be hard, but so very worth it. Patients are addicted, but so are we, that is the whole healthcare system. Drug companies make lots of money on these medicines and the medicines used to treat the side effects of the medicines. Doctors get to provide a quick fix and make patients (temporarily) happy just by writing a prescription. Return visits for these patients keep clinics busy. Eventually, though, increasing demands for controlled substances crowds out our ability to see other patients and to provide care that might actually reduce disability. Our opiate using patients burn physicians out because, with rare exceptions, they will never get well. Not writing these prescriptions in the first place or developing alternative strategies that get patients off of them is important work. It will help build healthy communities by reducing the supply of illegal substances. It may even help bring these people back to a place where they can move beyond their identity as chronic pain patients and get on with their lives.

*I am not presently telling the stories of the few patients for whom chronic opiate therapy is a good thing. They do exist, but they are uncommon. They are also usually on low doses and don't take them all the time. I am also not talking about patients with acute pain from injuries, illnesses or surgeries that will resolve. They, too, can have terrible consequences of opiates, but can also benefit a great deal from using them cautiously.

Friday, May 8, 2015

Doctors of tomorrow: please forgive us for thinking that it was a great idea to prescribe sedatives, opiates and stimulants to just about everybody

Lately I've had the opportunity to work in an outpatient clinic where the regular doctor is out sick for a prolonged period of time. It is a breathtakingly beautiful little community, with green hills and a crystal clear river. It is also troubled by methamphetamine and prescription drug abuse.

The little clinic in town is unwittingly a partner in this crime. Like the US itself, this small community clinic has been generous with prescribing controlled substances for those who appear to need them. Sedatives in the benzodiazepine (Valium, Ativan and Xanax are brand name examples) family are prescribed for those with anxiety. Opiates, from the family that includes morphine, are prescribed for patients with back pain and knee pain and a host of other long lasting pains, and continue to be prescribed monthly for round the clock use, sometimes at increasing doses, since these long term pains rarely go away, even on medications. Every young person these days seems to have attention deficit disorder, and many of them have found that they can study better if they take stimulant medications. These medications have been around for years, though there are newer formulations, and used to be called "speed." In moderate doses they make pretty much everybody able to study better. They have become extremely common on college campuses at exam time, since they also allow a person to go without sleep and sometimes without much food. One person with a regular prescription for this kind of medication can supply his or her friends with drugs as needed. Side effects can include heart rhythm disturbances and erratic behavior, especially in higher doses, as are sometimes used recreationally. Some of the patients in this little clinic get ADD drugs so they can work or study, sedatives so they aren't anxious and opiate pain killers for their bad backs or other maladies. Sometimes they take them, sometimes they sell them or give them away, and often they do both.

There is no good evidence that these medications are either safe or effective when used long term. In fact there is good evidence that they are NOT safe, and quite a bit of circumstantial evidence that they are not effective. We prescribe many times the number of controlled substances now than we did a decade ago, and overall Americans are not less anxious or less in pain or better able to concentrate than they were before. Those of us who prescribe opiates to patients with chronic pain very rarely see the pain become significantly more manageable though we do see the patients become less active and more likely to ask us for ever increasing amounts of the medications which don't work very well.

We have known for years that opiates cause constipation, nausea and vomiting, sleepiness and confusion and can cause people to stop breathing at high doses. We are also recognizing that they cause low testosterone levels which results not only in sexual dysfunction but weakness and mood alterations and bone thinning. In some patients overall tolerance to pain or anxiety is decreased. Combining them with sedatives increases the risk that patients taking these medications will stop breathing and die. Most of the patients who die of these medications do so while taking the medications as prescribed though many overdose deaths also occur in people taking the medications recreationally.

I, as a cutting edge physician of my generation, prescribed these drugs with enthusiasm, glad to be able to lessen the burden of anxiety, pain or distraction in my patients. Eventually I noticed that these patients were having real problems, including emergency room visits for confusion or for increased pain, worsening of their pre-existing breathing problems, severe constipation requiring hospitalization, one died by deliberately overdosing. Others' deaths were probably hastened. More subtle has been the increasing number of people who are becoming inactive, apathetic and stuck in poverty who appear to live mostly for their prescription medications. This group of people are not being identified at all by statistics on overdose.

I have been away from regular primary care practice for years now, so have not been writing long term opiate or sedative or stimulant prescription for patients. I have also been in the hospital more and have seen more desperately ill patients whose main problem were prescriptions for controlled substances.

Now I get to be on the receiving end of what goes around which apparently comes around. There are a bunch of patients on controlled substances which will likely kill them (unless they are selling them to people, including school children, who will take them and maybe die) for whom I am asked to write for refills. HELP. Can't do it, can't not do it. Patients can have serious withdrawal syndromes if they run out of their opiates or sedatives suddenly. (Stimulants are usually not an issue, though.) If I do prescribe these medications there is a reasonable chance that I will be responsible for some bad and preventable medical tragedy. If I don't, these patients will be shocked and betrayed, since they really think they need these drugs to be happy.

If this was just my (and their) problem it wouldn't be that interesting. What is interesting is that this is just a tiny microcosm of what is happening in the whole US. Physicians are discovering that these controlled substances are not safe and that their patients are mostly not doing better on them than they were off of them. A small number of patients are doing better, but it's infinitely hard to figure out who those are. Stimulants may have benefit in children with attention deficit disorder, but this is rarely relevant for me as an internist who doesn't see kids. Adults appear to be overusing them in an epidemic manner. The  medical community of the United States needs to make an abrupt about face while showing compassion for the patients who have been taking these medications and probably deteriorating because of them for years. In our opiate dependent patients, we need to re-assess their pain and the causes of it and research the options that might be helpful. We have to do all this while tapering these patients off of the medications which they think they love. We have to realize that many of the things we might do to improve our patients' pain, such as exercise, meditation, non-opiate type drugs, may not be truly effective until the patients are actually off of opiates.

In my experience in trying to deal with this situation, I have found some unexpected allies: the patients themselves. In every patient who I talk to about tapering off of controlled substances I expect anger and resistance. But this is not always the case. I have met patients who seemed like they had just been waiting for someone to help them get off of these meds. It's not even all that uncommon. People don't actually like to be passive and helpless and weak and sleepy and constipated, and some of them are willing to risk experiencing pain or other discomforts in trade for not being on drugs. I see patients on the other end of the process, too. They say that after their injury or operation they were heavily dependent on drugs and that they eventually got fed up and, with the help of a good doctor or nurse or family, got off of them and intend never to take them regularly again.

Opiate pain medications and benzodiazepines are some of the most miraculous drugs physicians can prescribe, and I am not in any way averse to using them when they are needed. The opium poppy and its derivatives can abruptly change the outlook of a person who has the acute pain of a broken bone, a toothache or a recent surgery. They can make the final weeks, days or hours of a person's life be more tolerable. Benzodiazepines can immediately relax a person whose anxiety is running away with them. These drugs are amazing. They just shouldn't be used on a regular basis except in extremely unusual cases.

I'm not positive that adult attention problems should be treated with medications. The rise in use of stimulants may be just an indication that our society expects everyone who intends to achieve financial independence to be able to focus on tasks or studies which are mostly irrelevant to them. As we've moved away from hunting and farming and manufacturing there are many round pegs attempting to pound themselves into square holes. Stimulants, with their known significant side effects and their unknown long term effects, should not be used to make people do things that bore them silly. On the other hand, the rare person who has narcolepsy (a disorder which is characterized by sleep attacks) has my whole hearted support in using stimulants on a regular basis. I will even sign the prescription.


Wednesday, May 6, 2015

Reducing variability in healthcare delivery--maybe not such a great idea

I just got back from the annual meeting of the American College of Physicians, an organization of internal medicine physicians with about 140,000 members. In the annual meetings organizational things take place, such as recognition of particularly hard working members and a kind of graduation ceremony in which members who have achieved a certain level of accomplishment are advanced to fellowship. Mostly, though, the tens of thousands who attend are there to go to lectures and discussions by doctors who know things that we all want to know.

It is possible when attending these meetings to get a general idea of what the leadership in internal medicine thinks is important or acceptable. This year one of the themes seemed to be "reduction of variability." Only one talk actually used those words, but many of the speakers mentioned that they were encouraged to present the "party line" meaning published guidelines by specialty organizations within the ACP. Guidelines are carefully built recommendations for managing various conditions, from diabetes to urinary tract infections, and are extremely helpful in swaying our practice away from things that don't work and toward things that do. They were never intended to be the last and final word.

The one talk that actually used the verbiage "reducing variability" was also addressing the Choosing Wisely campaign. A few years ago the American Board of Internal Medicine championed an initiative to reduce the number of wasteful and useless things physicians did in caring for patients. The idea was that specialty groups would point out the tests or treatments that were being done that really didn't make sense. There are lists now of what not to do (like a head CT scan for a fainting spell or an x-ray for uncomplicated back pain without "red flag" symptoms or antibiotics for the common cold). These lists will help doctors to feel supported when practicing good medicine. They are also an attempt to reduce variability by presenting a unified approach to common problems. I would have liked to see the talk about Choosing Wisely and reducing variability, but for some reason it required an advanced reservation.

I am actually a big fan of Choosing Wisely, since I think that many physicians do more testing and treatment than really makes sense, thus wasting their patients' time and money and cluttering their consciousness with useless and excessive data. But I am not entirely on board with reducing variability.

When I go to a lecture at the ACP meeting, what I hope for is to hear a physician speak who has immense experience in the practice of medicine and who will tell me what he or she does that works well. Sometimes there are controlled trials to support their practice but sometimes their subtle and individualized approaches are not amenable to controlled trials. This is as it should be: much of medicine is an art, and amazing and committed physicians are among us and we can learn a great deal from them. Sometimes different great teachers practice differently from one another. Doing things differently often means that thinking and innovation is going on and that people are not simply acting like sheep.

I heard one speaker, who seemed quite good at what she did, speak of the research regarding her field. She presented data to show that a certain medication worked no better than placebo for treating the condition in question. She said that when her patients asked about using the medication, she told them that they could try it but that it would work no better than a placebo. But she was wrong. The study showed that on average, for a group of patients the medication worked no better than placebo. But for some patients it, of course, worked significantly better than placebo and for some it worked less well. In saying this she made the assumption that there was no variability among patients and that her patient would have the same results as the average patient in the study. Because of this interpretation, those patients of hers who might have benefited from the treatment were probably unlikely to try it.

Because our patients are individuals and not groups of average subjects there should be some variability in how we practice. Because there are more ways than one of doing a job well, we should continue to rejoice in our variability, while striving not to do things that are clearly stupid. It is right that what we do as physicians should be informed by clinical trials and controlled studies, but we should not be convinced by them to ignore the individuality of both physiology and goals of the patient who sits in front of us.