Posts Tagged ‘drugs’
Shortages of a long list of medications have been a problem for some time now. Many, many important drugs are in short supply. The FDA even keeps a list of them. The reasons for this are fairly well known. All of the drugs in short supply are generics, meaning they are off patent. This means the profit margins to be had for any company making them are very slim. The shortages mostly affect injectable drugs, not pills or tablets, because injectables are more expensive to manufacture. Often a particular generic injectable drug is made by only a few, or even a single, company. If there is a problem at the manufacturing plant, the supply can dry up quickly. The pharmaceutical industry does not really make drugs based upon what people need; they look at potential profits. So a drug for a rare condition does not have much chance.
One family of drugs long affected by shortages is that of injectable anti-cancer drugs. When that happens, cancer specialists sometimes can find other ways to treat the cancer. But often there is no equivalent medicine. A recent, disturbing article in the New England Journal of Medicine documents what can happen then. Faced with a shortage of a standard anti-cancer drug, called mechlorethamine, doctors had to devise an alternative treatment program for children with a cancer called Hodgkin’s lymphoma. As cancers go, this is a very curable one. Yet the children with the alternative program, without the mechlorethamine, did worse — much worse.
The authors’ conclusion is clearly correct:
Almost 80% of children and adolescents with cancer can be cured with current therapy. Most of the curative treatment regimens are based on chemotherapeutic agents that have been available for decades, but some of these have recently been in short supply. These shortages are likely to have devastating effects on patients with cancer and must be prevented.
We simply must find another way of ending these chronic generic drug shortages. This is not a problem a market-based, profit-driven pharmaceutical industry will fix on its own. They must be given some incentive, some reason to make these drugs. We are talking life and death here. The authors of the article rightly call this . . .
“an intolerable situation for young people with curable diseases.”
This little cartoon, courtesy of xkcd, highlights a problem we have had for some time, but which is getting worse–highly antibiotic-resistant bacteria. Soon after the first antibiotics appeared, especially penicillin, doctors noticed the phenomenon of developing bacterial resistance to them. The cause is evolution in action. The replication time for bacteria is extremely fast, as short as twenty minutes in some cases. So the process of evolution, of random mutation and passing new traits on to offspring, happens in minutes rather than years.
Say a population of bacteria is 99.99% susceptible to being killed by an antibiotic, or sensitive. When the antibiotic has done its work there are 0.01% of the bacteria left. If their resistance to the antibiotic is heritable, they will pass that on to their offspring. Before too long, if the antibiotic is still present in the system and nothing else intervenes, all of the bacteria will be resistant. An important thing that can intervene is that the body has its own ways of killing bacteria on its own without the help of antibiotics. If the burden of infection is low, as when antibiotics kill nearly all the bacteria, our natural infection-fighting system can do the rest.
It’s been known for a long time how to at least slow down the process of bacteria acquiring antibiotic resistance — limit the use of antibiotics to when they are really needed, and use the ordinary, simple antibiotics whenever possible. So if a germ is sensitive to many antibiotics, which is often the case, use the simple one. This reserves our newest, most powerful drugs for when we really need them, which is when they are the only ones to which the germ is sensitive. In addition, don’t use antibiotics when they don’t do any good, such as with viral infection.
A recent article in the New England Journal of Medicine, “Preventing lethal hospital outbreaks of antibiotic-resistant bacteria,” describes how we are doing. It is a vital question, because bacteria resistant to many, and sometimes all, antibiotics are killers. It’s a particular problem in hospitals, which you can think of as gathering together many sick and vulnerable people in one spot. It’s a set-up for disaster if a highly resistant bacterial strain gets loose, and is why hospitals themselves can be dangerous places — you can acquire an infection there you didn’t come in with, called nosocomial infections. Reducing the problem means limiting the use of antibiotics only to those cases in which they are really necessary and choosing the correct antibiotic. It also means strict isolation and handwashing techniques for caregivers of patients infected with these bacteria to limit the spread to others.
This problem is not going to go away. It will probably get worse. Although researchers are always working to develop new antibiotics to stay one jump ahead of the bacteria, we can’t count on this approach, either.
Antibiotics have been miracle drugs since the 1940s, saving millions of lives. If we are complacent about the issue of resistance, we will be back in the dark days before that.
I’ve written before (here and here) about an alarming trend — shortages in hospitals of important, sometimes life-saving medications. The problem is most acute for drugs we inject into the body rather than pills. The Food and Drug Administration (FDA) keeps a list of drugs in short supply; it is long and getting longer. Things aren’t getting better; they’re getting worse. The items on the list now number in the hundreds. The list changes so frequently from day to day that hospitals scramble with a real-time way of keeping track.
Just yesterday I learned that chloral hydrate, an old, old medicine, will not be made anymore. The one company making it has decided to stop. Although it’s an old drug, chloral hydrate still has an important place in the toolkit of doctors like me who sedate infants and small children for procedures. Now we won’t have it anymore. Why do we have these shortages? What’s going on?
The problem is that the drugs in short supply are virtually all generic, off patent. They are cheap. So the profit margins for the manufacturer is slim. A drug company can make much, much more money by looking for yet another “me too” drug we don’t need. The old standby drugs, the injectable ones we need everyday, are cast aside. A related problem is that, for many of these drugs we still can get, only one factory makes them. So if there’s a problem at the factory, there is an instant nation-wide shortage.
What’s the solution? I see no other way than for some federal authority to subsidize the production of these medicines in a way that allows the companies making them to make a reasonable profit. The totally free market got us into this mess, and it won’t get us out. If anything, it will get worse.
I’ve written before about how the current standard of care is to provide some sort of sedation drugs — by mouth or by injection — to relieve pain and anxiety when we have to do things to children that make them uncomfortable, such as sewing up lacerations or doing x-ray studies that require them to lay still for a prolonged period. Pediatric intensivists in particular have become very involved in providing this service for children. There’s even a new professional organization, the Society for Pediatric Sedation, that gathers together doctors and nurses involved in this practice. (I’m a member.)
We have a menu of medications to choose from, but finding the perfect sedative for children is sometimes difficult. All of them have potential issues, although we are used to dealing with these things. Recently there’s been a new agent on the pediatric sedation scene, although it’s been around for many years for other uses — nitrous oxide, aka “laughing gas.” It’s been used in the operating room for many decades as a supplement to more potent anesthetics, and outside the operating room in dental offices for well over a century. It has an outstanding safety profile. One of the pioneers in using nitrous oxide for sedating children for medical procedures is Dr. Judy Zier, of Minneapolis Children’s Hospital. For the past year we’ve been using nitrous oxide at my hospital, and for many children it is very helpful. It seems to be most helpful for children between about two years of age and ten or so. We now typically use it for many things we just used to do without any sedation at all — placing intravenous (IV) lines, urinary catheters, and nasogastric tubes. I think it represents a real advance in what we can offer children. Being in the hospital is frightening enough for a child.
Open most any medical journal, including the most prestigious of them, such as the New England Journal of Medicine, and you will see page upon page of glossy advertisements from drug companies for their products. This has been going on for many decades. Do these ads affect physician behavior? Are we more likely to prescribe ones we read about in ads rather than in scientific reports?
There has always been a concern that advertising, not science, can affect doctors’ prescribing practices. Surely the drug companies think so, or they wouldn’t spend all the money on the ads. They’re not stupid. Now one medical journal, Emergency Medicine Australasia, has taken a stand against the practice; they’ve banned drug company advertising from their pages. In an editorial, they explained why.
This followed extensive debate on the growing evidence about the detrimental effects of the drug industry in medicine. Among the issues discussed were that the industry, one of the most profitable in the world, distorts research findings, such that drug company sponsored research is approximately four times as likely to be favourable to its product than independently funded research; authors of company-sponsored research are far more likely to recommend a company’s drug than independent researchers, and researchers with industry connections are more likely to publish data favourable to a company’s product than those without; selective reporting of results by industry is likely to inflate our views of the efficacy of company products; the drug industry has been shown to engage in dubious and unethical publishing practices, including guest and ghost authorship, and to apply pressure to academics to withhold negative findings; and the industry spends enormous amounts of money on advertising, which has been shown to change the prescribing practices of doctors, increasing sales in a dose-related manner to the volume of advertising.
Doctors, for their part, generally claim that such advertising has no effect at all on their prescribing practices. I know I would deny it. But really, how would I know? Advertisers put enormous effort into sending subliminal messages that work beneath the surface of our conscious radar. I could be manipulated as much as the next physician.
Drug companies value drug advertising in medical journals because it works. It is regarded as highly effective by pharmaceutical marketers, generating at least US $2-5 in revenue per dollar spent, with returns growing in the long term.
Not taking drug company ads has large financial consequences for journals, especially the second and third-rank ones; they more or less run on advertising revenue. The top ranking journals can depend upon high subscription fees; the lesser ones can’t. There are also many journals sent out to doctors that are actually free. We call them “throw-aways.” Trash cans next to the mailboxes in doctors’ lounges are stuffed with them. These can have a useful bit of information in them here and there, but mostly they are massive advertisements for the pharmaceutical industry. Doctors recognize this. But I think we’re less aware of the huge number of ads that appear in highly-ranked journals.
Emergency Medicine Australasia is a foreign journal, based in Australia, and has small impact on American physicians. But the principle they are arguing may well become a trend. I think the internet will help this, since the high costs of printing and mailing medical journals could be dramatically reduced by having the journals online only. Only a small paid editorial staff would be required, since the folks who review and decide on publication are nearly all unpaid as it is. (I used to do that a lot; you get an annual thank-you note — and maybe a calendar — for your efforts.)
I think it’s something to watch closely.
When most people go into the hospital it does not occur to them that, here in America, an acute scarcity of a standard medication will affect their health. But they would be wrong. Sudden, random, and dangerous shortages of key, life-saving medicines are happening increasingly frequently. For example, there is this recent shortage of chemotherapeutic drugs to treat cancer. We have also had recent shortages of such commonly used PICU drugs as phenobarbital and propofol. The latest shortage is with fentanyl, a synthetic narcotic pain-killer. I really need fentanyl in my practice to relieve pain and sedate children. There are other narcotics we can use, but none have the special attributes of fentanyl that make it, in experienced hands of course, a safe and key PICU medication.
Why do we have these drug shortages? Where do they come from? All of these drugs share the attribute of being generic medications. This means the patent has expired on them and any pharmaceutical company can choose to make and sell them. They can, but they won’t make much money doing so, because generic drugs are much, much cheaper than are ones still under patent. Injectable drugs, the drugs I and my ICU colleagues use every day, are especially expensive to make because they must be sterile. The result is that, for the majority of injectable generic drugs, there may only be a single company with a single factory even making it. If there is a problem at the factory, everything stops. And these are not esoteric drugs; they are ones hospital physicians rely on every day. People die when we don’t have them. The upshot is that our care of critically ill patients depends upon whether or not the roof of a factory somewhere leaks or not.
I don’t know what the answer to this problem is, but it is a serious danger. There are so-called “orphan drug” incentives to encourage drug companies to make rarely needed drugs that are essential for people with rare disorders. Since there is only a tiny market for such drugs, companies otherwise wouldn’t make them. To safeguard our nation’s injectable drug supply, I think we should figure out some sort of similar system for injectable generic drugs. The problem is getting worse, not better.
Update: President Obama, through the FDA, has taken steps to help the situation, offering incentives for companies to make injectable generic medications. You can read details here.
Another update: This editorial in the New England Journal of Medicine makes it clear: shortages of all manner of generic injectable drugs are popping up. These these shortages will cause people to die, if they haven’t already. For those lovers of the free market as the best way to practice medicine in America, this example shows how mistaken that viewpoint is.
(A couple of weeks ago Maggie Mahar, who writes the excellent Healthbeat blog for The Century Foundation asked me for my thoughts about a recent Perspectives piece in the New England Journal of Medicine by Treadway and Chatterjee regarding this question: can empathy and compassion be taught to medical students and resident physicians? She published my reply here — I cross-post it below.)
We want competent physicians, but we also want compassionate ones. How do we get them? Is it nature or is it nurture? Is it more important to search out more compassionate students, or should we instill compassion somehow in the ones we start along the training pipeline? I think the answer lies in nurturing what nature has already put there.
My background is in pediatric critical care, which I have practiced for nearly thirty years. Throughout most of my career I have taught medical students, residents, and fellows. So I have seen young physicians as they made their way as best they could through the long training process. I also served on a medical school admissions committee for some years and interviewed many prospective students, so I have had the opportunity to see and speak with them before the medical education system even got hold of them. After reading Doctor Treadway’s essay, I think my overall perspective on the question is similar to hers – the main principle to keep before us is not so much to figure out a way to teach compassion, but rather to devise ways such that the training process does not reduce, or even extinguish, the innate compassion all humans have toward one another. Unfortunately, our current way of doing things does not do a very good job at that task. But I do not think our present state of affairs is anyone’s fault. We are hobbled by our success. Some historical background is helpful, I think, to explain what I mean.
When my grandfather graduated from medical school in 1901, he had only a few tools to help the sick. He could do useful things to help injuries mend. He had the newly discovered techniques of aseptic surgery, as well as ether to allow him to do it painlessly. Other than that, though, he did not have much – narcotics to relieve pain, powdered digitalis leaf to help a failing heart, and a few other things. Mostly, though, he had bagful of useless nostrums. Some of them were even harmful. Because he had little to offer, compassion figured prominently in whatever therapy he did. It had to.
When my father graduated from the same medical school in 1944, things were better. Surgery had advanced further from his father’s day, although only brave surgeons entered the chest cavity. There was sulfa, and penicillin soon became available, working miracles with previously deadly infections. Streptomycin and later drugs made tuberculosis treatable. He soon had some drugs to treat hypertension, which by then had killed his father, plus a rapidly enlarging stock of other useful drugs to put in the black bag he took on house calls. But there were still many things for which he could do nothing. For a heart attack he gave some morphine to take away the pain and then waited to see what happened. If a cancer could not be removed surgically, he had nothing to offer. Although my father’s black bag held more than his father’s had contained, compassion was still a crucial part of my father’s armamentarium. As for his father, it had to be.
I graduated from medical school in 1978. If scientific medicine was just spreading its wings during my father’s training, I experienced it in full flight. By then our medical-industrial complex had rolled out nearly all of the varieties of therapies we have still, although of course we have polished and improved them. What has happened, I think, is not that we have become less compassionate on purpose, but that we came to act as if we no longer needed the compassion of my father or my grandfather’s era, now that we had so many really useful and exciting therapies to offer.
I also think one other historical change is key to understanding how our young doctors react to the experience of seeing death and dying. In my grandfather’s era, it was an unusual person, even an unusual child, who had not personally seen someone die. Children and young adults saw how those around them behaved and reacted to death. If they became doctors, both they and their patients had shared this common experience, so both knew how to act. I saw death for the first time when I was sixteen on my very first day working as an orderly in our local hospital. I was giving a bath to an old man; he looked at me oddly, and then he was dead. None of my friends or schoolmates had ever seen such a thing. I still recall it vividly. I also remember well how helpful the nurses, all women in their sixties, were to me afterwards. I watched them wash the body, a once sacramental task now largely done by nurses in hospitals instead of families in their homes. They were respectful, but matter-of-fact as they went about it. After all, it was a natural thing.
Getting back to Doctor Treadway’s observation, I agree with her that compassion for others is innate in all of us, although it is stronger in some than in others. All of us possess an inner light. Perhaps that opinion makes my theology show, but I think it is fair to say our medical school selection process already skews toward selecting students more compassionate than the average person. We need to encourage that quality, certainly, but that is not the key issue in my mind; mainly we need to prevent medical training from driving it into the background, belittling it, or even snuffing it out. So I do not think we need so much to ponder how to teach compassion as we need to find ways of letting students’ natural humanity shine through. For medical educators, that would seem to me to be good news. Framed that way, it ought to be doable – but how?
There are many things in medicine that can be taught with the old “see one, do one, teach one” model that those of us older than fifty remember. We also remember never seeing a faculty attending physician in the hospital at night, because, after sundown, the place belonged to the residents. Even during the day, attending physicians were more likely to be found in their offices or their research laboratories than out and about on the wards. I learned how to intubate a baby and place an umbilical artery catheter from my senior resident, who had learned the year before from her senior resident. But my senior resident was not much help when a premature baby died; she was at much at sea as I was. All she had learned about that from her senior resident was to cultivate the kind of hard-boiled persona described by Dr. Chatterjee. We aspired to it partly because it gave us a mental escape hatch in those situations. But mainly it was because nobody showed us any other way.
How to show that other way? In my mind, there is no substitute for senior, seasoned physicians demonstrating, in the moment, how to let out our own innate empathy and compassion. Good, experienced physicians are comfortable admitting their medical ignorance and failures to families; nothing terrifies residents more than that. When they see it in action, students and residents respond with a version of: “that’s why I became a doctor.” Structurally, medical education has already made great strides in the right direction. We now have rules for resident supervision that involve much more oversight, even at night, than I ever had. This was done mostly for patient safety, I think, with education as a secondary but important goal.
So the opportunities are there – we just need to implement them better. For example, after an unsuccessful resuscitation and a death, the folks with the grey hair should spend as much time discussing with students and residents the psychic dimensions of the death as they do the sequence of medical decisions. Most of my colleagues already do that to varying degrees, but it should be an expectation.
We should never again send a resident, alone and emotionally at sea, to comfort a grieving family without backup. We do not do that for complicated invasive procedures; we should not do it for this other, equally important task either. Certainly some organized instruction – seminars, discussion groups, lectures and the like – can be part of the process. But the training curriculum is already stuffed with subjects. Taking residents by the hand and leading them through these experiences does not require another fat syllabus. It only takes a little time. If we want to foster compassion in our students we should ourselves show them compassion for the situations we put them in.
When I started training in pediatrics nearly 35 years ago it was common practice when an infant or child needed something done that was going to be painful, anxiety-producing, or both, the child was often merely held (or tied) down. Looking back on it now, it reminds me of the 19th century, a time when somebody might just be given a stick to bite down on. I wonder how we could have been in the same place with children a century later.
To be fair, there were several reasons we did things that way. Chief among them was the notion — one we now know to be false — that children (infants in particular) did not feel pain in the same way as older persons. The other reason was that we simply didn’t have available many of the medications we have now to counteract pain and anxiety, and the few that we had had not been studied much in children.
Things are much different now. We have a menu of things we can use to prevent pain, ranging from numbing cream we can put on the skin to lessen (or even eliminate) the pain of a needle stick to powerful, short-acting anesthetic drugs we can use to put the child into a deep (and brief) slumber. We have reliable ways of greatly reducing or eliminating both pain and anxiety when a child needs medical procedures as varied as an MRI scan or some stitches in the scalp.
Most doctors who do these procedures are well aware of these things. But if you run across one who doesn’t seem to be, don’t be shy about speaking up and asking what can be done to make your child more comfortable.
Here is an excerpt from my recent book, How Your Child Heals. It’s about fever, from the chapter about symptoms and signs.
Fever means an abnormal elevation of body temperature. But what is abnormal? Most of us have heard or read that “normal” is 98.6 degrees Fahrenheit, which is 37 degrees centigrade. In fact, normal temperature varies throughout the day. It is as much as one degree lower in the morning than in the afternoon, and exertion of any kind raises it. Where you measure it also matters. Internal temperature, such as taken on a child with a rectal thermometer, is usually a degree or so higher than a simultaneous measurement taken in the mouth or under the arm pit.
There is also a range of what is normal for each individual — not all people are the same. So what is a fever in me may not be a fever in you. As a practical matter, most doctors stay clear of this controversy by choosing a number to label as fever that is high enough so this individual variability does not matter. Most choose a value of 100.4 degrees Fahrenheit, or 38 degrees centigrade, as the definition of fever. It is not a perfect answer, but it is a number that has stood the test of time in practice.
We maintain our normal body temperature in several ways. Chief among them is our blood circulation. Heat radiates from our body surface, so by directing blood toward or away from our skin we can unload or conserve heat. We can also control body temperature by sweating — evaporation of sweat cools us down. We know how important a mechanism this is because the rare person who cannot sweat, or who is taking a medicine that interferes with sweating, has trouble keeping his body temperature regulated when he gets sick. If a swing in blood flow inwards to raise temperature happens very fast, we respond by shivering. This is also why we shiver if we go outside without a coat in the winter; our bodies are redirecting blood flow from our skin to our core in order to maintain temperature.
All parents know that a common cause of fever in children is infection. A more precise way to think about it is that a common cause of fever is actually inflammation. Since in children infection is the most common cause of inflammation, we generally assume a child with a fever has an infection somewhere in her body unless we can prove otherwise.
Our brains have a kind of thermostat built into them. Like the thermostat in a house, it senses the temperature of the blood passing by it and uses a series of controlling valves in the blood circulation to fine-tune the temperature. Also like your house thermostat, it continues to sense the temperature, and adjust it as necessary, until it has reached the value for which the thermostat is set. Fever happens when the thermostat is reset, just as happens when you twist the dial on the wall for your furnace — the body reacts to bring itself to the new setting. What twists the knob on the brain’s thermostat to cause fever are substances in the blood.
These fever-inducing substances belong to a family of inflammatory molecules that are released from body cells. Mostly they come from a cell called a macrophage, but germs themselves can also release things that have the same effect. The sudden rises and falls a parent often sees in their child’s temperature when they have an infection reflect the usually brief time these substances are in the blood. Sustained fever for many hours can happen if these materials are steadily present.
Opinions vary among doctors about when fever needs treatment. Fever itself virtually never causes harm on its own. The only times it can do harm is when it gets very, very high — 106 degrees or more — for a sustained period. That only happens in highly unusual situations; ordinary childhood infections never get it that high. It is true fever can make a child uncomfortable, although children generally tolerate it much better than adults. For that reason alone many doctors advise treatment.
There is another reason to treat fever. Toddlers may experience brief convulsions – seizures — when their body temperature rises very fast. These so-called febrile seizures cause no harm to the brain itself, and often run in families, but fever treatment makes good sense for a child who has had them in the past.
We have two effective drugs to treat fever — acetaminophen (Tylenol) and ibuprofen (Motrin). Both work the same way: they reset the brain thermostat back down to a lower lever. Both only last a few of hours or so in their effect, which is why you will see your child’s fever go back up again when they wear off if there are still any of those fever-causing substances from the inflamed site still in the circulation.
Every patient wants the best care — what is known to work. Certainly nobody wants care that doesn’t work, especially if what doesn’t work carries some risk of its own. But what if we don’t know what treatment is best for a particular condition? Shouldn’t we find out?
It is well known that there are wide variations in medical practice across the country, even for the same conditions. Even in the same region, doctors choose different therapies for the same condition. This is often because the circumstances of patients differ. But what if doctors choose different therapies for no particular reason except personal preference? And what if those therapies, although producing the same outcomes, differ in cost by a large amount?
Enter comparative effective research (CER). The idea is simple: compare two treatments and see which works better. And, if one works only a little better and the cost difference is huge, is the tiny improvement worth the cost. It seems odd to nonphysicians, but this kind research is hard to do, and is in fact rarely done. We often compare some new, experimental treatment with the standard; but it is often hard to compare two standard treatments with each other to see which works better. Why?
A recent editorial in the New England Journal of Medicine examines why CER can be challenging to do. The reason often boils down to money. In the example given in the article, a very expensive drug was being compared with a much cheaper one. Both therapies were covered under the patients’ insurance (in this case Medicare). But one group of patients would have an enormously high out-of-pocket copay fee because the copay is often calculated as a percent of the total bill. How do we deal with that? The guiding principle of a randomized, controlled trial is that the patient groups are similar. It would affect the trial if one group of patients could afford (or was willing to pay) a higher copay than the other.
Another key principle of such trials is that neither the patient nor the evaluating physician knows which group the patient is in — which drug they are receiving. This is called blinding. For experimental drugs blinding is easy; the patient gets an unidentified drug, marked only with a code that will be broken later. But if the drugs being compared are both covered by insurance, the insurance statement shows to the patient what it is.
These problems are solvable. But it is important to realize that comparative effectiveness research, which we very much need if we are to control our exploding medical costs, will not be easy to do in many situations.