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Authors: David Healy

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There was an increase in productivity but much less than in other countries. Where US medicine led the world in the 1960s, in 2000 the World Health Organization ranked the United States 72
nd
on what it termed health system attainment and performance and 24
th
from among 191 countries worldwide in terms of overall health, as measured by indices such as infant mortality and life expectancy,
51
while in 2008 the Commonwealth Fund ranked the United States last among developed countries in terms of quality of healthcare.
52

One of the factors contributing to a comparative decline in American life expectancy rates is most visible among the elderly. Recent years have seen a startling rise in the extent of polypharmacy, where people are given several different drugs at the same time. It might not be so surprising to find that some people take both a treatment for asthma and for osteoporosis, but as Jane found when being treated for asthma alone few people end up with less than three different treatments. Similarly it is common in the mental health domain to find people on cocktails of four or more drugs rather than just an antidepressant. People with two conditions may be on seven to eight drugs. And ten drugs or more is fast becoming the norm for the elderly especially in the United States. But in this age group, in addition to the problems caused by each blockbuster drug, there are the problems caused by the increased likelihood of interactions between them. In the elderly the rate of hospitalization due to adverse drug reactions is six times higher than in the young and rises sharply in proportion to the number of drugs being taken.
53

It is almost impossible to get data linking polypharmacy to productivity, because doctors simply do not collect it and companies have no incentive to look at it. Pharmaceutical companies have detailed data on what every doctor prescribes and use the data to spur their sales force on just like an athlete uses a stopwatch, but doctors only record and report one in a hundred of the deaths or serious injuries that happen on drugs. None of our measurements track people. Whether you think we are dealing with poisons to be used judiciously or fertilizers to be given out indiscriminately, few people can ingest ten or more chemicals given together without toxic effects—but we don't track this.

A recent report from the Congressional Budget Office identified the growth of prescription-only medicines and other high-tech medical developments as the greatest contributor to escalating costs of medical care in the United States.
54
But aside from the raw costs of drugs, pharmaceuticals contribute in many other ways to our rising health costs. If the increasing costs of drugs led to people being more productive this could be justified, but as we have seen repeatedly many of our more recent treatments if used injudiciously, as the clinical trials we have reviewed have shown, will injure and kill more than they save. Despite this evidence, the media hype surrounding new treatments raises expectations and leads people to seek medical care when they don't really need it. When companies manufacture new diseases (disease mongering) they also pull people into medical care who don't need it. In all these cases, as Sanjeebit Jachuk found back in the 1980s, a significant proportion of people will be made less healthy and less productive.

Finally, the drugs bring in their wake a fetish with measurement. In the face of ever-escalating costs doctors can only afford to do things that come with an evidence base demonstrating they “work.” But here we run into a paradox. While the evidence from trials of many drugs, as discussed in
chapter 3
, shows that watchful waiting may help far more patients than intervening with an active drug, watchful waiting cannot be shown in its own right to “work.” It can't be measured against anything. As a result, there is no longer any basis for medical discretion, no basis for a consultation. This is a world in which doctors are forced to adhere to guidelines and provide unambiguous benefits that can be demonstrated for instance when the figures on a peak flow meter go the right way. A world in which it only makes sense for insurance companies to reimburse for visible disorders of the type demonstrable on DXA scans or through blood cholesterol markers and for treatments that look good on company-run trials and sold on the promise that despite their cost doing what works will ultimately bring healthcare costs down.

In a world where measurement has such powerful effects, it seems more than ironic that measurements such as the ones cited for healthcare costs and life expectancy have so little effect in galvanizing reform or seem only to demoralize us and perhaps inhibit our abilities to do anything. What is it that doctors and patients today are missing that might help them restore “care” to medicine, or what is it that they are up against that seems so difficult to grapple with?

7

The Eclipse of Care

Cora was eighteen and beautiful. Slim, with long blond hair, about average height. She had just finished high school, where she had been the homecoming queen. She was set to attend college, though she wasn't certain what direction to take there. She had a boyfriend but was worried he might want to leave her, while at the same time knowing her parents didn't approve of him.

At a rock festival with her boyfriend, she got lost and, trying to find him, had taken a fall and injured her arm. She was admitted to a local hospital for treatment and sent home from there. Several days later, in a state of perplexity she was brought to the psychiatric unit where I have inpatient beds.

Had she been traumatized or abused in some way? Had she been taking drugs and had a trip gone awry? Had her boyfriend left her? Her mental state was quite unstable, but despite having input from the many people involved in looking after someone in hospital I couldn't make a diagnosis I was happy with. Cora was not hearing voices, did not have delusional beliefs, and was not consistently depressed, elated, or anxious. But she was volatile. At times in the ensuing weeks, apparently improved, I gave her leave to go out with her parents, but she was typically brought back severely confused again—sometimes only minutes after having walked out through the hospital doors. At other times she was almost completely unresponsive and inaccessible. I could see no reason to give her an antidepressant or an antipsychotic. On occasion when she seemed particularly agitated I wrote her up for a minor tranquilizer—a benzodiazepine.

Finally after about six weeks she went on weekend leave with her parents, held steady on her own, and did not come back. I was happy to file her case as diagnosis unknown. I heard she was doing well at college and was still dating the same boyfriend.

I saw her again a year later—8 1/2 months pregnant. She was clearly too unwell to be managed at home. But where she had been mute and inaccessible previously, now she was overactive, manipulative, and attention-seeking while still seeming confused; her actions did not seem fully under her own control. She looked as though she might go into labor at any moment, so I held off medication.

After the birth, I sent her to a hospital that had a facility for new mothers and their babies. The psychiatric team that took over her care there, I learned, thought she had schizophrenia. She was put on regular antipsychotics but apparently was not making much progress and the baby was taken from her. Some months later, I heard she had been given weekend leave; one evening, having told her parents she was going out for a walk, she laid her neck on the track in the face of an oncoming express train.

Looking back at Cora's confusion, emotional lability, and switches between immobility and overactivity, I came to see that she had a textbook case of uncomplicated catatonia. Few readers of this book will know what catatonia is, as it has supposedly vanished, even though fifty years ago up to 15 percent of patients in asylums were estimated to suffer from it, and it was one of the most horrifying mental illnesses. While mental health professionals are aware catatonia is still listed in the
Diagnostic and Statistical Manual
, few would spot a case if faced with it.

If Cora had a rare condition that doctors do not now need to recognize, if she was the exception that proves the rule of medical progress, she would have been unfortunate. But in fact up to 10 percent of patients going through mental health units in the United States and indeed worldwide still have the features of catatonia—if these were looked for.
1
Sometimes the only condition they have is catatonia; other times catatonic features complicate another disorder and resolving the catatonia may make it easier to clear whatever other problem is present. But almost no one thinks of catatonia and so, like me, they miss the diagnosis. Cora was given antipsychotics, which are liable to make a catatonic syndrome worse. She died when a few days' of consistent treatment with a benzodiazepine would almost certainly have restored her to normal, making her death scandalous rather than accidental.

The benzodiazepines are a group of drugs that are no longer on patent, and thus no company has any incentive to help doctors see what might be in front of their eyes when it comes to a disease like catatonia. Instead, company exhortations are to attend to diseases for which on-patent drugs are designed, even if this means diseases conjured out of thin air—disease mongering—such as fibromyalgia to market on-patent medications such as Pfizer's Lyrica (pregabalin) or restless legs syndrome, a disorder conjured up as a target for GlaxoSmithKline's Requip (ropinirole).
2

No one has any idea how many versions of Cora's story play out in daily clinical practice, the opportunity cost of disease mongering. These deaths are lost in the chatter about disorders that match up with onpatent drugs, invisible to doctors pleased with themselves for making a fashionable diagnosis like fibromyalgia and who, even in the face of treatment failure, will add ever more on-patent drugs to a patient's treatment regimen rather than go back to the drawing board and look more closely at the patient in front of them. Once upon a time the height of medical art lay in being able to go back and look at cases afresh and match the profile of symptoms against less fashionable or apparently uncommon disorders—no longer.
3

But the outlines of an even more disturbing series of scandalous deaths have emerged from the pages of this book. Unlike catatonia, deaths in this case are from a disorder with no name. It is never recorded on death certificates as a cause of death even though we suspect that in hospital settings nearly two decades ago it was the fourth leading cause of death,
4
and reports to regulators of deaths from this cause increase annually.
5
It is almost certainly commoner now as drug prescriptions have escalated, and even commoner in community settings than in the hospital, but yet in an evidence-based medicine and guideline-driven era, there is no evidence base or guideline for its management.

If we are to cure this disease, we clearly need to name it. This is a disorder that was formerly sidelined as iatrogenic but if missing or corrupted data lie at the root of the problem, getting doctors to shoulder the blame—as iatrogenic suggests—no longer seems correct. A possible name is pharmakosis—a name that hints at some loss of insight.
6

Here is where the interplay between cure and care, outlined in earlier chapters, comes into clearest focus. The critical test of medical care lies in how a doctor or medical system deals with the possibility that the latest treatment might be responsible for part of a patient's current problems—that the poison may actually be poisoning. Rather than care, for over a century we have had a default option to regard cures as an excellent form of care. But here is a disorder to cure, which offers no choice between cure and care—they are one and the same.

Thalidomide is the drug disaster that is classically seen as inaugurating our modern medical era but retrospectively it looks more like a bookend for an older style of medicine than representative of the problems that drug treatments and pharmaceutical companies now pose. Most of us, whether doctors or patients, likely think we can link problems as obvious as those caused by thalidomide to treatments we might have taken. But we are not faced with such obvious problems any more. The difficulties in grappling with what happens when treatments go wrong now come instead from the mechanisms put in place to ensure thalidomide could not happen again—these include controlled trials, a prescription-only status for drug treatments, and efforts to restrict drug use to traditional medical diseases. The story of tolbutamide, whose development paralleled that of thalidomide, brings out far better the difficulties we now face.

WHEN TREATMENT GOES WRONG

The discovery of insulin in 1922 is one of the most celebrated breakthroughs in medicine. A disease that came with sweet-smelling and frequent urine had been recognized in antiquity and had been named diabetes. It was occasionally possible to manage the disorder, which we now know is caused by a lack of insulin leading to raised blood sugars, for a time in older people by restricting sugar intake, but sweetsmelling urine heralded the end for most people. In childhood, the disease was even more malignant; for juvenile-onset diabetes, the discovery of insulin was the difference between life and death.

After 1924, the availability of insulin meant that a growing number of people could survive for decades longer than had been possible before that. Still, as those treated aged, a series of complications of living with diabetes became clear. The blood vessels of the eye might deteriorate, leading to blindness. Damage to the blood vessels or nerves to the pelvis brought about impotence. The nerves or bloods vessels to the legs might be compromised, leading to ulcers, possibly gangrene, and potentially amputation. The risk of heart attacks and strokes was increased.

It seemed reasonable at the time to think that these problems in part stemmed from the mismatch between naturally and artificially controlled blood sugars and in part from the fact that the insulin initially used was bovine or porcine rather than human insulin. But whatever the cause of such problems, people were alive who wouldn't have been alive and while they were alive the problems could be worked on. Perhaps improved preparations of insulin would reduce the risk of complications.

In an effort to improve the care of patients with diabetes, researchers renewed their focus on blood sugars and discovered that these vary substantially during the day in everyone, but especially in patients with diabetes. Might a tight control of blood sugar variability improve outcomes? Controlling blood sugars requires gadgets to read sugar levels and a range of insulin preparations. It also requires close cooperation between the medical team delivering care and the patient with the disease.

The teamwork that grew up around monitoring the hazards of diabetes and its treatment during the 1940s and 1950s became a byword for good medical care. Giving injections of insulin sounds simple, but there is a technique to giving the treatment subcutaneously. You need to learn what the symptoms of an overdose might be—slightly too much insulin risks reducing blood sugars to the point where the taker becomes confused or slips into a coma. Strategies have to be worked out to manage this hazard. The effort to balance the risks that come from allowing blood sugar levels to ride at too high a level and the risks inherent in reducing them too aggressively has to be incorporated into lives that need to be lived. A workman doing heavy labor will have to juggle things in a different way than a ghostwriter working by computer from home. Some people need gadgets to check their blood sugar levels, others seem able to read their bodies.
7

Getting this right requires teamwork. The nurses of the diabetes team learn from Mr. X how he manages to slot the need for blood testing and injections into his schedule, while Ms. Y tells them of how she manages. They hear about how people juggle social situations, from business meals to outdoor activities with friends. And they pass these lessons on to new patients who have to be helped to handle the ramifications of a diabetes diagnosis at the right pace for them. If medical care is key to how well patients use the technologies available, and therefore how well they do, advance in technology is key to inching forward in treatment possibilities. Teamwork, in turn, helps make the best possible use of those new technologies—such as the new pills that were discovered in the 1950s that could, in tandem with insulin, better manage blood sugars.

While insulin mobilized all the best in medicine, it did not provide a good basis for business. Lilly attempted to wrest the American patent for insulin away from its discoverers—the University of Toronto—but failed.
8
But even had they succeeded, the commercial opportunities for an injection were limited, even though insulin was quickly used for all sorts of things other than just diabetes. The drug's appetite-increasing properties were put to use in rest cures aimed at “building people up” through a program of sleep and eating. In high doses insulin will induce a coma—the ultimate rest cure—and insulin-induced coma treatment was used to treat drug abuse and schizophrenia.
9
Despite all these uses, a pill would be far better for business than any injection because a much greater number of people have raised blood sugars (prediabetes) than have frank diabetes and this market would be easier to develop with a pill than with an injection.

The research that led to a pill that seemed promising stemmed from the first of modern medicine's magic bullets, the sulfanilamide antibiotics that were discovered in Germany just prior to the outbreak of World War II.
10
Building on these discoveries, French investigators soon developed a range of sulfa drugs, among which was one that lowered blood sugars. Despite the devastation of war, it was in fact a German company, Boehringer-Ingelheim, that in 1956 came up with the first oral blood-sugar-lowering drug (a hypoglycemic drug), carbutamide, and soon thereafter another—tolbutamide.

The Michigan-based Upjohn company bought the US rights for tolbutamide and began marketing it as Orinase in 1961. It effectively lowered blood sugar, but it turned out to be close to useless for the management of juvenile-onset diabetes. It would not replace insulin, then, but it might have a place in the treatment of patients who developed diabetes in their middle to older years who had been able to manage their condition by diet alone before they eventually graduated to insulin.

The availability of tolbutamide led to distinctions between type 1, or insulin-dependent diabetes, and type 2, or noninsulin-dependent diabetes. Where before there had been little emphasis on seeking out information on blood-sugar elevations, as few people wanted to know about diabetes until they had to, there was a new premium on detection. For people who had elevated levels of blood sugars but who were not overtly diabetic, dieting offered a means to help regulate their blood sugars, but this was hard work. Tolbutamide was an easier option. It even seemed possible that treating high blood sugars early might prevent people from developing diabetes. In addition, supplementing insulin with tolbutamide might minimize the requirement for insulin and offer better control of blood sugars, potentially reducing problems in the longer run.

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