Dopamine agonists (?particularly pramipexole) and compulsive gambling

When I first learned of a putative association between a particular medication ( pramipexole (Requip)) I was reminded of a defense in a bank holdup in which the attorney for the defendant argued that Halcion made the person rob the bank.

I am less skeptical after reading the report from Mayo clinic and the series of letters to the editor that followed. Dodd et al reported 11 patients with pathological gambling who were taking pramipexole for Parkinson Disease (PD). Other dopamine agonists and levodopa have also been implicated. Also other compulsive behaviors have been described.

The authors postulated that the apparent greater prevalence with this particular agonist may be due to its greater effect on the D3 dopamine receptors in the limbic cortex. However, one letter challenged the excess dopamine theory by relating one case of compulsive gambling in a PD patient who was treated with deep brain stimulation of the subthalamic nucleus.

The theory is that with increased dopaminergic stimulation there is increasing loss of impulse control. Supporting this association between dopamine agonist and gambling is the reported reversal of the condition by discontinuing the medication.

A pathologist with PD from Texas has filed a law suit against the manufacturer of the medication.

Does all of this raise philosophical questions about free will ? Can a medication really make some one carry out the complicated acts such as are required to take part in repeated gambling? I would be interested in hearing some thoughts about that.

NPR reports on investigation of possible mercy killing in New Orleans hospital after Katrina

NPR reported on the ongoing investigation of possible euthanasia at Memorial Hospital in New Orleans.

The report describes 4 eyewitnesses that testify about activites that suggest but do not prove patients on the 7th floor ( operated by the Lifecare Hospital) were given lethal doses of drugs after it was decided that the "critical" patients either could not or would not be evacuated. The 7th floor housed a long term facility not operated by the corporation who owned Memorial Hospital.

According to NPR, witnesses described hearing that the decision had been made that the DNR patients on 7 would not be evacuated or left alive after the other patients were evacuated.

Apparently there are no witness testifying that they saw anyone administer the medications.

The New Orleans coroner is quoted as saying the bodies were too decomposed to allow a definitive diagnosis of cause of death.

To date no charges have been filed.

Regardless of the final outcome of the investigation and legal actions that may be taken and what really happened , this is one more sad aspect of the tragic events of Katrina.

Knee osteoarthritis- glucosamine and chondroitin- we still don't know

Seldom are the results of a randomized controlled trial (RCT) so definitive that the issue is settled and and more questions are not raised. The GAIT trial is no exception.

Published in the February 23, 2006 issue of the NEJM this multi-center,placebo and celecoxib controlled trial found that glucosamine hydrocholride and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group..but the combo "may be effective" in the subgroup with moderate to severe knee pain.

"Hydrocholride" is in bold print because as the editorialist suggests, perhaps the"wrong" type of glucosamine was used. While one recent meta-analysis of 8 RCTs showed no difference from placebo when glucosamine hydrochloride was used, another meta-analysis of 7 RCTs which used a particular brand (Rotterpharm brand) of glucosamine sulfate showed significant symptom improvement and functional improvement versus placebo. On the face it appears to be another example of dueling meta-analysis but not if we consider different types of glucosamine. It is possible that the sulfate works better than the hydrocholride. Further, there are two trials that purport to show slowed radiographic progression from the sulfate preparation.

RCTs almost always are paired with an editorial that is replete with many "howevers", "Yes, buts" and "on the other hands" and typically a plea for more data collection. Yet, when the desired data is published there is usually another round of "howevers". There is a reason for that;RCTs often do not settle the issue.

Often , the best we can squeeze out of a RCT is a tentative general "Game plan", subject to future modification or even refutation. Here as the editorial suggested it may be:

If the patient wants to try a nutrional supplement, he should go with glucosamine sulfate plus chondroitin sulfate for about 3 months and if no better discontinue them.

Clinical trials are not rocket science. At its best rocket science deals with deterministic, differential equations that tell us with impressive precision where the rocket will hit absent the ambiguity, uncertainty, seemingly uncontrollable biological variability and the problems that arise from placing too much confidence in our statistical techniques to control for or "quantitate" the uncertainty that are intrinsic to clinical trials.

Flexible sigmoidoscopy (flex sig) -Is it being phased out?

Flex sig seems to be going the way of the doctor visit when enough time was available to discuss things in depth with the patient. With flex sig, however, time does not seem to be the issue.Money is part of it (low reimbursement may barely cover costs) as it the popularity of colonoscopy for cancer screening.

The February 17, 2006 issue of Medical Economics reports the following all of which speaks to the decline of sigmoidoscopy:

1.About 25 % of internists provided flex sig versus the 1986 figure of 75%.
2.A recent AAFP survey reported that about only 25 % of FPs preform the procedure.
3.Both ACP and AAFP no longer teach the procedure at their annual meetings.
4.Dr.Patrick Alguire,director of education at ACP,is quoted as saying that flex sig is now offered only as a elective in IM residency programs.

Colonoscopy got a big boost when Medicare added screening colonoscopy to its approved procedure list and GI docs had to be pleased with the publicity of Katie Couric's on air colonoscopy.

I used to tell patients if they wanted to have their colon examined for early cancer or polyps they needed to get their entire colon examined and I believed offering them a flex sig in place of a colonoscopy ran the risk of giving them a sense of false security not to mention the malpractice issue.

Estrogen only arm of WHI:Maybe estrogen does not increase heart risk

The Women's Health Initiative (WHI) has had a major impact on the use of hormone replacement therapy (HCT) for post-menopausal women. The latest and final analysis of the effect of conjugated equine estrogen (CEE) alone on cardiovascular events in women who had a hysterectomy is found in a recent issue of the Archives of Internal Medicine (subscription required for full text).

Overall, no increase in CV risk and in one age subgroup, the suggestion of an apparent benefit was found.

The study began in 1993 and 10,739 women were randomized to placebo or 0.625 conjugated equine estrogen daily.The follow up was 6.8 years. In the group who were 50-59 years of age at entry into the study the hazard ratio for coronary artery disease events was 0.63 ( C.I.-0.36 to 1.08) while the hazard ratio for revascularization was statistically significantly reduced with a hazard ratio of 0.55 ( C.I.- 0.35 to 0,86).

These results differ from the WHI estrogen plus progestin arm in which an increase in cardiovascular events was demonstrated (7 more events per 10,000 patients per year as well as 8 more strokes).

Why the difference? The simple or perhaps simplistic answer is maybe the progestin is the culprit.The study's authors tended to favor that explanation as their statistical analyses seemed to make baseline risk factor differences and differential statin use not likely to account for the difference between CEE alone and CEE plus a progestin.

I doubt we will see large scale recommendations for estrogen to prevent heart disease, but at least women who are post-menopausal and who are taking estrogen may be somewhat less concerned about their HRT increasing their heart attack risk.

Women's Health Initiative Study may demonstrate that vitamin D and calcium work only if you take it

A recent NEJM article will get wide press coverage as it will allegedly be shocking. The Women's Health Study strikes again, this time seemingly crushing the hopes of those women who take vitamin D and calcium with the expectation that they decrease the risk of osteoporosis.

I think the study demonstrated that vitamin D and calcium in the dose intended only decreased the risk of fractures in those women who actually took the medication.

The authors understate this by saying "It is also plausible that there was benefit only among those women who adhered to the study treatment."

In support of this radical theory,they report a statistically significant 29% decrease in hip fracture risk among adherent participants. Only 59 % of participants took the intended dose by the end of the study.

Another significant issue is that the 400 units of vitamin D may not be enough.The authors quote references that support that claim.

Another issue was the reported increase in kidney stones in the treatment group with a hazard ratio of 1.17 in the treatment group. So few participants actually took the medication as intended, and with such a slight increase in risk measurements it is hard to know what this means and the authors did not discuss this finding in any detail.

It has not been a good month of the WHI results-wise. One study showed that reduction of total dietary fat did not decrease risk of heart attack. Cardiologists,for some time now,have not recommended to decrease total fat but rather saturated and transfat. And now a major, expensive,randomized trial seems to show Vitamin D and calcium only decreases fracture risk if you actually take the pills.

It is currently trendy for folks in the medical policy arena to talk about value as defined by the ratio to quality to cost. Ignoring for the moment the monumental problems of measuring quality, if you consider this study enrolled 36,282 participants and the NEJM needed 9 printed lines to list the authors and only arguably demonstrated that medicine only works if you actually take it, you have to wonder about the value of that effort.

How low can a relative risk be and still mean anything?

A death blow or near death blow to the use of Vitamin E in the prevention of whatever it was supposed to prevent was dealt by an article that claimed Vitamin E increased the risk of death. The relative risk reported in that meta-analysis by Miller et al was 1.01.

Should a relative risk (RR) that tiny convince anyone of anything? What value should a RR be to have clout or significant evidentiary value?

That question was posed by the EBM folks at McMaster to a venerable guru of epidemiology, Sir Richard Doll ( see pg. 162 of the book, "Evidence Based Medicine", Sackett, D L et al, , second ed. Churchhill Livingstone Press, 2000). His reply was cautious. He is quoted as saying " It's almost impossible to set a level of risk which is so high that the findings in a well-conducted epidemiological study would necessarily exclude confounding." He continued saying that if the RR were 20 that would be almost sufficient to indicate causality.

Sackett and co workers went on to indicate that a RR of greater than 3 was "convincing".

A relative risk of greater than 2 is being used by courts to reach the threshold of more likely than not which is current level of proof in most tort cases.( I do not know what RR would be needed to reach the level of "clear and convincing evidence".) Weak associations, ie RRs barely above 1, are more likely to be explained by undetected biases.

We are bombarded by articles that report relative risks between 1 and 2 and some of these , such as the Vitamin E meta-analysis seem to be a tipping point in the discussion about a given medical intervention. Before medical students get too carried away by articles such as the Vit E meta-analysis they should take a moment or two to read the letters to the editor that meta-analysis almost always seem to generate. (When I read these it is not that I understand the often obscure arguments raised but that there is so much disagreement among the experts about how to analyze and interpret the data.) When they see how often and often how vehemently the statistical experts disagree, they will be less influenced by the latest meta-analysis headline of the day.

The two gaps between evidence and clinical practice

Dr. M.R. Tonelli in his 2001 article entitled " The Limits of Evidence Based Medicine" speaks of two gaps or two aspects of one gap between what is referred to by the body of evidence based medicine as "empirical" evidence and the clinical practice of medicine.

The EMB spokesmen acknowledge one gap, the gap requiring considerations of the patient and the professional values.

The second gap exists due to the fact that the evidence is not directly applicable to the individual patient.The data do not "directly answer the primary clinical question of what is best for the patient at hand."

That atorvastatin might in a clinical trial reduce the risk of stroke over a given period of observation by half does not mean Mr.Jones should necessarily take atorvastatin even if his clinical profile as defined by the relatively few parameters which characterized the study group seem to fit fairly closely with his.

The observations from that trial, for example, are only one of several imputs that should be considered in a clinical decision. Tonelli lists the following;

"empirical evidence,experiential evidence, physiologic principles, patient and professional values, and system features. The relative weight given to each of these areas is not predetermined, but varies from case to case "

He does not believe that empirical evidence (which is basically various types of clinical research) should automatically or necessarily supersede clinical experience and physiologic rationale.

Tonelli asserts that EBM has made a conceptual error by grouping knowledge that we derive from clinical experience and pathophysiologic reasoning under the heading of "evidence" and to make matters worse we developed a hierarchy that assigned those forms of knowledge to the bottom tier. Those forms of knowledge differ in kind from empirical data and should be used as complementary to empirical knowledge and are part of the tool set we need to use to bridge the gap.

Since I grew up in a medical era during which pathophysiologic reasoning was emphasized, I am sympathetic to the author's view but I am still processing what he said and my mental jury is still deliberating. The broad definition of EBM is to integrate the best available evidence with clinical expertise and patient values and I think clinical experience and physiologic rational could come to play in the "clinical expertise" category.

However,in the one version of the EBM bible (Evidence -Based Medicine,second edition, by Sackett et al,2000) we find a table of "level of evidence" in which the lowest level is " expert opinion ...based on physiology,bench research or first principles." This quote from scripture tends to support Tonelli's characterization of EBM hierarchy as denigrating physiologic reasoning and not my ad hoc attempt to salvage it under the heading of clinical expertise thus ending my short lived attempt to consider his thoughts as a straw man argument.

Annual "physical exam" as "touchstone for contextualized care"

The Feb. 13,2006 issue of the Archives of Internal Medicine published a letter to the editor which I will reference here to echo the thoughts expressed.

Dr. Christine A. Sinsky writes that she structures her practice around the annual examination. Regarding it she says:

"I structure my entire practice around the annual examination. It is when I address prevention, coach patients on healthy life-styles, and do the annual review of each chronic medical condition. Invariably, patients bring new symptoms for evaluation as well. It is a complex visit, focused on integrated, longitudinal care."

That is also, to a large degree, what I did. Replacing the annual exam with a series of admonitions of what to be screened for is to reduce the patient to an abstraction of eligibilities for various organizations's recommendations for screening rather personally dealing than the individual human being they are with their set of unique feelings,worries, concerns, and questions about their own health and what they should or should not do in regard to some perceived or real health issue.

Of course, one can deconstruct the examination and conclude such things as "listening to the heart is not cost effective" but placing the stethoscope to a person's chest is a "chance to touch" the patient and has value above and beyond the occasional discovery of a significant murmur. It is part of touching and hopefully connecting with a patient.

Her letter was in response to a recent editorial in the Archives that suggested that both patients and physicians support and value the annual examination. Some of the criticism of the annual exam may be from its name. The way Dr. Sinsky ( and I) performed it, it was much more than a exam, the mechanics of which took up a fairly small part of the time for the visit. Most of the time spent was talking.First, on whatever the patient wanted and secondly about what I wanted to impart to the patient regarding her current issue or whatever screening or preventive issues were pertinent to her particular situation. It is a time for assessment of issues, for giving advice, for expressing interest and concern about the patient, it is much more than what happens on a boy scout camp physical.

Was the WHI fat reduction trial asking the wrong question?

The Feb 8,2006 issue of JAMA published the results of a trial that will make headline news and reinforce the beliefs of some folks that the medical profession and research scientists still do not know what to tell people to eat or not eat.

The Women's Health Initiative Randomized Controlled Dietary Modification Trial consisted on over 48 thousand women aged 50-79 who were randomly assigned to a control or intervention group, the later of which was to reduced total fat intake to 20% of calories and increase the veggie-fruit servings to six/day.

The results: The intervention had had no effect on the risk of coronary disease,stroke or total cardiovascular disease.

Let the spinning begin. As the accompanying JAMA editorial asks "Why were there a null finding ?"

Here are some possible reasons:

1)The study did not follow the participants long enough (the follow up was 8.1 years, 2) both groups were fairly healthy and therefore it would be harder to show a difference. 3) there was not really that much difference in the fat intake between the two groups 4) the degree of fat reduction in the treatment arm was not sufficient to expect much of a difference. 5) The intervention was reduction in total fat not necessary in saturated and trans fats.

I believe number 5 is key. The WHI study was basically testing a hypothesis that by the time of publication was clearly outdated. The current party line is reduce saturated fat and trans fat to reduce heart disease risk and monounsaturated fat may actually be good for you.

This is major factor of life in these mega multiyear trials,the hypothesis of several years ago is often not even an issue by the time such a trial is underway less alone completed. Medical knowledge (or theory) grows much faster than we will even keep pace with randomized trials.

I have been advising patients for years that the issue is not to decrease total fat in an effort to decrease heart attack risk. I can now use this giant trial to illustrate how that ( the total fat reduction approach which no one really believe now anyway) does not seem to work.

Do we know how to give antibiotics?

There are several current and politically correct maxims regarding antibiotic use which include:

1.We must reduce the use of antibiotics for several categories of respiratory tract infections ( e.g. sinusitis and acute bronchitis) which will mitigate the rising tide of resistant organisms
2.It is more cost effective and therefore of course better to use less expensive antibiotics first and save the more expensive ones for more serious infections.
3.It is imperative that we take steps to decrease bacterial antibiotic resistance
and somewhat strangely
4.Resistance does not seem to matter in regard to clinical outcomes. (This perhaps has not risen to maxim level but there is evidence to that point)

In the premiere issue of Chest Physician, the new publication of the American College of Chest Physicians (subscription required) the Pulmonary Perspective section has some interesting thoughts.Let me preface with a caveat, the two authors are employed by Oscient Pharmaceuticals , which fortunately or unfortunately because of recent events may make the reader more skeptical than in the good old days.

The authors quote some interesting data ( Price et al, Respir Med 2004: 9817) from Great Britain regarding efforts there to decrease the use of antibiotics in respiratory infections. The bottom line is there was a 50 % increase in mortality from the beginning to the end of the two times periods studied concomitant with a 30% reduction in antibiotic use. The effect of the incidence of influenza was controlled for statistically. Association does not equal causality and this is a very broad brush analysis wherein lies many ways to reach the wrong conclusion. Still it is thought provoking . Was the unintended consequence of "educating" physicians not to use antibiotics responsible for an increased number of pneumonia death? Were folks considered to have viral bronchitis given the history of green phelgm who really had pneumonia and were not treated.Well, with this type of study we will never know.

The authors comment that simply cutting back on antibiotics may not be the right solution to mitigating microbial resistance. The WHO supports the authors ' suggestion to " hit hard and hit quickly" or more professionally put "use the most pharmacologically potent member of the relevant class of antibiotics for a short period to decrease the chance of developing resistance".

Is the key to managing what does appear to be a growing problem of drug resistance giving less antibiotics or it is giving the appropriate antibiotic in the correct dose? The problem is, of course, we are still working on the issues of what is appropriate and how long should we give antibiotics.

Medical Economics article:the demise of the doctors' lounge

The Feb 03, 2006 issue of Medical Economics has a interesting discussion of why the tradition of the doctors lounge is dying out. This seems to be something else we can blame managed care for.The authors cite managed care and the rise of the hospitalists as causes. I would spin it this way: the hospitalist movement is in no small measure also a indirect result of managed care.

How does that work? With managed care driven reimbursement decrements it economically behooved primary care docs to see more patients in the office as the pay per patient- encounter decreased.The hospitalist-according to Dr. Wackter-sprang up because their presence allowed the primary care docs to see more office patients by not having to round at the hospital.

Dr. Robert Wachter's version of how hospitalists appeared on the scene is found here and it will likely be the historical orthodoxy. Further, the days of the doctors' lounge being the primary site for networking and consulting each other are largely gone as the physicians that other docs refer to is largely determined by what plan the patient has.

This ties in with an earlier blog I wrote that discussed the observation that not only has managed care driven a wedge between doctor and patients but it has also did the same thing between physicians leading to a gradual withering away of the collegiality that in the best of times existed in the medical profession. I think the demise of the doctors lounge is symbolic of all of that.

The local internal medicine society that I have belonged to for over 25 years once had 75 or more in attendance at our monthly meetings,now has maybe 20 on a good night and usually the older and retired docs are in the majority.The younger internists who in part came to the meetings to become known and make important networking links see no need to do so now. It is basically attended by a few academic internists who are in the med center anyway at that time of day and the retired docs who don't have anything else to do. I believe the demise of this professional organization is probably another victim of managed care.

Does running keep your mind young ?Or do the sharp old folks continue to exercise ?

Observational studies have demonstrated that exercise delays (prevents) dementia to at least some degree. We will all run more confidently on the road to dementia free old age when there are randomized clinical trials that show what the observational data suggest. ( In the interest of complete disclosure I am a marathon runner and only a recalcitrant biceps tendonitis ( the biceps in the leg) kept me from running my 29 Houston marathon in a row in January.

A recent issue of the Annals of Internal Medicine has the latest data . A discussion of this and similar articles must include comments about the concept of "reverse causation". We observed those old folks ( now known as seniors) who exercised regularly had a lower attack rate of dementia. There have been similar studies showing that those folks who are more socially engaged, or more active in mental activities (cards, games,cross word puzzles etc) seem less likely to develop dementias.One explanation could be that something about the early phases of dementia may cloud their judgment or confidence or some combination of cognitive impairment may appear so that they withdraw from of all manner of activities including regular exercise.

Still, those of us who are obsessed exercisers like to think our plodding along generates or releases some sort of hormones or cytokines or something that is neuroprotective.