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Category Archives: Opinion/Editorial

Kalydeco: Science at Its Best

February 1, 2012 Dr. Pullen

I read with a personal interest the approval of Kalydeco (ivacaftor) this week for treatment of the 4% of cystic fibrosis patients carrying the G551D mutation. My first wife Lenore had cystic fibrosis and died at age 26. At that time in 1983 we knew a great deal less about CF than we know now. The introduction of Kalydeco this week brings several key issues in health care to the forefront. Development of drugs to treat disorders with a limited number of patients to use the drug can make the cost to each individual seem crazy expensive. The specific direct targeting of Kalydeco at a specific gene mutation is possibly an indicator of personalized treatments for more common disorders in the future. The whole fast-track process used by the FDA in approval of Kalydeco is an example of their faster approval of some drugs working as promised.

In the years since Lenore’s death CF has been found to be caused by a mutation in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene that regulates ion transportation (ions like chloride hence the traditional sweat chloride test for CF) and therefore fluid flow within cells. One specific mutation is the G551D mutation (substitution of aspartic acid for glygine at position 551), and the new drug Kalydeco specifically targets the abnormal protein in these specific CF patients. Kalydeco helps the defective protein work more normally, and so reduces the abnormalities in CF patients with this specific mutation.

Unfortunately only about 1 in 25 CF patients have this specific mutation in the CFTR genetic code. The rest have some combination of the other at least 1000 known mutations. The most common CFTR mutation is called F508del (a 3 nucleotide deletion at location 508 leading to a missing phenylalanine amino acid “F”) and about 1 in 30 Caucasians have this specific mutation in the CFTR gene. Kalydeco is not effective in patients who are homozygous for the F508del mutation. This homozygous F508del mutation is the most common genetic code in CF patients. IN the 4% of CF patients with at least one copy of the G551D mutation Kalydeco has been shown to be effective in reducing CF symptoms, and is an exciting breakthrough.

Patients with the G155D mutation produce a protein that is able to make it to the cell membrane, where Kalydeco allows it to function much more normally. In patients with the F508del mutation the protein fails to fold in a way that allows it to move to the cell membrane, and so a drug like Kalydeco cannot function. Scientists are working on possible medications that could allow the migration of the other defective genes to the cell membrane where use in combination with Kalydeco could potentially be effective.

It is exciting not just for the 1200 U.S. patients with this specific type of CF, but also because it is an example of how genetic research, gene analysis in genetic disorders, and great basic science can lead to novel therapy for genetic disorders.

The rapid approval of Kalydeco is a great example of the new expedited FDA approval process for drugs that have the potential to be novel or breakthrough products where there is currently no effective therapy, or the drug is a major advance in therapy. It took only 3 months for Kalydeco to get FDA approval, even faster than the promised fast-track approval promised for special circumstance drugs.

The catch in this whole process is the incredible anticipated cost of Kalydeco. In a Wall Street Journal article the estimated annual cost of Kalydeco is reported to be $294,000. Since the anticipated number of patients eligible to receive this orphan drug is so small, and because of the novel and documented improvements demonstrated in patients using Kalydeco it is expected that insurers will pay for the cost of the medication. If all 1200 eligible patients take Kalydeco the annual cost at this price would be $353 million annually. Still this price is not Guinness world record. Two more expensive drugs are Soliris for a rare condition parosysmal nocturnal hemoglobinuria at $409K annually and Elaprase for the rare genetic disorder Hunter Syndrome , a polysaccharide storage disorder, at $375K annually. These are examples of orphan drugs with very limited markets where the cost of development is shared by very few patients.

I look forward to seeing more examples of genetic research leading to personalized medications for individuals.

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Risks of Defensive Medicine

January 25, 2012 Dr. Pullen

There has been a lot of criticism of defensive medicine as a major contributor to the rapidly rising high cost of medical care in the United States. Although the real financial cost of defensive medicine is one issue, it is not the only problem with defensive medicine. Defensive medicine also has the risks of incidental findings on tests that are unnecessarily ordered, the risks patients encounter due to evaluation and treatment of these findings, and overdiagnosis.

Screening for prostate cancer has been all over the news recently, with the USPSTF proposed recommendation against routine PSA screening, and is a classic example of the risks of screening tests. The strongest argument against PSA screening is overdiagnosis and exposure of men to invasive prostate biopsies, and potentially dangerous therapy for prostate cancers that will never become clinically significant in some unknown but likely high percentage of cases. One of the primary reasons I don’t anticipate a dramatic reduction in PSA testing in primary care is because it is perceived by physicians that they are much less likely to be sued for complications of care caused by overdiagnosis of prostate cancer than if a patient is diagnosed with advanced prostate cancer and who has not been offered PSA screening. I suspect at least some physicians are going to be afraid to do the right thing even if they are convinced that the evidence supports not doing PSA screening.

Far less emotional and dramatic are consequences of defensive medicine precipitated by the ordering of imaging tests. It is commonplace for a physician to order an MRI of a patient’s knee early in the course of management of a knee injury. In an NEJM study of randomly chosen men without a complaint of knee pain the incidence of finding a meniscus tear on knee MRI was 31%. A finding of adrenal masses on abdominal CT scan is very common. In one study the incidence of an adrenal mass finding on abdominal CT in patients without a known malignancy was 5%. In this same study of 973 consecutive patients of the 973 zero were found to be malignant. This is exactly my experience, i.e. I’ve never had one of these turn out to be a cancer. Yet once an adrenal mass is found it is almost always recommended as a part of the radiologists report to have it reevaluated at least one, often twice or more to assure “stability.” It is unusual for a primary care physician not to order these follow up tests, more defensive medicine. The risk of radiation exposure from abdominal CT scanning is not insignificant.

Treatment of sore throat, acute short-duration sinusitis, otitis media and acute bronchitis with antibiotics is very common. It may be defensive medicine or just taking the path of least resistance, but there are very real risks of antibiotic therapy and almost all the evidence and expert opinion argues against the use of antibiotics in these conditions. With the increasing incidence of Clostridium difficiele infections, and increasingly virulent and antibiotic resistant C. diff as well as the other risks of side effects of specific antibiotics their use is far from risk free.

Nearly every new highly sensitive imaging technique is also very good at finding incidental variations of normal and abnormalities for which radiologists are reluctant to recommend no further evaluation, This is defensive medicine on the part of radiologists, as well as good business on their part in our fee-for-service environment. What business person of sound mind is going to put themselves at legal risk and at the same time recommend against a test that is in their financial interest. The risk to patients is more than just the risk of further radiation. Often the tests also lead to invasive tests or treatments, all of which have their own risks.

Many blood tests have the same risks, including tests like CA-125 for ovarian cancer, of course PSA, but also things as simple as a CBC. A CBC with a low white blood cell count is usually either normal or the result of a recent viral illness. Still it usually leads to a follow up test to assure a return to normal. If it persists low it may lead to referral to a hematologist who often orders a bone marrow evaluation. These are not only moderately painful but can have uncommon serious complications.

Essentially every test or procedure we do entails some risk. Ordering tests for defensive medicine reasons when the chances of finding clinically important and helpful results is fairly low makes the chances of finding false positives or overdiagnosis and leading to complications that would never have happened if the testing had not been done relatively higher. The cost of defensive medicine is not just in dollars.

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Latisse: Are Longer Lashes Worth the Cost and Risks?

January 13, 2012 Dr. Pullen

I find the most interesting thing about Latisse® is how it came to be used for growing longer thicker eyelashes. Latisse follows a familiar story like other hair growth products in that it was an incidentally discovered side effect/benefit of the active ingredient in Latisse® while it was being used for another indication. Latisse® got its FDA approval in December 2008, and was brought to market after discovering that the active ingredient in Latisse® called bimatoprost which was used as an eye drop for glaucoma was incidentally noted to lead to longer thicker eyelashes. This quickly led to a medical diagnosis in order to give an indication for a new drug. The medical term, or if you prefer medical diagnosis, for shorter or thinner than desired eyelashes is hypotrichosis of the eyelashes. Latisse® follows the list of other drugs which were incidentally noted to cause hair growth, Rogaine makes use of minoxidil, a seldom used oral medication for refractory hypertension that was noted to cause undesired hair growth when taken orally. Propecia uses the active ingredient finasteride (brand name Proscar®), which is used to shrink the size of the prostate and allow men with benign prostatic hypertrophy to urinate more easily. It was found later slow male pattern baldness hair loss and is now commonly used for that purpose.

The exact mechanism of action of Latisse is not clearly understood but it appears to be a prostaglandin receptor binder . Prostaglandin receptors are present in here and is thought that prostaglandin receptors are somehow involved in the development and regrowth of hair follicles.

Latisse® is a prescription only product that is designed to be applied once daily to the base of the upper eyelashes with a single use a sterile applicator. Despite the intention to make Latisse® prescription only, much like other drugs for which patients might wish to use but don’t want to get a prescription to see a physician about Latisse® is widely available online without direct physician supervision. This is unfortunate because the teeth can have very annoying and potentially permanent side effects. These include a plum shade discoloration of the eyelid, macular edema which can be very serious even lead to blindness, a condition called punctate epithelial keratitis which can lead to significant itching and irritation of the eyes, as well as dry eye, eyelid swelling and injection of the conjunctival blood vessels making the eye seem reddish or pink. In addition though not mentioned in the product insert there are reports of Latisse® leading to darkening of the iris.

Although Latisse is a prescription only product it’s very easy to purchase this drug online without a prescription. The top of the Google search list for pilot case online is a site where you simply submit a medical form history and a “patient marks licensed physician will carefully ensure Latisse is a safe option free you to use before we send your order.” They even advertise a discount for Valentine’s Day few by two more bottles. The retail price@drugstore.com for one bottle for peace is $115.99, but several online sources appear to be selling Latisse for between $70 and $85 per bottle. A bottle will last one month if applied as directed to both upper lids and even the manufacturer notes that Latisse only works as long as you continue to use it. Whether longer thicker eyelashes are worth approximately hundred dollars a month plus the risk of serious side disorders that could even affect vision and cosmetic or annoying eyelid problems is for each individual to decide.

Resource: Latisse side effects

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HPV Vaccine for Boys Now Recommended

January 5, 2012 Dr. Pullen

HPV vaccine for boys age 11-12 is now recommended by the Advisory Committee on Immunization Practices according to an MMWR report last month. They specifically recommend the use of Gardasil, the quadrivalent HPV vaccine that targets the HPV strains that cause cancers as well as the strains that cause genital warts. They also recommended the vaccine for use in males age 13 through 21 who have not been previously vaccinated and suggested that males age 22 through 26 may be vaccinated. This is a significant departure from the prior recommendation guidance that the HPV vaccine may be given to it males age 9 through 26 but fell short of recommending its use in this population.

There are several interesting things about this recommendation. First the quadrivalent Gardasil vaccine is chosen over the alternative bivalent vaccine (Cervarix). The obvious reason for this is because the quadrivalent vaccine gives immunity against the type 6 and 11 HPV that cause up to 90% of genital warts. As a family physician and a parent of a male child this alone would be enough reason for me to immunize my son against HPV. Despite this significant benefit of the vaccine, most of the data considered in this decision-making was based on risk reduction of the more serious consequences of HPV 16 and 18 infection. These can include anal intraepithelial neoplasia, various epithelial head and neck cancers, and penile cancer.

The MMWR article discusses the burden of cancer disease in males related to HPV infection. The article states that of the approximately 22,000 HPV 16 and 18 associated cancers in the US each year approximately 7000 are in males. Many of these are oropharyngeal and anal cancers. The incidence of new cases of genital warts each year in the US among sexually active males is estimated at a quarter million.

The MMWR article also addresses the efficacy of the quadrivalent vaccine in inducing adequate immunity. The efficacy in inducing antibodies against all four strains of genital warts was almost 90% in one large study. The reduction in the incidence of genital developing warts in the population who received at least one dose of vaccine was estimated at 68%. A subset of men in this study group who were immunized who have sex with other men was looked at separately. Their risk for developing anal epithelial neoplasia related to HPV 6 and 11 was reduced by approximately 50%. It seems reasonable to assume that the incidence of straight men getting this immunization will be less likely to carry the HPV 16-18 strains and put their female partners at risk for cervical dysplasia and cervical cancer.

Safety of HPV Vaccine for Boys: The safety data for the HPV for vaccine is very strong. The most common adverse events were mild or at most moderate, and were usually injection site swelling, with many fewer cases of headache and fever. Approximately 40,000,000 doses of HPC for vaccine have been used the United States in the first five years since licensure and no increase in incidence of any serious consequences have been noted. Don’t believe the ranting of fanatics who badmouth this along with many other safe and effective vaccines. Fainting after getting the shot seems to be the most serious adverse outcome and doesn’t seem to be any higher than with any other shot.

Cost of HPV Vaccine for Boys: At approximately $130./ dose, and $390./ 3 shot series, this is a real concern. Probably the strongest argument against routine HPV for vaccine of males is its cost. Any discussion of the benefits of immunization of males depends greatly on the incidence of immunizations of females. The rate of immunization of females in the US remains much lower than ideal with an estimated 47% of females age 13 through 17 having received at least one dose and only 32% having received all three doses. If a very high percent of females was immunized the risk of males who have female sexual partners acquiring genital warts would be considerably lower. Given the high current prevalence of the HPV virus it seems reasonable to assume that for some time now heterosexual young men will continue to have a significant chance of acquiring HPV virus. The estimates of the cost of per quality adjusted your of life in men vary from $20,000 to under $50,000 based on varying assumptions but unquestionably the cost of HPV vaccination of young men routinely is going to be high.

Why Give HPV Vaccine for Boys So Young?: Parents may ask why immunize my 11-12-year-old boy who I’m quite certain is ingrained have sex for many years. The answer is several fold. The first is that the highest efficacy for prevention of genital warts is in pre-sexual persons. The second is that children immunized between ages nine and 15 had higher antibody titers and therefore presumably better immunity than those vaccinated from age 16 through 26. The bottom line is that boys vaccinated prior to first sexual contact and purred age 15 have the best chance of immunity to genital warts and avoiding contracting them.

So what should you do for your boy? My recommendation is that you get your son immunized a relatively young age, certainly before age 15 but ideally with his pre-sixth-grade immunizations around age 12. Why so early? Why not is really the better question. The immunity seems to be long-lasting and getting the vaccine for your child while you still have considerable influence over their receiving the vaccine, while you’re still confident that their pre-sexual, and while they’re in the routine of getting other immunizations just seems to make the most sense to me. So is HPV for boys a good choice? My recommendation: A strong yes.

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Zohydro: The Next Oxycodone is On the Way

January 3, 2012 Dr. Pullen

A single ingredient sustained release hydrocodone product to be called Zohydro is currently in phase 3 clinical trials by Zogenix, and if it gets FDA approval is likely to become the next Oxydontin as a drug of abuse and addiction potential. I watched a segment on the evening news this week about Zohydro, and it is certainly not going to come to market without fanfare. Experts on the newscast did a pretty fair job of outlining the concerns of Zohydro, the potential for abuse and the issues with high dose single ingredient opioid products. Opioid overdose is much more likely with drugs where a very high dose of the drug is contained in a single pill.

Oxycontin has a reputation as probably the most abused of the prescription opioids because of its lack of acetaminophen, its high percentage of rapid release oxycodone, and its lack of properties preventing crushing the pills which eliminates the extended release properties and makes it possible to inhale, inject or smoke the drug. Sometimes known as Hillbilly Heroin, Oxycontin is among the leading causes of prescription drug overdose deaths and opioid addiction in the U.S.

If Zohydro receives FDA approval as a single ingredient, high dose hydrocodone product there is little doubt that it will join Oxycontin as a major drug of abuse. Proponents of non-acetaminophen opioid pain medications are correct when they state that acetaminophen has its own problems, and especially when too many pain pills are taken to get pain relief the daily acetaminophen dosage can exceed the 4000 mg / day maximum safe dose. Serious and even fatal acetaminophen liver damage can result. Still single ingredient opioid products are so prone to diversion, addiction, and abuse that I anticipate that Zohydro, if approved, will quickly become a major drug of abuse.

One thing physicians have on our side now is the Oxycontin experience. We will be much more skeptical of allowing escalating Zohydro doseage and addiction become commonplace. Still I am not looking forward to one more drug with few advantages and much abuse potential coming to market.

Oxycontin is available in doses of 10, 15, 20,30, 40, 60 and 80 mg tablets. Using the recommended opioid Morphine Equivalent Dosage calculator available for download at the Agency Medical Directors site, 30 mg of morphine is equivalent to 30 mg of hydrocodone but to only 20 mg of oxycodone (i.e. oxycodone is 1.5 x as potent on a mg for mg basis than hydrocodone). Using these equivalency ratios it would be expected that Zohydro might become available in doses up to 120 mg per pill. This would make it highly popular as a drug of abuse, as current hydrocodone products all contain acetaminophen, and maximum hydrocodone dosing even with products with 10 mg hydrocodone and 325 mg acetaminophen are 12 tablets daily, making 120 mg of hydrocodone the maximum daily hydrocodone dosage.

For related articles see:

Oxycontin vs. Oxycodone

How to Spot a Drug Seeking Patient

Oxycontin: What’s The Big Deal

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How Safe is Oral Sex?

December 12, 2011 Dr. Pullen

Bill Clinton didn’t consider it sex. Lots of teens today consider oral sex a safe alternative to intercourse. Headlines like on ABC news in 2009 cry out, “Oral Sex is the New Goodnight Kiss.” Data suggests that oral sex is becoming more common practice in teens than vaginal intercourse, a major change from a generation ago. In 2002 up to 24% of males and 22% of females teens who had never had vaginal intercourse reported having had oral sex with an opposite sex partner (1). In addition gay men want the real truth, is oral sex a safe alternative to more risky behaviors? The answers seem to all be relative. There are few absolutes in life, but one of the truths is that the only way to completely avoid risk of an STD is to avoid any type of sex. That said, how safe, or alternatively how dangerous, is oral sex?

Let’s look at the evidence for transmission of the various STDs by oral-genital contact.

HIV: Human Immunodeficiency Virus, the cause of AIDS, is the STD many fear most. It can be transmitted when a body fluid containing the virus gains access to another person’s mucous membranes or bloodstream. Unquestionably HIV is transmitted by anal and vaginal intercourse. There are at least a few cases where it is believed that the HIV virus was transmitted to the receptive partner after oral sex with ejaculation. Oral sex without ejaculation into the mouth is theoretically possible, but is felt to be extraordinarily unlikely. The risk of contracting HIV from a single incidence of anal intercourse with with ejaculation and no condom use with an HIV infected male has been estimated at 1:100. Extensive study has been done in trying to find out what the incidence of contracting HIV from oral sex with ejaculation with an HIV infected male, but these studies all have confounding variables. The real problem is that all of these studies have been in gay male populations, and a low percentage of the men had only oral sex. On second and subsequent interviews many times the history changed, and made other routes of transmission more likely. In one study it was estimated that there were zero cases of conversion in a population after over 35,000 incidences of oral sex. All said, although it is possible to contact HIV from oral sex, the chances are very low. Low enough that if oral sex is a behavior that replaces anal intercourse in gay men the benefit of avoiding the high risk behavior likely greatly outweighs the risks of oral sex in this situation.

Herpes Simplex: This may be the most common STD transmitted by oral sex. Up to 70% of teens are estimate d to have been infected with the herpes simplex 1 virus, the cause of >90% of oral herpes cases. Many others, and many of the same people also have been infected with the herpes simplex 2 virus, the cause of >90% of genital herpes. The problem with herpes simplex is that despite popular belief, an infected person can shed the herpes virus at times when they have no symptoms or visible evidence of infection. It is believed to be fairly common to transmit the herpes simplex virus either from the mouth to the genitalia, or from the genitalia to the mouth during oral sex. The incidence of HSV transmission by oral sex is not well studied.

Gonorrhea: Gonorrhea, caused by the bacteria Nisseria gonococcus, is an STD that typically causes painful urination and a discharge of pus from the urethra in men. In women it can be asymptomatic, can cause a vaginal or cervical discharge, or can cause more serious infection of the fallopian tubes and or ovaries, called Pelvic Inflammatory Disease (PID). Gonorrhea can also infect the throat or tonsils. The route of this infection appears to be oral sex, generally receptive oral sex with the penis in the mouth. It is less clear whether cunnilingus can transmit gonorrhea although it is felt that this is very rare if it ever happens. Men likely only contact gonococcus from vaginal or anal intercourse or from an infected partner during receptive oral sex.

Chlamydia: There is less data about transmission of Chlamydia by oral sex. It is generally felt to be possible to transmit Chlamydia both as the person performing and the person receiving fellatio. The incidence of this is just not known.

Syphilis: Syphilis is fairly uncommon in the US, but transmission of syphilis during oral sex is relatively easy, and is felt to be a relatively common cause of transmission, possibly up to 15% of cases in some areas of the US.

HPV: HPV is probably the most prevalent STD in the world today. The HPV virus can be transmitted to the throat or mouth during oral sex. The incidence of this is poorly understood, but there is an increasing rate of HPV positive head and neck cancers in the last 30 years. Many experts feel that this correlates to increasing acceptance of oral sex. Oral cancer has historically been primarily a disease of older adults with a long history of smoking and drinking, or in younger persons who use oral tobacco. In recent years the incidence in younger non-tobacco users has increased, and many of these cancers are HPV positive on testing.

Hepatitis: There is debate whether hepatitis B can be transmitted by oral sex, but if possible it is felt to be very unlikely. Hepatitis A can clearly be transmitted by oral-anal sex, and is much more common in the gay male population than in the heterosexual population.

In summary oral sex is not safe sex, but it is far less risky than either vaginal or anal intercourse regarding STD transmission. In addition the risk of pregnancy in heterosexual oral sex is near zero. Avoiding receiving ejaculate in the mouth greatly lowers the risk of transmission of HIV, though probably not the risk of herpes, gonorrhea, or HPV. Condom use for men, or use of a dental dam in women seems effective in markedly reducing the risk of most STDs with oral sex, but may not be common practice.

Psychological Issues: Oral sex is clearly an intimate act. Most psychologists agree that sex, either oral sex or sexual intercourse, brings a relationship to a different level. How this type of intimacy affects a relationship, the self esteem of the participants, and future feelings about relationships and intimacy are subjects worthy of consideration, but I know of no research into this topic.

So, “How safe is oral sex?” What do you want to tell your children about oral sex as a part of their sex education? You can decide now based on the discussion above and whether it involves men having sex with other men (MSM) vs. heterosexual oral sex. One risk of labeling oral sex a high-risk behavior in MSM is that it may leave gay men feeling that its risk is equal to anal intercourse, which is far from the truth. If oral sex is an alternative to anal intercourse for MSM then it greatly reduces the risk of HIV transmission.

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Giving Thanks for Uncertainty

November 24, 2011 Dr. Pullen

For most of my career as a family physician I have told patients and firmly believed that the hardest part of being a good family doctor is uncertainty. Almost every time I see a patient there is some uncertainty in the diagnosis, choice of treatment and in what to expect from the recommended treatment. Making decisions as to how much uncertainty to accept, when to seek a higher level of certainty, and how to present this all to my patients in a way that is both reassuring and truthful is the crux of the art of the practice of medicine.

When I see a patient with a typical fatty lump I’m confident is a lipoma, or a firm well circumscribed dermal level skin lesion I’m certain is a dermatofibroma, the level of uncertainty is very low. In these cases I feel very good about telling my patients their diagnosis and that no further diagnostic evaluation is needed, with the proviso that if the behavior of the lesion changes to let me look at it again. Certainly we could have a higher level of certainty if I excised all of these lesions and sent them for microscopic pathology evaluation, but the known risks of this option, i.e. scarring, pain, cost and risk of complications seem to clearly outweigh accepting a very low degree of uncertainty. This same balancing act plays out with nearly every office visit. Is the chest pain cardiac, reflux esophagitis or chest wall musculoskeletal pain? Is the headache a tension headache or something more serious like an aneurysm or a brain tumor? Making decisions about when to live with some level of uncertainty is the real decision.

Just today I was struck with the flip side of uncertainty. The beauty of our human existence is by its very nature filled with uncertainty. We all certainly will die, but when, how, and where are all uncertain. The exact prognosis for most disease processes is quite uncertain. My wife has ovarian cancer, and although she has accepted chemotherapy exceptionally well, has had very limited complications of the initial course of therapy and the second course after her first relapse, she is now in a time of waiting to decide when to treat the gradually increasing tumor marker that haunts us and tells us the cancer is not gone, it’s just lurking and trying to come back. After an all-too-brief three month hiatus of no CA-125 testing we anticipated a fairly high number, and were pleased yesterday when the marker came back only modestly higher than prior to the level three months ago. This was a reminder that nothing about this cancer is certain. The long term prognosis is poor, but what does that mean? Nothing is certain. Kay may live many months or even a year or two (or more?) before needing more treatment. The next treatment, whatever that turns out to be may be highly effective, totally ineffective, or anywhere in between. A poor prognosis maybe, but the uncertainty in times like this gives room for hope. Will a breakthrough in ovarian cancer happen in time for us? More uncertainty.

For some patients living with uncertainty is difficult, anxiety provoking, and hard to accept. In our situation I give thanks for the uncertainty. It is far easier to remain upbeat, positive and hopeful when a future that could be looked upon as filled with negatives has some uncertainty.

When you really think about life nearly everything is uncertain. As a Christian I feel confident that salvation is a certainty, but that is faith based. When I look at objective expectations nearly everything has some degree of uncertainty. Uncertainty is so much a part of our lives that we take great care to plan for the uncertainty. Insurance, be it health insurance, homeowner’s insurance, life insurance or auto insurance we are paying for insurance against uncertainty. Actuaries mathematically calculate the premiums of our insurance based on multiple sets of data and assumptions, but all of their calculations come with calculated degrees of confidence. On each of our medical study conclusions you will see a p-value. The lower the p-value the less likely the conclusion is wrong by random chance. You will never see a p-value of zero.

So this Thanksgiving I am giving thanks to my God for the uncertainties our lives. May we come to cherish this uncertainty, live each day and each minute with the certainty that there is some uncertainty about what the next minute, hour, day, week … will bring. May I continue to strive to achieve the optimal achievable levels of uncertainty in my management of my patient’s health care decisions, and may the uncertainties in my own and my family’s lives be a blessing so that we live each minute with only the certainty that we have the this minute to enjoy and cherish.

Another article you may enjoy is Citalopram HBr: Don’t Be Confused by the Name on the Bottle.

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Why Quit Smoking?

November 17, 2011 Dr. Pullen

This post is in appreciation of the 35th anniversary of the first “Smokeout”, actually the November 18, 1976 “Don’t Smoke Day” (D-Day) in San Francisco sponsored by the California Division of the American Cancer Society which received national (all 3 major national networks at the time ) and became a national event thereafter. The third Thursday of November each year, just one week prior to Thanksgiving is the Great American Smokeout. About 45.8 million Americans still smoke and most studies show more American smokers would like to quit smoking than those who don’t want to quit. Here are some great reasons to quit:
1. Retire Early(or take a nice vacation every year) on the Savings: If you smoke 1 pack of cigarettes a day for a year, at an average cost in Washington State where I live and work at the average cost in WA of $9.89/ pack you spend $3609.85 a year on cigarettes alone. If saved the 3609.85 annually and invested it at only 4% you would have $111,794.17 in 20 years. It would be more if you invested daily or monthly. Quit smoking now and you can be a long way towards a retirement fund. You may also live to retire. (I admit Washington is the second most expensive state to buy cigarettes in the U.S.)
2. It Stinks: Any non-smoker can tell you that they can smell the odor of cigarettes on your clothing, hair and body from several feet away. By quitting smoking you will avoid smelling repulsive to the majority of others in society.
3. Live Longer and Better: The average smoker dies 7 years earlier than the average non-smoker, and estimates of the time lost per cigarette smoked is 7-10 minutes per cigarette. The whole issue is really much more complex that this, but without doubt quitting smoking can add significant time to the average person’s lifespan.
4. Better Sex for Longer: Smokers have a much higher incidence of peripheral vascular disease, and erectile dysfunction is often the result of vascular disease. Quitting smoking can lead to a better sex life for many smokers.
5. Dying of COPD is Among the Worst Ways to Die: This is my personal opinion, but I’ve taken care of people who have died nearly every common cause of death. Respiratory failure has to be among the least desirable way to die. Being essentially immobile, gasping for air while on oxygen for months or years, and finally dying of a respiratory infection that leads to inability to breath is not among the ways I hope to die.
6. Get Your Kids/Grandkids/Spouse/…. Off Your Case: Nearly every smoker I see in the office comments that their loved ones are hoping the get them to quit, and often annoying them with encouragement and pestering. Why not change all that to congratulations and positive reinforcement after you quit?
7. Feel Proud that You Quit: Most smokers would like to quit smoking. Most who do tell me that they are happy and proud that they were able to quit. Join the ranks of proud ex-smokers.
Please leave comment with more and better reasons to quit. I’d love to have this post be a place for smokers to find the right reason for them and quit themselves. There is no time like today!

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The Real Costs of Defensive Medicine

November 15, 2011 Dr. Pullen

by Brittany Lyons

With estimates ranging from $35 billion to a whopping $850 billion, the true costs of “defensive medicine” are difficult to pinpoint. A variety of government reports, physician surveys and studies have attempted to pinpoint exactly how much of U.S. healthcare costs are generated by defensive medicine, but the varied definitions of “defensive medicine” make the real number hard to determine.

Defensive medicine refers to the costs associated with doctors protecting themselves from medical malpractice lawsuits. These costs include liability insurance premiums, malpractice judgments and settlements, and sometimes extend to unnecessary testing or other physician services provided to patients solely to avoid malpractice claims. Indirect costs associated with defensive medicine can also include “assurance behaviors,” such as ordering tests or delivering additional services that have only marginal medical value, or no value at all, to discourage malpractice lawsuits—which can cost more than even earning PhDs. A 2005 study published in the Journal of the American Medical Association discovered that doctors may perform these unnecessary services in the hopes that if a malpractice claim were to arise, the court would be satisfied that the physician met the standard of care.

A Look Behind the Numbers

The Congressional Budget Office estimated that defensive medicine accounted for $35 billion—or 0.2 percent—of the total U.S. healthcare expenditures for 2009. This figure is significantly lower than the estimated $650 to $850 billion in annual expenditures attributed to defensive medicine by Gallup and Jackson Healthcare surveys of physicians. The Jackson Healthcare survey gathered data from thousands of physicians across the United States on the indirect and direct costs generated by defensive medicine, concluding that physicians considered defensive medicine the primary driving force behind rising healthcare costs—the result of an overly litigious healthcare environment.

Nine out of ten surveyed physicians said they practice defensive medicine, and general estimates predicted an average of 34 percent of overall healthcare costs arise from defensive medicine. A subsequent Gallup poll of physicians found that approximately 73 percent of surveyed physicians admitted to practicing defensive medicine within the past year, but estimated overall costs at only 26 percent. The 2005 JAMA study by researchers from Columbia and Harvard Universities also revealed that for physicians practicing in “high-risk” specialties, these monetary figures may be much higher; 59 percent of the physicians surveyed admitted to ordering more diagnostic tests than medically necessary to prevent malpractice litigation. Plus, the physicians avoided caring for high-risk patients, referred patients to other specialists, prescribed more medications than medically necessary and suggested unneeded invasive procedures—all to avoid malpractice lawsuits. Another study by the American Academy of Orthopedic Surgeons discovered that defensive medicine accounts for a startling 20 percent of all imaging orders, and half of these imaging orders were for expensive MRIs.

Why the Disparities?

So why is the Budget Office’s number so low when the Jackson Healthcare survey is so high? Because physicians aren’t regularly logging every single expenditure arising from defensive medicine, and no one is entirely sure what even qualifies as “defensive,” quantifying the costs with exact accuracy is nearly impossible. The great differences in estimated costs, however, is likely due to the particular expenditures included in the figures for defensive medicine. For instance, the CBO’s low estimate of $35 billion includes “malpractice insurance premiums together with settlements, awards and administrative costs not covered by insurance,” but does not include unnecessary procedures, medications and other services, so long as they are covered by insurance. This difference in accounting is more than enough to explain the disparity.

The Jackson Healthcare survey adds a myriad of other direct and indirect costs to the CBO’s numbers, including all the excessive diagnostic testing and medical services provided in the spirit of defensive medicine. The survey results then translate the percentages into dollar amounts using the calculations of estimated overall U.S. healthcare spending released by the Centers for Medicare and Medicaid Services. Thus, this number includes more items than the CBO’s report, and bases its numbers on another estimate.

With healthcare costs rising rapidly in the United States, combined with increasing tort reform and malpractice fears, defensive medicine is becoming a more and more expensive slice of the healthcare-cost pie. Regardless of the actual monetary amount, defensive medicine practices strain not only Medicare and Medicaid, but also the insured and uninsured healthcare consumer alike, contributing to increasing prices for medical services and greater costs to insurance companies. Unless something is done to relieve the legal pressures placed on physicians, defensive medicine will continue to generate billions of dollars in healthcare expenditures every year.

Brittany is a blogger-in-residence at PhDs.org

Remember all the Drugs With a Narrow Therapeutic Window?

November 7, 2011 Dr. Pullen

The concept of the therapeutic window, the dose of a medication where the serum level is high enough to be effective but not so high as to be toxic, is much less of an issue today than it was in my days as a younger physician. I am sure I’m not alone in being delighted and relieved by this welcome change. I thought it would be fun to muse about the drugs we used to use routinely whose narrow therapeutic window was often a dilemma.

We still commonly use a relatively few medications with a narrow therapeutic window, notably warfarin, digoxin, and lithium, but many others have fallen out of favor because safer effective treatments have become available. For fun and historical perspective let’s look at some of the drugs with troublesomely narrow therapeutic windows.

Thoephylline: Prior to the widespread use of inhaled corticosteroids, long acting inhaled beta agonists, more aggressive use of short burst courses of oral corticosteroids, and new medications like spireva, Singular, and others the mainstay of asthma and COPD management was theophylline. With a non-linear metabolism (the serum levels do not gradually and steadily increase with increased dose, but rather jump quickly at times with minor dose changes), severe toxic side effects at only slightly supra-therapeutic serum levels, and many drug interactions, theophylline toxicity was a common cause of ICU admission for many years.

Digoxin: Digoxin is still used for many patients, but not nearly as often, and usually at considerably lower doses than when it was considered a key part of management of most patients with CHF and tachyarrythmias of many types. We have learned a great deal about CHF treatment in the last 20 years, and digoxin plays at most an ancillary role in cardiology today for most heart conditions. This is nice as often life threatening arrhythmias were commonplace in years past, and digoxin toxicity was extremely common.

Tricyclic Antidepressants: These are a prefect example of a narrow therapeutic window. At a daily dose of 300 mg daily, amitripylene ingestion of as little as 4-5 days of dosing could be lethal. In contrast ingestion of a full month prescription of most SSRIs is unlikely to be life-threatening. Amitriptylene, imipramine, nortriptylene, desipramine and later some tetracyclics like trazodone were the only effective antidepressants available prior to Prozac, and the SSRIs have been popular not just because of their lack of bothersome side effects. The fact that lethal overdose of an SSRI is extremely uncommon, whereas ICU admissions and deaths from tricyclic intentional and unintentional overdose were daily occurrences 30 years ago. We rarely use the tricyclic antidepressants in doses needed for depression today.

Warfarin: We still use warfarin plenty, but new directly acting drugs like Pradaxa, Xarelto and apixaban are becoming available for prevention of stroke in atrial fibrillation, and are likely to be used in the future for DVT therapy. It remains to be seen whether bleeding complications will be significantly less problematic, but it is clear that the therapeutic window with warfarin is about as narrow as they get. A patient therapeutic on 5 mg daily, may be significantly over-anticoagulated at a dose of 6 mg daily, and with many drug interactions, dietary variation of vitamin K ingestion, and patient compliance issues with frequent INR monitoring this is a major factor in patient care.

Aminoglycoside antibiotics: These remain a very effective therapy for many gram negative bacterial infections, but have in large part been replaced with much less toxic drugs. Use of these antibiotics requires close monitoring of serum levels and renal function to assure both therapeutic serum levels and non-toxic levels.

Lithium: Lithium remains an effective therapy for the mania associated with bipolar disorder, but the narrow therapeutic window where serum levels below 0.5 usually not effective, but levels much above 1.0 leading to toxicity, drugs with a much wider therapeutic window are often preferred by patients and physicians alike. (Visit this Lithium side effects resource)

Aspirin: No not 81-325 mg daily for their anti-platelet effect, but three Ecotrin or Bufferin 325 mg tablets four times daily. Prior to the huge list of NSAIDs beginning with ibuprofen and naproxen, high dose aspirin was the standard of therapy for rheumatoid arthritis, osteoarthritis and most inflammatory disorders. Who remembers checking salicylate levels, watching for tinnitis and bleeding ulcers or hemorrhagic gastritis from aspirin toxicity. I don’t miss those days.

Other drugs like many of our chemotherapy agents still remain in widespread use despite the need to push dosing to levels where toxicity is expected, but overall the development of safer and improved drugs has made consideration of the therapeutic window much less of a day-to-day concern than it was just a couple of decades ago.

Please leave your stories about use of drugs with narrow therapeutic window issues for readers to enjoy. Leave your e-mail in the subscribe area on the right side bar to be notified of future DrPullen.com posts, and follow on Twitter @DoctorPullen to get additional thoughts and health care commentary.

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