Monday, January 09, 2012

1900-2012: History of steroid use for asthma x

So now in our quest through the anals of asthma history we come to corticosteroids.  If we consider the discovery of Epinepherine to be the most important discovery as far as asthmatics are concerned, the discovery of cortisone must be considered the second greatest discovery of all time.

The discovery of cortisone occured the same year epinepherine was discovered in 1900.  According to Barry E. Brenner in his history of asthma, "at that time Solis-Cohen prepared a crude extract of the adrenal gland and used it in the treatment of acute asthma." (1)

In the late 1930s it was isolated, and it was used successfully for the first time in 1944, according to Meriam-Webster dictionary.  It was initially used to reduce inflammation for patients with rheumatoid arthritis, yet it was ultimately discovered that it would help reduce inflammation in the air passages of asthmatics. (2)

According to Answers.com, "Schering-Plough," cortisone was synthesized in 1949 by Merck & Co, yet through a series of legal loops Schering obtained access to cortisone information.  This made it possible to make cortisone, and made it easily available to physicians.  (3)

What you have to realize, however, is at this time asthma was believed to result in inflammation only during an asthma attack.  Brenner explained that several studies were completed in the 1940s and 50s, and in 1955 prednisone was discovered as the first synthetic corticosteroid and marketed as an effective treatment for acute asthma symptoms. (4)  Medicine.net reports that it was approved by the FDA in 1955. 

Medrol Steroid Pack
Schering marketed prednisone as Metricorton in 1957.  Paracort and Deltasone are other generic options on the market. 

Another similar product is prednisolone which was also approved by the FDA in 1955.  It was marketed as either Sterane or Delta-cortef, although is available under as variety of products such as Pediapred and Orapred as well as generic names.

Dexamethasone also entered the market in the 1950s as Decadron.  Some believe this is a more potent steroid that lasts anywhere from 1-3 days in your system, making it ideal for kids who won't reliably take yucky tasting pills or solutions. 

Dexamethasone was actually the first corticosteroid to be marketed as a solution to be nebulized, and this was shown to benefit asthmatics in studies done in the 1960s.  (5) 

Methylprednisolone was later marketed as a varient and marketed as Medrol and Solu-medrol.  Medrol is the pill form and comes in what is referred to as a Medrol Steroid pack, or simply a steroid pack.  If you're an asthmatic chances are you've been prescribed a steroid pack at one point or another. 

The pack comes with five rows of 4 mg pills:  7 in the top row, 5 in the second row, 4 in the third row, 3 in the fourth row, 2 in the fifth row, and 1 in the sixth row.  You take the top row on day one, the second row on day two and so forth.  The idea is you take fewer pills each day to wean yourself off. 

I often get asked what's the difference is between prednisone, prednisolone, and methylprednisolone.  The answer is that they are simply the same or simlar products made by different companies.  Some say that methylprednisolone has fewer side effects, yet that's like saying Albuterol is better than Xopenex, or snow is better than rain.  In other words, which one a doctor prescribes is based on personal preference.

To treat acute episodes of asthma the medicine could be given as an injection, or the pill or liquid version could be taken at home.

Yet once you start taking steroids you had to slowly be weaned off.  Your body produces corticosteroids, and if you take the pill form your body will think you have enough and stop production.  For this reason, if you're given a high dose of corticosteroid medicine and then you stop cold turkey you leave your body with no corticosteroids and you'll die.  So you must wean, and that was one of the nice things about the steroid pack.  A doctor gave you a shot of Solu-medrol at the office and sends you home with a pack to wean you off.   

Sales of systemic corticosteroids boomed during the late 1950s and 60s.  It didn't take long for doctors to note a major problem with this medicine.  There were certain individuals who had persistent or chronic arthritis or asthma who required steroids on a daily basis.  Since there was little data on ideal dosing, some physicians prescribed high doses long-term for some patients.  It soon became evident there were some severe consequences to such long term, and high dose use of systemic corticosteroids.

Beclovent Inhaler
Noting the success of the Medihaler-epi and Medihaler-iso, pharmaceuticals hoped to take take advantage of the booming inhaler market.  In 1960 beclomethasone was introduced as the first inhaled corticosteroid by Allen & Hanbury, the makers of the Albuterol inhaler.  (7)  The product was marketed as Becotide in 1972, and the recommended dose was four puffs daily. 

GlaxoSmithKline's version of beclomethasone was Vanceril, and Schering-Plough's version was Beclovent, and both were approved by the FDA for sale in the U.S. in 1982. 

I was prescribed Vanceril from the late 1970s until 1985, yet from time to time other generic forms entered my home.  (You can see a 1979 ad for Beclovent and Ventolin here.) 

After the CFC propellants were set to be phased out in 1989, the hunt was on to find an environmentally friendly inhaler.  3M Pharmaceuticals developed an HFA version of beclomethasone called Qvar, and it was approved by the FDA in 2000.  By 2001 GSK stopped production of Vanceril, and soon thereafter Schering-Plough ceased production of Beclovent.

Studies actually show that (aside from the spike in cost), this changeover might have worked to the advantage of asthmatics as the new version has been proven to get deeper into the lungs providing better distribution of the medicine (I wrote about this in more detail in this post). 

However, according to Dr. H. Morrow Brown at Allergiesexplained.com, beclomethasone was almost written off as a useless medicine.  Many doctors preferred to treat asthma by desensitization with allergy shots, and this was done with me. 

I have the medical records to prove it. I remember getting allergy shots through the 1970s all the way until 1985.  As some point you'd have thought my doctors would have caught on they weren't working, considering my asthma continued to get worse and worse instead of better.

So desensitization was a top line therapy for athma and inhaled steroids were relatively ignored by physicians until a study was reported in The British Medical Journal in 1971 and 1972 showing beclomethasone was effective in controlling asthma. (8)

Becotide Inhaler
This turned out to be a great achievement because the inhaled medicine is absorbed in the lungs where it's needed and very little gets in the system, as opposed to oral or injected steroids which cause systemic effects. 

From the 1970s until the early 1990s systemic steroids were prescribed for severe episodes of asthma, and other than that acute episodes were managed by rescue medicine and inhaled corticosteroids like Becotide because side effect (although still expected), were believed to be far less than systemic steroids. 

Perhaps as a result of this, between 1957 and 1985 the market for asthma inhalers (which also included bronchodilators) skyrocketed so that in 1985 asthma inhaler sales were 25 percent of the asthma prescription market (theophylline was also at 25 percent of this market). 

The problem that remained until the early 1990 -- perhaps due to the 1950s scare -- was that doctors were still afraid that inhaled steroids used long term would produce the same side effects as systemic steroids.  For this reason they were leary of prescribing them as an every day medicine, and recommended them for use only during an acute attack to limit side effects. 

A second problem was that scientists had yet to discover that inflammation in the lungs wasn't just there during an acute attack, that it was chronic (always there).  For both these reasons, corticosteroids -- either systemic or inhaled, were only prescribed for moderate and severe asthma, and rarely mild asthma. 
Vanceril Inhaler

In the 1960s triamcinolone entered the market as Azmacort.  In 1975  Schering-Plough introduced its version of beclomethasone as Vanceril.  In the early 1980s Budesonide was introduced to the market as Pulmicort. 

Studies showed Pulmicort was the safest and most effecteve nebulized corticosteroid.  Decadron is sometimes given by aerosol in hospitals in the emergency rooms, but rarely, and usually not for asthma but inflammation of the throat.  Pulmicort has earned the respect of physicians, and it's basically the only nebulized corticosteroid available for home use. 

Perhaps my doctor had me trial all these at some point, yet the one I remember becoming friends with was the Vanceril inhaler.   It was a little pink inhaler designed the same as the Ventolin inhaler.  I have a note from my doctor following a 1981discharge from a local hospital after an asthma admission that says:  "Use your Vanceril for two weeks, then use only when you have trouble breathing."

By 1985 my asthma continued to be high risk, and I was using my asthma rescue medicine several times daily.  Sometimes I'd use my Ventolin inhaler in less than a week, and made several unscheduled doctor visits and emergency room for uncontrolled asthma.  I survived this, yet many asthmatics did not. 

My local doctor decided he couldn't help me, so I was shipped to National Jewish Hospital/ National Asthma Center (Now National Jewish Health).  Doctors there were up to date on the latest asthma wisdom and weren't afraid to prescribe inhaled steroids. 

The Azmacort inhaler with built-in spacer
Knowing my asthma was high risk, my doctor at NJH put me on Azmacort, and instructed me to take four puffs four times every day to control my asthma.  I was not to stop taking it no matter what, even if I felt good. 

The neat thing about this inhaler was it was the first inhaled steroid with a pleasant taste (at least I thought so).  The only problem was you needed four puffs four times a day to equal two daily puffs of our modern inhaled corticosteroids. 

This many puffs was a pain in the butt, but when I was compliant it worked like a charm.  So long as I took my inhaled steroid every day there would be just enough steroid in my system to prevent an asthma attack. 

By 1989 there were enough studies to confirm the approach NJH doctors used on me was the best way to treat asthma.
The results of the research showed that NJH was on the right track in treating asthmatic children with a daily dose of inhaled corticosteroids.  That experts now had to come up with a way to educate regional doctors of this approach so that other asthmatic children could benefit.

Thus, in 1989 the NHBLI's asthma guidelines were created. The guidelines highlighted the following:
  • Asthma is often underdiagnosed
  • All asthmatics have some degree of chronic inflammation
  • A small amount of steroids in asthmatic lungs obtained from inhaled corticosteroids is often all that's needed to control this inflammation and prevent asthma symptoms.
  • The amount of steroid inhaled from an inhaler is very small compared to systemic steroids, and therefore side effects are rare and minimal at worse.  Thus, the benefits far outweighed the risks for many asthmatics with uncontrolled asthma.
  • Thus, the emphasis for asthma treatment was changed from focusing on controlling acute asthma symptoms to preventing asthma from occurring by treating the underlying inflammation and preventing bronchospasm.
  • Inhaled steroids should be used daily to prevent asthma, and rescue inhalers should only be used when needed to treat acute asthma episodes. 
  • Inhaled steroids are safe to use for mild asthma to prevent airway remodeling that may cause asthma to become moderate to severe. 

In 1992 A National Heart, Blood and Lung Institute-sponsored Childhood Asthma Management Program (CAMP) was created to study the impact of long-term inhaled steroid use in children.  The pediatric department at NJH conducted a landmark study of 1,041 children between the ages of 5 and 12 for 20 years.  The results confirmed the idea that daily inhaled corticosteroid use for asthma was effective and safe.

The inhaled steroid used in the study was Budesonide.  The results showed that Budesonide (inhaled corticosteroid use) for asthmatic children:
  1. Reduced hospitalizations by 43%
  2. Reduced Urgent Care visits by 45%
  3. Reduced Prednisone use by 43%
  4. Reduced use of Albuterol
  5. Increased episode free days (10)

Loaded with this new wisdom, physicians started prescribing inhaled corticosteroids more often.  This helped many asthmatics better control their asthma, and use of rescue medicine declined.  Now asthma experts refer to uncontrolled asthma as using rescue medicine more than twice in a two week period.

Greg Minton, in his book "Breathing Space" explained that after the release of the asthma guidelines sales of inhaled steroids soared, and flunisolide, marketed as Aerobid, lead the charge.  Minton described that "in the first three months of 1991, prescriptions of Aerobid doubled those of the entire previous year. Aerobid was the fastest growing inhaled steroid on the market." (9)

In 1992 the National Heart Blood and Lung Institute sponsored Childhood Asthma Management program (CAMP) provided research

At one point my regional doctor decided Azmacort wasn't good enough for me and he prescribed Aerobid as a replacement.  I took two puffs of it -- just once -- and rejected it on the grounds the mist tasted like rotten mints.  Surely Aerobid required fewer puffs, but I decided I'd rather puff away at the better tasting Azmacort.

By the late 1980s Pulmicort became the first dry powder inhaler on the market when the Pulmicort Turbohaler was introduced.  I never used this inhaler on myself, although I have instructed it to patients from time to time.  Considering the horibble taste, I can't fathom that Aerobid sold so well. 

The market for inhaled corticosteroids proved to greatly benefit asthmatics not simply by controlling and preventing asthma, but by reducing unscheduled doctor visits, emergency room visits, hospital admissions, and the cost of treating the disease. 

Other pharmaceuticals rushed to enter this market, and this brought about the longer lasting and more potent inhaled corticosteroids we use today. Fluticasone was introduced as Flovent in the 1990s and Mometasone furoate in the 2000s. 

Interesting to note that each new inhaled steroid was a little more selective than the previous, and lasted a little longer. This is the main reason some of the older inhaled steroids have been phased out in favor of fluticasone, mometasone furoate, and other new ones on the market or in the oven. (11)

Advair entered the market in the late 1990s ad the first combination inhaler with a long acting beta adrenergic (rescue medicine) and an inhaled steroid.  It was a combination of fluticasone and salmeterol.  It quickly became the best selling asthma product because it controlled asthma and only required two puffs a day.

Symbicort and Dulera are similar products to enter the market.  Since the patent for Advair expired in 2010 generic versions are expected to hit the market soon, and hopefully lower the price.

So you can see we have come a long way since cortisone was discovered at the turn of the century, since prednisone was discovered in the 1950s, and beclomethasone hit the market in 1972.  While physicians were once hesitent to prescribe a daily dose of inhaled corticosteroids to control asthma, steroid inhalers have since become a top line therapy for preventing and controlling asthma. 

Click here for more asthma history.

References:
  1. Brenner, Barry E, ed., "Emergency Medicine," 1998, from chapter one "Where have we been?  A history of acute asthma," page 18
  2. Meriam-Webster dictionary, "Corticosteroid," http://www.merriam-webster.com/dictionary/corticosteroid
  3. "Schering-Plough: Information," Answers.com, http://www.answers.com/topic/schering-plough-corp
  4. Brenner, op cit, page 18
  5. Schleimer, Robert P., et el, "Inhaled Steroids in Asthma," vol. 163, 2005, New York, page 5
  6. "Schering-Plough: Information," op cit
  7. Primary Care Respiratory Journal,"A brief history of inhaled asthma therapy over the last fifty years," Volume 15, Issue 6, December 2006, Pages 326-331
  8. Dr. H. Morrow Brown at Allergiesexplained.com http://allergiesexplained.com/
  9. "Mitmann, Gregg, "Breathing Space:  How allergies shape our lives and landscape, 2007,  page 247 (a great read if you want to learn more about the history of asthma/ allergies
  10. Werner, Alison, "Taking a Long-Term Look at Childhood Asthma Treatment," RT: For Decision Makers in Respiratory Care," January, 2012, www.rtmagazine.com, page 18-21
  11. Schleimer, op cit, page 45

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