40 years ago

40 years ago last month, two great things happened.  To me: I finished up 2 years in the air force.  To the USA: L-DOPA was released so patients in this country could get it by prescription.  The Europeans had been using it for years, and I’d read their papers and drool.  Our FDA (Food and Drug Administration) insisted that the European studies had to be repeated over here.  Patients at the Army hospital where I was stationed begged to get in the study done at the local medical school (where I finished my neurology residency).  I heard things like “I am Colonel X, and you will get me into that study — Captain”.  Pathetic to see a sick old man descend to using pull to get what he should have had.  If you think the brave new world of Obamacare will be different, think again.  Just being on Medicare made it rather difficult for me (a retired MD) to find a doc for myself when we moved 7 years ago.  

The L-DOPA experience engendered a lifelong hatred of the FDA.  No one over there ever got fired for holding up a drug. There was a period of 17 years where no new drug for epilepsy (anticonvulsant) was released in the USA.  Just after I retired in 2000 the floodgates opened.   Fortunately, now we have many more.  If the AIDS epidemic had a bright side (I saw plenty of it when it affected the brain), it was to get drugs out earlier and easier from the FDA.  

When Clonopin (now Klonopin to avoid confusion with other drugs) was finally released, I called the mother of two kids with severe epilepsy ( 2 – 3 convulsions a day, every day for years) to tell her to come to town and pick it up. They lived 220 miles away (this was Montana after all) and, as often happens, there was a blizzard blocking the Interstate, so they couldn’t come in for a few days.  During those few days the convulsions stopped completely.  Had they been able to come in, I would have been totally convinced of the drug’s efficacy (wouldn’t you be?).  It’s why we always need controlled studies in medicine.  Dramatic results are only suggestive. On this point, historical controls just won’t do, as most diseases have a better outcome now than they did 20 years ago.  The controls must be concurrent.  

Back to Parkinson’s disease.  Although we all knew what had been written about L-DOPA, you never really know a drug until you’ve used it.  So the chief put me in charge of the (newly formed) L-DOPA clinic.  Here’s where I saw people get out of wheelchairs, the nearly mute begin to converse freely etc. etc.  This is why all the hoopla about the various drugs for Alzheimer’s disease (up to 2000 anyway) left me cold.  I never saw any obvious benefit from them (nor did any clinical neurologist I spoke to, and I spoke to a lot).  Trust me, if we had a drug as good for Alzheimer’s as L-DOPA was for untreated Parkinsonians, we’d know in a month (although a trial should still be done).   For instance, dramatic results were seen with injecting various types of cells (adrenal medullary cells, fetal dopamine neurons) into the brain for Parkinsonism. Sham trials of this (patient put to sleep, but no brain injection, not even a brain injection with nothing in it — not sure if burr holes were placed in the placebo patients, but I think they were — you can’t inject something into brain tissue without making a hole in the skull, so the placebo group would know who they were if they didn’t feel a burr hold) also produced dramatic results (but as often in the placebo as in the treated).  Suppose a drug initially used for another condition worked for Alzheimer’s as L-DOPA does initially for Parkinson’s disease ?  Should docs be allowed to use it for an ‘off-label’ condition?  This happened with beta blockers and migraine (where they were being used for cardiovascular problems rather than migraine).  I think they should

Back in 1970 we were quite worried about weight loss on L-DOPA, because of its associated nausea (in some people).  So every patient in the L-DOPA clinic was weighed at each visit. The most prominent symptom of Parkinsonism is tremor of course.  But there are 3 more.  Difficulty initiating movements, muscular rigidity (not spasticity) and difficulty with postural adjustments.  It was an amazing thing to see an apparently normal individual walk up to the scale and find it nearly impossible to balance on one foot and get up to be weighed.   

One interesting point for the pharmacologists out there.  The drug didn’t work instantly, although effects were obvious in a week or so.  One mistake a lot of GPs made was to start the drug at a reasonable dose, but to increase it too quickly. Patients got lots of side effects this way.    I’d wait a few weeks on the same dose, and continue to see improvement week after week.   If Parkinsonism was just a simple deficiency of dopamine, you’d expect an immediate and total effect (like giving a diabetic in insulin shock some sugar).  But L-DOPA (and dopamine replacement therapy in general)  doesn’t work that way, and interestingly, neither do the drugs we use for depression. Something very subtle and complicated is going on in these diseases.

The drug worked so well, at later on in practice, I’d wonder if I’d really made the correct diagnosis.  Only when they got sick and couldn’t take their L-DOPA by mouth (such as when they had to have surgery) was their disease obvious.  In those early, heady days, we thought we were actually curing the disease.  Now, of course we know better.  The drug papers over the symptoms but doesn’t arrest the underlying disease (or even slow it down).  But L-DOPA gave most patients at least 5 good years.

Time has moved on, and we’ve discovered further complications of long term use (on-off effect etc. etc.), and now we have are other drugs.  One guy (Melvin Yahr) of Columbia (one of the major US neurology centers) got it into his head that L-DOPA was harmful, a notion I always found bizarre.  Huge amounts of money were sopped up (ELLDOPA study etc. etc.) calming him down.  He still wasn’t convinced, but hopefully now has to dig into his own pocket for future work.   Some 50,000 brain stimulators had been implanted by ’06 for patients who are no longer helped by L-DOPA (and the newer drugs).  I can’t comment on how well they work, as I retired when they were coming in.  

The next post will deal with some serious issues Galaxy Rising had with two previous posts.

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  • Wavefunction  On October 8, 2010 at 12:52 pm

    -Here’s where I saw people get out of wheelchairs, the nearly mute begin to converse freely etc. etc

    So I guess the film “Awakenings” got it right?

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