Friday, July 28, 2006

Levodopa – if this is the “gold standard,” we are in trouble

Parkinson’s disease (PD) is a degenerative neurological condition in which neurons in the brain that produce dopamine, a neurotransmitter that facilitates control and modulation of muscle movement, slowly die. Tremor is the symptom most commonly associated with PD in people’s minds, but it is the other two cardinal symptoms, rigidity and bradykinesia (slowness of movement (1)), that bring people with Parkinson’s (PWP) to a halt.

Described in that way, it sounds rather benign, doesn’t it – it is not. It doesn’t just rob one of niceties like being able to write with pen and paper, or dance, or play the piano, or type, or cut one’s food at dinner. Increasing disability forces people to quit working and try to survive on disability payments. Showering, shaving, getting dressed and eating become more and more challenging. People fall and break arms, legs, teeth. Sometimes they fall and can’t get up – for days, potentially, if they live alone – rigidity can be that severe. People end up in wheelchairs. Incontinence can occur, though I do not know with what frequency because I don't want to know. Swallowing can become a problem, which can lead to aspiration, pneumonia, and worse.

Given enough time, PD will result in disabling immobility and, ultimately, death, if nothing else gets you first.

In 1970 or so, the drug levodopa was introduced to treat PD. At first it appeared to be a miracle drug – people who had been immobilized by the disease were able to move again. However, even during clinical trials its most visible side effect, dyskinesias (uncontrollable, involuntary muscle movements) had become evident, and certainly by 1980, the research community was well aware the levodopa not only caused dyskinesias, but it also lost efficacy very quickly.

A study published in 1980 by Shaw, et. al. followed 178 patients who were evaluated at various points between the start of levodopa therapy, which occurred sometime between November 1969 and December 1972, and the final evaluation in 1977. (2)

Chart One (click chart for larger view)

Of the original 178 patients, only 81 made it through to six years on levodopa. 70 dropped out, most of them before the two-year mark, due to severity of side effects. An additional 27 were lost to follow-up, either because of death or unknown whereabouts.

Shaw et. al. categorize the benefit derived from levodopa as marked (50-100% improvement in rating score), moderate (25-50% improvement), slight (0-25% improvement) or none, and as you can see below, only 20%, or 36, of the original 178 were still taking levodopa and deriving moderate benefit at the six-year mark – and that was the best that anyone was doing – there was no one in the “markedly improved” category.

Chart Two (click chart for larger view)

As a 42 year old with PD, I don’t find that particularly encouraging, nor would I if I were 60, which is often cited as the average age of onset (though I have seen 50 cited, as well.) And that is only half the story. Levodopa has some pretty devastating side effects. Consider rates of occurrence of three of them in the chart below, as found in the Shaw study mentioned above.

Chart Three (click chart for larger view)

We all know what dementia is. “Wearing off” is a euphemism for loss of efficacy – it refers to the phenomenon in which over time, the length of time each dose is effective diminishes. After a few years, it is quite common for people to be medicating every two hours, and even then, the medication may “wear off” before the next dose is due, leaving them coping with some very dangerous and incapacitating symptoms.

Dyskinesias, as noted above, are involuntary, uncontrollable muscle movements. It is difficult to convey to one who has never seen them exactly what they look like and how disabling they can be, so I found a description of severe dyskinesias in a study.

At approximately 7:30 PM [each evening], he began to have violent flinging movements of the arms and legs and facial grimacing interrupted by severe dystonic spasms of the right limbs. He could only attempt to lie down but would flail his entire body from side to side and could not remain in bed due to the violence of the movements. These severe dyskinesias lasted until 11 PM or midnight. (3)

I do not have dyskinesias myself, but have come into contact with quite a few people who do. I saw one Parkinson’s patient whose body was in such motion that she was unable to simply pick up a glass and drink from it. Instead, she requested a straw, which allowed her to sip from it while leaving it on the table. I have spoken to people on the phone whose movements were so vigorous that I could hear the difficulty they were having keeping the handset positioned correctly. I spoke to one woman on the phone who said she was lying on the floor because her bodily movements were so violent that she could neither stand nor sit; I could barely hear her over the noise of the handset being knocked around. I witnessed a man whose involuntary writhing was so intense that he could barely keep from sliding off his chair onto the floor. At a fundraising dinner one night, I saw a woman whose head was flinging back and forth so wildly it was a miracle she didn’t smash it on the table.

And here’s the kicker; according to Shaw, et. al.:

“Movements were most severe when the patient was obtaining maximal relief from rigidity and akinesia…”

Excellent! Not only was there only a mere 20% chance of still deriving, at best, moderate benefit from levodopa at the six-year mark, and not only was there about an 100% chance that one would be dealing with dyskinesias, but the moderate benefit would come when the dyskinesias were the worst. Oh, and let’s not forget the dangers of dementia and wearing off.

Given the above, I have to say that I don’t quite get it when Shaw, et. al. say:

“Despite the unquestionable diminution of responsiveness to levodopa over the years and associated long-term adverse reactions, the quality of life for the average patient treated with levodopa has clearly improved considerably. For two to three years the majority do well, many patients remain gainfully employed and lead active lives for several more years and even even after six years most are still gaining benefit.”

Most didn’t even make it to the six year mark! 35% dropped out by the second year! Only 45% actually finished the study and only 20% finished the study at a moderate level of benefit, and that was being compromised by concomitant dyskinesias! And that was the best case scenario – the rest of the people who finished the study were experiencing slight to zero benefit but were almost certainly experiencing the joys of dyskinesias and wearing off, and if they got really lucky, dementia, too!

Unfortunately, such compartmentalization of the benefits and deficits of levodopa is standard. In cases in which a side effect may be troubling (i.e., dry mouth) but not interfere with the actual benefit being derived from the drug (e.g., the ability to move, and thereby accomplish tasks requiring movement, e.g., picking up and drinking from a glass of water), it might not be misleading to compartmentalize the benefit and present it as separate and distinct from the deficit. However, when the benefit itself is compromised by the side effect, it does become misleading to present them as separate and unrelated, as is almost always done

Levodopa may be better than nothing – I do not have enough information to comment on that designation – but to call it “the gold standard,” as has been done for many years, conveys the profoundly inaccurate impression that this drug is better than good enough by cavalierly disregarding side effects of such severity and impact that in any other field of medicine would be considered evidence of toxicity.

I have provided references below and I encourage anyone and everyone to take a look at them. My rational for calculating incidences a little differently than the authors of the Shaw study did is elucidated in footnote (4).

My next entry will focus on a more recent study to explore the degree to which the billions of dollars that have been invested in trying to fix levodopa over the last 40 or so years have succeeded.

  1. Bradykinesia: imagine you have been shoveling without gloves and your hands are really cold, and that you are now trying to get your keys out of your pocket and unlock the door – that is what bradykinesia feels like, only without the coldness - at least to me.

  2. The Impact of Treatment with Levodopa on Parkinson's Disease. K.M. Shaw, A.J. Shaw & G.M. Stern. Quarterly Journal of Medicine, New Series XLIX, No. 195, pp. 283-293, Summer 1980.

  3. Motor Response to Levodopa and the Evolution of Motor Fluctuations in the First Decade of Treatment of Parkinson’s Disease. CD McColl et. al. Movement Disorders, Vol 17 No 6. 2002. P,, 1227-1234.

  4. The authors of the study calculate the incidences of the different levels of benefit being derived at six years based only on the population that actually finished the study (n=81). However, since what is important to me as a person with PD is if I start taking levodopa now, what are the odds that it will continue to provide sufficient benefit up to and including the six year mark – in which case the fact that 70 out of 178 people dropped out due to severity of side effects is 100% relevant, and those 70 people are made irrelevant in the authors’ calculations. Therefore, I use the entire study population (n=178) as the denominator when calculating the likelihood of a certain degree of benefit at six years.

    However, with respect to side effects, I want to know what my odds are if making it to six years is taken as a given – and so for that calculation I use only the population completing the study (n=81) as the denominator.

* From Chart Three: The authors report incidences of three different kinds of dyskinesias in the group that made it to the final evaluation – peak dose, 80%; end of dose dystonia, 20%; and biphasic, 3%. Clearly, there is overlap somewhere, but since it is not elucidated, I have chosen to aggregate the percentages rather than try to guess how they might overlap.

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