The L-dopa Conundrum

Few episodes in medical history are as dramatic as the “discovery” back in the 1960’s of L-dopa therapy. University of Rochester Medical Center’s Karl Kieburtz, an authority on the history of the drug, describes L-dopa as “one of the most potent therapies in all of neurology – indeed in all of medicine – think about it: to take someone who was essentially rigid like a stone…and enable them to get up and walk and function…it’s unbelievable.” But clinicians soon discovered that L-dopa exacted a price for the miracle. In time, patients displayed disabling side effects, notably involuntary writhing movements called dyskinesias, and so-called on-off fluctuations – in which the medicine’s power to combat Parkinson's disease suddenly vanished without warning. Neurologists euphemistically called these L-dopa-induced side-effects “motor complications” (MCs).

As a comprehensive review article by Salat and Tolosa in the Journal of Parkinson’s disease makes clear, over the past four decades neuroscientists have made major efforts to develop new drugs and devices to both minimize MCs (e.g. Sinemet CR, Sinemet CRE, Duodopa, IPX066 ) and treat them (A2a antagonists (e.g. Istradefylene, preladenant, tozadenant), COMT inhibitors (e.g. opicapone), NMDA antagonists (e.g. amantadine), alpha-7 nachr inhibitors (e.g.  aqw0051), metabotropic glutamate receptor modulators (e.g. mavoglurant; dipragurant), partial dopamine agonists (e.g. pardoprunox) and more. But so far, all this effort has only delivered incremental improvements. While Salat and Tolosa write that “previous concerns that levodopa may have toxic effects on the brain have now been mostly discarded,” other concerns remain. Concerns, in particular, about when to start levodopa therapy.

Should newly diagnosed patients delay taking L-dopa as long as possible or seize the day? Neurologists are still divided on the question. The Parkinson’s Institute’s Bill Langston urges caution. “Once you are on levodopa, you start the clock; once the basal ganglia is sensitized there’s no going back. So save your ammo as long as you comfortably can.” Susie Ro of the Seattle-based Swedish Medical Center disagrees. “There is no convincing evidence that saving levodopa until the last possible minute does anything but delay and thereby lessen the time when a person could be having their best level of function.”

To resolve this Faustian conundrum, we need to tease apart three main factors: the disease, the drug kinetics, and the medicine’s long-term effects on the basal ganglia. First, there’s the disease. Sporadic PD is a progressive disorder, in which dopaminergic cells and axons in the substantia nigra continue to die. This means that over time there are fewer and fewer nerve terminals capable of (a) converting L-dopa to dopamine (b) storing the neurotransmitter and (c) releasing it as needed. Second, there’s the drug’s weird pharmacokinetics. L-dopa (which has a short half-life of around 90 minutes) has to be absorbed by the gastrointestinal tract, find its way to the brain and cross the blood brain barrier – before all the L-dopa has been metabolized. The artificially supplied dopamine in no way replicates normal controlled dopamine delivery. Rather it floods the brain, lurching between peaks, where there’s too much, and troughs, where there’s too little. Third, animal studies suggest that this uneven or pulsatile expression of dopamine wreaks havoc with the receiving (post synaptic) nerve terminals, which leads to dyskinesias and “on”/“off” fluctuations.

Which of these three factors is most critical for developing MCs and can that knowledge help patients with their L-dopa conundrum? A fascinating case report by Patricia Pita Lobo et al and a thoughtful commentary by Susan Fox provide some hints. Pita Lobo’s report tells the story of a 74-year-old man who had suffered head trauma in a car crash when he was 37. He experienced a coma, and developed – on the left side of his body – weakness and tremor (both resting and action tremor). For ten years, he responded well to L-dopa before developing classic motor complications (wearing off and dyskinesia) on his left side.

When Pita Lobo and her colleagues examined this patient 38 years after his accident, he was still taking three 250 mg– doses of L-dopa–per day and still had the left sided motor complications. Two things were striking. After four decades of L dopa use, he still had no MCs on the unaffected, right side of his body. Also, the symptoms on the affected left side were pure motor problems. His disease had not developed to include non-motor complaints like postural instability, depression and dementia.

What, then, does this case reveal? It tells us that even though his disease was not progressing like regular PD (rather, it resulted from a one off event), he still developed MCs in the damaged side of his brain. Pita Lobo’s study joins other documented cases of “non progressing” Parkinsonism, which displayed serious and permanent MCs – including the California “Frozen Addicts,” and the epidemic of von Economo’s encephalitis.

Such examples imply that, given sufficient damage to the substantia nigra and its striatal projections, the most important determinant of motor complications is the drug itself, “the consequence of chronic L-dopa on postsynaptic dopamine receptors and down-stream changes within the striatum,” as Fox puts it.

Does this help recently diagnosed patients resolve their dilemma of when to start L-dopa? Perhaps. A patient wants to delay L-dopa for as long as possible and then have the drug’s “honeymoon period” last for 5-10 years, before MCs kick in. The Pita Lobo case shows that this may be a risky strategy. MCs appear to result from the combination of drug and damage (whether that damage results from an acute event or from a progressive disease is not important). Wait too long, develop too much nigrostriatal damage, and you may end up with a very brief honeymoon.

How brief? Some of the first US cases to benefit from L-dopa-treated by George Cotzias and Roger Duvoisin in the 1960s developed MCs in less than a month. According to Duvoisin, there was a clear difference between advanced cases (stage IV and V) – with massive nigrostriatal damage who developed motor complications very quickly – and newly diagnosed cases (stage I and II) who did “very well for 4 or 5 years on levodopa. “

Patients must factor in another complication; clinical variability. Parkinson’s is a heterogeneous condition with radically different speeds of progression depending on clinical type (e.g. sporadic PD v  PD with Lewy body dementia) and subtype (e.g. tremor dominant v axial dominant). This changes the calculation for every patient and his/her neurologist.

Of course, the conundrum might go away if neuroscientists could come up with a way of delivering L-dopa smoothly over the day. But after nearly half a century – with the possible exception of the invasive duodopa solution (which requires patients to wear an external pump that delivers levodopa gel through a catheter to the duodenum) – there’s been almost no success. As Salat and Tolosa put it, “the quest for a levodopa formulation that safely provides consistent brain delivery remains unsolved.” Says Karl Kieburtz, “You’d think that it would be an easy puzzle to solve – give a steady dose – we do it with all the other drugs. People have tried for 50 years and the best physical chemists haven’t figured it out.”

But Parkinson’s Center of Oregon Director, Jay Nutt, says we should be grateful for what we have. As he puts it, “on some days, when I feel a little bit blue, I think ‘isn't it amazing that levodopa ever works at all – that you can sort of dump the drug in and actually have such powerful and effective therapy.’”

Last comment on by Anber Falcao,


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