Mentored by a Madman Page 10
Just before Christmas I received a letter from a brave man in his sixties describing his current predicament:
It is in fact difficult now to stick to the 2-hour regime because of this apparent unreliability. If for instance I find myself ‘over’, suffering from so-called involuntary movements, my limbs behaving as if controlled by a drunken marionette master, I am reluctant to take a pill. So I postpone it. And then before I know where I am I am ‘off’. ‘On’ is quite simply normal; I can survive a dinner party, drive a car, write a fair, round hand, my voice is normal. I can fall asleep rather easily unless I am trying not to. ‘Off’ on the other hand is very unpleasant. I lose almost all motor power in my legs; and this paralysis increasingly now spreads to my arms. Sometimes odd pains and cramps move round the body. There is no position in which I am comfortable. I can’t write, I can’t type, my speech is slurred and low powered. The ‘off’ comes on with increasingly little warning. One can adopt strategies to save oneself from various kinds of embarrassment; I have a radio taxi account to rescue me when my batteries begin to run down or if one goes ‘off’ suddenly in the street one holds on to a lamp post until a taxi comes past. People are extraordinarily sympathetic and helpful. I find an aluminium walking stick useful as it is a sign that something is wrong and holding on to a lamppost does not mean I am drunk. I find my ‘offs’ are accompanied by a curiously deep and malevolent depression. It isn’t suicidal; I actually feel as if I am dying. Almost as bad is the boredom and the frustration of not being able to work. I find I am tetchy and intolerant and that it is difficult not to be bitter and sarcastic.
When I met him in the New Year he was ‘off’ and as he walked into my room in the outpatient clinic, he took smaller and smaller and faster and faster steps until he stumbled to the ground before I could get up and break his fall. He was a Jack-in-the-Box waiting to burst forth, still stepping internally but diminished and confined within an infinite, closed space that allowed no exit. When his L-DOPA kicked in, he orbited a Möbius strip that shot him into a hyperkinetic stratosphere only for gravitational forces to pull him back into quaking immobility. He told me his only chance was to keep moving and try to outrun the disease. A morpho fluttering its wings in Santarém or a migration of jabirus over the Pantanal had the ability to alter his uncontrollable anchored trajectory. Everything was unexpected, nothing could be relied upon.
Many of my colleagues felt that these ‘on-off’ swings were untreatable. The chronic bombardment of the receptors over many years from L-DOPA had led to dopamine ‘burn out’ and lack of responsiveness. In their view the combination of ‘pharmacological blockade’ with a relentless dying back of the nerve terminals, indicated that disabling fluctuations in performance were an inevitable and irremediable consequence of treatment.
My experience with the postencephalitic patients at the Highlands Hospital had convinced me that it was possible to override the slowness of movement that characterised all parkinsonian states and was now marring the long-term response to L-DOPA. ‘Puskás’, the football-juggling patient, had used visual cues and motor tricks to propel himself forward but one of the other patients I had seen at Highlands Hospital who was still using L-DOPA had found that he could switch back ‘on’ if he smoked a cigarette. Neurologists had been accused of a nihilistic scepticism towards therapies throughout my training and now that I was in a position of power I was determined to try to do everything I could to refute this unfair accusation.
I now had my first research fellow, Richard Hardie, and the two of us sat down to devise experiments that would prove to the pessimists who considered L-DOPA to be more of a curse than a cure that they were mistaken.
A group of patients, most of whom were under the age of sixty and were now experiencing severe and prolonged ‘switch-offs’, were selected for the first studies. On admission to hospital all tablets they were taking for Parkinson’s disease were stopped and replaced by an intravenous saline infusion containing L-DOPA. Most of the volunteers had been on treatment for more than ten years and they were now forced to carry out all their essential everyday chores during their steadily shrinking islands of mobility. The dose of L-DOPA administered through the drip was slowly increased until they ‘switched on’ and was then maintained uninterrupted at this steady level for the next 72 hours. During this three day awakening, some of the volunteers told us that it was like going back to the early days of L-DOPA therapy. Instead of five or six hours of mobility, the infusion had provided them with fourteen good waking hours.
The blood levels of DOPA were much more constant than those we had taken before the infusion had been started. Delayed emptying of the stomach and erratic absorption of L-DOPA tablets in the small intestine had led to peaks and troughs that had contributed to the loss of effectiveness of treatment over time. We concluded that the unconstant handling of L-DOPA in the gut and at the blood-brain barrier played a considerable part in the ‘on-off phenomenon’. L-DOPA was very acidic and damaged veins, and the apparatus needed to infuse the amino acid was far too cumbersome for long term treatment, so the next step in trying to eradicate the highs and lows was to find a more viable way of continuously stimulating the dopamine system.
After a gap of too many years I was happy to be back swimming with the alkaloids, marvelling at their asymmetries adorned with rich chiral centres and decorated with dangling green heterocyclic quinolines. These intricate cyclic molecules were responsible for Nature’s exquisite colours, aromatic odours and distinct tastes, and I derived pleasure from drawing their formulae on scraps of paper. Sometimes in my dreams I was in the belly of a whale, watching three dimensional vibrating plankton glide by. One night sitting on the sea bed with a telescope, a diatom with a familiar benzene ring and two hydroxyl groups and a rigid side chain supported by three carbon rings, unfurled before my eyes. This was apomorphine and I was convinced it had appeared as a direct consequence of my re-reading of Naked Lunch in the weeks after I had been appointed a Consultant Neurologist. William Burroughs had enthused about the drug as a cure for drug dependence, and passages in ‘Deposition: Testimony Concerning a Sickness’ that I had glossed over on the first reading as a medical student, now seemed to have far more importance:
The apomorphine cure is qualitatively different from other methods of cure. I have tried them all. Short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. None of these cures lasted beyond the first opportunity to relapse. I can say that I was never metabolically cured until I took the apomorphine cure.
– Naked Lunch
Two British chemists working at St Bartholomew’s Hospital in London in 1869 had first made apomorphine by a simple process in which opium was mixed with concentrated hydrochloric acid and then heated to 150 degrees Celsius. Shortly after the new molecule’s synthesis, Samuel Gee, a physician who had trained at University College Hospital, injected two grains of the new substance into a dog, which caused it to vomit and then course the room in a peculiar repetitive way. After this, apomorphine started to be used by veterinary surgeons to treat the behavioural vices of horses, pigs and sheep.
Throughout the first half of the nineteenth century the drug was widely employed in medical practice as an emetic to expel poisons. In order to give herself a cast iron alibi, Nurse Hopkins in Agatha Christie’s first Poirot novel Sad Cypress, injects herself with apomorphine to ensure she vomits up the tea that she had drunk from the same pot she had laced with morphia in order to poison her wealthy charge. Apomorphine was also used as an aversive therapy for the treatment of sexual deviation and alcoholism. At the end of the nineteenth century it was used at my hospital for the treatment of pseudoseizures, and for the control of St Vitus’s dance (Sydenham’s chorea).
In 1951, Robert Schwab, a neurologist working at the Massachusetts General Hospital in Boston, gave apomorphine to patients with Parkinson’s disease on little more than a scientific hunch and reported improvement in their shakes and stiffness. U
nfortunately, the rest of the medical profession remained unenthusiastic about Schwab’s encouraging preliminary findings although he continued to treat some of his own patients in Boston with the drug for one or two years. Dopamine was still of little interest to scientists, and patients would have to wait another seventeen years for the arrival of L-DOPA.
Apomorphine’s molecular structure was much later found to closely resemble dopamine and on this basis it was predicted that it might be a powerful stimulator of dopamine receptors. Parallels were also drawn between its conformational structure and that of lysergic acid diethylamide (LSD-25).
Almost twenty years later, and now armed with a scientific rationale denied to Schwab, George Cotzias, working at the Brookhaven Laboratories in New Jersey, re-examined the effect of apomorphine in Parkinson’s disease. In a series of clinical experiments conducted in 1970, he confirmed apomorphine’s therapeutic potential and felt that it might also reduce the side effects of involuntary movements and psychosis seen with L-DOPA.
Unfortunately, a lingering concern in the United States that it might be a narcotic, the need for it to be injected, and the easy availability of L-DOPA meant that Cotzias’s findings were not followed through. There seemed to be no place in modern neurotherapeutics for ‘a nineteenth century injection that caused vomiting’.
A few weeks after my dream, I met a colleague and friend called Eduardo Tolosa at a medical meeting and explained to him what I now wanted to do. To convince sceptics I needed to find a rapidly acting drug that would effectively stimulate dopamine receptors so that I could follow up our experiments with infusions of L-DOPA and prove conclusively that the ‘highs and lows’ could be reversed by an improved delivery of dopamine to the brain. During his research fellowship, Eduardo had worked with Cotzias at Brookhaven and without hesitation he said, ‘Why not try apomorphine?’ The apomorphine dream of a few weeks earlier now had support from a respected colleague.
By the time of our new research studies, not a single pharmaceutical company was marketing apomorphine in the United Kingdom. After a lot of asking about, I tracked down a source of the drug suitable for human consumption. For reasons I can no longer recall, the pharmacy at the Royal Marsden Hospital on the Brompton Road had continued to manufacture supplies. One day, fifty small vials each containing two millilitres of colourless liquid arrived at the neurology office at University College Hospital.
On leaving work I took one of them home and jabbed myself with one milligram. Within a few minutes I started to feel pleasantly relaxed. I did not feel sick and the mild sedative effects disappeared in half an hour. One unexpected effect was a strong penile erection lasting about ten minutes. Only a green stain on my white shirtsleeve from a few spilled drops remained as a testimony to this first dummy run. None the worse for my experiment I returned to editing a paper Hardie had drafted and that we were keen to submit that week for publication.
After clearing it with the hospital ethics committee, we then proceeded to administer apomorphine to a group of patient volunteers during their predicted ‘off’ periods of DOPA unresponsiveness. Some needed reassurance that the drug was not addictive like morphine, but as in my earlier trials there was no shortage of volunteers. The long history of apomorphine use in clinical practice and my own experiment had left me in no doubt that it was safe to use.
The effects were spectacular. Every single patient was unlocked after about ten minutes and the beneficial effects of apomorphine were sustained for about an hour. A group of helpless invalids had sprung back to life and could now laugh, talk and stride effortlessly around the ward. Their ‘release’ reminded me of the more gradual but equally astonishing revival I had witnessed in the ticket collector who had been given L-DOPA in 1970. Hardie and I now had further evidence that the dopamine receptors in Parkinson’s disease had not lost their ability to light up, despite the unnatural pounding they had received from L-DOPA. We felt increasingly confident that the on-off syndrome could be defeated by pharmacological intervention.
Apomorphine was now centre stage in my ongoing research. The relief experienced by the patient volunteers after its injection had been far more powerful than anything I had witnessed with either bromocriptine or deprenil. Gerald Stern, my senior colleague, then told me that during his National Service in the Royal Navy he had used apomorphine as an aversion therapy in a despairing chain smoker. In reply I told Gerald that I had first encountered it as the ‘junk vaccine’ in William Burroughs’ book Naked Lunch. He smiled benevolently and I was secretly relieved that he had no idea what I was talking about. Medicine was still a very restrained profession. In the ensuing weeks I turned again to Naked Lunch and re-read ‘Deposition: Testimony concerning a sickness’:
The doctor explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme system of addiction is destroyed over a period of four or five days. Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse. (No one would take apomorphine for kicks. Not one case of addiction to apomorphine has ever been recorded).
Around the same time we were carrying out the studies with apomorphine, another drug called domperidone became available that would prevent nausea and vomiting by selectively blocking dopamine receptors in a small region in the hindbrain, which acts as a sensor for the detection of noxious substances. More sophisticated portable pump delivery systems had also just become available. This technological advance would allow me to deliver apomorphine continuously through a small needle inserted under the skin of the abdominal wall. The final decisive step came when I was able to obtain financial support to employ a research nurse specifically to work on the apomorphine programme.
The first two patient volunteers were young women who had courageously lived with deadness and a creeping powerlessness for the last five years. They seesawed several times a day between an upbeat, uncoordinated jerkiness and a weighed down weakness. Their switch-offs were unpredictable, making it impossible for them to plan ahead and there was never an equipoise. The interminable twirling that came as a blessed relief to the patients in their brief windows of drug responsiveness were even more distressing for their family to behold than their debilitating stasis. They had not lost their fight or their sense of humour but their existence had become wretched and their affliction had begun to put a heavy strain on their devoted partners.
After their oscillations had been recorded and quantified in hospital, both women were started on domperidone. Two days later we began the infusion of apomorphine at a very low dose and then gradually increased the setting on the pump until they ‘switched on’. It was apparent almost immediately that apomorphine was going to bring them back to life and that it would be possible to cut back on their L-DOPA. Within a few weeks in hospital their lifeless limbs had revived and their shakes had all but gone. Their periods of incapacity had been reduced from ten hours a day to two. They had been freed from the tyranny of Parkinson’s disease and could now discard their wheelchairs. The clock had been turned back on the malady by at least five years.
The miraculous improvements seen with apomorphine in Hilary B. and Liz D. and then in seventeen other severely disabled patients were described in The Lancet where we included a figure showing a representative ‘on-off’ diary to illustrate the magnitude of the improvement. Several other research groups in England and other parts of Europe confirmed our findings and within a relatively short time Burroughs’ ‘junk vaccine’ had been rebranded as Apo-go, a powerful remedy for the complications of advanced Parkinson’s disease. We concluded our paper with unprecedented optimism:
In general our results have been so encouraging that we would recommend that all patients seriously disabled with refractory on-off oscillations should be offered a trial of subcutaneous apomorphine, certainly before consideration of a foetal implant procedure with its attendant hazards and uncertain benefits.
The drug that had rescued Burro
ughs from ‘The Sickness’ had come to the aid of a group of desperate individuals with the shaking palsy. I will never be sure how much my belief in its awakening potential stemmed directly from Naked Lunch.
The structural formula of apomorphine on a pavement, probably drawn by Ian Sommerville in 1966. Photograph by William Burroughs.
Despite its unassailable efficacy, apomorphine failed to capture the public imagination or interest the scientific press. The implantation of foetal dopamine cells in Sweden filled the papers, even though the approach was unproven and only four people had been treated so far, without improvement. My only concern now was that I could continue to use apomorphine to treat my patients and that this fantastic ‘oldie but goodie’ would be made available to the thousands of patients who were turning once more to ice. I contacted the small family business of Britannia Pharmaceuticals The structural formula of apomorphine on a pavement, probably drawn by Ian Sommerville in 1966. Photograph by William Burroughs. who had also sold deprenil in the United Kingdom and with the patients’ consent showed their management team some of the videos we had recorded during the trial. With help from Gerald Stern and I, the firm obtained a licence from the Medicines Agency and in 1993 apomorphine returned triumphantly to the British Pharmacopoeia.
I was pleased that I had played an important part in the resurrection of a disregarded treatment. However, a ‘mature product’ that was simple to manufacture and had cost us just a few pounds to investigate was now costing the National Health Service several thousand pounds a year per patient. Britannia had successfully made the case to the authorities that apomorphine was a Rolls Royce drug that had been previously undersold for the price of a bicycle! In the first few years after the company had obtained a licence, it made great efforts to ensure quality control and close down a number of ‘illicit distilleries’ – National Health Service pharmacies who were making the drug at a cut rate and eating away at their business model. I understood the need to be profitable and was grateful to Britannia for making apomorphine available but I felt uncomfortable about a system where money was made out of illness and where the patient was treated as a customer. The company knew the price but not the value to the patients. I made it clear I was not for hire and that I wanted no shares or financial interest in the firm.