Journal ofNeurology, Neurosurgery, and Psychiatry. Special Supplement 1989:29-37

The on-off phenomenonA J LEES

From the National Hospitalfor Nervous Diseases, London UK

SUMMARY The on-off phenomenon is an almost invariable consequence of sustained levodopatreatment in patients with Parkinson's disease. Phases of immobility and incapacity associated withdepression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors areinvolved in its pathogenesis, but evidence is presented to indicate that the importance of levodopahandling has been underestimated and that progressive reduction in the storage capacity of survivingnigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage whichmay mean smaller, more frequent doses, or larger less frequent increments, may be helpful incontrolling oscillations in some patients. Dietary protein restriction, the use of selegiline hydro-chloride and bromocriptine may also temporarily improve motor fluctuations. New approaches tomanagement include the use of subcutaneous apomorphine, controlled-release preparations oflevodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenaladministration of levodopa.

The on-off phenomenon comprises profound diurnalfluctuations in the psychomotor state of patients withParkinson's disease treated with levodopa. Each swingusually lasts for one to three hours, but occasionallyseveral oscillations may occur over the course of 30minutes. It was first reported in the very first studyusing high doses oflevodopa in 1969' and the term wascoined by a patient of Duvoisin's2 who likened theglow ofthe levodopa awakening to the switching on ofa light and the equally abrupt return of Parkinsoniandarkness to the light going off. The American drugsubculture has also introduced to the English languagethe terms "switched on" and "switched off" to indicateeither an individual who is energetic, sophisticated andstreetwise or conversely one with a nostalgic dinosaurmentality. Although our concepts of the nature of thisremarkable disturbance have developed substantiallyover the last 20 years and disagreements remain evenwith respect to its definition, the on-offphenomenon iseasily understood by patients and the term still in mostcommon usage to describe levodopa-related motorswings. It is the most important therapeutic challengein the long-term management of Parkinson's diseaseand its occurrence has permitted the concurrent studyof behavioural effects related to dopaminergicstimulation and dopaminergic deficiency. It may alsopermit some insight into the progression of the

Address for reprint requests: Dr A J Lees, The National Hospital forNervous Diseases, Queen Sq, London WCIN 3BG, UK.

Accepted January 1989

underlying disease process seen during the "off" statewhich can then be compared with the period of "on"mobility seen even after 20 years of chronic levodopatreatment. The rapidity, severity of change andfrequency of this phenomenon is unique.

Greater understanding of the individual's responseto such violent and capricious biological changes mayshed light on other cyclical disease states such asbipolar depressive illness, periodic psychosis, brittlediabetes mellitus and catamenial epilepsy.

Historical introduction

In their pioneer high dose levodopa study Cotzias andhis colleagues' reported minor transitory episodes ofsub-optimal performance usually in the afternoon,and also noted significant fluctuations in motorperformance in some patients. On stopping levodopaand starting placebo those patients who had shownclinical fluctuations reverted to a severe Parkinsonianstate much more rapidly than those showing a stableresponse. In some patients the nadir did not occuruntil two weeks of placebo treatment. Yahr andcolleagues3 also reported that abrupt withdrawal oflevodopa was followed by a gradual loss of effect overseveral days. These observations were difficult tomarry with the short half-life of about one hour forlevodopa and a first phase half-life of no more thanfive to ten minutes. Single-dose levodopa tolerancetests led to the notion of two types of therapeuticresponse; a short or medium duration effect measuredin minutes or hours and generally related to the rise

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and fall in plasma dopa levels. Those patients withnoticeable swings in motor performance wereconsidered to have a short duration motor responsewhereas others who were unaware of their medicationtaking effect or wearing off were considered to have along duration response lasting days. The long durationresponse was also used to explain the delay indeterioration following levodopa withdrawal.4 By themid- 1970s most authorities recognised two apparentlydistinct types ofmotor fluctuations. The commoner ofthese was named "end-of-dose deterioration" or the"wearing-off effect" and was characterised by relativepredictability and a relation to falling plasma dopalevels. In our original study with high dose levodopastarted in 1969, 65% of 178 patients with a range ofpre-treatment disease severity had significant wearing-off effects after six years of continuous therapy.'Progression of the underlying disease process leadingto a progressive reduction in the capacity to storedopamine in surviving nigrostriatal terminals wasbelieved to be the most likely explanation. At this timethe on-off effect was restricted by many, to a muchrarer see-sawing effect in which vicissitudes frommobility to immobility occurred repeatedly over min-utes for up to half an hour. These seemingly unpredic-table fluctuations were also sometimes termed akin-esia paradoxica or yo-yoing. In our study, after sixyears we considered about 10% ofpatients to have thisdisturbance.5 Excessive levodopa dosage was believedto be at least partly responsible for this effect.

Differences in terminology between differentresearch groups bedevilled the study of levodopafluctuations throughout the 1970s making it extremelydifficult to compare long-term follow-up data fromdifferent centres. A generally accepted rule of thumb,however, was that approximately 10% of patientswould develop troublesome fluctuations per treatmentyear so that after ten years treatment virtually all caseswould be affected. Careful in-patient studies withsingle oral doses of levodopa has revealed that manypatients believed on the basis of their description inout-patient clinics to have unpredictable swings do infact have dose-related oscillations. It is also now clearthat most of the apparently complex fluctuatingresponses are artefactual and related to complexoverlapping dosage schedules. Akinesia paradoxicahas never been reported in patients receiving supra-threshold intravenous infusions or in single dose oralstudies and their occurrence may in fact be due tooverlap effects of serial doses or rebound deteriorationfollowing each dose of dopa. It may also occur if thedose of levodopa is relatively small, producing plasmadopa levels close to or around threshold levels. Noconvincing evidence exists to suggest that wearing-offeffects and akinesia paradoxica differ patho-physiologically.

Lees

The clinical pictureAn extract from a letter received in 1983 from a

patient with the on-offphenomenon:"It is in fact difficult now to stick to the 2-hour regimebecause of this apparent unreliability. If for instance Ifind myself "over", suffering from so-called involun-tary movements, my limbs behaving as ifcontrolled bya drunken marionette master, I am reluctant to take apill in the midst of these side-effects. 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 isnormal. I can fall asleep rather easily unless I am tryingnot to. "Off" on the other hand is very unpleasant. Ilose almost all motor power in my legs; and thisparalysis increasingly now spreads to my arms.Sometimes odd pains and cramps move round thebody. There is no position in which I am comfortable.I can't write, I can't type, my speech is slurred and lowpowered. The "off' comes on with increasingly littlewarning. One can adopt strategies to save oneselffromvarious kinds of embarrassment; I have a radio taxiaccount or if one goes "off" badly in the street oneholds on to a lamp post until a taxi comes past. Peopleare extraordinarily sympathetic and helpful. I find analuminium walking stick useful as it is a sign thatsomething is wrong and holding on to a lamp post isnot necessarily because one is drunk. I find my "offs"are accompanied by a curiously deep and malevolentdepression. It isn't suicidal; I actually feel as if I amdying. Almost as bad is the boredom and the frustra-tion of not being able to work. I find I am tetchy andintolerant and that it is difficult not to be bitter andsarcastic".A gratifying response to levodopa therapy occurs in

most patients with Parkinson's disease leading to aconsiderable reduction in disability. Most patientswith mild disease before the onset of treatment aretherefore unaware of any specific effects from eachdose of treatment, but appreciate what appears to be asustained effect with an improvement in all thecardinal signs of the disease. Tremor, however, isgenerally the last major sign to come under controland postural instability when prominent may alsolinger. As treatment continues, more and morepatients begin to become aware of the pharmaco-logical effect ofindividual doses. Inexplicable episodesof stiffness, slowness or tremor occur, lasting severalhours, especially in the afternoon or evening. Patientsbegin to complain that they are becoming allergic orimmune to the treatment and accuse their physician ofswitching them to placebo. Their lives now becomedominated by the clock and great care has to be takenin the timing of each dose. Some patients claim thattheir levodopa seems to be working for a progressivelyshorter period of time and the frequently quoted

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The on-offphenomenon

duration of benefit from each dose once the problemhas set in is two to three hours, compared to six hoursto eight hours at the outset of treatment. The morningdose almost invariably works better than subsequentdoses later in the day and a few patients report clearbut truncated responses of only 30 minutes to an hourin the afternoon. Once the tablet is working, however,most patients say that the effect is as good as when theystarted treatment, although their families may noteincreasing fidgetiness and restlessness due to dyskin-esia. The duration of benefit from individual doses isincreased when the patient is relaxed and at rest, andwhen excited and involved in an enjoyable pastime,many hours may pass without the tell-tale warnings ofpain, shaking or slowness down one side whichindicate that the "battery is running low". On theother hand if the patient is acutely stressed or involvedin intense physical exercise the duration of benefit isoften shortened. These effects generally becomeapparent after 2 to 5 years oftreatment and at this timetoo, patients may become aware of the time taken forthe first tablet to work in the morning which is usuallybetween 20 and 90 minutes. Smaller, extremelyfrequent doses of levodopa throughout the wakingday often reduce the severity of drug-induceddyskinesias, but may actually sometimes make theoscillations more capricious and baffling. Markeddiurnal mood swings and precarious balance add tothe patients' difficulties. As the disease continues toprogress the severity of the fluctuations becomes morestriking. At this stage half the day may be spent in a

mobile, hypomanic, choreic state while the remainderof the day is spent in a mute, akinetic, straitjacketaccompanied by feelings of dejection and hopeless-ness. After 10 years of treatment the islands of motorresponse become less satisfactory usually as a result ofincreasingly violent volleys of chorea, ballismus,stereotypies or dystonia, or associated psychiatricside-effects particularly visual hallucinations,hypomania, schizophreniform psychoses or con-

fusion. During off periods in addition to all theclassical parkinsonian signs, a number of other lessfrequently recognised disabilities are often prominentincluding severe pain in the limbs and back, torsion ofthe limbs, particularly the feet, urinary retention,anismus and distressing dysphagia sometimes withintractable belching. Although absence of responsive-ness to levodopa rarely occurs even after 20 years oftreatment, the quality of the motor responsedeteriorates as a result of secondary effects and escapeof particular symptoms and signs, especially posturalinstability and speech.

Clinical pharmacological observations

The post-synaptic dopaminergic striatal apparatus

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appears to remain intact and sensitive throughoutakinetic off periods. The subcutaneous administrationof the dopamine receptor agonist apomorphine,reliably and rapidly eliminates off periods.6 Positronemission tomography and post-mortem neuro-chemical studies have both failed to show any definiteabnormalities of the D2 receptor following long-termtreatment with levodopa.78 Bromocriptine, adopamine receptor agonist, does not cause significantoscillations in performance when given as mono-therapy to previously untreated patients.9 This may,however, be in part artefactual because the drug is lesspotent than levodopa and the difference between theon and off response is therefore substantially less.

There is marked inter-subject variability inlevodopa pharmacokinetics'° and many investigatorshave failed to find a consistent correlation betweenplasma dopa concentrations following a single oralloading dose and either the magnitude or the timing ofthe motor responses."'-" Difficulties in interpretingthese studies include age and body weight differences,problems with the accurate diagnosis of Parkinson'sdisease, the effect of a concurrently administeredperipheral dopa decarboxylase inhibitor, thefrequency of blood sampling and sensitivity of scoringand whether the patients were fasting or not. Tolosaand colleagues,'5 however, were able to report thatincreasing the size and frequency of levodopa dosagecould abolish motor fluctuations, but this was not apractical strategy because of the emergence of dose-limiting adverse reactions, particularly disablingdyskinesias.We have recently re-examined the relative influence

ofpharmacodynamic and pharmacokinetic factors onthe duration and quality of motor response to a singleoral morning dose of 200 mg of levodopa with 50 mgof benserazide in 31 randomly selected, fasting,levodopa-treated patients. The duration of benefit ofasingle dose depended on the degree to which theplasma levodopa level had declined over 4 hours. Themotor response wore off in each patient when theplasma level had dropped to about 50% of peakconcentrations irrespective of the duration of themotor response. The duration of the response was notsignificantly different in patients with short durationof disease and treatment compared with those havinglong disease duration who had been treated often formore than ten years with levodopa. In contrast theamplitude of motor response, that is the differencebetween the Parkinsonian score on and off, increasedprogressively with duration oftreatment. These resultssuggest that following a standard dose of levodopaabove that needed to produce a minimum effectiveplasma concentration, duration ofresponse appears tobe determined by peripheral levodopa pharmaco-kinetics.'6 The evolution of motor oscillations would

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32 Lees

be ideally studied by longditudinal studies over a concentration was between 0-3 and 1 6 mg per litre.62'number of years in the same group of patients as it is Using higher intravenous doses (70-143 mg/hour),conceivable that peripheral pharmacokinetic handling well above threshold, it has also proved possible tooflevodopa might change to some degree with chronic eliminate completely diurnal off periods for up to fiveadministration.'7 days.2223 These results clearly indicate that delivery ofWe have also conducted another study in which levodopa to the striatum is a critical determinant of

Parkinsonian patients with marked asymmetry of therapeutic response. As an approach to managementbasal ganglia signs fail to show a matching asymmetry it is impracticable because of the quantity of solutionin the duration ofmotor response to a single oral dopa required and its acidity. If the solution is administereddose. In a concurrent investigation using post-mortem via a peripheral vein thrombophlebitis developsmaterial from a group of patients with asymmetrical rapidly, so administration through a central venousphysical signs at death there is a 10-20% difference in line has to be considered in long-term management.the number of pigmented nigral cells on the two brain Levodopa methyl ester which is much more solublesides.'8 This provides further evidence that dopamine and readily hydrolysed to levodopa, permits thestorage capacity is not of major importance in deter- volume of solution to be reduced by as much as 97%mining the time course of levodopa motor responses. and its use in mini-pumps has been tried withApparent increase in severity and frequency of the encouraging results although concern exists about the

on-off phenomenon with progressively longer dura- long-term build-up of methanol levels in the blood.24tion of treatment may therefore be illusory and related Nutt and his colleagues from Portland, Oregon,to the increase in disease severity revealed during off have also argued against the reduced dopamineperiods as the malady progresses. Patients with severe storage capacity hypothesis. Using intravenouspre-treatment disease as frequently occurs in levodopa infusions of variable length and then plot-post-encephalitic parkinsonism and MPTP-induced ting the decline of motor response and plasma dopaParkinson's syndrome have levodopa-induced levels following abrupt discontinuation of the infusionfluctuations in the first few weeks of therapy, support- they have shown that there is a mimimum intravenousing this notion. Less prolonged striatal accumulation infusion rate and plasma dopa concentration requiredof fluorodopa has been demonstrated in vivo in to produce a motor response in an individual patient,oscillating patients compared with stable levodopa that there is a lag in the motor response with respect toresponders and normal controls.'9 However, the inter- the plasma dopa level and that the duration ofpretation of these data is clouded by problems of not response is directly related to peak plasma dopaknowing which levodopa metabolites contain the concentrations. They have also emphasised that theisotope visualised at various times and by the fact that magnitude of the motor response to levodopa is all orsignificant amounts of dopamine are known to be nothing and one cannot enhance the quality ofsynthesised outside dopaminergic neurones. therapeutic response by increasing the dose. Augmen-

Additional support for the importance of levodopa tation of the dose, however, increases the duration ofpharmacokinetics in the production of the on-off motor response.2526 It is uncertain whether otherphenomenon comes from continuous intravenous dopamine receptor agonists with different pharmaco-levodopa infusion studies. In 1975 continuous logical profiles may further improve the residualintravenous infusions of levodopa given at a constant disabilities during the levodopa-induced motorrate for several hours to five patients with on-off response. The Portland group have also demonstratedoscillations were sufficient to sustain mobility, but that the duration of motor response after a two-hourbecause the patients remained fasting and supine intravenous infusion of levodopa administered in thethroughout the experimental period only limited con- fasting state does not differ between stable andclusions could be drawn about the motor responses.'0 clinically fluctuating patients and that a poorIn a later controlled study in 12 severely oscillating correlation exists between disease severity and motorpatients using continuous subclavian vein infusions of response duration.27 ' Swings might be entirelylevodopa for seven to twelve hours, sufficient to reach explained on the variable absorption, short plasmasteady state plasma dopa levels, we were able to show half-life and modifiable transport across the blood-that at infusion rates between 32 and 80 mg an hour a brain barrier.marked reduction in off periods occurred when com- The frequent complaint of patients that they arepared with the patients' customary oral levodopa worse following a motor response to levodopa thandose. The patients were encouraged to remain mobile they are first thing in the morning before their firstthroughout this study and had standard hospital daily dose has also been confirmed in clinicalmeals. Plasma levodopa concentrations were main- pharmacological studies. It is proposed that this mighttained within a much narrower range than was seen be due to a biphasic action of dopa with inhibitoryduring oral administration, the optimum therapeuti'-'effects occumng at sub-threshold doses.9 The

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The on-offphenomenonpossibility of sleep benefit in the morning cannot,however, be totally excluded. Complete unresponsive-ness to individual doses of levodopa, especially in theafternoons and even when food has not been taken atlunch, is a well-recognised phenomenon which hasbeen suggested to be due in part to the erratic,intermittent absorption of levodopa.3 It does notappear to be due to variations in diurnal receptorresponsiveness throughout the day,3' but it is possiblethat successive serial levodopa doses lead topharmacodynamic changes or the build-up of toxicmetabolites.

Management ofthe on-offphenomenon

The standard approach to the emergence of disablingParkinsonian disabilities at the end of each interdoseperiod is to add in one or two additional doses oflevodopa with a peripheral dopa decarboxylaseinhibitor thereby reducing the interdose interval.However, if the patient's on periods are also com-promised because of disabling dyskinesias, balanceproblems or mild confusion, this incremental increasemay be impossible. In this circumstance small, morefrequent doses are given. Sometimes this is counter-productive because the response to each dose becomesshorter and more erratic because plasma dopa levelsmay be closer to, or even below, the minimum effectiveconcentration, and if the plasma level is hoveringaround threshold, yo-yo effects may be seen. In somepatients, particularly those with incapacitating onsetand end-of-dose (biphasic) involuntary movements itmay be better to settle for two to four larger doses oflevodopa a day.Levodopa is mainly absorbed from the proximal

duodenum and enters the brain by a saturable carriersystem which also transports large neutral aminoacidssuch as tryptophan, phenylalanine, tyrosine, leucine,isoleucine and valine. The transport of levodopa intothe brain is dependent on plasma concentrations ofthese aminoacids and their elevation by dietary intakecan reduce the therapeutic effect of levodopa.32 Com-petition at the blood-brain barrier has been directlyvisualised by positron emission tomography whenincreasing plasma long chain aminoacids threefoldprevents completely the entry of 18-fluoro-dopa intothe brain.33 Dietary protein competition mighttherefore explain the delayed action and occasionalfailure of response to some doses of levodopa and itwould seem logical for patients with disabling fluctua-tions to avoid high protein meals. A reduction in offperiods has been reported with stringent dietaryprotein restriction (less than 7 G a day up to a lateevening dinner during which there is a free proteinintake).35 It is by no means certain, however, that thisbeneficial effect is related to the reduced level of

33plasma neutral aminoacids. Elevation of dietary car-bohydrate, changes in gastric emptying and levodopaabsorption may also be important. If the start-up timein the morning is slow following the first daily dose oflevodopa it is useful to instruct the patient to grind upor dissolve his first daily dose and imbibe it in asweetened drink. This can improve the speed ofresponse by up to thirty minutes. If readjustment oflevodopa dosage and dietary protein restriction isunhelpful, selegiline hydrochloride (deprenyl), a selec-tive Type B monoamine oxidase inhibitor, should beintroduced in a dose of 5 mg in the morning and 5 mgat lunchtime. Partial substitution of levodopa by thelonger acting bromocriptine or pergolide may also betemporarily effective in a minority of patients, butleads to a complicated drug regimen, control is oftenshort-lived and side-effects may be frequent.38 Never-theless it is possible that the use of sub-maximumdoses of levodopa in combination with bromocriptinefrom an earlier stage may reduce the severity of on-offoscillations as has been suggested by Rinne.39

New therapeutic strategies(1) Controlled release oral levodopa/peripheral dopadecarboxylase inhibitor preparations. The firstgeneration of sustained-release levodopa preparationswere developed in the early 1970s in an attempt toreduce the frequency of gastrointestinal side-effectsand drug-induced dyskinesias. Disappointing resultsoccurred with the prototype preparations and thisapproach was not pursued.'" The recent research withintravenous levodopa infusions which has shown thatprovided plasma dopa levels can be kept above aminimum effective concentration for an individualpatient mobility is preserved, has encouragedphysicians to put pressure on the pharmaceuticalcompanies to develop a second wave of these prepara-tions. Two galenical formulations have now beenextensively tested throughout the world and one(Madopar CR) has already been marketed in severalEuropean countries including the UK. Madopar CRcomprises hydrocolloids, soluble excipients,hydrogenated fat, lubricants and glidants as well aslevodopa and benserazide. When the matrix comesinto contact with gastric fluid, a hydrated boundarylayer is formed and the drug is released slowly bydiffusion. The exhausted boundary layer is continuallydissipated and each successively exposed rim thenbecomes hydrated. The capsule remains floating onthe top of the stomach contents after a standard mealfor six to twelve hours.

Pharmacokinetic studies have shown that the drugis released and absorbed over 4 to 5 hours maintainingsignificant plasma concentrations for up to 8 hours.The plasma dopa level rises more slowly than withconventional preparations with a lower plateau peak

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34at 1 5 to 3 hours. The oral bioavailability of MadoparCR is 65% that of standard levodopa/benserazide.Madopar CR has been reported to benefit up to two-thirds of patients with fluctuations, but the results aremuch better in patients with a shorter duration ofdisease and duration of therapy. In order to achievesatisfactory results in oscillating patients it is essentialto combine Madopar CR with a morning dose ofconventional Madopar in order to give the patient a"kick start". A proportion ofpatients who have grownaccustomed to the cycles they experience withconventional levodopa preparations find the strikingchange in motor response unacceptable. A mean 50%increase in total dosage is required to obtain goodresults in oscillating patients and there is no overallreduction with Madopar CR in the frequency ofdosage. In our own study some patients experiencedprolonged bouts of unresponsiveness followed bywhat we termed "time bomb effects" with suddenunanticipated relief of disability together with violentabnormal involuntary movements.42 It remains to beshown whether treatment ab initio with controlled-release formulations will reduce the frequency of on-off oscillations and whether they will be able toproduce better overall control of nocturnal disabilitiesthan conventional levodopa.A series of controlled-release prototypes of

levodopa/carbidopa combinations have simul-taneously been developed (Sinemet CR1-CR5) withSinemet CR4 looking the most promising for furtherdevelopment. These are all formulated using apolymeric matrix which releases levodopa andcarbidopa by surface erosion. Studies with these drugshave also indicated a reduced bioavailability (70%that of Sinemet) and the best effects in mildoscillators.43" In a recent randomised studycomparing Madopar CR with Sinemet CR4 inpatients with on-off phenomenon, both preparationsled to a reduction in dose-dependent motor fluctua-tions and there was no major difference between thetwo preparations. Both groups required considerablylarger daily doses of levodopa when on controlled-release therapy (62% for the Madopar CR group and52% for the Sinemet group).45 It seems likely thereforethat there is little to choose between these preparationsand both may confer benefit in a few patients withotherwise refractory motor oscillations. The limitingfactor however in their efficacy is the capricious gastricemptying time and the delay in onset of action.(2) Subcutaneous apomorphine. The use of apomor-phine in the treatment of Parkinson's disease was firstproposed more than a century ago. It was notconfirmed to have beneficial effects until 1954. Cotziasand his colleagues, following their report of thesuccessful use ofhigh doses ofdopa in the treatment ofParkinson's disease, looked for other dopamine

Leesagonists which might confer additional benefit andconducted some careful studies on apomorphineadministering it both orally and parenterally. Theywere able to confirm that the drug had powerful anti-Parkinsonian properties and in some respects was seento complement the effects of levodopa. For example,apomorphine appeared to be most effective in therelief of tremor and had sedative rather than alertingeffects. It was also reported to reduce levodopa-induced dyskinesias and it abolished off periods seenduring sustained levodopa therapy when givenparenterally.When it was given by mouth doses of several grams

were required to obtain good effect and the studies hadto be stopped because of reports of pre-renal uraemia.When it was given subcutaneously apomorphine wasfound to be short-acting and a high incidence ofadverse reactions, particularly nausea, sedation andpostural hypotensions occurred. Interest thereforefaded and greater attention was paid to the develop-ment of longer acting orally administered dopaminereceptor agonist drugs.

In 1982 we investigated the clinical pharmacologicaleffects of subcutaneous apomorphine (1 mg) andcompared it with lisuride, another water solubledopamine receptor agonist (75-150 pg) and salineplacebo in 13 patients with levodopa-provoked on-offeffects. The pharmacological challenges were given 10to 15 minutes after spontaneous off periods and 20 of22 exposures to apomorphine produced positiveresponses with a rapid switch-on, compared to only 16of 35 with lisuride and none from 39 with salinecontrols. The duration of effect with apomorphinelasted from between 45 minutes and 2 hours: thequality of response with lisuride was generally lessgood, some doses wearing off after only 5 to 10minutes or producing intermittent or shifting effects.6Encouraged by these findings we embarked on acomparative study using continuous subcutaneousinfusions of apomorphine and lisuride in refractoryoscillators, using an ambulatory mini-pump systemwith a needle inserted into the abdominal wall. Ourpreliminary results seemed to show a clear difference inresponse between the two drugs with lisuride pro-ducing much less satisfactory therapeutic responsesand a higher frequency ofintolerable side-effects.' Wetherefore decided to concentrate on the use ofapomor-phine administered either as a single shot injectionthrough a penject or by continuous pulsed sub-cutaneous administration. Domperidone (10-20 mgtds), a peripheral dopamine antagonist, was given ascover in the first few weeks of treatment after which itwas often possible to withdraw this without reboundadverse reactions.

Initial long-term results showed that apomorphineproduced a therapeutic response analogous to the

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The on-offphenomenonintravenous injection of levodopa and that it couldmarkedly reduce the mean offtime per day, transform-ing the lives ofmany previously severely handicappedindividuals. The mean dose used in the pump systemwas 89 mg per day (24-207) and it was possible toreduce the mean levodopa dose by 200 mg (from 992-775 mg/day). Psychiatric side-effects were rare, themain complications being tender nodules and panni-culitis with scab formation at the site of the infusionneedle in the abdominal wall. Comparable results wereobtained in patients with more predictable fluctua-tions using a penject system, (mean daily dose 10 mg(1-28 mg), mean number of injections 5 (2-18)), theonly serious adverse reactions occurring in this groupwas one patient who broke the needle in the abdominalwall at the time of injection. Success with bothapproaches depended to a large extent on the anticipa-tion of off periods with the use of the bolus demandsystem (2 mg boluses, mean 9/day) in the pumppatients or the rapid use of the penject beforeimmobility ensued.47We have now given apomorphine to 21 patients by

pump and 32 patients by penject for periods up to 2-5years. With the pump patients, three patients are nowreceiving apomorphine alone, the majority continue torequire some additional levodopa (overall 36%reduction in requirements). This is probably becausemost patients find that it is simpler to have a buffer oflevodopa than use a low background continuous levelof subcutaneous apomorphine and then have tocontinually use the booster at times of relativeunresponsiveness. However, there may of course beadditional pharmacological explanations. Somepatients run their apomorphine continuously for 24hours and have done so for many months withoutapparent loss of long-term responsiveness whereasothers elect to remove the pump system on retiring tobed. No signs of tachyphylaxis have occurred withsupra-threshold doses and a few patients have actuallybeen able to reduce their apomorphine requirementswith time despite keeping their levodopa levels thesame. On the other hand, some patients using penjectsystems have had to increase their mean injection(dose range 1-5 mg) in order to consistently get an onresponse. In those patients receiving penjects whohave always complained that the afternoon period isthe worst time of the day for them, frequently theresponse to apomorphine is less gratifying at this timethan earlier in the day.

Provided a patient's main disabilities occur in the offperiod, apomorphine is consistently of benefit andmay help such varied disturbances as frequency ofmicturition, constipation, pain, dystonia and swallow-ing problems as well as the cardinal signs of thedisorder. If, however, the on period is marred bypostural instability and hypotonia or distressingbiphasic dyskinesias the results are less good. Our

35experience of biphasic dyskinesias has been thatalthough one may get the patient through these into agood on, non-dyskinetic, phase rather more quicklythere is a tendency for the involuntary movements tobreak through at successively higher doses andeventually transform into continuous dyskinesiasduring the "on" period.Our present strategy is to try all oscillators on

penject treatment first because of its relative simplicityand switch to the more expensive pump only if thenumber of injections required to produce smoothmotor control is unacceptably large or the patientcannot react rapidly enough to the vagaries of hismotor state. These encouraging results have now beenconfirmed by several other European groups.49 s' Untila severely oscillating patient has tried subcutaneousapomorphine it would seem unethical to offerexperimental implantation procedures.

(3) Continuous duodenal infusions of levodopa.Erratic gastric emptying may be a factor in theunpredictable absorption of orally administeredlevodopa and the continuous delivery of the amino-acid into the duodenum is one way of attempting toovercome this problem. Direct duodenal infusions oflevodopa via a nasoduodenal tube and mechanicalpump markedly reduced on-off effects and producedmore stable plasma levels in three patients withresistant fluctuations.5 In a further study continuousduodenal infusion of levodopa was found to be moreeffective than intermittent duodenal infusion orSinemet CR4 in controlling offs and producing steadyplasma levels.52 Intolerance of the naso-duodenal tubehas led to consideration of intestinal pouches forlevodopa delivery.53 Infusions have been given forseveral months through a gastrostomy in two patientswith the tube fed on into the proximal duodenum.Local irritation occurred in one patient at the gastricinsertion site, but the results were generally satisfac-tory. Interestingly, a biphasic reduction in levodoparequirements with continuing improvement occurredin both patients, a later more gradual dosage declineoccurring over a sixty day period, raising thepossibility of up-regulation of striatal dopaminereceptors.4' 5 Although this approach may prove to bean interim measure for control of a few compliant,refractory oscillators it is more complex and lesseffective than subcutaneous apomorphine and doesnot get over the difficulty of protein competition withlevodopa at the blood-brain barrier. The approachmight stand a better chance ofpractical success ifdopamethyl ester is used and percutaneous delivery systemsto the proximal duodenum can be devised.

Conclusion

Encouraging inroads are now being made on a

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36phenomenon which for some time was considereduntreatable. Now that it is possible to reduce thedisability induced by diurnal off periods in manypatients the new challenge to long-term managementhas focused on ways of improving the quality of ontime. Although levodopa-induced dyskinesias areclosely yoked to the therapeutic response in mostpatients, it should be possible to devise selective anti-dyskinetic drugs which do not aggravate Parkinsoniandisabilities. Experience with apomorphine shows thatit is possible to have a drug with potent dopaminereceptor stimulant effects which does not cause seriouspsychiatric morbidity. Postural instability appears toescape more readily from dopaminergic control thanthe other cardinal signs and this may ultimately proveto be the single most difficult management problem.Attempts to modify it with drugs acting on differentneurotransmitter systems must be considered. It ispossible that if a long-acting, powerful dopaminereceptor agonist with pharmacological effects similarto those of apomorphine can be devised extension ofduration of effective medical therapy in Parkinson'sdisease could be achieved. Whether continuousparenteral or even intraventricular delivery will proveto be more beneficial than oral administration remainsto be determined.

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