Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:96-101

Subcutaneous apomorphine in the treatment ofParkinson's disease

J P Frankel, A J Lees, P A Kempster, GM Stern

Department ofNeurology, TheMiddlesex andUniversity CollegeHospitals School ofMedicine, LondonJ P FrankelA J LeesP A KempsterGM SternCorrespondence to:Dr A J Lees, Department ofNeurology, The MiddlesexHospital, Mortimer Street,London WIN 8AA, UnitedKingdom.Received 9 June 1989 and inrevised form 26 September1989.Accepted 16 October 1989

AbstractApomorphine a dopamine receptor agon-ist was given subcutaneously to 57levodopa treated parkinsonian patientswith refractory off-period disabilities fora median period of 16 months. In 30 givenintermittent suprathreshold injectionsthe mean number of hours spent in adisabling off state fell from 6-9 to 2-9.Similar benefit was observed in 21patients receiving continuous infusionswith additional boluses on demand bymini-pump (mean reduction of hoursoff from 9-9 to 4-5). Twelve patients havebeen treated for over two years withouttachyphylaxis or loss of response. Theincidence of neuropsychiatric side-effects has been low (7%). Six patientsfailed to show a sustained worthwhileresponse; severe disabilities during "on"9periods being the major problem. Sub-cutaneous apomorphine is proposed asan effective treatment for patients withincapacitating "off" period disabilitiesrefractory to oral medication and shouldbe considered before experimentalimplantation procedures.

The incidence of disabling "on-oft" fluctua-tions increases with the duration of levodopatreatment and after ten years of sustainedtherapy most patients are affected.' For themajority treatment is difficult. The use ofselegiline,23 partial substitution of levodopa byorally administered dopamine agonists4 andcontrolled-release levodopa preparations56may temporarily extend "on" periods in somepatients. Subcutaneous apomorphine, a direc-tly acting dopamine agonist with affinity forboth D 1 and D2 receptors, rapidly and consis-tently reverses the "off" period motor deficit.78We have previously described our initial

experience with either continuous subcutan-eous infusion or intermittent parenteral injec-tion of apomorphine in 19 patients with severe"on-off" fluctuations.9 Eleven patients treatedwith subcutaneous infusion showed markedand sustained improvement; mean "off' hoursper day were reduced from 10-1 to 3-8 andduring the remaining "off" periods the meandisability score fell. Comparable results wereobtained in eight patients with less severedisabilities given intermittent injections. Otherreports have supported these observations.112We report our further experience in 57

patients with disabling levodopa related motor

oscillations treated with subcutaneous apo-morphine for periods up to 32 months.The effects of apomorphine in patients with

additional disabilities including biphasic dys-kinesias, urinary dysfunction and "oft" periodpain, dystonia, dyspnoea, anismus and belch-ing have also been studied.

Patients and methodsFifty seven levodopa treated patients withidiopathic Parkinson's disease were treatedwith apomorphine. In all cases disabling "on-off" fluctuations in motor performance re-mained despite attempts to improve control byredistribution of levodopa doses, concurrentuse of dopamine agonists (57%) or selegiline(91 %), controlled release levodopa prepara-tions (10%), and dietary protein restriction.Their mean age was 58-9 years and diseaseduration 15 9 years. All patients were admittedto hospital for pre-treatment assessment andinstruction in the use of subcutaneous injectionor infusion techniques.

It was first established that patients hadincapacitating fluctuations, despite optimallytimed doses of levodopa, by both clinical ob-servation and the use of self-scoring patientdiaries. If necessary, oral challenges of levo-dopa after withdrawal of overnight medicationwas followed by assessment to determine theduration of motor response and quality of the"on" period.

Patients with significant cardiovascular,hepatic or renal pathology were excluded. NQpatients with current evidence of neuro-psychiatric disturbance or dementia wereincluded. Routine haematological and bi9-chemical indices were measured before therapyand thereafter at monthly intervals.To avoid side-effects such as nausea, vomit-

ing and postural hypotension, domperidone,13a peripherally acting dopamine receptor

Figure 1 The 'Penject' multiple injection device.

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Subcutaneous apomorphine in the treatment of Parkinson's disease

antagonist (20 mg orally) was given two hoursbefore a test dose of apomophine. One mg ofapomorphine (apomorphine HCl 10 mg/ml)was given subcutaneously during an "off"period, provoked by witholding levodopamedication. Incremental increases of 1 mg ofapomorphine every 20 minutes were then givenuntil an unequivocal motor response occurred.This was defined as improvement in motorperformance equivalent to that previouslyobserved during the patient's "on" periods.Measurement of standing and sitting bloodpressure was performed every ten minutes andfor up to 40 minutes after the onset ofthe motorresponse.Double the threshold dose was then given

by intermittent subcutaneous injection froman insulin syringe mounted in a 'Penject'(Hypoguard Ltd, Melton, Suffolk) (fig 1). Thisfacilitates the administration of several pre-setdoses, can be conveniently carried by thepatient and is easier to use for many patientsthan a conventional syringe alone. While re-maining on their usual levodopa regimepatients learned the technique of subcutaneousinjection into the abdomen or thighs and werealso taught to anticipate "off" periods. If thiswas not possible they were advised to injectthemselves as soon as the "off" period had setin. Whenever possible spouses were also taughtthe technique. Most patients returned homewithin 10 days. With initial weekly outpatientreviews the process of education was continuedand it was usually clear within a few weekswhether or not a patient was benefitting.

Patients whose overall control remainedunsatisfactory but were known to have good"on"' period response to single intermittentdoses of apomorphine were transferred to con-tinuous subcutaneous infusion by minipump.The Graseby MS 26 (fig 2) or MS 16A

syringe drivers (Graseby Medical Ltd,Watford, Herts) were used, the MS 26 is able todeliver apomorphine solution (10 mg/ml) up to5 mg per hour (by increments of 0 05 mg perhour) and also provide bolus doses of 0 3 mg(the MS 16A has a maximum rate of 25 mg/hour, increments of 1 25 mg/hour and bolusdoses of 1 25 mg).The delivery needle (Travenol Auto Syringe

Microvolume Infusion Set-CambridgeHealth Care Ltd, Cambridge, United King-dom) was inserted subcutaneously into theabdominal wall and the site changed at leastdaily. Continuous infusion was started at a rateof 1 mg per hour then increased according tothe individual response each day. Patients wereencouraged to make use of the booster functionof the pump in anticipation of "off" periods.The basal rate of infusion and the size andfrequency of bolus doses were titrated againstthe response, increasing the former to reduceseverity and duration of "off" periods and thelatter as a fine tuning to control remaining"offs". Whenever possible patients were en-couraged to employ the bolus function ratherthan increasing the background continuousrate. Adjustment of the patients' levodoparegimes, by reducing the size and frequency ofdose, was attempted once apomorphine treat-

Figure 2 (a) The Graseby MS 26 syringe driver,(b) A patient with the driver in a shoulder holster,alternatively it can be carried in the pocket orfrom a belt.

ment was in progress. Statistical analysis wasby Student's t test with comparison of pairedsamples.

ResultsA. On-off oscillations(i) Intermittent dosesThirty-two patients (19 men; 13 women),mean age 59 0 years (range 40-73), were treatedwith multiple intermittent injections. Theirmean duration of disease was 14-5 years (range5-23), mean duration of levodopa therapy 12 8years (3-20) and mean Hoehn and Yahr score3 5 (2-5).Diary records in the first eight patients

treated, showed a mean reduction in "off"hours from 6-0 to 2-7 (p < 0-01) shortly afterstarting apomorphine; at one year mean "off"hours was 3-2. The 30 patients who remainedon long-term treatment were reviewed after amean duration of 13 5 months (range 5-26).Total daily "off" hours fell from 6-9 beforetreatment to 2 9 (p < 0 02); this improvementhas been maintained.

Individual injections of apomorphine, givenduring "off' periods, produced benefit subjec-tively equivalent to the levodopa "on" periodmotor response. Larger doses increased dura-tion of action and the severity of dyskinesias.Some patients would vary the dose dependingupon the severity of an "off" period. Dosefailure was reported more often later in the day.This appeared to correlate with the increased

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Frankel, Lees, Kempster, Stern

Table 1 Total number ofpatients treated with both intermittent injection and continuous infusion

Total number Number of Number treated Number oftreated early failures long-term late failures

Intermittent doses 32 (19 males, 13 females) 2 (inter-dose dyskinesia) 30 0Continuous infusion 25 (15 males, 10 females) 3 (biphasic dyskinesia) 21 1 (problem with pump

technique)1 (hallucinosis/paranoia) 1 (hypotonia/mutism)

occurrence of "off" periods -at that time ratherthan to reduced effectiveness of the injections.When doses were not adequate a repeat injec-tion after 15 minutes usually produced benefit.

Patients remained on similar doses of levo-dopa (mean pre-treatment dose 854 mg/daypost-treatment 815 mg/day). Domperidoneneeded to be continued in 600O of patientsmean dose 41 1 mg/day (range 10-60 mg), fif-teen (500') continued to take bromocriptine,amantadine or anticholinergic medication and12 (400,o) remained on selegiline HCl.The dose of apomorphine ranged between

0-2-5 mg (mean 2-2 mg), mean frequency ofinjection 4 8 per day (range 2-18) and meantotal daily dose 10-2 mg (0 8-27 5). The onsetof response to apomorphine began after a meanof 7-5 minutes (range 3-5-12 5). Typically asingle injection of apomorphine had a durationof action of about one hour (range 20-120minutes). Thirty three per cent of the patientsreported some reduction in the duration ofaction of apomorphine doses but only 13%complained of any loss of benefit. The reversalofmotor deficit was often preceded by repeatedyawning sometimes associated with som-nolence especially during the first few days oftreatment. Ten patients (330o0) used apomor-phine at night to improve nocturnal akinesia orother "off" period disabilities.

(ii) Continuous infusionTwenty-five patients (15 men; 10 women) havebeen treated by continuous subcutaneousinfusion of apomorphine; mean age 58 8 years(range 40-74), duration of disease 17-8 years(7-24) duration of levodopa therapy 15 6 years(3-20) and Hoehn and Yahr stage 41 (4-5).Twenty one continued on long-term treatmentfor up to 32 months, with little change in totaldaily apomorphine requirements. Infusionrates ranged between 1-25-5 5 mg/hour (mean3.3 mg/hour), equivalent to 0 02-0-08 mg/kg/hour (mean 0 05 mg/kg/hour); with themajority of patients requiring between 2-4 mg/hour. Patients supplemented the continuousinfusion with an average of 9 5 bolus doses perday (range 0-32) at a mean dose of 2 4 mg perbolus (range 1 0-7 5). Onset of action followinga booster dose was slightly slower in this groupcompared with those on intermittent in-

jections, the mean delay being 9-0 minutes(range 5-15). The total daily dose for indi-vidual patients varied between 24 and 207 mg(mean 89 mg/day). Seven patients (33%O) tookapomorphine for 24 hours per day with noapparent loss of efficacy.Diary records from the first 11 cases treated

showed a fall in mean total "off" hours from10-1 to 3 8 (p < 0 01); at one year. Review ofthe 21 patients who received long-term treat-ment (mean duration 22 months, range 5-32)showed a fall in mean total daily "off" hoursfrom 9-9 to 4 5 (p < 0-01).Levodopa requirements fell in over 60% of

patients, irrespective of duration of treatment,with a mean reduction of 21 87% (from 992 to775 mg/day: nsp < 0-1); when the data forcases on treatment for over 18 months wereanalysed separately this reduction was 32%(p < 0 02). Three patients were able to dis-continue levodopa.

Seven patients (3300) continued to requireoral domperidone at a mean daily dose of 35 mgthe remainder were able to withdraw the drugwithout ill-effect. Ten remained on some formof oral antiparkinsonian medication other thanlevodopa: six taking anticholinergics, threebromocriptine, two amantidine and one selegi-line HC1. One patient elected to change backfrom continuous infusion to intermittent injec-tion.

B DyskinesiasMost patients had only moderately severedrug-induced involuntary movements during"on" periods. There were however four withdisabling biphasic dyskinesias and nine withsevere inter-dose involuntary movements. Bi-phasic dyskinesias initially responded favour-ably to both single injections and continuousinfusions of apomorphine, but improvementwas maintained for at most a few days afterwhich dyskinesias broke through and event-ually occurred almost continually during "on"periods. In five of the patients with severeinter-dose chorea it was possible to reduce thefrequency and severity of drug-induced dys-kinesia, by reducing the frequency and size oflevodopa doses and treating the resulting in-crease in "off" periods with appropriately

Table 2 Daily "off" hours, apomorphine and levodopa requirements before treatment and on long-term follow up.

Mean duration Total daily "off" hours Mean total daily levodopa dose, mgof treatment Mean total dailymonths Before After Before After apomorphine dose,(range) treatment treatment treatment treatment mg (range)

Intermittent injection 13 5 6 9 2-9* 854 815 10-2(n = 30) (5-26) (08-27-5)

Continuous infusion 22 9 9 4 5** 992 775 89(n = 21) (5-32) (24-207)

*p < 0 02; **p < 0-01.

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timed doses of apomorphine. However, worth-while improvement was not always possibleparticularly when this feature alone had beenthe main incapacity. In two patients in whom itwas not possible to reduce dyskinesia severitythey elected to continue occasional apomor-phine injections to treat particularly severe"off" episodes, when conversion to a dyskin-etic state was felt to be preferable. One, of fourtreated, with biphasic dyskinesias remained onapomorphine, using single injections ap-proximately once per day to provide a rapid andreliable "on" usually in the late afternoon whentheir response to levodopa had been unpre-dictable.

C Positive "off' period phenomenaInjections of apomorphine were useful interminating other parkinsonian disabilities.Two patients with "off" period functionalbladder outlet obstruction'4 benefited fromappropriately timed injections; three withparkinsonian obstructive defaecation (anis-mus)'5 16 were able to empty their bowels moreeffectively; three with severe "off" period limband pelvic pain and two with early morningdystonia responded promptly; two sufferingfrom distressing paroxysmal belching during"off" periods'7 resistant to oral levodopa foundthat appropriately timed doses almost com-pletely suppressed the symptom; and one manwith "off" period hallucinations respondedwell to intermittent injection. We also gaveapomorphine infusions to two patients withadvanced disease who had critically deterio-rated; in one precipitated by a chest infectionand in the other following a profound depres-sive illness when the patient had discontinuedlevodopa. Both were in extremis with general-ised rigidity, akinesia and fever despite maxi-mal tolerated doses of levodopa. They weregiven apomorphine and the dose graduallyincreased up to 14 mg per hour. Both respon-ded well.

D Treatment failuresTwo patients with marked inter-dose dyskin-esia on levodopa were withdrawn from treat-ment with intermittent doses of apomorphinebecause of a worsening of their involuntarymovements. Four patients (on continuous in-fusion) initially thought suitable were with-drawn from treatment because of side effects;in three because of an unacceptable increase inbiphasic dyskinesias and hallucinations in theother. Late withdrawal oftreatment was neces-sary in two of the 21 patients, on subcutaneousinfusion, whose initial response was satisfac-tory. The first had marked oscillations in motorfunction with severe inter-dose dyskineticmovements on levodopa. With apomorphinesignificant improvement in overall mobilitywas achieved in hospital but this could not bemaintained at home. She was unable to copewith the technique and returned to conven-tional drug therapy. A second patient withinitial sustained benefit developed late hypo-tonia and mutism.

E Adverse reactions(i) CutaneousAll patients on continuous infusions developednodules at the needle sites. Severity was relatedto the total daily dose of apomorphine. In threepatients infusion site nodules became infectedrequiring incision and drainage. Excessivebleeding from the needle site immediately afterinsertion occurred in a patient who had vonWillebrand's disease; a second patient bledprofusely from an old infected abdominal in-fusion site (with a particularly severe nodularreaction) and required blood transfusion.Intermittent injections caused itchy nodules ina minority of patients.

(ii) NeuropsychiatricVisual hallucinations and confusion occurredin three patients, on continuous apomorphineinfusions. After six months of treatment, a 60year old woman complained of seeing smallworms on her food and in her home, thesesymptoms resolved when her apomorphine wasreduced. A 67 year old man experienced visualpseudo-hallucinations which had previouslyoccurred when taking levodopa and a 62 yearold man, given a trial of apomorphine, devel-oped paranoid ideas and complained of seeinganimals and people. His mental state returnedto normal on withdrawal oftreatment. Also a 67year old woman with severe disability, who hadresponded favourably for over six months oncontinuous infusion, became gradually moredisabled by hypotonia during "on" periods.She then became increasingly paranoid andwithdrawn, and later mute. Both levodopa andapomorphine were withdrawn in turn withoutimprovement.Three patients with histories of psychosis on

other antiparkinsonian medication were notaffected.(iii) Other symptomsMost patients initially experienced mild drow-siness usually accompanied by yawning butthis persisted only in two. Many reportedoccasional nausea in relation to apomorphineinjections and postural hypotension was en-countered on two occasions, this was usuallyattributable to the omission of domperidone.A 62 year old man consistently noticed a

generalised unpleasant sensation followingapomorphine injections which he had not ex-perienced after doses of levodopa producing acomparable benefit. Two patients describedrhinorrhoea and increased lacrimation shortlyafter injections; one had previously noted thesame phenomena after levodopa.A 58 year old man, complained of reduced

facial hair growth and loss of libido afterstarting treatment with intermittent injectionsof apomorphine. On the other hand, a 64 yearold man became embarrassingly hyperlibidin-ous.An overdose of apomorphine occurred in a

62 year old man on a continuous infusion. Hiswife accidentally injected subcutaneouslyabout 25 mg of apomorphine. After three min-utes he felt faint, nauseated, lost consciousnessand recovered within 20 minutes. He was thenfound to be alert with a pulse rate of 40/minute

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and his supine blood pressure was 90/50 mmHg. He recovered completely within an hour.One patient broke a needle during injection andthe fragment remains in the subcutaneoustissue.

(iv) Laboratory investigationsPeripheral blood eosinophilia of up to 10 percent occurred shortly after starting therapy inall patients treated by continuous infusion; thisreturned to normal in about half of the patientstreated for over one year. Other haematologicalindices, including plasma urea and creatinineconcentrations remained normal.A 44 year old woman on treatment with

levodopa for 12 years and apomorphine for 28months developed an autoimmune haemolyticanaemia with a positive Coomb's test; theagglutinating antibody was identified as IgG.This picture was typical of that described inlevodopa induced autoimmune haemolyticanaemia. 189

DiscussionSubcutaneous apomorphine has led to a sus-tained marked improvement in a selected groupof parkinsonian patients hitherto disabled byrefractory and severe "off" period disabilities.Providing a patient's "on" response tolevodopa is not marred by severe dyskinesia,hypotonia or psychotoxicity, apomorphine isusually beneficial, improving the quality of lifeand often restoring functional independence.Although it may be possible to diminish dys-kinesias by giving apomorphine with conco-mitant reduction of levodopa, we have foundthe antiparkinsonian effects of apomorphineand levodopa to be strikingly similar and havebeen unable to confirm the specific anti-dys-kinetic effects reported by Duby and col-leagues.20 When inter-dose dyskinesia persists,it is the overall improvement when comparedwith the "off" period motor state which deter-mines the success of treatment. This alsodepends on the patient understanding therationale for using apomorphine and his or herability to anticipate or at least identify "off"periods. Our usual strategy is, to first treat withintermittent injections only changing later tocontinuous minipump infusion if oscillationsremain prominent. In most cases the formerregime is found to be adequate.

In only three cases was it possible to achievestable control on apomorphine without levo-dopa. This was not because apomorphine wasweaker than levodopa but because the dosesand therefore volumes of solution needed formonotherapy led to problems with skinnodules.

In general, apomorphine was well toleratedwith relatively few side effects and no sig-nificant tolerance to the therapeutic antipark-insonian effect was seen. On the other hand,tachyphylaxis to nausea and postural hypoten-sion occurred rapidly. Reversible neuropsy-chiatric toxicity was uncommon. It may be thatpsychotoxic effects seen more frequently withother dopamine agonists occur as a result ofdifferent actions on dopamine receptor sub-

types or other transmitter systems or perhapsapomorphine has intrinsic anti-psychoticactivity,2' possibly from the piperidine moietyof the molecule.22

Intermittent injections may also be useful intreating a variety of isolated "off" periodproblems such as pain, dystonia, voiding dys-function, anismus, hallucinosis, backache andbelching.""'7 We consider some of these phe-nomena to be directly related to sustainedlevodopa therapy and not simply a return offormer parkinsonian disability. Our experiencewith two patients with critical deterioration as aresult of intercurrent illness suggests that theremay be an emergency role for subcutaneousapomorphine including the management of thelevodopa withdrawal syndrome which closelyresembles the "neuroleptic malignant syn-drome". Finally an apomorphine challenge,after domperidone pre-treatment, may prove tobe a useful quick test for dopaminergicresponsiveness.2'These clinical observations using apomor-

phine may have some bearing on understand-ing the mechanism of the motor response tolevodopa. The exact mode ofaction oflevodopais disputed but it has been suggested that pre-synaptic conversion to dopamine and intra-neuronal storage are essential to its action.'Even if therapeutic responses to levodopa arenot dependent on synaptic release of dopamineby surviving nigro-striatal terminals, theseterminals are the major sites of dopamineformation from exogenous levodopa in thestriatum.24 Apomorphine while possessingboth D1 and D2 receptor agonist propertiesdoes not share transport or metabolic pathwayswith levodopa. Although in intact experimentalanimals, administration of apomorphine sup-presses the rate of firing of nigro-striatal cells25and in low dose has been found to produce areduction in locomotor activity, thought torepresent pre-synaptic inhibition of endo-genous dopamine release, its actions on parkin-sonian motor disability are likely to bemediated totally at post-synaptic receptor sites.Comparison therefore of motor responses to

levodopa and apomorphine may be relevant intrying to elucidate the mechanism of differentdegrees of levodopa responsiveness betweenindividual parkinsonian patients. If impairedresponsiveness is due to pre-synaptic changesin nigro-striatal terminals, differences in res-ponsiveness to levodopa and apomorphinemight be expected; whereas similarity in thepattern and magnitude of levodopa and apo-morphine responses would suggest that dif-ferences in post-synaptic receptors cause dif-ferences in responsiveness. Our findings sup-port the latter, but we have only looked atpatients with prolonged disease duration whohave either developed symptomatic motor os-cillations or other problems during medium orlong term treatment, we have not done com-parative levodopa/apomorphine studies onuntreated patients or those treated for a shorttime.However, these considerations may still be of

relevance to the practical long term manage-ment ofparkinsonian patients with levodopa or

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dopamine agonist medication. If limitations indrug responsiveness are caused by striatal post-synaptic factors such as loss of receptor num-bers or sensitivity, and motor responses tolevodopa and apomorphine are equivalent inindividual patients, it follows that the quality of"on" phase motor function on levodopatherapy is unlikely to be surpassed by otherantiparkinsonian agents acting on the dopa-minergic system. The maximum expectedbenefit from treatment with levodopa ordopamine agonist medication would be tomaintain individual patients in "on" states forthe greatest proportio.1 of the time. If thedifference between "on" and "off' phasemotor function is small, especially when thedegree of disability is large, use of dopamineagonist therapy in conjunction with drug de-livery technology (including subcutaneousdelivery of apomorphine) or of surgical tech-niques to deliver levodopa or dopamine direct-ly into the brain or CSF is unlikely to producesignificant benefit.

Despite these reservations it seems likely thatthe duration of effective medical treatment canbe significantly extended for many patients.These results also suggest that a search shouldcontinue for a long-acting powerful orallyadministered dopamine receptor agonist with apharmacological profile similar to apomor-phine. In the meantime the use of parenteralapomorphine provides an effective safe way ofdiminishing disabling "off" periods in levo-dopa treated patients.

This paper was presented at the 41st annualmeeting of the American Academy ofNeurology, Chicago, April 1989.

PAK and JPF were Kate Stillman ResearchFellows. Support was also provided by theParkinson's Disease Society of Great Britain.We thank Diana Wade and Jenny Wooten ofthe North iMiddlesex Hospital Sterile Produc-tion Unit for preparation of the apomorphinesolution.

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