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96 Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:96-101 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from Subcutaneous in the treatment of Parkinson's disease

J P Frankel, A J Lees, P A Kempster, G M Stern

Abstract oscillations treated with subcutaneous apo- Apomorphine a agon- for periods up to 32 months. ist was given subcutaneously to 57 The effects of apomorphine in patients with levodopa treated parkinsonian patients additional disabilities including biphasic dys- with refractory off-period disabilities for kinesias, urinary dysfunction and "oft" period a median period of 16 months. In 30 given pain, dystonia, dyspnoea, anismus and belch- intermittent suprathreshold injections ing have also been studied. the mean number of hours spent in a disabling off state fell from 6-9 to 2-9. Similar benefit was observed in 21 Patients and methods patients receiving continuous infusions Fifty seven levodopa treated patients with with additional boluses on demand by idiopathic Parkinson's disease were treated mini-pump (mean reduction of hours with apomorphine. In all cases disabling "on- off from 9-9 to 4-5). Twelve patients have off" fluctuations in motor performance re- been treated for over two years without mained despite attempts to improve control by tachyphylaxis or loss of response. The redistribution of levodopa doses, concurrent incidence of neuropsychiatric side- use of dopamine (57%) or effects has been low (7%). Six patients (91 %), controlled release levodopa prepara- failed to show a sustained worthwhile tions (10%), and dietary protein restriction. response; severe disabilities during "on"9 Their mean age was 58-9 years and disease periods being the major problem. Sub- duration 15 9 years. All patients were admitted cutaneous apomorphine is proposed as to hospital for pre-treatment assessment and an effective treatment for patients with instruction in the use ofsubcutaneous injection incapacitating "off" period disabilities or infusion techniques. refractory to oral medication and should It was first established that patients had be considered before experimental incapacitating fluctuations, despite optimally implantation procedures. timed doses of levodopa, by both clinical ob- servation and the use of self-scoring patient diaries. If necessary, oral challenges of levo- http://jnnp.bmj.com/ The incidence of disabling "on-oft" fluctua- dopa after withdrawal of overnight medication tions increases with the duration of levodopa was followed by assessment to determine the treatment and after ten years of sustained duration of motor response and quality of the therapy most patients are affected.' For the "on" period. majority treatment is difficult. The use of Patients with significant cardiovascular, selegiline,23 partial substitution of levodopa by hepatic or renal pathology were excluded. NQ

orally administered dopamine agonists4 and patients with current evidence of neuro- on September 29, 2021 by guest. Protected copyright. controlled-release levodopa preparations56 psychiatric disturbance or dementia were may temporarily extend "on" periods in some included. Routine haematological and bi9- patients. Subcutaneous apomorphine, a direc- chemical indices were measured before therapy tly acting dopamine with affinity for and thereafter at monthly intervals. both D 1 and D2 receptors, rapidly and consis- To avoid side-effects such as nausea, vomit- tently reverses the "off" period motor deficit.78 ing and postural , ,13 Department of We have previously described our initial a peripherally acting Neurology, The Middlesex and experience with either continuous subcutan- University College eous infusion or intermittent parenteral injec- Hospitals School of tion of apomorphine in 19 patients with severe Medicine, London "on-off" fluctuations.9 Eleven treated J P Frankel patients A J Lees with subcutaneous infusion showed marked P A Kempster and sustained improvement; mean "off' hours G M Stern per day were reduced from 10-1 to 3-8 and Correspondence to: Dr A J Lees, Department of during the remaining "off" periods the mean Neurology, The Middlesex disability score fell. Comparable results were Hospital, Mortimer Street, London WIN 8AA, United obtained in eight patients with less severe Kingdom. disabilities given intermittent injections. Other Received 9 June 1989 and in reports have supported these observations.112 revised form 26 September 1989. We report our further experience in 57 Accepted 16 October 1989 patients with disabling levodopa related motor Figure 1 The 'Penject' multiple injection device. Subcutaneous apomorphine in the treatment of Parkinson's disease 97 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from antagonist (20 mg orally) was given two hours , './ .r..: before a test dose of apomophine. One mg of go"..'. t-.. .eR.I apomorphine (apomorphine HCl 10 mg/ml) was given subcutaneously during an "off" period, provoked by witholding levodopa medication. Incremental increases of 1 mg of apomorphine every 20 minutes were then given until an unequivocal motor response occurred. This was defined as improvement in motor performance equivalent to that previously observed during the patient's "on" periods. Measurement of standing and sitting was performed every ten minutes and for up to 40 minutes after the onset ofthe motor response. Double the threshold dose was then given by intermittent from an insulin syringe mounted in a 'Penject' (Hypoguard Ltd, Melton, Suffolk) (fig 1). This facilitates the administration of several pre-set doses, can be conveniently carried by the patient and is easier to use for many patients than a conventional syringe alone. While re- maining on their usual levodopa regime , patients learned the technique of subcutaneous injection into the abdomen or thighs and were also taught to anticipate "off" periods. If this was not possible they were advised to inject themselves as soon as the "off" period had set in. Whenever possible spouses were also taught the technique. Most patients returned home within 10 days. With initial weekly outpatient reviews the process of education was continued and it was usually clear within a few weeks Figure 2 (a) The Graseby MS 26 syringe driver, whether or not a patient was benefitting. (b) A patient with the driver in a shoulder holster, Patients whose overall control remained alternatively it can be carried in the pocket orfrom a belt. unsatisfactory but were known to have good ment was in progress. Statistical analysis was "on"' period response to single intermittent by Student's t test with of doses of apomorphine were transferred to con- comparison paired tinuous subcutaneous infusion by minipump. samples. The Graseby MS 26 (fig 2) or MS 16A syringe drivers (Graseby Medical Ltd, Results http://jnnp.bmj.com/ Watford, Herts) were used, the MS 26 is able to A. On-off oscillations deliver apomorphine solution (10 mg/ml) up to (i) Intermittent doses 5 mg per hour (by increments of 0 05 mg per Thirty-two patients (19 men; 13 women), hour) and also provide bolus doses of 0 3 mg mean age 59 0 years (range 40-73), were treated (the MS 16A has a maximum rate of 25 mg/ with multiple intermittent injections. Their hour, increments of 1 25 mg/hour and bolus mean duration of disease was 14-5 years (range

doses of 1 25 mg). 5-23), mean duration of levodopa therapy 12 8 on September 29, 2021 by guest. Protected copyright. The delivery needle (Travenol Auto Syringe years (3-20) and mean Hoehn and Yahr score Microvolume Infusion Set-Cambridge 3 5 (2-5). Health Care Ltd, Cambridge, United King- Diary records in the first eight patients dom) was inserted subcutaneously into the treated, showed a mean reduction in "off" abdominal wall and the site changed at least hours from 6-0 to 2-7 (p < 0-01) shortly after daily. Continuous infusion was started at a rate starting apomorphine; at one year mean "off" of 1 mg per hour then increased according to hours was 3-2. The 30 patients who remained the individual response each day. Patients were on long-term treatment were reviewed after a encouraged to make use ofthe booster function mean duration of 13 5 months (range 5-26). of the pump in anticipation of "off" periods. Total daily "off" hours fell from 6-9 before The basal rate of infusion and the size and treatment to 2 9 (p < 0 02); this improvement frequency of bolus doses were titrated against has been maintained. the response, increasing the former to reduce Individual injections of apomorphine, given severity and duration of "off" periods and the during "off' periods, produced benefit subjec- latter as a fine tuning to control remaining tively equivalent to the levodopa "on" period "offs". Whenever possible patients were en- motor response. Larger doses increased dura- couraged to employ the bolus function rather tion of action and the severity of . than increasing the background continuous Some patients would vary the dose depending rate. Adjustment of the patients' levodopa upon the severity of an "off" period. Dose regimes, by reducing the size and frequency of failure was reported more often later in the day. dose, was attempted once apomorphine treat- This appeared to correlate with the increased 98 Frankel, Lees, Kempster, Stern J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from Table 1 Total number ofpatients treated with both intermittent injection and continuous infusion

Total number Number of Number treated Number of treated earlyfailures long-term latefailures Intermittent doses 32 (19 males, 13 females) 2 (inter-dose ) 30 0 Continuous 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 rather jections, the mean delay being 9-0 minutes than to reduced effectiveness of the injections. (range 5-15). The total daily dose for indi- When doses were not adequate a repeat injec- vidual patients varied between 24 and 207 mg tion after 15 minutes usually produced benefit. (mean 89 mg/day). Seven patients (33%O) took Patients remained on similar doses of levo- apomorphine for 24 hours per day with no dopa (mean pre-treatment dose 854 mg/day apparent loss of efficacy. post-treatment 815 mg/day). Domperidone Diary records from the first 11 cases treated needed to be continued in 600O of patients showed a fall in mean total "off" hours from mean dose 41 1 mg/day (range 10-60 mg), fif- 10-1 to 3 8 (p < 0 01); at one year. Review of teen (500') continued to take , the 21 patients who received long-term treat- or medication and ment (mean duration 22 months, range 5-32) 12 (400,o) remained on selegiline HCl. showed a fall in mean total daily "off" hours The dose of apomorphine ranged between from 9-9 to 4 5 (p < 0-01). 0-2-5 mg (mean 2-2 mg), mean frequency of Levodopa requirements fell in over 60% of injection 4 8 per day (range 2-18) and mean patients, irrespective of duration of treatment, total daily dose 10-2 mg (0 8-27 5). The onset with a mean reduction of 21 87% (from 992 to of response to apomorphine began after a mean 775 mg/day: nsp < 0-1); when the data for of 7-5 minutes (range 3-5-12 5). Typically a cases on treatment for over 18 months were single injection of apomorphine had a duration analysed separately this reduction was 32% of action of about one hour (range 20-120 (p < 0 02). Three patients were able to dis- minutes). Thirty three per cent of the patients continue levodopa. reported some reduction in the duration of Seven patients (3300) continued to require action of apomorphine doses but only 13% oral domperidone at a mean daily dose of35 mg complained of any loss of benefit. The reversal the remainder were able to withdraw the drug of motor deficit was often preceded by repeated without ill-effect. Ten remained on some form yawning sometimes associated with som- of oral antiparkinsonian medication other than nolence especially during the first few days of levodopa: six taking , three treatment. Ten patients (330o0) used apomor- bromocriptine, two amantidine and one selegi- phine at night to improve nocturnal akinesia or line HC1. One patient elected to change back other "off" period disabilities. from continuous infusion to intermittent injec- tion. (ii) Continuous infusion Twenty-five patients (15 men; 10 women) have been treated by continuous subcutaneous B Dyskinesias http://jnnp.bmj.com/ infusion of apomorphine; mean age 58 8 years Most patients had only moderately severe (range 40-74), duration of disease 17-8 years drug-induced involuntary movements during (7-24) duration of levodopa therapy 15 6 years "on" periods. There were however four with (3-20) and Hoehn and Yahr stage 41 (4-5). disabling biphasic dyskinesias and nine with Twenty one continued on long-term treatment severe inter-dose involuntary movements. Bi- for up to 32 months, with little change in total phasic dyskinesias initially responded favour- daily apomorphine requirements. Infusion ably to both single injections and continuous on September 29, 2021 by guest. Protected copyright. rates ranged between 1-25-5 5 mg/hour (mean infusions of apomorphine, but improvement 3.3 mg/hour), equivalent to 0 02-0-08 mg/kg/ was maintained for at most a few days after hour (mean 0 05 mg/kg/hour); with the which dyskinesias broke through and event- majority ofpatients requiring between 2-4 mg/ ually occurred almost continually during "on" hour. Patients supplemented the continuous periods. In five of the patients with severe infusion with an average of 9 5 bolus doses per inter-dose chorea it was possible to reduce the day (range 0-32) at a mean dose of 2 4 mg per frequency and severity of drug-induced dys- bolus (range 1 0-7 5). Onset ofaction following kinesia, by reducing the frequency and size of a booster dose was slightly slower in this group levodopa doses and treating the resulting in- compared with those on intermittent in- crease in "off" periods with appropriately

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

Mean duration Total daily "off" hours Mean total daily levodopa dose, mg of treatment Mean total daily months 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. Subcutaneous apomorphine in the treatment of Parkinson's disease 99 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from timed doses ofapomorphine. However, worth- E Adverse reactions while improvement was not always possible (i) Cutaneous particularly when this feature alone had been All patients on continuous infusions developed the main incapacity. In two patients in whom it nodules at the needle sites. Severity was related was not possible to reduce dyskinesia severity to the total daily dose of apomorphine. In three they elected to continue occasional apomor- patients infusion site nodules became infected phine injections to treat particularly severe requiring incision and drainage. Excessive "off" episodes, when conversion to a dyskin- bleeding from the needle site immediately after etic state was felt to be preferable. One, of four insertion occurred in a patient who had von treated, with biphasic dyskinesias remained on Willebrand's disease; a second patient bled apomorphine, using single injections ap- profusely from an old infected abdominal in- proximately once per day to provide a rapid and fusion site (with a particularly severe nodular reliable "on" usually in the late afternoon when reaction) and required blood transfusion. their response to levodopa had been unpre- Intermittent injections caused itchy nodules in dictable. a minority of patients. (ii) Neuropsychiatric C Positive "off' period phenomena Visual and occurred Injections of apomorphine were useful in in three patients, on continuous apomorphine terminating other parkinsonian disabilities. infusions. After six months of treatment, a 60 Two patients with "off" period functional year old woman complained of seeing small bladder outlet obstruction'4 benefited from worms on her food and in her home, these appropriately timed injections; three with symptoms resolved when her apomorphine was parkinsonian obstructive defaecation (anis- reduced. A 67 year old man experienced visual mus)'5 16 were able to empty their bowels more pseudo-hallucinations which had previously effectively; three with severe "off" period limb occurred when taking levodopa and a 62 year and pelvic pain and two with early morning old man, given a trial of apomorphine, devel- dystonia responded promptly; two suffering oped paranoid ideas and complained of seeing from distressing paroxysmal belching during animals and people. His mental state returned "off" periods'7 resistant to oral levodopa found to normal on withdrawal oftreatment. Also a 67 that appropriately timed doses almost com- year old woman with severe disability, who had pletely suppressed the symptom; and one man responded favourably for over six months on with "off" period hallucinations responded continuous infusion, became gradually more well to intermittent injection. We also gave disabled by hypotonia during "on" periods. apomorphine infusions to two patients with She then became increasingly paranoid and advanced disease who had critically deterio- withdrawn, and later mute. Both levodopa and rated; in one precipitated by a chest infection apomorphine were withdrawn in turn without and in the other following a profound depres- improvement. sive illness when the patient had discontinued Three patients with histories ofpsychosis on levodopa. Both were in extremis with general- other antiparkinsonian medication were not ised rigidity, akinesia and fever despite maxi- affected. mal tolerated doses of levodopa. They were (iii) Other symptoms http://jnnp.bmj.com/ given apomorphine and the dose gradually Most patients initially experienced mild drow- increased up to 14 mg per hour. Both respon- siness usually accompanied by yawning but ded well. this persisted only in two. Many reported occasional nausea in relation to apomorphine injections and postural hypotension was en- D Treatment failures countered on two occasions, this was usually Two patients with marked inter-dose dyskin- attributable to the omission of domperidone. on September 29, 2021 by guest. Protected copyright. esia on levodopa were withdrawn from treat- A 62 year old man consistently noticed a ment with intermittent doses of apomorphine generalised unpleasant sensation following because of a worsening of their involuntary apomorphine injections which he had not ex- movements. Four patients (on continuous in- perienced after doses of levodopa producing a fusion) initially thought suitable were with- comparable benefit. Two patients described drawn from treatment because of side effects; rhinorrhoea and increased lacrimation shortly in three because of an unacceptable increase in after injections; one had previously noted the biphasic dyskinesias and hallucinations in the same phenomena after levodopa. other. Late withdrawal oftreatment was neces- A 58 year old man, complained of reduced sary in two of the 21 patients, on subcutaneous facial hair growth and loss of libido after infusion, whose initial response was satisfac- starting treatment with intermittent injections tory. The first had marked oscillations in motor of apomorphine. On the other hand, a 64 year function with severe inter-dose dyskinetic old man became embarrassingly hyperlibidin- movements on levodopa. With apomorphine ous. significant improvement in overall mobility An overdose of apomorphine occurred in a was achieved in hospital but this could not be 62 year old man on a continuous infusion. His maintained at home. She was unable to cope wife accidentally injected subcutaneously with the technique and returned to conven- about 25 mg of apomorphine. After three min- tional drug therapy. A second patient with utes he felt faint, nauseated, lost consciousness initial sustained benefit developed late hypo- and recovered within 20 minutes. He was then tonia and mutism. found to be alert with a pulse rate of 40/minute 100 Frankel, Lees, Kempster, Stern J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from and his supine blood pressure was 90/50 mm types or other transmitter systems or perhaps Hg. He recovered completely within an hour. apomorphine has intrinsic anti-psychotic One patient broke a needle during injection and activity,2' possibly from the piperidine moiety the fragment remains in the subcutaneous of the molecule.22 tissue. Intermittent injections may also be useful in treating a variety of isolated "off" period (iv) Laboratory investigations problems such as pain, dystonia, voiding dys- Peripheral blood eosinophilia of up to 10 per function, anismus, hallucinosis, backache and cent occurred shortly after starting therapy in belching.""'7 We consider some of these phe- all patients treated by continuous infusion; this nomena to be directly related to sustained returned to normal in about half of the patients levodopa therapy and not simply a return of treated for over one year. Other haematological former parkinsonian disability. Our experience indices, including plasma urea and creatinine with two patients with critical deterioration as a concentrations remained normal. result of intercurrent illness suggests that there A 44 year old woman on treatment with may be an emergency role for subcutaneous levodopa for 12 years and apomorphine for 28 apomorphine including the management of the months developed an autoimmune haemolytic levodopa withdrawal syndrome which closely anaemia with a positive Coomb's test; the resembles the "neuroleptic malignant syn- agglutinating antibody was identified as IgG. drome". Finally an apomorphine challenge, This picture was typical of that described in after domperidone pre-treatment, may prove to levodopa induced autoimmune haemolytic be a useful quick test for anaemia. 189 responsiveness.2' These clinical observations using apomor- phine may have some bearing on understand- Discussion ing the mechanism of the motor response to Subcutaneous apomorphine has led to a sus- levodopa. The exact mode ofaction oflevodopa tained marked improvement in a selected group is disputed but it has been suggested that pre- of parkinsonian patients hitherto disabled by synaptic conversion to dopamine and intra- refractory and severe "off" period disabilities. neuronal storage are essential to its action.' Providing a patient's "on" response to Even if therapeutic responses to levodopa are levodopa is not marred by severe dyskinesia, not dependent on synaptic release of dopamine hypotonia or psychotoxicity, apomorphine is by surviving nigro-striatal terminals, these usually beneficial, improving the quality of life terminals are the major sites of dopamine and often restoring functional independence. formation from exogenous levodopa in the Although it may be possible to diminish dys- striatum.24 Apomorphine while possessing kinesias by giving apomorphine with conco- both D1 and D2 receptor agonist properties mitant reduction of levodopa, we have found does not share transport or metabolic pathways the antiparkinsonian effects of apomorphine with levodopa. Although in intact experimental and levodopa to be strikingly similar and have animals, administration of apomorphine sup- been unable to confirm the specific anti-dys- presses the rate of firing of nigro-striatal cells25 kinetic effects reported by Duby and col- and in low dose has been found to produce a

leagues.20 When inter-dose dyskinesia persists, reduction in locomotor activity, thought to http://jnnp.bmj.com/ it is the overall improvement when compared represent pre-synaptic inhibition of endo- with the "off" period motor state which deter- genous dopamine release, its actions on parkin- mines the success of treatment. This also sonian motor disability are likely to be depends on the patient understanding the mediated totally at post-synaptic receptor sites. rationale for using apomorphine and his or her Comparison therefore of motor responses to ability to anticipate or at least identify "off" levodopa and apomorphine may be relevant in periods. Our usual strategy is, to first treat with to trying elucidate the mechanism of different on September 29, 2021 by guest. Protected copyright. intermittent injections only changing later to degrees of levodopa responsiveness between continuous minipump infusion if oscillations individual parkinsonian patients. If impaired remain prominent. In most cases the former responsiveness is due to pre-synaptic changes regime is found to be adequate. in nigro-striatal terminals, differences in res- In only three cases was it possible to achieve ponsiveness to levodopa and apomorphine stable control on apomorphine without levo- might be expected; whereas similarity in the dopa. This was not because apomorphine was pattern and magnitude of levodopa and apo- weaker than levodopa but because the doses morphine responses would suggest that dif- and therefore volumes of solution needed for ferences in post-synaptic receptors cause dif- monotherapy led to problems with skin ferences in responsiveness. Our findings sup- nodules. port the latter, but we have only looked at In general, apomorphine was well tolerated patients with prolonged disease duration who with relatively few side effects and no sig- have either developed symptomatic motor os- nificant tolerance to the therapeutic antipark- cillations or other problems during medium or insonian effect was seen. On the other hand, long term treatment, we have not done com- tachyphylaxis to nausea and postural hypoten- parative levodopa/apomorphine studies on sion occurred rapidly. Reversible neuropsy- untreated patients or those treated for a short chiatric toxicity was uncommon. It may be that time. psychotoxic effects seen more frequently with However, these considerations may still be of other dopamine agonists occur as a result of relevance to the practical long term manage- different actions on dopamine receptor sub- ment ofparkinsonian patients with levodopa or Subcutaneous apomorphine in the treatment of Parkinson's disease 101 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.2.96 on 1 February 1990. Downloaded from medication. If limitations in deprenyl in Parkinson's disease. Lancet 1977;ii:439-43. 3 Lees AJ, Shaw KM, Kohout LJ, et al. Deprenyl in Parkin- drug responsiveness are caused by striatal post- son's disease. Lancet 1977;ii:791-6. synaptic factors such as loss of receptor num- 4 Hoehn MM, Elton RL. Low dosages of bromocriptine added to levodopa in Parkinson's disease. Neurology bers or sensitivity, and motor responses to 1985;35:199-206. levodopa and apomorphine are equivalent in 5 Nutt JG, Woodward WR, Carter JH. Clinical and bio- chemical studies with controlled-release levodopa/ individual patients, it follows that the quality of . Neurology 1986;36:1206-1 1. "on" phase motor function on 6 Pezzoli G, Tesei S, Ferrante C, Cossutta E, Zecchinelli A levodopa Scarlato G. Madopar HBS in fluctuating parkinsonian therapy is unlikely to be surpassed by other patients: two-year treatment. Movement Disorders 1988; antiparkinsonian agents acting on the dopa- 3:37-45. 7 Hardie RJ, Lees AJ, Stern GM. On-off fluctuations in minergic system. The maximum expected Parkinson's disease. A clinical and neuropharmacological benefit from treatment with levodopa or study. Brain 1984;107:487-506. 8 Corsini GU, Del Zompo M, Gessa GL, Mangoni A. dopamine agonist medication would be to Therapeutic efficacy of apomorphine combined with an maintain individual patients in "on" states for extracerebral inhibitor of dopamine receptors in Parkin- son's disease. Lancet 1979;i:954-6. the greatest proportio.1 of the time. If the 9 Stibe CMH, Kempster PA, Lees AJ, Stern GM. Sub- difference between "on" and "off' phase cutaneous apomorphine in parkinsonian on-off oscilla- tions. Lancet 1988;i:403-6. motor function is small, especially when the 10 Poewe W, Kleedorfer B, Gerstenbrand F, Oertel W. Sub- degree of disability is large, use of dopamine cutaneous apomorphine in Parkinson's disease. Lancet 1988;i:943. agonist therapy in conjunction with drug de- 11 Chaudhuri KR, Critchley P, Abbott Rj, Pye IF, Millac livery technology (including subcutaneous PAH. Subcutaneous apomorphine for on-off oscillations in Parkinson's disease. Lancet 1988;ii:1260. delivery of apomorphine) or of surgical tech- 12 Pollak P, Champay AS, Hommel M, Perret JE, Benabid AL. niques to deliver levodopa or dopamine direct- Subcutaneous apomorphine in Parkinson's disease. J Neurol Neurosurg Psychiatry 1989;52:544. ly into the brain or CSF is unlikely to produce 13 Agid Y, Pollak P, Bonnet AM, Signoret JL, Lhermitte F. significant benefit. Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson's disease. Lancet Despite these reservations it seems likely that 1979;i:570-2. the duration of effective medical treatment can 14 Christmas TJ, Kempster PA, Chappel CR, Frankel JP, Lees AJ, Stem GM, Milroy EJG. Role of subcutaneous be significantly extended for many patients. apomorphine in parkinsonian voiding dysfunction. Lancet These results also suggest that a search should 1988;ii: 1451-3. 15 Mathers SE, Kempster PA, Swash M, Lees AJ. Constipa- continue for a long-acting powerful orally tion and paradoxical puborectalis contraction in anismus administered dopamine receptor agonist with a and Parkinson's disease: a dystonic phenomenon? JNeurol Neurosurg Psychiatry 1988;51:1 503-7. pharmacological profile similar to apomor- 16 Mathers SE, Kempster PA, Law P, Frankel JP, Bartram C, phine. In the meantime the use of parenteral Lees AJ, Stem GM, Swash M. Anal sphincter dysfunc- tion in Parkinson's disease. Arch Neurol 1989;46:1061-4. apomorphine provides an effective safe way of 17 Kempster PA, Lees AJ, Crichton P, Frankel JP, Shorvon P. diminishing disabling "off" periods in levo- Off-period belching due to a reversible disturbance of oesphageal motility in Parkinson's disease and its treat- dopa treated patients. ment with apomorphine. Movement Disorders 1989;4: 47-52. 18 Territo MC, Peters AW, Tanaka KR. Autoimmune This paper was presented at the 41st annual hemolytic anemia due to levodopa therapy. JAMA 1973; meeting of the American Academy of 226:1347-8. 19 Lindstrom FD, Lieden G, Engstrom MS. Dose-related Neurology, Chicago, April 1989. levodopa-induced haemolytic anaemia. Ann Int Med 1977;83:298-300. 20 Duby SE, Cotzias GC, Papavasiliou PS, Lawrence WH. PAK and JPF were Kate Stillman Research Injected apomorphine and orally administered levodopa Fellows. Support was also provided by the in . Arch Neurol 1972;27:474-80. 21 Corsini GU, Pitzalis GF, Bocchetta A, Del Zompo M. The Parkinson's Disease Society of Great Britain. use of dopamine agonists in the treatment of schizo- http://jnnp.bmj.com/ We thank Diana Wade and Jenny Wooten of phrenia. Neuropharmacology 1981;20:1309-13. 22 Cotzias GC, Papavasiliou PS, Tolosa ES, Mendez JS, Bell- the North iMiddlesex Hospital Sterile Produc- Midura M. Treatment of Parkinson's disease with apor- tion Unit for preparation of the apomorphine phines; possible role of growth . N Eng J Med 1 976;294:567-72. solution. 23 Barker R, Duncan J, Lees A. Subcutaneous apomorphine as a diagnostic test for dopaminergic responsiveness in parkinsonian syndromes. Lancet 1989;i:675. 24 Melamed E. Mechanisms of action of L-dopa. In: Koller W, Marsden CD, Parkes JD, Quinn N. Fluctuations of dis- ed. Handbook of Parkinson's disease. New York: Dekker, abilities in Parkinson's disease-clinical aspects. In: 1987:355-70. on September 29, 2021 by guest. Protected copyright. Marsden CD, Fahn S, eds. Movements disorders. London: 25 Bunney BS, Aghajanian GK, Roth RH. Comparison of Butterworths, 1982;96-122. effects of L-dopa, and apomorphine on 2 Birkmayer W, Riederer P, Ambrozi L, Youdim MBH. firing rate of rat dopaminergic neurones. Nature New Implications of combined treatment with madopar and L- Biology 1973;245:123-5