Long-Term Therapy of Parkinson's Disease with Amantadine, Alone and Combined with Levodopa L

ORIGINAL ARTICLE

Long-term therapy of Parkinson's disease with amantadine, alone and combined with levodopa L. R. Zeldowicz, m.d., f.r.c.p.[c]* and John Huberman, PH.D.,t Vancouver, B.C.

Summary: A dual study was conducted to assess (1) Chez 37 malades presentant un deficit residuel the long-term antiparkinsonian action of amantadine considerable apres un traitement avec un seul medicament, without levodopa and (2) the advantage of combined on a constate une amelioration apres instauration du amantadine and levodopa over single-drug therapy, second medicament (levodopa ou amantadine). including changes in symptom severity when placebo L'amelioration des signes neurologiques et des activites replaces amantadine but levodopa is maintained. de la vie quotidienne (AVQ) se situait entre 50 et Good to excellent results were obtained in 25% of the 60% et, en ce qui conceme la dexterite chronometree, total pool of 77 patients on amantadine. No decline in aux environs de 25%. Selon les indices individuels, therapeutic effect took place during a mean follow-up de 64 a 100% des malades ont ete ameliores avec le of 21 months. second medicament. Thirty-seven patients with considerable residual Le remplacement d'amantadine par un placebo s'est deficit after single-drug therapy derived improvement solde par une deterioration de I'etat general: on notait from the second drug (levodopa or amantadine). une perte de 75% de I'AVQ, une perte de 45% dans la Gains in neurological signs and activities of daily living dexterite chronometree et les pertes relatives aux signes (AOL) ranged between 50 and 60% and for timed skills neurologiques depassaient les gains obtenus de close to 25%. Depending on the individual indices, I'association medicamenteuse. between 64 and 100% of patients improved with the second drug. Since 1969 a number of investigators have indicated that Placebo instead of amantadine deterioration. "Symmetrer® (amantadine HC1) is the second best drug produced in the treatment of Parkinson's but There was 75% loss in AOL, 45% loss in timed skills after levodopa disease, and losses in neurological signs exceeded gains produced controversy still exists regarding its effectiveness1"4 and by two-drug therapy. its sustained action in long-term therapy.5'6 It has been observed that the initial improvement may be followed by Resume: Traitement a long terme de la maladie de a decline.5,7 The advantage of combined levodopa and Parkinson au moyen d'amantadine, seule ou associde amantadine treatment has not been conclusively estab¬ £ la l6vodopa lished.8*14 Some authors8*12 have suggested that levodopa may compensate for the loss of benefit initially obtained On a entrepris une etude ayant un double objectif: from amantadine. Others3'5,9"11'1314 favour eValuer I'action d'amantadine sans comme two-drug therapy (1) levodopa particularly for those patients who are unable to tolerate a medication antiparkinsonienne a long terme et (2) estimer dose of de la medication associee high levodopa. I'avantage amantadine-levodopa This was undertaken in an to resolve sur le traitement les study attempt simple, y compris changements existing controversies. we wished to assess the sur la severite des symptdmes qu'entrainait le remplacement Specifically d'amantadine par un dans I'association. following: placebo 1. The results of a long-term (close to two years) amanta¬ Sur le groupe de 77 malades traites a I'amantadine, dine without in who derived on a obtenu des regimen levodopa patients resultats variant de bons a excellents good to excellent improvement from the start and the chez 25% du total. On n'a note aucune diminution decline of benefit with time. de I'effet au cours possible therapeutic therapeutique d'une periode 2. The a d'observation advantage of stabilized two-drug regimen over de 21 mois en moyenne. single-drug therapy in patients whose initial treatment was with either amantadine or ?Division of Neurology, Department of Medicine, University of levodopa. British Columbia, Vancouver General Hospital 3. The change in symptom severity when, after stabiliza- tDepartment of Psycholo&y, University of British Columbia, tion on the was main¬ Vancouver two-drug regimen, levodopa tained at the same while amantadine HC1 was Reprint requests to: Dr. L. R. Zeldowicz, Suite 1112, 750 W. dosage Broadway, Vancouver », B.C. replaced by placebo. 588 CMA JOURNAL/OCTOBER 6, 1973/VOL. 109 Table I.Subject data on 19 patients on long-term amantadine therapy

Part I . Long-term treatment with amantadine Confusional states in two patients were not worse than they had been with standard medication. Swollen ankles Out of a total of 77 patients receiving amantadine 19 and livedo reticularis occurred in about 20% of patients. (approximately 25%) derived good to excellent improve¬ The livedo had a tendency to fade or change into brown ment and were selected for long-term treatment. Forty-six pigmented spots after a prolonged intake of amantadine. (approximately 60%) who derived slight or moderate im- prpvement were given levodopa in addition to amantadine Methods and included in the two-drug study (Part II). Twelve patients (approximately 16%) were excluded from further The same method of assessment was used as described study because of lack of improvement or lack of co- in our previous paper4 for the following: operation. 1. Activities of daily living (ADL) under four indices: Table I sets forth data of patients on long-term amanta¬ walking, dressing, feeding and toiletry, with scores dine treatment. The 19 patients took amantadine for a graded from 0 (no symptoms) to 4 points for maximal mean of 21 months: 11 for over two years, 5 for 8 to 20 score deficit (total possible deficit, 16 points). months and 3 for 6 months. Most received 200 mg./day, but 2. Neurological signs under five indices: tremor, rigidity, four took 300 mg. daily. Standard medication was stopped akinesia, speech and salivation, grading each from by seven patients prior to starting amantadine since it had 0 to 4 points (total possible deficit, 20 points). been of no help, in six it was reduced to between one half 3. Time scores in seconds for general mobility and finger and one third when improvement was observed with aman¬ dexterity for nine tests: walking 30 feet, rising from tadine, and six remained on a moderate amount of standard a chair and walking 10 feet, rolling over, turning 360 drugs. degrees standing, dealing 10 cards, counting on digital Clinical and laboratory side effects were mild. BUN, counter up to 50, putting 15 pegs into pegboard, sign- alkaline phosphatase and, in a few, uric acid became elev¬ ing name, and drawing a six-inch line. ated in the early stages and returned to normal later. Examination was carried out at least once monthly at first and every two to three months in the second year. or contact was made with the Table in functional level in Telephone personal patient II.Improvement 19 patients or a member when needed. on amantadine family Results Tables II and III indicate the improvement in functional and neurological deficits at the end of long-term amantadine treatment. The mean reduction in functional deficit in the four activities ranged from 57.3 to 64.7% (mean improve¬ ment in scores, 0.75 to 1.27 points). The mean reduction in neurological deficit in the five signs ranged from 67.0 to 92.7% (mean improvement in scores, 0.63 to 1.53 points). Salivation was invariably controlled and distressful drooling much improved. Mild to moderate tremor showed complete or almost complete arrest and severe grade three Point scores: 0 = no symptoms, 4 = maximum disability. to four tremors became Note: None of patients scored worse on any of the four indicators when on reduced. Improvement in akinesia medication. was spectacular in some patients. Two wheelchair cases

Point scores: 0 = no symptoms, 4 = maximum disability. Not a single patient obtained a worse score on medication on any of the five indicators. CMA JOURNAL/OCTOBER 6, 1973/VOL. 109 589 became independent in walking and self-care. They re- not produce distressful and uncontrollable side effects (e.g. gressed to acute parkinsonism when they were without severe dyskinesias, postural hypotension, mental and gastro¬ medication over a weekend. Both improved when medica¬ intestinal symptoms) was considered the maximum for a tion was resumed. given patient. Improvements in time scores for general mobility, shown Subject data are shown in Table V. Twenty-nine patients in Table IV, were all statistically significant, the lowest, had received amantadine first and 17 levodopa. for walking, at P<0.025 and for using the digital counter Seventeen patients were stabilized on 4.0 to 5.0 g., 20 at P<0.01. The gait disorder, which consisted of short on 3.0 to 3.5 g., and nine patients could not tolerate more steps and progressively accelerated speed, showed improve¬ than 2.0 g. of levodopa. More than one third received ment by slowing and lengthening of stride. This accounted 300 mg./day of amantadine, while the majority took 200 for lesser gains in time scores for walking. Other time mg. Standard medication in this group was reduced in 23 scores all showed improvements significant at P<0.005 patients during stabilization on the two-drug regimen, to P<0.001. discontinued in 13 and maintained at the previous dose All 19 patients have continued much improved without in 10. signs of decline of amantadine effect over a mean of 21 Evaluation of improvement attributable to single-drug months of controlled study. therapy was beyond the scope of this paper. All patients began the two-drug regimen with some level of improve¬ Part II . Two-drug regimen and single-blind ment from a single drug, and the residual deficit was con¬ placebo replacing amantadine sidered the baseline of 100%. Out of a group of 69 patients (46 on amantadine and Methods 23 on levodopa) 37 completed a two-drug regimen and two placebo study periods. An additional nine who received The same technique of examination was used as for levodopa originally have remained on a two-drug controlled single-drug therapy. Assessment included five stages: (1) regimen with considerable improvement but were not stabilization on two drugs for at least two or three months, available for placebo trials and therefore were not included (2) levodopa plus placebo for two weeks, (3) return to in the statistical analysis. Also excluded for various reasons two-drug regimen for two months, (4) levodopa plus placebo were 23 other patients. for two weeks, and (5) six months on both drugs. Examina¬ In this study the highest dosage of levodopa which did tion was carried out by the same investigator at least once

Table IV.Improvement in time scores in 19 patients on amantadine

"These nine patients missed placebo trials. 590 CMA JOURNAL/OCTOBER 6, 1973/VOL. 109 monthly during the stabilization period, just before and Results after each two-week placebo period, once monthly when on the between the and Gains on two-drug therapy in 37 patients are presented in two-drug regimen placebo trials, Table VI.* The with amantadine once two to three months the final six-month levodopa-first group every during added lost a mean 59.3% in ADL deficit and a mean on the two Side clinical and labora¬ period drugs. effects, 57.5% in residual In the amantadine- tory, were recorded at the end of the five stages or more neurological signs. often if first group with levodopa added a mean of approximately needed. 50% reduction took for both ADL and was assessed, levels at place neurological Symptom severity comparing deficits. Improvement from addition of amantadine was (a) the end of single-drug therapy and the end of the two- than that addition of in drug stabilization period; and (b) at the end ot the two-drug greater produced by levodopa stabilization period and the end of the second placebo five out of the nine functional and neurological indices, were similar in first and second namely walking (P<0.01), dressing (P<0.001), feeding period (changes placebo (P<0.01), (P<0.01) and akinesia (P<0.05). trials; the latter was selected as providing the longer period rigidity of Time scores for mobility also improved but the dif¬ observation). ference between the was not Amantadine and placebo were issued under recorded groups statistically significant; control and levodopa checked against the prescription therefore they are not tabulated here but are shown in issued. Fig. 1. There was a mean 21% gain (2.94 sees.) with amantadine added to levodopa and a mean 26.3% gain (4.02 sees.) with levodopa added to amantadine. Table VI.Gains on two-drug therapy and losses on The proportion of patients changed or unchanged by levodopa plus placebo addition of the second drug is shown in Table VII. "X" indicates "no range", i.e. all patients react similarily in all Functional indicators indices in a specific class. For instance, all levodopa-first Two-drug regimen Levodopa plus placebo patients improved (by varying degrees) on all four ADL none remained unaffected and none Levodopa Amantadine P<" Levodopa Amantadine tests; worsened when first first first first *Tables VI, VII and VIII are condensed from detailed tables available Improvement % Improvement % Loss of Loss of from the author. gains % gains %

POINTS POINTS 1.2-] Functional Deficit Neurological Signs . (Means %) (Means %) 1-1 1=100.0%

Two-drug regimen Levodopa plus placebo

LDOPA + placebo 2 drugs one drug + placebo 2 drug*

-. LDOPA first group -. Amantadine first group FIG. 1.Synopsis of improvement from two drugs and worsening on placebo plus levodopa. Changes are shown as ?Statistical significance by Mann-Whitney U-test, two-tailed percentages against baseline scores on single drug taken NS = not significant as 100%.

Table Vll.Proportion of patients improved, unchanged or worsened on two-drug regimen Functional symptoms Neurological symptoms Time scores Levodopa first Amantadine Levodopa first Amantadine Levodopa first Amantadine (amantadine first (levodopa (amantadine first (levodopa (amantadine first (levodopa added) added) added) added) added) added)

X = all patients behaved in identical mannerfor all indicators. CMA JOURNAL/OCTOBER 6, 1973/VOL. 109 591 amantadine was added to their medication. The table shows bo, which indicates that levodopa compensated for the range and median percentage of patients for the three loss of amantadine in about 10 patients out of 29 when classes of tests (ADL, neurological and time scores, com¬ functional abilities were assessed. bined, instead of referring separatery to each of the 18 Time score differences between the two groups were indices). To illustrate this for neurological signs: in the minimal. A median of 61.5 to 62.5% of patients worsened levodopa-first group the range of patients who improved and 20.7 to 25.0% showed no change. Improvement in was 57.2 to 100% with a median of 71.7% of patients. 12.5 to 16.9% of patients probably was fortuitous. Data from a detailed table not included here showed the Fig. 1 is a composite of results and shows the decline following percentage of patients improved for the specific in residual signs on two-drug therapy and increase in signs: akinesia 57.2%, speech 62.5%, tremor 71.7% deficit when placebo replaced amantadine. Percentages are (which represents the median), rigidity 87.5% and saliva¬ calculated against a baseline of residual symptoms after tion 100%. single-drug therapy, taken as 100.0%. Score points at Table VII shows a median of 64.5% of amantadine each stage and seconds for timed tests are presented on patients improved with regard to functional indices when the abscissae. levodopa was added to their drug regimen. This figure is reciprocal to Table VI, i.e. gains from two- Neurological signs improved a median of 71.0% almost drug therapy (approximately 50 to 60%) are shown here equally in both groups of patients with addition of the as a decline in residual signs (approximately 50 to 40%). second drug. A median of 28.3% in the levodopa-first Time scores show a reduction in deficit to approximately group and a median of 35.5% in the amantadine-first 73 to 78%, or 22 to 27% gains on two-drug therapy. group did not respond to the second drug. On placebo with levodopa, the mean losses in neuro¬ For the time scores a median of 75.0% of patients in the logical signs were greater than in the other two classes levodopa-first group and a median of 65.4% in the aman¬ of tests. tadine-first group improved with the second drug. A fraction of patients showed worsening but this was variable Discussion and probably fortuitous. We attempted to assess (a) the action of amantadine as an antiparkinsonian agent for extended treatment without Levodopa with placebo instead of amantadine levodopa and (b) the advantages of combined amantadine Results are shown in Table VI. In functional abilities and levodopa therapy. Substitution of placebo for amanta¬ both groups lost close to 75% of gains derived from two- dine while maintaining levodopa served two purposes: (1) drug therapy. Deterioration in time scores was less pro¬ assessment for possible losses when amantadine is with- nounced, with close to 45.0% of two-drug gains lost in drawn, and (2) determination of action of levodopa when both groups. unsupported by amantadine. For neurological signs the situation was different. The Amantadine without levodopa proved in our study to mean loss in the levodopa-first group was 87.7% while be a highly effective antiparkinsonian drug. Good to ex¬ in the amantadine-first group it was 121.5%. Specifically, cellent improvement was obtained by one patient in four the latter group lost 182.0% of their previous two-drug and no loss of therapeutic effect was observed in up to gains in tremor and 115.0% in rigidity, while the greatest 30 months* (mean 21 months) follow-up. The results cor¬ loss in the levodopa-first group did not exceed 100%. respond to our short-term previous study with MacFadyen Table VIII shows the proportions of patients deteriorated, et al.4 unchanged or improved on levodopa plus placebo. Neuro¬ Patients with only slight or moderate improvement from logical signs deteriorated in a median of 87.6% of patients amantadine and those levodopa patients with considerable on levodopa-first and 74.1% of those on amantadine-first, residual deficit proved particularly suited for two-drug but the degree of symptom deterioration in the amantadine- therapy. Forty-six patients improved significantly on the first group was greater, as seen in Table VI: levodopa two-drug regimen, but only the 37 participants in the two could not prevent severe deterioration of neurological signs placebo trials were included in statistical analysis. In ac- in a large majority of patients upon withdrawal of aman¬ cord with Fieshi et al,3 Scotti11 and Walker et al,9 and tadine. A median of 81.0% of levodopa-first patients de¬ contrary to Goodwin-Austen et al* Hunter et al,11 and teriorated while on placebo, with regard to functional Barbeau13 we found no definite relationship between the symptoms, as did a median of 62.3% of amantadine-first optimal tolerated dose of levodopa and gains from added patients, in spite of levodopa maintenance. However 33.1% amantadine. Among our 17 patients stabilized on levodopa of amantadine-first patients remained unaffected by place¬ with amantadine added, two patients on 5 and 4.5 g. re-

Table VIII.Proportion of patients deteriorated, unchanged or improved on levodopa with placebo instead of amantadine Functional symptoms Neurological signs Time scores Levodopa Amantadine Levodopa Amantadine Levodopa Amantadine first first first first first first

X = all patients behaved in identical mannerfor all indicators. 592 CMA JOURNAL/OCTOBER 6, 1973/VOL. 109 spectively of levodopa derived slight, questionable improve- nal synapses. The observed fast action of amantadine and ment; eight on 2.0 to 3.0 g. improved markedly, but so did fast decline upon its withdrawal lend some support to seven others on 3.5 to 4.5 g. which was their optimal dose. such a view. Amantadine could facilitate access or release A marked deterioration took place on placebo with levo- of dopamine from available stores or from the levodopa dopa maintained. A mild to moderate retention of gains supply, as has been indicated by Grelak et al,"5 or amanta- derived from two-drug therapy was observed on functional dine might possibly facilitate catecholamines" other than tests and in timed scores. This was attributed to extended levodopa or antagonize inhibitory neurotransmitter sub- action of levodopa. On the other hand, neurological test stances, the equilibrium between which is thought to be results fell in spite of levodopa to below the levels of deranged in Parkinson's disease. residual deficits after single-drug amantadine therapy. Recently another drug, a tripeptide, a synthetic product Such sudden deterioration with amantadine withdrawal of a hypothalamic factor (MIF), was reported by Kastin has been observed by MacFadyen et ar and Appleton, and Barbeau"7 to possess an antiparkinsonian action. Further Eadie and Sutherland.7 In other words, levodopa did not correlated biochemical and clinical studies are needed to compensate for withdrawal of amantadine in neurological elucidate the properties of various antiparkinsonian drugs signs but partly compensated in ADL and timed scores. and their interaction. Placebo trials confirmed the value of amantadine whether it was used as first or second drug in two-drug therapy. References Several factors may account for the difference between our results and those of some 1. PARKES JD, CALVER DM, ZILKHA KJ, et al: Controlled trial of other workers. Firstly, this ainantadine HCI in Parkinson's disease. Lancet 1: 259, 1970 is the longest-term dual study so far reported and therefore 2. PARKES JD, ZILKHA KJ, MARSDEN P, et al: Amantadine dosage in treatment of Parkinson's disease. Ibid, p 1130 it permitted us to eliminate misinterpretation of fluctuations 3. FIESHI C, NARDINI M, CASACHIA M, et al: Amantadine for Parkin- for decline of son's disease. Ibid, p 945 amantadine action: it gave us the oppor- 4. MACFADYEN DJ, PicTON TW, ZELDOWICZ L, et al: Amantadine HCI tunity to observe "bouncing back" on the same medical in treatment of Parkinson's disease: a controlled trial. J Clin Pharmacol 12: 274, 1972 regimen when the unrelated condition cleared up. Secondly, 5. SCHWAB RS. ENGLAND AC, POSKANzER DC, et al: Amantadine in clinical evaluation was primarily based treatment of Parkinson's disease. JAMA 208: 1168, 1969 upon neurological 6. HUNTER KR, STERN GH, LAWRENCE DR, et al: Amantadine in parkin- and functional findings which at times differed from self- sonism. Lancet I: 1127, 1970 7. APPLETON DB, EADIE MJ, SUTHERLAND JM: The continued use of assessment, the latter not infrequently being coloured by amnantadine hydrochloride in parkinsonism. Med J Aust II: 707, the patient's expectation of full recovery. Relapses during 1971 8. GOODWIN-AUsTEN RB, FREARS cc, BERGMANN S, et al: Combined placebo trials re-affirmed the patient's confidence in the treatment of parkinsonism with L-Dopa and( amnantadine. Lancet II: 388, 1970 effectiveness of amantadine. Thirdly, included in our two- 9. WALKER JE, POTVIN A, TOURTELOTTE W, et al: Amantadine and levodopa in treatinent of Parkinson's disease. Clin Pharmacol Ther drug regimen were patients with marked residual deficit 13: 28, 1972 after single-drug therapy; when improvement occurred it lo4. PARKES JD, BAXTER RCH, CURZON G, et al: Treatment of Parkinson's disease with amantadine and levodopa. Lancet I: 1088, 1971 was easily recognized by the patient and unequivocally 11. ScoTrT G: Combined treatment of Parkinson's disease with amanta- confirmed by tests. (line and L-Dopa. Lancet I: 394, 1970 12. Hi,NTER KR, STERN GM, LAWRENCE DR, et al: Combined treatment No increase in side effects common to levodopa oc- of parkinsomiism with L-Dopa and amnantadine. Lancet I: 1087, 1971 13. BARREAU A: Amantadine HCI (Symimnlletrel) in the management of curred with the addition of amantadine, nor were any of Parkinson's disease: a double blinid crossover study. Can Med the typical side effects of Assoc J 105: 42, 1971 levodopa reported with toxic 14. MANN DC, PEARCE LA, WATERBURY LP: Aniantadine for Parkinson's doses of amantadine. This observation and the finding of disease. Neurology (Minneap) 21: 958, 1971 15. GRELAK RP, CLARK R, STuMp JM, et al: Amantadine-dopamine in- Mann, Pearce and Waterbury14 of no change in dopamine teraction: possible mode of action in parkinsonism. Scienee 169: metabolites in urine and 203, 1970 cerebrospinal fluid deny the par- 16. FIBIGER HC, Fox M, McGEER EG, et al: The effect of amantadine ticipation of amantadine in dopamine on spontaneous locomotor activity in the rat. J Phar m Pharmacol metabolism. The 28: 724, 1971 mode of amantadine action therefore remains unknown. 17. KASTIN AJ, BARREAU A: Preliminary clinical studies withi Lprolyl- it L,-leucyl-glycine ainide itl Parkinson's disease. Can Med Assoc J is suggested that amantadine could act directly on neuro- 107: 1079, 1972

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