L-DOPA is used to replace dopamine lost in Parkinson's disease because dopamine itself cannot cross the blood-brain barrier where its precursor can. However, L-DOPA is converted to dopamine in the periphery as well as in the CNS, so it is administered with a peripheral DDC (dopamine decarboxylase) inhibitor such as carbidopa, without which 90% is metabolised in the gut wall, and with a COMT inhibitor if possible; this prevents about a 5% loss. The form given therapeutically is therefore a prodrug which avoids decarboxylation in the stomach and periphery, can cross the blood-brain barrier, and once in the brain is converted to the neurotransmitter dopamine by the enzyme aromatic-L-amino-acid decarboxylase.

Side Effects

Possible side effects include:

Hypotension, especially if the dosage is too high.
Arrhythmias, although these are uncommon.
Nausea, which is often helped by taking the drug with food, although protein interferes with drug absorption.
Gastrointestinal bleeding.
Disturbed respiration. This is not always harmful, and can actually benefit patients with upper airway obstruction.
Hair loss.
Confusion.
Extreme emotional states, particularly anxiety, but also excessive libido.
Vivid dreams and/or fragmented sleep.
Visual and possibly auditory hallucinations. It can reveal dementia that was previously subclinical.
Effects on learning. There is some evidence that it improves working memory, while impairing other complex functions.
Sleepiness and sleep attacks.
a condition similar to amphetamine psychosis.

Although there are a number of side-effects associated with L-DOPA, particularly psychiatric ones, it has fewer than other Parkinson's drugs, including anticholinergics, selegiline, amantadine, and dopamine agonists.

More serious are the effects of chronic L-DOPA administration, which include:

End-of-dose deterioration of function.
On/off oscillations.
Freezing during movement.
Dose failure (drug resistance).
Dyskinesia at peak dose.

Clinicians will try to avoid these by limiting L-DOPA dosages as far as possible until absolutely necessary.

Synthesis

L-Dopa is produced from the amino acid tyrosine by the enzyme tyrosine hydroxylase. It is also the precursor molecule for the catecholamine neurotransmitters dopamine and norepinephrine (noradrenaline), and the hormone epinephrine (adrenaline). The prefix L- references its property of levorotation (compared with dextrorotation or D-DOPA).

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Investigation by Parkinson's Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegeline treatment in patients
From British Medical Journal, 4/18/98 by Y. Ben-Shlomo

Introduction

The Parkinson's Disease Research Group of the United Kingdom reported increased mortality in patients with early, mild Parkinson's disease who were randomly allocated combined levodopa and selegiline treatment (arm 2) compared with levodopa alone (arm 1).[1] Relative mortality was increased by about 60%, equivalent to one excess death for every 54 patients treated for 1 year. No clinically important differences in disability ratings were noted after either 1[2] or 4 years.[1] These results were unexpected as selegiline was thought to protect against nigral cell death,[3] to slow disease progression,[4] and to reduce death rates.[5]

This trial has generated much controversy. about the role of selegiline in the management of Parkinson's disease. The number of selegiline prescriptions has almost halved in the United Kingdom since the findings of the trial were published (fig 1). Objections about the validity of the findings include inconsistency with other studies, the inappropriate use of an intention to treat analysis, lack of adjustment of results for early termination of arm 2, overall death rates being too high, the unreliability of death certification, and the possibility of differential misdiagnosis.[6-9]

[FIGURE 1 ILLUSTRATION OMITTED]

Despite many of these criticisms being addressed,[10 11] the reason for the excess mortality remains unclear. One suggested mechanism was that selegiline might increase the risk of a disturbance of cardiac rhythm or compromise the cardiovascular system through orthostatic hypotension.[1] Other possibilities are that combination treatment may have accelerated nigral cell death or that selegiline may have had an adverse drug interaction with a drug not included in the trial.

We report updated and new death rates in subjects in arms 1 and 2 and in those who were randomised from arm 3 (bromocriptine) to arms 1 or 2. Results are also presented from the cause of death inquiry study, which reviewed the clinical course, cause of death, and circumstances around the time of death for all participants who died before December 1993.

Subjects and methods

The trial methods have been reported.[1 2] Briefly, 782 patients with early, mild Parkinson's disease were randomly allocated to one of three treatment arms: levodopa and a dopa decarboxylase inhibitor alone (arm 1); levodopa, a dopa decarboxylase inhibitor, and selegiline (arm 2); and bromocriptine alone (arm 3). If a patient could not tolerate the drugs or showed little functional improvement they could be rerandomised to one of the other two arms. The principal outcomes were mortality and disability ratings. After an interim analysis of deaths up to December 1993 it was decided to terminate arm 2; patients were informed of this in October 1995.

The clinical record of every death before December 1993 was obtained from the relevant consultant, general practitioner, or nursing home. The records were systematically examined by JO, who recorded all drug treatment before death and deleted any references to antiparkinsonian drugs to conceal the trial arm. Data on severity of the disease within 3 months of death, comorbidity within 1 month of death, mobility within 1 month of death, and mode of death were recorded by AC on a standardised form.

A clinical summary of the clinical course, atypical clinical features, and comorbid medical conditions and a detailed resume of events around the terminal illness was produced. Details of special investigations such as radiography and pathological and postmortem examination were included when available, but there was no access to the cause of death from the death certificate. A panel comprising a neurologist (AJL), geriatrician (PO), general practitioner (BH), and clinical epidemiologist (YB-S) reviewed each summary and assigned a cause of death according to ICD-9 (international classification of diseases, 9th revision).[12] The panel was blind to the death certificate and trial arm. Parkinson's disease was coded as the underlying cause of death if it contributed to the death because of severe debility.

The panel rated diagnostic certainty for the cause of death from 1 (confident) to 5 (guessing)[13] and determined whether the diagnosis of Parkinson's disease might have been incorrect and whether the patient might have had dementia.

The reliability of the panel was ascertained by presenting again 20 cases selected at random and stratified on confidence rating at least 3 months later. This was to maximise the likelihood that the cases had been forgotten. Cause specific mortality rates were recalculated using the panel's classification to ascertain whether this altered the results based on death certificates in the previous report.[1] When the panel was unable to reach a diagnosis the cause was taken from the death certificate.

Statistical analysis

The death rates in arms 1 and 2 were compared using the log rank test and Kaplan-Meier survival curves. The relative mortality hazard ratio and 95% confidence intervals were calculated using Cox's proportional hazards model, which enabled adjustment for possible prognostic factors. The adequacy of the proportional hazards model was tested using a log-time interaction with treatment group to check whether the hazard ratio changed with follow up.[14]

Codes for specific causes were grouped under the standard classification headings except for the more common conditions such as ischaemic heart disease (410-414) and cerebrovascular disease (430-438). Comparison of categorical and continuous variables were analysed using the [X.sup.2] test or Fisher's exact test for categorical variables and the t test for continuous variables.

Results

Mortality

Our previous paper reported the results of the interim analysis of December 1994.[1] This analysis included deaths only before the end of 1993 because of the delay in notification of deaths from the NHS central register. This report provides data on mortality up to the end of September 1995, when arm 2 was terminated, providing an additional 21 months of follow up (average 6.8 years) and new results on 104 patients randomised from the bromocriptine arm to either arm 1 (53 patients) or 2 (51 patients).

Death rates were similar in arms 1 and 2 during the additional follow up (table 1). They were higher in patients who were rerandomised to arm 2 (levodopa and selegiline) than in those rerandomised to arm 1 (levodopa alone) (hazard ratio 1.54 (95% confidence interval 0.83 to 2.87). The overall hazard ratio for mortality in arm 2 (levodopa and selegiline) compared with arm (levodopa alone) when subjects who had been randomised a second time were included was 1.33 (1.02 to 1.74) (P = 0.038 in log rank test); this was little altered when subjects who had been rerandomised were excluded. The confidence intervals have not been adjusted to take account of the early termination of arm 2; the inclusion of additional information means that this updated result is much less affected by the decision to stop treatment early. After adjustment for other baseline factors-age, sex, duration of Parkinson's disease, disability before treatment, year of entry to trial-the hazard ratio was 1.30 (0.99 to 1.72). Analysis based on patients receiving treatment ("on treatment analysis") gave a hazard ratio of 1.39 (0.94 to 2.05).

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

Figure 2 shows the updated Kaplan-Meier curve. Although a test of departure from the assumption of proportional hazards ratio was not significant, the excess mortality was greatest in the third and fourth years of follow up and was more apparent for the on treatment analysis (table 2).

[FIGURE 2 ILLUSTRATION OMITTED]

[TABULAR DATA 2 NOT REPRODUCIBLE IN ASCII]

As entry to the trial stopped in September 1990, information on mortality was complete for the first 5 years of follow up, so the results for the first 5 years were unaffected by the early termination of arm 2. The hazard ratio for the first 5 years for arm 2 compared with arm 1 was 1.38 (0.95 to 2.04).

Cause of death

Up to December 1993, 120 patients died (44/249 (17.7%) in arm 1 and 76/271 (28.0%) in arm 2). Twenty four cases had information from a postmortem examination. As information was not available for 21 cases because notes had been destroyed or lost we relied only on information from the trial assessments, which may not have had information about the terminal event. The kappa coefficient[15] for the 20 cases classified by the panel on the two occasions was 0.76 for the underlying cause of death, 0.73 for the confidence rating, and 1.0 for the diagnosis of Parkinson's disease (kappa [is greater than] 0.75, excellent; 0.40 to 0.75, fair to good; [is greater than] 0.40, poor). The panel reached a diagnosis in 90 cases. It decided that information was insufficient for the remaining 30 cases to be certain of the cause of death. The pattern of cause specific mortality based on the panel's classification was similar to that previously reported (table 3). Only Parkinson's disease showed an excess of deaths (hazard ratio 2.50 (1.32 to 4.73), whereas for other causes combined the hazard ratio was 1.21 (0.76 to 1.93).

[TABULAR DATA 3 NOT REPRODUCIBLE IN ASCII]

When arms 1 and 2 were compared there were no significant differences between any of the clinical features and the mode of death (table 4). Patients in arm 2 were more likely to have possible dementia, and within three months of death they were more likely to have falls, postural dizziness, and shortness of breath. However, the proportion of cases with a revised diagnosis-for example, multiple system atrophy, progressive supranuclear palsy, Alzheimer's disease, and cerebrovascular disease -- was slightly greater in arm 1.

[TABULAR DATA 4 NOT REPRODUCIBLE IN ASCII]

The mean confidence score was slightly worse in arm 2 (3.00 v 2.59, P = 0. 19) and the postmortem rate was slightly lower. In arm 2 more deaths were classified as sudden, but the proportion of unexpected deaths and the proportion of deaths that occurred at home were similar. There was no evidence that patients in arm 2 had greater cardiovascular comorbidity as assessed by clinical disease or cardiac drugs, and patients in arm 2 were less likely to be taking antidepressants before death.

Disability subscales

Previous analyses showed that progression of disability was similar in the two treatment groups. As this contrasts with the excess mortality from Parkinson's disease seen in arm 2, we examined this further by analysing the disability rating before death (table 5). There were no significant differences in any of the subscales between the two arms. Fifty two per cent of the disability ratings (91/176) were made within the year preceding death, 20% (35/176) within 1-2 years before death, and 28% (50/176) more than 2 years before death. This distribution was similar for arms 1 and 2.

Table 5 Average disability scores by treatment arm based on last disability rating before death for 176 patients who died among those originally randomised to arms 1 and 2

(*) Scored from 0 to 10, where 10=normal.

([double dagger]) scored from 0 to 3, where 0=normal.

Drugs

Ascertainment of the type of drugs taken around the time of death is important if the excess mortality observed with selegiline and levodopa is due to some acute toxic mechanism. We obtained drug information on 91 of the 120 patients who died, which was similar for arm 1 (31/44 (71%)) and arm 2 (60/76 (79%)) Almost all of the patients were taking levodopa 3 months before death (arm 1, 30/31 (97%); arm 2, 59/60 (98%)). In contrast, 23% (7/31) of the patients in arm 1 were no longer in the arm of treatment to which they had been randomised compared with 87% (52/60) taking selegiline in arm 2.

Discussion

The updated results show a relatively increased mortality for the combined levodopa and selegiline treatment compared with treatment with levodopa alone of around 35%, equivalent to one excess death per 75 patients treated for 1 year. The mortality ratios were remarkably consistent regardless of whether all deaths, deaths of patients who were rerandomised, or deaths in the first 5 years were considered. These estimates are lower than previously reported' and are more realistic, as the previous result was based on an interim analysis. Although our confidence intervals are comparatively narrow, they are all around unity so that some results are significant while others are not. Had arm 2 of the trial continued, it is possible that the mortality would have diminished further, and body previous and current results could simply reflect chance. However, the similarity of the size of the effect in patients rerandomised from arm 3 provides an independent replication of the findings seen for the main group allocated to arms 1 and 2. Whereas subjects withdrawn from arm 3 may be unrepresentative, the randomisation process ensures that the internal comparison is valid and can be viewed as a separate trial. In addition, the complete mortality results based on the first 5 years of follow up were not affected by the decision to terminate arm 2 of the trial and so are less likely to represent a random high value.

We emphasise that this fails to support the hope that combined treatment might be associated with reduced mortality or improvement in disability rating scales. Unfortunately, no data were collected on quality of life or mood, so we cannot comment on whether combined treatment may have benefited these measures.

Possible explanations

One problem with the observed excess mortality is the lack of a clear reason for this observation. Other conditions which mimic Parkinson's disease are difficult to diagnose as atypical features often develop only after several years[6] and they have a worse prognosis than Parkinson's disease.[17 18] We did not, however, find a higher rate of revised diagnosis in arm 2 compared with arm 1 (11% v 15%) Another criticism was that an intention to treat analysis was inappropriate because of the comparatively large number of patients who withdrew.[9] Ideally, we would like to have had accurate drug data on all of the patients, including those who withdrew at the time arm 2 was terminated. For the subgroup of patients who died for whom data were available, most patients in arm 2 were still receiving combined treatment while only a fifth of patients in arm 1 had selegiline added to their drug regimen before they died.

Since the original publication two studies have shown that selegiline diminishes autonomic responsiveness and increases risk of orthostatic hypotension.[19 20] We postulated that if this mechanism was clinically important we should observe more sudden or unexpected deaths, hypotensive episodes, falls, and possibly a higher postmortem rate in arm 2. Our findings provide limited support for this hypothesis, though none of the differences were significantly However, retrospective analysis of clinical notes is likely to significantly underestimate the true rate of any hypotensive effect of selegiline and levodopa. The most marked difference in clinical characteristics between the two arms was for falls before death and possible dementia. Falls commonly occur among patients with severe Parkinson's disease because of postural instability and akinesia as well as any autonomic effect. A randomised controlled trial of selegiline, a tocopherol, or increase in falls and syncope in patients receiving selegiline in combination with a tocopherol.[12]

Dementia is not uncommon in association with Parkinson's disease and is a poor prognostic factor.[22 23] Selegiline and levodopa treatment may directly result in increased confusion. Alternatively, dementia may be a marker for general frailty and increased risk of adverse drug effects.[24]

One explanation could be that selegiline and levodopa contribute to hypotensive episodes which increase the risk of either a heart attack or stroke, especially in elderly patients with pre-existing atherosclerotic disease. However, both our analyses of cause specific mortality and of comorbidity did not support this notion. If combined treatment actually accelerated disease progression, and hence death from Parkinson's disease, subjects in arm 2 would be expected to have worse disability scores and to be more disabled or bedbound before death. The data do not, however, support this hypothesis either. The use of cardiac or antidepressant drugs was no greater in arm 2 than arm 1, although we cannot rule out the possibility of a drug interaction because some of the patients records were destroyed.

One remaining possibility is that combined treatment is harmful to a subgroup of patients. This might explain why the greatest comparative mortality ratio was seen for the analysis of patients on allocated treatment between 2 and 4 years. If susceptible subjects are selectivity removed from arm 2 the mortality ratios would be expected to return to unity with further follow up because only non-susceptible subjects would then remain in the study.

Clinical implications

Despite uncertainties there are some clear clinical implications from these results. There is no evidence that combined treatment with levodopa and selegiline confers advantages over levodopa treatment alone in terms of mortality or morbidity in patients with early, mild Parkinson's disease. There seems little logic in giving patients with newly diagnosed disease combined treatment, although treatment might be started with selegiline alone and then withdrawn if levodopa treatment was indicated. Clinicians should determine whether the addition of selegiline for severely disabled patients provides additional symptomatic benefit. In these patients quality of life is generally more important that quantity of life, and each case should be reviewed on its merits. However, if patients have clinically significant orthostatic hypotension, cardiac arrhnythmias, confusional states, hallucinations, or deteriorating cognitive function, gradual and slow withdrawal of selegiline over 4 to 6 weeks should be seriously considered.

Members of the Parkinson's Disease Research Group of the United Kingdom who recruited subjects and followed up patients for the trial: R Abbott, N Banerji, M Banie, G Boddie, P Bradbury, C Clarke, R Clifford-Jones, R Corston, E Critchley, P Critchley R Cull, J Dick, I Draper, C Ellis, G Elrington, L Findley, T Fowler, J Frankel, A Gale, C Gardner-Thorpe, W Gibb, J D Gibson, J M Gibson, R Godwin-Austen, R Greenwood, R Hardie, D Harley, C Hawkes, S Hawkins, M Hildick-Smith, R Hughes, L Illis, J Jestico, K Kafetz, R Kapoor, C Kennard, R Knight, R Kocen, A Lees, N Leigh, L Loizou, R Lenton, D MacMahon, C D Marsden, W Michael, J Mitchen, P Monro, P Murdoch, W Mutch, P Overstall, D Park, J D Parkes, B Pentland, G D Perkin, R Ponsford, N Quinn, M Rawson, J Rees, M Rice-Oxley, D Doch, F Schon, A Schapira, D Shepherd, G Stern, B Summers, C Turnbull, A Turner, S Vakil C Ward, A Whiteley, A Williams.

Contributors: YB-S participated in designing, analysing, and interpreting results from the cause of death inquiry study, as well as in interpreting the results of the Parkinson's Disease Research Group of the United Kingdom trial and in writing the paper. JH participated in the design, analysis, and interpretation of the trial of the Parkinson's Disease Research Group of the United Kingdom, as well as helping to write the paper. JO participated it) the design of the cause of death inquir-y study, procured all the material, and blinded all the notes for the drugs for Parkinson's disease. AJL was involved in the design and conduct of the trial of the Parkinson's Disease Research Group of the United Kingdom as well as helping to write the paper; he will also act as guarantor for the paper. AC designed the standardised form, reviewed all the case notes, and produced the vignettes for the cause of death inquiry study. BH, PO, YB-S, and AJL reviewed all the vignettes and assigned the causes of death for the cause of death inquiry study. All the contributors read and critically commented on the paper.

Funding: Continued support from the Parkinson's Disease Society of the United Kingdom, which also provided additional funding for the cause of death study, and Roche Products. Uncondifional sponsorship from Britannia Pharmaceuticals and Sandoz Products.

Conflict of interest: None.

[1] Lees AJ, on behalf of the Parkinson's Disease Research Group of the United Kingdom. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. BMJ 1995;311:1602-7.

[2] Parkinson's Disease Research Group of the United Kingdom. Comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson's disease: three years interim report. BMJ 1993;307:469-72.

[3] Tatto, WG, Greenwood CE. Rescue of dying neurones: a new action for deprenyl in MPTP parkinsonism. J Neurol Sci 1991;30:666-72.

[4] Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease, N Engl J Med 1989;321:1364-71.

[5] Birkmayer W, Knoll J. Riederer P, Youdim MBH, Hars V, Marton J. Increased life expectancy resulting from addition of 1-deprenyl to Madopar treatment in Parkinson's disease: a long-term study. J Neural Transm 1985;64:113-27.

[6] Olanow CW, Fabn S, Langston JW, Godbold J. Selegiline and mortality, in Parkinson's disease. Ann Nleuot 1996;40:841-5.

[7] Silva M, Watts P, Jenner P Effect of adding selegiline to levodopa in early, mild Parkinson's disease: Parkinson's disease is rarely a primary cause of death. BMJ 1996;312:703.

[8] Jellinger KA. Effect of adding selegiline to levodopa in early, mild Parkinson's disease: causes of death need confirmation. BMJ 1996;312:704.

[9] Gerlach M, Riederer P, Vogt H. Effect of adding selegiline to levodopa in early, mild Parkinson's disease: `on treatment' rather than intention to treat analysis should have been used. BMJ 1996;312:704.

[10] Lees AJ, Head J, Ben-Shlomo Y. Effect of adding selegiline to levodopa in early, mild Parkinson's disease. BMJ 1996;312:704-5.

[11] Lees AJ, Head J, Ben-Shlomo Y. Selegiline and mortality, in Parkinson's disease: another view. Ann Neurol 1997;41:282-3.

[12] World Health Organisation. Manual of the international classification of diseases, injuries, and causes of death, 9th revision. Geneva: World Health Organisation, 1978.

[13] Alderson MR, Meade TW. Accracy of diagnosis on death certificates compared with that in hospital records. Br J Prev Soc Med 1967;21:22-9.

[14] Collett D. Modelling survival data in medical research. London: Chapman and Hall, 1994.

[15] Fleiss JL. The measurement of interrater agreement. In: Fleiss JL ed. Statistical method, for rates and proportions 1st ed. New York: Wiley, 1981:212-36.

[16] Rajput AH. Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism -- a pospectie study. Can J Neurol Sci 1991;18:275-8.

[17] Wenning GK, Ben-Shlomo Y, Magalhes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atophy: an analysis of 100 cases. Brain 1994;117:835-45.

[18] Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger K, et al. Natural history of progressive supranuclear palsy Steele-Richarson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiat 1996;60:615-20.

[19] Turkka J, Suominen K, Tolonen U, Sotaniemi K, Myllyla VV. Selegiline diminishes cardiovascular autonomic responses in Parkinson's disease. Neurology 1997;48:662-7.

[20] Churchvard A, Matthias CJ, Boonhongchue, P, Lees AJ. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson's disease. J Neurol Neurosurg Psychiatry 1997;63:228-34.

[21] Sano M, Ernesto C, Thomas RG, Klauber Mr, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997;336:1216-22.

[22] Brown, RG, Marsden CD. How common is dementia in Parkinson's disease. Lancet 1984;1:1262-5.

[23] Ben-Shlomo Y, Whitehead AS, Davey Smith G. Parkinson's, Alzheimer's, and motor neurone disease: clinical and pathological overlap may suggest common genetic and enviromental factors. BMJ 1996;312:724.

[24] Campbell AJ, Buchner DM. Unstable disability and the fluctuations of frailty. Age Ageing 1997;26:315.