Medication	Indication & Benefits	Drawbacks
Co-careldopa IR	parkinsonism (but not drug-induced extrapyramidal symptoms) mobility issues	Levodopa becomes less effective over time. motor complications - especially in young  response fluctuations dyskinesia (Involuntary movements) ‘end-of-dose’ deterioration nocturnal immobility rigidity
Co-beneldopa IR	parkinsonism (but not drug-induced extrapyramidal symptoms) mobility issues
Controlled release co-careldopa & co-beneldopa	idiopathic Parkinson's disease reduces off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations
Levodopa dispersible	rapid onset of action early morning or afternoon akinesia ‘delayed on’ or ‘wearing off’ phenomena
Ropinrole Dopamine agonists		concurrent dose of levodopa may be reduced by approx. 20%
Pramipexole	Parkinson’s disease Restless legs syndrome	levodopa dose may be reduced. Pramipexole has been associated with somnolence and episodes of sudden sleep onset in a rare number of cases. Patients should be informed of this and advised to exercise caution when driving or operating machinery during treatment with the medication.
Rotigotine patch	Parkinson’s disease transdermal route facilitates treatment
selegiline		confusion and agitation
selegiline oral lyophilisate	difficulty in swallowing
safinamide	h idiopathic Parkinson’s disease as add-on therapy to a stable dose of levodopa alone or in combination with other medicinal products for Parkinson’s disease in mid to late-stage fluctuating patients.
trihexydil	tremor in younger Parkinson’s disease patients. sialorrhoea	little effect on bradykinesia and propensity for causing neuropsychiatric side effects.
procyclidine	dystonia delusions
entacapone	Parkinson’s disease and ‘end-of-dose’ motor fluctuations	adjunct to levodopa
tolcapone		adjunct to levodopa Due to the risk of hepatotoxicity, tolcapone should be prescribed under specialist supervision only
opicapone	adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors in adult patients with Parkinson’s disease and endof-dose motor fluctuations who cannot be stabilised on those combinations.	Opicapone enhances the effects of levodopa. Hence, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating treatment with opicapone.
Levodopa/Carbidopa/Entacapone (Stanek)	Parkinson’s disease and end of dose motor fluctuations not adequately controlled with levodopa and dopa decarboxylase treatment.
Amantadine	Parkinson’s disease (but not drug-induced extrapyramidal symptoms).
Apomorphine	refractory motor fluctuations in Parkinson’s disease (‘off’ episodes) inadequately controlled by levodopa with dopa-decarboxylase inhibitor or other dopaminergics	Requirements for initiation: Hospital admission see notes below

Levodopa

Levodopa is the amino-acid precursor of dopamine. It acts by replenishing depleted striatal dopamine. Levodopa already occurs naturally in the body and taking it as a drug treatment boosts the supply meaning more nerve cells can make more dopamine in the brain. 

Levodopa therapy should be initiated at a low dose and increased in small steps, with the final dose as low as possible. Intervals between doses should be suited to the individual patient needs. Levodopa treatment is associated with the development of potentially troublesome motor complications including response fluctuations and dyskinesias. Response fluctuations are characterised by large variations in motor performance, with normal function during the ‘on’ period, and weakness Levodopa Formulations 8 and restricted mobility during the ‘off’ period. ‘End-of-dose’ deterioration also occurs, where the duration of benefit after each dose becomes progressively shorter. Modified-release preparations may help with ‘end-of-dose’ deterioration or nocturnal immobility and rigidity. Motor complications are particularly problematic in young patients treated with levodopa.

Co- careldopa (Sinemet) and Co-beneldopa (Madopar)

Co-careldopa and co-beneldopa are indicated for Parkinsonism (but not drug-induced extrapyramidal symptoms). In these preparations, Levodopa is combined with an extracerebral dopa-decarboxylase inhibitor that reduces the peripheral conversion of levodopa to dopamine allowing less side effects and lower doses of levodopa to be used. Co-beneldopa contains the extracerebral dopa-decarboxylase inhibitor benserazide and co-careldopa contains carbidopa. At least 70 mg carbidopa daily is necessary to achieve full inhibition of peripheral dopa-decarboxylase. These combinations are used in the elderly or frail, in patients with other significant illnesses, and in those with more severe symptoms. The preparations are effective and well-tolerated in most patients. When transferring patients from another levodopa/dopa-decarboxylase inhibitor preparation, the previous preparation should be discontinued at least 12 hours before.

Levodopa controlled release formulations: Co-careldopa (Sinemet CR, Caramet, Lecado) & Co-beneldopa (Sinemet CR, Half Sinemet CR)

These are indicated for idiopathic Parkinson's disease, in particular to reduce off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations. The experience is limited with 'Sinemet CR' and 'Half Sinemet CR' in patients who have not been treated with Levodopa before. In clinical trials, patients with motor fluctuations experienced reduced 'off'-time with 'Sinemet CR' when compared with 'Sinemet'. The reduction of the 'off'-time is rather small (about 10%) and the incidence of dyskinesias increases slightly after administration of 'Sinemet CR' compared to standard 'Sinemet'. Global ratings of improvement and activities of daily living in the 'on' and 'off' state, as assessed by both patient and physician, were better during therapy with 'Sinemet CR' than with 'Sinemet'. Patients considered 'Sinemet CR' to be more helpful for their clinical fluctuations, and preferred it over 'Sinemet'. In patients without motor fluctuations, 'Sinemet CR‘ under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with 'Sinemet'. Generally, there was no further improvement of other symptoms of Parkinson's disease. Supplementary dose of immediate-release Madopar may be needed with first morning dose; if response still poor to total daily dose of Madopar CR plus Madopar corresponding to 1.2 g levodopa, consider alternative therapy.

Levodopa dispersible formulation: Co-beneldopa (Madopar dispersible)

This is beneficial for patients requiring a more rapid onset of action, e.g. from early morning or afternoon akinesia, or who exhibit ‘delayed on’ or ‘wearing off’ phenomena. The tablets can be dispersed in water or orange squash (not orange juice) or swallowed whole.

Dopamine Agonists

Dopamie agonists work by mimicking the action of dopamine. They can be used as monotherapy or in conjuction with levodopa resulting in lower doses of levodopa, reducing the risk of dyskinesia and to help when levodopa wears off or doesn’t work as well. Dopamine agonists have longer half lives and and can reduce the ‘on/off’ effect associated with levodopa. Dopamine agonist medications can also be used for restless legs syndrome.

Ropinirole (Requip)

Licensed to treat Parkinson’s disease, either used alone or as an adjunct to levodopa with a dopa-decarboxylase inhibitor. When administered as adjunct to levodopa, concurrent dose of levodopa may be reduced by approx. 20%. 

Ropinirole XL (Requip XL, Ipinnia XL)

For use in stable Parkinson’s disease in patients transferring from ropinirole immediaterelease tablets, initially Ipinnia XL once daily substituted for total daily dose equivalent of ropinirole immediate-release tablets; if control not maintained after switching, in patients receiving less than 8 mg once daily, increase in steps of 2 mg at intervals of at least 1 week to 8 mg once daily according to response; in patients receiving 8 mg once daily or more, increase in steps of 2 mg at intervals of at least 2 weeks according to response; max. 24 mg once daily. Patients can also be initiated on Ipinnia XL with a usual starting dose of 2mg once daily. After a week this dose can be increased to 4mg once daily, when a therapeutic response may be seen. If sufficient symptom control is not achieved or maintained, the daily dose may be increased by 2mg at weekly or longer intervals. When administered as adjunct to levodopa, concurrent dose of levodopa may be reduced.

Pramipexole (Mirapexin)

Licensed to treat Parkinson’s disease, used alone or as an adjunct to levodopa with dopa-decarboxylase inhibitor. During pramipexole dose titration and maintenance, levodopa dose may be reduced. Doses and strengths are stated in terms of pramipexole (base); equivalent strengths in terms of pramipexole dihydrochloride monohydrate (salt) are as follows:

• 88 micrograms base ≡ 125 micrograms salt;
• 180 micrograms base ≡ 250 micrograms salt;
• 350 micrograms base ≡ 500 micrograms salt;
• 700 micrograms base ≡ 1 mg salt

Pramipexole has been associated with somnolence and episodes of sudden sleep onset in a rare number of cases. Patients should be informed of this and advised to exercise caution when driving or operating machinery during treatment with the medication.

Pramipexole prolonged release (Pipexus)

The majority of patients are able to switch from immediate release Pramipexole to the prolonged release formulation without the need for dose adjustment.

Rotigotine patch (Neopro)

Licensed to treat Parkinson’s disease, either used alone or as an adjunct to levodopa with dopa-decarboxylase inhibitor and it is a useful product where the transdermal route facilitates treatment. 

Patient video using Rigotine patches

Monoamine oxidase B inhibitors

MAO–B inhibitors aid nerve cells to make better use of existing dopamine. Monoamine oxidase type B wrongly hoovers up dopamine that is not being used by your brain. MAO-B inhibitors stop this enzyme so that more dopamine becomes available. They can be beneficial for motor fluctuations however dyskinesia and sickness may get worse as they strengthen the effects of levodopa. MAO-Bs take 2-3 weeks to work and when stopped will take the same amount of time before they stop working. They interact with many medications and have many side efects.

Rasagiline (Azilect)

Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa with dopa-decarboxylase inhibitor. The benefits of rasagiline are the once daily dosage and their effect on motor fluctuations that happen at the end of or prior to levodopa dose.

Selegiline (Eldepryl, Zelapar)

Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa with dopa-decarboxylase inhibitor. 

Selegiline oral lyophilisate (Xadago)

The lyophilisate can be taken daily before breakfast. The tablets should be placed on the tongue and allowed to dissolve. The patient should be advised not to drink, rinse or wash mouth out for 5 minutes after taking the tablet. Patients receiving the 10mg conventional Selegiline tablet can be switched to Zelapar 1.25mg. The lyophilisate may be useful for patients who have difficulty in swallowing as Zelapar dissolves completely within 10 seconds of placing on the tongue and, in contrast to conventional tablets, Selegiline is absorbed primarily pregastrically.

Safinamide

Licensed for the treatment of adult patients with idiopathic. Parkinson’s disease as add-on therapy to a stable dose of levodopa alone or in combination with other medicinal products for Parkinson’s disease in mid to late-stage fluctuating patients. 

Antimuscarinics

Acetylcholine is a chemical messenger between the brain, nerves and muscles. In Parkinson’s the effect of acetylcholine is stronger, leading to part of the brain becoming overactive and resulting in tremors. Anticholinergics block acetylcholine thus reducing this effect. Anticholinergics may also help with rigidity, slowness of movement, speech and writing difficulties, gait, sweating, involuntary movements of the eyes and feeling depressed. They may also reduce the flow of saliva to helo with drooling or sialorrhoea (producing too much saliva). However, anticholinergics can also lead to a dry mouth, memory problems, 

 

Trihexyphenidyl

It may be helpful if you experience dystonia (muscle spasms), tremor or sialorrhoea (excessive saliva production). If it causes dry mouth take trihexyphenidyl before meals. If this causes nausea take after food. This may cause increased thirst; drink water, peppermint or chewing gum.

Procyclidine (Kemadrin)

Helpful in muscle spasms (dystonia) and more complex Parkinson’s symptoms such as delusions

 

COMT inhibitors

Levodopa boosts the supply of dopamine in your brain. COMT inhibitors work by preventing the peripheral breakdown of levodopa, by inhibiting catechol-O-methyltransferase, allowing more levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa or cocareldopa for patients with Parkinson’s disease who experience ‘end-of-dose’ deterioration and cannot be stabilised on these combinations.

Tolcapone (Tasmar)

Due to the risk of hepatotoxicity, tolcapone should be prescribed under specialist supervision only, when other catechol-O-methyltransferase inhibitors combined with cobeneldopa or co-careldopa are ineffective.

Entacapone (Comtess)

Licensed as adjunct to levodopa with dopa-decarboxylase inhibitor in Parkinson’s disease and ‘end-of-dose’ motor fluctuations. 

Opicapone (Ongentys)

Licensed as adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors in adult patients with Parkinson’s disease and endof-dose motor fluctuations who cannot be stabilised on those combinations. Dose should be taken at bedtime, at least one hour before or after levodopa combinations. Opicapone enhances the effects of levodopa. Hence, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating treatment with opicapone.

Levodopa/Carbidopa/Entacapone (Stanek, Stalevo, Sastravi)

Licensed for Parkinson’s disease and end of dose motor fluctuations not adequately controlled with levodopa and dopa decarboxylase treatment. Only 1 tablet to be taken for each dose. Patients receiving standardrelease co-careldopa or co-beneldopa alone, initiate Stanek at a dose that provides similar (or slightly lower) amount of levodopa Patients with dyskinesia or receiving more than 800 mg levodopa daily, introduce entacapone before transferring to Stanek (levodopa dose may need to be reduced by 10–30% initially). Patients receiving entacapone and standardrelease co-careldopa or co-beneldopa, initiate Stanek at a dose that provides similar (or slightly higher) amount of levodopa. Stanek is most cost effective at higher doses.

Amantadine

Licensed for Parkinson’s disease (but not drug-induced extrapyramidal symptoms).

Apomorphine

Licensed for refractory motor fluctuations in Parkinson’s disease (‘off’ episodes) inadequately controlled by levodopa with dopa-decarboxylase inhibitor or other dopaminergics (for capable and motivated patients under specialist supervision).  Requirements for initiation: Hospital admission and at least 2 days of pretreatment with domperidone for nausea and vomiting, after at least 3 days withhold existing antiparkinsonian medication overnight to provoke ‘off’ episode, determine threshold dose, reestablish other antiparkinsonian drugs, determine effective apomorphine regimen, teach to administer by subcutaneous injection into lower abdomen or outer thigh at first sign of ‘off’ episode, discharge from hospital, monitor frequently and adjust dosage regimen as appropriate (domperidone may normally be withdrawn over several weeks or longer)—for full details of initiation requirements, consult product literature.

 

References: 1. British National Formulary (2017) British National Formulary 73. Available at www.bnf.org. (Accessed 27 July 2017). 2. National Institute for Clinical excellence (20017) NICE clinical guideline 71 Parkinson’s disease in adults. Available at : www.nice.org.uk (Accessed 27 July 2017). 3. Scottish Intercollegiate Guidelines Network (2010) SIGN 113 Diagnosis and pharmacological management of Parkinson’s disease. Available at: www.sign.ac.uk (Accessed 10 September 2012). 4. Giladi, N., Boroojerdi, B., Ko/>rczyn, A.D., Burn, D.J., Clark, C.E., Schapira, A.H.V. (2007) Rotigotine transdermal patch in early Parkinson’s disease: A randomized, double-blind, controlled study versus placebo and ropinirole. Movement Disorders, 22(16), pp 2398-2404. 5. Poewe, W.H., Rascol, O., Quinn, N., Tolosa, E., Oertel, W.H., Martignoni, E., Rupp, M., Boroojerdi, B. (2007) Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurology, 6, pp 513-520. 18 6. Lew, M.F., Pawha, R., Leehey, M., Bertoni, J., Kricorian, G., Zydis Selegiline Study, (2007) Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson’s disease. Current Medical Research and Opinion, 23(4) pp 741-750. 7. National Institute for Clinical excellence (2017) Parkinson’s disease with motor fluctuations:safinamide. Evidence summary (ES6). Available at : www.nice.org.uk (Accessed 20 March 2017) 8. Martin, W.E., Loewenson, R.B., Resch, J.A., Baker, A.B. (1974) A controlled study comparing trihexyphenidyl hydrochloride plus levodopa with placebo plus levodopa in patients with Parkinson’s disease. Neurology, 24/10 (912- 9), 0028-3878. 9. Ferreira, J.J., Lees, A., Rocha, J.F., Poewe, W., Rascol, O., Soares-daSilva, P. (2015) Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurology. 10. Lees, A.J., Ferreira, J., Rascol, O., Poewe, W., Rocha, J.F., McCrory, M., et al., (2016) Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson’s Disease and Motor Fluctuations: A Randomised Clinical Trial. JAMA Neurology. 11. National Institute for Clinical excellence (2017) Parkinson’s disease with end of dose motor fluctuations: opicapone: Evidence summary (ES9). Available at : www.nice.org.uk (Accessed 20 March 2017) 12. Verhagen Metman, L., Del Dotto, P., Van Den Munckhof, P., Fang, J., Mouradian, M.M., Chase, T.N. (1998) Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology, 50/5 (1323-1326), 0028-3878. 13. Chen, J.J., Obering, C. (2005) A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson’s disease. Clinical Therapeutics, 27(11), pp1710-1724. 14. Ruiz, P.J.G., Ignacio, A.S., Pensado, B.A., Garcia, A.C., Frech, F.A., Lopez, M.A.., Gonzalez, J.A., Octavio, J.B. (2008) Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations : a multicenter study. Movement Disorders, 23(8) pp 1130-1136.