German PD Pharmacotherapy Guideline (DGN S2k, 2024)
This is a condensed summary of the German Society for Neurology (DGN) S2k-Leitlinie for the diagnosis and treatment of Parkinson’s disease, developed in collaboration with the Austrian and Swiss Neurological Societies. The guideline was revised at the S2k evidence level (last updated November 2023) and published in 2024. Recommendation strength follows the Oxford Centre for Evidence-based Medicine classification: “should be recommended” (strong), “can be recommended” (moderate), and “may be considered” (weaker evidence). The guideline adopts the MDS clinical diagnostic criteria and the terminology “Parkinson’s disease” over “idiopathic Parkinson syndrome.”
Bottom Line: Key Recommendations
- Initial therapy: Individualized based on age, comorbidities, and symptom severity — non-ergoline dopamine agonists or MAO-B inhibitors for younger patients; levodopa when rapid effect needed or in multimorbid patients
- Ergoline DAs: Should NOT be used (bromocriptine, cabergoline, pergolide) due to fibrotic complications
- Anticholinergics: Should no longer be used except rare cases for tremor
- Motor fluctuations: Multimodal approach — adjust levodopa dosing, add DA/MAO-B/COMT inhibitors; opicapone and entacapone largely equivalent
- Advanced therapies: Four pump options now available (apomorphine, LCIG, LECIG, foslevodopa/foscarbidopa); STN-DBS preferred for motor fluctuations
- Non-motor: Comprehensive recommendations for depression, dementia, sleep, orthostatic hypotension, pain, and psychosis
Initial Pharmacotherapy (De Novo PD)
Initial therapy selection should consider “differing efficacy, side effects, patient age, comorbidities, and psychosocial profile.” There is no single universal first-line agent.
| Agent Class | Specific Agents | Best Suited For | Key Notes |
|---|---|---|---|
| Non-ergoline dopamine agonists | Pramipexole, ropinirole, piribedil, rotigotine | Younger patients; delay of motor fluctuations/dyskinesias | Monitor for impulse control disorders at every visit; pramipexole preferred in hepatic impairment; ropinirole/rotigotine/piribedil preferred in renal impairment |
| MAO-B inhibitors | Selegiline, rasagiline | Younger patients with mild symptoms | Lower motor efficacy than DA or levodopa; may delay need for levodopa |
| Levodopa | Levodopa/carbidopa, levodopa/benserazide | Severe symptoms requiring rapid effect; multimorbid patients; elderly; better individual tolerability | Most potent motor symptomatic agent; use lowest effective dose; consider early combination with COMT or MAO-B inhibitor |
Agents to Avoid
- Ergoline dopamine agonists (bromocriptine, cabergoline, pergolide): Should NOT be used due to risk of cardiac valvulopathy and fibrotic complications
- Anticholinergics: Should no longer be used due to unfavorable risk-benefit profile (cognitive impairment, hallucinations); restricted to rare cases for tremor control in younger patients without cognitive concerns
Management of Motor Fluctuations
A multimodal approach is recommended:
| Strategy | Details |
|---|---|
| Optimize levodopa | Adjust dosing intervals and formulations (modified-release, soluble, inhaled); fractionation of doses to reduce wearing-off |
| Add COMT inhibitor | Opicapone or entacapone (largely equivalent in efficacy); tolcapone requires rigorous hepatic monitoring (hepatotoxicity risk) |
| Add MAO-B inhibitor | Rasagiline or safinamide (safinamide also has glutamatergic properties) |
| Add dopamine agonist | Non-ergoline agents; consider patient-specific factors including impulse control risk |
| Istradefylline | Adenosine A2A receptor antagonist; add-on to levodopa for wearing-off fluctuations |
Management of Dyskinesias
- Amantadine: Should be used to reduce dyskinesias; caution for anticholinergic and hallucinogenic side effects, especially in elderly
- Safinamide: May be considered for moderate-to-severe dyskinesias, though evidence is not conclusive
- Dose fractionation: Reduce individual levodopa doses while increasing frequency
Advanced Therapies
Pump Therapies
| Therapy | Mechanism | Key Evidence | Notes |
|---|---|---|---|
| CSAI (subcutaneous apomorphine infusion) | Continuous DA stimulation | Reduces off-phases and dyskinesias; improves non-motor symptoms | Skin nodules at injection sites; requires caregiver support |
| LCIG (levodopa-carbidopa intestinal gel) | Continuous jejunal levodopa delivery via PEG-J | Significantly increases on-time without troublesome dyskinesias | PEG-J complications (tube kinking, infection); requires specialized center |
| LECIG (levodopa-entacapone-carbidopa intestinal gel) | Same as LCIG with added COMT inhibition | Similar efficacy to LCIG | Additional entacapone monitoring required |
| CSFLI (foslevodopa/foscarbidopa subcutaneous infusion) | Continuous subcutaneous levodopa delivery | Recently approved (2023); reduces off-time | Limited long-term data; skin reactions at infusion site |
All pump therapies require close monitoring by experienced physicians.
Deep Brain Stimulation
| Target | Recommendation | Indications |
|---|---|---|
| STN-DBS | Preferred over GPi-DBS for motor fluctuations | Levodopa responsiveness ≥33% (or ≥50% in patients <60 years with disease duration ≥4 years) |
| GPi-DBS | Alternative to STN | Consider when medication reduction is not a goal or dyskinesia is primary concern |
| VIM-DBS | Should NOT be used for fluctuations | Medication-resistant tremor when STN/GPi is contraindicated |
- Ablative procedures: Pallidotomy may be considered; thalamotomy and subthalamotomy should NOT be performed; gamma-knife/cyber-knife not recommended
Non-Motor Symptom Management
Cognitive Disorders
| Condition | Recommendation |
|---|---|
| PD-MCI | Cognitive training should be offered; pharmacotherapy (AChEIs) should NOT be used at this stage |
| PD dementia | Rivastigmine should be used (approved indication); donepezil can be used (off-label) |
Depression
Depression Treatment Algorithm
- Step 1: Optimize dopaminergic therapy first
- Step 2: If dopamine agonist therapy is possible, pramipexole is recommended (dual motor + antidepressant benefit)
- Severe depression: Venlafaxine or desipramine
- Moderate depression with lethargy: Venlafaxine, citalopram, or sertraline
- Moderate depression with agitation: Mirtazapine or trazodone
Other Non-Motor Symptoms
| Symptom | Recommendations |
|---|---|
| Apathy | Optimize dopaminergic medication with levodopa; pramipexole, rotigotine, or piribedil as adjuncts |
| Anxiety | Constant anxiety without affective fluctuations should NOT be treated with adjusted dopaminergic therapy; citalopram may be attempted |
| Psychosis | Reduce/discontinue anticholinergics, amantadine, DA agonists, then MAO-B inhibitors; quetiapine or clozapine for persistent symptoms; pimavanserin where available |
| Orthostatic hypotension | First-line: midodrine (should be recommended); second-line: fludrocortisone (can be recommended); third-line: droxidopa (may be considered, off-label) |
| Pain | Nociceptive: WHO three-step scheme; neuropathic: gabapentin and/or duloxetine preferred; severe: ER oxycodone/naloxone may be considered |
| REM sleep behavior disorder | Clonazepam and/or melatonin may be considered |
| Insomnia | Eszopiclone, doxepin, zolpidem, trazodone, melatonin, venlafaxine, nortriptyline, or mirtazapine (weak evidence for all) |
| Sialorrhea | Botulinum toxin injections into salivary glands (Class A evidence); glycopyrrolate as alternative |
Notable Differences from MDS EBM Reviews
- Broader scope: The DGN guideline covers the full disease spectrum from diagnosis through palliative care, while MDS EBM reviews focus on specific symptom domains
- Genetic diagnostics: Contains first-time concrete recommendations for genetic testing in PD (GBA1, LRRK2, PRKN, PINK1, etc.)
- Piribedil: Included as a non-ergoline DA option (more commonly used in Europe than North America)
- Foslevodopa/foscarbidopa: Included as the newest approved pump therapy (2023) with subcutaneous delivery
- Evidence grading: Uses Oxford Centre for Evidence-based Medicine system rather than MDS-specific quality scoring
- Terminology: Formally recommends “Parkinson’s disease” over “idiopathic Parkinson syndrome,” recognizing identified genetic and environmental causes
Limitations
- S2k-level guideline (systematic literature search but consensus-based recommendations rather than fully systematic grading of each recommendation)
- Some recommendations are based on weak evidence or extrapolated from non-PD populations
- Foslevodopa/foscarbidopa has limited long-term data at time of guideline publication
- Several off-label recommendations included (donepezil for PDD, droxidopa for OH)
Reference
Höglinger G, Trenkwalder C, et al. Diagnosis and treatment of Parkinson’s disease (guideline of the German Society for Neurology). Neurol Res Pract. 2024;6:30. doi: 10.1186/s42466-024-00325-4