Table 1.
Evidence supporting treatment strategies to manage nocturnal hypokinesia and early-morning OFF/akinesia in people with Parkinson’s disease.
| Treatment strategy | Recommended strategy/drug dosage | Benefits | Possible side effects | Efficacy and safety | Long-term outcomes |
|---|---|---|---|---|---|
| Non-pharmacological therapies | |||||
| Strategies for getting out of bed [31], [45], [47] | Multistep strategy, using arms and legs to move the trunk. Mentally rehearsing a movement before attempting it, and breaking a movement down into steps to avoid the need for simultaneous actions with consultant |
Improvement in mobility in bed. | − | NA | NA |
| Bedroom environmental adaptation [48], [49], [50] | Bed rail. Suitable bed height and size. Friction-reducing bedsheets, lightweight quilt, or blanket. |
Improvement in mobility in bed. | − | NA | NA |
| Pharmacologic therapies | |||||
| Dopamine agonists | |||||
| Rotigotine transdermal patch [58], [59], [60], [61], [62] | 2–16 mg. | Improvement in nocturnal hypokinesia, early-morning OFF/akinesia, pain. Improvement in frequency and degree of turning in bed. Improvement in PDSS-2, modified PDSS, total UPDRS, UPDRS-III, early morning UPDRS-III, UPDRS-axial score, MDS-UPDRS-III and IV, time up and go, NADS, PDQ-8. |
Nausea and vomiting Application site reaction Dizziness Other typical dopamine agonist adverse events. |
2–4 mg of rotigotine with single drug use, added on to levodopa, and zonisamide improved MDS-UPDRS-III (−11.1 points), IV (−1.1 points), off time (34.6 min), PDSS-2 (−7.3) at 3 months [58]. 10.46 ± 4.63 mg rotigotine improved frequency and degree of turning in bed, total UPDRS, UPDRS-III, UPDRS-axial score, Modified PDSS, NADCS compared to placebo at 12 weeks [59]. 11.83 mg rotigotine improved early morning UPDRS-III (−9.3 points and 46 % of patients improved UPDRS-III by > 30 %), time up and go test (−1.4 sec), mean finger tapping (26.5 taps/min), 61 % of patients improved NADCS by 32 % at 12 weeks [60]. 2–16 mg rotigotine improved early morning UPDRS-III (−3.55 points) and PDSS-2 (−4.26 points), and NADCS (−0.41 points) compared to placebo at 12 weeks. 16 % of rotigotine-treated group decreased dosage to 2 mg due to tolerability concern [62]. |
weeks. |
| Ropinirole prolonged release (PRP) [63], [64], [65] | 2–24 mg (adjunctive). | Reduction in frequency of nocturnal awakening. Improvement in PDSS, PSQI, ESS, and UPDRS-III. |
Risk of impulse control disorders. Risk of sudden onset of sleep. Other typical dopamine agonist adverse events. |
Switching of ropinirole intermediated release (PIR) to 17.2 ± 6 mg of PRP improved ON UPDRS-III (−3.1 points), PDSS, PSQI, and ESS at 5–13 weeks. New onset and worsening leg edema and nighttime confusion were reported [63]. Adjunct ropinirole 2–24 mg (19.0 – 19.3 ± 5.73––5.94 mg) improved on time during nighttime and early morning, PDSS compared to placebo at week 24 [64], [65]. |
5–24 Weeks. |
| Subcutaneous apomorphine injection and infusion [66], [67] | 34.8 ± 6.5 mg (extended nocturnal infusion). 1–10 mg (single injection for rescue therapy). |
Reduction of nocturnal awakenings, nocturnal OFF periods, pain, early-morning OFF/ akinesia, dystonia and nocturia. Improvement in frequency, speed, and degree of turning in bed. Improvement in PDSS-2, NADCS, UPDRS- II, III, and IV, and axial score of UPDRS. |
An infusion-free gap of at least four hours is required for each 24-hour infusion period. Tolerance. Discomfort. Skin nodule or injection site reaction. Other typical dopamine agonist adverse events. |
6 PD with overnight apomorphine improved nocturnal off time, pain, dystonia, and nocturia while 3 placebo improved nocturnal pain, spasm, and sleep disruption [66]. 34.8 ± 6.5 mg, extended nighttime dosage improved in frequency, speed, and degree of turning in bed assessed by wearable sensor and improved PDSS-2, NADCS, UPDRS- II, III, and IV, and axial score of UPDRS [67]. |
NA |
| Pramipexole (sustained-release and immediate-release formulations) [68] | 1.5 mg/day | Improvement in PDSS-2, NHQ, SCOPA-S, EMO, ESS. | Risk of impulse control disorders. Risk of sudden onset of sleep. Other typical dopamine agonist adverse events. |
The mean improvements of PDSS-2 in pramipexole SR and IR were 13.7 points and 14.4 points. At least 50 % reported at least one mild to moderate intensity adverse effect and equal in both formulas [68]. | 18 weeks |
| Monoamine oxidase inhibitor | |||||
| Rasagiline [69], [70], [71] | 1 mg | Improvement in sleep quality and excessive daytime sleepiness. May be beneficial for treating early-morning OFF/akinesia by improving axial impairment (rising from a chair). Improvement in ESS. Improvement in sleep maintenance, wake after sleep onset, numbers of arousal, light sleep. |
Risk of hallucinations. | Adjunctive double-blind placebo-controlled trial of 1 mg rasagiline and entacapone. Rasagiline improved UPDRS-III (−5.64 points) compared to placebo, while entacapone was not significant compared to placebo (−3.22 points) at week 18 [71]. | 18 weeks. |
| Levodopa | |||||
| Standard or sustained-release levodopa carbidopa [51], [53] | NA | Improvement in nocturnal hypokinesia and possible improvement of early morning akinesia. Increase sleep duration. Improvement of NADCS. |
General side effects of levodopa. | Double-blind placebo-controlled cross-over study. Single dose of sustained-release levodopa carbidopa improved NADCS (1.9 ± 0.14) compared to placebo (2.9 ± 0.14) [51]. Double-blind placebo-controlled cross-over study. Morning dose of standard levodopa carbidopa to sustained-release levodopa carbidopa improved morning on time (47 min vs 58 min) [53]. |
2 weeks |
| Immediate-release levodopa/carbidopa [52] | 200 mg levodopa bedtime | Earlier improvement of nocturnal hypokinesia and early morning off/ akinesia. | General side effects of levodopa and insomnia, nightmare, restlessness, and reflex daytime somnolence. | 200 mg levodopa bedtime improved early morning walking time and number of spontaneous moves in beds compared to placebo and divided dose (100 mg bedtime and 100 mg at 3 A.M.) [52]. | NA |
| Sustained-release levodopa/benserazide [54], [55], [72] | 450 mg. [300–600 mg] combination with 360 mg. [250–750] standard release levodopa/benserazide. | Improvement in nocturnal hypokinesia, early-morning OFF/akinesia. Stable long-lasting improvement when combined with standard levodopa/carbidopa. |
General side effects of levodopa. | Improved of nocturnal akinesia and early morning akinesia severity [54]. | 24 months |
| Levodopa/carbidopa intestinal gel infusion [73] | 1,412 mg continuous infusion 14.3 h/day. | Improvement of PDSS-2 at 3, 6, 12, 18, and 24 months. Improvement of ESS at 6, 12 months. |
Abdominal cramps. Weight loss. |
Improvement of PDSS-2, ESS including nocturnal motor symptoms [73]. | 12––24 months |
| Dispersible levodopa/carbidopa [56], [74] | NA | May be beneficial for treating early-morning OFF/ akinesia (rescue therapy). | General side effects of levodopa. | NA | NA |
| Levodopa powder for orally inhalation (CVT-301) [57] | 84 mg. orally inhale adjunct to standard first dose levodopa/ carbidopa | May be beneficial for treating early-morning OFF/ akinesia (rescue therapy). | Cough (mild and transient). Nausea. Upper respiratory tract infection. Discoloration of mucus coughed up from the lungs. Should not be taken by patients taking non-selective MAOI, or who have asthma, COPD, other chronic lung diseases. |
Randomize, double-blind, placebo-controlled, 2-way crossover study. Better time-to-ON in treatment group (25.0 min) compared to placebo group (35.5 min) with well-tolerated and no notable safety-concerned [57]. | NA |
COPD, Chronic Obstructive Pulmonary Disease; ESS, Epworth Sleepiness Scale; EOM, early morning OFF; MAOI, Monoamine Oxidase Inhibitor, MDS-UPDRS, Movement Disorder Society–Unified Parkinson’s Disease Rating Scale; N/A, not available; NADS: Nocturnal Akinesia Dystonia Scale; NHQ, Nocturnal Hypokinesia Questionnaire; PDSS-2, Parkinson’s Disease Sleepiness Scale-2; PDQ-8, Parkinson’s Disease Questionnaire 8-item; NA: not applicable, NADCS: Nocturnal Akinesia Dystonia and Cramp Score; PSQI, Pittsburgh Sleep Quality Index; SCOPA-S, Scales of Outcomes in Parkinson’s Disease – Sleep.