Sleep changes experienced by patients on apomorphine infusion were indicated by scores on Insomnia Severity Index and Clinical Global Impression-Improvement Scale.
Valeria Cochen De Cock, MD
Recently published findings in Lancet Neurology from a placebo-controlled study (NCT02940912)showed that night-time subcutaneous apomorphine infusion (Orkyn; Aguettant Pharma) for up to 5 mg/h is safe and improves Parkinson disease (PD)-related insomnia, as demonstrated by scores on Parkinson’s Disease Sleep Scale (PDSS) scores.1
"Night-time administration could render apomorphine infusion more acceptable (compared with a 24-h infusion) because patients will not have to deal with the device-related constraints during the daytime," lead investigator Valeria Cochen De Cock, MD, professor of sleep and neurology, Beau Soleil Clinic, and colleagues wrote. "Our study supports the concept of continuous dop-aminergic stimulation, not only during the day but also at night, in patients with advanced Parkinson’s disease."
The study, which spanned 11 expert centers in France, enrolled 46 patients aged 35 to 80 years with fluctuating PD and moderate to severe insomnia, defined by scores of at least 15 on Insomnia Severity Index (ISI). There were 2 treatment periods separated by a washout period, then crossover to the other intervention. Each treatment period consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. During the washout period, the dose was gradually reduced over 3 nights, and patients remained free of medication for the following 14 nights.
Among the cohort, 91% (n = 42) completed the 2 medication periods. Between the 2 treatment groups, change in PDSS score was greater in those on night-time apomorphine infusion than placebo (treatment effect, 9.95; 95% CI, 0.88-19.03; P = .041). In terms of individual PDSS grouped-item scores, apomorphine outperformed placebo for the items "overall quality of night’s sleep" (1.63; 95% CI, 0.49-2.77; P = .0063) and "sleep onset and maintenance insomnia" (1.51; 95% CI, –0.01 to 2.70; P = .024).
The apomorphine treatment period was also associated with greater change in ISI score (treatment effect, –2.23; 95% CI, –3.83 to –0.64; P = .011) and self-estimated clinical global impression of sleep quality (change in CGI score, 1.40; 95% CI, 0.62-2.19; P = .0007). On morning awakening, compared with the placebo period, the apomorphine period was associated with an improvement in motor condition, as demonstrated by change in Likert scale score (–0.57; 95% CI, –0.98 to –0.16; P = .012) but without change in pain (–0.20; 95% CI, –0.59 to 0.19; P = .36).
Apomorphine infusion was also found to be safe, as 54% (n = 25) of those on active therapy reported adverse events (AEs) vs 37% (n = 17) of those on placebo. Apomorphine was associated with more frequent dizziness, found in 7 (15%) participants compared with none in the placebo group.
One of the identified loci related to clinical progression in Parkinson disease expresses ADORA2A in the cerebellum, which encodes the adenosine A2A receptor, a promising target for therapeutics in PD.
Additional findings from the study showed that night-time apomorphine led to greater increase in percentage of sleep stage N2 (6.59%; 95% CI, 0.96-12.23; P = .021) and reduction in percentage of non-REM sleep stage N3 (–5.08%; 95% CI, –9.67 to –0.50; P = .040) and percentage of REM sleep (–3.57%;95% CI, –6.70 to –0.44; P = .031). Notably, the duration of non-REM stage N3 was unchangeded (–7.91 min; 95% CI, –24.89 to 9.07; P = .037).
Compared with placebo, apomorphine infusion was associated with a greater increase in the arousal index (4·88 events per h; 95% CI, 1.03-8.73; P = .021), and reduction in the periodic leg movement index during sleep (–5·74 events per h; 95% CI, –10.72 to –0.75; P = .050), whereas the apnea and hypopnea index and the percentage of enhanced submental tonic and phasic EMG activity remained unchanged. Between the two treatment periods, the mean sleep latency on the MSLT was unchained during daytime; however, the number of sleep-onset REM periods was higher with apomorphine (0.19; 95% CI, 0.00-0.38; P = .061).
