Changes in Sleep Architecture, Comorbidities Observed in Long-Term Treatment With Sodium Oxybate
At 1 and 3 years follow-up, sodium oxybate-treated patients showed significant increases in periodic leg movements index and significantly higher apnea-hypopnea index.
Maria Rosa Periata-Adrados, MD, PhD
Findings from a small-scale, longitudinal study assessing patients with narcolepsy with cataplexy (NT1) showed that after 3 years of treatment with low to medium doses of sodium oxybate, there were significant differences in sleep structure and an increase in comorbidities that led to drug withdrawal.
To the study authors knowledge, this was the longest recorded trial evaluating the effect of sodium oxybate on sleep architecture and comorbidity with video-polysomnography. The trial featured 23 adults with NT1 who were treated with an initial nocturnal dose of 4.5 g of sodium oxybate, with sleep parameters compared after 6 months (FU-1), 1 year (FU-2), and 3 years (FU-3) of uninterrupted treatment.
Senior investigator Maria Rosa Periata-Adrados, MD, PhD, head of the Sleep & Epilepsy Unit at the University General Hospital Gregorio Maranon, and colleagues performed a standard video-polysomnography at the follow-up time points to analyze several parameters, including sleep efficiency index, sleep latency, REM latency, and wakefulness after sleep onset. Additionally, patients were analyzed on stages N1, N2, N3, and REM, as well as total number of awakenings/hour, and apnea-hypopnea and periodic leg movements indexes.
Findings on video polysomnography showed an increase in stage N3 in the first sleep cycle and a REM-onset in 90% of patients after the administration of the first dose. When comparing the time spent in the different sleep stages between FU-1 and FU-2, patients increased the time spent in stage N2 (z = –2.17; P = .03). At FU-3, there was a significant increased observed in the time spent in stage N1 (z = –2.09; P = .03). Furthermore the time spent in stages N1 and N2 were significantly longer in the latest follow-up than at FU-1 (z = –2.36; P = .001).
Throughout the trial, in terms of sleep disorder comorbidities, 2 patients developed REM sleep behavior disorder while on 4.5 g/day of sodium oxybate and in another patient who appeared de novo at the same dose. While there was no significant differences in body mass index in subsequent follow-ups, apnea hypopnea index increased significantly in obese patients. Additionally, the apnea-hypopnea index was significantly higher at the last follow-up (z = –2.66; P = 0).
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Treatment with the therapy was associated with an increase in periodic leg movements index, as shown by higher scores at FU-2 (z = –2.52; P = .01) and FU-3 (z = –2.02; P = .04) when compared with FU-1. A total of 13 (56.5%) patients discontinued the therapy throughout the trial; however, none of these patients showed rebound cataplexy. Comorbidities and adverse events, which accounted for 3 discontinuations, included 1 case of unspecified psychosis that occurred after the initiation of sodium oxybate in a patient treated with 200 mg of modafinil, 1 case of hypertension, and 1 case of depression.
Sleep fragmentation in the third part of the night was found to be “very unpleasant” by all patients from FU-1 onwards, and was independent of the second dose administered. Aside from comorbidities and AEs, the reasons for withdrawal included pregnancy (n = 1) and insufficient compliance. Most patients complained about the 2 nightly doses, with mild AEs of dizziness, enuresis, unpleasant feeling of coldness after the first dose, and unintentional weight loss in female non-obese patients common in the first 3 months of treatment, were all observed.
Main limitations of the study included the fact that there were a small number of patients who continued treatment for the total 3 years. Another limitation was that some of the changes observed between the interval of diagnosis and successive follow-ups with sodium oxybate treatment may have been due to aging and the disease progression.
