Meta-analysis looks at safety, efficacy, and response to compound in patients with narcolepsy symptoms of excessive daytime sleepiness and cataplexy.
Due to its potential for misuse, sodium oxybate, the sodium salt of gamma-hydroxybutyrate (GHB), can only be procured legally in the United States via a prescription written by a doctor registered in the Xyrem Success Program and filled through a centralized pharmacy.
The safety and efficacy of the drug in treating narcolepsy symptoms was recently reaffirmed in a meta-analysis of randomized controlled trials (RCTs) going back 50 years published in the journal Sleep and presented as a poster at SLEEP 2017.
Beyond investigating the safety and efficacy of sodium oxybate, the researchers were seeking to learn more about the properties of the compound, and what makes it an effective treatment for narcolepsy symptoms of cataplexy (extreme muscle weakness and sleep attacks) and extreme daytime sleepiness (EDS). Sodium oxybate, known by the brand name of Xyrem in the United States, is a neurotransmitter that stimulates GABA-B receptors, although how exactly that treats narcolepsy symptoms is not entirely clear.
“It is a very interesting compound, and it is unique in a lot of ways,” says lead study author, Milton Erman, MD, of the Pacific Sleep Medicine Institute in Oceanside, Calif. “Initial studies of sodium oxybate were done to study its benefits for cataplexy. And then later, follow-up tests looked at its capacity to independently improve alertness.” The alerting ability was not appreciated at the outset, Erman says, adding ”part of the goal for our study was to look at better ways that we can identify how the compound is working the way it is.”
Toward that end, Erman and the other researchers conducted a systematic literature search all of the available RCTs on sodium oxybate for EDS in narcolepsy between 1966 and 2016 on all of the major online databases, from PubMed to Google Scholar. According to the study abstract, a total of 265 eligible articles were reviewed before 3 were identified for the meta-analysis. Outcomes were assessed subjectively by patients using the self-reported Epworth Sleepiness Scale (ESS) and objectively based on increased sleep latency using the Maintenance of Wakefulness Test (MWT) and the Clinical Global Impression of Change (CGI-C) scale.
“What we were able to do was to reinforce that the compound is effective for residual sleepiness in narcolepsy,” says Erman, adding that the study not only documents sodium oxybate as a benefit for patients with EDS, but also “shows slightly different benefits based on whether we are looking at subjective or objective measures.”
To close any gaps in the data, such as mean data scores and standard deviation, the investigative team poured through reports from clinical studies and documents created by regulatory agencies. Accounting for standard deviation in this meta-analysis was especially important because it was not reported in a previous meta-analysis of sodium oxybate studies, which was found to have “methodological limitations” that also included a triple-counting of the placebo arm.
“In looking at the methodology of some of the earlier papers we realized that it was possible to do a more complete meta-analysis and evaluate the data more appropriately,” says Erman. “It was mostly trying to ensure that we a) we had the best data, and b) we would be able to include more data than might have been available to some of the prior analyses,” he explains. “We were actually able to go back and look at study reports for all of the studies that Jazz [Pharmaceuticals] had done. So we were able to include data that some of the earlier analyses did not have.”
In the meta-analysis by Erman, et al, which was supported by Jazz Pharmaceuticals, manufacturer of Xyrem, the 3 RCTs identified by the researchers involved 634 patients. Data pooled from all of the studies showed significant improvements in the patient self-reported ESS scores for the 2 groups categorized by sodium oxybate dosage (9-g and 6-g), when compared with those in a placebo group, according to the researchers.
MWT sleep latency also significantly improved in the 9-g group, by 6.99 minutes compared with the placebo group. These results showed significant heterogeneity as well, while the odds ratio for responder rate as measured by CGI-C scores was also significantly better than the placebo group, states the study abstract.
Trying to determine if individual responders to the anti-cataleptic properties of sodium oxybate also respond favorably to the alerting properties of the compound became one of the goals of the study and will be the focus of future research, Erman says.
“Not everybody responds perfectly to either the anti-cataleptic properties or the alerting properties of the compound,” he says. “And one question that came up while we were discussing this was, ‘Are we defining two separate populations or are we defining one population that seems to have similar response?’ There are uncertainties about how the compound works in the first place, so it would be great to find out.”
Chuck Holt is a Florida-based freelance writer and editor.