Opioids Improve Disturbed Nocturnal Sleep and Excessive Daytime Sleepiness in Narcolepsy Type 1

Rolf Fronczek, MD, PhD

In a recent systematic literature review and questionnaire study published in Sleep Medicine, findings showed that opioids, specifically oxycodone and codeine, were associated with improvements in self-reported narcolepsy symptoms such as disturbed nocturnal sleep and excessive daytime sleepiness. Overall, these findings suggest that opioid use could provide symptom relief in patients with narcolepsy type 1.¹

Among 7 studies selected for possible effects of opioids on narcolepsy symptom severity, 3 involved codeine, including 2 case reports and 1 report combining a case series, open label study and a randomized controlled trial. The analysis also yielded 1 conference presentation on methadone, 1 case series on tramadol, 1 case report on oxycodone and buprenorphine, and 1 postmortem study on the effects of morphine and heroin on hypocretin-producing neuron counts.

In a questionnaire of 100 respondents, recent opioid use was reported in 16% of patients comprising of 20 opioids (codeine, n = 7; tramadol, n = 6; oxycodone, n = 6; fentanyl, n = 1). Among these patients, narcolepsy symptom changes were reported in 11 individuals (95% CI, 32%-76%]) with 9 considered positive (95% CI, 24%-68%), 1 mixed (95% CI, 0%-27%]) and 1 negative report (95% CI, 0%-27%). Positive effects were observed on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13), with effects most pronounced in patients who took oxycodone (4 of 6). Moderate positive effects were seen in patients who took codeine, with 4 of 7 individuals reporting a beneficial impact.

Senior author Rolf Fronczek, MD, PhD, neurologist at Leiden University Medical Centre, in Leiden, Netherlands, and colleagues wrote, “Within the interview, multiple people reported that it was easier for them to sleep through the night as they had fewer awakenings when taking the opioid. Fewer potential cataplexy triggers were also encountered by some respondents because of the indication for which they were taking the opioid. All respondents who had narcolepsy symptom severity changes reported that the effect waned within days when the opioid was discontinued.”¹

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Researchers systematically reviewed 31 literatures on opioid use and its self-reported effect on narcolepsy type 1 symptom severity. In addition to the literature review, the study also recruited 100 patients with narcolepsy type 1 from the Sleep-Wake Center SEIN between 2010 and 2021 who completed an online questionnaire on opioid use in the previous 3 years. Patients answered topics on the indication for opioid use and the possible effects on their narcolepsy symptom severity. Following the questionnaire, researchers conducted follow-up interviews for when opioid use was reported.

Among those who had an indication for opioid use (n = 16), respiratory complaints (n = 5), back pain/spinal hernia (n = 4), leg surgery (n = 3), shoulder pain (n = 2), tooth removal/pain (n = 2), lung cancer (n = 1), generalized muscle/joint pain (n = 1), disturbed nocturnal sleep ( n = 1), and recreational use (n = 1) served as the reasons for use. The duration of opioid use ranged from days to multiple months or years, with a median duration of use ranging from about 14 days and 1 day-multiple years.

“Future research should target a larger general population of people with narcolepsy type 1, and also use other inclusion sources such as patient organizations and self-help groups. The results of our small study indicate the need for a randomized controlled trial to confirm our results. Those treated outside tertiary clinics should also be included in this trial to better represent all people with narcolepsy type 1,” Fronczek and colleagues noted.1 “Our systematic literature review could also be subject to publication bias of positive results. Grey literature searches in multiple trial registries and Google Scholar yielded no results for trials on opioid use in narcolepsy making the presence of unpublished negative trials less probable.”

In November 2018, Fronczek sat with NeurologyLive at the 24th Congress of the European Sleep Research Society in Basel, Switzerland, to discuss the connection between narcolepsy and opiates. Fronczek and colleagues examined a number of hypocretin neurons in postmortem brains and found that some individuals presented with an unexpectedly large cell number increase. Looking back, researchers discovered that those patients were opiate addicts. Similar increases in hypocretin-producing cells were induced in a mouse model by administration of morphine.²

Researchers then examined cases of narcolepsy from the Dutch Brain Bank. Similar to previous findings, 1 patient whose hypocretin neurons were present while on opiates experienced an improvement in narcolepsy symptoms during that time period. There was about a 50% return of hypocretin neurons when compared with a typical narcoleptic brain where there were hardly any neurons left. These findings were considered relevant for not only opiate users, as an increased number of hypocretin-producing cells may play a role in maintaining opiate addiction, but also raised the question about a potential treatment option for narcolepsy.

REFERENCES
1. Gool JK, van Heese EM, Schinkelshoek MS, et al. The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study. Sleep Med. 2023;109:118-127. doi:10.1016/j.sleep.2023.06.008
2. Thannickal TC, John J, Shan L, et al. Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy. Sci Transl Med. 2018;10(447):eaao4953. doi:10.1126/scitranslmed.aao4953