Sleep Breath (2010) 14:77–79
`DOI 10.1007/s11325-009-0283-1
`
`ORIGINAL ARTICLE
`
`Clinical perspective: monitoring sodium oxybate-treated
`narcolepsy patients for the development
`of sleep-disordered breathing
`
`Neil T. Feldman
`
`Received: 28 April 2009 / Revised: 24 June 2009 / Accepted: 26 June 2009 / Published online: 23 July 2009
`# The Author(s) 2009. This article is published with open access at Springerlink.com
`
`Abstract
`Purpose While the symptoms of narcolepsy are often
`amenable to treatment with sodium oxybate (SXB), the
`respiratory effects of long-term SXB treatment have not
`been systematically studied. Recent reports have implicated
`SXB with several cases of worsening sleep-related breath-
`ing disturbances and accidental death. In addition, these
`patients are at risk for obesity, which may aggravate co-
`morbid obstructive sleep apnea.
`Methods Based on a review of the literature and the clinical
`experience of the author, recommendations for the use of
`SXB in patients with sleep-disordered breathing have been
`developed.
`Results Among narcolepsy patients with evidence of sleep
`disordered breathing during baseline polysomnography,
`SXB should be prescribed only to those patients who fully
`comply with nasal continuous positive airway pressure
`therapy. The respiratory status of other SXB-treated patients
`should be periodically evaluated with nocturnal oximetry.
`Conclusions Based on the currently available data, physi-
`cians prescribing SXB should remain vigilant for the
`possible development of sleep-disordered breathing during
`long-term treatment with SXB.
`
`Keywords Narcolepsy . Sodium oxybate . Sleep-disordered
`breathing . Obstructive sleep apnea
`
`N. T. Feldman (*)
`St. Petersburg Sleep Disorders Center,
`Palms of Pasadena Hospital,
`2525 Pasadena Avenue South, Suite S,
`St. Petersburg, FL 33707, USA
`e-mail: nfeld@msn.com
`
`Introduction
`
`Narcolepsy is a life-long neurological disorder character-
`ized by excessive daytime sleepiness, cataplexy, and other
`abnormal expressions of rapid eye movement sleep [1]. It is
`now believed that
`the pathophysiology of narcolepsy
`involves the absence of a fully functional hypocretin
`signaling system [1]. In addition to frequent awakenings
`and abnormal REM sleep, the nocturnal sleep of narcolepsy
`is often further disrupted by obstructive sleep apnea (OSA)
`which is more common in these patients [2–4]. Additional
`evidence suggests that the lack of hypocretin predisposes
`this population to obesity [5–7] which also occurs with
`significantly greater frequency among patients with narco-
`lepsy. These patients are at risk for further weight gain even
`after treatment is initiated [8], making OSA more likely to
`occur over time.
`The symptoms of cataplexy and excessive daytime
`sleepiness are often amenable to treatment with sodium
`oxybate (SXB) [9]. Based on the results of several level 1
`studies [10], SXB is recognized as an effective treatment of
`cataplexy, daytime sleepiness, and disrupted sleep due to
`narcolepsy [11]; however, SXB is a central nervous system
`and respiratory depressant, and these safety issues are
`described in the product labeling, which includes a black
`box warning [12].
`The use of other central nervous system (CNS) depres-
`sants, such as ethanol, has been associated with worsening
`sleep apnea symptoms [13, 14], and these concerns have
`recently been extended to include SXB. One recent report
`described the worsening of sleep-related breathing distur-
`bances during polysomnography in two SXB-treated
`narcolepsy patients with OSA. One was a 60-year-old
`woman [body mass index (BMI), 26] who demonstrated an
`apnea–hypopnea index (AHI) of 8/h and 10/h during two
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`78
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`Sleep Breath (2010) 14:77–79
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`consecutive nights while taking SXB. These decreased to
`3/h and 6/h when SXB was discontinued. The other patient
`was a 58-year-old man (BMI, 32) whose AHI increased
`from 5/h and 11/h on two consecutive nights to 24/h and
`45/h following the administration of SXB. Following the
`initiation of nasal continuous positive airway pressure
`(CPAP), the AHI improved to 1/h and 3/h. Although these
`authors suggest that the use of SXB therapy should be
`initiated in the sleep lab, this precautionary measure cannot
`predict which patients may develop sleep-disordered
`breathing with prolonged exposure [15].
`Other reports have implicated the use of SXB with fatal
`outcomes. One report described a 53-year-old woman with
`sleep apnea who was receiving treatment with nightly SXB
`for narcolepsy. Concomitant medications included trama-
`dol, gabapentin, cetirizine, modafinil, and carisoprodol. In
`this case,
`the combined use of SXB with other CNS
`depressants was felt to be a contributing factor in her death
`[16]. Another report also described three deaths associated
`with the use of SXB. One was clearly an intentional
`overdose; however, the other two were unexpected deaths
`than occurred during sleep. One patient was also taking
`zolpidem and the other was taking alprazolam and
`quetiapine and was not wearing his CPAP mask [17].
`Although the actual cause of death is not known with
`certainty in all of these cases [18],
`they raise safety
`concerns about SXB to a level
`that requires proactive
`monitoring of all patients on SXB for
`the possible
`development of respiratory depression. An extensive review
`of post-marketing adverse events associated with SXB
`including other fatalities is currently in press [19].
`To date, only one randomized, placebo-controlled trial
`has evaluated the use of SXB in patients with OSA. In that
`study, the use of SXB was associated with statistically but
`not clinically significant improvements in the AHI of some
`patients. Three patients experienced clinically significant
`decreases in arterial oxygen saturation to approximately
`55%. In two patients, this decrease was for a brief duration,
`and they continued SXB treatment without further incident
`while the third was withdrawn from the trial [20]. Thus,
`while the use of SXB may slightly improve the AHI in most
`patients, it appears there may be a subset of patients that are
`more susceptible to the respiratory depressant effects of
`SXB. It addition, patient exposure to SXB in this study was
`
`limited to 2 weeks. The respiratory effects of long-term SXB
`treatment have not been systematically studied.
`Based on the limited amount of available information, it
`is clear that a systematic study of the long-term exposure to
`SXB and patient
`risk of developing OSA should be
`undertaken. In the meantime, however, the clinician must
`take the initiative to carefully monitor these patients for the
`possible development of worsening sleep-disordered
`breathing. Obese patients are at significantly greater risk
`for OSA and need to be aggressively monitored. Each
`clinician should develop their own standard operating
`procedure for prescribing SXB to their patients. As a
`guideline, the author uses the following parameters when
`prescribing SXB to patients with narcolepsy.
`Baseline polysomnography is generally performed in
`most patients with narcolepsy. If sleep-disordered breathing
`is present, then SXB should only be prescribed for patients
`who are fully compliant with nasal CPAP therapy. Although
`not studied systematically, the author's experience suggests
`that SXB may improve CPAP compliance in patients with
`narcolepsy due to improved sleep maintenance. Therefore,
`the use of SXB should not necessarily be limited to the
`treatment of narcolepsy patients with only mild OSA;
`however, patients should be instructed not to take SXB if
`they do not wear their CPAP mask.
`If OSA is not present at baseline, then patients should be
`followed with nocturnal oximetry as follows:
`& Every 2 years for all SXB-treated patients
`& Annually for obese patients (BMI, >30)
`&
`Following a 15-lb (6.8 kg) gain in body weight
`&
`Following an increase in visual analog snoring severity
`scale score (see Fig. 1)
`& When starting a newly prescribed sedating medication
`which may worsen OSA.
`
`Although there are no available data on the effect of SXB
`on CPAP pressure requirements, patients on CPAP who are
`taking SXB should also have periodic oximetric testing. It
`is the author's opinion that worsening Epworth Sleepiness
`Scale scores alone should not be used as an indication of
`the development of OSA in patients taking SXB.
`If nocturnal oximetric monitoring on or off nasal CPAP
`reveals a saw-tooth pattern of oxygen desaturation, patients
`taking SXB should undergo further evaluation with
`
`Fig. 1 Snoring evaluation
`questionnaire
`
`Evaluation of snoring as reported by bed partner (circle a number):
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`0-3 Occasional soft snoring, not bothersome to bed partner
`4-6 Persistent snoring, bothersome to bed partner
`7-9 Persistent loud snoring, frequently annoying to bed partner
` 10 Heroic snoring, continuous loud snoring not tolerated by bed partner
`
`AMN1025
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`

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`Sleep Breath (2010) 14:77–79
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`79
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`nocturnal polysomnography. The author has observed the
`development of classic Cheyne–Stokes respiration or
`periodic breathing in patients taking SXB. If a sustained
`pattern of desaturation is documented, SXB should be
`discontinued. Pulmonary function tests should be per-
`formed, and a pulmonary consultation for these patients
`should be considered.
`The choice of therapeutic options for the treatment of
`narcolepsy is limited and leaves many of these patients with
`a poor quality of life [21]. SXB remains a valuable option
`for a significant number of patients with narcolepsy.
`Although the available data is limited, the author suggests
`that patient safety requires continuing attention to the
`possible development of sleep-disordered breathing during
`long-term treatment with SXB.
`
`Open Access This article is distributed under the terms of the
`Creative Commons Attribution Noncommercial License which per-
`mits any noncommercial use, distribution, and reproduction in any
`medium, provided the original author(s) and source are credited.
`
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