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Respiration and Sleep Medicine

Knowledge Gaps in the Perioperative Management of Adults With Narcolepsy: A Call for Further Research

Hershner, Shelley MD*; Dauvilliers, Yves MD, PhD; Chung, Frances MBBS; Singh, Mandeep MD, MSc§,‖; Wong, Jean MD; Gali, Bhargavi MD; Kakkar, Rahul MD, FRCPC#,**; Mignot, Emmanuel MD, PhD††; Thorpy, Michael MB, ChB‡‡; Auckley, Dennis MD§§

Author Information
doi: 10.1213/ANE.0000000000004088
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Abstract

There is increasing recognition that sleep disorders, notably obstructive sleep apnea, can increase perioperative risk.1 Narcolepsy is a central hypersomnolence disorder characterized by excessive daytime sleepiness, along with hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and cataplexy.2 Recently, there is increasing evidence to suggest that patients with narcolepsy may have increased perioperative risk that may include worsening of baseline narcolepsy symptoms, cardiopulmonary events, drug–drug interactions, and medication withdrawal.3,4

Further compounding the potential of increased perioperative risk is that many anesthesiologists, surgeons, and training programs have limited experience with patients with narcolepsy and related symptoms and may lack familiarity with narcolepsy-related medications.5 These issues necessitate a better understanding of perioperative risk, practice patterns, and experience of perioperative health care providers to assist in the development of evidence-based guidelines for the perioperative management of patients with narcolepsy.

DEFINING NARCOLEPSY

The International Classification of Sleep Disorders requires ≥3 months of excessive daytime sleepiness despite adequate nighttime sleep for the diagnosis of narcolepsy.6 The diagnostic criteria include ≥3 months of an irrespirable need to sleep that is not explained by another cause such as insufficient sleep, obstructive sleep apnea, circadian rhythm sleep-wake disorder, or medication effect. The current criteria further differentiate between 2 narcolepsy subtypes, narcolepsy type 1 (associated with cataplexy or a proven hypocretin deficiency) and narcolepsy type 2 (without cataplexy and normal hypocretin level if measured).6 Cataplexy is a pathognomonic symptom of narcolepsy type 1, defined by a sudden loss of muscle tone, while conscious, and triggered by emotions. Other symptoms associated with narcolepsy, but not specific to the condition, include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and being overweight especially for narcolepsy type 1.2,6

The diagnosis of narcolepsy generally requires a polysomnogram followed by a daytime sleep study called the multiple sleep latency test. Narcolepsy type 1 is characterized by mean sleep latency of ≤8 minutes and ≥2 sleep-onset rapid eye movement periods (1 sleep-onset rapid eye movement period may be attributed to the preceding polysomnogram) on the multiple sleep latency test and polysomnogram, coupled with either cataplexy or hypocretin deficiency.6 Hypocretin, also called orexin, is a neuropeptide implicated in arousal systems.7 In narcolepsy type 2, the multiple sleep latency test findings are the same, although cataplexy is not present and hypocretin is normal or has not been evaluated. Although hypocretin levels in the cerebrospinal fluid may be used to make a definitive diagnosis of narcolepsy type 1 (low in narcolepsy type 1, and normal or not tested in narcolepsy type 2), this test is often reserved for research studies, and not routinely used in clinical practice. Patients with narcolepsy type 1 have a positive association with the human leukocyte antigen subtype DQB1*0602.8 It is noteworthy that 12%–40% of the adult American population may carry this antigen, and it is thus not a specific marker for narcolepsy.

Narcolepsy has been found to be associated with other comorbid conditions such as obstructive sleep apnea, rapid eye movement sleep behavior disorder, hypercholesterolemia, disease of the digestive system, heart diseases, upper respiratory tract disease, hypertension, depression, social anxiety disorder, and panic disorder.9–11

Treatment of narcolepsy is targeted at symptom management.12,13 Stimulant medications (eg, modafinil/armodafinil, methylphenidate and amphetamines) represent the primary symptomatic treatment for excessive daytime sleepiness in patients with narcolepsy. Sodium oxybate and pitolisant (only available in Europe in 2016) are effective for excessive daytime sleepiness and cataplexy, while antidepressants may be used for treatment for cataplexy as well.13,14

PERIOPERATIVE RISKS AND ADVERSE EVENTS

Patients with narcolepsy undergoing surgery may experience several types of perioperative adverse events that can be due to the disease itself, medication effects and interaction, and medication withdrawal. Adverse events may consist of worsening of narcolepsy symptoms, cardiopulmonary events, and perioperative complications. Worsening of narcolepsy symptoms may manifest by an exacerbation of excessive daytime sleepiness and increased episodes of sleep paralysis, hypnagogic and hypnopompic hallucinations, and cataplexy. Cardiopulmonary complications may consist of hemodynamic instability, cardiac arrhythmias, and respiratory depression. Perioperative complications may include changes in sensitivity to anesthetic agents, delayed emergence from anesthesia, as well as inadequately controlled pain and the possibility of intraoperative awareness.

CURRENT EVIDENCE OF INCREASED PERIOPERATIVE RISK

A recent systematic review of literature reported on 16 case reports and 3 case series, yielding a total of 49 cases of narcolepsy undergoing a variety of surgical procedures.4 Preoperative sleep study data and postoperative sleep medicine follow-up were not discussed in any of the reports. The most commonly reported complications were autonomic dysregulation (significant hypertension, hypotension, and bradycardia) and worsening of narcolepsy symptoms around the time of surgery. It was noted that narcolepsy symptoms worsened only in patients for whom narcolepsy-related medications were either discontinued preoperatively or doses reduced. Factors associated with favorable perioperative outcomes included monitoring the depth of anesthesia, ensuring complete recovery from anesthetics, and utilization of a multimodal analgesia regimen and regional anesthesia techniques aimed at minimizing the use of long-acting opioid medications.

A subsequent case–control study of 76 patients with narcolepsy found that patients with narcolepsy had similar intraoperative courses as the matched controls but a higher rate of emergency response team activations than control subjects.3 Emergency response team activation was for hemodynamic instability and 1 case due to respiratory depression. Of note, patients with narcolepsy had a higher prevalence of obstructive sleep apnea than controls. These results suggest that patients with narcolepsy may be at increased perioperative risk, although not all studies have shown similar findings.15,16

Obstetric patients with narcolepsy, especially those with cataplexy, may be at increased risk during pregnancy and delivery.17 Potential for exposure of the fetus to narcolepsy medications through uteroplacental circulation is a concern. Similarly, transmission via breast milk poses a risk to the newborn baby. In a multinational survey of sleep physicians, >60% physicians reported having either stopped or reduced the narcolepsy medications at conception or during pregnancy.17 Two large-scale retrospective cohort studies reported worsening of narcolepsy symptoms such as cataplexy and status cataplecticus during pregnancy, labor, and postpartum periods.18,19 While incidence of cesarean delivery and narcolepsy-related complications was higher in patients with narcolepsy, incidence of obstetric complications was similar to patients without narcolepsy.18,20 Another more recent retrospective cohort study found more single pregnancies, gestational diabetes, and induced deliveries in patients with narcolepsy, but no other increased complications pre- or postdelivery.19 Worsening of narcolepsy-related symptoms may be secondary to the discontinuation of patients’ regular narcolepsy medications before or during pregnancy.

Patients with narcolepsy may have difficulty emerging from anesthesia. This was first recognized in a report of a patient with narcolepsy requiring up to 12 hours to emerge from general anesthesia on 3 different occasions.21 Delayed emergence from commonly used inhaled anesthetics was noted in the hypocretin/orexin/ataxin-3 narcoleptic mouse model and orexin-1 receptor antagonist–treated mice.22 The orexin/ataxin-3 mouse model acquires narcolepsy several weeks after birth when hypocretin neurons are lost, and is therefore a better model of human narcolepsy than hypocretin/orexin knockout mice. In this study, delayed emergence from sedation was not related to changes in anesthetic pharmacokinetics or induction.

In summary, after surgery, due to the disease itself, medication use or changes, patients with narcolepsy may have worsening of their baseline narcolepsy symptoms, delayed emergence from anesthesia, and hemodynamic and pulmonary instability.

POTENTIAL MECHANISMS

There are a number of potential mechanisms by which patients with narcolepsy could be at increased risk for perioperative complications. Physiologically, narcolepsy itself, due to the loss of the orexin neurons, could increase perioperative risk. Medications commonly used to treat narcolepsy may directly increase perioperative risk, or abrupt withdrawal of the same medications, may also be associated with adverse perioperative outcomes. Narcolepsy medications may be involved with drug–drug interactions in the perioperative setting and/or interact with anesthesia and pain medications. Finally, comorbid conditions, including associated sleep disorders (particularly obstructive sleep apnea) and obesity, could compound the perioperative risk.

Cardiovascular autonomic control may be impaired in patients with narcolepsy. While studies lack standardization and not all results have been replicated, there is some support for an imbalance on autonomic functions, especially with regard to the control of heart rate (HR) and body temperature.23 A significant reduction in the amplitude of periodic limb movement–related HR responses for both tachycardia and bradycardia has been noted in patients with narcolepsy type 1.24 This suggests that hypocretin/orexin modulates autonomic responses, with potential clinical significance, that is, increasing cardiovascular risk.24 Loss of nocturnal blood pressure dipping, one of the most sensitive predictors of cardiovascular disease, has been consistently reported in untreated patients with narcolepsy type 1 and in animal models of narcolepsy.25 Blunted nonrapid eye movement and rapid eye movement sleep–related decreases in blood pressure have also been shown in hypocretin-deficient mice.26 Conversely, during wakefulness, animal models of narcolepsy type 1 have shown lower arterial blood pressure compared to wild-type animals. Data in humans with narcolepsy type 1 have also revealed a decrease in muscle sympathetic nerve activity, HR, and blood pressure during wakefulness in narcolepsy type 1, suggesting an intrinsic imbalance between the sympathetic and parasympathetic systems in the disease.27 The administration of hypocretin stimulates arousal and elevates arterial blood pressure, HR, oxygen consumption, body temperature, and plasma catecholamine levels in animal studies. The increased blood pressure and HR effects have been shown to be mediated mainly by sympathetic activation.24,28,29 As such, narcolepsy itself may predispose patients to cardiovascular instability when placed in a perioperative environment.

The impact of pain control may also be an issue for patients with narcolepsy subjected to surgery. Chronic pain is significantly more common and disabling in narcolepsy type 1 compared to the general population, although this has not been found in all studies.30 Preclinical studies have highlighted a role for hypocretin in the modulation of nociceptive transmission.31,32

The hypocretin/orexin system may also impact anesthesia.22 Orexin A (hypocretin) given via intracerebroventricular injections to rats decreased time to emergence from propofol anesthesia without changing anesthetic induction.33 Intraventricular orexin A reduces ketamine anesthesia time.34

NARCOLEPSY-RELATED MEDICATIONS

Narcolepsy-related medications may cause or contribute to perioperative complications. Stimulant medications may increase cardiovascular adverse events in adults irrespective of the perioperative period and a narcolepsy diagnosis.35 This has been discussed in a recent review, as well demonstrated in retrospective cohort studies.4,36–39 In a study examining specifically patients with narcolepsy type 1 treated with stimulant medications, higher 24-hour, daytime and nighttime diastolic blood pressure and HR values were found compared with untreated patients with narcolepsy type 1.11 The prevalence of tachyarrhythmias, psychosis, polysubstance use, weight loss, and anorexia was higher among patients with narcolepsy treated with high-dose stimulant dosages, defined as a dose ≥120% of the maximum dose recommended by the American Academy of Sleep Medicine Standards of Practice Committee.40

Regarding the perioperative period, case reports suggest that amphetamine use may be associated with adverse events.41–44 Stimulant medications may affect a patient’s cardiovascular stability during anesthesia and surgery.45 A potential mechanism is stimulation of the adrenergic and peripheral nerve terminals causing a depletion of catecholamine receptor storage leading to a blunted physiologic and sympathetic response to hypotension during anesthesia.46 However, a small case series of 8 patients on chronic amphetamines did not report cardiovascular instability.47 Studies have found an increased risk of cardiovascular events among adults treated with stimulant medications, although other studies have not found the same results.35–38,47 It is, however, important to note that the above-mentioned perioperative case reports and studies were not specific of patients with narcolepsy.

Sodium oxybate, also called γ-hydroxybutyric acid, was initially developed as an anesthetic agent.13 It is a strong central nervous system depressant and has the potential of being a respiratory depressant.48 It likely works through gamma-aminobutyric acid B receptors, although other mechanisms have been suggested. It has a modulating effect on γ-aminobutyric acid–mediated dopaminergic, serotonergic, and noradrenergic neurons.13,49 The initial dose is 4.5 g divided into 1 dose at sleep onset with the second dose given 2.5–4 hours later. The maximum dose is 9 g divided into 2 doses. Higher doses >9 g may induce significant CNS depression, bradycardia, hypotension, and severe respiratory depression.50,51 Sodium oxybate can precipitate the development or increase the severity of central and obstructive sleep apnea.52 Perioperative risk is increased in patients with obstructive sleep apnea and untreated obstructive sleep apnea increases the risk of cardiac and respiratory complications.53,54

MEDICATION WITHDRAWAL

The withdrawal of narcolepsy medications during the perioperative period or a delay in restarting medications during the postoperative period may increase the risk for adverse events.4,17 The slow withdrawal of drugs (stimulants and anticataplectic medications) may result in the return of more severe baseline narcolepsy symptoms such as excessive daytime sleepiness and cataplexy symptoms compared to a previously stable period of regular drug intake controlling symptoms.

The abrupt withdrawal of antidepressants, but not sodium oxybate, can result in an increase in cataplexy-related symptoms including status cataplecticus.55 It should be noted that the sudden cessation of sodium oxybate has been associated with various withdrawal syndromes that may include disturbed nighttime sleep, increased pain, cardiovascular instability, hallucinations and psychosis, and agitation with aggressive behavior, but this occurs typically with misuse, and not among patients with narcolepsy who are properly treated with dosing that is exclusively during the nighttime.56

The abrupt withdrawal of stimulants generally leads to increased sleepiness, but may also delay emergence from anesthesia. In a study utilizing adult rats, administration of IV methylphenidate shortened emergence from isoflurane from 280 to 91 seconds.57 Dextroamphetamine had similar results.58 Blood gas experiments have shown that methylphenidate increases minute ventilation, thereby increasing the rate of anesthetic elimination from the brain. Modafinil taken postoperatively among patients without narcolepsy was found to reduce postanesthesia symptoms of fatigue and exhaustion compared to placebo.59 Taken together, these results suggest that the practice of stopping narcolepsy-related medications before surgery could theoretically further delay emergence from anesthesia in patients with narcolepsy and worsen baseline narcolepsy symptoms; however, more data are needed to confirm the generalizability of this finding.

MEDICATION AND ANESTHESIA

Narcolepsy-related medications have the potential for interacting pharmacologically with anesthesia and opioid medications. Chronic use of amphetamines has been thought to interact with medications utilized perioperatively.42,43 These may increase the analgesic effects of opioids, decrease the sedative effects of some medications, and cause catecholamine depletion, leading to increased hemodynamic instability during the perioperative period.60 A case–control study found increased need for postoperative emergency response activation in patients with narcolepsy, primarily due to issues related to autonomic instability.3 Because of these interactions, it is suggested that chronic amphetamine use may affect the intraoperative requirements for volatile anesthetics and other agents such as propofol. Similarly, ketamine should be used with caution in patients on chronic amphetamines because these agents may interact, leading to impaired cognitive recovery after anesthesia, and transient increases in blood pressure and HR. It is likely that similar effects also occur with other stimulants such as methylphenidate and modafinil. As described previously, stimulant medications may shorten time for emergence from anesthesia. It is unclear what effect these may have on the intraoperative and immediate postoperative course and time to recovery from anesthesia.

Amphetamines, other stimulants, and opioids may also affect analgesic requirements during the postoperative period, but further mechanistic and clinical research is needed.61,62 The impact of increased utilization of multimodal analgesic regimens on pain control and postoperative complications in patients with narcolepsy is also unclear.63

Finally, sodium oxybate itself is an anesthetic agent. As mentioned above, it is also a respiratory depressant and thus cannot be coadministered with other anesthetic agents.48 Considering its short half-life of only 30 minutes, drug–drug interactions are rarely a problem at the practical level.

COMORBID CONDITIONS

Patients with narcolepsy can have comorbid conditions that may affect risk of adverse events during the perioperative time period. Hypocretin/orexin signaling is involved in the control of upper airway patency and decreased activity of orexinergic neurons may contribute to upper airway collapse during sleep favoring obstructive sleep apnea.64 Approximately 35% of patients with narcolepsy are obese, and 25%–40% will have obstructive sleep apnea, an independent predictor of postoperative complications, increased susceptibility to opioid/sedative medications, and increased resource utilization.1,65–67 It is therefore important to ensure that narcolepsy patients with comorbid obstructive sleep apnea are appropriately treated for obstructive sleep apnea, especially in the perioperative setting. The diagnosis of obstructive sleep apnea in this patient population may be overlooked because the symptoms of obstructive sleep apnea may overlap with some narcolepsy symptoms, and thus, unrecognized obstructive sleep apnea could place these patients at higher risk for adverse events after general anesthesia and opioid therapy.

Narcolepsy has also been associated with hypertension and diabetes, particularly gestational diabetes.19,20,68,69 Hypertension and diabetes are factors commonly considered in evaluating perioperative risk (ie, National Surgical Quality Improvement Program surgical risk calculator, https://riskcalculator.facs.org/RiskCalculator/PatientInfo.jsp). Recently, there has been increasing attention drawn to the association between narcolepsy and obesity which is hypothesized to be related to a reduced basal metabolic rate in patients with narcolepsy.66,70 While it is controversial whether or not obesity itself is an independent risk factor for postoperative complications, it could serve as an intermediary between narcolepsy and the conditions mentioned above (obstructive sleep apnea, hypertension, diabetes).

Because cataplexy is triggered by emotion, the stressful and emotional aspect of surgery itself could exacerbate cataplexy. Patients with narcolepsy and cataplexy suffer from psychological and emotional stress.71,72 Fears of delayed emergence from anesthesia, sleep paralysis during emergence from anesthesia, and exacerbation of cataplexy in the postoperative period could provoke anxiety and stress in patients and exacerbate both frequency and intensity of cataplexy.

LACK OF AVAILABLE GUIDELINES

At present, there are no established guidelines or standards of care regarding the perioperative management of patients with narcolepsy. In large part, these are due to limited data detailing the increased risk for perioperative complications associated with narcolepsy and essentially no quality data regarding management strategies for these patients. The remainder of this article will address areas in need of research with hopes that this highlights the vital need for additional research in the perioperative management of patients with narcolepsy.

RESEARCH PRIORITIES

Narcolepsy has a prevalence of roughly 56 cases per 100,000 individuals.73 Due to its relative rarity, few clinicians are experienced with the disorder outside of Sleep Medicine, Neurology, and Pulmonary Medicine, and thus, perioperative providers should be made aware of the considerations of perioperative management of these patients. The perioperative management of medications prescribed for narcolepsy, particularly in the context of anesthesia, surgery, or delivery, has not been well studied in the literature thus far. As noted above, the perioperative management of patients with narcolepsy requires further investigation to ensure that patients are safely and well cared for during the perioperative period. The outline below details what we believe are the major questions and areas where research in this field should be focused.

Relevant Research Questions

  • 1. Outcomes:
    • a. What is the current state of understanding of perioperative providers regarding narcolepsy, its management, and the potential for adverse outcomes?
    • b. What are the potential interactions of the clinical features of narcolepsy with anesthesia and the operative procedure, with an emphasis on the differences between the phenotype of narcolepsy type 1 and narcolepsy type 2?
    • c. Can the clinical impact of the potential medication interaction of narcolepsy-related medications with anesthetic agents be better defined?
  • 2. Adverse events:
    • a. What are the medical risks, cardiovascular or otherwise, to patients with narcolepsy who might be associated with anesthesia and surgery?
    • b. Do specific narcolepsy-related medications have a greater association with adverse events?
  • 3. Perioperative management
    • a. What is the appropriate management of narcolepsy-related medications during the preoperative, intraoperative period, immediate and delayed postoperative period?
    • b. Does the type of anesthetic technique (regional versus general) impact the progression or severity of perioperative symptoms of patients with narcolepsy?
    • c. Are there better techniques available to enhance monitoring of patients with narcolepsy in the perioperative period?
    • d. Does immediate postoperative management of the patients with narcolepsy require tailoring, particularly with regard to the possibility of prolonged emergence?
    • e. Is pain management adequate during the preoperative, intraoperative, and postoperative periods in patients with narcolepsy?
    • f. Is there sufficient perioperative counseling regarding resumption of medications and driving?

Methodologies

Further research is needed to establish the perioperative risk of patients with narcolepsy, because currently available literature is limited. This could best be accomplished through the following.

Assessment of Perioperative Outcomes via Existing Databases.

Although isolated retrospective case series of patients with narcolepsy undergoing surgery have been published, no prospective studies are available. Most of the available information comes from single-center medical record review or is based on patients’ subjective recall of prior operative procedures. Existing databases have the potential of containing better quality data. However, these databases may be limited in terms of sleep study diagnosis and multiple sleep latency test/hypocretin measurements, and an assessment bias may exist. Moreover, patients with severe disease are more likely to report symptoms, introducing the potential for selection bias.

Assessment of Perioperative Outcomes via Larger Multicenter Retrospective Case–Control Studies.

The majority of available evidence is based on retrospective reviews of individual cases and case series. The recent systemic review highlights the paucity of quality literature.4 Since the systematic review was completed, additional single-center retrospective data have emerged, although these studies remain relatively small.3 Larger multicenter studies are needed to increase the power of detecting significant postoperative outcomes.

Assessment of Perioperative Outcomes via Prospective Studies.

These studies would provide the best evidence for adverse perioperative events in patients with narcolepsy; however, due to the low prevalence of narcolepsy, this would require large, expensive, and logistically challenging multicenter trials

Assessment of Medication Effects, Drug–Drug Interactions, Withdrawal of Medications, and Resumption of Medications via Prospective Controlled Trials.

While animal models and laboratory-based research studies are providing important information to help design clinical research, well-designed prospective controlled trials of different medication regimens, that is, withholding, reducing, or continuing medications, will be needed to determine how to best manage patients clinically.

Survey Studies to Assess Perioperative Providers’ Clinic Experience With Patients With Narcolepsy and Understanding of the Disease, Its Treatment, and the Potential for Adverse Outcomes.

Little is known about the knowledge of perioperative providers regarding narcolepsy or its therapies. Unlike obstructive sleep apnea, for which a growing body of literature detailing the perioperative risk associated with obstructive sleep apnea is available, narcolepsy is a relatively uncommon condition, and data on its impact on the perioperative course are sparse.1,74 As such, perioperative considerations for patients with narcolepsy may not be well-addressed during the training of perioperative providers.5 Likewise, considering the limited body of literature and the lack of any published guidelines, practice patterns regarding perioperative management of narcolepsy are expected to be highly variable. In support of this, a survey study of sleep physicians who managed patients with narcolepsy during pregnancy found a diverse approach to the care of these patients.17 This highlights the need to better understand the knowledge base of perioperative care providers about narcolepsy and the narcolepsy-related medications. Research into current practice habits will help to standardize the care of patients with narcolepsy undergoing general anesthesia and sedation.

GUIDELINE DEVELOPMENT

At this time, the available literature is neither adequate nor robust enough to support any specific evidence-based guidelines. Even expert consensus may be a challenge based on the small amount available literature and the limited clinical experience of most perioperative providers, including sleep physicians experience regarding the perioperative management of narcolepsy. That said, future research should target the knowledge required to develop evidence-based practice guidelines.

Recommendations

Patients with narcolepsy may be at an increased risk of perioperative complications and worsening of narcolepsy symptoms due to the disease itself, related dysautonomia, medication interaction, and withdrawal. Future research should prioritize collaborative research to examine the perioperative risks of patients with narcolepsy undergoing anesthesia and surgery. A better understanding of perioperative providers’ experience and exposure to narcolepsy and narcolepsy-related medications is needed. Determination of relevant patient-centered outcomes is necessary. Only through this research can guidelines and best practices for perioperative management of patients with narcolepsy be developed.

ACKNOWLEDGMENTS

We would like to thank The Society of Anesthesia and Sleep Medicine Narcolepsy Perioperative Task Force for supporting this project.

DISCLOSURES

Name: Shelley Hershner, MD.

Contribution: This author helped develop the overall position paper, research the questions, attend the developmental meetings, and write and review the manuscript.

Conflicts of Interest: None.

Name: Yves Dauvilliers, MD, PhD.

Contribution: This author helped develop the overall position paper, research the questions, and write and review the manuscript.

Conflicts of Interest: Y. Dauvilliers consulted for UCB Pharma, Jazz Pharmaceuticals, Theranexus, Flamel, Idorsia, Takeda, Harmony Biosciences, and Bioprojet. This is not related to our position paper.

Name: Frances Chung, MBBS.

Contribution: This author helped develop the position paper, research the questions, attend and develop the meetings, and write the manuscript.

Conflicts of Interest: None.

Name: Mandeep Singh, MD, MSc.

Contribution: This author helped develop the overall position paper, research the questions, attend the developmental meetings, and write and reviewed the manuscript.

Conflicts of Interest: None.

Name: Jean Wong, MD.

Contribution: This author helped develop the overall position paper, research the questions, attend the developmental meetings, and write and review the manuscript.

Conflicts of Interest: None.

Name: Bhargavi Gali, MD.

Contribution: This author helped write and review the manuscript.

Conflicts of Interest: None.

Name: Rahul Kakkar, MD, FRCPC.

Contribution: This author helped write and review the manuscript.

Conflicts of Interest: None.

Name: Emmanuel Mignot, MD, PhD.

Contribution: This author helped write and review the manuscript.

Conflicts of Interest: E. Mignot occasionally consults and has received contracts from Merck and Jazz Pharmaceuticals, and he has been a Principal Investigator on clinical trials using sodium oxybate and Solriamfetol, Jazz Pharmaceutical products, for the treatment of narcolepsy type 1; none of these have any scientific relationships to the study.

Name: Michael Thorpy, MB, ChB.

Contribution: This author helped develop the overall position paper, research the questions, attend the developmental meetings, and write and reviewed the manuscript.

Conflicts of Interest: None.

Name: Dennis Auckley, MD.

Contribution: This author helped develop the questionnaire and review and write the manuscript.

Conflicts of Interest: None.

This manuscript was handled by: David Hillman, MD.

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