Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population.
A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003–2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff.
A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (± 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1–250). None of the 105 patients was found to have evidence of stimulant misuse.
This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy.
Mantyh WG, Auger RR, Morgenthaler TI, Silber MH, Moore WR. Examining the frequency of stimulant misuse among patients with primary disorders of hypersomnolence: a retrospective cohort study. J Clin Sleep Med 2016;12(5):659–662.
Narcolepsy and idiopathic hypersomnia (hereafter referred to as primary disorders of hypersomnolence) are commonly treated by sleep specialists and encountered by other providers within the medical arena. Although pharmacotherapy with modafinil and the traditional stimulants (i.e., methylphenidate and amphetamine preparations) are considered the mainstays of treatment,1,2 physicians are often uncomfortable with their long-term prescription due to concerns regarding misuse.
This discomfort is not entirely unfounded. Methylphenidate and amphetamine-containing prescription products are regularly illicitly traded.3 The former (the predominantly prescribed drug within our patient population) is classified as a Drug Enforcement Agency (DEA) Schedule II medication and is associated with numerous nonmedical/recreational uses, including intravenous injection, inhalation, and intranasal “snorting.”4–7 The effects of recreational methylphenidate have been described as similar to cocaine, and neuroimaging along with neuropharmacological comparisons between the two drugs show striking similarity in their activation of the dopamine pathways thought to contribute to addiction.8–11
Patients with attention deficit hyperactivity disorder (ADHD), who are prescribed similar stimulant medications, are routinely requested to sell, trade, or offer their medications for nonmedical use.7,12–15 This market for prescription stimulants has reached levels where up to 35% of a surveyed college population was found to use these substances for nonmedical purposes.7,15 These same patients may also misuse their medications.12,15,16 In one study, up to 8% of college students with ADHD reported intranasal use of their prescribed stimulant medication over the past 6 months, and 31% reported taking larger or more frequent doses than prescribed.7
Current Knowledge/Study Rationale: Although pharmacotherapy with modafinil and the traditional stimulants is considered the mainstay of treatment for narcolepsy and idiopathic hypersomnia, physicians are often uncomfortable with their long-term prescription because of concerns regarding misuse.
Study Impact: The goal of this study was to assess the frequency of stimulant misuse within this patient population. As there was no evidence of such, providers should not withhold pharmacotherapy because of a fear of patient medication misuse.
Unlike the above data, there is a paucity of information regarding the risk of stimulant misuse among patients with primary disorders of hypersomnolence. One previous study, performed at our center, examined various psychophysiological consequences of high-dose stimulant medications, but did not focus specifically on stimulant misuse.17 The present study aims to investigate the frequency of prescription stimulant misuse in a more direct manner, and during an historical time period with important distinguishing characteristics. The public health related dynamics of stimulant prescription and use have been affected by the following variables: (1) the demographic patterns of abuse of stimulant medications in the U.S. has changed, notably among students who hope to increase cognitive performance16,18; (2) new prescription drug monitoring systems have been put in place with the more widespread use of electronic medical records; and (3) new drugs have reached the market, namely modafinil, a novel Schedule IV stimulant medication whose mechanism of action is still relatively unknown. These circumstances have created a unique opportunity to analyze stimulant misuse among those with primary disorders of hypersomnolence.
We used the Mayo Narcolepsy Research Center database to identify all patients treated at the Mayo Center for Sleep Medicine between January 1, 2003, and December 31, 2008. Patient data were included if subjects met the following inclusion criteria: (1) ≥ 18 years of age; (2) records contained appropriate authorization for research review; (3) International Classification of Sleep Disorders (ICSD), Second Edition19 (the ICSD edition current at the time of study)-adherent diagnoses of narcolepsy with or without cataplexy or idiopathic hypersomnia with or without long sleep time as confirmed by board-certified sleep specialists; (4) documentation of ≥ 1 follow-up visit subsequent to diagnosis, and containment of the entirety of the treatment course within the Mayo electronic medical record; and (5) stimulant prescribed subsequent to initial visit, with subsequent refills obtained solely though the Mayo Clinic Center for Sleep Medicine.
Patient charts were excluded from the current study if they met the following criteria: (1) receipt of non-stimulant drugs within DEA schedule categories I-IV, with the exception of sodium oxybate (to limit confounding); (2) ICSD disorder of hypersomnolence other than what is described above (i.e., recurrent hypersomnia, behaviorally induced insufficient sleep syndrome, hypersomnia due to medical condition, hypersomnia due to drug or substance, and nonorganic and organic hypersomnias not otherwise specified); (3) during diagnostic polysomnography, an apnea hypopnea index (AHI) ≥ 5, a respiratory effort-related arousal index ≥ 10, or a periodic limb movement index (PLMI) ≥ 15; and (4) seen by providers outside of the Mayo Clinic Healthcare System, which we ascertained via any mention of such in the patient charts. AHI and PLMI thresholds were observed to maintain subject homogeneity, consistent with ICSD-2 diagnostic criteria for the conditions of interest.
In our practice, registered nurses tightly monitor ongoing prescriptions for stimulants. Measures include assessments of date of last visit, documentation of an established plan for follow-up, and assurance that patients' requests are reflective of the documented treatment plan. The dates of monthly requests and shipping information are tracked. Patients must designate a pharmacy and prescriptions are mailed directly. If medication requests are made “early,” confirmation as to reason for this request is obtained. If patients report medications as stolen, a copy of the police report of the theft must be presented prior to provision of a new prescription. All incidents related to prescription renewal are documented in the medical record. If a patient is suspected of medication misuse, the state registry of controlled prescriptions is reviewed and/or the pharmacist is contacted.
For present study purposes, medication misuse was defined as documentation of requesting refills in advance of the anticipated date (without verified mitigating circumstances) and/ or documentation of taking more than the prescribed amount of medication at any time during the treatment course. Note that although misuse and abuse are overlapping terms, we use the former term in the current study, as the latter connotes a formal diagnosis with associated diagnostic criteria. Similarly, denotation of psychiatric conditions was based upon review of a master list of diagnoses for each patient (i.e., not necessarily based upon formal diagnostic criteria), in addition to a thorough review of the chart for diagnoses inadvertently omitted from the master list. The Mayo Foundation Institutional Review Board approved this research.
Demographic and Treatment Data
One-hundred five patients (45 male) were identified who met the above inclusion and exclusion criteria. The mean age at multiple sleep latency test was 42 ± 16 (standard deviaton [SD]) years. Twelve (11%) patients had a past history of substance misuse (one with past history of stimulant misuse), and 57 (54%) carried psychiatric diagnoses (88% of whom endorsed depression; Table 1).
Twenty-six patients (25%) carried a diagnosis of idiopathic hypersomnia without long sleep, 25 (24%) carried a diagnosis of narcolepsy without cataplexy, and 54 (51%) carried a diagnosis of narcolepsy with cataplexy.19 The mean duration of patient follow-up was 46 months, with a median time of 26 months (range: 1–250 months). Thirty-seven (35%) patients were prescribed modafinil, 58 (55%) patients were prescribed methylphenidate, and 10 (10%) patients were prescribed an amphetamine derivative (dextroamphetamine, methamphetamine, or mixed salts) at the time of the study. Twenty-one (20%) of the above patients were prescribed more than one medication during the course of treatment. Ten (10%) were prescribed dosages above the American Academy of Sleep Medicine (AASM) maximum dosage guidelines20 for only one of their medications, and 6 (6%) of the above patients exceeded dosage guidelines for 2 medications (Table 2). Our data show that 0 of the 105 patients were found to have evidence of stimulant misuse.
Patient pharmacotherapy characteristics (n = 105).
Patient pharmacotherapy characteristics (n = 105).
To our knowledge, this is the first study to examine the frequency of stimulant misuse among patients suffering from primary disorders of hypersomnolence. Over the course of a mean follow-up time of 46 months (median 26 months), no patient exhibited misuse of his or her stimulant medications. Perhaps this is a surprising result, considering that 55% of our patients were prescribed methylphenidate, and an additional 10% were prescribed other amphetamine derivatives, both drugs with high potential for addiction. As discussed above, there is a high frequency of stimulant misuse in patients with ADHD and in the general population.5,8,12,16–18,21–24
There are several potential theories for the lack of evident misuse among the patient cohort studied. One obvious point is that our patients were older, with a mean age of 42 ± 16 (SD) years, whereas many of the reports of stimulant misuse arise from school and college-aged students. Patients with primary disorders of hypersomnolence typically present at a similarly young age,25 but diagnoses are often delayed, and our sleep center commonly sees patients seeking a second opinion (necessitating repeat testing). It should, however, be kept in mind that misuse of prescription stimulants exists among older populations as well, as determined by reports of theft and misuse of ADHD children's medications by parents.6,12 Another potential reason for our observed lack of stimulant misuse is that 35% of our study's patients were prescribed modafinil, a medication that has shown little abuse potential to date. While one study demonstrated similar elevations in brain dopamine with modafinil compared to methylphenidate,26 and another demonstrated reward and addiction behavior among modafinil-receiving mice,27 actual surveillance data and reports among illicit drug users show limited addictive potential.8,28,29 Finally, several studies have postulated that patients with narcolepsy with cataplexy (who comprised 51% of our study) may have reduced long-term potentiation of dopaminergic signaling in areas of the brain responsible for addiction, which may be a necessary part of this reward pathway.30–32 From this neuro-chemical perspective, these patients would tend to use stimulants for therapeutic rather than drug-seeking purposes. Future studies should investigate more thoroughly the reasons for differing stimulant and other substance misuse among varying diagnostic groups.
The limitations of the current study include its retrospective nature, which is susceptible to any omissions or inaccuracies of the medical chart. Another potential drawback relates to our means of detecting medication misuse. As we relied on chart evidence of early or multiple prescriptions for detection, it is possible that our study population abused medications without reverting to this behavior. Additionally, to our knowledge, all previous studies examining stimulant misuse have relied on querying the patient, i.e., during the course of structured face-to-face interviews, surveys, or phone questionnaires. We cannot exclude the possibility that patients were obtaining additional prescriptions from physicians outside of Mayo Clinic. Thus, our study design is novel and untested on a larger scale. Generalizability of our results represents a separate limitation. Many of the patients at Mayo Clinic are seeking second opinions after living with their disease for years, which is reflected in the age demographics at the time of narcolepsy or primary idiopathic hypersomnia diagnosis (mean age 42 years). Thus, we may be omitting a younger population more prone to stimulant misuse. As mentioned before, however, adults aged 26–49 years have also shown high levels of misuse.16,33 As a final major limitation, although 26 months was the median amount of time for patient follow-up data, our range was large at 1–250 months. Thus, some patients were observed during quite a small time window.
Although the current study may appear to indicate that it is safe to prescribe stimulant medication to patients with narcolepsy or idiopathic hypersomnia, there are several important points to keep in mind. First, providers should be aware of other potential complications of high dose stimulant medications, such as psychosis, tachyarrhythmias, anorexia, and weight loss, all of which have been demonstrated in patients with primary disorders of hypersomnolence prescribed methylphenidate and amphetamine derivatives.17 Second, although we did not detect stimulant misuse among the 11% of patients with substance misuse histories, previous studies have demonstrated a significantly increased risk of misuse among patients with such a history.12,13,34 On a similar note, although none of the 10 (10%) patients prescribed higher-than-recommended stimulant doses were found to misuse medication, a previous study done at our center (with a larger number of “high-dose” patients) affirmed such a risk.17 Taken together, these points suggest that providers should exercise caution when prescribing stimulants for patients with histories of substance misuse and/or among patients on high doses of stimulant medications. Nevertheless, our results suggest that the overall frequency of stimulant misuse is low among patients with primary disorders of hypersomnolence, at least within this particular clinical environment. A final point to make is that clinicians should not prescribe modafinil instead of amphetamines solely because of a “fear of abuse” of the latter agents, as two-thirds of the patients in our present study were prescribed amphetamine derivatives and showed no evidence of misuse.
This was not an industry supported study. This study was supported by funding from Small Grant Awards 2009, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN. Dr. Silber receives royalties from Oakstone Publishing and UpToDate. The other authors have indicated no financial conflicts of interest.
The authors thank Hailey M. Malay and Lori L. Solmonson for technical assistance.
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