http://dx.doi.org/10.5665/sleep.5530 NEUROLOGICAL DISORDERS Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study Lucie Barateau1; Isabelle Jaussent, PhD2; Régis Lopez, MD1,2,3; Benjamin Boutrel, PhD4; Smaranda Leu-Semenescu, MD3,5; Isabelle Arnulf, MD, PhD3,5; Yves Dauvilliers, MD, PhD1,2,3 Sleep Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France; 2Inserm, U1061, Montpellier, France; Université Montpellier 1, Montpellier, France; 3National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome, Paris, France; 4Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Switzerland; 5Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, Brain Research Institute (CRICM-UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225), Sorbonne Universities, UPMC Univ Paris 06, Paris, France 1 Significance Experiments in animal models showed that disruption of hypocretin signaling reduced drug-seeking behaviors with a key impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Conversely, there is a lack of convincing human narcolepsy data on addiction. Our results emphasized the low frequency of addictive behaviors among patients with central hypersomnia, whether hypocretin-deficient or not, whether drug free or not, comparable to our control group and the general population. This observation was intriguing since psychostimulant drugs (methylphenidate, amphetamine, and modafinil to a lesser extent) are known to promote impulsivity, risk-taking behaviors and addiction. The absence of increased risk of addiction is reassuring for clinicians who manage patients with central hypersomnia, as they need to prescribe addictive drugs for years. Further research studies may focus on drug craving and relapse in these patients. INTRODUCTION Narcolepsy with cataplexy has been recently renamed narcolepsy type 1 (NT1) or hypocretin (Hcrt) deficiency syndrome in the new classification of sleep disorders.1 NT1 is frequently comorbid with obesity, reduction of quality of life, mood symptoms, cognitive alterations, abnormal reward processing, and risk-taking behavior.2–8 Hcrt-containing neurons arise in the lateral hypothalamus (LH) and project widely through the brain,9 with a dense innervation of anatomical sites involved in arousal regulation, motivation and stress conditions. Hcrts have been implicated in the modulation of noradrenergic,10,11 cholinergic,12 serotoninergic,13 and dopaminergic systems.14 Several preclinical studies demonstrated the key role of the Hcrt system in the regulation of food- and drug-seeking behaviors using either pharmacological studies or transgenic mice models.12–19 Indeed, Hcrt knockout (KO) mice showed reduced signs of withdrawal from morphine20 and nicotine.21 Hcrt receptor-1 KO mice selfadministered less cannabinoids22 and showed a blockade of SLEEP, Vol. 39, No. 3, 2016 reinstatement of cocaine seeking after abstinence.23 In addition, daily injections of Hcrt receptor-1 (Hcrtr-1) antagonist prevented cocaine-induced locomotor sensitization and Hcrt transmission played an important role in regulating alcohol, cannabis, nicotine, and opiate seeking behaviors.19–26 Reward processing for food and abused drugs are conveyed primarily by Hcrt receptor-1, whereas Hcrt receptor-2 with different brain distribution regulates arousal and response to stress that also maintain alertness in such conditions. The Hcrt system is also involved in the affective dysregulation observed in alcohol-dependent patients during alcohol withdrawal27 in abstinent smokers during nicotine withdrawal28 and in cannabis abusers.29 All these observations indicate a strong functional interaction between Hcrt and reward pathways, in both animals and human beings. Clinical experience suggests that NT1 patients treated with addictive amphetamine-like stimulants and/or sodium oxybate for years rarely develop substance abuse. Indeed, these observations together with recent studies suggested that hypersomniac 573 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 Study Objectives: Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. Methods: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric Interview. Results: An increased proportion of both tobacco and heavy tobacco smokers was found in NT1 compared to controls and other hypersomniacs, despite adjustments for potential confounders. We reported an increased regular and frequent alcohol drinking habit in NT1 versus controls but not compared to other hypersomniacs in adjusted models. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive drug use (codeine, cocaine, and cannabis), substance dependence, or abuse was low in all subgroups, without significant differences between either hypersomnia disorder categories or compared with controls. Conclusions: We first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drug-free or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. Although disruption of hypocretin signaling in rodents reduces drug-seeking behaviors, our results do not support that hypocretin deficiency constitutes a protective factor against the development of drug addiction in humans. Keywords: narcolepsy, hypersomnia, addiction, hypocretin/orexin, substance abuse Citation: Barateau L, Jaussent I, Lopez R, Boutrel B, Leu-Semenescu S, Arnulf I, Dauvilliers Y. Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: a case-control study. SLEEP 2016;39(3):573–580.
were determined in duplicate from CSF samples by direct I125 radioimmunoassay (Phoenix Pharmaceuticals, Belmont, CA). CSF Hcrt-1 levels ≤ 110 pg/mL were considered as low, intermediate between 110 and 200, and normal > 200 pg/ mL. All values were back-referenced to Stanford reference samples (HHMI Stanford University Center for Narcolepsy, Palo Alto CA). All participants gave their written informed consent for the study, which was approved by the local ethics committees (Comité de Protection des Personnes – Ile de France 06). Main Study Outcome: Addiction The face-to-face clinical interview for both patients (drugnaïve or not) and controls included questions on regular alcohol consumption (wine, beer, aperitif, or strong alcohol), and on smoking status by reported cigarette consumption at time of study. Substance (alcohol and illicit drug) use, abuse, and dependence diagnosis during the last 12 months were determined using the corresponding Mini International Neuropsychiatric Interview (MINI) sections.32 Only trained clinicians can use this questionnaire for a diagnosis of abuse or dependence. Excessive alcohol consumption was assessed with the following question: “In the past 12 months, have you had 3 or more alcoholic drinks within a 3-hour period on 3 or more occasions?” If yes, other questions on alcohol habituation and withdrawal symptoms were asked to assess dependence according to guidelines.32 If not, other questions were presented to assess alcohol abuse (i.e., dependence preempts abuse) (see supplemental material). Excessive drug use was assessed with the following question: “I am going to show you a list of street drugs or medicines: cannabinoids, cocaine, inhalants, tranquilizers, hallucinogens, narcotics, and miscellaneous. In the past 12 months, did you take any of these drugs more than once, to get high, feel better, or change your mood?”32 We excluded the use of psychostimulant (amphetamines and methylphenidate) category for this study as being potential treatment for central hypersomnia per se. Dependence and abuse were defined when the patient answered “yes” to further systematically asked questions (see supplemental material). METHODS Participants Four hundred fifty consecutive adult patients (median age: 35 years [range 17 to 84]; 41.3% men and 58.7% women) with a central disorder of hypersomnolence were recruited and classified based on their primary International Classification of Sleep Disorders diagnosis.1 Data were collected from a national research program for rare hypersomnia diseases (Narcobank study) carried out in reference centers between 2008 and 2011. Patients were diagnosed on the basis of the following criteria: (1) NT1 (i.e., history of clear-cut cataplexy and mean MSLT latency ≤ 8 min with ≥ 2 sleep onset REM periods (SOREMPs) or CSF Hcrt-1 deficiency, < 110 pg/mL); (2) NT2 (i.e., mean MSLT latency ≤ 8 min with ≥ 2 SOREMPs, no cataplexy, absence of CSF Hcrt-1 deficiency if performed); and (3) IH (i.e., normal polysomnography, mean MSLT latency < 8 min with < 2 SOREMPs, or total sleep time ≥ 11 h/24 h on longterm polysomnography, and normal CSF Hcrt-1 levels > 200 pg/mL, if performed). At time of study, patients were drugnaïve or treated with psychostimulants, and/or anticataplectic drugs for NT1 only. Seven hundred ten adult subjects (median age: 29 years [range 18 to 81]; 70% women) were recruited as controls from the general population. All controls were community-dwelling adults who were recruited during the same period by means of advertisements and from local association networks. The eligibility criteria for the group controls included being > 18 years old, French speaking, and without any significant sleep or neurological disorders. All participants agreed to take part in this research program, which included a systematic interview, a clinical examination, completion of questionnaires, and a biological collection. A lumbar puncture was performed in 54 patients prior to the study to measure cerebrospinal fluid (CSF) Hcrt-1 levels. CSF samples were collected and aliquots were frozen SLEEP, Vol. 39, No. 3, 2016 Demographic and Clinical Variables For all patients and controls the standardized interview also included questions on (1) gender; (2) age at inclusion; (3) educational level (dichotomized as high [ ≥ 12 years of studies] and low [ < 12 years]); (4) body mass index (BMI) category (< 25, 25–29, ≥ 30 kg/m2); (5) presence and severity of depressive symptoms assessed by the Beck Depression Inventory (BDI) (dichotomized as “none/mild symptoms” [ ≤ 19] and “moderate/severe symptoms” [ > 19]); (6) delay at the diagnosis (i.e., delay between the onset of narcolepsy symptoms and diagnosis of narcolepsy); and (7) Epworth Sleepiness Scale (ESS) score at time of evaluation. For sub-analyses, the following additional disease-related features were considered for patients only: (1) drug to treat excessive daytime sleepiness (modafinil, methylphenidate, amphetamine, pitolisant, mazindol, and sodium oxybate) and cataplexy (antidepressants 574 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 patients, especially those Hcrt deficient, could be less vulnerable to drug abuse and addiction compared to the general population.4,8,30,31 A small clinically based well-characterized population sample revealed similar substance/alcohol abuse between patients with NT1, NT2, and healthy controls; however, patients with a past history of addiction were excluded.8 Recently, a phone interview (Sleep-EVAL) study addressing the frequencies of comorbid psychiatric disorders in patients with narcolepsy showed similar alcohol abuse and dependence compared to the general population.4 Although human narcolepsy could provide a fascinating insight into the role of the Hcrt system in addiction development, treatment and prevention, there is a lack of convincing human narcolepsy data on this topic. The aim of this study was to evaluate by face-to-face clinical interview the frequency of smoking, alcohol and drug use and addiction in NT1 patients (Hcrt-deficient) compared to patients affected by other central hypersomnias: narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), which are not associated with Hcrt-deficiency, and controls from the general population.
daily doses of drugs defined by methylphenidate > 100 mg, modafinil > 800 mg, sodium oxybate > 9 g, or mazindol > 6 mg were specifically reported; (3) the presence of hypnagogic hallucination, sleep paralysis, and the frequency of cataplectic attacks at time of study on a scale from 0 to 5 as defined earlier33 (for NT1 patients), and the mean sleep latency and the number of sleep onset REM periods on MSLT at diagnosis. Table 1—Demographic and clinical features of patients with NT1 compared with controls. Variable Gender Men Women Age, in years < 30 30–44 45–59 ≥ 60 Controls (n = 710) n % NT1 (n = 243) n % Global P 213 497 30.0 70.0 118 125 48.6 51.4 < 0.0001 377 149 107 77 53.1 21.0 15.0 10.9 90 68 33 52 37.0 28.0 13.6 21.4 < 0.0001 SLEEP, Vol. 39, No. 3, 2016 575 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 Statistical Analysis The sample is described using percentages for cateEducational level, in years gorical variables and median and range for quantita < 12 138 19.4 82 33.7 < 0.0001 tive variables; the latter are mostly skewed according ≥ 12 572 80.6 161 66.3 to the Shapiro-Wilk test. BMI, kg/m2 The first step was to compare tobacco, alcohol, < 25 533 75.4 104 43.3 < 0.0001 and drug use between 2 groups (Controls and NT1 25–30 130 18.4 89 37.1 patients). A comparison of demographic and clinical > 30 44 6.2 47 19.6 characteristics between NT1 patients and controls was BDI score done using χ2 test or Fisher exact test (for categorical ≤ 19 673 95.2 175 76.4 < 0.0001 variables) and Mann-Whitney test or Kruskal-Wallis > 19 34 4.8 54 23.6 test (for continuous variables) (Table 1). Univariate ESS at study inclusion 5 (0–19) 17 (1–24) < 0.0001 comparisons between NT1 patients and controls were ≤ 10 678 95.5 23 9.5 < 0.0001 made using logistic regression analysis and quanti > 10 32 4.5 220 90.5 fied using odds ratios (OR) and 95% confidence intervals (CI) for exposure variables (tobacco, alcohol, Continuous variables were expressed by median (minimum–maximum) value. and drug use). ORs were adjusted for variables assoBDI, Beck Depression Inventory; BMI, body mass index; ESS, Epworth Sleepiness Scale; NT1, narcolepsy type 1. ciated with NT1 (at P < 0.10) in Table 1 which could be potential confounders (Table 2). When appropriate (i.e., when for example, excessive alcohol consumpnormal levels). The presence of HLA DQB1*06:02 was found tion and weekly regular alcohol consumption were signifiin 88.2% of NT1, 32% of NT2, and 16.2% of IH. cantly associated with an outcome variable), the interaction Comparisons between patients with NT1 and controls reterms were tested using the Wald-χ2 test given by the logistic vealed significant differences for gender, age, educational level, regression model. BMI, BDI, and obviously ESS scores (P < 0.0001, for all the The second step was to compare tobacco, alcohol, and drug comparisons; Table 1). Subsequent analyses on the relationuse among the 3 groups of hypersomnia patients (IH, NT2, and ship between tobacco, alcohol, drug use, and NT1 were thus NT1). Chi-square tests were used to compare demographic and adjusted for these factors, except for ESS associated with NT1 clinical characteristics among the 3 groups (Table 3). When per se (Table 2). a significant relationship was found, two-by-two comparisons Between-group differences in central hypersomnias were were required to know whether groups within the study were found for gender, age, BMI, ESS, and use of stimulant at time significantly different. A correction for multiple comparisons of study (P < 0.05 for all the comparisons; Table 3). Subsequent with the Bonferroni method was used for the two-by-two comanalyses were thus adjusted for these factors plus educational parisons. Multinomial regression models were used to study level associated with P < 0.10 (Table 4). Two-by-two comparithe association between tobacco, alcohol, and drug use among sons revealed more women and lower BMI in patients with IH the 3 groups (Table 4). than NT1, and higher ESS in NT1 than NT2. Patients with NT1 Significance level was set at P < 0.05. Analyses were perwere older than IH and NT2. Individual post hoc comparisons formed using SAS statistical software (version 9.4; SAS Inc, revealed no significant differences between drug intake and Cary, North Carolina). disease categories. RESULTS Regular Tobacco and Alcohol Use The proportion of tobacco smokers was significantly higher Subject Characteristics in NT1 than controls (37.2% vs 21.7%) even after adjustments Among the 450 consecutive patients with a diagnosis of central (Table 2). Heavy tobacco smokers (> 10 cigarettes/day) were hypersomnia, 243 were affected with NT1, 116 with NT2, and more frequent in NT1 vs controls in both crude associations 91 with IH. CSF Hcrt-1 levels were determined in 54 patients: and adjusted models (Table 2, Model 2, P < 0.0001). The pro31 NT1 (all with low levels), 17 NT2 (one patient with interportion of tobacco smokers was also significantly higher in NT1 mediate level and 16 with normal levels), and 6 IH (all with
Variable Regular alcohol use No Yes, ≤ 4 drinks/week Yes, > 4 drinks/week Controls (n = 710) n % NT1 (n = 243) n % Model 0 OR (95% CI) Global P Model 1 OR (95% CI) Global P Model 2 OR (95% CI) Global P 48.3 44.5 7.2 87 100 46 37.4 42.9 19.7 1 < 0.0001 1.25 (0.90;1.73) 3.56 (2.24;5.67) 1 1.13 (0.80;1.58) 2.85 (1.70;4.75) 0.0002 1 < 0.0001 1.41 (0.97;2.06) 3.44 (1.96;6.04) Regular tobacco use No current smoker Yes ≤ 10 cigarettes/day Yes, > 10 cigarettes/day 556 124 30 78.3 17.5 4.2 147 34 53 62.8 14.5 22.7 1 < 0.0001 1.04 (0.68;1.58) 6.68 (4.12;10.8) 1 < 0.0001 1.07 (0.69;1.66) 6.37 (3.84;10.6) 1 < 0.0001 1.29 (0.80;2.07) 7.33 (4.24;12.7) Excessive alcohol use No Yes 602 108 84.8 15.2 221 18 92.5 7.5 1 0.45 (0.27;0.77) 0.003 1 0.42 (0.24;0.73) 0.002 1 0.50 (0.28;0.89) 0.02 Alcohol abuse or dependence No Yes 689 19 97.3 2.7 234 4 98.3 1.7 1 0.62 (0.21;1.84) 0.38 1 0.57 (0.18;1.75) 0.32 1 0.63 (0.20;1.98) 0.43 Excessive drug use No Yes 667 42 94.1 5.9 215 16 93.1 6.9 1 1.18 (0.65;2.14) 0.58 1 1.26 (0.67;2.37) 0.48 1 1.33 (0.67;2.64) 0.41 Drug abuse or dependence No Yes 699 10 98.6 1.4 226 4 98.3 1.7 1 1.24 (0.38;3.98) 0.76 1 0.96 (0.28;3.28) 0.95 1 0.77 (0.20;3.03) 0.71 Model 0 is crude association. Model 1 was adjusted for gender, age, and educational level. Model 2 was adjusted for Model 1 plus BMI and BDI score. BDI, Beck Depression Inventory; BMI, body mass index; CI, confidence interval; NT1, narcolepsy type 1; OR, odds ratio. Table 3—Demographic and clinical features of patients according to categories of central hypersomnias. Variable Gender Women Men IH (n = 91) n % NT2 (n = 116) n % NT1 (n = 243) n % Global P Post Hoc 66 25 72.5 27.5 73 43 62.9 37.1 125 118 51.4 48.6 0.001 IH < NT1* Age, in years < 30 30–44 45–59 ≥ 60 22 36 27 6 24.2 39.6 29.7 6.6 48 49 15 4 41.4 42.2 12.9 3.5 90 68 33 52 37.0 28.0 13.6 21.4 < 0.0001 NT2 < IH < NT1 Educational level, in years < 12 ≥ 12 25 66 27.5 72.5 26 90 22.4 77.6 82 161 33.7 66.3 0.08 BMI, kg/m2 < 25 25–30 > 30 54 20 17 59.3 22.0 18.7 66 31 18 57.4 27.0 15.6 104 89 47 43.3 37.1 19.6 0.02 BDI score ≤ 19 > 19 69 20 77.5 22.5 87 27 76.3 23.7 175 54 76.4 23.6 0.97 ESS at study inclusion < 16 ≥ 16 17 (6–24) 40 44.0 51 56.0 16 (4–24) 67 57.8 49 42.2 17 (1–24) 107 44.0 136 56.0 0.04 0.04 NT2 < NT1 NT2 < NT1 Drugs intake at inclusion No Yes 39 52 45 71 72 171 0.04 – 42.9 57.1 38.8 61.2 29.6 70.4 IH < NT1 Continuous variables were expressed by median (minimum–maximum) value. *A significant association was found between gender and the 3 groups (global P value < 0.05) and two-by-two comparisons indicate that only the percentage of men was greater in IH group than in NT1 group. BDI, Beck Depression Inventory; BMI, body mass index; ESS, Epworth Sleepiness Scale; IH, idiopathic hypersomnia; NT1, narcolepsy type 1; NT2, narcolepsy type 2. SLEEP, Vol. 39, No. 3, 2016 576 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 337 310 50
Variable Regular alcohol use No Yes, ≤ 4 drinks/week Yes, > 4 drinks/week IH (n = 91) n % NT2 (n = 116) n % NT1 (n = 243) n % Model 0 Global P Model Global P Model 2 Global P 48.3 42.5 9.2 51 55 7 45.1 48.7 6.2 87 100 46 37.4 42.9 19.7 0.009 0.33 0.26 Regular tobacco use No current smoker Yes ≤ 10 cigarettes per day Yes, > 10 cigarettes per day 73 8 9 81.1 8.9 10.0 86 19 10 74.8 16.5 8.7 147 34 53 62.8 14.5 22.7 0.002 0.0003 0.0004 Excessive alcohol use No Yes 89 2 97.8 2.2 109 5 95.6 4.4 221 18 92.5 7.5 0.16 0.26 0.33 Alcohol abuse or dependence No Yes 90 1 98.9 1.1 114 0 100.0 0.0 234 4 98.3 1.7 NA NA NA Excessive drug use No Yes 87 2 97.7 2.3 105 4 96.3 3.7 215 16 93.1 6.9 0.19 0.11 0.12 Drug dependence or abuse No Yes 88 0 100.0 0.0 108 1 99.1 0.9 226 4 98.3 1.7 NA NA NA Model 0 is crude association. Model 1 was adjusted for gender, age, educational level and BMI. Model 2 was adjusted for Model 1 plus ESS at the evaluation and drugs intake at the evaluation. BMI, body mass index; ESS, Epworth Sleepiness Scale; IH, idiopathic hypersomnia; NA, not applicable; NT1, narcolepsy type 1; NT2, narcolepsy type 2. addition, no significant differences were found between regular alcohol and tobacco consumption between either patients with IH vs controls, or NT2 vs controls. However excessive alcohol consumption was lower in patients with either IH or NT2 versus controls even after adjustment for potential confounders (OR = 0.19 95% CI = 0.04–0.80 P = 0.02, OR = 0.21 95% CI = 0.07–0.59, P = 0.003, respectively). The percentage of patients with alcohol dependence or abuse was low (from 0 to 1.7% across the different hypersomnia categories, and 2.7% in healthy controls; Tables 2 and 4). Only 3 patients with NT1 were diagnosed with alcohol dependence, 2 patients (one NT1 and one IH) with alcohol abuse, and 19 healthy controls with alcohol dependence (n = 6) or abuse (n = 13). No between-group (either NT1 versus controls or between-hypersomnia disorder categories) differences were found for alcohol abuse or dependence. Excessive drug use during the past year was rare (from 2.3% to 6.9% across the different hypersomnia categories, and 5.9% in controls) without any significant group differences between either NT1 versus controls, or between central hypersomnia categories (Tables 2 and 4). Only 3 illicit substances (codeine, cocaine, and cannabis) were used by 22 patients and 40 controls. Twenty patients smoked cannabis (15 NT1), 2 patients used cocaine (one NT1 and one NT2), and 2 patients took codeine—for non-medical use (one NT1 and one NT2). Overall, 40 controls smoked cannabis and 2 of them also used cocaine. Current illicit substance dependence or abuse was extremely low (from 0 to 1.74% across the different hypersomnia categories, and 1.4% in controls) that includes 4 NT1 (3 with patients compared to NT2 and IH patients (37.2%, 25.2%, and 18.9%, respectively) even after adjustments (Table 4). Similar results were also observed for heavy smokers in both crude associations and adjusted models (Table 4, Model 2, P = 0.0004) with post hoc analyses showing an increased smoking habit in NT1. Current regular alcohol consumption (> 1 drink/week) was significantly higher in NT1 compared to controls (62.7% vs 51.6%), even in adjusted models (Table 2). We also observed an increased proportion of frequent alcohol drinkers (> 4 drinks/ week) among NT1 patients, even after adjustment (Table 2, Model 2, P < 0.0001). A significant proportion of frequent alcohol users was reported in NT1 compared to either NT2 or IH patients (Table 4, Model 0, P = 0.009); however, this difference was nonsignificant after adjustment. Alcohol and Drug Addictive Behaviors In contrast to an increased proportion of regular but controlled alcohol consumption, we report a decreased proportion of heavy drinkers among NT1 patients compared to controls (7.5% vs 15.2%, respectively) even in adjusted models (Table 2, Model 2, OR = 0.50, 95% CI = 0.28–0.89). This result remained significant even after further adjustment for regular alcohol consumption (OR = 0.30, 95% CI = 0.16–0.58), without significant interaction between excessive alcohol consumption and weekly regular alcohol consumption in NT1 (P = 0.49). Excessive alcohol consumption was found in 7.5% of NT1, 4.4% of NT2, and 2.2% of IH patients, with no between-group differences in crude and adjusted associations (Table 4). In SLEEP, Vol. 39, No. 3, 2016 577 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 42 37 8
This large cross-sectional study explored the frequency of tobacco, alcohol and illicit drug use, abuse and dependence in a well-defined population of patients with NT1, NT2, and IH in comparison to controls, and took into account a large variety of potential confounders. We report here an increased proportion of alcohol and tobacco users among NT1 compared to controls, and an enhanced proportion of tobacco smokers in NT1 compared to other hypersomniacs, whereas alcohol drinking habit did not differ between-hypersomnia categories after adjustment for potential confounders. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive illicit drug use, substance dependence, or abuse was low in all hypersomniacs, and in controls as well. The prevalence of tobacco use was recently estimated between 20% and 30% in the French general population,34 and is consistent with our results, which show 21.7% of tobacco smokers in our control group. Smoking habits were higher in NT1 patients compared to controls and other hypersomnia categories. This observation was unexpected due to recent evidence supporting the reinforcing properties of the Hrct system in major drug abuse including nicotine.25–29,35,36 Since we adjusted our results for ESS, increased smoking behavior found in NT1 compared to NT2 and IH subjects did not support the idea that Hcrt deficiency may prevent tobacco addiction, or at least smoking habit. However, nicotine is considered as a cognitive enhancer, even a psychostimulant.36,37 Thus, tobacco smoking likely helps alleviate signs of sleepiness and should be considered as a self-treatment for the stimulant effect of nicotine. Interestingly, nicotine was shown to activate Hcrt neurons, suggesting a possible hypocretinergic contribution to its effects on arousal and cognition.38 One assumption which needs to be further examined is that the stimulant effect of tobacco smoking is reduced in NT1 patients, thus eliciting increased tobacco consumption in order to get the stimulant effects of cigarette smoking. We found here an increased proportion of regular and frequent alcohol drinking habit in NT1 versus controls, but not compared to other hypersomniacs in adjusted models. In contrast, heavy alcohol drinkers were significantly reduced in NT1, N2, or IH versus controls, without between-hypersomnia SLEEP, Vol. 39, No. 3, 2016 578 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 group differences. The reduced heavy alcohol drinking found in all three groups may relate to its sedative properties, patients with central hypersomnia being less likely to use sleep-inducing substances given their difficulty maintaining alertness. Another significant contribution of our study is the demonstration of a low frequency of illicit substance/alcohol abuse or dependence in hypersomniac patients, whether being Hcrt-deficient or not. For this assessment, we focused on the “alcohol and drug dependence/abuse” categories based on the validated MINI diagnostic interview developed for DSM IV-TR and ICD-10 psychiatric disorders.32 At the beginning of each section, screening questions on excessive substance use within the past year are presented followed by further questions to assess dependence and abuse. Current excessive alcohol or illicit substance (i.e., codeine, cocaine, and cannabis) use was found in 26 cases (11.2%), while dependence or abuse was found in only 8 NT1 patients (3.3%). Most importantly, we did not observe any significant differences among demographic, clinical, depressive symptoms, neurophysiological data, and drug status between addict and non-addict NT1 patients. Our current findings are consistent with our previous study, which showed the absence of association between phenotype characteristics and increased risk-taking behavior in NT1.6 Accordingly, abnormal activity in reward brain circuits with absence of modulation of ventral tegmentum area during high reward expectancy was found in a functional magnetic resonance imaging study in NT1.39 We found here no significant differences for illicit substance use, dependence or abuse between either NT1 patients versus controls or between- hypersomnia disorder categories. Narcolepsy was previously reported to be associated with comorbid psychiatric disorders, including major depression and social anxiety2,39; however, only one study assessed alcohol abuse or dependence in patients with narcolepsy compared to controls, without any significant differences.4 Interestingly, recent studies highlighted that 23 million people reported using cannabis during the past year in Europe including France, while cocaine users were around 4 million, ranging respectively from 0.8% to 11.2% and 0.1% to 3% of the general population.34,40 Although major discrepancies in methods made the comparison between studies really problematic, they provided data for comparison. Our results emphasized the low frequency of addictive behaviors among patients with central hypersomnia, comparable to our control group and the general population. Moreover, patients with excessive alcohol or drug use, dependence, or abuse did not differ in terms of demographic, narcolepsy symptoms, stimulant use, and depressive symptoms compared to patients without addictive behaviors. In contrast to patients with NT1, all patients with IH and 80% to 90% of patients with narcolepsy without cataplexy have normal CSF Hcrt-1 levels, especially in absence of HLA DQB1*06:0241; however, we found no significant differences between hypersomnia-group for excessive illicit substance/alcohol consumption, dependence, or abuse. Our results are consistent with a previous experimental study using the Balloon Analog Risk Task performed on a modest sample size population showing that substance/alcohol abuse and compulsive gambling were similar between patients with NT1, NT2, and healthy controls, although patients with a past history of addiction were surprisingly excluded from this study.8 dependence and one abuse), one NT2 with dependence and 10 controls (6 dependence and 4 abuse) (Table 2). Patients with NT1 with drug dependence did not overlap with those with alcohol dependence. Only one patient among the 450 (a patient with IH) took high doses of stimulants, with a mean daily dose of modafinil at 1,600 mg. No significant differences were found for excessive alcohol and drug use, abuse or dependence in patients with a central hypersomnia diagnosis or with NT1 only, whether being treated with stimulants or not. Finally, NT1 patients with excessive alcohol or drug use, dependence or abuse (n = 26) compared to other NT1 patients did not differ in terms of age, age at onset, gender, level of education, BMI, ESS, depressive symptoms, cataplexy frequency, presence of hypnagogic hallucination or sleep paralysis, stimulant use, and MSLT results (mean sleep latency and number of SOREMPs).
REFERENCES 1. American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014. 2. Dauvilliers Y, Paquereau J, Bastuji H, et al. Psychological health in central hypersomnias: the French Harmony study. J Neurol Neurosurg Psychiatry 2009;80:636–41. 3. Fortuyn HA, Mulders PC, Renier WO, et al. Narcolepsy and psychiatry: an evolving association of increasing interest. Sleep Med 2011;12:714–9. 4. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med 2013;14:488–92. 5. Bayard S, Croisier Langenier M, Cochen De Cock V, et al. Executive control of attention in narcolepsy. PLoS One 2012;7:e33525. 6. Bayard S, Abril B, Yu H, et al. Decision making in narcolepsy with cataplexy. Sleep 2011;34:99–104. 7. Delazer M, Hogl B, Zamarian L, et al. Executive functions, information sampling, and decision making in narcolepsy with cataplexy. Neuropsychology 2011;25:477–87. 8. Dimitrova A, Fronczek R, Van der Ploeg J, et al. Reward-seeking behavior in human narcolepsy. J Clin Sleep Med 2011;7:293–300. 9. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18:9996–10015. 10. Bourgin P, Huitron-Resendiz S, Spier AD, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000;20:7760–5. 11. Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 1999;96:10911–6. 12. Burlet S, Tyler CJ, Leonard CS. Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 2002;22:2862–72. 13. Brown RE, Sergeeva O, Eriksson KS, et al. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001;40:457–9. 14. Korotkova TM, Sergeeva OA, Eriksson KS, et al. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 2003;23:7–11. 15. Borgland SL, Chang SJ, Bowers MS, et al. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 2009;29:11215–25. 16. Borgland SL, Taha SA, Sarti F, et al. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006;49:589–601. 579 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 To conclude, we first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drugfree or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. From a clinical point of view, this observation supports the prescription of drugs for alleviating signs of excessive daytime sleepiness, without any addiction risk. Meanwhile, from a basic scientific point of view, although disruption of Hcrt signaling in rodents seems to reduce drug-seeking behaviors, our results suggest that Hcrt-deficient narcoleptics patients are as vulnerable as controls and other hypersomniacs of developing drug addictions. However, further research studies may focus on drug craving and relapse in Hcrt deficient patients with a past or current history of addiction. Our present study also demonstrated that patients with central hypersomnias whether Hcrt-deficient or not, drugfree, or medicated with psychostimulant (± anticataplectic) did not differ in the risk of excessive illicit substance/alcohol use, dependence, or abuse. This observation was intriguing since psychostimulants are known to promote impulsivity and risk-taking behaviors, notably by stimulating dopaminergic pathways.42 We previously reported that patients with central hypersomnia whether Hcrt-deficient or not, drug-free or medicated with psychostimulant, did not differ in risk-taking behaviors.43 Clinical experience suggests that patients with hypersomnia, including those with Hcrt deficiency (NT1) and those without (NT2 and IH), rarely exhibit stimulant abuse despite years of treatment with addictive compounds (methylphenidate, amphetamine, gamma-hydroxybutyrate, and modafinil to a lower extent). Moreover, these patients rarely developed withdrawal symptoms after stopping their stimulant medication.31 The absence of increased risk of addiction is reassuring for clinicians who manage patients with central hypersomnia, as they need to prescribe addictive drugs for years. Although all of these observations do not support any change in vulnerability to develop drug addiction in Hcrt-deficient patients, they contrast with the promising use of non-selective Hcrt receptor antagonists to treat drug addiction.30,31 This study has limitations. First, all 450 patients were not assessed for CSF Hcrt-1 levels which limits the comparison between Hcrt and non-Hcrt deficiency categories. However, almost all patients with narcolepsy with clear-cut cataplexy had low CSF Hcrt-1 levels, 10% to 20% in narcolepsy without cataplexy, with normal values for patients with IH.41,44 Second, although 450 orphan disease patients were included, the sample size is limited and under-powered to assess addictive behavior and its determinants when major endpoints occur in less than 2% of the population. The proportion of patients with excessive alcohol/drug use, substance dependence or abuse was low in all subgroups, with a potential under-power to detect significant differences between central hypersomnia categories whether Hcrt-deficient or not. Similarly, the impact of the different classes of stimulant compounds, and anticataplectic drugs (for NT1 patients) on addictive behaviors could not be assessed due to the small sample size of each subgroup. However we included for this study a well-defined population of patients with central hypersomnia in comparison to controls, and took into account a large variety of potential confounders including depressive symptoms but no other psychiatric comorbidities. Third, the method for acquiring subject responses with inperson interview may contribute to the low prevalence of substance abuse and recreational drug use. Hence, patients may be reluctant to disclose substance abuse with clinical interviews if assessment appeared linked to their clinical care. However, the MINI questionnaire is well-validated, was used by trained clinicians, the interviews took into account both opinions of the clinicians and participants. Patients are aware that the data are anonymized for this study. Finally, our study focused on alcohol/illicit drug use, abuse and dependence occurrence for the last 12-month period that precludes to evaluate its lifetime prevalence and whether addiction, if any, started before hypersomnolence onset or not.
35. Kenny PJ. Tobacco dependence, the insular cortex and the hypocretin connection. Pharmacol Biochem Behav 2011;97:700–7. 36. Newhouse PA, Potter A, Singh A. Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 2004;4:36–46. 37. Rusted JM, Sawyer R, Jones C, et al. Positive effects of nicotine on cognition: the deployment of attention for prospective memory. Psychopharmacology (Berl) 2009;202:93–102. 38. Pasumarthi RK, Fadel J. Activation of orexin/hypocretin projections to basal forebrain and paraventricular thalamus by acute nicotine. Brain Res Bull 2008;77:367–73. 39. Ponz A, Khatami R, Poryazova R, et al. Abnormal activity in reward brain circuits in human narcolepsy with cataplexy. Ann Neurol 2010;67:190–200. 40. Degenhardt L, Chiu WT, Sampson N, et al. Toward a global view of alcohol, tobacco, cannabis, and cocaine use: findings from the WHO World Mental Health Surveys. PLoS Med 2008;5:e141. 41. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007;369:499–511. 42. Pattij T, Vanderschuren LJ. The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 2008;29:192–9. 43. Bayard S, Langenier MC, Dauvilliers Y. Effect of psychostimulants on impulsivity and risk taking in narcolepsy with cataplexy. Sleep 2013;36:1335–40. 44. Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014;37:1035–42 ACKNOWLEDGMENTS Author contributions: L. Barateau - drafting/revising the manuscript for content, including medical writing for content; interpretation of data; I. Jaussent - drafting/revising the manuscript for content; statistical analysis and interpretation of data analysis; Y. Dauvilliers - drafting/revising the manuscript for content, including medical writing for content; study concept or design; interpretation of data analysis, study supervision and coordination; R. Lopez, S. Leu-Smenescu, and I. Arnulf - acquisition of data and revising the manuscript for content; B. Boutrel - Interpretation of data analysis, revising the manuscript for content. SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication July, 2015 Submitted in final revised form September, 2015 Accepted for publication October, 2015 Address correspondence to: Pr. Yves Dauvilliers, Service de Neurologie, Hôpital Gui-de-Chauliac, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France; Tel: (33) 4 67 33 74 78 (72 77); Fax: (33) 4 67 33 72 85; Email: ydauvilliers@yahoo.fr DISCLOSURE STATEMENT This was not an industry supported study. The study was financed by the PHRC AOM07-138 from the French Health Ministry (promotor: Assistance Publique Hôpitaux de Paris, IA). Dr. Dauvilliers has received funds for speaking, board engagements, and travel to conferences with UCB Pharma, Jazz, and Bioprojet. Dr. Arnulf has received funds for speaking and board engagements and travel to conferences with UCB pharma. The other authors have indicated no financial conflicts of interest. 580 Addiction and Narcolepsy—Barateau et al. Downloaded from https://academic.oup.com/sleep/article/39/3/573/2453974 by guest on 28 June 2024 17. Boutrel B, Kenny PJ, Specio SE, et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 2005;102:19168–73. 18. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005;437:556–9. 19. Hollander JA, Lu Q, Cameron MD, et al. Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A 2008;105:19480–5. 20. Georgescu D, Zachariou V, Barrot M, et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 2003;23:3106–11 21. Plaza-Zabala A, Flores A, Martin-Garcia E, et al. A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotineseeking behavior. Neuropsychopharmacology 2013;38:1724–36. 22. Flores A, Maldonado R, Berrendero F. The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biol Psychiatry 2014;75:499–507. 23. Hollander JA, Pham D, Fowler CD, et al. Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Front Behav Neurosci 2012;6:47. 24. Lawrence AJ, Cowen MS, Yang HJ, et al. The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 2006;148:752–9. 25. Narita M, Nagumo Y, Hashimoto S, et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006;26:398–405. 26. Smith RJ, Aston-Jones G. Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci 2012;35:798–804. 27. Bayerlein K, Kraus T, Leinonen I, et al. Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal. Alcohol 2011;45:541–7. 28. von der Goltz C, Koopmann A, Dinter C, et al. Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward. Psychoneuroendocrinology 2010;35:570–7. 29. Rotter A, Bayerlein K, Hansbauer M, et al. Orexin A expression and promoter methylation in patients with cannabis dependence in comparison to nicotine-dependent cigarette smokers and nonsmokers. Neuropsychobiology 2012;66:126–33. 30. Boutrel B, Steiner N, Halfon O. The hypocretins and the reward function: what have we learned so far? Front Behav Neurosci 2013;7:59. 31. Bayard S, Dauvilliers YA. Reward-based behaviors and emotional processing in human with narcolepsy-cataplexy. Front Behav Neurosci 2013;7:50. 32. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59:22–33. 33. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001;57:2029–33. 34. Sommet A, Ferrieres N, Jaoul V, et al. Use of drugs, tobacco, alcohol and illicit substances in a French student population. Therapie 2012;67:429–35.
Fleepit Digital © 2021