Treating insomnia with medications

Treating insomnia with medications Insomnia is a conspicuous problem in modern 24 h society. In this brief overview, medications used to treat insomnia such as hypnotics, sedatives, medications inducing sedation as a side effect, medications directed at the sleep-associated circadian neuroendocrine system, and agents utilized in treating insomnia-inducing sleep diagnoses such as restless leg syndrome are discussed. The newer GABA-effective hypnotics are the only medications with demonstrated effectiveness in treating chronic insomnia with the majority of evidence supporting treatment efficacy for cognitive-behavioral therapy and short acting GABA-receptor agonists. In patients with comorbid insomnia the use of hypnotics can improve outcomes and potentially reduce morbidity and mortality associated with the use of more toxic medications. Except in individuals whose insomnia is secondary to circadian disturbance, mood disorder/depression and/or restless leg syndrome , there is minimal evidence supporting the efficacy of other medications used to treat insomnia despite their widespread use. Sedatives and other medications used off-label for sedative side-effects are a contributing factor to drug induced hypersomnolence, a factor in more than 30% of motor accident deaths. Hypnotic medications with low toxicity, addictive potential, minimal next day sleepiness, and an otherwise benign side-effect profile can be utilized safely and effectively to treat and improve function and quality of life for patients suffering from insomnia. These are the agents that should be exclusively classified as hypnotics and utilized to induce sleep when medications are required to treat the complaint of insomnia. Other pharmacological agents producing sedation (sedatives and agents used off-label for sedative side-effects) should be used cautiously for the treatment of insomnia due to the increased risk of next day sleepiness as well as for known toxicities and adverse side effects. Keywords: Insomnia, Medications, Hypnotics, Sedatives, Benzodiazepine Introduction of Clinical Sleep Medicine 2005). Chronic insomnia is Insomnia, defined as the subjective perception of diffi- significantly associated with a decrease in quality of life culty with sleep initiation, duration, consolidation, or measures, the exacerbation of co-morbid diagnoses, and quality that occurs despite adequate opportunity for an increased likely-hood for developing mood disorders sleep, is a conspicuous problem in modern 24-h society / de[ression (Sateia et al. 2017). While there are dozens (Sateia et al. 2017). Episodes of acute or transient insom- of insomnia-associated sleep diagnoses, any medical or nia each year affect > 80% of adults. Chronic insomnia psychiatric disorder or environmental stress that pro- (> 3 months in duration) includes difficulty falling asleep, duces nighttime discomfort is likely to induce insomnia. insufficient sleep, or perceived nonrestorative sleep pro- Medications for treating insomnia are classified as hyp- ducing daytime complaints of somnolence, fatigue, irrit- notics, sedatives, medications inducing sedation as a side ability, or difficulty concentrating and performing effect, medications directed at the sleep-associated circa- everyday tasks, and has a population prevalence of ap- dian neuroendocrine system, and agents utilized in treat- proximately 14 % (Hauri 2005; NIH State of the Science ing insomnia-inducing sleep diagnoses such as restless Conference Statement on Manifestations and Manage- leg syndrome (RLS) (Curry et al. 2006; Bhat et al. 2008). ment of Chronic Insomnia in Adults Statement, Journal * Correspondence: pueo34@gmail.com Sleep hygiene and cognitive behavioral therapies University of Colorado School of Medicine, Couthern Colorado Residency Sleep behaviors must be addressed for any patient pre- Program, Pueblo, CO, USA 4 senting with insomnia. Insomnia can be treated without Rocky Mountain Sleep, 1306 Fortino Blvd, Pueblo, CO 81008, USA Full list of author information is available at the end of the article medications, using sleep hygiene combined with © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pagel et al. Sleep Science and Practice (2018) 2:5 Page 2 of 12 cognitive and behavioral therapies (CBT). This approach neurotensin, muramyl peptides, endotoxins, cytokines avoids potential drug side effects and toxicities and has [interleukin-1B, tumor necrosis factor-α], interleukin 1B, shown long-term persistence in treating chronic insom- tumor necrosis factor-α (TNFα), prostaglandin D2 nia that can be superior to results obtained using drug (PGD2) and melanin concentrating hormone (MCH) therapies (Morin 2005). Sleep hygiene refers to environ- (García-García et al. 2009; Urade and Hayaishi 2011; mental factors, dietary approaches, drugs, and a lack of Pabst et al. 1999). Sedation is among the most common required sleep facilitating approaches that can induce in- effects and/or side effects of prescription medications. somnia. Insomnia inducing drugs include caffeine, nico- The list of agents inducing sedation as an effect and/or tine, weight loss preparations, and activating agents of side effect is extensive and includes most medication both prescription and abuse. CBT extends sleep hygiene classifications (Table 1) (Pagel 2017). Sedation is com- into the use of sleep facilitating cognitive and behavioral monly induced by over the counter (OTC) preparations approaches for treating insomnia (Finley and Perlis (particularly anti-histamines), and commonly used drugs 2014). CBT has proven its usefulness in treating chronic of abuse such as cannibis and ethanol. When the use of insomnia, working best when administered by a trained Table 1 Medications Not Classified As Sedative/Hypnotics provider over several extended visits (Riemann and Inducing Daytime Sleepiness As A Side Effect Perlis 2009). Insomnia treatment can be limited to the Medication Class Neurochemical Basis For Sleepiness use of hygiene and CBT, but such an approach has clear Antiparkinsonian Agents Dopamine Receptor Agonists limitations. Behavioral approaches are rarely effective in Antimuscarinic/ Antispasmodic Varied effects treating acute and transient episodes of insomnia and have limited usefulness in treating comorbid insomnia. Skeletal Muscle Relaxants Varied Effects CBT requires patient interest and effort and as a clinical Alpha- Adrenergic Alpha-1 Adrenergic Antagonists approach is unavailable to many affected individuals due Blocking Agents to both cost and limitations in provider access (Lichstein Beta-Adrenergic Beta Adrenergic Antagonists Blocking Agents et al. 2005). Even when appropriately utilized, CBT does not work for every patient (Trauer et al. 2015). Gamma-Hydroxy-Butyrate GABA Agonist Opiate Agonists Opioid Receptor Agonists Sleep neurophysiology (General Cns Depression) From a behavioral stand-point, sleep is a complex, re- Opiate Partial Agonists Opioid Receptor Agonists (General Cns Depression) versible behavioral state of perceptual disengagement from, and unresponsiveness to, the environment Anticonvulsants (Carskadon and Dement, 2011). To this point, no specific Barbiturates GABA Agonist anatomical site or required neurochemical trigger has been –Benzodiazepines GABA Agonist identified. Neuroanatomical structures in the CNS are - Hydantoins Neurotransmitter effect poorly defined - affected globally by sleep associated changes in neurochem- electrophysiolic? ical, electrophysiological and neuroendocrine systems. - Succinimides Neurotransmitter effect poorly defined - electrophysiolic? The neurochemistry of sleep Other Antidepressants Sleep is a global state involving multiple factors and sys- - Maoi Norepinephrine, 5ht & Dopamine tems, with no single neurochemical identified as neces- - Ssri Serotonin Uptake Inhibition sary for modulating sleep (Brown et al. 2012). In most -Agents With Mixed Effects Serotonin, Dopamine, & Norepinephrine cases, the CNS effects of drugs can be ascribed to pri- mary effects on specific neurotransmitters and neuromo- Other Antipsychotics Dopamine Receptor Blockage, Varied Effects On Histaminic, Cholinergic dulators. Most hypnotics affect GABA, the primary And Alpha Adrenergic Receptors negative neurotransmitter in the CNS, or affect specific Other Benzodiazepines GABA Agonist neuromodulators of GABA that include serotonin, Not Used For Sedation acetylcholine, and dopamine (Pagel 2017). Other drugs, Anxiolytics, misc. Sedative GABA Agonist, Varied Effects particularly those classified as sedatives, induce sedation & hypnotics by antagonizing one or more of the central activating Antitussives Neurotransmitter Effect Poorly Defined neuromodulators. These activating neuromodulators in- Antidiarrhea agents Neurotransmitter Effect Poorly Defined - clude serotonin, norepinephrine, histamine, acetylcho- Opioid In Some Cases line, dopamine, and orexin. Other substances known to Antiemetics Antihistamine & Varied Effects affect sleep include adenosine, substance P, cortico- Genitourinary Smooth Neurotransmitter Effect Poorly Defined trophin releasing factor (CRF), thyrotrophin releasing Muscle Relaxants factor (TRF), vasoactive intestinal peptide (VIP), Pagel et al. Sleep Science and Practice (2018) 2:5 Page 3 of 12 these agents is coupled with the use of sedating prescrip- movements and diminished skeletal EMG activity. Medi- tions, additive sedation, toxicity, and side-effects increase cations producing CNS-related behavioral effects generally the danger of life-threatening over-dose (National Insti- affect background EEG frequencies (Mamdema and Dan- tue on Drug Abuse: National Institutes of Health 2015). hof 1992). In most cases, a consistent pattern of EEG change produced by a drug is associated with a consistent The electrophysiology of sleep pattern of behavioral change (Hermann and Schaerer In the clinical laboratory, sleep is defined by its electro- 1986). Psychoactive drugs produce alterations in physio- encephalography (EEG) in concert with electromyog- logic EEG rhythms consistent across therapeutic classifica- raphy (EMG), electrooculography (EOG) and other tions and utilized to predict the behavioral activity of new telemetry. Using polysomnographic recordings, sleep can preparations, drug interactions and toxicities (Blume be classified into rapid eye movement (REM) sleep and 2006)(Table 2). non-rapid eye movement (NREM) sleep. The NREM sleep is further classified into 3 sleep stages namely The neuroendocrinology of sleep Stage N1 sleep, Stage N2 sleep, and stage N3 sleep (also Sleep regulation is a complex interaction between the known as slow wave sleep, delta sleep or deep sleep), homeostatic and the endogenous circadian processes based primarily on the occurrence of synchronous (Borbély et al. 2016). The circadian processes of sleep physiologic EEG potentials. Drowsy awake with eyes are largely controlled by the suprachiasmatic nucleus closed is defined by the presence of alpha - the fre- (SCN) in the hypothalamus (Dai et al. 1998; Hofman et quency with the most power on spectral analysis. Sleep al. 1996; Swaab et al. 1985; Vimal et al. 2009). This in- onset (Stage N1) is generally defined as occurring at the ternal human clock responds to external factors with the point in which there is a decline of alpha rhythm (9– greatest influence being exposure to light/dark (LD) 11 Hz) to less than 50% of the recorded epoch. Stage N2 cycle (Lewy et al. 1980; Morin 2015). The other import- sleep is denoted by bursts of sleep spindles at sigma fre- ant element to the timing of the sleep/wake cycle is the quency (11–16 Hz) and K-complex events - electro- endogenously produced neural hormone melatonin, pro- physiological down states known to negatively affect the duced by the pineal gland in response to signals from general tendency of neurons to develop spike potential the SCN. Melatonin can induce sedation, an effect activity (Cash et al. 2009). Deep sleep (stage N3 sleep) oc- sometimes utilized to assist children in tolerating med- curs in association with delta frequency oscillations (0.5– ical procedures (Johnson et al. 2002). In addition to 1.5 Hz). REM sleep is characterized by bursts of intracra- regulation of the sleep/wake cycle, body temperature nial theta (5–8 Hz), with alpha and gamma oscillations and numerous other processes vary with circadian noted in scalp recordings, associated with conjugate eye rhythm (Sack et al. 2007). Externally introduced Table 2 Consistent quantitative alteration in physiologic EEG frequencies induced by psychoactive medications Class of drugs Eeg frequencies Treatment indications Delta Theta Alpha Sigma Beta/Gamma (0.5–1.5 Hz) (5.5–8.5 Hz) (8.5–11 Hz) (12–16 Hz) (21–32 Hz) Benzodiazepines (BZDs) Decrease Increase Increase Anxiety Sedation Barbiturates Increase Increase Anxiety Sedation Epilepsy Tricyclic Antidepressants (TCAs) decrease Decrease Increase Depression SSRI Antidepressants decrease Increase Depression Anxiety OCD Amphetamines decrease Decrease increase Somnolence Narcolepsy AD/HD Opiates increase decrease Pain Anticonvulsants increase Epilepsy Phenytoin, valproate, carbamazepine Gamma hydroxy butyrate (GHB) increase Cataplexy Narcolepsy Classic Neuroleptics increase decrease decrease Schizophrenia Psychosis Pagel et al. Sleep Science and Practice (2018) 2:5 Page 4 of 12 melatonin can be utilized to reset circadian rhythms of 1989). In the 1990’s newer agents were developed and sleep and body core temperature through its actions on marketed that had selective effects on GABA receptors in- the SCN (Abbott et al. 2014). cluding Zolpidem (Ambien), Zaleplon (Sonata), Eszopi- clone (Estorra) and Indiplon. While all hypnotics have The optimal hypnotic abuse potential for individuals with addictive histories and Sleep-inducing drugs (hypnotics) are medications specif- personalities, these agents have been noted to have min- ically designed to induce sleepiness directly after intake. imal additive potential (Hajak et al. 2003). These agents Optimal agents affect cognitive performance during this are less likely to have deleterious side effects than most period while inducing minimal sleepiness in the waking OTC treatments for insomnia, however, with increased day after use. An optimal hypnotic would have low tox- use, more side effects including next effects on driving icity and addictive potential, as well a minimal side effect have been reported. This effect as well as next day re- profile (Oswald 1970). Among the first hypnotics, and bound insomnia has particularly been reported for higher an agent still in use is chloral hydrate - the original doses of zolpidem (Verster et al. 2002). In many cases, “Mickey Finn” - slipped into the drinks of unsuspecting MVA’s occurred in the period of somnolence and cogni- marks for the purposes of criminal activity. Unfortu- tive impairment during the first few hours after ingestion. nately, this medication is difficult to use since the LD-50 Comparatively normal results on psychomotor tests can (potentially fatal dose) is quite close to the therapeutic be obtained 3.25 h. after zaleplon ingestion and 6.25 h. dose. In the years leading up to the 1970’s, rapidly acting after zopiclone ingestion (Paul et al. 2003). While these barbiturates were commonly utilized for their hypnotic agents have excellent efficacy with minimal side effects, at effects. Unfortunately, these medications, also drugs of higher doses these agents can exhibit benzodiazepine-like abuse, had a significant danger of overdose and contrib- effects. Idiosyncratic reactions of persistent daytime som- uted to an era that was characterized in part by deaths nolence and/or memory loss have been reported. Some due to overdoses of sleeping pills. These medications patients will report next day sedation after the nighttime and similar barbiturate-like medications [Methaqualone use of these agents, as well as demonstrate an increased (Quaalude, Sopor) Glutethimide (Doriden), Ethchlor- error rate in driving tests (Verster et al. 2007). Such infor- vynol (Placidyl), Methyprylon (Nodudar)] have limited mation was forthcoming only after these drugs became availability and are rarely used due to limited efficacy, generic and widely utilized in clinical practice. Most sedat- cognitive effects, the potential for abuse and lethal tox- ing drugs if adopted into such widespread use would also icity associated with overdose (Oswald 1970). Today be at least as likely to demonstrate epidemiological effects their primary therapeutic uses include executions and fa- on MVA’s and MVA associated deaths. In the elderly, cilitated euthanasia (Lossignol 2008). chronic use of sedating drugs (particularly those with Most currently utilized hypnotics affect the widely dis- anti-cholinergic side effects) can be associated with an persed negative neurotransmitter GABA. In the 1970’s increased risk for falls, and confusion (American benzodiazepines (GABA agonists) were first marketed as Geriatrics Society 2015). Reported next day sleepiness hypnotics. Some of these agents had an extremely short and other side effects associated with hypnotic use duration of action [Triazolam (Halcion)]. While this are summarized in Table 3. agent-induced minimal next day somnolence, use was as- The newer GABA-effective hypnotics are the only sociated with daytime memory impairment, particularly at medications with demonstrated effectiveness in treating higher dosages (Roehrs et al. 2000; Adam and Oswald chronic insomnia (NIH State of the Science Conference Table 3 Hypnotics - Agents Utilized To Induce Sleep With Minimal Next Day Sleepiness After Used Based On Pharmacodynamics, Clinical Trials, And/Or Performance Testing Drug & Class 1/2 Life Next Day Sleepiness [Clinical Trials] Toxicity And/Or Significant Side Effects Short acting gaba agonist 1–2 HR. Anecdotal and per survey Antegrade Amnesia, Confusion At Higher Dose - triazolem [placebo Equivalent] GABA selective agents 1 HR. [Placebo No consistent reports - zaleplon Equivalent] [not in widespread use] Zolpidem 1.5 HR. Anecdotal [placebo Symptomatic Equivalent] Parasomnias, Per survey when dosed outside Next night rebound insomnia pharmacodynamic profile and in the elderly Eszopiclone 6 HR. Anecdotal Possible Parasomnia Associations [placebo [Agent Not In Widespread Generic Use] Equivalent] Pagel et al. Sleep Science and Practice (2018) 2:5 Page 5 of 12 Statement on Manifestations and Management of in sedation. Some of these agents had active breakdown Chronic Insomnia in Adults Statement, Journal of products that produced an extraordinarily long active Clinical Sleep Medicine 2005). According to the NIH, half-life (11 days) (Oswald 1970). The prolonged effect is the majority of evidence supports the efficacy of one of waking calming and sedation, associated with in- cognitive-behavioral therapy and short acting benzodi- creased auto accidents and falls with hip fractures. azepine receptor agonists in the treatment of chronic in- Medium 1/2 life agents including alprazolam, temaze- somnia, at least in the short term. Chronic insomnia is pam, and lorazepam affect next day performance tests often, however, a lifelong illness, and the longest clinical (Ray et al. 1989). The use of these agents may be associ- trials for these agents have been one year in duration. ated with an increased level of next day MVA’s (Ceutel These agents can be safely utilized chronically or in an 1995; Buysse 1991). “as needed” (prn) basis in individuals with both short Other sedating agents affect the GABA neuromodua- and long term insomnia (Morin and Espie 2003; tors - acetylcholine, dopamine, and serotonin. Most of Schutte-Rodin et al. 2008). Except in individuals whose these agents are classified as sedating antidepressants. insomnia is secondary to circadian disturbance, mood Sedating antidepressants include the tricyclics (amitryp- disorder/depression and/or restless leg syndrome, there tiline, imipramine, nortriptyline, etc.), and atypical anti- is minimal evidence supporting the efficacy of other depressants: Trazodone (Deseryl), and Mirtazapine medications used to treat insomnia despite their (Remeron). Trazondone is among the most widely pre- widespread use (NIH State of the Science Conference scibed agents for inducing sleep. There are few studies Statement on Manifestations and Management of Chronic addressing the efficacy this off-label approach to treating Insomnia in Adults Statement, Journal of Clinical Sleep insomia, but there are more describing trazadone’s sig- Medicine 2005; Morin, Medalie and Cifu 2017). nificant side-effects including next day sleepiness and psychomotor impairment in the elderly (Mendelson Sedatives 2005). Among the SSRI’s, Paroxetine (Paxil) can induce Sedatives induce calming and reduce arousal during mild sedation. Use of sedating antidepressants has been waking. At the extreme end of the spectrum of use, associated with declines in daytime performance, driving sedative agents are utilized in anesthesia. The sedative test performance, and an increased potential for involve- category included the opiates, a drug class developed ment in motor vehicular accidents (Volz and Sturm from the domesticated poppy with evidenced utilization 1995). Both tricyclic and atypical antidepressants are from neolithic archeologic sites (5000–7000 B. C.) widely used as a hypnotics despite significant next day (Heinrich 2013). At the dawn of medicine as a specialty, sedation (Settle 1998). among the few agents useful as a medication was Many of the sedating medications treat hyperarousal laudanum - a tincture of opium that mixed with water by antagonizing the wake-producing neuromodulating or wine was used as a soporific even for crying infants. systems: serotonin, norepinephrine, dopamine, hista- Most sedative drugs selectively affect specific neuro- mine, and orexin. Both prescription and over the coun- transmitters and neuromodulators in the CNS (Schwartz ter (OTC) agents are marketed for sedative effects 2000). Multiple factors and systems are involved. Seda- produced pharmacologically by antagonizing orexin, his- tive drugs can exert primary effects either at the inhibi- tamine, and norepinephrine. tory neurotransmitter gamma-Aminobutyric acid Antihistamines and antipsychotics induce sedation (GABA), or on sedating neuromodulators. Others po- based on their antihistaminic effects (Monti et al. 2016). tentiate sedation by antagonizing one of the widely dis- Over the counter sleeping pills contain sedatingH-1 anti- persed central activating neuromodulators: serotonin, histamines, usually diphenhydramine, hydroxyzine or norepinephrine, dopamine, histamine, and orexin. triprolidine (Monti and Monti 2000). These agents in- Many patients suffering from chronic insomnia are duce sedation with acute use, and often induce increased hyperaroused, unable to fall asleep even after minimal daytime sleepiness and cognitive impairment persisting sleep the night before. Treatment of this hyperarousal into the day following nighttime use (O’Hanlon and presenting clinically as agitation and sometimes anxiety Ramaekers 1995). In comparative studies, driving per- can produce improved sleep. Unfortunately, sedation formance at 2.5 h. after administration of 50 mg. of di- and reduced arousal are variants of the same cognitive phenhydramine is worse than in individuals with a blood calming effect. Because of this, sedatives induce daytime alcohol concentration (BAC) of 0.1% - the level of legal sleepiness in many users. The idea sedative agent, like intoxication in most states (Wiler et al. 2000). Nighttime the ideal hypnotic, should have low toxicity, low addic- drug use can produce drowsiness severe enough to affect tion potential, and a benign side effect profile. next day performance and driving tests (Gango et al. Fifty years ago, longer acting benzodiazepines, particu- 1989). Sedation is infrequent with H2 antagonists (e.g. larly Diazepam (Valium) preempted the role of opiates cimetidine, ranitidine, famotidine, and nizatidine), but Pagel et al. Sleep Science and Practice (2018) 2:5 Page 6 of 12 somnolence as a side effect is reproducible in susceptible Clinically these agents are sometimes used off-label for individuals (White and Rumbold 1988). Sedation is a com- their sedative effects. Among antihypertensives in wide mon side effect of the traditional antipsychotics, with use, the complaints of tiredness, fatigue and daytime chlorpromazine and thioridazine somewhat more sedating sleepiness are commonly associated with drugs having than haloperidol. Clinical studies have shown a high inci- antagonistic effects at the norepinephrine neuroreceptor dence of persistent sedation with clozapine (46%) with less (Dimsdale 1992). The complaints of tiredness, fatigue frequent reports of sedation with risperidone, olanzapine, and daytime sleepiness (2–4.3%) associated with sertindole and quetiapine (Monti et al. 2016). The sed- beta-blocker use may occur secondary to disturbed sleep ation associated with these agents is most likely associated or direct action of the drug. Beta-blocking drugs with with their known effects on histaminic receptors. vasodilating properties (e.g. carvedilol, labetalol) are also Doxepin, a sedating psychotropic agent with pro- associated with reported fatigue and somnolence nounced histamine (H-1) receptor antagonism exerts at (3–11%). Sedation is among the most common side ef- least part of its effects by antagonizing orexin (Krystal et fects reported for the alpha-2 agonists clonidine and al. 2013). Suvorexant, is an orexin antagonist designed methyldopa (30–75%) (AHFS 2003). Alpha-1 antagonists to lower waking arousal (Norman and Anderson 2016). (e.g. terazosin, prazosin) are sometimes associated with Currently, it is being heavily marketed as a hypnotic transient sedation. Prazosin, a norepinephine antagonist, (Rhyne and Anderson 2015). As based on performance has demonstrated value in treating insomnia associated and driving tests, this agent is known to produce a with PTSD nightmares (Raskind et al. 2003). Clonidine dose-related next day increase in somnolence for all age is sometimes utilized to treat the agitation and insomnia groupings tested (Farkus 2013). Sedative drug effects on that result from using amphetamines to treat AD/HD in daytime sleepiness are summarized in Table 4. pediatric patients (Ming et al. 2011). Sedation is a common side effect induced by Other agents inducing sedation anti-epileptic drugs, reported at levels of 70% with phe- Many other agents induce significant sedation as part of nobarbitol, 42% with carbamazepine and valproate, and their clinical effect or as an untoward side-effect. in 33% of patients using phenytoin and primidone Table 4 Sedatives - Agents Used To Induce Sleep And Sedation With Significant Next Day Sleepiness After Used Based On Pharmacodynamics, Clinical Trials, And/Or Performance Testing CLASS (DRUG) [Neuromodulator Effected] 1/2 LIFE Next Day Sleepiness Next Day Effects On Toxicity And/Or [Clinical Trials] Performance & Driving Tests Significant Side Effects Antidepressants 10–20 HR. Significant Significant With Anticholinergic, - tricyclics (amitriptyline etc.) Minimal Study Respiratory suppression [serotonin] in overdose - Atypicals traza- done (8 h) Significant Significant With Respiratory Suppression (trazadone, mirtazapine) mirtaza-pin 20–40 HR. Minimal Study In Overdose [serotonin] H1 antihistamine 2–12 HR. Significant Significant - Confusion [Black Boxed Diphinhydramine, Multiple studies For The Elderly] hydroxyzine, triprolidine) [histamine] Antipsychotic 6–8 HR. Significant Significant with Potentially persistent - Olanzapine minimal study extra-pyramidal [histamine] Side effects - Doxepin 1/2–15 h. (dose based) Significant Significant With Potentially persistent [histamine, orexin] active metabolite Minimal Study extrapyramidal Side effects Gaba agonists 7–10 HR. Significant Significant Disinhibition - medium ½ life benzodiazepi-nes Multiple studies (estalolam, clonazepam, temezepam, etc.) [GABA] - Long ½ life benzodiazepi- nes Up To 11 Days Significant Significant Disinhibition (flurezepam, diazepam, etc.) Multiple studies Falls in the elderly [GABA] Orexin antagonists 10–22 HR. Significant Significant Unknown (suvorexant) New agent [orexin] Key: the term “Significant” indicates comparison to placebo or hypnotics Pagel et al. Sleep Science and Practice (2018) 2:5 Page 7 of 12 (Schweitzer et al. 2003). In clinical trials sedation is has increasingly become a problem. In 1993, about one reported as a side effect to treatment with topiramate in eight drivers were using more than one drug, but by (15–27%) at at levels of 5–10% for gabapentin, lamotri- 2010, it was closer to one in five. The number of drivers gine, vigabatrin, and zonisamide (AHFS 2003). The dying in MVA’s with three or more sedating drugs in neurochemical basis for the sedation induced by many their system increased from 11.5 to 21.5% during this of these agents remains poorly defined except for those period. Among drivers who tested positive for any drug, agents know to have GABA agonist effects (e.g. gabapen- 48% also tested positive for alcohol (Disney et al. 2011). tin, phenobarbitol) (Westbrook 2000). Some drugs may act by glutamate antagonism and others by having direct Comorbid insomnia effects on CNS electrophysiology (Pagel 1996). In indi- The term secondary insomnia has historically been ap- viduals being treated with such medications for seizure plied to patients with insomnia associated with either a disorders, the clinical differential between medication ef- medical or psychiatric condition or a primary sleep dis- fects and sedation secondary to recurrent seizures can order. Until 2005 the NIH guidelines regarded such in- be difficult to determine (Manni and Tartara 2000). somnia as being a consequence of the primary diagnosis. Almost all drugs with CNS activity induce sleepiness This led to recommendations that indicated the key was as a side effect in some patients (Bittencourt et al. 2005; treating the primary or underlying condition with the as- Guilleminault and Brooks 2001). The sedative side ef- sumption that this would, in turn, lead to resolution of fects of some of these agents are clinically utilized in insomnia. In 2005 the NIH convened another “State of specific situations. However, sleepiness is a common and the Science” conference to review the manifestations often-unwanted side effect for many types of prescrip- and management of chronic insomnia (NIH State of the tion medications including commonly used antitussives, Science Conference Statement on Manifestations and skeletal muscle relaxants, antiemetics, antidiarrheal Management of Chronic Insomnia in Adults Statement, agents, genitourinary smooth muscle relaxants, and Journal of Clinical Sleep Medicine 2005). The committee others (Table 1). These sedative side effects can limit the concluded that most cases of insomnia are comorbid use of these agents in patients in which the level of per- with other conditions. The concern over continuing to sistent daytime sleepiness affects waking. All sedating use the term “secondary” insomnia is that in many cases agents can contribute to an increased risk for motor ve- we do not have clear proof of cause and effect and, of hicular accidents. greater concern; the use of the term may lead to under-treatment of insomnia. This recommendation to Drug induced Hypersomnolence view insomnia as comorbid has to lead to a shift in treat- Drug induced hypersomnolence is a significant problem ment paradigms. While identification and treatment of in today’s society. Approximately 30% of traffic deaths in the “primary” condition remain a priority, concurrent the United States can be attributed at least in part to the treatment of insomnia is now viewed as desirable. In use of ethanol - the most commonly abused sedating general treatment of comorbid insomnia is now essen- medication (Department of Transportation (US), Na- tially the same as treating primary insomnia with a tional Highway Traffic Safety Administration (NHTSA) growing number of studies confirming that this ap- 2015). Sedating drugs other than ethanol are contribut- proach is effective (Morin and Benca 2012; Sateia and ing factors in 16% of motor vehicular accidents (Berning Nowell 2004; Winkelman 2015). Treatment of insomnia et al. 2015).While not nearly as great a risk factor for can often improve the symptoms of the “primary” or a driving as alcohol, marijuana may nearly double the risk comorbid condition. of having a vehicle collision (Sewell et al. 2009). In the United States, marijuana users are about 25% more likely Circadian system disturbances to be involved in an MVA than drivers with no evidence Sleep disorders related to circadian rhythm are caused of marijuana use (Compton and Berning 2015). by a misalignment of the approximately 24-h endogen- The prescription and OTC medications known to in- ous circadian rhythm and the “normal” 24 h day/night crease the risk of sleepiness-related crashes include lon- cycle (Melatonin can act as a hypnotic and is a useful ger acting benzodiazepine anxiolytics, sedating adjunct to treatment in individuals with circadian dis- antihistamines (H1 class), and tricyclic antidepressants turbance (Pandi-Perumal et al. 2008). Prescription syn- (TCAs). The risks are higher with higher drug doses and thetic analogs of melatonin such as ramelteon are for people taking more than one sedating drug simultan- available. Sleep tendency and reduced sleep latency are eously (Ceutel 1995; Gengo and Manning 1990;Van affected from 1 3/4–4 3/4 h post ingestion (Stone et al. Laar et al. 1995). Since a high percentage of the popula- 2000). Melatonin has been used as a hypnotic with in- tion uses drugs of abuse as well as medications for consistent results (Monti et al. 2013). The impact of this underlying illness, the use of multiple sedating drugs use agent on next day performance is generally considered Pagel et al. Sleep Science and Practice (2018) 2:5 Page 8 of 12 to be minimal. Next day psychomotor test results may unpleasant sensations are worse in the evening (Verma not be affected, although one study has demonstrated and Kushida 2014). Sleep disruptionand complaints of de- significant effects on next day deviation of lateral pos- creased quality of life is present in 3/4 of the patients with ition in driving tests (Mets et al. 2011). thesyndrome(Allenand Earley 2001). A majority of RLS Melatonin and light exposure have proven especially patients will have repetitive periodic limb movements effective when used to treat Delayed Sleep Phase Syn- (PLMS) on polysomnogram. The RLS/PLMD has a genetic drome most prevalent in adolescents and young adults basis and increases with age so that in the geriatric popula- (Pandi-Perumal et al. 2008). Patients with this syndrome tion (> 80 years) over 30% of individuals may meet criteria have difficulty falling asleep at the desired bedtime, often for the diagnosis. RLS/PLMD is also more common in chil- falling asleep between 2 and 6 AM and then, if their life- dren with AD/HD, patients in renal failure, individuals with style permits, sleeping approximately a normal 8 h, low serum ferritin levels (< 50), and in patients taking some awakening at between 10 AM and 2 PM. Individuals medications such including antidepressants, antiemetics with this common disorder often suffer from chronic in- and antihistamines (Phillips et al. 2006). sufficient sleep time with all its daytime consequences. The treatment of the sleep disruption, primarily sleep Treatment involves exposure to bright light at the onset, relies predominately on the treatment of the RLS proper time in the circadian phase response curve. In rather than the treatment of resultant insomnia. the case of delayed phase syndrome, this is after the Dopaminergic agonists have become the primary initial nadir of body temperature. Treatment with 10,000 lx for treatment for RLS. Pramipexole and ropinirole have both 30 min on awakening and timed melatonin administra- received FDA approval for this indication and are used tion in the early evening 3–6 h before sleep time (before in doses low relative to their use for Parkinson’s Disease. the Dim Light Melatonin Onset (DLMO) or 12+ hours Pramipexole is used in a range of 0.125 to 2 mg and before the temper nadir are effective. Since melatonin ropinirole at 0.25 to 4 mg. Dopaminergic agents, espe- can be soporific so caution needs to be exercised if used cially pramipexole, can induce significant somnolence as when the patient has wakeful activities to perform. Ad- well as sleep attacks in some individuals (Micalief et al. vanced Sleep Phase Syndrome (ASPS) is the mirror 2009). Benzodiazepines have been used, historically clo- image of DSPS with patients sleep onset and awakening nazepam but also temazepam. There are no recent stud- both several hours earlier than desired with the total ies of the efficacy of these but historically they have been sleep period remaining fairly normal. This is less com- useful and still have a role when side effects limit the mon than DSPS and tends to occur more in use of the dopaminergic agents or in combination in re- middle-aged to elderly adults. Treatment options are fractory cases. When lack of response or side effects are similar to those for delayed phase syndrome with the still present opioids with significant addictive potential timing of treatment designed to delay rather than ad- in this situation such as codeine or oxycodone are some- vance the circadian rhythm. In shift workers, melatonin times utilized (Comella 2014). Gabapentin, and pregablin can be used to help shift the worker’s circadian rhythm used off-label to treat RLS/PLMD induce significant as required. When taken before bedtime in the early hypersomnolence, interact with opiates, and have been de- morning it can improve sleep quality. For individuals suf- scribed as drugs of abuse (Schifarno 2014). A varient of fering from Jet Lag Disorder melatonin can be used to these agents, the alpha-2-delta ligand gabapentin enacarbil speed the adjustment to the new time zone (Brown et al. recently approved as a treatment for RLS is known to in- 2009; Srinivasan et al. 2010). Visually blind and incarcer- duce significant sedation and dizziness (Lee et al. 2011). ated individuals can have non-24 h. and free-running cir- cadian patterns that can be responsive to melatonin Insomnia associated with sleep apnea and its treatment agonists such as tasimelteon (Neubauer et al. 2015). Obstructive sleep apnea (OSA) induces daytime sleepi- ness in a significant percentage of affected individuals. Restless legs syndrome and periodic leg movement disorder Both apnea severity and the level of daytime sleepiness Restless Legs Syndrome (RLS) is a common neurologic affecting waking function can be negatively affected by condition marked by the urge to move, particularly the the concomitant use of sedatives - particularly opiates legs, which occurs primarily at rest in the evening or and ethanol (Pagel 2017). In a subset of individuals with bedtime. The essential criteria for making the diagnosis OSA, breathing disruption contributes to disordered include: 1) The urge to move the legs, usually accom- sleep and insomnia. The treatment of OSA with positive panied or caused by uncomfortable and unpleasant sen- airway pressure (PAP) can improve sleep quality for such sations in the legs; 2) The urge to move or unpleasant individuals (Nigram et al. 2017). However for others, sensations begin or worsen with rest or inactivity; 3) The PAP therapy can exacerbate insomnia (particularly in urge to move or unpleasant sensations are partially or those patients with co-morbid PTSD) (Nigram et al. totally relieved by movement; 4) The urge to move or 2016). At altitude and in patients with concomitant Pagel et al. Sleep Science and Practice (2018) 2:5 Page 9 of 12 heart failure, PAP therapy can induce the development result of treating depression. Combining treatment with of complex / central apnea - a diagnosis associated with antidepressants with cognitive-behavioral therapy for in- significant complaints of insomnia (Pagel et al. 2011). somnia also demonstrated that the combined treatment was superior to the antidepressants alone both in terms Comorbid psychiatric disorders of depression outcome (61.5% vs 33.3% remission, re- Psychiatric disorders commonly comorbid with insomnia spectively) and insomnia outcome (50% vs 7.7% remis- include major depression, bipolar mood disorder, anxiety sion, respectively) (Manber et al. 2008). A similar result disorders, psychotic disorders, and amnestic disorders occurred with the use of eszopiclone with escitalopram such as Alzheimer’s disease. Estimates of the incidence for generalized anxiety disorder compared to the escita- of insomnia with these diagnoses are in the 50–75% lopram alone (Pollack et al. 2008). range (Grandner and Perlis 2015). The most common psychiatric association is with the diagnosis of depres- Comorbid pain sion in which insomnia and depression have a circular Chronic pain leads to poor sleep in a majority of patients or bidirectional relationship (Sateia and Nowell 2004). (Cheatle et al. 2016). Pain can be an acute or chronic There are several studies that show that insomnia pa- part of a broad range of medical ailments but most com- tients are at risk to develop depression. In a large study monly cancer, rheumatologic disorders and headache. of young adults over a period of 20 years, 2 weeks of in- Chronic pain and sleep disruption produce a cycle of somnia or longer predicted major depressive episodes pain causing poor sleep and poor sleep leading to greater and major depressive disorders (Buysse et al. 2008). Re- pain (Abad et al. 2008). Management is suggested as fol- current insomnia can also be the earliest sign that a pa- lows: diagnosis of the sleep problem, emphasis on sleep tient in remission from their depression is at risk of a hygiene and then CBT techniques followed by pharma- relapse (Breslau et al. 1996). Chronic insomnia problems cologic interventions including medications for both may contribute to the persistence of depression. This pain and insomnia (Riemann and Perlis 2009) In rheu- issue is of particular importance in light of the signifi- matologic disorders treatment of sleep with hypnotics or cant rate of residual sleep disturbance in persons who sedating antidepressants improves sleep but also im- have been otherwise successfully treated for depression proves pain tolerance. It should be noted that the United (Ohayon and Roth 2003). Insomnia persisting after treat- States is currently in the midst of an epidemic of opiate ment of depression can be the most refractory symptom use that is resulting in a large number of deaths. of depression. Drawing on data from a large interven- Hypnotics have reduced side-effects, less addiction po- tional study of enhanced care for depressed elderly per- tential, and much lower toxicity than the opiates often sons, the investigators found that persistent insomnia used to treat chronic pain. was associated with a 1.8 to 3.5 times greater likelihood of remaining depressed, compared with the population Other comorbid medical conditions without continued sleep disturbance (Perlis et al. 1997). Patients with respiratory problems often have disruption The relationship between insomnia and depression is of their sleep. COPD patients frequently have fragmen- further complicated by the fact that many common ted sleep (Crinion and McNicholas 2014). This can im- anti-depressants, especially the selective serotonin re- prove with oxygen if hypoxia is part of the problem. uptake inhibitors (SSRI’s), can induce disturbed sleep While Obstructive Sleep Apnea commonly induces day- (McCrae and Lichstein 2001). In patients with insomnia time sleepiness, it can induce disturbed sleep as well and a psychiatric diagnosis treatment options include (Talih et al. 2017). About a 1/3 of asthma patients who those also used for primary insomnia, either pharmaco- are poorly controlled have nocturnal asthma attacks that logic treatment, cognitive behavior treatment (psycho- interfere with their sleep and may lead to daytime symp- logical and behavioral) or a combination of both. toms. Patients with gastroesophageal reflux often have Eszopiclone has been studied in patients with major de- sleep disruption for the reflux. In addition, reflux can pression along with the simultaneous use of fluoxetine trigger asthma attacks in vulnerable patients. Patients (Fava et al. 2006). The combination was well tolerated with end-stage renal disease suffer from a variety of and resulted in a rapid improvement in sleep. Of note, sleep disorders with a very high prevalence (Parish there was also a more rapid and larger antidepressant re- 2009). These can include insomnia, sleep apnea and a sponse. This does not suggest an antidepressant effect of high incidence of secondary RLS. Menopause is associ- eszopiclone but rather suggests that improved sleep has ated with insomnia which can respond to treatment with a beneficial effect on depression. This makes a strong hormones but also with treatment using a hypnotic case for the comorbid approach to treatment, simultan- (Soares et al. 2006). Chronic neurological conditions in- eous treatment of the two entities rather than the trad- cluding Parkinsons disease are associated with signifi- itional approach of waiting for insomnia to improve as a cant insomnia, as are gastrointestinal disorders inducing Pagel et al. Sleep Science and Practice (2018) 2:5 Page 10 of 12 pain and/or reflux, nocturia and enuresis, and other Competing interests The authors declare that they have no competing interests. sleep associated disorders such as narcolepsy (Sateia et al. 2017). Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published The appropriate use of hypnotic and sedative medications maps and institutional affiliations. Sedative/hypnotic agents were among the first known Author details phamaceudical therapies. Many have had significant toxic- University of Colorado School of Medicine, Couthern Colorado Residency ities and side effects. Some with addictive potential have Program, Pueblo, CO, USA. Somnogen Canada Inc, College Street, Toronto, ON, Canada. School of Medicine Clinics Hospital, University of the Republic, developed into major drugs of abuse that continue to Montevideo, Uruguay. Rocky Mountain Sleep, 1306 Fortino Blvd, Pueblo, CO negatively effect our modern society. For the physician ad- 81008, USA. dressing the patient complaint of insomnia, these agents Received: 27 November 2017 Accepted: 24 May 2018 can be difficult to appropriately utilize. This brief overview argues that today there are medications with very low tox- icity, addictive potential, minimal next day sleepiness, and References Abad VC, Sarinas PSA, Guilleminault C (2008) Sleep and rheumatologic disorders. an otherwise benign side-effect profile that can be utilized Sleep medicine reviews 12(3) . safely and effectively to treat and improve function and Abbott S, Soca R, Zee P. Circadian Rhythm Sleep Disorders. 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Treating insomnia with medications

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Abstract

Insomnia is a conspicuous problem in modern 24 h society. In this brief overview, medications used to treat insomnia such as hypnotics, sedatives, medications inducing sedation as a side effect, medications directed at the sleep-associated circadian neuroendocrine system, and agents utilized in treating insomnia-inducing sleep diagnoses such as restless leg syndrome are discussed. The newer GABA-effective hypnotics are the only medications with demonstrated effectiveness in treating chronic insomnia with the majority of evidence supporting treatment efficacy for cognitive-behavioral therapy and short acting GABA-receptor agonists. In patients with comorbid insomnia the use of hypnotics can improve outcomes and potentially reduce morbidity and mortality associated with the use of more toxic medications. Except in individuals whose insomnia is secondary to circadian disturbance, mood disorder/depression and/or restless leg syndrome , there is minimal evidence supporting the efficacy of other medications used to treat insomnia despite their widespread use. Sedatives and other medications used off-label for sedative side-effects are a contributing factor to drug induced hypersomnolence, a factor in more than 30% of motor accident deaths. Hypnotic medications with low toxicity, addictive potential, minimal next day sleepiness, and an otherwise benign side-effect profile can be utilized safely and effectively to treat and improve function and quality of life for patients suffering from insomnia. These are the agents that should be exclusively classified as hypnotics and utilized to induce sleep when medications are required to treat the complaint of insomnia. Other pharmacological agents producing sedation (sedatives and agents used off-label for sedative side-effects) should be used cautiously for the treatment of insomnia due to the increased risk of next day sleepiness as well as for known toxicities and adverse side effects. Keywords: Insomnia, Medications, Hypnotics, Sedatives, Benzodiazepine Introduction of Clinical Sleep Medicine 2005). Chronic insomnia is Insomnia, defined as the subjective perception of diffi- significantly associated with a decrease in quality of life culty with sleep initiation, duration, consolidation, or measures, the exacerbation of co-morbid diagnoses, and quality that occurs despite adequate opportunity for an increased likely-hood for developing mood disorders sleep, is a conspicuous problem in modern 24-h society / de[ression (Sateia et al. 2017). While there are dozens (Sateia et al. 2017). Episodes of acute or transient insom- of insomnia-associated sleep diagnoses, any medical or nia each year affect > 80% of adults. Chronic insomnia psychiatric disorder or environmental stress that pro- (> 3 months in duration) includes difficulty falling asleep, duces nighttime discomfort is likely to induce insomnia. insufficient sleep, or perceived nonrestorative sleep pro- Medications for treating insomnia are classified as hyp- ducing daytime complaints of somnolence, fatigue, irrit- notics, sedatives, medications inducing sedation as a side ability, or difficulty concentrating and performing effect, medications directed at the sleep-associated circa- everyday tasks, and has a population prevalence of ap- dian neuroendocrine system, and agents utilized in treat- proximately 14 % (Hauri 2005; NIH State of the Science ing insomnia-inducing sleep diagnoses such as restless Conference Statement on Manifestations and Manage- leg syndrome (RLS) (Curry et al. 2006; Bhat et al. 2008). ment of Chronic Insomnia in Adults Statement, Journal * Correspondence: pueo34@gmail.com Sleep hygiene and cognitive behavioral therapies University of Colorado School of Medicine, Couthern Colorado Residency Sleep behaviors must be addressed for any patient pre- Program, Pueblo, CO, USA 4 senting with insomnia. Insomnia can be treated without Rocky Mountain Sleep, 1306 Fortino Blvd, Pueblo, CO 81008, USA Full list of author information is available at the end of the article medications, using sleep hygiene combined with © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pagel et al. Sleep Science and Practice (2018) 2:5 Page 2 of 12 cognitive and behavioral therapies (CBT). This approach neurotensin, muramyl peptides, endotoxins, cytokines avoids potential drug side effects and toxicities and has [interleukin-1B, tumor necrosis factor-α], interleukin 1B, shown long-term persistence in treating chronic insom- tumor necrosis factor-α (TNFα), prostaglandin D2 nia that can be superior to results obtained using drug (PGD2) and melanin concentrating hormone (MCH) therapies (Morin 2005). Sleep hygiene refers to environ- (García-García et al. 2009; Urade and Hayaishi 2011; mental factors, dietary approaches, drugs, and a lack of Pabst et al. 1999). Sedation is among the most common required sleep facilitating approaches that can induce in- effects and/or side effects of prescription medications. somnia. Insomnia inducing drugs include caffeine, nico- The list of agents inducing sedation as an effect and/or tine, weight loss preparations, and activating agents of side effect is extensive and includes most medication both prescription and abuse. CBT extends sleep hygiene classifications (Table 1) (Pagel 2017). Sedation is com- into the use of sleep facilitating cognitive and behavioral monly induced by over the counter (OTC) preparations approaches for treating insomnia (Finley and Perlis (particularly anti-histamines), and commonly used drugs 2014). CBT has proven its usefulness in treating chronic of abuse such as cannibis and ethanol. When the use of insomnia, working best when administered by a trained Table 1 Medications Not Classified As Sedative/Hypnotics provider over several extended visits (Riemann and Inducing Daytime Sleepiness As A Side Effect Perlis 2009). Insomnia treatment can be limited to the Medication Class Neurochemical Basis For Sleepiness use of hygiene and CBT, but such an approach has clear Antiparkinsonian Agents Dopamine Receptor Agonists limitations. Behavioral approaches are rarely effective in Antimuscarinic/ Antispasmodic Varied effects treating acute and transient episodes of insomnia and have limited usefulness in treating comorbid insomnia. Skeletal Muscle Relaxants Varied Effects CBT requires patient interest and effort and as a clinical Alpha- Adrenergic Alpha-1 Adrenergic Antagonists approach is unavailable to many affected individuals due Blocking Agents to both cost and limitations in provider access (Lichstein Beta-Adrenergic Beta Adrenergic Antagonists Blocking Agents et al. 2005). Even when appropriately utilized, CBT does not work for every patient (Trauer et al. 2015). Gamma-Hydroxy-Butyrate GABA Agonist Opiate Agonists Opioid Receptor Agonists Sleep neurophysiology (General Cns Depression) From a behavioral stand-point, sleep is a complex, re- Opiate Partial Agonists Opioid Receptor Agonists (General Cns Depression) versible behavioral state of perceptual disengagement from, and unresponsiveness to, the environment Anticonvulsants (Carskadon and Dement, 2011). To this point, no specific Barbiturates GABA Agonist anatomical site or required neurochemical trigger has been –Benzodiazepines GABA Agonist identified. Neuroanatomical structures in the CNS are - Hydantoins Neurotransmitter effect poorly defined - affected globally by sleep associated changes in neurochem- electrophysiolic? ical, electrophysiological and neuroendocrine systems. - Succinimides Neurotransmitter effect poorly defined - electrophysiolic? The neurochemistry of sleep Other Antidepressants Sleep is a global state involving multiple factors and sys- - Maoi Norepinephrine, 5ht & Dopamine tems, with no single neurochemical identified as neces- - Ssri Serotonin Uptake Inhibition sary for modulating sleep (Brown et al. 2012). In most -Agents With Mixed Effects Serotonin, Dopamine, & Norepinephrine cases, the CNS effects of drugs can be ascribed to pri- mary effects on specific neurotransmitters and neuromo- Other Antipsychotics Dopamine Receptor Blockage, Varied Effects On Histaminic, Cholinergic dulators. Most hypnotics affect GABA, the primary And Alpha Adrenergic Receptors negative neurotransmitter in the CNS, or affect specific Other Benzodiazepines GABA Agonist neuromodulators of GABA that include serotonin, Not Used For Sedation acetylcholine, and dopamine (Pagel 2017). Other drugs, Anxiolytics, misc. Sedative GABA Agonist, Varied Effects particularly those classified as sedatives, induce sedation & hypnotics by antagonizing one or more of the central activating Antitussives Neurotransmitter Effect Poorly Defined neuromodulators. These activating neuromodulators in- Antidiarrhea agents Neurotransmitter Effect Poorly Defined - clude serotonin, norepinephrine, histamine, acetylcho- Opioid In Some Cases line, dopamine, and orexin. Other substances known to Antiemetics Antihistamine & Varied Effects affect sleep include adenosine, substance P, cortico- Genitourinary Smooth Neurotransmitter Effect Poorly Defined trophin releasing factor (CRF), thyrotrophin releasing Muscle Relaxants factor (TRF), vasoactive intestinal peptide (VIP), Pagel et al. Sleep Science and Practice (2018) 2:5 Page 3 of 12 these agents is coupled with the use of sedating prescrip- movements and diminished skeletal EMG activity. Medi- tions, additive sedation, toxicity, and side-effects increase cations producing CNS-related behavioral effects generally the danger of life-threatening over-dose (National Insti- affect background EEG frequencies (Mamdema and Dan- tue on Drug Abuse: National Institutes of Health 2015). hof 1992). In most cases, a consistent pattern of EEG change produced by a drug is associated with a consistent The electrophysiology of sleep pattern of behavioral change (Hermann and Schaerer In the clinical laboratory, sleep is defined by its electro- 1986). Psychoactive drugs produce alterations in physio- encephalography (EEG) in concert with electromyog- logic EEG rhythms consistent across therapeutic classifica- raphy (EMG), electrooculography (EOG) and other tions and utilized to predict the behavioral activity of new telemetry. Using polysomnographic recordings, sleep can preparations, drug interactions and toxicities (Blume be classified into rapid eye movement (REM) sleep and 2006)(Table 2). non-rapid eye movement (NREM) sleep. The NREM sleep is further classified into 3 sleep stages namely The neuroendocrinology of sleep Stage N1 sleep, Stage N2 sleep, and stage N3 sleep (also Sleep regulation is a complex interaction between the known as slow wave sleep, delta sleep or deep sleep), homeostatic and the endogenous circadian processes based primarily on the occurrence of synchronous (Borbély et al. 2016). The circadian processes of sleep physiologic EEG potentials. Drowsy awake with eyes are largely controlled by the suprachiasmatic nucleus closed is defined by the presence of alpha - the fre- (SCN) in the hypothalamus (Dai et al. 1998; Hofman et quency with the most power on spectral analysis. Sleep al. 1996; Swaab et al. 1985; Vimal et al. 2009). This in- onset (Stage N1) is generally defined as occurring at the ternal human clock responds to external factors with the point in which there is a decline of alpha rhythm (9– greatest influence being exposure to light/dark (LD) 11 Hz) to less than 50% of the recorded epoch. Stage N2 cycle (Lewy et al. 1980; Morin 2015). The other import- sleep is denoted by bursts of sleep spindles at sigma fre- ant element to the timing of the sleep/wake cycle is the quency (11–16 Hz) and K-complex events - electro- endogenously produced neural hormone melatonin, pro- physiological down states known to negatively affect the duced by the pineal gland in response to signals from general tendency of neurons to develop spike potential the SCN. Melatonin can induce sedation, an effect activity (Cash et al. 2009). Deep sleep (stage N3 sleep) oc- sometimes utilized to assist children in tolerating med- curs in association with delta frequency oscillations (0.5– ical procedures (Johnson et al. 2002). In addition to 1.5 Hz). REM sleep is characterized by bursts of intracra- regulation of the sleep/wake cycle, body temperature nial theta (5–8 Hz), with alpha and gamma oscillations and numerous other processes vary with circadian noted in scalp recordings, associated with conjugate eye rhythm (Sack et al. 2007). Externally introduced Table 2 Consistent quantitative alteration in physiologic EEG frequencies induced by psychoactive medications Class of drugs Eeg frequencies Treatment indications Delta Theta Alpha Sigma Beta/Gamma (0.5–1.5 Hz) (5.5–8.5 Hz) (8.5–11 Hz) (12–16 Hz) (21–32 Hz) Benzodiazepines (BZDs) Decrease Increase Increase Anxiety Sedation Barbiturates Increase Increase Anxiety Sedation Epilepsy Tricyclic Antidepressants (TCAs) decrease Decrease Increase Depression SSRI Antidepressants decrease Increase Depression Anxiety OCD Amphetamines decrease Decrease increase Somnolence Narcolepsy AD/HD Opiates increase decrease Pain Anticonvulsants increase Epilepsy Phenytoin, valproate, carbamazepine Gamma hydroxy butyrate (GHB) increase Cataplexy Narcolepsy Classic Neuroleptics increase decrease decrease Schizophrenia Psychosis Pagel et al. Sleep Science and Practice (2018) 2:5 Page 4 of 12 melatonin can be utilized to reset circadian rhythms of 1989). In the 1990’s newer agents were developed and sleep and body core temperature through its actions on marketed that had selective effects on GABA receptors in- the SCN (Abbott et al. 2014). cluding Zolpidem (Ambien), Zaleplon (Sonata), Eszopi- clone (Estorra) and Indiplon. While all hypnotics have The optimal hypnotic abuse potential for individuals with addictive histories and Sleep-inducing drugs (hypnotics) are medications specif- personalities, these agents have been noted to have min- ically designed to induce sleepiness directly after intake. imal additive potential (Hajak et al. 2003). These agents Optimal agents affect cognitive performance during this are less likely to have deleterious side effects than most period while inducing minimal sleepiness in the waking OTC treatments for insomnia, however, with increased day after use. An optimal hypnotic would have low tox- use, more side effects including next effects on driving icity and addictive potential, as well a minimal side effect have been reported. This effect as well as next day re- profile (Oswald 1970). Among the first hypnotics, and bound insomnia has particularly been reported for higher an agent still in use is chloral hydrate - the original doses of zolpidem (Verster et al. 2002). In many cases, “Mickey Finn” - slipped into the drinks of unsuspecting MVA’s occurred in the period of somnolence and cogni- marks for the purposes of criminal activity. Unfortu- tive impairment during the first few hours after ingestion. nately, this medication is difficult to use since the LD-50 Comparatively normal results on psychomotor tests can (potentially fatal dose) is quite close to the therapeutic be obtained 3.25 h. after zaleplon ingestion and 6.25 h. dose. In the years leading up to the 1970’s, rapidly acting after zopiclone ingestion (Paul et al. 2003). While these barbiturates were commonly utilized for their hypnotic agents have excellent efficacy with minimal side effects, at effects. Unfortunately, these medications, also drugs of higher doses these agents can exhibit benzodiazepine-like abuse, had a significant danger of overdose and contrib- effects. Idiosyncratic reactions of persistent daytime som- uted to an era that was characterized in part by deaths nolence and/or memory loss have been reported. Some due to overdoses of sleeping pills. These medications patients will report next day sedation after the nighttime and similar barbiturate-like medications [Methaqualone use of these agents, as well as demonstrate an increased (Quaalude, Sopor) Glutethimide (Doriden), Ethchlor- error rate in driving tests (Verster et al. 2007). Such infor- vynol (Placidyl), Methyprylon (Nodudar)] have limited mation was forthcoming only after these drugs became availability and are rarely used due to limited efficacy, generic and widely utilized in clinical practice. Most sedat- cognitive effects, the potential for abuse and lethal tox- ing drugs if adopted into such widespread use would also icity associated with overdose (Oswald 1970). Today be at least as likely to demonstrate epidemiological effects their primary therapeutic uses include executions and fa- on MVA’s and MVA associated deaths. In the elderly, cilitated euthanasia (Lossignol 2008). chronic use of sedating drugs (particularly those with Most currently utilized hypnotics affect the widely dis- anti-cholinergic side effects) can be associated with an persed negative neurotransmitter GABA. In the 1970’s increased risk for falls, and confusion (American benzodiazepines (GABA agonists) were first marketed as Geriatrics Society 2015). Reported next day sleepiness hypnotics. Some of these agents had an extremely short and other side effects associated with hypnotic use duration of action [Triazolam (Halcion)]. While this are summarized in Table 3. agent-induced minimal next day somnolence, use was as- The newer GABA-effective hypnotics are the only sociated with daytime memory impairment, particularly at medications with demonstrated effectiveness in treating higher dosages (Roehrs et al. 2000; Adam and Oswald chronic insomnia (NIH State of the Science Conference Table 3 Hypnotics - Agents Utilized To Induce Sleep With Minimal Next Day Sleepiness After Used Based On Pharmacodynamics, Clinical Trials, And/Or Performance Testing Drug & Class 1/2 Life Next Day Sleepiness [Clinical Trials] Toxicity And/Or Significant Side Effects Short acting gaba agonist 1–2 HR. Anecdotal and per survey Antegrade Amnesia, Confusion At Higher Dose - triazolem [placebo Equivalent] GABA selective agents 1 HR. [Placebo No consistent reports - zaleplon Equivalent] [not in widespread use] Zolpidem 1.5 HR. Anecdotal [placebo Symptomatic Equivalent] Parasomnias, Per survey when dosed outside Next night rebound insomnia pharmacodynamic profile and in the elderly Eszopiclone 6 HR. Anecdotal Possible Parasomnia Associations [placebo [Agent Not In Widespread Generic Use] Equivalent] Pagel et al. Sleep Science and Practice (2018) 2:5 Page 5 of 12 Statement on Manifestations and Management of in sedation. Some of these agents had active breakdown Chronic Insomnia in Adults Statement, Journal of products that produced an extraordinarily long active Clinical Sleep Medicine 2005). According to the NIH, half-life (11 days) (Oswald 1970). The prolonged effect is the majority of evidence supports the efficacy of one of waking calming and sedation, associated with in- cognitive-behavioral therapy and short acting benzodi- creased auto accidents and falls with hip fractures. azepine receptor agonists in the treatment of chronic in- Medium 1/2 life agents including alprazolam, temaze- somnia, at least in the short term. Chronic insomnia is pam, and lorazepam affect next day performance tests often, however, a lifelong illness, and the longest clinical (Ray et al. 1989). The use of these agents may be associ- trials for these agents have been one year in duration. ated with an increased level of next day MVA’s (Ceutel These agents can be safely utilized chronically or in an 1995; Buysse 1991). “as needed” (prn) basis in individuals with both short Other sedating agents affect the GABA neuromodua- and long term insomnia (Morin and Espie 2003; tors - acetylcholine, dopamine, and serotonin. Most of Schutte-Rodin et al. 2008). Except in individuals whose these agents are classified as sedating antidepressants. insomnia is secondary to circadian disturbance, mood Sedating antidepressants include the tricyclics (amitryp- disorder/depression and/or restless leg syndrome, there tiline, imipramine, nortriptyline, etc.), and atypical anti- is minimal evidence supporting the efficacy of other depressants: Trazodone (Deseryl), and Mirtazapine medications used to treat insomnia despite their (Remeron). Trazondone is among the most widely pre- widespread use (NIH State of the Science Conference scibed agents for inducing sleep. There are few studies Statement on Manifestations and Management of Chronic addressing the efficacy this off-label approach to treating Insomnia in Adults Statement, Journal of Clinical Sleep insomia, but there are more describing trazadone’s sig- Medicine 2005; Morin, Medalie and Cifu 2017). nificant side-effects including next day sleepiness and psychomotor impairment in the elderly (Mendelson Sedatives 2005). Among the SSRI’s, Paroxetine (Paxil) can induce Sedatives induce calming and reduce arousal during mild sedation. Use of sedating antidepressants has been waking. At the extreme end of the spectrum of use, associated with declines in daytime performance, driving sedative agents are utilized in anesthesia. The sedative test performance, and an increased potential for involve- category included the opiates, a drug class developed ment in motor vehicular accidents (Volz and Sturm from the domesticated poppy with evidenced utilization 1995). Both tricyclic and atypical antidepressants are from neolithic archeologic sites (5000–7000 B. C.) widely used as a hypnotics despite significant next day (Heinrich 2013). At the dawn of medicine as a specialty, sedation (Settle 1998). among the few agents useful as a medication was Many of the sedating medications treat hyperarousal laudanum - a tincture of opium that mixed with water by antagonizing the wake-producing neuromodulating or wine was used as a soporific even for crying infants. systems: serotonin, norepinephrine, dopamine, hista- Most sedative drugs selectively affect specific neuro- mine, and orexin. Both prescription and over the coun- transmitters and neuromodulators in the CNS (Schwartz ter (OTC) agents are marketed for sedative effects 2000). Multiple factors and systems are involved. Seda- produced pharmacologically by antagonizing orexin, his- tive drugs can exert primary effects either at the inhibi- tamine, and norepinephrine. tory neurotransmitter gamma-Aminobutyric acid Antihistamines and antipsychotics induce sedation (GABA), or on sedating neuromodulators. Others po- based on their antihistaminic effects (Monti et al. 2016). tentiate sedation by antagonizing one of the widely dis- Over the counter sleeping pills contain sedatingH-1 anti- persed central activating neuromodulators: serotonin, histamines, usually diphenhydramine, hydroxyzine or norepinephrine, dopamine, histamine, and orexin. triprolidine (Monti and Monti 2000). These agents in- Many patients suffering from chronic insomnia are duce sedation with acute use, and often induce increased hyperaroused, unable to fall asleep even after minimal daytime sleepiness and cognitive impairment persisting sleep the night before. Treatment of this hyperarousal into the day following nighttime use (O’Hanlon and presenting clinically as agitation and sometimes anxiety Ramaekers 1995). In comparative studies, driving per- can produce improved sleep. Unfortunately, sedation formance at 2.5 h. after administration of 50 mg. of di- and reduced arousal are variants of the same cognitive phenhydramine is worse than in individuals with a blood calming effect. Because of this, sedatives induce daytime alcohol concentration (BAC) of 0.1% - the level of legal sleepiness in many users. The idea sedative agent, like intoxication in most states (Wiler et al. 2000). Nighttime the ideal hypnotic, should have low toxicity, low addic- drug use can produce drowsiness severe enough to affect tion potential, and a benign side effect profile. next day performance and driving tests (Gango et al. Fifty years ago, longer acting benzodiazepines, particu- 1989). Sedation is infrequent with H2 antagonists (e.g. larly Diazepam (Valium) preempted the role of opiates cimetidine, ranitidine, famotidine, and nizatidine), but Pagel et al. Sleep Science and Practice (2018) 2:5 Page 6 of 12 somnolence as a side effect is reproducible in susceptible Clinically these agents are sometimes used off-label for individuals (White and Rumbold 1988). Sedation is a com- their sedative effects. Among antihypertensives in wide mon side effect of the traditional antipsychotics, with use, the complaints of tiredness, fatigue and daytime chlorpromazine and thioridazine somewhat more sedating sleepiness are commonly associated with drugs having than haloperidol. Clinical studies have shown a high inci- antagonistic effects at the norepinephrine neuroreceptor dence of persistent sedation with clozapine (46%) with less (Dimsdale 1992). The complaints of tiredness, fatigue frequent reports of sedation with risperidone, olanzapine, and daytime sleepiness (2–4.3%) associated with sertindole and quetiapine (Monti et al. 2016). The sed- beta-blocker use may occur secondary to disturbed sleep ation associated with these agents is most likely associated or direct action of the drug. Beta-blocking drugs with with their known effects on histaminic receptors. vasodilating properties (e.g. carvedilol, labetalol) are also Doxepin, a sedating psychotropic agent with pro- associated with reported fatigue and somnolence nounced histamine (H-1) receptor antagonism exerts at (3–11%). Sedation is among the most common side ef- least part of its effects by antagonizing orexin (Krystal et fects reported for the alpha-2 agonists clonidine and al. 2013). Suvorexant, is an orexin antagonist designed methyldopa (30–75%) (AHFS 2003). Alpha-1 antagonists to lower waking arousal (Norman and Anderson 2016). (e.g. terazosin, prazosin) are sometimes associated with Currently, it is being heavily marketed as a hypnotic transient sedation. Prazosin, a norepinephine antagonist, (Rhyne and Anderson 2015). As based on performance has demonstrated value in treating insomnia associated and driving tests, this agent is known to produce a with PTSD nightmares (Raskind et al. 2003). Clonidine dose-related next day increase in somnolence for all age is sometimes utilized to treat the agitation and insomnia groupings tested (Farkus 2013). Sedative drug effects on that result from using amphetamines to treat AD/HD in daytime sleepiness are summarized in Table 4. pediatric patients (Ming et al. 2011). Sedation is a common side effect induced by Other agents inducing sedation anti-epileptic drugs, reported at levels of 70% with phe- Many other agents induce significant sedation as part of nobarbitol, 42% with carbamazepine and valproate, and their clinical effect or as an untoward side-effect. in 33% of patients using phenytoin and primidone Table 4 Sedatives - Agents Used To Induce Sleep And Sedation With Significant Next Day Sleepiness After Used Based On Pharmacodynamics, Clinical Trials, And/Or Performance Testing CLASS (DRUG) [Neuromodulator Effected] 1/2 LIFE Next Day Sleepiness Next Day Effects On Toxicity And/Or [Clinical Trials] Performance & Driving Tests Significant Side Effects Antidepressants 10–20 HR. Significant Significant With Anticholinergic, - tricyclics (amitriptyline etc.) Minimal Study Respiratory suppression [serotonin] in overdose - Atypicals traza- done (8 h) Significant Significant With Respiratory Suppression (trazadone, mirtazapine) mirtaza-pin 20–40 HR. Minimal Study In Overdose [serotonin] H1 antihistamine 2–12 HR. Significant Significant - Confusion [Black Boxed Diphinhydramine, Multiple studies For The Elderly] hydroxyzine, triprolidine) [histamine] Antipsychotic 6–8 HR. Significant Significant with Potentially persistent - Olanzapine minimal study extra-pyramidal [histamine] Side effects - Doxepin 1/2–15 h. (dose based) Significant Significant With Potentially persistent [histamine, orexin] active metabolite Minimal Study extrapyramidal Side effects Gaba agonists 7–10 HR. Significant Significant Disinhibition - medium ½ life benzodiazepi-nes Multiple studies (estalolam, clonazepam, temezepam, etc.) [GABA] - Long ½ life benzodiazepi- nes Up To 11 Days Significant Significant Disinhibition (flurezepam, diazepam, etc.) Multiple studies Falls in the elderly [GABA] Orexin antagonists 10–22 HR. Significant Significant Unknown (suvorexant) New agent [orexin] Key: the term “Significant” indicates comparison to placebo or hypnotics Pagel et al. Sleep Science and Practice (2018) 2:5 Page 7 of 12 (Schweitzer et al. 2003). In clinical trials sedation is has increasingly become a problem. In 1993, about one reported as a side effect to treatment with topiramate in eight drivers were using more than one drug, but by (15–27%) at at levels of 5–10% for gabapentin, lamotri- 2010, it was closer to one in five. The number of drivers gine, vigabatrin, and zonisamide (AHFS 2003). The dying in MVA’s with three or more sedating drugs in neurochemical basis for the sedation induced by many their system increased from 11.5 to 21.5% during this of these agents remains poorly defined except for those period. Among drivers who tested positive for any drug, agents know to have GABA agonist effects (e.g. gabapen- 48% also tested positive for alcohol (Disney et al. 2011). tin, phenobarbitol) (Westbrook 2000). Some drugs may act by glutamate antagonism and others by having direct Comorbid insomnia effects on CNS electrophysiology (Pagel 1996). In indi- The term secondary insomnia has historically been ap- viduals being treated with such medications for seizure plied to patients with insomnia associated with either a disorders, the clinical differential between medication ef- medical or psychiatric condition or a primary sleep dis- fects and sedation secondary to recurrent seizures can order. Until 2005 the NIH guidelines regarded such in- be difficult to determine (Manni and Tartara 2000). somnia as being a consequence of the primary diagnosis. Almost all drugs with CNS activity induce sleepiness This led to recommendations that indicated the key was as a side effect in some patients (Bittencourt et al. 2005; treating the primary or underlying condition with the as- Guilleminault and Brooks 2001). The sedative side ef- sumption that this would, in turn, lead to resolution of fects of some of these agents are clinically utilized in insomnia. In 2005 the NIH convened another “State of specific situations. However, sleepiness is a common and the Science” conference to review the manifestations often-unwanted side effect for many types of prescrip- and management of chronic insomnia (NIH State of the tion medications including commonly used antitussives, Science Conference Statement on Manifestations and skeletal muscle relaxants, antiemetics, antidiarrheal Management of Chronic Insomnia in Adults Statement, agents, genitourinary smooth muscle relaxants, and Journal of Clinical Sleep Medicine 2005). The committee others (Table 1). These sedative side effects can limit the concluded that most cases of insomnia are comorbid use of these agents in patients in which the level of per- with other conditions. The concern over continuing to sistent daytime sleepiness affects waking. All sedating use the term “secondary” insomnia is that in many cases agents can contribute to an increased risk for motor ve- we do not have clear proof of cause and effect and, of hicular accidents. greater concern; the use of the term may lead to under-treatment of insomnia. This recommendation to Drug induced Hypersomnolence view insomnia as comorbid has to lead to a shift in treat- Drug induced hypersomnolence is a significant problem ment paradigms. While identification and treatment of in today’s society. Approximately 30% of traffic deaths in the “primary” condition remain a priority, concurrent the United States can be attributed at least in part to the treatment of insomnia is now viewed as desirable. In use of ethanol - the most commonly abused sedating general treatment of comorbid insomnia is now essen- medication (Department of Transportation (US), Na- tially the same as treating primary insomnia with a tional Highway Traffic Safety Administration (NHTSA) growing number of studies confirming that this ap- 2015). Sedating drugs other than ethanol are contribut- proach is effective (Morin and Benca 2012; Sateia and ing factors in 16% of motor vehicular accidents (Berning Nowell 2004; Winkelman 2015). Treatment of insomnia et al. 2015).While not nearly as great a risk factor for can often improve the symptoms of the “primary” or a driving as alcohol, marijuana may nearly double the risk comorbid condition. of having a vehicle collision (Sewell et al. 2009). In the United States, marijuana users are about 25% more likely Circadian system disturbances to be involved in an MVA than drivers with no evidence Sleep disorders related to circadian rhythm are caused of marijuana use (Compton and Berning 2015). by a misalignment of the approximately 24-h endogen- The prescription and OTC medications known to in- ous circadian rhythm and the “normal” 24 h day/night crease the risk of sleepiness-related crashes include lon- cycle (Melatonin can act as a hypnotic and is a useful ger acting benzodiazepine anxiolytics, sedating adjunct to treatment in individuals with circadian dis- antihistamines (H1 class), and tricyclic antidepressants turbance (Pandi-Perumal et al. 2008). Prescription syn- (TCAs). The risks are higher with higher drug doses and thetic analogs of melatonin such as ramelteon are for people taking more than one sedating drug simultan- available. Sleep tendency and reduced sleep latency are eously (Ceutel 1995; Gengo and Manning 1990;Van affected from 1 3/4–4 3/4 h post ingestion (Stone et al. Laar et al. 1995). Since a high percentage of the popula- 2000). Melatonin has been used as a hypnotic with in- tion uses drugs of abuse as well as medications for consistent results (Monti et al. 2013). The impact of this underlying illness, the use of multiple sedating drugs use agent on next day performance is generally considered Pagel et al. Sleep Science and Practice (2018) 2:5 Page 8 of 12 to be minimal. Next day psychomotor test results may unpleasant sensations are worse in the evening (Verma not be affected, although one study has demonstrated and Kushida 2014). Sleep disruptionand complaints of de- significant effects on next day deviation of lateral pos- creased quality of life is present in 3/4 of the patients with ition in driving tests (Mets et al. 2011). thesyndrome(Allenand Earley 2001). A majority of RLS Melatonin and light exposure have proven especially patients will have repetitive periodic limb movements effective when used to treat Delayed Sleep Phase Syn- (PLMS) on polysomnogram. The RLS/PLMD has a genetic drome most prevalent in adolescents and young adults basis and increases with age so that in the geriatric popula- (Pandi-Perumal et al. 2008). Patients with this syndrome tion (> 80 years) over 30% of individuals may meet criteria have difficulty falling asleep at the desired bedtime, often for the diagnosis. RLS/PLMD is also more common in chil- falling asleep between 2 and 6 AM and then, if their life- dren with AD/HD, patients in renal failure, individuals with style permits, sleeping approximately a normal 8 h, low serum ferritin levels (< 50), and in patients taking some awakening at between 10 AM and 2 PM. Individuals medications such including antidepressants, antiemetics with this common disorder often suffer from chronic in- and antihistamines (Phillips et al. 2006). sufficient sleep time with all its daytime consequences. The treatment of the sleep disruption, primarily sleep Treatment involves exposure to bright light at the onset, relies predominately on the treatment of the RLS proper time in the circadian phase response curve. In rather than the treatment of resultant insomnia. the case of delayed phase syndrome, this is after the Dopaminergic agonists have become the primary initial nadir of body temperature. Treatment with 10,000 lx for treatment for RLS. Pramipexole and ropinirole have both 30 min on awakening and timed melatonin administra- received FDA approval for this indication and are used tion in the early evening 3–6 h before sleep time (before in doses low relative to their use for Parkinson’s Disease. the Dim Light Melatonin Onset (DLMO) or 12+ hours Pramipexole is used in a range of 0.125 to 2 mg and before the temper nadir are effective. Since melatonin ropinirole at 0.25 to 4 mg. Dopaminergic agents, espe- can be soporific so caution needs to be exercised if used cially pramipexole, can induce significant somnolence as when the patient has wakeful activities to perform. Ad- well as sleep attacks in some individuals (Micalief et al. vanced Sleep Phase Syndrome (ASPS) is the mirror 2009). Benzodiazepines have been used, historically clo- image of DSPS with patients sleep onset and awakening nazepam but also temazepam. There are no recent stud- both several hours earlier than desired with the total ies of the efficacy of these but historically they have been sleep period remaining fairly normal. This is less com- useful and still have a role when side effects limit the mon than DSPS and tends to occur more in use of the dopaminergic agents or in combination in re- middle-aged to elderly adults. Treatment options are fractory cases. When lack of response or side effects are similar to those for delayed phase syndrome with the still present opioids with significant addictive potential timing of treatment designed to delay rather than ad- in this situation such as codeine or oxycodone are some- vance the circadian rhythm. In shift workers, melatonin times utilized (Comella 2014). Gabapentin, and pregablin can be used to help shift the worker’s circadian rhythm used off-label to treat RLS/PLMD induce significant as required. When taken before bedtime in the early hypersomnolence, interact with opiates, and have been de- morning it can improve sleep quality. For individuals suf- scribed as drugs of abuse (Schifarno 2014). A varient of fering from Jet Lag Disorder melatonin can be used to these agents, the alpha-2-delta ligand gabapentin enacarbil speed the adjustment to the new time zone (Brown et al. recently approved as a treatment for RLS is known to in- 2009; Srinivasan et al. 2010). Visually blind and incarcer- duce significant sedation and dizziness (Lee et al. 2011). ated individuals can have non-24 h. and free-running cir- cadian patterns that can be responsive to melatonin Insomnia associated with sleep apnea and its treatment agonists such as tasimelteon (Neubauer et al. 2015). Obstructive sleep apnea (OSA) induces daytime sleepi- ness in a significant percentage of affected individuals. Restless legs syndrome and periodic leg movement disorder Both apnea severity and the level of daytime sleepiness Restless Legs Syndrome (RLS) is a common neurologic affecting waking function can be negatively affected by condition marked by the urge to move, particularly the the concomitant use of sedatives - particularly opiates legs, which occurs primarily at rest in the evening or and ethanol (Pagel 2017). In a subset of individuals with bedtime. The essential criteria for making the diagnosis OSA, breathing disruption contributes to disordered include: 1) The urge to move the legs, usually accom- sleep and insomnia. The treatment of OSA with positive panied or caused by uncomfortable and unpleasant sen- airway pressure (PAP) can improve sleep quality for such sations in the legs; 2) The urge to move or unpleasant individuals (Nigram et al. 2017). However for others, sensations begin or worsen with rest or inactivity; 3) The PAP therapy can exacerbate insomnia (particularly in urge to move or unpleasant sensations are partially or those patients with co-morbid PTSD) (Nigram et al. totally relieved by movement; 4) The urge to move or 2016). At altitude and in patients with concomitant Pagel et al. Sleep Science and Practice (2018) 2:5 Page 9 of 12 heart failure, PAP therapy can induce the development result of treating depression. Combining treatment with of complex / central apnea - a diagnosis associated with antidepressants with cognitive-behavioral therapy for in- significant complaints of insomnia (Pagel et al. 2011). somnia also demonstrated that the combined treatment was superior to the antidepressants alone both in terms Comorbid psychiatric disorders of depression outcome (61.5% vs 33.3% remission, re- Psychiatric disorders commonly comorbid with insomnia spectively) and insomnia outcome (50% vs 7.7% remis- include major depression, bipolar mood disorder, anxiety sion, respectively) (Manber et al. 2008). A similar result disorders, psychotic disorders, and amnestic disorders occurred with the use of eszopiclone with escitalopram such as Alzheimer’s disease. Estimates of the incidence for generalized anxiety disorder compared to the escita- of insomnia with these diagnoses are in the 50–75% lopram alone (Pollack et al. 2008). range (Grandner and Perlis 2015). The most common psychiatric association is with the diagnosis of depres- Comorbid pain sion in which insomnia and depression have a circular Chronic pain leads to poor sleep in a majority of patients or bidirectional relationship (Sateia and Nowell 2004). (Cheatle et al. 2016). Pain can be an acute or chronic There are several studies that show that insomnia pa- part of a broad range of medical ailments but most com- tients are at risk to develop depression. In a large study monly cancer, rheumatologic disorders and headache. of young adults over a period of 20 years, 2 weeks of in- Chronic pain and sleep disruption produce a cycle of somnia or longer predicted major depressive episodes pain causing poor sleep and poor sleep leading to greater and major depressive disorders (Buysse et al. 2008). Re- pain (Abad et al. 2008). Management is suggested as fol- current insomnia can also be the earliest sign that a pa- lows: diagnosis of the sleep problem, emphasis on sleep tient in remission from their depression is at risk of a hygiene and then CBT techniques followed by pharma- relapse (Breslau et al. 1996). Chronic insomnia problems cologic interventions including medications for both may contribute to the persistence of depression. This pain and insomnia (Riemann and Perlis 2009) In rheu- issue is of particular importance in light of the signifi- matologic disorders treatment of sleep with hypnotics or cant rate of residual sleep disturbance in persons who sedating antidepressants improves sleep but also im- have been otherwise successfully treated for depression proves pain tolerance. It should be noted that the United (Ohayon and Roth 2003). Insomnia persisting after treat- States is currently in the midst of an epidemic of opiate ment of depression can be the most refractory symptom use that is resulting in a large number of deaths. of depression. Drawing on data from a large interven- Hypnotics have reduced side-effects, less addiction po- tional study of enhanced care for depressed elderly per- tential, and much lower toxicity than the opiates often sons, the investigators found that persistent insomnia used to treat chronic pain. was associated with a 1.8 to 3.5 times greater likelihood of remaining depressed, compared with the population Other comorbid medical conditions without continued sleep disturbance (Perlis et al. 1997). Patients with respiratory problems often have disruption The relationship between insomnia and depression is of their sleep. COPD patients frequently have fragmen- further complicated by the fact that many common ted sleep (Crinion and McNicholas 2014). This can im- anti-depressants, especially the selective serotonin re- prove with oxygen if hypoxia is part of the problem. uptake inhibitors (SSRI’s), can induce disturbed sleep While Obstructive Sleep Apnea commonly induces day- (McCrae and Lichstein 2001). In patients with insomnia time sleepiness, it can induce disturbed sleep as well and a psychiatric diagnosis treatment options include (Talih et al. 2017). About a 1/3 of asthma patients who those also used for primary insomnia, either pharmaco- are poorly controlled have nocturnal asthma attacks that logic treatment, cognitive behavior treatment (psycho- interfere with their sleep and may lead to daytime symp- logical and behavioral) or a combination of both. toms. Patients with gastroesophageal reflux often have Eszopiclone has been studied in patients with major de- sleep disruption for the reflux. In addition, reflux can pression along with the simultaneous use of fluoxetine trigger asthma attacks in vulnerable patients. Patients (Fava et al. 2006). The combination was well tolerated with end-stage renal disease suffer from a variety of and resulted in a rapid improvement in sleep. Of note, sleep disorders with a very high prevalence (Parish there was also a more rapid and larger antidepressant re- 2009). These can include insomnia, sleep apnea and a sponse. This does not suggest an antidepressant effect of high incidence of secondary RLS. Menopause is associ- eszopiclone but rather suggests that improved sleep has ated with insomnia which can respond to treatment with a beneficial effect on depression. This makes a strong hormones but also with treatment using a hypnotic case for the comorbid approach to treatment, simultan- (Soares et al. 2006). Chronic neurological conditions in- eous treatment of the two entities rather than the trad- cluding Parkinsons disease are associated with signifi- itional approach of waiting for insomnia to improve as a cant insomnia, as are gastrointestinal disorders inducing Pagel et al. Sleep Science and Practice (2018) 2:5 Page 10 of 12 pain and/or reflux, nocturia and enuresis, and other Competing interests The authors declare that they have no competing interests. sleep associated disorders such as narcolepsy (Sateia et al. 2017). Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published The appropriate use of hypnotic and sedative medications maps and institutional affiliations. Sedative/hypnotic agents were among the first known Author details phamaceudical therapies. Many have had significant toxic- University of Colorado School of Medicine, Couthern Colorado Residency ities and side effects. Some with addictive potential have Program, Pueblo, CO, USA. Somnogen Canada Inc, College Street, Toronto, ON, Canada. School of Medicine Clinics Hospital, University of the Republic, developed into major drugs of abuse that continue to Montevideo, Uruguay. Rocky Mountain Sleep, 1306 Fortino Blvd, Pueblo, CO negatively effect our modern society. For the physician ad- 81008, USA. dressing the patient complaint of insomnia, these agents Received: 27 November 2017 Accepted: 24 May 2018 can be difficult to appropriately utilize. This brief overview argues that today there are medications with very low tox- icity, addictive potential, minimal next day sleepiness, and References Abad VC, Sarinas PSA, Guilleminault C (2008) Sleep and rheumatologic disorders. an otherwise benign side-effect profile that can be utilized Sleep medicine reviews 12(3) . safely and effectively to treat and improve function and Abbott S, Soca R, Zee P. Circadian Rhythm Sleep Disorders. 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Sleep Science and PracticeSpringer Journals

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