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Guide to Insomnia.  Part IV: 

Pharmacological Approaches to Treatment of Sleep Disorder

 by

Farinde, Abimbola, PharmD., MS1, Bordini, Ernest J., Ph.D.2 and President, Mattie, B.S.3

 1 Walden University, Minneapolis, MN

2Clinical Psychology Associates of North Central Florida, Gainesville Florida

3 California School of Professional Psychology at Alliant International University, California

 All rights reserved by                      Clinical Psychology Associates of North Central Florida     CPANCF.COM

                                              2121 NW 40th Terrace, Suite B, Gainesville Florida, 32605  Tel. (352) 336-2888


Review:   This is Part IV of our series of articles on management of insomnia.  Part I provides an overview and discusses cognitive-behavioral approaches, Part II consists of a Sleep Hygiene set of recommendations, Part III addresses overt-the-counter, herbal and supplement approaches, and the current article primarily focuses on consideration of prescription medicine approaches in insomnia treatment.  Part V will address the classification of sleep disorders.  The importance of medical and psychological evaluations to first rule out medical or co-morbid conditions that may be producing secondary insomnia is discussed earlier in this series.  The American Academy of Sleep Medicine emphasizes the use of cognitive-behavioral psychological treatments for insomnia as an effective first-line treatment for insomnia.  However, some people will require other therapeutic interventions in addition to these techniques.

The decision to initiate pharmacological intervention requires medical evaluation which includes examination, review of medical history, current medication and supplements, substance abuse history, history of medication successes and failures, review of sleep habits and non-pharmacological efforts to improve sleep, medical, laboratory and other tests as indicated to rule out medical causes of insomnia, and a review the specific risks and benefits of various pharmacological interventions.  It is also wise to discuss the medication with your pharmacist and review risk of medication interaction effects.  Any adverse reaction, or unusual changes in mood or behavior, any bizarre or unusual thoughts or any unusual physical symptoms should be promptly reported to the physician and pharmacist. 

In older adults, nocturia (nighttime episode of needing to wake for urination) often is a cause or contributory to insomnia.  This issue can be treated with medications for urinary urgency or benign prostate hypertrophy (enlarged prostate).  This is a good example of the importance of evaluating and treating comorbid medical conditions contributing to insomnia (Zeitzer, Bliwise,  Hernandez, Friedman and Yesavage, 2013).  It is important to note that cognitive-behavioral approaches are also effective for treatment of insomnia in elderly patients (Haimov & Shatil,  2013)

Pharmacological Approaches

 The American Academy of Sleep Medicine (AASM) generally recommends at least one behavioral intervention before considering pharmacotherapy (see below), and finds cognitive-behavioral therapy (CBT) should be included as an initial treatment. AASM has found CBT to be an effective treatment for older adults, adults, adolescents and children for individuals with primary or secondary insomnia and for individuals who are being chronically treated with sleep medications. The use of behavioral or psychotherapeutic approaches to treat insomnia or other sleep disturbances is generally recommended before considerations of drug treatment for primary insomnia (Lande & Gragnani, 2010). 

Though emphasizing cognitive-behavioral therapy as an initial treatment for insomnia, AASM guidelines recognize that multicomponent therapy (without cognitive therapy) is effective and recommended therapy in the treatment of chronic insomnia.  Guidelines note that when an initial psychological/ behavioral treatment has been ineffective, other psychological/ behavioral therapies, combination CBT therapies, combined treatments, or occult comorbid disorders may next be considered.”

AASM guidelines include a consensus statement that when pharmacotherapy is utilized, the choice of a specific pharmacological agent within a class, should be directed by: (1) symptom pattern; (2) treatment goals; (3) past treatment responses; (4) patient preference; (5) cost; (6) availability of other treatments; (7) comorbid conditions; (8) contraindications; (9) concurrent medication interactions; and (10) side effects.

The treatment of insomnia with pharmacological agents would ideally consist of a medication with properties that would include rapid sleep induction, no hangover effects, normal sleep patterns, and which would not have significant drug interactions.   A brief review of the medications below will make it obvious why cognitive-behavioral and sleep hygiene approaches to insomnia are recommended before trials of combination behavioral and pharmacotherapy for primary insomnia.  Obviously, as one examines risks and side effects, there really is no ideal sleep medication.  Pharmacotherapy for primary insomnia largely rests on decisions of risks and benefits.

Chloral Hydrate is perhaps one of the oldest prescription sedative hypnotic medications used for treatment of insomnia.  It has also been used for treatment of alcohol withdrawal, pre-surgical sleep induction and treatment of post-surgical pain.  Drowsiness and sleep often occur within 30-60 minutes.  Combination with alcohol is particularly dangerous and historically referred to as a “Mickey Finn”.  Chloral hydrate carries serious risks in individuals with heart, kidney, or liver disease, allergy to similar medications, the elderly, breast-feeding mothers, and those who use alcohol or other sedating medications.  Serious side effects included confusion, seizures, difficulty breathing, slurred speech, cardiac rhythm changes or disruption, vomiting, weakness, hypothermia, and liver damage.  Regular use can lead to tolerance and dependency, along with severe and dangerous withdrawal.  This medication can be abuses and cause addiction.

The AASM adopted consensus guidelines which find the above older approved drugs for insomnia including barbiturates, barbiturate-type drugs and chloral hydrate are not recommended for the treatment of insomnia.

Modern pharmacotherapy for insomnia primarily includes medications which target the benzodiazepine receptor (BZDR). Non-specific BZRAs include flurazepam, temazepam, triazolam, or estazolam (Ernman, 2005). The selection of a BZDR is based on sleep pattern, medical history, and the pharmacokinetic/pharmacodynamics profile of the BDZR. The mechanism of action of these agents is believed to involve binding to the benzodiazepine site between the µ and ƴ subunits on the GABA-benzodiazepine-chloride ionophore receptor complex. This binding increases the frequency of the opening of the chloride channels in the presence of GABA.

The traditional benzodiazepines are generally viewed as safe and effective short-term treatment options for transient initial insomnia when insomnia is related to acute environmental stressors and not by a chronic problem (Preston & Johnson, 2011). There are potential problematic adverse effects associated with the traditional benzodiazepines such as central nervous system depression (e.g. impaired alertness, impaired coordination, tolerance to sedative effects over time, and next-day “residual” or “hangover” effects. Abuse and dependency risk is the primary reason that only short-term use of benzodiazepines is advised for treatment of insomnia. As with all potentially addictive medication, efforts should be made to avoid use benzodiazepines in individuals with history or high risk for alcohol or substance abuse. Higher risk for abuse and dependence is associated with benzodiazepines that have long-lives (e.g. quazepam, flurazepam). Side effects of sedation are also a safety consideration for operating machinery, driving or performance of tasks which require alertness, focus, and concentration (Schatzberg, Cole, & DeBattista, 2010).

Barbiturates are extremely potent medication that can cause considerable somnolence within 24 hours after ingestion. Barbiturates can be fatal when mixed with alcohol or other central nervous system depressant so these combinations are contraindicated. As with benzodiazepines there is an abuse and addiction risk. If dependency occurs gradual discontinuation must be performed because rapid withdrawal can result in agitation, increased cardiac stress, delirium, seizures or even death. In the wake of the serious side effects and/or adverse effects that are associated with benzodiazepine and barbiturates there have been efforts to develop or use newer medications with fewer negative side effects and risk.

The BZDR agonists also consist of the newer non-benzodiazepine GABA (“Z drugs” - zolpidem, zaleplon, and eszopiclone) which are generally considered to be safer than the traditional benzodiazepines. These have less severe side effects such as drowsiness and dizziness but still are far from the “ideal” medication as there are interactions and side effects.  Zolpidem (Ambien) and zaleplon (Sonata) bind selectively to the GABA-A α-1 subunit, which mediate sedation. Eszopiclone (Lunesta) has been shown to improve sleep latency and sleep quality. Long term studies demonstrate efficacy during 6 months of therapy. The “Z-drugs” have a short half-life and induce sleep or assist with maintaining sleep in individuals with insomnia. Individuals with poor sleep latency may benefit from these short-acting agents. The long-acting BZR agonists that are available as extended-release and controlled-release may be effective in those with poor sleep maintenance or interrupted sleep. 

Adverse effects that can be experienced with the “Z-drugs” include headaches, next day somnolence, gastrointestinal upset, and sleep related behaviors in which an individual carries on simple to complex and dangerous activities in their sleep (e.g. sleep driving, making/eating food during sleep, or sleep walking).   Effective May 2014, the U.S. Food and Drug Administration  required that Lunesta (eszopiclone) lower the recommended starting dose. Eszopiclone levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake. Taken at bedtime, the recommended starting dose of Lunesta (eszopiclone) was decreased from 2 milligrams to 1 mg for both men and women.

At the time of this article, Ramelteon (Rozerem) is the only non-scheduled, melatonin receptor agonist that is approved in the United States. While its exact mechanism of action is not clear it is a melatonin-1 (M1) and Melatonin-2 (M2) receptor agonist and has no activity on melatonin-3 receptor (Borja, & Daniel, 2006). It is highly specific for M1 AND M2 receptors that are located in the suprachiasmatic nucleus, which is an area of the hypothalamus that controls circadian rhythm, wakefulness, and alertness. Ramelteon is the only prescription hypnotic that does not have an abuse potential and is not a controlled substance. It has displayed effectiveness in shortening latency to sleep onset but its influence on total sleep time is still not clearly understood. Unlike the BDZR agonists there is currently no restriction on the duration of use as a result of six month trial demonstrating continued efficacy (Roth & Roehrs, 2008).

As discussed in the article on non-prescription approaches, medications which impact melatonin receptors seem more consistently helpful for reducing symptoms of jet lag or for treating adolescent onset insomnia and nightmares, but there is still controversy about general efficacy for insomnia. Other studies have even questioned safety for individuals under age 20. There are concerns Melatonin drugs may worsen depression and there are warnings about use in individuals with liver problems, with women who are pregnant or nursing and potentially dangerous interactions with anticoagulants (blood-thinners), immunosuppressant medication, birth control pills and diabetes medications.  There are also some reports of hallucinatory dreams or hallucinations.

Due to side effects of sedation, antidepressant medication including some of the older tricyclic antidepressant medications have been used to treat insomnia, often at doses that are sub-therapeutic for depression. These are non-addictive but do have unpleasant side effects of dry mouth, gastrointestinal complaints and some people complain of morning light-headedness, disorientation or “hangover”. These can be effective in decreasing sleep-onset latency and wakefulness after sleep onset, increase total sleep time, sleep efficiency and sleep quality. Side effects and risks can vary with the specific antidepressant used and some may suppress REM sleep, cause more intense dreams or nightmares, cause weight gain, or have sexual side effects. While antidepressants are often an excellent and effective treatment option for those with co- morbid disorders of insomnia and depression, or insomnia and anxiety, at this time they do not appear indicated for long-term treatment of solely primary insomnia. AASM guidelines note that other classes of sedating medications such as anti-epilepsy medications (e.g. gabapentin, tiagabine) and atypical antipsychotics (e.g. quetiapine and olanzapine) may only be suitable for patients with comorbid insomnia who may benefit from the primary action of these drugs as well as from the sedating effect. These often have more serious long-term and short-term side effects than traditional medications for insomnia.



DISCLAIMER – The above discussion about prescription, OTC, herbal or supplement approaches to insomnia is for educational purposes only.  It is not intended to provide medical or other advice, or a list of all possible negative consequences or side effects. Any approach an individual uses of such should be reviewed with a medical doctor and a pharmacist in the context of medical history and other medications and supplements.

References

Borja, N.L. & Daniel, K.L. (2006).Ramelton for the treatment of chronic insomnia: A review, Psychiatric Services, 28(10),1540-55.

Ernman, M.K. (2005). Therapeutic options in the treatment of insomnia, Journal of Clinical Psychiatry, 66,18-23.  

Haimov I, Shatil E (2013) Cognitive Training Improves Sleep Quality and Cognitive Function among Older Adults with Insomnia. PLoS ONE 8(4): e61390. doi:10.1371/journal.pone.0061390

Lande, R.G.,Gragnani, C. (2010). Nonpharmacologic approaches to the management of insomnia. The Journal of the American Osteopathic Association, 110(12),695-701.

Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, Coleman J, Kapur V, Lee-Chiong T, Owens J, Pancer J, Swick T; American Academy of Sleep Medicine. Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep. 2006 Nov 1;29 (11):1415-9.

Preston, J. & Johnson, J. (2011).Clinical psychopharmacology (6th ed.). Miami, FL: MedMaster Inc.

Roth, T., & Roehrs,T. (2008). Efficacy and safety of sleep-promoting agents.Journal of Clinical Sleep Medicine, 3,175-87.

Schatzberg, A.F., Cole, J.O., DeBattista, C. (2010). Manual of Clinical Psychopharmacology American Psychiatric Publishing,

Zeitzer, Bliwise, J.M., Hernandez, D.L., Friedman, L.,  andYesavage, J.A., 2013.  Nocturia Compounds Nocturnal Wakefulness in Older Individuals with Insomnia.  Journal of Clinical Sleep Medicine, Vol. 09 Number 5, 2013


 

Other Articles in this Series on the Clinical Psychology Associates of North Central Florida Website:

 A Basic Guide to Insomnia:Part I: Insomnia the Basics

 A Basic Guide to Insomnia:PartII:Sleep Hygiene Handout

 

 A Basic Guide to Insomnia: Part III  Psychotherapeutic, OTC, and Nonprescription Treatment Approaches to Insomnia

 A Basic Guide to Insomnia Part V: Sleep Disorder Classification

 

 
First Published July 1, 2013 in the Articles and Archives of the Clinical Psychology Associates of North Central Florida, CPANCF.COM website

update 5/15/14 re: Lunesta

 
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