This site is intended for healthcare professionals.

Insomnia-pharmacotherapy

CBTi is the preferred treatment for both acute and chronic insomnia and is backed by evidence , both short and long term Pharmacological treatment can be considered as an adjunctive therapy to CBTi / other behavioral therapies in the comprehensive management of insomnia for both acute and chronic insomnia In the acute phase of CBTi adding a medication to alleviate insomnia may have a slightly better effect compared to CBT-i alone

Decide which agent based on predominant symptom pattern what is the goal of the treatment previous treatment trials/ response patient preference , circumstances cost of treatment comorbidities contraindications/interactions potential adverse effects- sedation is among the most common effects and / or SE of prescription medications

Neurotransmitters and sleep –Sleep is regulated by a variety of neurotransmitters for e.g in forebrain and hypothalamus- gamma-aminobutyric acid ( GABA ) and histamine- these have opposing action on the sleep-awake cycle GABA is the most important and copious inhibitory neurotransmitter in the nervous system GABA controls the state of excitability in all brain areas and the balance between excitatory inputs and inhibitory GABAergic activity decides the prevailing level of neuronal activity Increased GABA and decreased histamine release induce NREM sleep by deactivating the cortex of thalamus-ie stimulating GABAergic action promotes sleep The circadian processes of sleep are largely controlled by the suprachiasmatic nucleus ( SCN ) in the hypothalamus

How do the drugs work-Most CNS effects of drugs can be ascribed to primary effects on specific neurotransmitters and neuromodulators They act by simulating the action of a brain neurotransmitter on the receptor ( agonist or partial agonist )
- blocking neurotransmitter action on the post-synaptic receptors ( antagonists )
- changing receptor sensitivity ( allosteric modulators )
- increasing the amount of neurotransmitter available Most hypnotic affect GABA which is the primary negative neurotransmitter in the CNS or
Specific neuromodulators of GABA as serotonin , acetlycholine and dopamine ( Pagel 2017 ) Sedatives induce sedation by antagonizing one or more of the central activating neuromodulators as serotonin , norepinephrine , histamine , acetylcholine , dopamine and orexin No long term studies or large RCTs are available of using these drugs in chronic insomnia Duration of treatment of hypnotic drugs is a controversial issue in psychopharmacology Strong placebo effect is considered to account for up to 2/3rd of the drug response.

Benzodiazepine Receptor Agonists ( Z-drugs ) or NBBzRAs-Non benzodiazepine short-acting hypnotics-positive allosteric modulators at GABA (a) receptors – unlike BZDs the Z drugs bind more selectively to certain subunits of GABA (A) receptor primarily targeting the sedative effect of the receptor rather than the anxiolytic effect Have less overall risk of adverse effects and less addictive potential
( considered safer compared to BZDs ) Amnesia , dizziness , sedation and headaches are the most common reported SEs All are rapidly absorbed and have short 1/2 lives which vary ,mainly eliminated by hepatic mechanism At higher doses they can exhibit benzodiazepine like SEs Have proven evidence of efficacy atleast in short term and they can be safely utilized chronically or in an ‘ as needed ‘ PRN basis in individuals with both short and long term insomnia (Morin and Espie 2003 ; Schutte- Rodin et al 2008 ) Zolpidem has a documented efficacy for sleep onset and maintenance problems in younger adults , but for sleep onset problems only in older adults Use lower dose- hepatic , renal, respiratory insufficiency , elderly

Zopiclone –Onset of action about an hour Longest duration of action 4-8 hrs 
( amongst Z drugs ) 
○ used when patients c/o waking throughout the night
○ negligible residual effects are seen the following morning Rapidly initiates and sustains sleep with ↓ of total REM sleep and with preservation of slow sleep wave Warn- may adversely affect the ability to drive or to use machines ( if taken within 12 hrs ) Licensed duration 4 weeks.

Zolpidem – Rapid absorption ( works in 15-20 mins ) and short duration of action ( up to 6 hrs ) Shown to preserve sleep stages and no influence on paradoxical sleep duration ( REM ) Atleast 8 hrs is recommended between taking zolpidem and driving , using machinery and working at heights Lowest effective dose , in a single intake just before bedtime- should not be retaken in the same night Licensed duration 4 weeks Modified versions available in US and have separate dose warning for ♀ from FDA

Zaleplon-Fast onset of action ( 15-20 mins ) and ultra short acting
( 2-4 hrs ) Decreases sleep-onset latency Produces less memory and psychomotor impairment Can be used up to 5 hrs before driving Useful for sleep onset insomnia Licensed duration 2 weeks.

Melatonin-Melatonin is a hormone that plays an integral role in diurnal rhythms Psycholeptic melatoninn receptor agonist Monotherapy for short term treatment of primary insomnia in pts > 55 yrs 
( up to 13 weeks ) Can restore sleep pattern Most common SE is headache and slowing of reaction time and sedation can occur during the day Avoid alcohol use with Circadin
( ↓ effectiveness ) Endogenous melatonin production is ↓ in elderly- hence rationale for use in over 55s with primary insomnia No data exists for use in people with autoimmune disease- hence not used British Association of Psychopharmacology states that prolonged release melatonin improves sleep onset latency and quality in patients over 55 yrs Contains lactose – avoid if known to suffer with galactose intolerance , the LAPP lactase deficiency or glucose- galactose-galactose malabsorption.

Ramelteon- agonist at MT1 and MT2 receptors but is substantially more potent at these receptors than melatonin it is a synthetic melatonin agonist short half life ( 1.36 hrs ) known to cause sleepiness which can persist for 12-14 hrs ( Cohen en at 2010 ) approved for use in insomnia charecterized by difficulty with sleep onset and is the only MT agonist with this indication dizziness , nausea and fatigue are the most common SEs does not affect patient balance.

Benzodiazepines –Benzodiazepines bind to GABA and GABAA receptors acting as antagonists They exhibit sedative , anxiolytic , myorelaxant and anticonvulsant properties They ↑ sleep time and improve sleep quality by ↓ ing sleep-onset latency and wakefullness after sleep onset and by ↑ ing sleep efficiency Triazolam , flurzepam , temazepam , quazepam and estazolam have been demonstrated to to have therapeutic effects on both sleep onset and maintenance in double blinded placebo controlled trials in younger adults The short term gains are offset by significant increased risk-particularly in the elderly of cognitive impairment , dizziness , morning sedation , delirium , falls , fractures and RTAs . Tolerance to hypnotic effect is a frequent phenomenon seen with chronic BZD use.

American Geriatric Society Beers Criteria for Potentially Inappropriate Medication use in the Older Adults recommends to avoid BZD of any type for treatment of insomnia.

Temazepam –Rapidly absorbed – peak plasma levels within 50 mins 1/2 life between 8-15 hrs Mainly metabolised in liver and excreted in urine Duration of use should be as short as possible but should not exceed 4 weeks for insomnia 
( including tapering off process ) Start of treatment patients may suffer from drowsiness and light headedness the next day
○ confusion and ataxia ( particularly elderly )
○ amnesia may occur
○ reduced alertness , dizziness
○ fatigue , muscle weakness
○ numbed emotions
○ double vision
○ respiratory depression
○ slurred speech Can impair cognitive function and affect ability to drive safely Dependence →can lead too physical dependence : discontinuation may result in withdrawal or rebound phenomena Risk of dependence ( physical or psychological ) ↑es with dose and duration of Rx and is greater in patients with a h/o alcohol or drug abuse or pts with marked personality disorder.

Antidepressants –Trazodone Doxepin Mirtazepine Amitriptyline

These are the most common antidepressant agents used to treat insomnia and they promote sleep by antagonizing the effect of wake-promoting monoamines including histamine , Ach , NA and serotonin
 Trazodone -agonist at 5HT1A receptors an antagonist at 5HT2 and alpa 1 adrenergic receptors and a weak 5-HT reuptake inhibitor
- it is the 2nd most prescribed medication for insomnia in the USA
- only 1 study @ 50 mg ( controlled study ) vs placebo found a significant effect on sleep maintenance parameters at week 1 but not week 2 and a high incidence of daytime somnelescence
 ( main SEs are orthostatic hypotension and sedation )
Not been found to have therapeutic effect in any randomized double blind placebo controlled trial ie evidence for use in weak Doxepin ( a tricylic AD ) at 25-50 mg has been show in to have therapeutic effects in insomnia patients in atleast one placebo-controlled double blind small RCT
There is some evidence from placebo-controlled trial on use of low dose doxepin ( 3-6 mg ) in improving both sleep maintenance and early morning awakenings , with no withdrawal effects upon discontinuation
-Mirtazepine – has sedative properties that may benefit patients with insomnia.
- sedation by potent antagonist effects on H1 receptors Tricyclics -others with sedative properties as amitriptyline , nortriptyline and imipramine have been used off label to treat insomnia with amitriptyline being the drug of choice in UK primary care.

Non-selective antihistamines- OTC sleeping pills generally contain sedating H1 anti-histamines -diphenhydramine , hdroxyzine , triprlolidine , doxylamine More profound acute effects on sleep have been reported for both promethazine and hydroxyzine in healthy volunteers 
( Adam and Oswald , 1986 , Alford et al 1992 ) Clinical use lacks supporting data Tolerance develops rapidly sedative antihistamines have significant anti-cholinergic effects 
( avoid in patients with glaucoma and those at risk of urinary retention ) Daytime sleepiness and cognitive impairment persisting into the day following night-time use is common BAP states that non-selective antihistamine antagonists have a limed role in psychiatric and primary care practice for the management of insomnia.

Anti-psychotics –Atypical antipsychotic agents used include olanzepine , quetiapine and risperidone Work by broad antagonism of wake promoting neurotransmitter receptors like dopamine , histamine , serotonin , cholinergic and adrenergic receptors Little evidence of use – no rigorous double blind randomised , placebo controlled trials demonstrating the efficacy of any anti- Risk of tardive dyskinesia and weight gain.

Suvorexant –It is thought that orexin ( also known as hypocretins -secreted by lateral hypothalamus ) changes the activity of the neurotransmitters involved in the regulation of sleep / awake cycle Oxerin producing neurons are located in specific parts of the hypothalamus Patients with narcolepsy are thought to deficient in orexin Suvorexant is a reversible dual orexin receptor antagonist – approved in 2014 for use in insomnia Multiple studies have demonstrated the efficacy of suvorexant.

References

  1. Lie, Janette D et al. “Pharmacological Treatment of Insomnia.” P & T : a peer-reviewed journal for formulary management vol. 40,11 (2015): 759-71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634348/
  2. Prescription Drugs Used in Insomnia Dujardin, Sylvie et al. Sleep Medicine Clinics, Volume 13, Issue 2, 169 – 182 https://www.ncbi.nlm.nih.gov/pubmed/29759268
  3. Matheson E, Hainer BL. Insomnia: Pharmacologic Therapy. Am Fam Physician. 2017;96(1):29–35. https://pubmed.ncbi.nlm.nih.gov/28671376/
  4. Recommended diagnosis and management of insomnia
    Sue Wilson PhD and David Nutt DM, FRCP, FRCPsych, FMedSci https://www.prescriber.co.uk/wp-content/uploads/sites/23/2015/11/Recommended-diagnosis-and-management-of-insomnia.pdf
  5. Pagel, J.F., Pandi-Perumal, S.R. & Monti, J.M. Treating insomnia with medications. Sleep Science Practice 2, 5 (2018). https://doi.org/10.1186/s41606-018-0025-z
  6. Insomnia management Natalie A Grima    Bei Bei    Darren Mansfield   AJGP > 2019 > April > Insomnia management Volume 48, Issue 4, April 2019 https://www1.racgp.org.au/ajgp/2019/april/insomnia-management

     

  7. Kay-Stacey Margaret, Attarian Hrayr. Advances in the management of chronic insomnia
  8. Brasure M, MacDonald R, Fuchs E, et al. Management of Insomnia Disorder [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Dec. (Comparative Effectiveness Reviews, No. 159.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK343503/
  9. Advances in the management of insomnia Wilfred R. Pigeon, Todd M. Bishop and Jonathan A. Marcus F1000 Faculty Reviews via https://f1000.com/prime/reports/m/6/48

  10. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update Sue Wilson1, Kirstie Anderson2, David Baldwin3, Derk-Jan Dijk4, Audrey Espie5, Colin Espie6, Paul Gringras7, Andrew Krystal8, David Nutt1, Hugh Selsick9 and Ann Sharpley10
    Journal of Psychopharmacology 2019, Vol. 33(8) 923 –947 https://www.bap.org.uk/pdfs/BAP_Guidelines-Sleep.pdf
  11. The assessment and management of insomnia: an update Andrew D. Krystal 1,2 , Aric A. Prather 1 , Liza H. Ashbrook 2 1 Department of Psychiatry and 2 Department of Neurology, University of California SanFran cisco School of Medicine, San Francisco, CA, USA  World Psychiatry 2019;18:337–352 https://onlinelibrary.wiley.com/doi/epdf/10.1002/wps.20674
  12. The assessment and management of insomnia in primary care Karen Falloon,1 Bruce Arroll,1 C Raina Elley,1 Antonio Fernando2 BMJ 2011;342:d2899 doi: 10.1136/bmj.d2899 https://www.bmj.com/bmj/section-pdf/186315?path=/bmj/342/7809/Clinical_Review.full.pdf
  13. An overview of Insomnia Management T.Bheemsain , Sujit Kumar Kar Delhi Psychiatry journal Vol 15 No.2 Oct 2012 http://medind.nic.in/daa/t12/i2/daat12i2p294.pdf
  14. Z drugs : their properties and use in treating insomnia Steve Chaplin et al Prescriber volume 24 , Issue 10 https://onlinelibrary.wiley.com/doi/abs/10.1002/psb.1061
  15. The Maudsley Prescribing Guidelines in Psychiatry Edited by David Taylor , Carol Paton , Shitij Kapur
  16. Gunja, Naren. “The clinical and forensic toxicology of Z-drugs.” Journal of medical toxicology : official journal of the American College of Medical Toxicology vol. 9,2 (2013): 155-62. doi:10.1007/s13181-013-0292-0 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657020/
  17. Treatment Options for Insomnia Am Fam Physician .2007 Aug 15;76 94) : 517-526
  18. Medicines Agency -review of Zolpidem containing medications accessed via http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Zolpidem-containing_medicinal_products/European_Commission_final_decision/WC500170560.pdf

Comments - to make a comment on the above chart please log in.


Register

START TYPING AND PRESS ENTER TO SEARCH