Pharmacotherapy of Insomnia

Gretchen L. Johnson, PharmD, BCPS

 Insomnia
• Defined as difficulty falling asleep, difficulty
maintaining sleep or experiencing nonrestorative
sleep.
• Most common complaint in general medical
practice
• 40% of pts with chronic insomnia have a psych
diagnosis (depression, anxiety, substance abuse)
• 10-20% self-medicate with OTC meds or alcohol
 Insomnia
• Three types of Insomnia
– Transient- lasting 2-3 nights (Ex. jetlag)
– Short-term- lasting < 3 months (Ex. situational)
– Chronic- lasting > 3 months
 Common Causes of Insomnia
• Situational
– Work or financial stress, major life events,
interpersonal conflicts, jet lag or shift work
• Medical
– Cardiac: angina, arrhythmias, HF
– Respiratory: asthma, sleep apnea
– Chronic pain
– Endocrine: DM, hyperthyroidism
– GI: GERD, ulcers
– Neurologic: delirium, Parkinson’s, Seizures, RLS
– Pregnancy
 Common Causes of Insomnia
• Psychiatric
– Mood disorders: depression, mania
– Anxiety disorders: GAD, OCD
– Substance abuse: alcohol, sedative-hypnotic withdrawal
• Drug-induced Insomnia
– Anticonvulsants
– Central adrenergic blockers
– Stimulants
– SSRIs, Bupropion
– Steroids
– Diuretics
 Determining Management
• Determine if transient, short-term, or chronic
• Assess onset, duration and frequency of sx
• Assess effect on daytime functioning
• Assess for underlying causes
• Assess sleep hygiene
• Assess stress
 Nonpharmacologic Treatment
• Cognitive behavioral therapy
– May be more effective than drugs in > 55yo
– Stimulus control, good sleep hygiene, cognitive
therapy, relaxation therapy
• Table 72-2 Stimulus Control and Sleep
Hygienehttp://accesspharmacy.mhmedical.co
m.suproxy.su.edu/ViewLarge.aspx?figid=1341
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 OTC options
• Antihistamines
– Diphenhydramine (Tylenol PM, Sominex)
– Doxylamine (Unisom)
• Herbal meds
– Melatonin
– Valerian
– Kava Kava
 Nonprescription Treatments
• Antihistamines
– Watch for anticholinergic side effects- esp.
problematic in elderly
– Tolerance develops to sedative effects after 1 week
– Diphenhydramine- Pregnancy Category B; Lactation-
may dry up milk
• Herbals
– Little if any evidence of efficacy
• Melatonin may be helpful in jet lag
• Hepatotoxicity reported with Kava Kava and Valerian root
 Prescription Treatments
• Benzodiapezines (BZDs)
– Temazepam (Restoril)
– Flurazepam (Dalmane)
– Triazolam (Halcion)
– Estazolam(Prosom)
– Quazepam (Doral)
• Non-BZD GABA-A agonists- “Z- hypnotics”
– Zolpidem (Ambien)
– Zaleplon (Sonata)
– Eszopiclone (Lunesta)
 Prescription Treatments (cont’d)
• Melatonin receptor agonist
– Ramelteon (Rozerem)
• Sedating antidepresants
– Amitriptyline (Elavil)
– Doxepin (Silenor)
– Trazodone (Deseryl)
– Mirtazepine (Remeron)
 Benzodiazepines
• MOA: GABA-A receptor agonists
• Controlled subtance
Drug Onset Duration T 1/2
Triazolam 30 min 2-4 hrs 2-5 hrs
Temazepam 60-120 min 8-10 hrs 9-12 hrs
Estazolam 60-120 min 8-10 hrs 10-20 hrs
Quazepam 30-60 min 8-10 hrs 40 hrs
Flurazepam 30-60 min 8-20 hrs 40-150 hrs

• Effective in dec. time to fall asleep and inc. total

sleep time
 Benzodiazepines
• Do not use in:
– Pregnancy
– Substance abuse
– Untreated sleep apnea
• Avoid use with alcohol and other CNS
depressants
• Caution with driving or operating heavy
machinery
 Benzodiazepines
• ADRs: daytime sedation, psychomotor incoordination, decreased
concentration and mental alertness, cognitive deficits, respiratory
depression
• ADRs are dose-related- use lowest effective dose
• Tolerance can develop
• Scheduled substance
– Can be habit forming
• Rebound insomnia can occur with abrupt DC
• Anterograde amnesia, an impairment of memory and recall of
events occurring after the dose is taken, can occur
• Can accumulate in the elderly
– Avoid BZDs with long t1/2- flurazepam and quazepam
– Inc. risk of falls and hip fracture
• Pregnancy Category X- cleft pallette, resp. depression
• Breastfeeding- not recommended
 Non-BZD GABA-A agonists
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)

• MOA: selective GABA-A receptor agonist

subtype 1
• Controlled substance
 Non-BZD GABA-A agonists
• Zolpidem
– Formulations available: IR (Ambien), CR (Ambien CR), lingual
spray (Zolpimist), SL (Edular, Intermezzo)

Product Onset Duration

Zolpidem IR,Edular SL, 30 min 6 hours
Zolpimist
Zolpidem CR 30 min >6 hours
Intermezzo SL 30 min 4-6 hours

– Useful to initiate and maintain sleep; some residual effects

• Intermezzo for middle of the night wakenings- Need 4 hours of sleep left
 Non-BZD GABA-A agonists
• Zaleplon (Sonata)
– Onset: 30 min Duration: 2 hours
– Useful to initiate sleep; Can take in middle of night but need 4
hr left in bed; Not for maintaining sleep unless redosed
– Least likely to cause next-day impairment or anterograde
amnesia
• Eszopiclone (Lunesta)
– Onset: 45 min Duration = 5-8 hr
– Useful to initiate sleep and maintain sleep
– No evidence of tolerance after 6 months of use
– ADR: unpleasant/metallic taste (20-33% incidence)
 Zolpidem Dosing Change 2013
• FDA Recommends Lower Dose
• Reason:
– Morning blood levels in some pt (females) may be
high enough to impair activities requiring alertness –
driving
– Highest risk with ER forms and women eliminate the
drug more slowly than men
• Use 5mg vs. 10mg for IR; Use 6.25mg vs. 12.5mg
for CR
• Intermezzo (no change) already at a lower dosage
(11/2011)
 Eszopiclone Dosing Change 2014
• FDA recommended lower dose
• Reason
– 3mg dose can impair driving ability, coordination,
and memory for over 11 hours
• Start with 1mg for all pts
– Do not exceed 2mg for elderly and 3mg for young
pts
 Non-BZD GABA-A agonists
• High fat/heavy meal can delay absorption – delays onset
• CYP3A4 inhibitors can increase plasma levels
• Hepatic impairment may require lower doses
• Side effects:
– Headache
– Dizziness
– GI: nausea, dyspepsia
– Anterograde amnesia (high dose zolpidem)
• Withdrawal reactions uncommon but reported
• Pregnancy Category C; Breastfeeding: zolpidem compatible
BZD and Non-BZD GABA-A agonists
• FDA Labeling Changes
• Caution
– Anaphylaxis, facial angioedema
– Complex sleep behaviors- engaging in these activites while
not fully awake and with no recollection afterwards
• Sleep driving
• Sleep eating
• Phone calls
• Risk increased with concurrent alcohol use and doses above
maximum recommended
 Ramelteon (Rozerem)
• Selective MT1 and MT2 receptor agonist
• Onset: 30 min T1/2= 1-2.6 hours
• Effective for dec. time to fall asleep
• Not effective for maintaining sleep
• ADRs: HA, dizziness, somnolence
• Not a controlled substance
– May be an option in substance abuse pts
• Pregnancy Category C; Breastfeeding- unknown
 Sedating Antidepressants
• Alternatives for pt who cannot take BZD or if concommitant
depression
• Improve sleep in depression with stimulating SSRI or bupropion
– Mostly see Trazodone used
• Doses used for insomnia are not effective for treating depression
• Amitriptyline 10-50mg Qhs; Doxepin (Silenor®) 3-6mg Qhs
– Disadvantages
• Anticholinergic side effects, adrenergic blockade (orthostatic
hypotension), cardiac conduction problems, daytime
sedation
• Trazodone 25-150mg QHS
– Watch for orthostatic hypotension, priapism
• Mirtazapine 7.5 – 30mg QHS
– Watch for daytime sedation, weight gain
 Suvorexant(Belsomra)
• New class of sleep agent
• MOA: orexin receptor antagonist
– Orexins are involved with promoting wakefulness
so antagonising their effect would cause sedation
• Schedule IV
• Same precautions about combining with
alcohol and other sedating drugs and risk for
impairment in driving and other activities the
next day
 Treatment of Insomnia
• Stepwise approach to select hypnotic
– ? Type of insomnia
• Difficulty initiating sleep
• Difficulty maintaining sleep/early morning awakening
– ? Duration
– ? Etiologies
• Sleep apnea, psychiatric/medical issues
– ? Sleep habits
– Substance abuse history
 Select agents based on symptoms, kinetic and ADR
profile
 Clinical Practice Guideline
General Treatment Approach
1. Short-intermediate acting BZD, Non-BZD RA or ramelteon
Ex. Zolpidem, eszoplicone, zaleplon, temazepam
2. Alternate short-intermediate acting BZD, Non-BZD RA or
ramelteon
3. Sedating antidepressant
Ex. Amitriptyline, trazodone, doxepin, mirtazepine
4. Combined BzRA or ramelteon + sedating antidepressant
5. Other sedating agents- with appropriate comorbid
conditions
Ex. Quetiapine, gabapentin

Journal of Clinical Sleep Medicine, Vol. 4, No. 5, 2008

 Algorithm
Adapted and Used With Permission from Mitsi Lizer, Pharm.D.

Hypnotic Selection

DFA DMS MNA

Ramelteon, Zolpidem, Zaleplon

triazolam, Eszopiclone,
zaleplon, zolpidem Temazepam Intermezzo

DFA: Difficulty falling asleep; DMS: maintaining sleep: MNA: middle of the night awakening