Drug Treatment of Insomnia

Dr Ranjita Santra (Dhali)Assistant ProfessorDept. of Clinical & Experimental PharmacologySchool of Tropical MedicineKolkata

What is Insomnia? The perception of inadequate or poor-quality sleep

accompanied by significant distress or impaired function

Chronic if it occurs on most nights and lasts a month or more

You might suffer from insomnia if:◦ It takes you more than 30 to 45 minutes to get to sleep◦ You wake up during the night◦ If you wake up early and cannot get back to sleep◦ You wake up feeling un-refreshed in the morning

A symptom, not a disease or sign, therefore difficult to measure

Source: www.nih.gov.in.Accessed : 20.06.2015

DiagnosisComplaint that the sleep is:

◦Brief or inadequate◦Light or easily disrupted◦Non-refreshing or non-restorative

Which patient populations have the highest prevalence of insomnia?

Women Especially in 3rd trimester and after menopause

Elderly Up to 65% ((Ohayon, 2002; Morphy, 2007; Foley,

1995) Those with various disorders

Psychiatric disorders, including depression, anxiety, substance abuse, and posttraumatic stress disorder, are also strongly associated with insomnia (Spiegelhalder, 2013; Baglioni, 2011)

Individuals with coexisting medical disorders (particularly pulmonary disease, heart failure, and conditions associated with pain such as cancer) are at increased risk for insomnia, as are patients with neurologic diseases (such as Alzheimer dementia and Parkinson disease) (Taylor, 2007)

Which patient populations have the highest prevalence of insomnia?

An increased prevalence of insomnia is also associated with a variety of rheumatologic, endocrine, urologic, and dermatologic disorders (Dikeos, 2011).

Population studies – unemployed, divorced, widowed, separated, or of lower socioeconomic status have a higher prevalence of insomnia (Gellis, 2005; Paine, 2004).

 Stimulants (e.g., caffeine, nicotine), antidepressants, β-antagonists, calcium channel blockers, and glucocorticoids.

Additionally, individuals withdrawing from certain medications, such as alcohol or hypnotic medications, may have resulting insomnia.

ClassificationThe 3rd edition of the International Congress of Sleep Disorders Classification (ICSD-3) was published in 2014 and includes 7 major categories of sleep disorders, one of which is insomnia

Three major forms of insomnia are recognized: short term (< 3 months), chronic (symptoms occur at least 3 times / week for 3 months or more & are not related to another sleep disorder, and other (for conditions not meeting the criteria for acute or chronic insomnia)

ClassificationSleep initiating insomniaSleep maintaining insomniaEarly morning insomnia

◦Short period of sleepNon-restorative sleep

◦Multiple awakenings◦Combination of above patterns

DefinitionsMild

◦ Almost nightly complaint of non-restorative sleep

◦ Associated with little or no impairment of social or occupational functioning

Moderate◦ Nightly complaints of disturbed sleep◦ Mild to moderate impairment of social or

occupational functionSevere

◦ Nightly complaints of disturbed sleep◦ Severe daytime dysfunction

Physical, Emotional, and Cognitive Effects of InsomniaMood changes, irritability, poor

concentration, memory defects, etc. Impairs creative thinking, verbal processing,

problem solvingRisk of errors, accidents due to excessive

daytime sleepiness◦ Markedly increases if awake more than 16-18 hours

(micro-sleep attacks) Increased appetite, decreased body

temperaturePhysiologic effects

◦ Rats die after 11-12 days of sleep deprivation◦ Hippocampal atrophy in chronic jet lag or shift work

Sleep is an integral portion of human existence which is sensitive to most physiological or pathological changes (aging, stress, illness, etc.)

Why do we sleep?◦ Not clear, but has to do with regeneration (NREM) and brain

development/memory (REM) – REM sleep is essential for the development of the mammalian brain

◦ Stages III & IV are involved in synaptic “pruning and tuning”

Why do we get sleepy?◦ Circadian factors◦ Process S: linear increase in sleepiness◦ Process C: rhythmic fluctuations of the circadian alert

system◦ Other factors: sleep duration, quality, time awake, etc.

Normal Sleep ValuesNormal sleep per day is between 6-8

hours4-6 NREM/REM cycles per nightWakefulness after sleep

◦ Less than 30 minutesSleep Onset Latency (SOL)

◦ Less than 30 minutesREM Sleep Latency

◦ 70-120 minutes

Brain regions of current interest to the neurobiology of sleep.

Subcortical regions (blue boxes), which control sleep–wake transitions and, within sleep, REM–NREM sleep alternation. The top tier includes areas that are key to the generation of the EEG rhythms of sleep, the subjective experience of sleep mentation or dreaming, and sleep's effects on cognition.

Schematic representation of the regulatory circuits that control sleep–wake and REM–NREM transitions, as well as their key inputs and outputs.

EEG, electroencephalogram; NREM, non-REM; REM, rapid eye movement.

Role of melatonin

Causes of Insomnia

Historical Perspective Chloral hydrate and laudanum (opium and alcohol

mixture) were first used for treating insomnia in the mid1800s

The barbiturates and related medications dominated much of the 20th century

The benzodiazepines first were used for sleep in the 1960s and 1970s, and the more selective nonbenzodiazepine analogues became available in the 1980s and 1990s

The earlier compounds had the advantage of efficacy in promoting sleep, but had significant safety problems

Newer FDA-approved insomnia medications have little or no abuse liability, much less likely to cause residual daytime sedation or impairment

Historical Perspective

Treatment ModalitiesTreatment of insomnia includes

alleviating any physical and emotional problems that are contributing to the condition and exploring changes in lifestyle

There are a myriad of treatments available for insomniacs, which fall into three major categories◦ Drug Therapy◦ Cognitive-Behavioral Therapy◦ Alternative Treatments

When should clinicians consider prescription drug therapy for insomnia?

When other approaches prove inadequate

Considerations The nature of the sleep disturbance Whether insomnia is acute or chronic Presence of other medical or psychiatric

conditions Side effects Cost

Drugs prescribed for Insomnia

Prescription & Non-prescription medications: Insomnia

FDA-approved prescription drug treatments for insomnia

Benzodiazepines (flurazepam, temazepam, triazolam)

Nonbenzodiazepine (zolpidem, eszopiclone, zaleplon)

Orexin-receptor antagonist (suvorexant)

Melatonin Receptor Agonists (ramelteon)

Antidepressants (doxepin) Others options Barbituates Antipsychotics Anticonvulsants

Antidepressants: Sleep physiology

Sedative-hypnotic drugs. In: Basic and clinical pharmacology, 8th edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:364–381.

Suvorexant is a potent dual orexin receptor antagonist approved by the US-FDA march 2014 that blocks both OX1R and OX2R

Roughly 70,000 orexin neurons are in the

human brain, located in the perifornical lateral hypothalamus, which send signals throughout the brain and spinal cord.

Promotes the natural transition from wakefulness to sleep by inhibiting the binding of orexin A and B, neuropeptides that promote wakefulness

Also improves sleep onset and sleep maintenance

Suvorexant

Table: 1 PK determinants for Suvorexant

Should clinicians screen for insomnia, and if so, how?

Consider screening as part of regular patient care

Ask patients if they haveDifficulty initiating or maintaining sleepEarly morning wakingNonrestorative sleep

Insomnia screening instruments Sleep Condition Index questionnaire (2

questions) Epworth Sleepiness Scale Insomnia Questionnaire

Sleep Condition Index questionnaire “Thinking about a typical night in the last month, how

many nights do you have a problem with sleep?” (with ≥3 representing a positive response), and “Thinking about the past month, to what extent has poor sleep troubled you in general?” (with “somewhat” to “very much” being a positive response)

Positive responses to these 2 questions correlate with other more extensive assessments and may be effective for clinicians as a screening tool to detect insomnia (Espie, 2014).

Insomnia questionnaire I have real difficulty falling asleep. Thoughts race through my mind and this prevents me

from sleeping. I wake during the night and can’t go back to sleep. I wake up earlier in the morning than I would like to. I’ll lie awake for half an hour or more before I fall asleep. I anticipate a problem with sleep almost every night

If you checked three or more boxes, you show symptoms of insomnia, a persistent inability to fall asleep or stay asleep.

(Insomnia questionnaire : American College of Sleep Medicine)

When do activities occurGoing to bed, waking up, getting out of bed

What are the components of a comprehensive sleep history?

How much sleep Sleep latency, frequency of awakening, duration

awake after awakening, total sleep time Quality of sleep

How well rested do you feel after awakening? Environmental factors

Light, sound, temperature, telephone, TV

Behaviors that might affect sleep Sleep habits, daytime napping, exercise,

stimulant use

What are the components of a comprehensive sleep history?

A sleep diary may be more accurate than general questioning alone in characterizing sleep issues by formally documenting these factors and minimizing recall bias. Several instruments are available for patient use, and should be used daily for at least 1 to 2 weeks (National Sleep Foundation Diary; Carney, 2012).

Things to Ask about When Taking a Comprehensive Sleep History

Problems of sleep initiation, sleep maintenance, early morning waking, or nonrestorative sleep

Ascertain if the patient has acute, short-term, or chronic insomnia Stability or progression of symptoms—that is, if the insomnia is

stable, worsening, or improving Precipitating causes of insomnia Bedtime, wake time, length of sleep time Caffeine and alcohol use Any current or previous behavioral therapies used to treat insomnia Previous over-the-counter or prescription sedative-hypnotic use Shifting work and irregular sleep schedule Potential acute stressors, such as: Medical or psychiatric illness Medication use, both prescribed and illicit Acute stress at home or work Circadian rhythm stressors, such as jet lag

Sleep Disorder Differential Diagnosis of Insomnia

Sleep-related breathing disorders◦ The obstructive sleep apnea syndrome◦ The central sleep apnea syndrome

Sleep-related movement disorders◦ The restless legs syndrome◦ Periodic limb movement disorder◦ Nocturnal leg cramps

Circadian rhythm sleep–wake disorders◦ Time zone change syndrome (jet lag)◦ Shiftwork sleep disorder◦ The delayed sleep-phase syndrome◦ The advanced sleep-phase syndrome

Parasomnias related to non–rapid eye movement

When a possible underlying sleep disorder is suspected When insomnia may be linked to concomitant disease

Laboratory testing in the evaluation of insomnia

Possible tests Polysomnography Multiple Sleep Latency Test Sleep Actigraphy Tests for disorders contributing to insomnia Urine drug screening (to check for substance use)

What is sleep hygiene, and what is its role in the treatment of patients with insomnia?

Sleep hygiene refers to the optimization of the environmental and behavioral factors associated with sleep (Stepanski, 2003). Poor sleep hygiene can contribute to sleep fragmentation, disturbance of normal circadian rhythms, and overstimulation.

Good sleep hygiene behaviors Maintain constant bed times and rising times Allow adequate time for sleep (7 h to 8 h for adults) Do not force sleep, and avoid clock watching Maintain a quiet, dark bedroom Remove potential disruptors of sleep (tv, phone) Avoid sleep-fragmenting substances near bedtime Exercise regularly but avoid exercise just before

bedtime Resolve stressful situations and relax before bedtime Avoid daytime naps

Things to consider when prescribing drugs to treat insomnia

Use the minimal effective dose Avoid medications with a long half-life Be aware of potential drug-drug interactions Caution patients about interaction with alcohol Review potential side effects, especially daytime

sleepiness Agree on an appropriate duration of use Start with a GABA agonist for acute or short-term

insomnia Look for rebound insomnia after discontinuation Consider intermittent use of hypnotic medications when

long-term therapy is required Consider consultation with a sleep specialist before

starting continuous, long-term therapy with hypnotic medication

What is the appropriate duration of prescription drug therapy for insomnia?

Avoid prolonged or excessive therapyDiscuss risks and benefits of drug therapy

Continuous therapy Limit to 1 month Conduct periodic tapering and discontinuation

trials to determine when continuous therapy can be stopped

As-needed therapy Limit to 6 months Reserve for patients who can assess when drug

treatment will be helpful

What are contraindications to drug therapy?

Sedating antihistamines◦ Cardiopulmonary disease, glaucoma, problems w/ urination

Sedative-hypnotics If pregnant or breastfeeding Underlying medical disorders in which sedation

detrimental Any sedating mediation Alcohol or another sedating medication Driving or using hazardous equipment

All medications History of alcohol or drug abuse

Use more cautiously in elderly Beware potential interaction with complementary

and alternative medications

When should clinicians consider speciality referral for patients with insomnia?Suspicion of an underlying sleep disorderPoor response to behavioral interventions /

drug therapy Psychiatrist: possible psychiatric

disorder Pulmonologist: suspected sleep

disordered Otolaryngologist, oral surgeon, or

dentist: excessive snoring or other oropharyngeal or airway issues

Neurologist: possible Parkinson disease, cerebrovascular disease, or dementia

Treatment: Alternative Therapies

Valerian extracts cause both CNS depression and muscle relaxation.

Ginseng has an inhibitory effect on the CNS and may modulate neurotransmission.

Kava Kava possibly acts on GABA and benzodiazepine binding sites in the brain.

Passion flower is associated with significantly prolonged sleeping time in rats, and may be applicable to humans.

Hops, when infused in tea, are reported to have a calming effect within 20-40 minutes of ingestion

Treatment: Alternative Therapies

Physiological Agents◦ Melatonin increases sleep quality when compared

with baseline and placebo in night-shift workers◦ Tryptophans reduce sleep latency by increasing

subjective “sleepiness” and also decreasing waking time

Other Approaches◦ Acupuncture therapy can affect the regulation of

sleep-wake cycles and possibly reharmonize a disturbed sleep-wake cycle.

◦ Low energy emission therapy, in healthy volunteers, 15 minutes of LEET treatment induced EEG changes, and was associated with objective and subjective feelings of relaxation

Resources for Insomnia patients

Conclusion

Insomnia can be problematic if not dealt with

Although many treatments are

available, few people seek treatment

Proper sleep hygiene is integral to daily life