1. Assessing and treating sleep disturbances in pediatric IBD patients Eva Szigethy MD, PHD Associate Professor of Psychiatry, University of Pittsburgh Director, Medical Coping Clinic, Children’s Hospital of Pittsburgh Director, Visceral Inflammation and Pain (VIP) Center Division of Gastroenterology, Hepatology, and Nutrition December 14, 2013

2. Disclosure Sources of Funding –CCFA Senior Investigator Award –NIMH R01 Grants –American Psychiatric Press Inc., Book Editor –Merck- Consultant, Advisory Board All medication suggestions in this presentation are off-label uses unless noted otherwise.

4. Normal Stages of Sleep Sleep is organized into cycles- 4 non-REM and one REM cycle…deepest sleep early REM accounts for 25% of sleep and in humans occurs every 90 minutes

5. Different electrophysiological processes in different stages: REM vs NREM

7. What controls sleep?  Sleep Drive -- how long you have been awake  Biological Clock- complex mechanism in the brain that works to keep us awake, then works to keep us asleep  Mental activity and physical or medical issues- thinking, worrying, bad dreams, injuries, medications, other sleep problems

8. What controls sleep? How long you’ve been awake Time of Day 7:00 a.m. 11:00 p.m. Awake Asleep Sleep Drive A HIGH LEVEL OF SLEEP DRIVE IS NEEDED TO FALL ASLEEP QUICKLY!

9. What controls sleep? Biological Clock YOUR BRAIN TRACKS THE TIME TO STAY AWAKE AND TO BE ASLEEP.

10. Sleep Disorders DSM-IV-TR Dyssomnias – Insomnia – Hypersomnia – Narcolepsy – Breathing-related sleeping disorders – Circadian rhythm sleep disorders Parasomnias – Nightmare disorder – Sleep terror disorder – Sleepwalking disorder

11. Sleep and IBD Sleep disturbances have been documented in adults with IBD (Ranjbaran 2009) Sleep mediated effects of steroids on mood and attention (Mrakotsky 2012) In all 991 youth with IBD screened for depression, 42% reported sleep disturbance (Benhayon, 2011) 80% if depressed

12. PSQI Sleep Component Subscores by Frequency in Pediatric Patients with IBD and Depression The frequency of patients with disturbance in each of the 7 subscales of the PSQI is shown above (0 = no disturbance, 3 = severe disturbance). Benhayon 2012

13. Sleep and inflammation Disease activity correlated with self-reported sleep quality and sleep duration Inflammatory biomarkers correlated with daytime fatigue Inflammation, sleep and depression all correlated

14. Potential Reasons for Poor Sleep Depression Anxiety Social stressors Nighttime bowel movements Pain Prednisone Active disease (inflammation)

15. Assessing Sleep Disturbance Increasing Complexity History/ Physical Physical Polysomnography(PSG) Actigraphy Questionnaires Increasing Cost/Burden

16. Sleep History History –Bedtime Routine –Excessive Daytime Sleepiness –Arousals –Regularity –Snoring Pittsburgh Sleep Quality Index/Sleep diaries

17. Actigraphy Actigraph: measures movement and light, worn continuously.Actigraph: measures movement and light, worn continuously. –Advantages: Non-obtrusive, gives daytime information, durable. –Disadvantages: No information about stages of sleep or apnea.

18. Actigraphy

19. Treatment of sleep disturbance

20. Neurobiology of Sleep and Treatment Effects on Sleep- Wake Function in Insomnia Buysse 2012 Cognitive behavioral treatments Pharmacological Treatments

21. Interventions for Sleep Disturbance Behavioral Pharmacological Phototherapy

22. Good sleep results from the two main sleep controls being aligned... The sleep drive & biological clock must be in sync for good sleep to occur.

23. Behavioral Treatment-Insomnia A set of principles taught to patients 1. Consistency 2. Don’t go to bed unless tired 3. If not falling asleep after 20 minutes, go do something else. 4. Don’t watch the clock. GOAL: Time in bed = Actual Sleep time

24. Behaviors that hurt sleep:  Irregular daily and sleep habits  Alcohol and caffeine  Some prescription meds, most recreational drugs, over-the-counter medications  Thinking about bad dreams  A poor sleep environment  Using your bed for things other than sleep  Napping for longer than 20 minutes at a time

25. Relaxation/Hypnotherapy Often used to target pain, a common complaint in this population. Refocusing attention and conditioned response

26. Pharmacotherapy for Sleep

27. Neurotransmitters of sleep Wake promoting Glutamate Acetylcholine Dopamine Norepinephrine Serotonin Histamine Hypocretin Sleep promoting Acetylcholine (REM) GABA Galanin Adenosine Glycine Melatonin

28. Pharmacological Interventions Pros and cons to medications: Medications work, and work quickly Can alter sleep architecture (REM versus NREM sleep) Addictive potential (benzodiazepines) Side effects/adverse effects

29. General Psychopharmacological Principles Based on systematic evaluation on contributing factors Medication rarely first or only choice Behavioral therapy most effective and addressing unhealthy sleep habits Consider drug-drug interactions (pharmacokinetic/dynamic) Side effects- (e.g., SSRIs can exacerbate restless leg syndrome)

30. Sleep medications to facilitate sleep Consider timing of administration- timing of sleep Avoid hazardous activities after dose Review side effect- paradoxical disinhibition REM suppression (disturbing nightmares if rapid withdrawal)

31. Medications for pediatric insomnia None are FDA approved for sleep Few randomized controlled trials Clinical experience guides usage Most medications change sleep architecture…effects on neuronal growth and synaptogenesis in developing brains …..unknown.

32. Medications for insomnia Over the counter – Antihistamines – Melatonin Prescription – Benzodiazepines (BZD) – Non-BZD – Melatonin-receptor antagonists – Alpha agonists – Antidepressants – Antipsychotics

33. Antihistamines (diphenhydramine) Binds to H1 receptor in CNS Rapid absorption, crosses BBB Tolerance to sedation common Side effects- morning drowsiness, dry mouth constipation, urinary retention, constipation- anticholinergic

34. Benzodiazepines GABA A receptor agonist Anticonvulsant, anxiolytic, myorelaxant Suppresses slow wave sleep, increase total sleep time Side effects- daytime sedation, cognitive impairment, rebound insomnia, anterograde amnesia Limited utility in children

35. Non-BZD agents (zolpidem, eszopiclone) Short-acting (hypnotic) versus longer acting (sleep maintenance) Binds GABA, high affinity BZD receptor agonist Little effect on sleep architecture; some suppression of slow wave sleep Side effects- daytime drowsiness, headache, dizziness, hallucinations, complex sleep related behaviors -nasal and sublingual now available (zolpidem)

36. Alpha agonists Central alpha2 agonist; reduces noradernergic tone Rapid absorption; onset of action within 1 hour Increases SWS, Decreases REM (REM rebound with discontinuation) Side effects- hypotension, anticholinergic, irritability, dysphoria, worsens parasomnias

37. Antidepressants Most suppress REM (except bupropion); reduce SWS (SSRIs) Most utility with comorbid mood disorder TCAs- most sedating (amitriptyline, doxepin) – Side effects- agitation, anxiety, anticholinergic, cardiotoxicity Mirtazapine- alpha 2 adrenergic and 5HT antagonist- sedating at low dose (7.5 mg) Trazadone – 5HT, alpha receptor antagonist, blocks histamine- two trials failed to show effects in adolescents for insomnia

38. Melatonin Synthesized from Tryptophan Hypnotic and chronobiotic properties Antioxidant Plasma levels peak 1 hour Side effects- hypotension, decrease seizure threshold Increases immune reactivity

39. Phototherapy Seasonal Affective Disorder pattern of Major Depressive Disorder Using for fatigue and to regulate sleep cycle.

40. szigethye@upmc.edu