A practical guide to melatonin prescribing in GP

Transcription

1 A practical guide to melatonin prescribing in GP A/PROF JEREMY GOLDIN HEAD OF SLEEP MEDICINE ROYAL MELBOURNE HOSPITAL DIRECTOR WESTERN SLEEP & BREATHING CLINIC AND BREATHE WEST Mobile Phone Conflicts of Interest Research funding from Philips Respironics and Fisher and Paykel Honoraria from Aspen for previous speaking engagements Honoraria from Astra Zeneca, Boehringer Ingelheim, Novartis, Mundipharma Scientific Advisory Committee - Oventus TAKE HOME MESSAGES Sleep presentations may be complex and often there are a number of factors/conditions that contribute to patients symptoms OSA can be a by-stander and not clinically relevant i.e. neither a cause for symptoms or a risk for long term health consequences Insomnia is best managed with non pharmacological strategies (CBT-I) Benzodiazipines, Z drugs, antihistamines may be useful for short term management of insomnia but not indicated for long term management MR Melatonin is useful in managing insomnia in patients > 55y.o however should be timed and part of a sleep/wake routine Melatonin short acting 0.5-5mg is effective in phase shifting circadian rhythm and in reducing impact of jet lag OUTLINE Overview of Sleep Neurophysiology Performing a sleep clinical assessment Sleep Studies, Actigraphy and Sleep Diaries Sleep in different populations Complexity of Sleep Presentations What is insomnia? What is Melatonin Prescribing modified release melatonin as part of a comprehensive sleep management plan Explaining the NEW sleep MBS item numbers Mrs JP 76y.o lady Sleep maintenance insomnia and sleepiness Husband passed away 12 months ago onset of symptoms around this time No comorbitidies Referred directly for portable sleep study Moderate-Severe OSA RDI 22 per hour, SpO2 < 90% for 20 minutes Patient told by CPAP Retailer cannot drive, may have heart attack or die early must purchase a CPAP pump Daughter suggested patient is seen by sleep physician patient extremely anxious Low risk for OSA Hx suggestive of circadian dysrhythmia and age effects on sleep together with the effects of grief/ loneliness PSG at RMH Normal RDI 2 per hour and SpO2 > 90%. 1

2 WHERE WAS THIS PATIENT LET DOWN ABSENCE OF CLINICAL ASSESSMENT MODEL OF CARE? QUALITY OF SLEEP STUDY LACK OF EVIDENCE BASED CARE AND ADVICE? COMMERCIAL INTERESTS SLEEP APNOEA CENTRIC CARE SLEEP REGULATION OVERVIEW SLEEP PHYSIOLOGY Non REM hypocretin VLPO Extended VLPO Monoaminergic neurons REM SLEEP Cholinergic WAKE UPTODATE GABA, adenosine, melatonin ACH, histamine, NA, serotonin, dopamine, hypocretin HISTORY AND EXAMINATION Age and Gender Work shift work, retired, regular day shift Do you have a problem with sleep? Comorbidities (HTN, DM, CVD, Thyroid disease etc ) Medications/ Smoking/ Etoh/ Caffeine Sleep/Wake times sleep onset, sleep duration Nocturnal Awakenings and Cause (?Nocturia) Refreshing sleep Morning Headaches Snoring/ Observed Apnoeas/ Choking/ Dry Mouth Restless Legs/ Periodic Leg Movements/ Parasomnia Sleep paralysis/ hypnogogic hallucinations/ cataplexy Sleep Environment Menopause Status Mood/ Hx of Depression? Constipation, anosmia (if considering RBD) Epworth Sleepiness Score HISTORY AND EXAMINATION BMI Mallampati Score? Retrognathia? Nasal Obstruction Neck Circumference Signs of Parkinsonism (RBD) Signs of Anaemia Signs of Thyroid Disease 2

3 SLEEP STUDIES There are 4 levels of sleep studies choosing the wrong sleep study may result in poor patient outcome Sleep Studies consist of multiple signals all of which are prone to artefact. Artefact can significantly alter the results leading to incorrect diagnosis. Different models of care may produce very different results Treatment decisions in most cases can be determined either by the clinical assessment alone or together with the results of the sleep study Assessment: Sleep/wake Diary Actigraph SLEEP SYMPTOMS ARE COMMON AND OFTEN NOT SPECIFIC Snoring is common 50-80% of adult population Excessive daytime sleepiness has a wide differential diagnosis Apnoeic Events are commonly observed Nocturnal Awakenings may increase with age Nocturnal Choking asthma, GORD, apnoeic event, nocturnal panic attacks Control Insomniac TABLE 2. Risk factors for EDS based on multiple logistic regression ES, Effect size. Lancet Resp Med 2015 Apr;3(4): Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Heizner et al. Parameter ES P OR Depression 10.6 < Log BMI (kg/m 2 ) 4.3 < SD SD 2.10 Age 3.6 < SD SD 0.38 Typical sleep duration +1 SD SD 0.58 Diabetes (glucose > ) Smoke OHI > Bixler et al. JCEM

4 WHAT HAPPENS TO SLEEP WITH AGE? Changes to sleep micro-architecture Increased total sleep time in stage 1 sleep Reduction in amount of slow wave sleep (males > females) Small reduction in amount of REM Increased frequency of spontaneous cortical arousals Increased number of awakenings and reduced sleep efficiency Circadian Rhythm Changes Decline in sleep homeostasis Flattening of diurnal sleep/wake rhythm amplitude Impairment of phase shifting Phase advancement of sleep/wake cycle More frequent awakenings (however similar duration) and increased awareness of those awakenings PSYCHOSOCIAL/ ENVIRONMENTAL Environment Nursing Home/ Hospital/ Home Retirement loss of routine Loss of Spouse and Friends Fear of Death in Sleep Anxiety and Depression Many symptoms that older individuals complain about may be as a consequence of age related sleep changes therefore they may be normal Often the responses to these symptoms are abnormal Differences in patient perceptions and acceptance SLEEP IN WOMEN 53% of women aged experience one or more symptom of insomnia Ovarian steroids and sleep physiological changes in ovarian hormones influence sleep therefore puberty, menstrual cycle, pregnancy and menopause all will impact on sleep Oestrogen is the main sex hormone that suppresses sleep (promotes wake and decreases sleep particularly REM) MENOPAUSE Disturbed sleep and fatigue are common complaints in menopause Sleep onset insomnia Nocturnal awakenings (hot flushes, sleep disordered breathing) Sleep state misperception Depression/ anxiety states Probable circadian rhythm disruption Restless legs/ periodic leg movements 4

5 Sleep, Fatigue & Circadian Rhythm Abnormalities in Cancer Physiological Factors pain, nausea etc... Social and Cultural Factors Psychological Factors depression, grief CANCER RELATED FATIGUE Chronobiological Factors Morning bright light treatment may prevent overall fatigue from worsening during chemotherapy (39 women with breast cancer) Ancoli Israel et al. Supp Care in Ca 2011 CBT is an effective treatment for insomnia in breast cancer survivors Florentina et al. Melatonin may improve subjective sleep quality Chen et al. Breast Cancer Res Treat 2014 CANSLEEP PROGRAM EFFECTS OF COMMON MEDICATIONS ON SLEEP Benzodiazepines sleep latency, TST, SWS and REM, respiratory depression, exac. OSA and CSA Corticosteroids melatonin secretion - REM and SWS SSRIs REM, TST Opioids REM and SWS, respiratory depression, exac. OSA and CSA B Blockers awakenings, REM Post traumatic stress Obesity disorder Shift work OSA Anxiety and depression Sleep Menstrual disruption in disturbances, women chronic pelvic pain Premenstrual phase Adolescence, Ageing menarche Menopause Fibromyalgia, chronic pain Pregnancy New baby Cancer Hospital admission Potential causes of sleep disturbance in women Thanks to Prof Martha Hickey What is Insomnia? Subjective dissatisfaction with sleep quality or duration difficulty falling asleep waking up in the middle of the night or too early non-restorative or poor quality sleep. Associated daytime symptoms Functional impairments 25% of adults dissatisfied with their sleep, 10 15% report symptoms of insomnia Primary Insomnia Idiopathic Psychophysiological maladaptive conditioned response to an acute stressor where the bedroom is a place of heightened arousal Sleep state misperception mismatch between the patient s perceived and actual sleep duration/ quality. 5

6 pii: jc Predisposing Factors Precipitating Factors Perpetuating Factors Secondary Insomnia Active psychosocial stressor Poor sleep hygiene/ behaviours Psychiatric disorder (i.e. depression, anxiety) Abnormality of sleep causing arousal/ awakening (OSA, RLS, Chronic Pain, Hot Flushes) Drug or Substance (caffeine alcohol, B Blockers etc.) Belanger et al. Cognitive and Behavioural Practice 2012 Treatment Sleep hygiene Treat co-morbid disorders Behavioural Therapies (CBT) Bright Light Therapy +/- Melatonin Short term hypnotics (as needed), Buyse at al Michael J. Sateia, MD 1 ; Daniel J. Buysse, MD 2 ; Andrew D. Krystal, MD, MS 3 ; David N. Neubauer, MD 4 ; Jonathan L. Heald, MA 5 Pharmacotherapy for Insomnia Aimed at treating symptoms, not treating the cause MOST IMPORTANT MANAGEMENT STRATEGY IN MANAGING INSOMNIA IS TO ADDRESS SLEEP HYGIENE, THE CIRCADIAN RHYTHM AND TO CONSIDER COGNITIVE BEHAVIOURAL THERAPY (CBT-I) Geisel School of Medicine at Dartmouth, Hanover, NH; 2 University of Pittsburgh School of Medicine, Pittsburgh, PA; 3 University of California, San Francisco, San Francisco, CA; 4 Johns Hopkins University School of Medicine, Baltimore, MD; 5 American Academy of Sleep Medicine, Darien, IL Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for treatment of insomnia, as well as several drugs commonly used to Pharmacotherapy for Insomnia treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults. Methods: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted S PECIAL ARTICLES to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, Clinical and patient Practice values and preferences. Guideline Literature reviews for are the provided Pharmacologic for those pharmacologic agents Treatment for which sufficient of evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations. Chronic Insomnia in Adults: An American Academy of Sleep Medicine Recommendations: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of Clinical chronic insomnia Practice in adults, when Guideline such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all Michael patients, J. but Sateia, should MDnot 1 ; Daniel be construed J. Buysse, as an MDindication 2 ; Andrew of D. ineffectiveness. Krystal, MD, MSGRADE 3 ; David recommendation N. Neubauer, MDstrengths 4 ; Jonathan do L. not Heald, refer to MAthe 5 magnitude of treatment effects 1 Geisel in School a particular of Medicine patient, Dartmouth, but rather, Hanover, to the strength NH; 2 University of evidence of Pittsburgh in published School of data. Medicine, Downgrading Pittsburgh, the PA; quality 3 University of evidence of California, San these Francisco, treatments San Francisco, predictable CA; in 4 GRADE, Johns Hopkins due University to the funding School source of Medicine, for most Baltimore, pharmacological MD; 5 American clinical Academy trials of and Sleep the Medicine, attendant Darien, risk IL of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, 1. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual 2. We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to 3. We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and 4. We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) treatment of chronic insomnia in adults. 5. We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) Methods: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted 6. We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to 7. We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and 8. We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to 9. We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) establish recommendations. The AASM Board of Directors approved the final recommendations. 10. We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) Recommendations: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment 11. We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most (WEAK) circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for 12. We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment 13. We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable 14. We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible Keywords: insomnia, treatment, pharmacologic, guideline trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by Citation: Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) 2. We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) 3. We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) 4. We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) 5. We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) 6. We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) 7. We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) There is a lot of WEAK evidence 6

7 Glass etal, sedative hyponotics in older people with insomnia: meta-analysis of risks and benefits, BMJ, 2005 Glass etal, sedative hyponotics in older people with insomnia: meta-analysis of risks and benefits, BMJ, 2005 Number needed to treat: 13 Number needed to harm: 6 Benzodiazepines and GABA A receptor Enhancers in Sleep Atypical antipsychotics Benefits Effective Harms Next day fatigue Tolerance/Dependence/Addiction Functional impairments Increased falls risk Benefits Questionable for primary insomnia Harms Increase in cardiovascular mortality, metabolic syndrome Thompson, sleep medicine, 2016 Correll, World psychiatry, 2015 Anti-histamines in sleep Orexin antagonists - Suvorexant Benefits Effective Harms Next day sleepiness Falls Absence of data regarding driving safety and mortality. benefits effective in producing sleep harms Next day somnolence/excess fatigue Abnormal dreams Mild rebound insomnia was observed This is still a new drug 7

8 MELATONIN Night time peak melatonin levels in subjects of different ages Produced in the pineal gland Peak level post sleep onset suppressed during the day Reduces sleep latency, increases sleep efficiency and total sleep time Together with morning bright light, Melatonin controls the circadian rhythm Uptodate 2010 Efficacy data for melatonin (prolonged-release) Efficacy data for melatonin (prolonged release) Wade etal, BMC medicine, 2010 Wade etal, BMC medicine, 2010 Melatonin (prolonged-release): evidence for harm Melatonin therapy Collisions in a simulation Recall after medication Benefits Evidence for efficacy Does not appear to be associated with similar risks of cognitive impairment, postural instability, and tolerance Harms Serious adverse events are low?interference with ovulation? Still and emerging therapy, but gaining more widespread use. Otani etal, Human Psychopharmacology,

9 How to prescribe Melatonin MR in insomnia Manage those factors that may be contributing to insomnia sleep hygiene/ routine, medications, patient s expectations, pain/ grief/ anxieties, other sleep conditions (note OSA may be present but often a bystander and may not require any treatment at all) Consider CBT-I Add melatonin together with either a self delivered, on line delivered or sleep psychologist delivered CBT program Melatonin MR 2mg taken minutes prior to usual bedtime (consistency with timing is important) Increasing dose does not improve efficacy Trial for 3 months before re-assessing If no improvement consider referral to sleep physician and/or sleep psychologist Circadian Rhythm Disorders Delayed Sleep Phase Syndrome Advanced Sleep Phase Syndrome Non-24 hour circadian rhythm Free-running rhythm Jet Lag Shift Work Disorder Seasonal Affective Disorder Treating Circadian Rhythm Abnormalities Using combination bright light therapy and melatonin (short acting) to either phase advance or phase delay patient Doses of Melatonin 0.5-5mg approximately 30 minutes before bed time Gradually bring forward wake time and then move sleep time forward a couple of days later Ensuring appropriate sleep hygiene Avoiding Day time naps Jet Lag west is best, east is a beast Melatonin (short acting) 0.5-5mg 30 minutes prior to likely bed time in new time zone commencing 2-3 days before travel Try to arrive in the morning Sunlight and exercise and avoid napping until bed time when arriving at destination NEW SLEEP ITEM NUMBERS WHY Overdiagnosis of OSA CPAP centric models of care Concerns regarding quality control in a number of commercial sleep study entities Failure to recognize other sleep issues where OSA may be clinically irrelevant (and not necessarily requiring treatment) REFERRER RESPONSIBILITY If OSA suspected and request for direct referral for sleep study complete validated questionnaires to determine likelihood of significant OSA Recognise variability in quality between service providers and protect patients from services that may have conflicts of interest or perform poor quality studies EPWORTH SLEEPINESS SCALE Use the following scale to choose the most appropriate number for each situation: 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Chance of Dozing (0-3) Sitting and reading Watching TV Sitting, inactive in a public place (e.g. a theatre or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in the traffic M.W. Johns Lower Normal Daytime Sleepiness 6-10 Higher Normal Daytime Sleepiness Mild Excessive Daytime Sleepiness Moderate Excessive Daytime Sleepiness Severe Excessive Daytime Sleepiness 9

10 STOP-BANG Sleep Apnea Questionnaire Chung F et al Anesthesiology 2008 and BJA 2012 High risk of OSA: Yes 5-8 Intermediate risk of OSA: Yes 3-4 Low risk of OSA: Yes 0-2 STOP Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)? Do you often feel TIRED, fatigued, or sleepy during daytime? Has anyone OBSERVED you stop breathing during your sleep? Do you have or are you being treated for high blood PRESSURE? BANG Yes Yes Yes Yes BMI more than 35kg/m2? Yes No AGE over 50 years old? Yes No NECK circumference > 16 inches (40cm)? Yes GENDER: Male? Yes No TOTAL SCORE No No No No No TAKE HOME MESSAGES Sleep presentations may be complex and often there are a number of factors/conditions that contribute to patients symptoms OSA can be a by-stander and not clinically relevant i.e. neither a cause for symptoms or a risk for long term health consequences Insomnia is best managed with non pharmacological strategies (CBT-I) Benzodiazipines, Z drugs, antihistamines may be useful for short term management of insomnia but not indicated for long term management MR Melatonin is useful in managing insomnia in patients > 55y.o however should be timed and part of a sleep/wake routine Melatonin short acting 0.5-5mg is effective in phase shifting circadian rhythm and in reducing impact of jet lag Mobile Phone admin@jeremygoldin.com.au THANK YOU