Case 1. A. Insomnia B. Restless leg syndrome C. Peripheral neuropathy D. Osteoarthritis of the hip. Disclosures. Diagnosis for trouble falling asleep

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1 Disclosures I have no disclosures Case 1 Liza Ashbrook, MD Assistant Clinical Professor UCSF Department of Neurology History of Present Illness Diagnosis for trouble falling asleep 70-year-man with obstructive sleep apnea and right hip replacement who presents for trouble falling asleep He complains of leg discomfort and an overwhelming urge to move his legs at night, feels legs will jump on their own, and he often gets up to walk around when in bed at night to relieve this urge Symptoms began years ago and have worsened over time, hard to tolerate for the past two months Symptoms keep him up at night on 5/7 nights per week A. Insomnia B. Restless leg syndrome C. Peripheral neuropathy D. Osteoarthritis of the hip I n s o m n i a R e s t l e s s l e g s y n d r o m e 96% 2% 2% 0% P e r i p h e r a l n e u r o p a t h y O s t e o a r t h r i t i s o f t h e h i p 1

2 Diagnosis of restless leg syndrome Additional history Also called Willis-Ekbom disease (WEB) Criteria: An urge to move the legs, often triggered by unpleasant sensation Begins/worsens during inactivity Urge relieved, at least in part, by movement Worse during the evening Symptoms cause distress or impairment ** rule out other etiologies including myalgias, venous stasis, edema, cramping, position, habitual foot tapping PMH: Obstructive sleep apnea (OSA), hypertension, hyperlipidemia, degenerative joint disease Medications: pramipexole 0.25 mg nightly, tramadol 50 mg prn, hydrocodone/acetaminophen 5/325 prn, diphenhydramine prn Physical Exam: No hip pain, intact strength and sensation in legs What would you choose as initial nightly treatment? A. Pregabalin (Lyrica) 75 mg B. Pramipexole (Mirapex) 0.5 mg C. Carbidopa/levodopa (Sinemet) 25/100 D. Ropinirole (Requip) 0.25 mg E. Clonazepam (Klonopin) 0.5 mg 12% 36% 4% 43% 6% What would you choose as initial nightly treatment? A. Pregabalin (Lyrica) 75 mg B. Pramipexole (Mirapex) 0.5 mg C. Carbidopa/levodopa (Sinemet) 25/100 D. Ropinirole (Requip) 0.25 mg E. Clonazepam (Klonopin) 0.5 mg P r e g a b a l i n ( L y r i c a ) 7 5 m g P r a m i p e x o l e ( M i r a p e x ) 0. 5 m g C a r b i d o p a / l e v o d o p a ( S i n e m e.. R o p i n i r o l e ( R e q u i p ) m g C l o n a z e p a m ( K l o n o p i n ) 0. 5 m g 2

3 Recommended dosing Dopamine Agonists Starting Dose Maximum recommended dose Pramipexole (Mirapex) 0.125mg 0.75mg Ropinirole (Requip) 0.25mg 4mg Rotigotine (Neupro) 1mg/day 3mg/day Alpha-2 Delta Ligands Starting Dose Maximum recommended dose Pregabalin (Lyrica) 50-75mg mg Gabapentin (Neurontin) mg mg Gabapentin enacarbil (Horizant) mg mg D. Garcia-Borreguero et al. / Sleep Medicine 21 (2016) 1 11 Dopamine agonists vs Alpha-2-delta ligands: NEJM 2014 Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome (sponsored by Pfizer) 719 participants IRLS severity at 12 weeks vs placebo pramipexole 0.5 mg (<0.001) pregabalin 300 mg (<0.001) not pramipexole 0.25 mg (0.36) At 52 weeks: More augmentation with pramipexole Pregabalin 300 mg 5/235 (2.1%) Pramipexole 0.25 mg 12/225 (5.3%, P=0.08) Pramipexole 0.5 mg 18/235 (7.7%, P=0.001) Allen RP et al. NEJM, 2014 Additional history He has noted leg discomfort on airplane rides for many years but did not seek care In 2011 periodic leg movements were noted in a sleep study, he was questioned about restless leg symptoms and was started on pramipexole 0.25mg (note recommended starting dose is mg), this helped for several years In 2014 symptoms returned and pramipexole dose increased from 0.25 mg to 0.5 mg to 1 mg (maximum recommended dose is 0.75 mg) The time of onset and intensity of his symptoms worsened: starting 5-6 pm, now include arm symptoms, more severe Characteristics of augmentation RLS symptoms start earlier in the day (two hours used as cut off) more severe faster onset of symptoms following rest affect other parts of the body (arms) shorted duration of medication efficacy and/or paradoxical response to treatment 3

4 Management of augmentation: step 1 Check serum iron: Serum ferritin goal >50-75 ng/ml Screen for other triggers such as exacerbating medications including dopamine antagonists, antihistamines, antidepressants (except bupropion) sleep deprivation or sleep disruptor (OSA) Medical conditions such as renal insufficiency or pregnancy alcohol use decreased mobility Management of augmentation: Step 2 1. If mild, consider keeping the same medication a) move the timing earlier b) split the dose to two times c) increase the dose if still below maximum recommended dose (do only once) 2. Change medications to long acting DA agonist (rotigotine) or alpha-2- delta ligand a) Switch medications b) Cross titration c) Wash out period Our patient further clinical course Reduced pramipexole to 0.5 then 0.25, but was increasingly using tramadol and hydrocodone/acetaminophen from hip surgery Ferritin 71.2, iron tabs did not help Cross taper: gabapentin 300mg ->600mg with wean of pramipexole Timing did improve, but symptoms still very bothersome in legs and arms Rotigotine patch prescribed, patient did not want to pursue DA agonist Changed to gabapentin enacarbil (Horizant) without improvement Told stop taking diphenhydramine prn Still taking 2 hydrocodone/acetaminophen nightly to control symptoms After 2.5 months of inadequately treated symptoms despite trial of gabapentin, gabapentin enacarbil, iron supplementation, stopping pramipexole, tramadol, and diphenhydramine and prescription of rotigotine patch What would you do next? A. Push for trial of rotigotine patch (Neupro) B. Pregabalin 75 mg with plan to increase to 150 C. Intravenous iron infusion D. Methadone 5 mg P u s h f o r t r i a l o f r o t i g o t i n e p... P r e g a b a l i n 7 5 m g w i t h p l a n t... 71% 13% 13% 4% I n t r a v e n o u s i r o n i n f u s i o n M e t h a d o n e 5 m g 4

5 Our patient Management of refractory RLS He has no personal history of substance abuse Methadone 5mg started Provided great relief and patient reported urge to move the legs resolved Around the clock symptoms DA agonist and alpha-2 delta ligand do not work Consider opioids Low dose oxycodone Methadone **Screen for history of substance abuse, use of other sedating medications Opioids for RLS Opioids for RLS 10 year longitudinal study (Silver et al. Sleep Medicine, 2011) Subjects: 164 patients on pramipexole, 77 patients on pergolide, and 76 patients on methadone. First year discontinuation (side effects): pramipexole 17%, pergolide 23%, methadone 15% Annual discontinuation rate over 5 years: pramipexole 9%, pergolide 8%, methadone 0% Methadone dose: Median dose at six months: 10mg, median daily dose after 8 10 years no more than 10 mg greater than at 6 months RCT of long acting oxycodone/naloxone 5mg/2.5mg (Trenkwalder et al. Lancet Neurol 2013, study funded by Mundipharma Research) Subjects: 132 to prolonged release oxycodone/naloxone vs 144 to placebo At 12 weeks of treatment mean IRLS rating scale drop on oxycodone/naloxone: 16.5 vs placebo: 9.4 (p<0 0001) Before using ensure risk of abuse is low by screening for a history of substance abuse 5

6 A note about supplemental iron Data mixed slow but can be very effective for some patients PO iron: 325 mg of ferrous sulfate BID, combine with vitamin C IV iron: (Cho Y et al. Sleep Med 2013) Low-molecular weight iron dextran 250mg weekly x 4 (total dose of 1 g) Side effects: allergic reaction headache, nausea, muscle pain, edema One and six weeks after treatment and the treatment benefits lasted from one month to 22 months. NOTE parenteral infusion risk with low molecular weight iron dextran is lower (1 per 200,000) than that with high molecular weight iron dextran. Other formulations also available. Take home points RLS Pitfalls Starting medication when not needed or prn dosing would be enough Starting higher dose than needed to control symptoms Escalating DA agonist dose despite worsening symptoms Missing iron deficiency Missing exacerbating medications that can be safely discontinued For severe RLS symptoms Consider supplemental intravenous iron Consider long acting, low dose opioid Case 2 Patient history 20-year-old woman with a history of chronic refractory migraine and hip pain who presents for trouble falling asleep and staying asleep for 1.5 years Sleep/wake pattern: Bedtime: 10 pm, sleep latency: 6 hours, wake time: 5 pm When awake in bed at night watches television, colors, talks on the phone Awakenings from sleep: 6-7 times with frequent trouble falling asleep Ideal (dessert island) bedtime: 2 am; Goal sleep schedule: 11:30 pm-7:30 am Never feels well rested, endorses daytime sleepiness Snores sometimes, no gasping, choking, witnessed pauses 6

7 Diagnosis Typical habitual sleep period A. Delayed sleep-wake phase disorder B. Chronic insomnia C. Obstructive sleep apnea D. Idiopathic hypersomnia 75% 17% 2% 7% Advanced sleep-wake phase disorder Delayed sleep-wake phase disorder D e l a y e d s l e e p - w a k e p h a s e d... C h r o n i c i n s o m n i a O b s t r u c t i v e s l e e p a p n e a I d i o p a t h i c h y p e r s o m n i a 6pm 12am 6am 12pm Hour of the day Circadian misalignment Treatment to shift her schedule DSPS accounts for 10% of insomnia patients Negative health impacts of circadian misalignment Negative effect on memory, concentration, attention (Wright et al. Journal of Cognitive Neuroscience. 2006) Causes insulin resistance (Scheer et al. Proceedings of the National Academy of Sciences. 2009) Possible cancer progression (Hahm et al. Chronobiology international. 2014) May negatively impact seizure control (Kendis et al. Behavioural neurology. 2015) A. Begin rising at desired wake time of 7:30 am and get sunlight exposure on waking B. Get into bed at habitual sleep time (i.e. 4 am not 10 pm) and take melatonin 5mg, then move bedtime progressively 30 minutes earlier everyday until at desired sleep time C. Get into bed at habitual sleep time (i.e. 4 am not 10 pm) and progressively delay bedtime by 2 hours until at desired bedtime B e g i n r i s i n g a t d e s i r e d w a k e... 32% G e t i n t o b e d a t h a b i t u a l s l e.. 51% G e t i n t o b e d a t h a b i t u a l s l e.. 17% 7

8 Chronotherapy Our patient Delay bedtime by 2-3 hours each night until at desired bedtime. Based on idea that it is easier for those with delayed sleep phase disorder to delay bedtime than to awaken earlier No randomized control trials, only case series Evidence from case series that there is a high rate of relapse, one report of resultant free-running schedule She was able to shift schedule using chronotherapy to desired time for several months She then traveled over the summer and after return had worsening of headaches, no longer able to keep her schedule Bedtime: 11 pm Sleep latency: 5 hours Wake time: 2 pm (variable) Anchors of circadian treatment: melatonin and light Entrainment of the biologic clock is achieved primarily by light Other zeitgeibers (environmental cues that help entrain): physical activity, social interaction, eating Light regulates the production of melatonin by the pineal gland Melatonin release begins in the evening 19:30-21:30 in dim light conditions, peaks overnight, and is suppressed by bright light Recommended melatonin dosing to shift the clock (assume bedtime is when patient is falling asleep) A. 3 mg 30 minutes prior to bedtime B. 10 mg 30 minutes prior to bedtime C. 0.5 mg 5 hours prior to bedtime D. 3 mg 5 hours prior to bedtime 37% 32% 5% 26% 3 m g 3 0 m i n u t e s p r i o r t o b e m g 3 0 m i n u t e s p r i o r t o b m g 5 h o u r s p r i o r t o b e d... 3 m g 5 h o u r s p r i o r t o b e d t i m e 8

9 Recommended melatonin dosing to shift the clock How to use melatonin A. 3 mg 30 minutes prior to bedtime B. 10 mg 30 minutes prior to bedtime C. 0.5 mg 5 hours prior to bedtime D. 3 mg 5 hours prior to bedtime Melatonin can be used to help with sleep initiation or clocking shifting It can be a soporific (sleep aid) at 3-5 mg at bedtime For clock-shifting, dose of melatonin is less important than the timing of the dose 0.5 mg similar to 3 mg Give 5 hours before bedtime Dim light melatonin onset Core body temperature minimum Dim light melatonin onset Core body temperature minimum Typical habitual sleep sleep period period Typical habitual sleep sleep period period Melatonin-> delay Light -> advance Melatonin -> advance Light -> delay 6pm 12am 6am 12pm 6pm 12am 6am 12pm 9

10 Our patient Blue light For circadian misalignment: 30 minutes of bright light (sunlight or light box of 10,000 Lux) on waking and melatonin 0.5 mg 5 hours before bedtime Progressive move light exposure, melatonin, and wake 30 minutes earlier each day Do not go to bed until sleepy, limit time in bed Consider: sleep study (frequent awakenings, snoring, daytime sleepiness) Melanopsin photoreceptors respond most strongly to blue light (around nm) This suppresses melatonin release Concern that blue light (from indoor lighting, computers, cell phones) in the evening may phase delay some users Consider blue blocking glasses, phone applications (Night Shift on iphone, Twilight or other apps on Android) Summary Think about the interplay of sleep with commonly treated neurologic conditions (headache, epilepsy, multiple sclerosis, concussion, Parkinson s) Consider diagnosis of delayed sleep-wake phase disorder for those with complaint of trouble falling asleep as night Bright light (sunlight or light box) with melatonin can be powerful tools to help shift the circadian clock and improve sleep Do you have patients with a neurologic or psychiatric diagnosis and sleep concerns? Consider referral to UCSF s new Neuro/Psyc Sleep Clinic (housed within neurology) Phone: Fax: