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Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Alan G. Pocinki, M.D. Ehlers-‐Danlos Na.onal Founda.on Learning Conference
August 1-‐3, 2013
Disclaimers � “Off-‐label” uses of medica.ons � No financial conflicts of interest
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Overview � Autonomic nervous system (ANS) regulates all body processes, including sleep
� ANS dysfunc.on is very common in Ehlers-‐Danlos and other hypermobility syndromes, and underlies many of their symptoms
� The most common type of sleep disorder seen in the hypermobility syndromes appears to have an autonomic basis
Basics of the ANS � Sympathe.c nervous system: “fight or flight,” the accelerator
� Parasympathe.c nervous system: “rest and digest,” the brake
Autonomic Instability “Failure to Modulate” � Concept of adrenaline reserve � Central paradox: the lower the reserves, the more exaggerated your stress response, so your body “overresponds” to minor stresses
� The overresponse oXen triggers an overcorrec.on, then an overresponse…
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Sympathetic and Parasympathetic Activity with Autonomic Maneuvers
Normal EDS with Dysautonomia
A B C D E F
A=Baseline, B=Deep Breathing, C=Rest, D=Valsalva, E=Rest, F=Stand
Sympathe.c and Parasympathe.c Ac.vity Before and AXer Treatment
At Diagnosis After 18 months of treatment
A=Baseline, B=Deep Breathing, C=Rest, D=Valsalva, E=Rest, F=Stand
Non-‐Restora.ve Sleep in EDS � Frequent arousals and awakenings � Li\le or no deep sleep
Normal Sleep
Non-‐Restorative Sleep
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Sleep “Mispercep.on” Another Paradox
� Many EDS pa.ents report that they “sleep fine.” � “I’m a great sleeper. I can sleep any .me, anywhere.” � But… do you feel rested when you get up?
� “No, I never feel rested.” � “I wake up feeling like I haven’t slept.” � “I don’t think I know what feeling rested would feel like.”
� Not just a problem in EDS, e.g. as many as 90% of people with sleep apnea are not aware of it
Heart Rate Variability Associated with Sleep Disruptions
Sleep Stages
Heart Rate
N3 N2
N1 REM
Awake 60
80
100
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Heart Rate Variability-‐-‐Another Paradox � The lower sympathe.c ac.vity is, the greater heart variability, or
� The more exhausted you get, the more “depleted” your energy reserves, the more exaggerated heart rate fluctua.ons will be
� The more your heart rate fluctuates, the more disrupted your sleep (not to men.on day.me ac.vi.es)
� The more disrupted your sleep, the more exhausted you get—a nasty vicious cycle
Non-‐Restora.ve Sleep � Frequent arousals and awakenings � Li\le or no deep sleep
Normal Sleep
Non-‐Restorative Sleep
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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And to Improve Autonomic Func.on, You Need to Improve Sleep
Sympathe.c and Parasympathe.c Ac.vity Before and AXer Treatment
At Diagnosis After 18 months of treatment
A=Baseline, B=Deep Breathing, C=Rest, D=Valsalva, E=Rest, F=Stand
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Treatment of Non-‐Restora.ve Sleep � Address underlying causes of autonomic dysfunc.on: � Pain � Fa.gue � Dehydra.on � Low blood sugar � Emo.onal/cogni.ve stresses
Restoring Autonomic Balance, or Refilling the Pool
� Be\er sleep—quan.ty and quality � Adequate—really—pain control � Don’t “push through” fa.gue; take breaks � Adequate salt and fluid � Avoid hypoglycemia � Minimize emo.onal and other stresses
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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EDS, Untreated (Sleep Lab)
EDS, Untreated (Same Pa.ent, Home Sleep Monitor)
EDS, AXer Treatment (Home Sleep Monitor)
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Treatment of Sleep Disorders
� Don’t overlook the basics: � Good sleep hygiene � Comfortable ma\ress � Dark and quiet � Elevate head of bed (if lightheaded during the day)
� Treat sleep apnea, limb movements only if significant
Treatment of Sleep Disorders: Medica.on
� Complex medica.on “regimen” is oXen required: � Mul.ple medica.ons with complementary effects, e.g. one medica.on for pain, one to reduce arousals, one to increase deep sleep
� Finding the right combina.on can be a frustra.ng trial and error process
� Home sleep monitor can be helpful
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Treatment of Sleep Disorders: Medica.on
� Block extra adrenaline (beta and alpha blockers, clonidine and guanfacine)
� Offset extra adrenaline (benzodiazepines, SSRI’s) � Reduce pain (analgesics, muscle relaxants, Neuron.n™, Lyrica™)
� Increase deep sleep (trazodone, amitryp.line, doxepin)
� Use “Sleeping pills” sparingly
Beta Blockers � Propranolol
� Start with 10 mg at bed.me � Increase by 10 mg every 4-‐5 days un.l fewer awakenings, side effects, or no further benefit
� Switch to long-‐ac.ng if needed � Take some earlier to offset “second wind” � OXen need smaller day.me dose as well � If ineffec.ve or not tolerated, try a different one
Other Beta Blockers � Metoprolol
� Start with half a 25 mg tablet (metoprolol tartrate) � Increase by half a tablet every 4-‐5 days � Add long-‐ac.ng (metoprolol succinate) for day.me symptoms
� Nadolol � Generally safe in pa.ents with asthma � Start with 20 mg. increase by 20 every 4-‐5 days � Add smaller AM dose if needed for day.me symptoms
� Carvedilol � Start with 3.125 mg, increase by one tablet every 4-‐5 days � Add smaller AM dose if needed for day.me symptoms
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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Clonidine/Guanfacine � Clonidine
� Start with 0.1 mg at bed.me � Increase by 0.1 mg no sooner than one week � No more than 0.3 mg � Usually lasts about 6 hours
� Guanfacine � Very similar to clonidine but lasts longer � Recently remarketed as Intuniv™ for ADD
Alpha Blockers � Prazosin best studied, shown to reduce nightmares in PTSD, where “a hypersensi.vity to adrenaline triggered many of their nightmares.” In a VA study, 75-‐80% of PTSD pa.ents stopped having nightmares.
� Start with 1 mg, increase gradually;usual dose is about 5mg, but average dose in VA study was about 10 mg
� Can worsen orthosta.c intolerance � Not clear if combina.on alpha-‐beta blockers (e.g. carvedilol) are as effec.ve, but probably not.
Benzodiazepines � All have beneficial proper.es:
� Seda.ve � An.-‐anxiety � Muscle relaxant � An.-‐movement, an.convulsant � “An.-‐adrenaline”
� But also poten.al problems: � Impair cogni.on, motor performance � Depress mood, respira.on � Cause or worsen fa.gue � Tolerance � Dependence � Withdrawal
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Some Common Benzodiazepines � Clonazepam (Klonopin™)
� Longest-‐las.ng, most likely to have residual effects � Also effec.ve for restless leg, PLMS
� Diazepam (Valium™) � Typically lasts about 8 hours � Probably best muscle relaxant
� Temazepam (Restoril™) � Typically lasts about 7 hours � Capsule limits dosage adjustment
� Lorazepam (A.van™) � Typically lasts about 6 hours � Metabolized differently (less variability, interac.ons)
Analgesics � An.-‐inflammatories
� NSAIDs: Ibuprofen, Naproxen, Meloxicam, Celebrex™etc � Prednisone
� Tramadol, short-‐ and long-‐ac.ng � Narco.cs, short-‐, long-‐ac.ng; patches (fentanyl, Butrans™) � Cymbalta™, Savella™ � Gabapen.n (Neuron.n™), Lyrica™ � Lidoderm™, Flector™, Voltaren Gel™, Pennsaid™
Muscle Relaxants � Cyclobenzaprine
� Shown to improve sleep quality in fibromyalgia � Has analgesic, seda.ve, muscle relaxant proper.es
� Soma � Less seda.ng, ? more analgesic effect, especially with narco.cs
� Skelaxin � Less seda.ng, some can tolerate day.me doses
� Tizanidine � More seda.ng, high margin of safety
� Baclofen � Potent, use for severe painful spasm only
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Other Agents � Trazodone
� Probably most effec.ve at increasing deep sleep � Low dose, 50-‐150 mg, most people take 50 mg
� Amitryp.line � Also increases deep sleep, especially with pain � Start at 10 mg, most people take 20-‐40 mg
� Doxepin � Enhances sleep more at lower doses � 10 mg tablet, liquid, or Silenor™ 3 mg, 6 mg
� DDAVP (Desmopressin)?
“Sleeping Pills” � Zolpidem, short-‐ and long-‐ac.ng
� Doesn’t reduce arousals or improve sleep architecture � Use for onset/maintenance only if needed, e.g. un.l other meds effec.ve � Can cause retrograde amnesia � Zolpidem usually lasts 5 hours, ER about 7
� Lunesta � Doesn’t seem to reduce arousals or improve sleep architecture � Occasionally helps with sleep onset and maintenance, e.g. un.l other
medica.ons become effec.ve � Usually lasts about 7 hours
� Zaleplon � Good for sleep onset, especially gesng back to sleep � Lasts 2-‐3 hours, no cogni.ve impairment
� Melatonin/Rozerem � Occasionally helpful for Circadian problems e.g. evening “second wind”
An.depressants � SSRI’s oXen cause shallower sleep, more dreams
� Prozac worst, Lexapro best � Use lowest effec.ve dose, consider liquid formula.ons
� Cymbalta sleep neutral if taken in AM � Tricyclics, e.g. amitryp.line, generally improve sleep, but oXen cause day.me seda.on at an.depressant doses
� Wellbutrin impairs sleep if taken late in day, so take once-‐daily (XL) form early in day or consider AM only dosing of twice a day (SR) form
� Remeron can improve sleep; also can cause weight gain
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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DO YOU HAVE ANY DATA?
ONLY THE TWO-‐LEGGED KIND!
� Last night I took one metropolol and the effect was astounding. I woke up at 4am wide awake. For the first .me in my life I woke up refreshed and didn't want to fall back to sleep. So I got up and started the day! (Before if I have had to get up while it was dark I felt physically ill, like I was going to throw up.) I was hungry for breakfast too. I'm sisng here ea.ng carrots and hummus. Usually I'm not hungry un.l noon. Amazing.
Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference
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� “I am stunned, amazed, and grateful at the benefits of taking propanolol. The improvement in my sleep quality alone is fantas.c.”
� “The medicine you gave me is amazing. Two worked great but three worked even be\er. I forgot to take it one night and slept 12 hours and felt terrible. The next night I took it and slept 6 hours and felt great.”
� The metoprolol seems to help considerably with my sleep. In fact, between metoprolol, flexeril, and good old advil, I’m able to fall asleep and stay asleep. The metoprolol really seems to be par.cularly important for quality of sleep.
� I just wanted to let you know again how much the Prazosin helps me. I am sleeping be\er now than I ever have in my life. If I get 7 hours of sleep, it's always uninterrupted and I awake feeling rested and ready for the day. It's changed my life!
Summary � The most common type of sleep disorder seen in the hypermobility syndromes appears to be characterized by excessive heart rate variability at night.
� Medica.ons to suppress, offset, or block this excessive ac.vity are effec.ve in improving sleep quality, as measured both by sleep study data and symptom relief.
Summary (con.nued) � Improving sleep and minimizing day.me stresses helps to replenish autonomic reserves, which in turn improves day.me autonomic balance and also helps improve sleep, which in turn improves day.me func.on, which in turn improves circadian rhythms and sleep, which …..
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EDNF (Sandy Chack) and Dr. Heidi Collins for invi.ng me Dr. Peter Rowe for encouraging me when others thought I was nuts Dr. Clair Francomano and Dr. Fraser Henderson for teaching me about EDS and s.mula.ng my interest in it All my pa.ents, for having the confidence in me to let me experiment on them and learn from them!