Steven D Bender DDS Fellow, American Headache Society Fellow,
American Academy of Orofacial Pain North Texas Center For Head,
Face & TMJ Pain [email protected] Pharmacotherapeutics:
Headache and Sleep
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Steven D Bender DDS
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Disclosure I have received consulting honoraria from Nautilus
Neurosciences and am a member of their advisory board
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Steven D Bender DDS Drugs for Sleep
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Steven D Bender DDS Diagnosis, NOT complaint, should determine
treatment and medication use. Hypnotic drugs do little to directly
enhance sleep. The major benefit is to reduce arousal, therefore
allowing sleep to occur.
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Steven D Bender DDS Guidelines for Treating Chronic Insomnia
Patient education; goals, expectations, potential side effects,
interactions, other tx options, augmentation, tolerance, rebound
insomnia Regular follow-up; efficacy, AEs, need for ongoing
medication Lowest possible dose; taper when condition allows Use
CBT when possible
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Steven D Bender DDS Chronic pharmacotherapy may be indicated
for long term use in those with severe or refractory insomnia or
chronic comorbid illness Long term prescribing implies consistent
follow up, ongoing assessment, monitoring for AEs Long term therapy
may be qhs, intermittent, or PRN Principles for Treating Chronic
Insomnia
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Steven D Bender DDS Options for Treating Insomnia OTC ETOH
Alternative meds Benzos New Z drugs (benzo receptor agonist)
Melatonin and receptor agonists Antidepressants AEDs Anti-psychotic
meds
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Steven D Bender DDS OTC Sleep Aids First generation
anti-histamines diphenhydramine, doxylamine, etc. Drowsiness major
side effect Also; anticholinergic at higher doses Not recommended
by AASM guidelines due to lack of efficacy and safety data
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Steven D Bender DDS ETOH Causes sedation; may promote
relaxation and sleep onset ETOH associated sleep not normal sleep
Increased N1 and N2 Decreased N3 Decreased REM Increased arousals
Evidence lacking of safety and efficacy
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Steven D Bender DDS Alternative Therapies Valerian Kava-Kava
Hops Lavender Passion flower Skullcap Data on effectiveness and
safety limited
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Steven D Bender DDS Benzodiazepines (BZ) Onset of Generic Brand
Action (Min) life estazolam none 15 - 30 interm flurazepam Dalmane
15 - 30long temazepam Restoril 45 60 interm (H2O rather than lipid
soluble) triazolam Halcion 15 - 30short (sublingual administration
possible)* clonazepam Klonapin 15 30 long Sleep Academic Award
12
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Steven D Bender DDS Benzodiazepines - Like (non-BZ but mediated
through GABA receptors) Onset of Generic Brand Action (Min) life
zolpidemAmbien15 - 30Short zaleplonSonata15 - 30 Ultra short
eszopiclone Lunesta 15 30 Short Sleep Academic Award 13
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Steven D Bender DDS Adverse Events Complex Sleep Related
Behaviors Sleep driving, walking, eating Especially when combined
with alcohol or other sedating drugs Occurs in 1 in 1,000 pts Pts
should be warned about this side effect and to avoid other sedating
drugs
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Steven D Bender DDS Sublingual Zolpidem Zolpidem sublingual
tablets (Intermezzo) Approved November 2011 Dose 1.75 mg (women)
and 3.5 mg (men) Approved for middle of the night insomnia Should
be taken when at least 4 hours of bedtime remain
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Steven D Bender DDS Summary of Benzodiazepines Use short acting
drugs without active metabolites: temazepam, zolpidem, zaleplon Use
longer acting drugs with caution but when necessary to achieve
daytime anxiolytic effects Periodic follow up important to assess
for efficacy, dose escalation, side effects Use in combination with
CBT when possible
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Steven D Bender DDS Ramelteon (Rozerem) Melatonin receptor
agonist approved for use in insomnia Affinity for MT-1 and MT-2
receptors 3-5X greater affinity than melatonin 17X more potent No
affinity for BNZ receptor
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Steven D Bender DDS Rapid absorption, metabolized in the liver,
excreted via the kidneys Contraindicated in liver disease Inhibitor
of CYP 1A2 system Increased concentrations of ETOH, azole
antifungal drugs, fluvoxamine Decreased rifampin levels
Ramelteon
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Steven D Bender DDS Antidepressants Major depressive disorders
associated with disrupted sleep Increased sleep latency, wake after
sleep onset, early morning awakenings Decreased slow wave sleep
Early initial REM latency and increased REM density Antidepressants
used to treat insomnia Takes advantage of anticholinergic and
antihistamine properties
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Steven D Bender DDS Tricyclic Antidepressants Amitriptyline
Suppresses REM in both depressed and non- depressed pts. Increases
sleep efficiency and total sleep time Doxepin Reduces sleep latency
and increased total sleep time REM suppressant at higher doses
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Steven D Bender DDS Trazadone Commonly used drug for insomnia
Associated with significant sedation Less frequently used in mono
therapy in depression Improves sleep efficiency, increased delta
sleep, decreased sleep latency, suppresses REM sleep, lengthens REM
latency
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Steven D Bender DDS Other Antidepressants Nefazadone (Serzone-
not available in US) Improve sleep efficiency, lengthens sleep
time, increases REM sleep Minimal daytime drowsiness Mirtazapine
(Remron) Decreased sleep latency, improves sleep efficiency, no
effect on REM sleep May be good choice in pts. With depression and
insomnia
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Steven D Bender DDS Low Dose Doxepin Doxepin 3 and 6 mg
available for use Selective histamine receptor antagonist in CNS at
low doses Histamine in CNS promotes wakefulness Do not use with
MAOI inhibitor No significant AEs observed No daytime sedation,
cognitive impairment or complex sleep behaviors observed
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Steven D Bender DDS Alerting Antidepressants Protriptyline:
Anticholinergic, Strong REM Sleep Suppression Bupropion: No REM
Sleep Suppression. No/ Little Anticholinergic Activity
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Steven D Bender DDS Gabapentin and Pregabalin Mechanism
uncertain Both drugs are structural analouges of GABA Do not
interact with GABA Interacts with voltage-gated calcium channels in
CNS Small studies in normals and in pts. With epilepsy show small
improvements in sleep No published studies in treating
insomnia
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Steven D Bender DDS Tiagabine Anticonvulsant drug Small studies
show minor improvements in sleep parameters Significant increase in
percentage of N3 sleep
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Steven D Bender DDS Orexin Antagonist Currently being developed
as potential hypnotic agents
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Steven D Bender DDS Selective Antipsychotic Agents Olanzapine
(Zyprexa) and Quetiapine (Seroquel) Sedation and somnolence
frequent side effect Small studies show improved sleep parameters
Not FDA approved; not recommended for chronic primary insomnia
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Steven D Bender DDS Non Hypnotic Hypnotics Examples Analgesics:
Improve Sleep Disturbed by Pain Antidepressants: Improve Sleep
Disturbed by Depression Finasteride (Proscar): Improves Sleep
Disturbed by Nocturia (Flomax also)
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Steven D Bender DDS Non Hypnotic Hypnotics (cont) Examples GERD
Medications: Improve Sleep Disturbed by Reflux Sinemet
(carbidopa-levodopa): Improves Sleep Disturbed by Restless Leg
Syndrome (Requip, Mirapex)
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Steven D Bender DDS Older Agents Barbiturates and chloral
hydrate no longer recommended Unfavorable side effect profile
relative to efficacy
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Steven D Bender DDS Risks of Long Acting Benzodiazepines
Accumulation with repeated use Rebound insomnia Residual hangover
effect next day Impaired daytime cognition Anterograde amnesia
Worsen OSA Increased risk of falls in the elderly
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Steven D Bender DDS AASM Guidelines For patients with primary
insomnia; Short intermediate acting BZ or Z- drugs or ramelteon
Alternate short intermediate BZ, Z-drug or ramelteon
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Steven D Bender DDS Sedating antidepressants; Trazadone,
amitriptyline, doxepin, mirtazapine Combined BZ or ramelteon with
sedating antidepressant Other sedating agents such as;
Anti-epilepsy drugs; gabapentin, tiagabine, or Atypical
antipsychotics; quetiapine, olanazepine AASM Guidelines
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Steven D Bender DDS Summary Be certain of the diagnosis first
Combine drug treatment with CBT when possible Short or intermediate
acting benzodiazepine receptor agonist are generally safe,
effective in short term Melatonin receptor agonist Some
antidepressants (off label/low dose) Low dose doxepine
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Steven D Bender DDS STRATEGIES FOR MIGRAINE TREATMENT
Preemptive treatment Migraine trigger time-limited and predictable
Preemptive treatment Migraine trigger time-limited and predictable
Preventive Treatment Decrease in migraine frequency warranted
Preventive Treatment Decrease in migraine frequency warranted Acute
treatment To stop pain and prevent progression Acute treatment To
stop pain and prevent progression
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Steven D Bender DDS Goals of Acute Treatment and Strategies to
Achieve Them Where current drugs were designed to work Achieve
rapid and consistent relief without recurrence Restore the patients
ability to function Minimize the use of back up and rescue
medications Be cost effective for overall management Have minimal
or no adverse events Avoid acute medication overuse
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Steven D Bender DDS Stratified care/evidence based Early
treatment Back up treatment plan (2nd dose, rescue drug) Consider
non pharmacologic techniques Consider prevention Goals of Acute
Treatment and Strategies to Achieve Them
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Steven D Bender DDS The Triptans sumatriptan (brand names
Imitrex; Sumavel; and Treximet, a combination of sumatriptan and
naproxen sodium), naratriptan (brand name Amerge), rizatriptan
(brand name Maxalt), zolmitriptan (brand name Zomig), eletriptan
(brand name Relpax), almotriptan (brand name Axert), and
frovatriptan (brand name Frova).
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Steven D Bender DDS Ergotamines injectable dihydroergotamine
(D.H.E.-45) dihydroergotamine nasal (Migranal Nasal Spray)
ergotamine tartrate and caffeine tablets and suppositories (brand
names Cafergot, Migergot - discontinued ) ergotamine tartrate
sublingual tablets (brand name Ergomar)
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Steven D Bender DDS Other Midrin: isometheptene mucate,
dichloralphenazone, and acetaminophen. The original brand name has
been discontinued. All but one equivalent products have been
removed from the market as of 3/11/12. The remaining product is
produced by Macoven Pharmaceutical of Magnolia, Texas. It is
uncertain whether this product will remain on the market.
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Steven D Bender DDS Rescue diclofenac potassium for oral
solution (brand name Cambia)
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Steven D Bender DDS
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Opioids 10 fold increases in ER utilization in patients using
opioids for headache management Buse, 2011
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Steven D Bender DDS TRIPTANS As a class, relative to
nonspecific therapies, triptans provide Rapid onset of action High
efficacy Favorable side effect profile Few Adverse events and
contraindications Selective 5-HT 1B/1D/1F agonists Silberstein SD.
Neurology. 2000.
Steven D Bender DDS Triptan Drug Interactions Cady RK
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Steven D Bender DDS Plasma Elimination Half-life of the
Triptans Cady RK
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Steven D Bender DDS Conventional Wisdom All triptans have
similar mechanism of Action therefore are more similar than
different Some distinction based on half life - Fast vs. slow
acting - Longer duration equates to lower recurrence Meta-analysis
suggest some distinction in efficacy; methodology questioned
Comparator trials conflicting conclusions
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Steven D Bender DDS Migraine Prophylaxis
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Steven D Bender DDS When to Consider Starting a Migraine
Prophylactic Favors abortives only Low Frequency Short duration Not
disabling Good response to abortive medications Favors prophylactic
High Frequency Long Duration Disabling Poor response US Headache
Consortium Guidelines
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Steven D Bender DDS Choosing and Starting a Prophylactic When
choosing a prophylactic med, consider: Comorbid disorders
Contraindications Sideeffect profiles Drugdrug interactions Cost
Start with lowest effective dose Increase slowly until desired
benefit and/or limited by side effects Give treatment adequate
trial (8-12 weeks) AAN Practice Parameter. Neurology 2000.
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Steven D Bender DDS Prophylactic Options: High Level of
Evidence topiramate divalproex sodium gabapentin
venlafaxine/fluoxetine onabotulinum A valproic acid beta blockers
(propranolol, timolol) TCAs magnesium butterbur
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Steven D Bender DDS lithium neuroleptics (antipsychotics)
NSAIDs hydroxyzine (H1 antagonist) cyproheptadine amantadine
(anti-viral) benzodiazepines nimodipine (Ca channel blocker)
zonisamide pregabalin memantine (Namenda) Prophylactic Options:
Without High Level of Evidence
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Steven D Bender DDS Other Considerations Oral appliance therapy
Psychological/behavioral treatment Deep cervical blockade &
peripheral blockade (face, jaw, neck) Neurostimulation Biofeedback
Exercise, sleep, and diet control Physical therapy Hypnosis
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Steven D Bender DDS PREVENTIVE DRUGS: Relative Risks &
Safety
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Steven D Bender DDS PREVENTIVE DRUGS: Relative Risks &
Safety
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Steven D Bender DDS Medication Adherence Adherence = the extent
to which patients follow agree recommendations regarding treatment.
Rates on nonadherence in headache management Filling initial
prescription = 11% Prophylactic Regimen = 25% 50% Nonadherence is a
potential problem with all patients. Not related to age, sex, race,
intelligence or education level Reasons for poor adherence to
prophylactic headache medications: Consider migraine an episodic
disorder, thus not requiring daily medications. Concern about
requiring prophylactic med for a long/indefinite time Not effective
or not effective quickly enough Side effects Rains J et. al.
Headache 2006 D'Amico D et. al. Neuropsychiatric Disease and
Treatment 2008. Rahimtoola H et. al. Cephalalgia 2003 McDonald HP
et. al. JAMA 2002
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Steven D Bender DDS Improving Adherence Let the patient be
involved in formulating the treatment plan. Adherence is higher if
the treatment plan is negotiated rather than dictated. Simplify the
treatment plan. Once per day dosing highest rate of adherence If
not possible, link med administration to daily cues (e.g. waking,
bedtime, meals). Although sometimes necessary, patients using
multiple migraine therapies have lower adherence. Ask patient to
write down treatment plan as you discuss it or provide them with a
written copy of the treatment plan Haynes RB et. al. JAMA
2002;288:28802883. Rahimtoola H et. al. Cephalalgia 2003
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Steven D Bender DDS Its not so much what you give to the head,
but to whose head you give it Saper, 1992
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Steven D Bender DDS Preventive choices are determined more by
the head than the drug Saper
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Steven D Bender DDS When to Use a Preventive? Youll know it
when you see it Joel R. Saper, M.D.