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Steven D Bender DDS Fellow, American Headache Society Fellow, American Academy of Orofacial Pain North Texas Center For Head, Face & TMJ Pain

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Presentation on theme: "Steven D Bender DDS Fellow, American Headache Society Fellow, American Academy of Orofacial Pain North Texas Center For Head, Face & TMJ Pain"— Presentation transcript:

1 Steven D Bender DDS Fellow, American Headache Society Fellow, American Academy of Orofacial Pain North Texas Center For Head, Face & TMJ Pain steve@benderdds.com Pharmacotherapeutics: Headache and Sleep

2 © Steven D Bender DDS

3 Disclosure I have received consulting honoraria from Nautilus Neurosciences and am a member of their advisory board

4 © Steven D Bender DDS Drugs for Sleep

5 © 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.

6 © 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

7 © 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

8 © Steven D Bender DDS Options for Treating Insomnia OTC ETOH Alternative meds Benzo’s New “Z” drugs – (benzo receptor agonist) Melatonin and receptor agonists Antidepressants AEDs Anti-psychotic meds

9 © 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

10 © 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

11 © Steven D Bender DDS Alternative Therapies Valerian Kava-Kava Hops Lavender Passion flower Skullcap Data on effectiveness and safety limited

12 © Steven D Bender DDS Benzodiazepines (BZ) Onset of Generic Brand Action (Min) ½ 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

13 © Steven D Bender DDS Benzodiazepines - Like (non-BZ but mediated through GABA receptors) Onset of Generic Brand Action (Min)½ life zolpidemAmbien15 - 30Short zaleplonSonata15 - 30 Ultra short eszopiclone Lunesta 15 – 30 Short Sleep Academic Award 13

14 © 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

15 © 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

16 © 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

17 © 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

18 © 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

19 © 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

20 © 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

21 © 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

22 © 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

23 © 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

24 © Steven D Bender DDS Alerting Antidepressants Protriptyline: Anticholinergic, Strong REM Sleep Suppression Bupropion: No REM Sleep Suppression. No/ Little Anticholinergic Activity

25 © 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

26 © Steven D Bender DDS Tiagabine Anticonvulsant drug Small studies show minor improvements in sleep parameters – Significant increase in percentage of N3 sleep

27 © Steven D Bender DDS Orexin Antagonist Currently being developed as potential hypnotic agents

28 © 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

29 © 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)

30 © 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)

31 © Steven D Bender DDS Older Agents Barbiturates and chloral hydrate no longer recommended Unfavorable side effect profile relative to efficacy

32 © 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

33 © 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

34 © 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

35 © 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

36 © 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

37 © 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 patient’s 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

38 © 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

39 © 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).

40 © 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)

41 © 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.

42 © Steven D Bender DDS Rescue diclofenac potassium for oral solution (brand name Cambia)

43 © Steven D Bender DDS

44 Opioids 10 fold increases in ER utilization in patients using opioids for headache management Buse, 2011

45 © 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.

46 © Steven D Bender DDS TRIPTANS: TREATMENT CHOICES Zolmitriptan (Zomig) Tablet (2.5, 5 mg) Nasal spray (5 mg) Rizatriptan (Maxalt) Tablet (5, 10 mg) Naratriptan (Amerge) Tablet (1, 2.5 mg) Almotriptan (Axert) Tablet (6.25, 12.5 mg ) Frovatriptan (Frova) Tablet (2.5 mg) Sumatriptan (Imiterex) Tablet (25, 50, 100 mg) Injection (6 mg) Nasal spray (5, 20 mg*) Eletriptan (Relpax) Tablet (20, 40 mg)

47 © Steven D Bender DDS Triptan Drug Interactions Cady RK

48 © Steven D Bender DDS Plasma Elimination Half-life of the Triptans Cady RK

49 © 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

50 © Steven D Bender DDS Migraine Prophylaxis

51 © 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

52 © Steven D Bender DDS Choosing and Starting a Prophylactic When choosing a prophylactic med, consider: – Co‐morbid disorders – Contraindications – Side‐effect profiles – Drug‐drug 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.

53 © 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

54 © 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

55 © 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

56 © Steven D Bender DDS PREVENTIVE DRUGS: Relative Risks & Safety

57 © Steven D Bender DDS PREVENTIVE DRUGS: Relative Risks & Safety

58 © Steven D Bender DDS Medication Adherence Adherence = the extent to which patients follow agree recommendations regarding treatment. Rates on non‐adherence in headache management – Filling initial prescription = 11% – Prophylactic Regimen = 25% ‐ 50% Non‐adherence 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

59 © 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;288:2880‐2883. Rahimtoola H et. al. Cephalalgia 2003

60 © Steven D Bender DDS “It’s not so much what you give to the head, but to whose head you give it” Saper, 1992

61 © Steven D Bender DDS Preventive choices are determined more by the head than the drug Saper

62 © Steven D Bender DDS When to Use a Preventive? “You’ll know it when you see it” Joel R. Saper, M.D.


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