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

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

4. Drugs for Sleep

5. Diagnosis, NOT complaint, should
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. 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. Principles for Treating Chronic Insomnia
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

8. 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. 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. 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. Alternative Therapies
Valerian
Kava-Kava
Hops
Lavender
Passion flower
Skullcap
Data on effectiveness and safety limited

12. Benzodiazepines (BZ)
Onset of Generic Brand Action (Min) ½ life estazolam none interm flurazepam Dalmane long temazepam Restoril 45 – 60 interm (H2O rather than lipid soluble) triazolam Halcion short (sublingual administration possible)* clonazepam Klonapin 15 – 30 long
Point out that in most studies an onset of action of >30 minutes would not make a difference from placebo. Can also mention problems with long ½ life drugs in the elderly, e.g., greater frequency of hip fractures.
Sproule BA, Busto UE, Buckle C, Herrmann N, Bowles S. The use of non-prescription sleep products in the elderly. Int J Geriatr Psychiatry 1999;14:
Sleep Academic Award

13. Benzodiazepines - Like (non-BZ but mediated through GABA receptors)
Onset of Generic Brand Action (Min) ½ life zolpidem Ambien Short zaleplon Sonata Ultra short eszopiclone Lunesta 15 – 30 Short
Zaleplon may be good drug to help sleep on the plane flying to Europe. Can discuss pros and cons of this and ways to adjust circadian rhythm to European time.
Ware JC, Walsh JK, Scharf, MB, Roehrs T, Roth T, Vogel GW. Minimal rebound insomnia after treatment with 10-mg zolpidem. Clinical Neuropharmacology 1997;20:
Sleep Academic Award

14. 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. 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. 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. 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. Ramelteon
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

19. 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. 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. 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. 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. 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. Alerting Antidepressants
Protriptyline: Anticholinergic, Strong REM Sleep Suppression Bupropion: No REM Sleep Suppression. No/ Little Anticholinergic Activity
What other antidepressants don’t suppress REM? (Bupropion, nefazodone & trimipramine.)
Ware JC, Brown FW, Moorad PJ, Pittard JT, Cobert B. Effects on sleep: A double-blind study comparing trimipramine to imipramine in depressed insomniac patients. SLEEP 1989;12:

25. 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. Tiagabine Anticonvulsant drug
Small studies show minor improvements in sleep parameters
Significant increase in percentage of N3 sleep

27. Orexin Antagonist
Currently being developed as potential hypnotic agents

28. 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. 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)
Actually, probably the best category to use because their use requires a diagnosis other than “insomnia.”

30. Non Hypnotic “Hypnotics” (cont)
Examples
GERD Medications: Improve Sleep Disturbed by Reflux
Sinemet (carbidopa-levodopa): Improves Sleep Disturbed by Restless Leg Syndrome (Requip, Mirapex)
Actually, probably the best category to use because their use requires a diagnosis other than “insomnia.”

31. Older Agents Barbiturates and chloral hydrate no longer recommended
Unfavorable side effect profile relative to efficacy

32. 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. 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. AASM Guidelines 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

35. 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. STRATEGIES FOR MIGRAINE TREATMENT
Acute
treatment
To stop pain
and prevent
progression
Preventive
Treatment
Decrease in
migraine frequency
warranted
Preemptive
treatment
Migraine trigger
time-limited and
predictable
Treatment can be acute, preemptive (short-term), or preventive.
Preemptive treatment is used when there is a known headache trigger, such as exercise or sexual activity. Patients can be instructed to pretreat prior to the exposure or activity. For example, single doses of indomethacin can be used to prevent exercise-induced migraine.
Preemptive treatment also is used in patients undergoing a time-limited exposure to a trigger, such as ascent to a high altitude or menstruation. These patients can be treated with daily medication just before and during the exposure.
Preventive treatment is maintained for months or even years to reduce attack frequency, severity, and duration.
Patients taking preventive medication can also use acute medication.
Silberstein SD. Preventive treatment of migraine: an overview. Cephalalgia. 1997;17(2):67-72.
Silberstein SD, Saper JR, Freitag F. Migraine diagnosis and treatment. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain. 7th ed. New York, NY: Oxford University Press; 2001:

37. Goals of Acute Treatment and Strategies to Achieve Them
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
Where current drugs were designed to work

38. Goals of Acute Treatment and Strategies to Achieve Them
Stratified care/evidence based
Early treatment
Back up treatment plan (2nd dose, rescue drug)
Consider non pharmacologic techniques
Consider prevention

39. 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. 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. 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. Rescue
diclofenac potassium for oral solution (brand name Cambia)

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

45. TRIPTANS Selective 5-HT1B/1D/1F agonists
Silberstein SD. Neurology
As a class, relative to nonspecific therapies, triptans provide
Rapid onset of action
High efficacy
Favorable side effect profile
Triptans, as a class, represent a significant advancement in the therapeutic management of migraine. These agents have been described as receptor-specific agonists toward serotonin or 5-HT receptors. Specifically, they are selective 5-HT1B/1D agonists having the greatest affinity for these receptors. Blockade of 5-HT1 receptors has been shown to result in acute migraine relief.
Triptans, relative to nonspecific therapies, including analgesics and NSAIDs, provide rapid onset of action (between 15 minutes and 1 hour, depending on the formulation), are highly effective in relieving migraine pain symptoms, and have a favorable side effect profile. All agents in this class have proven therapeutic efficacy.
In the majority of patients, the intensity of adverse effects is mild and of short duration. Adverse effects can include chest pressure, flushing, dizziness, drowsiness, and nausea. Patients who are at risk for coronary heart disease, diabetes, obesity, severe uncontrolled hypertension, or hypercholesterolemia should be screened prior to administration of triptans.
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):
Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. Oxford, England: Isis Medical Media; 1998.
Few Adverse events and contraindications

46. TRIPTANS: TREATMENT CHOICES
Almotriptan (Axert)
Tablet (6.25, 12.5 mg)
Sumatriptan (Imiterex)
Tablet (25, 50, 100 mg)
Injection (6 mg)
Nasal spray (5, 20 mg*)
Frovatriptan (Frova)
Tablet (2.5 mg)
Zolmitriptan (Zomig)
Tablet (2.5, 5 mg)
Nasal spray (5 mg)
Eletriptan (Relpax)
Tablet (20, 40 mg)
There are several triptans currently available in the United States. The first is sumatriptan (Imitrex®), which is considered to be the “gold standard” in the class. The oral formulation is available in 25-mg, 50-mg and 100-mg doses. Since its introduction in the early 1990s, over 400 million doses of sumatriptan have been given.
Zolmitriptan (Zomig®), the second product in the triptan class, has a longer half-life than sumatriptan and a more rapid Tmax. It is available as a tablet, orally disintegrating tablet, and as a nasal spray.
Naratriptan (Amerge®) has a longer half-life than sumatriptan, and lower recurrence rate. Naratriptan is considered to have lower efficacy than sumatriptan with minimal adverse events.
Rizatriptan (Maxalt®) has a rapid onset of action and a shorter Tmax of 1 hour compared to oral sumatriptan. This product is available as a tablet and in a dissolvable wafer form.
Almotriptan (Axert®) is available as an oral tablet and has a good adverse event profile.
Frovatriptan (Frova®) is available as a tablet. It, like naratriptan, has a long half-life, low rate of adverse events, and a low recurrence rate.
Eletriptan (Relpax®) will be available as an oral tablet.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):
Worldwide Product Safety and Pharmacovigilance Document. December 1999.
Naratriptan (Amerge)
Tablet (1, 2.5 mg)
Rizatriptan (Maxalt)
Tablet (5, 10 mg)

47. Triptan Drug Interactions
Cady RK

48. Plasma Elimination Half-life of the Triptans
Cady RK

49. 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. Migraine Prophylaxis

51. 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. 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. Prophylactic Options: High Level of Evidence
• topiramate
divalproex sodium
• gabapentin
• venlafaxine/fluoxetine
• onabotulinum A
• valproic acid
• beta blockers (propranolol, timolol)
• TCAs
• magnesium
• butterbur

54. Prophylactic Options: Without High Level of Evidence
• lithium
• neuroleptics (antipsychotics)
• NSAIDs
• hydroxyzine (H1 antagonist)
• cyproheptadine
• amantadine (anti-viral)
• benzodiazepines
• nimodipine (Ca channel blocker)
• zonisamide
• pregabalin
memantine (Namenda)

55. 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. PREVENTIVE DRUGS: Relative Risks & Safety

57. PREVENTIVE DRUGS: Relative Risks & Safety

58. 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. 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. “It’s not so much what you give to the head, but to whose head you give it” Saper, 1992

61. Preventive choices are determined more by the head than the drug
Saper

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