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 steve@benderdds.com

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

Drugs for Sleep

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.

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

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

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

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

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

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

Benzodiazepines (BZ) Onset of Generic Brand Action (Min) ½ life estazolam none 15 - 30 interm flurazepam Dalmane 15 - 30 long temazepam Restoril 45 – 60 interm (H2O rather than lipid soluble) triazolam Halcion 15 - 30 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;14:851-857. Sleep Academic Award 12

Benzodiazepines - Like (non-BZ but mediated through GABA receptors) Onset of Generic Brand Action (Min) ½ life zolpidem Ambien 15 - 30 Short zaleplon Sonata 15 - 30 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;20:116-125. Sleep Academic Award 13

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

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

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

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

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

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

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

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

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

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

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;12:537-549.

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

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

Orexin Antagonist Currently being developed as potential hypnotic agents

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

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.”

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.”

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

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

AASM Guidelines For patients with primary insomnia; Short – intermediate acting BZ or Z- drugs or ramelteon Alternate short – intermediate BZ, Z-drug or ramelteon

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

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

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; 2001:121-237.

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

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

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).

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)

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.

Rescue diclofenac potassium for oral solution (brand name Cambia)

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

TRIPTANS Selective 5-HT1B/1D/1F agonists Silberstein SD. Neurology. 2000. 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):754-762. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. Oxford, England: Isis Medical Media; 1998.   Few Adverse events and contraindications

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):1668-1675. Worldwide Product Safety and Pharmacovigilance Document. December 1999. Naratriptan (Amerge) Tablet (1, 2.5 mg) Rizatriptan (Maxalt) Tablet (5, 10 mg)

Triptan Drug Interactions Cady RK

Plasma Elimination Half-life of the Triptans Cady RK

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

Migraine Prophylaxis

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

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.

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

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)

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

PREVENTIVE DRUGS: Relative Risks & Safety

PREVENTIVE DRUGS: Relative Risks & Safety

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

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

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

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

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