Headache in Adults PDF

3/13/24, 12:39 AM Headache in Adults Headache in Adults Meagan Guay, BSc, MB, BCh, BAO, FRCPC Irene Worthington, BScPhm Ana Marissa Lagman-Bartolome, BSc, MD, FRCPC, FAHS Date of Revision: June 29, 2023 Peer Review Date: April 1, 2021 CPhA acknowledges the contribution of Dr. Nily Osman as a previou...

3/13/24, 12:39 AM Headache in Adults Headache in Adults Meagan Guay, BSc, MB, BCh, BAO, FRCPC Irene Worthington, BScPhm Ana Marissa Lagman-Bartolome, BSc, MD, FRCPC, FAHS Date of Revision: June 29, 2023 Peer Review Date: April 1, 2021 CPhA acknowledges the contribution of Dr. Nily Osman as a previous author of this chapter. Introduction This chapter focuses on the outpatient treatment of 3 of the most common headache disorders: tension-type headache, migraine (both primary headache disorders) and medicationoveruse headache (secondary headache disorder). The International Classification of Headache Disorders 3rd edition (ICHD-3) diagnostic criteria for common headache disorders are outlined in Table 1.​ Table 1: Diagnostic Criteria for Common Headache Disorders​ Headache Disorder Diagnostic Criteria Episodic Tension Headache At least 10 episodes occurring >1 (infrequent episodic) but 15 days per month for a duration >3 months. Episodic Migraine Without Aura At least 5 attacks fulfilling the following criteria: Headache attacks lasting 4–72 h (untreated or unsuccessfully treated) Minimum of 2 of the following: unilateral location pulsating quality moderate to severe aggravated by routine physical activity such as walking or climbing stairs During the headache, at least 1 of the following nausea or vomiting both photophobia and phonophobia Not better accounted for by another ICHD-3 diagnosis Episodic Migraine With Aura At least 2 attacks fulfilling the following criteria: One or more of the following fully reversible aura symptoms: visual/retinal (scintillations or loss of vision) sensory (numbness, feeling of “pins and needles”) speech and/or language (aphasia, dysarthria) motor (weakness on 1 side of body, face) brainstem (vertigo, tinnitus, diplopia, ataxia, hypacusis, decreased level of consciousness) At least 3 of the following 6 characteristics: at least 1 aura symptom spreads gradually over >5 min 2 or more aura symptoms occur in succession each individual aura symptom lasts 5–60 min at least 1 aura symptom is unilateral at least 1 aura symptom is positive (e.g., scintillations, feeling of “pins and needles”) aura is either accompanied with or within 60 min of headache onset Not better accounted for by another ICHD-3 diagnosis Chronic Migraine +/- Aura Medication-Overuse Headache Same criteria as episodic migraine with the exception of an increase in frequency of headache to >15 days per month for a duration of >3 months. Headache occurring on ≥15 days/month in a patient with a pre-existing headache disorder Regular overuse for >3 months of 1 or more drugs used for treatment of acute headache; medication overuse defined as: ≥10 days/month for ergot derivatives, triptans, opioids and combination analgesics; this also includes combinations of agents from different drug classes that are not individually overused ≥15 days for non-opioid analgesics: acetaminophen and NSAIDs Not better accounted for by another ICHD-3 diagnosis Pathophysiology https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 1/18 3/13/24, 12:39 AM Headache in Adults Tension-Type Headache Globally, tension-type headache (TTH) is the most common of the headache disorders, with a lifetime prevalence of 30–78%.​ The exact pathophysiology of TTH is unknown, but it is believed to be multifactorial.​ Historically, TTH was attributed to muscle tenderness combined with psychological stress. Recent research has identified other contributors, including nitric oxide, pro-inflammatory cytokines (e.g., bradykinin, histamine, prostaglandin E2) and central pain sensitization mediated by neuropeptides (e.g., calcitonin gene-related peptide [CGRP], substance P and vasoactive intestinal peptide [VIP]).​ Lower cortisol levels in TTH patients, possibly due to chronic stress, may also contribute to the pathogenesis.​ Another possible mechanism involves increased myofascial pain sensitivity within the supraspinal region and spinal dorsal horn.​ Note, TTH can coexist with other primary headache disorders of different underlying pathophysiology. Migraine Migraine is the second-most-common primary headache disorder and the most disabling neurological condition globally.​​ Despite its high prevalence and index of disability, migraine remains a commonly undiagnosed and undertreated condition.​ Previous theories of migraine attributed solely to cerebral vascular pathology secondary to vasodilation/constriction are no longer supported by modern research.​ Migraine is now attributed to activation of the trigeminovascular system, causing a cascade of inflammatory neuropeptides (e.g., VIP, neurokinin A, substance P, CGRP), which contribute to cerebral vascular pathology and pain transmission.​ Migraine with aura is caused by cortical spreading depression, a depolarizing wave of cortical activity involving neuronal activation and hyperperfusion for 1–2 minutes followed by neuronal suppression and hypoperfusion that may persist for 1–2 hours.​ Medication-Overuse Headache Medication-overuse headache (MOH) is one of the most common secondary headache disorders globally.​ Due to the accessibility of analgesics (e.g., acetaminophen, aspirin, NSAIDs) without health-care professional intervention, patients may be unaware that progressively increased use of these medications can lead to chronicity of headache disorder.​ Chronic opioid use may also contribute to MOH, in addition to hyperalgesia syndrome, leading to refractory disease. The pathophysiology of MOH is poorly understood; possible mechanisms include pathologic serotonergic modulation, upregulation of vasoactive and pro-inflammatory mediators, and genetic predisposition for dopaminergic dysregulation (DRD4, DRD2, SLC6AC3).​ Goals of Therapy Acute treatment:​ Rapid and consistent freedom from pain and associated symptoms without recurrence (pain-free at 2 hours, headache relief at 2 hours, 24-hour sustained headache relief) Restored ability to function Minimal need for repeat dosing or rescue medications Optimal self-care and reduced subsequent use of resources (e.g., emergency room visits, diagnostic imaging, health-care provider and ambulatory infusion centre visits) Minimal or no adverse effects from medications Preventative treatment:​ Reduce attack frequency, severity, duration and disability Improve responsiveness to and avoid escalation in use of acute treatment Improve function and reduce disability Reduce reliance on poorly tolerated, ineffective or unwanted acute treatments Reduce overall cost associated with migraine treatment Enable patients to manage their own disease to enhance a sense of personal control Improve health-related quality of life Reduce headache-related distress and psychological symptoms Patient Assessment Prior to recommending a medication, screen for red flag causes of possible secondary headaches based on the SNNOOP10 mnemonic (see Table 2 and Figure 1). If any red flags are present on history, then further investigation and/or a referral is required. Patients with sudden, severe headache should go to an emergency room. Table 2: Headache Red Flags (SNNOOP10) ​ Signs or Symptoms Related Secondary Headache Systemic symptoms (including fever) Infection or nonvascular intracranial disorder Neoplasm in history Neoplasm of the brain; metastasis Neurologic deficit or dysfunction (including decreased consciousness) Vascular or nonvascular intracranial disorders; infection (e.g., brain abscess) Onset of headache is sudden or abrupt Cranial or cervical vascular disorder (e.g., subarachnoid hemorrhage) Older age (>50 y) Giant cell arteritis Pattern change or recent onset of headache Neoplasm, vascular or nonvascular Positional headache Intracranial hypotension or hypertension Precipitated by sneezing or coughing Chiari malformation or posterior fossa malformation https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 2/18 3/13/24, 12:39 AM Headache in Adults Signs or Symptoms Related Secondary Headache Papilledema Neoplasm or intracranial hypertension Progressive headache and atypical presentations Neoplasm or other nonvascular intracranial disorders Pregnancy or postpartum Cranial or vascular disorder (e.g., cerebral venous sinus thrombosis) Painful eye with autonomic symptoms (e.g., eye redness/tearing, sinus congestion, facial flushing) Neoplasm or other nonvascular intracranial disorders Post-traumatic onset of headache Acute or chronic post-traumatic headache, subdural hematoma Pathology of immune system (e.g., HIV) Opportunistic infections Pain killer overuse or drug-induced headache Drug side effect, medication-overuse headache Patients with occasional TTH do not require further assessment unless the headaches become chronic (≥15 days/month). Patients with features of migraine require assessment, diagnosis and appropriate treatment, but do not typically require imaging unless there are neurological abnormalities, worsening severity or unusual presentations.​ If migraine is suspected, ID Migraine is an appropriate and quick screening tool to use (see Table 3). It contains only 3 questions and provides 81% sensitivity, 75% specificity and 93% positive predictive value.​ When a more thorough assessment is required, refer to the IHS diagnostic criteria (see Table 1). There are no diagnostic tests for primary headache disorders. A thorough history and physical examination are most important for a correct diagnosis. The physical examination should be normal; if any abnormalities are found (especially visual, motor, reflex, sensory, speech or cognitive), further investigations are warranted, as follows: CT/MRI scans are not routine but must be done if any organic etiology is suspected (see Table 2)​ Lumbar puncture if subarachnoid hemorrhage, encephalitis, high- or low-pressure headache syndromes or meningitis is suspected Laboratory tests (on an individual basis): erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for suspected temporal arteritis endocrine, biochemical, infection workup Facial pain may need a thorough assessment by a dental specialist familiar with headaches and facial pain and/or an ENT specialist if sinus or other ENT disorders are suspected Table 3: ID Migraine Screening Tool​ In the past 3 months, did any of the following occur? 1. Did you ever feel nauseous when you had headache pain? 2. Did light trouble you when you had headache pain (much more than when there was no headache)? 3. Did your headache ever limit your ability to work, study or do something you needed to, for at least 1 day? If ≥2 of the questions are answered “yes,” a migraine diagnosis may be considered. Adapted with permission from Lipton RB, Dodick D, Sadovsky R et al. A self-administered screener for migraine in primary care: The ID Migraine validation study. Neurology 2003;61(3):375–82. If serious structural CNS causes for headache and facial pain have been ruled out, the primary headache disorders can be managed as follows (see also Figure 1). Nonpharmacologic Therapy The management of headache requires a great deal of clinical skill and thorough communication with the patient. After serious causes and secondary headache disorders are excluded, it is important to take time to understand the patient’s medical and social history, as this can help guide therapeutic choices. Patient education is an important aspect of headache management. Reassure them that their headache disorder is a medical diagnosis. Provide them with an explanation of their headache disorder and with published or electronic printed materials to reinforce the verbal information. Many patients may experience anxiety related to their headaches, especially if they are concerned about a secondary headache disorder such as an intracranial tumor. These concerns should be directly addressed once these secondary causes have been ruled out. Address and understand patient expectations, as patients often have unreasonable expectations of complete resolution of their primary headache disorder with pharmacological treatment. While this is ideal, it is important for patients to understand that this expectation may not be realistic. Advise patients to: Maintain a headache diary (available from www.migrainecanada.org), which includes any change in sleep, stress, weather or food ingested within 24 hours prior to attack to identify headache triggers.​ Note, food cravings may be an indication of the premonitory phase of migraine rather than a trigger.​ Apply ice or heat to the head during a headache, depending on what gives them the most relief. Sleep or rest in a dark, noise-free room during a headache. If history of adverse childhood events are present (e.g., unstable childhood home, familial discord, divorce, abuse or bullying), patients may benefit from professional psychological assessment and treatment. If a psychiatric comorbidity is present, refer to a psychologist or psychiatrist. Patients may try biofeedback, mindfulness, relaxation therapy, cognitive behavioural therapy or psychotherapy.​ While aerobic exercise (e.g., 40 min 3 times weekly) may worsen a primary headache for some patients, in others it may reduce headache frequency and provide an option for patients who cannot or choose not to take prophylactic medication.​ Noninvasive neuromodulation with vagus nerve stimulators (nVNS) and external trigeminal nerve stimulation (eTNS) have had positive results in randomized controlled trials for the treatment and prevention of migraine headache.​ ​ These devices are available in Canada, but may be cost-prohibitive for some patients and are not readily covered by many insurance plans. They generally have minimal adverse effects and may be considered in patients who have contraindications to pharmacological agents, such as in pregnancy or in patients who prefer to use non-pharmacologic treatment. Refer to neurologist and/or specialized headache or pain management unit if problems are too complex, such as chronic daily headache, or require a multidisciplinary approach. Pharmacologic Therapy https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 3/18 3/13/24, 12:39 AM Headache in Adults For comparative ingredients of nonprescription products, consult the Compendium of Products for Minor Ailments—Analgesic Products: Internal Analgesics and Antipyretics; Herbal and Natural Health Products: Single Entity; Vitamin and Mineral Products: Single Entity. Acute Treatment See Table 7 for information on drug therapy for acute headache. Tension-Type Headache Analgesics Mild TTH may not require pharmacological treatment. Appropriate doses of simple analgesics (e.g., acetaminophen, ASA) or NSAIDs (e.g., ibuprofen, naproxen sodium) will often alleviate TTH.​ Migraine The goal of acute drug therapy for migraine headaches is to alleviate headache pain and associated symptoms within 2 hours of treatment and/or 24 hours of sustained headache relief; guidelines are available from the Canadian Headache Society.​ All acute treatments appear to be more effective if taken early in the migraine attack. Several agents may be tried before finding the most effective therapy. Patients may need ≥1 medication depending on the migraine severity. Moderate to severe migraine attacks often require the use of triptans with or without simple analgesics, NSAIDs and possibly antiemetics.​ For further information on treatment strategies, refer patients to the traffic light system available at www.migrainecanada.org, a quick and simple guide on how to choose an acute migraine treatment based on the Canadian guidelines.​ Analgesics Acetaminophen , ASA, and NSAIDs (e.g., diclofenac, ibuprofen, naproxen), are effective for mild to moderate headache pain.​ Medication-overuse headache can result from overuse of analgesics, when taken 15 or more days per month for at least 3 months. This limits their long-term potential as described earlier in this chapter. Consider ASA and NSAIDs first line as they may have greater efficacy, likely attributed to their anti-inflammatory properties, compared to acetaminophen.​ However, acetaminophen is generally better tolerated and may be preferred in patients with contraindications to or intolerance of NSAIDs or ASA.​ The combination of naproxen with an antiemetic is effective and generally well-tolerated; however, GI irritation with increased use may occur.​ It is important to adequately dose ASA and NSAIDs in order to optimize efficacy (see Table 7 for dosing information). Unfortunately, many migraine sufferers do not achieve adequate pain relief by relying exclusively on analgesics.​ Furthermore, most published trials of nonprescription agents in migraine have systematically excluded patients with more severe attacks. Codeine, tramadol, butalbital and butorphanol nasal spray have limited use in headache disorders because there is no evidence of superior effectiveness, yet there is potential for dependency, medication-induced headache and withdrawal syndrome. Therefore, these medications are not recommended for acute migraine treatment. Triptans The triptans currently available to abort migraine include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. All act on serotonin (5-HT) subclass 1B and 1D receptors found on blood vessels and neurons to inhibit the release of vasoactive neuropeptides and cause vasoconstriction of the pain-sensitive blood vessels. Triptans are considered to be the most specific and efficacious agents for acute migraine treatment.​​ They alleviate headache pain and migraine-associated symptoms (nausea/vomiting, photophobia/phonophobia). Overall, there is good evidence that the available triptans are generally well tolerated and safe.​ All triptans are contraindicated in patients with cardiac disorders, sustained hypertension, basilar and hemiplegic migraine. To avoid MOH, triptans should be used less than 10 days per month. Meta-analyses reveal that differences among the triptans are relatively small, but may be clinically meaningful to patients;​​​ however, the benefits in individual patients may vary, as may patient preference for specific formulations (injection, nasal spray, tablets or fast-melt tablets).​ For more information to guide selection of therapy, see Table 7. Ergotamine Derivatives Dihydroergotamine mesylate (DHE) has similar actions to the triptans but also interacts centrally with dopamine and adrenergic receptors, accounting for some of its side effects. It produces no dependence but may lead to MOH if used 10 days per month or more. DHE can be considered in patients who do not respond well to triptans or have frequent headache recurrences after triptans, acute intractable headache or withdrawal from analgesics.​ Nasal or injectable dihydroergotamine (DHE) has been shown to be effective for migraine. Two randomized clinical trials of nasal DHE demonstrated an average of 47–73% reduction in headache pain, compared to placebo.​ Although DHE may be less effective than triptans, it is associated with a lower headache recurrence rate.​ Oral ergot preparations, e.g., ergotamine tartrate (no longer available in Canada), have limited efficacy and excessive side effects.​ ​ Antiemetics Antinauseants (e.g., dimenhydrinate) and antiemetic/prokinetic agents (e.g., metoclopramide and domperidone) are useful as adjunctive therapy in headache disorders associated with nausea and vomiting, or to facilitate absorption of medications in some patients. The best evidence exists for metoclopramide.​ For more information on antiemetics, see Nausea and Vomiting. Combination Therapy The combination of an NSAID (e.g., naproxen sodium) and a triptan (e.g., sumatriptan) has better efficacy compared with either agent alone and reduces headache recurrence.​ ​ A Cochrane review determined that the combination of naproxen sodium (500 mg) and sumatriptan (50 mg or 85 mg) was more effective than monotherapy with naproxen sodium, sumatriptan or placebo.​ Offer the naproxen/sumatriptan combination to the following: Patients whose response to triptan monotherapy is inadequate​​ or Patients who experience frequent headache recurrences after successful treatment with triptan monotherapy​ https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 4/18 3/13/24, 12:39 AM Headache in Adults Novel Agents Two new drug classes have been recently approved internationally. Ubrogepant and rimegepant are small-molecule calcitonin gene-related peptide receptor antagonists (CGRP-RA).​ ​ Lasmiditan acts on the serotonin (5-HT) 1F receptor, which is found only on neurons and bypasses the cardiovascular safety issues posed by triptans.​ These new classes of medication offer novel treatment options for patients who have been refractory to or to those precluded from available agents. Ubrogepant was approved for the treatment of acute migraine by Health Canada in April 2023; rimegepant may become available in Canada in the near future. Medication-Overuse Headache Most MOHs will improve in weeks, or occasionally in a few months, with the discontinuation of medications, especially combination analgesics. Management includes recognition of these disorders, tapering and stopping the offending agent(s), providing bridge therapy and starting a prophylactic medication.​ If withdrawal headaches emerge, bridge therapy with agents for acute migraine treatment, such as triptans or long-acting NSAIDs, is appropriate; nerve blocks may also be considered. If psychological comorbidities such as depression are present, they must be managed and treated concurrently. Dependence on and withdrawal from opioids is more complex and requires referral to a multidisciplinary opioid addiction clinic. Preventive Therapy Tension-Type Headache Most strategies to prevent TTH are nonpharmacologic (see Nonpharmacologic Therapy). For disabling and/or chronic TTH, pharmacologic prophylaxis may be considered. Commonly prescribed agents include tricyclic antidepressants (e.g., amitriptyline), serotonin norepinephrine reuptake inhibitors (e.g., venlafaxine) and mirtazapine. The most robust clinical evidence exists for tricyclic antidepressants, although the overall efficacy was rated as moderate.​ Migraine Guidelines for migraine prophylaxis provide general principles for using preventive therapies.​​​ See Table 4 for indications for preventive treatment and Figure 2 for a general approach. Clinical guidelines include recommendations for several medications for migraine prophylaxis, discussed below. Consider efficacy, adverse effects, comorbid conditions (such as hypertension, depression, obesity) and concomitant medications, migraine severity, provider experience, patient preference and pregnancy planning when deciding which prophylactic agents to try.​ See Table 5 and Table 8 for information on medications used for migraine headache prophylaxis. Table 4: Indications for Preventive Treatment of Migraine​ Attacks significantly interfere with patient’s daily routine despite acute treatment Frequent attacks (≥4 monthly headache days) Contraindication to, failure, or overuse of acute treatment Adverse reaction to acute treatment Beta-1 Adrenergic Antagonists Beta-blockers are commonly used and efficacious in migraine prophylaxis; their mechanism of action is uncertain. Effective agents lack partial agonist activity, but CNS penetration, membrane stabilization and cardioselectivity do not influence efficacy. Propranolol, metoprolol and timolol are good initial choices;​ propranolol has been studied more than other beta-blockers for migraine prophylaxis.​ Atenolol and nadolol are also effective and may have fewer CNS side effects due to comparatively lower blood-brain barrier penetration.​ Antiepileptics Valproic acid and divalproex sodium are effective in migraine prophylaxis and may work by modulating gamma-aminobutyric acid (GABA) receptors in the peripheral trigeminovascular system.​​ Topiramate can reduce migraine frequency; weight loss is a side effect that can be beneficial in some patients. Start topiramate at a very low dose and increase very slowly to avoid cognitive side effects.​ ​ ​ ​ There is some evidence to recommend the use of gabapentin for migraine prophylaxis.​ It is generally well tolerated with somnolence as a common side effect; thus, it may be helpful for patients with comorbid insomnia. Antidepressants Amitriptyline and nortriptyline are effective for the prevention of migraine, especially in patients who also have TTH. Analgesic doses are lower than those required for affective disorders.​ They do not produce dependence and are relatively safe medications in this setting. Nortriptyline may be better tolerated, particularly in older patients, because of fewer anticholinergic side effects. Tricyclic antidepressants have been linked to serious cardiovascular outcomes, such as conduction abnormalities, arrhythmias, QTc prolongation, heart block and orthostatic hypotension. Thus, these agents should be used with caution in individuals with a personal or family history of cardiovascular disease or any of the conditions mentioned above.​ Venlafaxine reduces the number of headache days in patients with migraine​ and may be useful in some patients with comorbid depression or anxiety.​ Calcium Channel Blockers These drugs may work by modulating neurotransmitter function rather than producing vasodilation or protecting against hypoxia. Verapamil has very limited evidence for migraine prophylaxis;​ its evidence is more robust for cluster headache prophylaxis. At therapeutic doses, verapamil may be poorly tolerated; dose escalation requires https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 5/18 3/13/24, 12:39 AM Headache in Adults closer cardiac monitoring. A baseline ECG is required before initiation. Communicate to patients that should they develop symptoms suggestive of an arrhythmia, they need to seek urgent medical attention.​ Flunarizine is a selective calcium entry blocker and has potential efficacy in migraine prophylaxis, but can precipitate weight gain and depression; it should be avoided in patients with a history of depression.​ Angiotensin-Related Agents Limited evidence suggests lisinopril may be effective in reducing headache frequency.​​​ Proposed mechanisms for efficacy include altered sympathetic activity, decreased free radical activity, increased prostacyclin synthesis, and reduced degradation of bradykinin, encephalin and substance P. Moderate-quality evidence supports the efficacy of candesartan in the prevention of migraine and it has minimal side effects.​ ​ ​ Efficacy in migraine prophylaxis may be due to blocking the direct vasoconstriction, increased sympathetic discharge and/or adrenal medullary catecholamine release mediated by angiotensin II. Serotonin Modulators Pizotifen (pizotyline), a serotonin antagonist, may be helpful in migraine prophylaxis, although with low evidence at maximal dosage if tolerated.​ ​ Triptans may be effective for the prevention of menstrually associated migraine. This requires the patient to have a regular menstrual cycle and clearly documented headache pattern associated with the cycle. Triptans are typically used for 5–7 days/cycle, starting 2 days before anticipated onset of headache.​​​​ Localized Injections Evidence of efficacy of onabotulinumtoxinA for the preventive management of chronic migraine has been demonstrated in 2 phase 3 randomized controlled clinical trials.​ ​ OnabotulinumtoxinA is injected at specific sites in the head, neck and shoulders every 3 months and is generally well tolerated, since it is a localized therapy and less likely to cause the systemic effects often experienced with oral preventive therapy. The most common adverse effects include injection site reactions, neck pain and headache. Although this treatment is expensive, it may still be cost-effective for patients with chronic migraine, as it can significantly decreased headache frequency and thus reduce the use of or improve the response to rescue medications (e.g., triptans). Occipital nerve blocks using anesthetics (e.g., lidocaine, bupivacaine) were found to significantly alleviate pain, reduce headache days and medication consumption in migraine patients.​ Peripheral nerve blocks are easily performed in outpatient setting and are generally well tolerated, fast acting in providing pain relief and safe. Moreover, trigger-point injections with anesthetics, when performed by experts and in appropriate settings, have a role in the adjunctive treatment of most common headache disorders.​ Calcitonin Gene-Related Peptide Monoclonal Antibodies Calcitonin gene-related peptide monoclonal antibodies (CGRP mABs) are novel agents approved for the prevention of both episodic and chronic migraine headaches. The agents approved in Canada include erenumab, galcanezumab, fremanezumab and eptinezumab. The efficacies of the CGRP mABs are comparable with a significant 50% reduction in headache days compared to placebo.​ ​ ​ ​ Most CGRP mABs are administered subcutaneously; erenumab and galcanezumab are administered monthly while fremanezumab may be administered quarterly. Eptinezumab is an exception and is administered as a quarterly IV infusion. These agents may be cost prohibitive for patients without adequate drug coverage. Furthermore, patients must have failed multiple first-line preventive treatments before qualifying for use of CGRP mABs.​ In March 2023, Health Canada approved the first oral CGRP-receptor antagonist, atogepant, for the prevention of episodic migraine.​ Rimegepant, which has indications for both acute and preventative treatment of migraine, is currently pending approval by Health Canada.​ Natural Health Products Natural health products, given evidence for efficacy and safety, are often favoured as first-line options in migraine patients. Butterbur (Petasites hybridus extract) was significantly more effective than placebo in a controlled trial.​ Sixty-eight percent of patients receiving butterbur achieved ≥50% reduction in attack frequency after 4 months compared with 49% for the placebo arm. Butterbur was well tolerated; the most frequently reported adverse events included mild GI events, primarily burping. There have been rare reports of hepatotoxicity due to pyrrolizidine alkaloids (PA) in butterbur.​ PA toxins have been removed from certain butterbur preparations. Caution patients to use butterbur only if the product is labelled and certified as PA-free. The potential role of magnesium deficiency in the pathogenesis of migraine has been investigated. Prophylactic oral magnesium supplementation was effective in 2 doubleblind studies. The lack of response in a third study is thought to be due to the poor absorption of magnesium preparation used.​ ​ ​ In 1 study that demonstrated the efficacy of magnesium, patients received trimagnesium dicitrate (not available in Canada; an alternative may be magnesium citrate).​ More definitive, large-scale studies are needed to assess the role of magnesium in migraine prevention. Riboflavin (vitamin B2) was superior to placebo in a small randomized study.​ Significantly more patients taking riboflavin had ≥50% reduction in frequency of attacks compared with placebo. In a randomized, double-blind study of 48 children with migraine, a high placebo response rate suggested that riboflavin is not effective in preventing migraine in children.​ Further large-scale and comparative studies are needed to determine the efficacy of riboflavin in migraine prophylaxis. Coenzyme Q10 was well tolerated and superior to placebo in a small, randomized, controlled trial of migraine prophylaxis in 42 patients.​ In another small, randomized, controlled trial coenzyme, Q10 plus carnitine resulted in significant reduction in severity of headache attacks in migraineurs.​ Better studies are needed to determine the efficacy of coenzyme Q10 in migraine prophylaxis. Melatonin was found to be more effective than placebo and as effective as amitriptyline in reducing headache frequency in a randomized, double-blind, placebo-controlled study of 196 patients (18–65 years of age) experiencing 2–8 migraine attacks per month.​ Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency (secondary end-point). Melatonin was significantly better tolerated than amitriptyline; sleepiness was the most common side effect. As it is well tolerated, readily available without a prescription and affordable, melatonin can be recommended as an option for migraine prevention in patients who do not tolerate other preventive drugs or with a preference for natural products.​ Although feverfew (Tanacetum parthenium) has been used for migraine prophylaxis, evidence for its efficacy is conflicting and it appears to be no better than placebo. Therefore, it is no longer recommended for migraine prophylaxis in the Canadian guidelines.​ Furthermore, discontinuation of feverfew can result in post-feverfew syndrome, characterized by severe headache, insomnia, nervousness and joint pain.​ Selection of Migraine Prophylactic Therapy https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 6/18 3/13/24, 12:39 AM Headache in Adults For guidance on selection of preventive agent for migraine patients, see Table 5. Table 5: Selection of Migraine Prophylactic Therapy Patient Factors Agent of Choice Rationale Comorbid mood disorder Tricyclic antidepressants Concurrent treatment of mood disorder Venlafaxine Comorbid insomnia Tricyclic antidepressants Improvement of sleep Gabapentin Melatonin Overweight/obese Topiramate Appetite suppression Candesartan (weight neutral) Comorbid hypertension Beta-blockers Concurrent treatment of hypertension Candesartan Comorbid epilepsy Valproic acid Concurrent treatment of epilepsy Topiramate Gabapentin Patients of childbearing age who may become pregnant Propranolol Lower risk of teratogenicity Medication averse Natural health products Better side effect profile Failed 2+ trials of prophylactic therapy May consider calcitonin gene-related peptide monoclonal antibodies, atogepant, onabotulinumtoxinA Refractory patients may need more targeted treatment Medication-Overuse Headache To prevent the development of MOH when treating primary headache disorders such as migraine or TTH, avoid overusing acute therapy. The key strategies to preventing MOH are patient education and monitoring of acute medication use and misuse, as well as starting preventive treatment once headache frequency increases or as indicated. Headache associated with overuse of analgesics tends to resemble a TTH (migraine headaches can also be superimposed), whereas triptan overuse manifests as increased migraine frequency.​ Choices during Pregnancy and Breastfeeding Migraine and Pregnancy/Postpartum Period Migraine often improves during pregnancy, but in roughly 30–40% it either worsens or does not change. Postpartum migraine flares are common. The occurrence of migraine during pregnancy does not appear to increase the risk of preterm labour, low birth weight or congenital abnormalities. However, migraine may be associated with a higher risk of maternal complications of pregnancy such as gestational hypertension, pre-eclampsia and pregnancy-related stroke. When treating headache during pregnancy and the postpartum period, a high degree of suspicion is prudent to avoid missing serious causes such as cerebral venous thrombosis, pre-eclampsia/eclampsia, intracranial hemorrhage or headache associated with epidural anesthesia.​ Pre-pregnancy Considerations When possible, preventive and acute headache medications should be discontinued before attempting to conceive; this is also a logical time to begin training in nonpharmacologic measures (see Nonpharmacologic Therapy).​ Patients taking medications for migraine that can interfere with folate function (e.g., valproic acid) should discontinue them, if possible. In particular, valproic acid, topiramate and ARBS/ACE inhibitors, should be used with great caution in patients of childbearing potential. The Society of Obstetricians and Gynaecologists of Canada recommends patients treated with antiepileptic drugs take a multivitamin supplement containing 1 mg folic acid daily at least 3 months prior to conception until 12 weeks’ gestational age, at which time they can switch to a multivitamin with 0.4–1 mg folic acid daily.​ However, the Canadian Headache Society guidelines recommend 4–5 mg of folic acid daily for patients of childbearing potential when valproic acid is involved, along with effective contraception.​ Management during Pregnancy and Postpartum Period The management of headache is an important aspect of prenatal and postnatal care.​ Nonpharmacologic approaches (see Nonpharmacologic Therapy) should be used first line; for the majority of patients whose headache improves during pregnancy, nonpharmacologic measures supplemented with occasional use of acetaminophen may suffice. For patients with frequent disabling headaches or who experience severe nausea and vomiting leading to dehydration, the benefits of further drug treatment may outweigh the risks. When prophylactic medication is deemed necessary during pregnancy due to frequent, severe and disabling migraine attacks, a discussion with the patient and any other involved individuals is required, as all preventive medications have potential teratogenic effects. For more information, see Table 6. Procedure-based treatment options including physical therapy, acupuncture and peripheral nerve blocks using lidocaine may be considered.​ Neuromodulation devices including external trigeminal nerve stimulator (e-TNS), non-invasive vagal nerve stimulator (nVNS) and transmagnetic stimulator (TMS) may provide benefit for migraine treatment during pregnancy.​ Nutritional supplements, such as magnesium salts, should be used with caution. Recent data demonstrated that magnesium sulfate administered during pregnancy was associated with neonatal hypotonia and fetal bone abnormalities, including osteopenia and fractures. Riboflavin and coenzyme Q10 have not been studied for migraine prophylaxis in pregnancy.​ When possible, refer patients with severe migraine during pregnancy to a neurologist or headache specialist and/or to a high-risk pregnancy clinic. https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 7/18 3/13/24, 12:39 AM Headache in Adults Table 6: Pharmacological Management of Headache During Pregnancy Likely Safe Generally Avoided Absolutely Avoided Acetaminophen Triptans, although there is growing evidence for safety of sumatriptan. Should also be avoided in postpartum period because of a possible increased risk of postpartum stroke or angiopathy. Ergot derivatives (restrict uterine blood flow); should also be avoided in postpartum period because of a possible increased risk of postpartum stroke or angiopathy. Opioids: avoid near term due to risk of respiratory depression to the fetus. Monitor for medication overuse, which can worsen headache and response to treatment. NSAIDs; avoid in third trimester because they may cause constriction of the fetal ductus arteriosus. NSAIDs are not recommended after 20 wk gestation Topiramate (risk of oral cleft). Metoclopramide or prochlorperazine for severe Preventive medications other than memantine, cyproheptadine and propranolol. nausea.​ ​ due to increased risk of oligohydramnios.​​ If NSAIDs are necessary, prescribe the lowest effective dose and for the shortest duration possible. Use beyond 48 h may require ultrasound monitoring of amniotic fluid. NSAIDs should be discontinued if fetal oligohydramnios is detected. Memantine or cyproheptadine have limited data in migraine prophylaxis, but are considered lower risk based on minimal human and animal studies.​ Valproic acid (risk of birth defects and an increased risk of decreased intelligence quotient [IQ] in children exposed in utero).​ ​ ACE inhibitors/ARBs (known teratogens). Propranolol, although beta-blockers have been associated with intrauterine growth retardation and reduced placental weight.​ Discontinue betablockers a few days before delivery if possible; monitor neonates exposed to beta-blockers near term for symptoms such as bradycardia, hypoglycemia and other potential effects of beta-blockade.​ ​ Management during Breastfeeding In breastfeeding patients, it is important to provide appropriate management of headache.​ ​ Lactation may have a positive effect on migraine activity, and breastfeeding should be encouraged. As in pregnancy, use nonpharmacologic measures first line during breastfeeding. When medication is required, acetaminophen is the preferred abortive agent. Ibuprofen is considered the NSAID of choice in breastfeeding. Avoid ergot derivatives and opioids (including codeine). Sumatriptan has been studied more than other triptans in lactation and is considered compatible with breastfeeding, although it is prudent to avoid vasoconstricting agents in the initial postpartum period; other triptans should be used with caution. Eletriptan may be another triptan with minimal concentration in the infant, based on limited data.​ Metoclopramide, domperidone, dimenhydrinate and prochlorperazine are all considered safe in breastfeeding. Several treatment strategies could be considered when using rescue medications during breastfeeding, including “pumping and dumping,” which involves pumping and discarding breast milk after taking a rescue medication. Another strategy involves delayed feeding, based on the half-life of the drug, to clear the medication.​ Among the beta-blockers used for migraine prophylaxis, propranolol and metoprolol are the preferred options, due to low passage into breast milk. Valproic acid/divalproex sodium and topiramate are considered compatible with breastfeeding.​ Other prophylactic agents should be avoided or used with appropriate caution and monitoring of the infant. For a discussion of general principles of drug use during pregnancy and breastfeeding, see Drugs Use during Pregnancy and Drug Use during Breastfeeding. Other specialized reference sources are included in these appendices. Monitoring of Therapy Acute/Symptomatic Therapy Ideally, medications should relieve headaches (no pain or mild pain), associated nausea/vomiting and photophobia/phonophobia within about 2 hours.​ The Migraine Treatment Optimization Questionnaire (mTOQ-4) is a validated tool used to assess a patient’s clinical response to acute therapy. With only 4 questions, it can be easily administered in an office or pharmacy setting.​ Advise patients to report any significant adverse effects to their health-care practitioner (see Table 7 for side effects and drug interactions of medications). Preventive Therapy Continue prophylactic medications for migraine for at least 2 months to determine efficacy, except for onabotulinumtoxinA, which requires at least 2 to 3 treatments (6–9 months) prior to determining its efficacy. A ≥50% reduction in the frequency of migraine attacks is considered a good response. Advise patients to record exercise, food intake, medication use and migraine attacks in a headache diary, and to report any medication adverse effects to their health-care practitioner (see Table 8 for side effects of medications used for migraine prophylaxis). Therapeutic Tips Give abortive treatment, without exceeding recommended dosages, as soon as possible after headache onset. A calendar or diary of headaches is very useful in follow-up assessment.​ Have patients keep a record of medications (usefulness, dosage and side effects). Different medications may need to be tried, including different members of the same class, such as triptans. https://cps-pharmacists-ca.login.ezproxy.library.ualberta.ca/print/new/documents/MA_CHAPTER/en/headache 8/18 3/13/24, 12:39 AM Headache in Adults Follow-up is critical in managing chronic headache. Reassurance and explanation are most important to the patient in the long term to improve compliance to treatment recommendations. Always offer hope to patients with chronic headache, even if no cure is available; most primary headaches can be controlled.​ Algorithms Figure 1: Assessment and Management of Patients with Headache [a] [b] Limit use of simple analgesics (e.g., acetaminophen, NSAIDs) to