2. Headache epidemiology
2.1 Headache classification and pathogenesis
|Primary headache classification||Headache type||Description and comments|
|Migraine||Migraine without aura||Headache has at least two of the following four characteristics:|
|Migraine with typical aura||Aura consisting of visual, sensory and/or speech/language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms|
At least two of the following four characteristics:
|Migraine with brainstem aura||As with migraine with typical aura, but with at least two of the following brainstem symptoms:|
|Hemiplegic migraine||Similar to migraine with typical aura, but aura consisting of both of the following:|
|Chronic migraine||Headache occurring on 15 or more days per month for more than three months, which, on at least 8 days per month, has the features of migraine headache|
|Tension-type headache||Headache is typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting minutes to days. The pain does not worsen with routine physical activity and is not associated with nausea, but photophobia or phonophobia may be present.|
May be classified as infrequent episodic, frequent episodic, or chronic.
May be associated with pericranial tenderness.
|Trigeminal autonomic cephalalgias (TACs)||Hemicrania continua, cluster headache, paroxysmal hemicranias, and short-lasting neuralgiform headache attacks||The TACs exist along a spectrum (|
Newman, 2015) and are associated with symptoms of craniofacial autonomic alterations ipsilateral to the pain, such as lacrimation, ptosis, pupillary changes, tear production, conjunctival injection, rhinorrhea, or sweating.
Magnetic resonance imaging and pituitary testing should be performed to exclude pituitary tumors, which can rarely cause TAC-like pain.
Hemicrania continua and paroxysmal hemicrania are typically responsive to indomethacin
|Other||Primary stabbing headache||Transient and localized stabs of pain in the head that occur spontaneously in the absence of organic disease of underlying structures or of the cranial nerves. No accompanying cranial autonomic symptoms|
|Other migraine||Episodic and other syndromes that may be associated with migraine||Recurrent gastrointestinal disturbance (cyclical vomiting syndrome and abdominal migraine)|
Benign paroxysmal vertigo/chronic persistent perceptual dizziness
- Buse D.C.
- Loder E.W.
- Gorman J.A.
- Stewart W.F.
- Reed M.L.
- Fanning K.M.
- et al.
2.2 Approaches to the treatment of primary headache syndromes
2.2.1 Behavioral headache management
2.2.2 Pharmacologic management of migraine
- Holland S.
- Silberstein S.D.
- Freitag F.
- Dodick D.W.
- Argoff C.
- Ashman E.
2.2.3 Treatment of other primary headache disorders
2.2.4 Starting preventive headache therapies
2.3 Secondary headache syndromes in POTS
|Medication Class||Medication||Evidence level (||Typical daily dose||Comorbidities that may be worsened||Comorbidities that may be improved||Other considerations|
|Anti-seizure drugs||Divalproe × sodium, sodium valproate||A||500–2000 mg||Fatigue; dizziness; nausea; anorexia; abdominal pain; main worsen headache in some individuals||Mood disorders||Teratogenicity severely restricts use in women of childbearing potential|
Start at 250 to 500 mg daily
|Topiramate||A||50–200 mg||Anhidrosis/heat intolerance; cognition (“brain fog”); weight loss||May promote weight loss||Start 25 mg at bedtime, then increase 25 mg per week to 75–100 mg.|
|Beta-blockers||Metoprolol||A||100–200 mg daily||Fatigue, orthostatic intolerance, sexual||Palpitations/tachycardia|
|Propranolol||A||40–240 mg||The short-acting form dosed at 20 mg 2 or 3 times per day is often better tolerated.|
|Tricyclics||Amitriptyline||B||10–200 mg||Dry mouth, constipation, fatigue||Insomnia, chronic pain, depression||Start 10–25 mg at bedtime, increase weekly to 75–100 mg|
|Nortriptyline||Anecdotal||10–150 mg||Insomnia||Insomnia, chronic pain, depression||Start 10–25 mg at bedtime, increase weekly to 75–100 mg.|
If insomnia occurs, take in the morning.
|SNRI||Venlafaxine||B||75–225 mg||Tachycardia, insomnia||Chronic pain|
|Natural supplements||Feverfew||B||50–300 mg||Lack of long-term safety data; varied potency of commercially-available preparations|
|Riboflavin (vitamin B2)||B||400 mg||Maximal clinical effect starting at about two months|
|Magnesium citrate||B||400–600 mg||Constipation||Effectiveness of oral magnesium oxide (9 mg/kg/day) was equivocal, but magnesium oxide is often used at the same dose due to availability.|
May paradoxically worsen constipation in some individuals.
3. Pain epidemiology in POTS
3.1 Mechanisms of chronic pain
3.2 Approaches to treating chronic pain
|Medication or medication class||Comorbidities that may be worsened||Comorbidities that may be improved|
|Tricyclic antidepressants||Dry mouth, constipation, fatigue, orthostatic intolerance||Sleep disturbance; migraine; depression (may require higher doses); bladder pain|
|Serotonin reuptake inhibitors||Insomnia, headache, dizziness, fatigue, nausea, sexual dysfunction||Sleep disturbance|
|Cyclobenzaprine||Fatigue, dry mouth||Sleep disturbance|
|Alpha-2-delta calcium channel agonists (gabapentin, pregabalin)||Fatigue, weight gain||Sleep disturbance.|
May promote weight gain
|Serotonin and norepinephrine reuptake inhibitors (duloxetine, venlafaxine, desvenlafaxine, milnacipran)||Headache; nausea; palpitations; dry mouth (in adults); abdominal pain (in children and adolescents); weight loss (in children and adolescents)||Depression|
- Pergolizzi Jr., J.V.
- Raffa R.B.
- Taylor Jr., R.
- Rodriguez G.
- Nalamachu S.
- Langley P.
- Metyas S.K.
- Yeter K.
- Solyman J.
- Arkfeld D.
- Patten D.K.
- Schultz B.G.
- Berlau D.J.
- Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies.Dev. Med. Child Neurol. 2010; 52: 1088-1097
- Treatment of neuropathic pain with venlafaxine: a systematic review.Pain Med. 2017; 18: 1999-2012
- Spontaneous intracranial hypotension: recommendations for management.Can. J. Neurol. Sci. 2013; 40: 144-157
- The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature.Harv. Rev. Psychiatry. 2000; 7: 257-277
- Vestibular functioning and migraine: comparing those with and without vertigo to a normal population.J. Laryngol. Otol. 2013; 127: 1169-1176
- Treatment of tension-type headache: from old myths to modern concepts.Neurol. Sci. 2014; 35: 17-21
- Acute migraine treatment.Continuum (Minneap. Minn). 2015; 21: 953-972
- Early epidural blood patch in spontaneous intracranial hypotension.Neurology. 2004; 63: 1950-1951
- Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain.Expert Opin. Ther. Targets. 2017; 21: 695-703
- Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial.Cephalalgia. 2010; 30: 1426-1434
- Sleep hygiene and migraine in children and adolescents.Cephalalgia. 1999; 19: 57-59
- The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies.Headache. 2015; 55: 21-34
- Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study.Headache. 2013; 53: 1278-1299
- Topiramate monotherapy use in women with and without epilepsy: pregnancy and neonatal outcomes.Epilepsy Res. 2014; 108: 717-724
- Cephalalgia. 2013; 33: 629-808
Chelimsky G. Article in this issue. 2018.
- Benign joint hypermobility minimally impacts autonomic abnormalities in pediatric subjects with chronic functional pain disorders.J. Pediatr. 2016; 177: 49-52
- Spontaneous intracranial hypotension: efficacy of radiologic targeting vs blind blood patch.Neurology. 2011; 76: 1139-1144
- Milnacipran for pain in fibromyalgia in adults.Cochrane Database Syst. Rev. 2015; Cd008244
- Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice.Clin. J. Pain. 2015; 31: 108-114
- A survey-based analysis of symptoms in patients with postural orthostatic tachycardia syndrome.Proc. (Baylor Univ. Med. Cent.). 2015; 28: 157-159
- Triazolam improves sleep but fails to alter pain in TMD patients.J. Orofac. Pain. 1998; 12: 116-123
- Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia.Pain. 2015; 156: 2319-2325
- CDC guideline for prescribing opioids for chronic pain - United States, 2016.MMWR Recomm. Rep. 2016; 65: 1-49
- Pharmacologic management of neuropathic pain: evidence-based recommendations.Pain. 2007; 132: 237-251
- Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research.Am. Psychol. 2014; 69: 153-166
- The association of sleep and pain: an update and a path forward.J. Pain. 2013; 14: 1539-1552
- Cognitive-behavioral therapy for comorbid insomnia and chronic pain.Sleep Med. Clin. 2014; 9: 261-274
Francomano C RP. Article in this issue. 2018.
Fu Q, Levine B. Article in this issue. 2018.
- TMD and chronic pain: a current view.Dent. Press J. Orthod. 2015; 20: 127-133
- Treatment of patients with diabetic peripheral neuropathic pain in China: a double-blind randomised trial of duloxetine vs. placebo.Int. J. Clin. Pract. 2015; 69: 957-966
- Postural tachycardia syndrome: beyond orthostatic intolerance.Curr. Neurol. Neurosci. Rep. 2015; 15: 60
- Small nerve fiber involvement in patients referred for fibromyalgia.Muscle Nerve. 2014; 49: 757-759
- Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.PLoS One. 2013; 8e84716
- The relationship between sleep and headache in children: implications for treatment.Cephalalgia. 2014; 34: 767-776
- Distinct mechanisms underlying pronociceptive effects of opioids.J. Neurosci. 2011; 31: 16748-16756
- Association between topiramate and zonisamide use during pregnancy and low birth weight.Obstet. Gynecol. 2014; 123: 21-28
- Symptoms predictive of postural tachycardia syndrome (POTS) in the adolescent headache patient.Headache. 2013; 53: 947-953
- Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.Neurology. 2012; 78: 1346-1353
- Persistent postural-perceptual dizziness: a matter of higher, central dysfunction?.PLoS One. 2015; 10
- Behavioral approaches to the treatment of migraine.Semin. Neurol. 2006; 26: 199-207
- Improvement in headaches with continuous positive airway pressure for obstructive sleep apnea: a retrospective analysis.Headache. 2013; 53: 333-343
- Overactive bladder and autonomic dysfunction: lower urinary tract symptoms in females with postural tachycardia syndrome.Neurourol. Urodyn. 2017; 36: 610-613
- The triggers or precipitants of the acute migraine attack.Cephalalgia. 2007; 27: 394-402
- Orthostatic and non-orthostatic headache in postural tachycardia syndrome.Cephalalgia. 2011; 31: 409-415
- Central mechanisms of pathological pain.Nat. Med. 2010; 16: 1258-1266
- Spinal excitatory mechanisms of pathological pain.Pain. 2015; 156: S11-S17
- Migraine in women.Neurol. Clin. 2009; 27: 503-511
- Orthostatic headache without CSF leak.Neurology. 2008; 71: 1902-1906
- Dynamic CT myelography: a technique for localizing high-flow spinal cerebrospinal fluid leaks.AJNR Am. J. Neuroradiol. 2003; 24: 1711-1714
- Migraine management during menstruation and menopause.Continuum (Minneap. Minn). 2015; 21: 990-1003
- High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial.J. Child Neurol. 2008; 23: 1300-1304
- A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial.Headache. 2004; 44: 885-890
- Toward a rational understanding of migraine trigger factors.Med. Clin. North Am. 2001; 85: 911-941
- Application of IHS criteria to headache attributed to spontaneous intracranial hypotension in a large population.Cephalalgia. 2009; 29: 418-422
- Med. Lett. Drugs Ther. 2008; 50: 57-58
- Low dose naltrexone in the treatment of fibromyalgia.Curr. Rheumatol. Rev. 2017; (Epub ahead of print)https://doi.org/10.2174/1573397113666170321120329
- Nociceptive TRP channels: sensory detectors and transducers in multiple pain pathologies.Pharmaceuticals (Basel). 2016; 9
- Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks.Headache. 2013; 53: 1034-1053
- Spontaneous CSF leaks: low CSF volume syndromes.Neurol. Clin. 2014; 32: 397-422
- Spontaneous intracranial hypotension.Continuum (Minneap. Minn). 2015; 21: 1086-1108
- Orthostatic headaches without CSF leak in postural tachycardia syndrome.Neurology. 2003; 61: 980-982
- Estimates of pain prevalence and severity in adults: United States, 2012.J. Pain. 2015; 16: 769-780
- Trigeminal autonomic cephalalgias.Continuum (Minneap. Minn). 2015; 21: 1041-1057
- The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review.Ann. Intern. Med. 2017; 167: 319-331
- Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes.Pediatrics. 2013; 131: e1091-e1100
- Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.Pain. 2013; 154: 2310-2316
- Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome.Clin. Sci. (Lond.). 2012; 122: 227-238
- Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome.J. Pediatr. 2011; 158: 20-23
- Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes.Clin. Sci. (Lond.). 2012; 122: 183-192
- The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn's disease, and other chronic pain disorders.Pharmacotherapy. 2018; 38 (Epub 2018 Feb 23): 382-389https://doi.org/10.1002/phar.2086
- A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain.Pain Pract. 2013; 13: 239-252
- Central pain mechanisms in chronic pain states—maybe it is all in their head.Best Pract. Res. Clin. Rheumatol. 2011; 25: 141-154
- Behavioral therapy for chronic migraine.Curr. Pain Headache Rep. 2013; 17: 304
- Synaptic inhibition and disinhibition in the spinal dorsal horn.Prog. Mol. Biol. Transl. Sci. 2015; 131: 359-383
- Tension-type headache and sleep.Curr. Neurol. Neurosci. Rep. 2015; 15: 520
- Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more.Circulation. 2009; 120: 725-734
- The face of postural tachycardia syndrome: a cross-sectional community-based survey.Heart Rhythm. 2016; 13: PO03-194
- Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy.Curr. Opin. Neurobiol. 2016; 36: 31-37
- Transcutaneous and percutaneous neurostimulation for headache disorders.Headache. 2017; 57: 4-13
- Opioid-induced hyperalgesia: cellular and molecular mechanisms.Neuroscience. 2016; 338: 160-182
- Improving sleep: initial headache treatment in OIF/OEF veterans with blast-induced mild traumatic brain injury.J. Rehabil. Res. Dev. 2009; 46: 1071-1084
- Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American academy of sleep medicine clinical practice guideline.J. Clin. Sleep Med. 2017; 13: 307-349
- Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.JAMA. 2006; 295: 2286-2296
- Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial.Neurology. 1998; 50: 466-470
- Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial.Neurology. 2013; 80: 697-704
- The efficacy of epidural blood patch in spontaneous CSF leaks.Neurology. 2001; 57: 1921-1923
- The extracranial vascular theory of migraine—a great story confirmed by the facts.Headache. 2011; 51: 409-417
- Unlearning chronic pain: a randomized controlled trial to investigate changes in intrinsic brain connectivity following cognitive behavioral therapy.NeuroImage Clin. 2014; 5: 365-376
- Preventive migraine treatment.Continuum (Minneap. Minn). 2015; 21: 973-989
- How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature.Sleep Med. Rev. 2004; 8: 119-132
- Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief.J. Pain. 2008; 9: 1006-1017
- Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia.Curr. Rheumatol. Rep. 2008; 10: 463-466
- Cognitive-behavioral therapy for sleep abnormalities of chronic pain patients.Curr. Rheumatol. Rep. 2009; 11: 451-460
- Nutraceutical and other modalities for the treatment of headache.Continuum (Minneap. Minn). 2015; 21: 1018-1031
- Postural orthostatic tachycardia syndrome: the Mayo clinic experience.Mayo Clin. Proc. 2007; 82: 308-313
- Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis.Ann. Intern. Med. 2015; 163: 191-204
- Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms.Pharmacol. Ther. 2006; 109: 57-77
- Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy.J. Neurol. 2014; 261: 579-588
- Sleep disturbance and affective comorbidity among episodic migraineurs.Headache. 2014; 54: 116-124
- Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial.Headache. 2003; 43: 601-610
- Heavily T2-weighted MR myelography vs CT myelography in spontaneous intracranial hypotension.Neurology. 2009; 73: 1892-1898
- Propranolol blocks cardiac and neuronal voltage-gated sodium channels.Front. Pharmacol. 2010; 1: 144
- Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury.PLoS One. 2011; 6e28908
- Carbamazepine for acute and chronic pain in adults.Cochrane Database Syst. Rev. 2011; Cd005451
- Pain: moving from symptom control toward mechanism-specific pharmacologic management.Ann. Intern. Med. 2004; 140: 441-451
- Sleep in patients with chronic migraine.Curr. Pain Headache Rep. 2017; 21: 39
- The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population.Pain Med. 2009; 10: 586-593
- Epidemiology of migraine.Neurol. Clin. 2016; 34: 849-861
☆Dr. Cook is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.
☆The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
☆Financial support: Not applicable.