Professor of Neurology Tension Type Headache Rob Cowan, MD, FAHS, FAAN Professor of Neurology Stanford University USA

Disclosures I have no disclosures relevant to this presentation other than consulting for Tonix Pharmaceuticals which is developing a novel isomer of Isometheptine for the treatment of Tension-type Headache

Objectives To present the current ICHD 3 (beta)diagnostic criteria for Tension-type Headache To review the current understanding of the pathophysiology of Tension-type Headache To discuss the differential diagnosis, work-up and management of Tension-type Headache

Previously used terms: Tension headache muscle contraction headache Psychomyogenic headache Stress headache Ordinary headache Essential headache Idiopathic headache Psychogenic headache

ICHD 3 (beta)Diagnostic criteria 2. Tension-type headache (TTH) 2.1 Infrequent episodic tension-type headache 2.1.1 Infrequent episodic tension-type headache associated with pericranial tenderness 2.1.2 Infrequent episodic tension-type headache not associated with pericranial tenderness 2.2 Frequent episodic tension-type headache 2.2.1 Frequent episodic tension-type headache associated with pericranial tenderness 2.2.2 Frequent episodic tension-type headache not associated with pericranial tenderness 2.3 Chronic tension-type headache 2.3.1 Chronic tension-type headache associated with pericranial tenderness 2.3.2 Chronic tension-type headache not associated with pericranial tenderness 2.4 Probable tension-type headache 2.4.1 Probable infrequent episodic tension-type headache 2.4.2 Probable frequent episodic tension-type headache 2.4.3 Probable chronic tension-type headache

Abbreviations TTH = Tension-type Headache (of any type) ETTH = Episodic Tension-type Headache CTH = Chronic Tension-type Headache CDH = Chronic Daily Headache (of any type) CM = Chronic Migraine ICHD = International Classification of Headache Disorders

Introduction - History Previously considered to be primarily psychogenic, studies strongly suggest a neurobiological basis, at least for the more severe subtypes of tension-type headache. The division of Tension-type headache into episodic and chronic subtypes, introduced in ICHD-I, has proved extremely useful. Infrequent episodic tension-type headache, which occurs in almost the entire population, usually has very little impact on the individual and, in most instances, requires no attention from the medical profession. Frequent episodic tension-type headache can be associated with considerable disability, and sometimes warrants treatment with expensive drugs. Chronic tension-type headache is a serious disease, causing greatly decreased quality of life and high disability.

Introduction - Pathogenesis Multifactorial Peripheral Mechanisms Myofascial nociception Predominates in Episodic Tension-type Headache Central Mechanisms Sensitization and inadequate endogenous pain control Predominates in Chronic Tension-type Headache

Primary or secondary headache or both? Tension-type headache can exist in isolation as a primary headache The existence of identifiable trigger(s) does not make the headache secondary Tension-type headache can co-exist with another primary headache (such as migraine) Tension-type headache can co-exist with another secondary headache (such as Giant Cell Arteritis or Post-traumatic headache

Epidemiology TTHLifetime prevalence 79% (3% CTTH) 1 year prevalence (age 40) = 48.2% 1 year prevalence (age 26) = 11.1% Mean life time prevalence is 46% Higher in women 4:5) and declines with age Prevalence increases with educational level Can occur in children Li S, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193-210

Causes The exact mechanisms of Tension-type headache are not known. Peripheral pain mechanisms most likely play a role in Infrequent and Frequent episodic tension-type headache. Central pain mechanisms play a more important role in Chronic tension-type headache Increased pericranial tenderness recorded by manual palpation is the most significant abnormal finding in patients with tension-type headache. The tenderness is typically present interictally, increased during actual headache and increases with the intensity and frequency of headaches. Pericranial tenderness is recorded by manual palpation by small rotating movements and a firm pressure with the second and third fingers on the frontal, temporal, masseter, pterygoid, sternocleidomastoid, splenius and trapezius muscles.

TTH and Muscle Tension? Overall electromyographic activity is greater in CTTH than in controls, but not in individual muscles. Onobotulinum toxin decreases temporalis EMG readings but does not affect TTH Lactate levels in trapezius not different in TTH than in controls. No inflammatory changes in muscles in CTTH Ashina M, et al. Tender points are not sites of ongoing inflammation- in vivo evidence in patients with chronic tension-type headache. Cephalalgia 2003;23:109-16

Pericranial Tenderness in TTH? Pericranial Tenderness is greater interictally in patients with TTH Physical therapy improves neck mobility and anterocollis without any effect on TTH outcomes Pain thresholds and pericranial tenderness are abnormal in CTTH but not in ETTH Bendtsen L, et al. Decreased pain detection and tolerance thresholds in chronic tension-type headache. Arch Neurol 1996;53:373-6

Are ETTH and CTTH separate diseases? Nociceptive reflexes are normal in ETTH and abnormal in CTTH (measured with painful stimulus to trigeminal region) Pharmacologic modulation of temporalis exteroceptors blunts silent period (ES2) in CTTH, suggesting serotonergic inhibition. May explain why Amitriptyline works only in CTTH Biceps Femoris flexion reflex and Laser-evoked nociceptive potentials are abnormal in CTTH deTommaso M, et al. Heat pain thresholds and cerebral event0related potentials following painful CO2laser stimulation in chronic tension-type headache. Pain 2003;104:111-19

Structural Brain Changes in TTH fMRI shows DECREASED brain tissue mass in pain matrices in CTTH Changes are similar to that seen in low back pain and phantom limb pain These changes contrast with the INCREASED density seen in migraine. Schmidt-Wilcke T, et al: Gray matter decrease in patients with chronic tension-type headache. Neurology 2005;65:1483-6

Neuropeptides in TTH Glyceryl trinitrate induces TTH in patients with TTH as it induces Migraine in patients with Migraine! Suggests central sensitization to nitric oxide. CGRP levels are not affected in TTH (but in CTTH with migrainous features, they are) Neither are Substance P or neuropeptide Y. Serotonin data is very mixed and not consistent with finding in Migraine.

Genetics of TTH Risk of TTH same as general population in twin studies High frequency ETTH and CTTH show greater risk in twin studies. Genetic data is sparse Russell MB, Genetics of Tension-type headache. The J Headache and Pain. 2007 Apr :8(2): 71-6

Model of TTH Pathogenesis After Fumal A, Schoenen J. Tension-type headache: current research and clinical management. Lancet Neurology. 2008;7(1) 70-83

Migraine or Tension-type? Spectrum Study: 71% of patients who were initially diagnosed with TTH had their diagnosis changed to Migraine after chart review. Lipton RB, et al. Diagnostic lessons from the spectrum study. Neurology 2002; 58:S27-31

Challenges to Diagnosis Parameter Migraine Tension-type Frequency Variable Duration* 4-72 hours** 30 min-7 days Location Unilat (40% bilat) Bilateral Description Pulsating (50% non-pulsating) Pressing/tighten- ing (non pulsate) Intensity Moderate-Severe Mild-Moderate Effect of activity Aggravates Does not aggravate Nausea or Vomit Yes No Photo/Phonophobia One or both None or one only Attribution None Discrimination between tension-type headache and mild migraine without aura. Patients with frequent headaches often suffer from both disorders *untreated or unsuccessfully treated ** 2-72 hours in children ICHD-3 (beta) Cephalalgia 2013; 33:629-808

Differential diagnosis Migraine – in chronic form characteristic features disappear and pain is less severe Cervical Cephalgia– muscle tenderness of tension type headache may involve the neck Medication overuse headache – consider in patients taking opioid or combination analgesics for an average of 10 days/month New Daily Persistent Headache – abrupt onset, check for precipitating event

Infrequent episodic tension-type headache typically bilateral pressing or tightening in quality mild to moderate intensity lasting 30 minutes to 7 days not worsened with routine physical activity not associated with nausea photo or phonophobia may be present.

Formal Diagnostic Criteria: A. At least 10 episodes of headache occurring on <1 day per month on average (<12 days per year) and fulfilling criteria B-D B. Lasting from 30 minutes to 7 days C. At least two of the following four characteristics: 1. bilateral location 2. pressing or tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no nausea or vomiting 2. no more than one of photophobia or phonophobia E. Not better accounted for by another ICHD-3 diagnosis.

Infrequent episodic tension-type headache and pericranial tenderness A. Episodes fulfilling criteria for 2.1 Infrequent episodic tension-type headache B. Increased pericranial tenderness on manual palpation. OR B. No increase in pericranial tenderness.

Frequent episodic tension-type headache Frequent episodes of headache typically bilateral pressing or tightening in quality mild to moderate intensity pain not worsened by routine physical activity not associated with nausea, photo or phonophobia may be present.

Formal Diagnostic criteria: A. At least 10 episodes of headache occurring on 1-14 days per month on average for >3 months (12 and <180 days per year) and fulfilling criteria B-D B. Lasting from 30 minutes to 7 days C. At least two of the following four characteristics: 1. bilateral location 2. pressing or tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no nausea or vomiting 2. no more than one of photophobia or phonophobia E. Not better accounted for by another ICHD-3 diagnosis.

Comments Frequent episodic tension-type headache often coexists with 1.1 Migraine without aura. Coexisting tension-type headache in migraineurs should preferably be identified through use of a diagnostic headache diary. The treatment of migraine differs considerably from that of tension-type headache. It is important to distinguish between these headache types in order to select the right treatment for each while avoiding medication overuse.

2.3 Chronic tension-type headache A disorder evolving from frequent episodic tension-type headache, with daily or very frequent episodes of headache typically bilateral pressing or tightening in quality mild to moderate intensity lasting hours to days, or unremitting pain does not worsen with physical activity may be associated with mild nausea, photo or phonophobia.

Diagnostic criteria: A. Headache occurring on 15 days per month on average for >3 months (180 days per year), fulfilling criteria B-D B. Lasting hours to days, or unremitting C. At least two of the following four characteristics: 1. bilateral location 2. pressing or tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no more than one of photophobia, phonophobiaor mild nausea 2. neither moderate or severe nausea nor vomiting E. Not better accounted for by another ICHD-3 diagnosis.

Comments: Chronic tension-type headache evolves over time from Frequent episodic tension-type headache When these criteria are fulfilled by headache that, unambiguously, is daily and unremitting from less than 24 hours after its first onset, code as New daily persistent headache. Chronic tension-type headache, headache on at least 15 days must meet the criteria for Tension-type headache Chronic tension-type headache with migraine headache on at least 8 days meets the criteria for Chronic Migraine. Therefore, a patient can fulfill criteria for both these diagnosesby having headache on 25 days per month meeting migraine criteria on 8 days and tension-type headache criteria on 17 days. In these cases, only the diagnosis Chronic migraine should be given.

Chronic Tension-type headache and medication overuse In cases in which there is overuse of medication and the criteria for Chronic tension-type headache are also fulfilled, the rule is to code for both Chronic tension-type headache and Medication-overuse headache . After drug withdrawal, the diagnosis should be re-evaluated: not uncommonly the criteria for Chronic tension-type headache will no longer be fulfilled, with reversion to one or other episodic subtype.

Probable tension-type headache Tension-type-like headache missing one of the features required to fulfill all criteria for a subtype of tension-type headache, and not fulfilling criteria for another headache disorder.

Clinical Presentation May be episodic or chronic on presentation Constitutional or neurological symptoms are uncommon Detailed history Natural history Exacerbating/alleviating factors Comorbidities

Examination and investigation Head and Neck (ROM, auscultation, posture) Neurological examination Manual palpation of pericranial muscles ( frontal, temporal, masseter, pterygoid, sternomastoid, splenius and trapezius. Fundoscopy for papilledema Lab work and Testing If neuro examination normal none needed

Imaging Neuroimaging should be arranged if Atypical pattern of headache History of seizures Neurological signs or symptoms Symptomatic illness Immunocompromise

Acute Treatment Infrequent headache Good results from non prescription medication May need reassurance Always consider non-pharmacologic options Monitor for medication overuse Rosen NL, Psychological issues in the evaluation and treatment of tension-type headache. Curr Pain Headache Rep. 2012 Dec, 16(6):545-53

Acute Pharmacologic Treatment Simple analgesia Aspirin 500 – 1000mg NSAIDS Paracetamol less effective than NSAIDS Combination drugs helpful – watch for medication overuse Opioids or sedatives should not be used Steiner TJ, Voelker M. Gastrointestinal tolerability of aspirin and the choice of over-the-counter analgesia for short-lasting acute pain. J Clin Pharm Ther. 2009 APR,34(2):177-86 Diener HC at al. Use of a fixed combination of actylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized double-blind placebo-controlled, crossover studies. J Headache Pain 2014 Nov 19;15;76

Preventive Treatment Consider when headaches are frequent or acute attacks don’t respond to abortive treatment Best evidence is for Amitriptyline 75- 150mg/day. It helps both pain and muscle tenderness. Works best when started at low dose and increased weekly Mirtazipine 15-30mg/day Unhelpful SSRI’s Botulinium toxin Banzi R, et al. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for the prevention of tension-type headache in adults. Cochrane Database Syst Rev 2015 May 1;5CD)11681

Preventive Treatment Should be considered when: diary or patient report indicates increasing frequency of headache days/mo. there is evidence of medication overuse headaches are significantly interfering with patient’s quality of life

Non-pharmacologic Treatment Education, lifestyle and non-pharmacological treatment Education, reassurance Lifestyle modification (sleep, exercise, eating) Cognitive and Behavioral therapies Orr SL. Diet and nutraceutical interventions for headache management: A review of the evidence Cephalalgia. 2015 Jun 11. Christiansen S et al. Outpatient combined group and individual cognitive-behavioral treatment for patient with migraine and tension-type headache in a routine clinical setting. Headache. 2016 Sep:55(8):1072-91

Treatment Summary After Fumal A, Schoenen J. Tension-type headache: current research and clinical management. Lancet Neurology. 2008;7(1) 70-83

Advanced Treatment Refer to Specialist when: Diagnosis is unclear or complex Patient does not respond to treatment Complicated by medication overuse Local resources and facilities are not adequate

Prognosis Remission from Chronic to Episodic form range from 30 to 67%. 25% of patients with Episodic will carry progress to Chronic 15 to 31% will remain Chronic 21% develop medication overuse Crystal SC, Robbins MS. Epidemiology of tension-type headache. Current Pain and Headache Rep Dec 2010, 14(6); 449-54

Poor prognosis Chronic headache at presentation Co-existing migraine, TMD, Depression, Anxiety, Medication Overuse Not being married Sleep problems Other Pain Syndromes

Good prognosis Onset of Older age Episodic tension type headache at baseline No co-existent pain syndromes Obesity Wang Y, et al. The prevalence of primary headache disorders and their associated factors among nursing staff in North China. J Headache Pain 2015 Jan13,16:4

Conclusions TTH is a clinically and pathophysiologically heterogeneous entity. Misdiagnosis is common in particular among those suffering from mild migraine Pericranial myofascial mechanisms are probably of importance in episodic TTH, while sensitization of pain pathways in the CNS—due to prolonged nociceptive stimuli from pericranial myofascial tissues and inadequate endogenous pain control may account for the conversion from ETTH to CTTH. Acute therapy with NSAIDs is generally effective for the treatment of ETTH There is little scientific evidence to guide the selection of treatment modalities in CTTH but best evidence is for tricyclics.

Thank you for your kind attention Please feel free to contact me at any time with qustions or comments rpcowan@stanford.edu