Faculty Bibliography

OBJECTIVES/OBJECTIVE:To provide a unique perspective on geriatric headache and a number of novel treatment options that are not well known outside of the headache literature. DESIGN/METHODS:Review of the most current and relevant headache literature for practitioners specializing in geriatric care. RESULTS:Evaluation and management of headache disorders in older adults requires an understanding of the underlying pathophysiology and how it relates to age-related physiological changes. To treat headache disorders in general, the appropriate diagnosis must first be established, and treatment of headaches in elderly adults poses unique challenges, including potential polypharmacy, medical comorbidities, and physiological changes associated with aging. CONCLUSION/CONCLUSIONS:The purpose of this review is to provide a guide to and perspective on the challenges inherent in treating headaches in older adults.

Background: Overuse of acute or symptomatic headache medications, such as triptans, ergot derivatives, opioids, and combination analgesics, can cause medication overuse headache (MOH). Chronic migraine (CM) is often accompanied by MOH, and prevention of MOH is one of the main goals of preventive treatment of migraine. In clinical trials, fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, reduced the frequency and severity of headaches in patients with CM. We assessed the effect of fremanezumab versus placebo on medication overuse and acute headache medication use in patients with CM. Methods: In this multicenter, randomized double-blind placebo-controlled Phase 3 study, eligible patients with CM were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly dosing (675 mg at baseline, and placebo at Weeks 4 and 8), fremanezumab monthly dosing (675 mg at baseline, and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. Medication overuse was defined as use of acute headache medication on >15 days, use of migraine-specific acute medication on >10 days, or use of combination medications for headache on >10 days during the 28-day baseline period. As a post hoc analysis, we assessed the proportion of patients who reverted from overusing medications at baseline to not overusing medications at Week 12, and the change from baseline in the number of days of acute headache medication use among these patients. Analyses were performed in the full analysis set (all randomized patients who received at least one dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint). Results: Among patients with medication overuse at baseline (quarterly n5201; monthly n5198; placebo n5188), significantly more fremanezumab-treated patients reported no medication overuse during the 12-week treatment period (quarterly: 111/201 patients [55%], P50.0389; monthly: 120/198 patients [61%], P50.0024) than those who received placebo (87/188 patients [46%]). This response to treatment was seen as early as Week 4 (quarterly: 102/201 patients [51%], P50.0091; monthly: 107/198 patients [54%], P50.0014; vs placebo: 73/188 patients [39%]). Among the patients who responded to treatment over the 12-week treatment period (quarterly n5111; monthly n5120; placebo n587), the baseline number of days with medication overuse was similar across treatment groups (quarterly [mean 6 standard error]: 16.6 60.32 days; monthly: 16.7 6 0.33 days; placebo: 16.6 6 0.35). Within this population, fremanezumab treatment significantly reduced the days of acute headache medication use over the 12-week treatment period (quarterly: 29.0 6 0.41 days, P50.0017; monthly: 28.9 6 0.41 days, P50.0040) compared with those who received placebo (27.1 60.46 days). Conclusion: In this Phase 3 study, fremanezumab treatment was associated with a reduction in overuse of acute medications and a corresponding decrease in days using acute medications

BACKGROUND:Low back pain is common in the general population and in individuals with primary headaches. We assessed the relative frequency of self-reported back pain in persons with and without primary headaches and examined pain sensitivity. METHOD/METHODS:A population of 796 individuals completed a headache interview based on ICHD criteria and provided data of interest in a self-administered questionnaire. Headache cases were classified into chronic (≥15) (CH) or episodic (<15 headache days/month) (EH). A total of 495 had a pericranial total tenderness score (TTS), and 494 had cephalic and extracephalic pressure pain thresholds (PPTs) assessed. RESULTS:Adjusted for age, gender, education and poor self-rated health, 1-year relative frequency of back pain was higher in individuals with CH (82.5%) and EH (80.1%) compared to no headache group (65.7%). In persons with back pain, TTS was higher in CH, (26.3 ± 12.1) than in EH, (18.5 ± 10.0; p < 0.001) and higher in both groups than in those with no headache, 10.8 ± 8.5 (p < 0.001 and p < 0.001, respectively). In persons with back pain, temporalis PPT were lower in CH, 169.3 ± 57.8, than in EH, 225.2 ± 98.1, and in no headache group, 244.3 ± 105.4 (p = 0.02 and p = 0.01, respectively). In persons with back pain, finger PPT were lower in CH, 237.1 ± 106.7, than in EH, 291.3 ± 141.3, or in no headache group, 304.3 ± 137.4 (p = 0.02 and p < 0.001, respectively). CONCLUSION/CONCLUSIONS:Back pain is highly frequent in individuals with CH, followed by EH and no headache. In persons with CH, back pain is associated with lower cephalic and extracephalic PPTs suggesting central sensitization may be a substrate or consequence of comorbidity. SIGNIFICANCE/CONCLUSIONS:We found that back pain has high relative frequency in individuals with CH followed EH and no headache. Back pain is associated with low cephalic and extracephalic PPTs in individuals with CH. Central sensitization may be a substrate or consequence of this comorbidity of back pain and CH.

Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been clarified. METHODS: We performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials. RESULTS: The literature search identified 375 citations of which 50 contained relevant original data. An association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain was found. In 13 out of 20 studies in somatic pain conditions, CGRP levels had a positive correlation with pain. Increased CGRP levels were reported in plasma, synovial and cerebrospinal fluid in subjects with musculoskeletal pain. A randomized clinical trial on monoclonal antibody, which selectively binds to and inhibits the activity of CGRP (galcanezumab) in patients with osteoarthritis knee pain, failed to demonstrate improvement of pain compared with placebo. No studies to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions. CONCLUSION: The present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act as a neuromodulator in non-headache pain conditions. However, more studies are needed to fully understand the role of CGRP in nociceptive processing and therapy of chronic pain.

OBJECTIVES: People with migraine and tension-type headache (TTH) have psychiatric comorbidities. We aimed to test differences in mental health constructs by type and frequency of primary headache and associated pain sensitivity. MATERIALS AND METHODS: Data on headache features, neuroticism (Eysenck Personality Questionnaire) and depression (Major Depression Inventory) were obtained from 547 individuals classified into chronic (>/=15) or episodic (<15 headache days/month) and into pure migraine (n=43), pure tension type headache (TTH, n=97), migraine and TTH (n=83) and no headache diagnosis (controls, n=324) groups. A pericranial total tenderness score (TTS) and pressure pain thresholds (PPTs) were measured. Differences in mental health constructs were examined by headache frequency and type using generalized linear mixed models adjusting for sociodemographic covariates. RESULTS: Depression scores were highest among people with chronic headache, lower in those with episodic headache, and lowest in controls. The chronic and episodic headache groups had higher neuroticism scores than controls. Mental health construct scores were highest for the migraine and TTH group and lowest in the control group. TTS and cephalic PPTs were correlated with neuroticism and depression and were higher in the chronic headache group compared to the no headache group even when adjusted for neuroticism and depression. CONCLUSIONS: Neuroticism and depression scores are associated with headache frequency (chronic vs episodic) and are highest for migraine and TTH followed by pure TTH then migraine. Mental health constructs were correlated with but did not influence differences in TTS and PPTs between headache groups.

OBJECTIVE: To assess the evidence for blood flow velocity changes in the middle cerebral artery during and outside of spontaneous migraine attacks. METHODS: A systematic literature search on PubMed was performed and reference lists of assessed articles to identify studies on spontaneous migraine attacks that used transcranial Doppler on the middle cerebral artery with comparisons to interictal measurements were reviewed. Studies on non-spontaneous attacks and intervention studies were excluded. RESULTS: A total of 17 original articles reporting blood flow velocity values in the middle cerebral artery using transcranial Doppler in migraine patients both with and without aura were identified. A total of 24 subgroups (ie, migraine patients without aura = 11, migraine patients with aura = 9, and mixed = 4) of migraine patients were investigated during and outside spontaneous migraine attacks in the 17 studies. No change was reported in 15 subgroups (63%), while decreased blood flow velocity was found in 8 subgroups (33%) and increased blood flow velocity was found in one study (4%). Exploratory analysis revealed that studies showing decreased blood flow velocity were carried out earlier after onset of attack (mean time, 4.1 h) compared with those showing no change (mean time, 6.0 h). CONCLUSIONS: Overall, spontaneous migraine attacks are not accompanied by blood flow velocity changes in the middle cerebral artery. However, explorative analyses on the time from attack onset to examination revealed side-specific attack-related decrease in blood flow velocity in the early, but not late phases. This is the first systematic review focusing on the flow changes in the middle cerebral artery of spontaneous migraine attacks. Future studies should focus on the early blood flow velocity changes in migraine attacks.

Classification has played a major role in the diagnosis of primary headache conditions including migraine with and without aura. With many updates and changes, the International Classification of Headache Disorders (ICHD)-3 beta is currently considered as the gold standard for classification of migraine and other headaches. Correct diagnosis of migraine and its subtypes is a first step toward appropriate treatment and crucial to minimizing disability and optimizing health-related quality of life. The ICHD-3 beta version represents the state of the art in migraine diagnosis but is expected to evolve as biological knowledge advances. Future research should focus on identification of biologically homogeneous subgroups of migraine based on genes and biomarkers.