Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study.

BACKGROUND: Dihydroergotamine (DHE), like triptans, is contraindicated in patients with ischemic heart disease or coronary vasospasm. Its true safety, tolerability, and efficacy in patients with cardiovascular risk without ischemic heart disease or coronary vasospasm remain unclear. OBJECTIVES: To assess the safety, tolerability, and effectiveness of repetitive intravenous DHE in patients with cardiovascular risk factors. METHODS: A single-center, retrospective cohort study was conducted at the Jefferson Headache Center inpatient unit for refractory chronic migraine patients treated with our intravenous DHE protocol between January 1, 2019, and October 15, 2019. We evaluated tolerability and effectiveness outcomes based on atherosclerotic cardiovascular disease 10-year calculated risk scores, stratified into low (<5.0%) and elevated (≥5.0%) risk. Data were presented in mean ± standard deviation or median (25th percentile, 75th percentile) if non-normally distributed. RESULTS: Among 347 patients (median age of 46 [36, 57], female n = 278 [80.1%]), who received inpatient intravenous DHE, 227 patients (age 53 [45, 60], female 81.1%) had calculable risk scores, 64 (28.2%) had elevated risk, and 38 (16.7%) had cardiology consultations. There were no clinically significant electrocardiogram abnormalities or cardiovascular adverse events. The median hospital length of stay was 6 (5, 7) days. Compared to the low-risk group, those with elevated risk had higher nausea (31.3% vs. 14.1%, p = 0.008), but similar initial DHE dose (0.5 [0.25, 0.5] vs. 0.5 [0.25, 0.5], p = 0.009), lower final DHE dose (0.75 [0.5, 1] vs. 1 [0.75, 1] p < 0.001), and lower pain reduction after admission (-3.8 [2.1, 6] vs. -5 [3, 7] p = 0.037). CONCLUSION: Patients receiving intravenous DHE by the Jefferson Headache Center inpatient headache protocol had significantly reduced pain severity at discharge. No clinically significant cardiac or electrocardiogram abnormalities were detected in patients with elevated (or low) atherosclerotic cardiovascular disease risk. Repetitive intravenous DHE used by our protocol was safe in refractory chronic migraine patients.

Real-world study of intranasal ketamine for use in patients with refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Subanesthetic ketamine infusion has been used for managing refractory headache in inpatient or outpatient infusion settings. Intranasal ketamine may be an alternative option for outpatient care. METHODS: A retrospective study was conducted at a single tertiary headache center to assess the clinical effectiveness and tolerability of intranasal ketamine in patients with refractory chronic migraine. Candidates who received intranasal ketamine between January 2019 and February 2020 were screened through an electronic medical record query. Manual chart reviews and structured telephone interviews were conducted on obtaining informed consent. RESULTS: Of 242 subjects screened, 169 (79.9% women) of median (IQR) age 44 (22) years were interviewed. They reported a median (IQR) of 30 (9) monthly headache days and tried 4 (1) classes of preventive medications. Overall, they used 6 (6) sprays per day, with a median (IQR) of spray use of 10 (11) days per month. Intranasal ketamine was reported as 'very effective' in 49.1% and the quality of life was considered 'much better' in 35.5%. At the time of the interview, 65.1% remained current intranasal ketamine users and 74.0% reported at least one adverse event. CONCLUSION: In this descriptive study, intranasal ketamine served as an acute treatment for refractory chronic migraine by reducing headache intensity and improving quality of life with relatively tolerable adverse events. Most patients found intranasal ketamine effective and continued to use it despite these adverse events. Given the potential for overuse, it should be reserved for those clearly in need of more effective rescue treatment with appropriate safety precautions. Well-designed prospective placebo-controlled trials are necessary to demonstrate the efficacy and safety of intranasal ketamine in patients with migraine.

Central Nervous System Involvement of Multiple Myeloma Presenting as Short-lasting Unilateral Neuralgiform Headache with Conjunctival Injection and Tearing: A Case Report.

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are part of the trigeminal autonomic cephalalgia (TAC) group of headache disorders. Attacks present with repeated, severe, sharp, stabbing, or throbbing pain. Patients may experience a single attack, recurrent attacks with pain-free interictal periods, or a sawtooth pattern background pain with superimposed stabs.1,2 Although SUNCT typically presents as a primary headache disorder, it may be secondary to an underlying pathology, such as pituitary tumors or posterior fossa lesions, both intra and extra-axial (vascular lesion, tumor, or bony abnormalities). Multiple Myeloma (MM) with central nervous system involvement (CNS MM) most commonly presents with visual changes (36%), radiculopathy (27%), headache (25%), confusion (21%), dizziness (7%) and seizures (6%).3,4 Secondary SUNCT cases have been sparsely described (less than 60), and CNS MM presenting as SUNCT has not been previously described in the literature.2,5 Our case describes a previously unreported clinical presentation of CNS MM. The report highlights the need for a timely and thorough diagnostic work-up of headache in patients with risk factors for a secondary etiology, which in this case included new-onset, autonomic features, older age, and history of malignancy. A misdiagnosis will preclude a potentially life-extending or saving targeted therapy for the underlying illness. We also aim to remind practitioners of the variability in the clinical symptoms of SUNCT, which are known to occur in a significant number of cases, including migrainous features and dull interictal pain.

Lidocaine infusions for refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Patients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly 'break the cycle' of pain. Lidocaine infusions may be effective but evidence is limited. METHODS: The records of 832 hospital admissions involving continuous multiday lidocaine infusions for migraine were reviewed. All patients met criteria for refractory chronic migraine. During hospitalization, patients received additional migraine medications including ketorolac, magnesium, dihydroergotamine, methylprednisolone, and neuroleptics. The primary outcome was change in headache pain from baseline to hospital discharge. Secondary outcomes measured at the post-discharge office visit (25-65 days after treatment) included headache pain and the number of headache days, and percentage of sustained responders. Percentage of acute responders, plasma lidocaine levels, and adverse drug effects were also determined. RESULTS: In total, 609 patient admissions met criteria. The mean age was 46±14 years; 81.1% were female. Median pain rating decreased from baseline of 7.0 (5.0-8.0) to 1.0 (0.0-3.0) at end of hospitalization (p<0.001); 87.8% of patients were acute responders. Average pain (N=261) remained below baseline at office visit 1 (5.5 (4.0-7.0); p<0.001). Forty-three percent of patients were sustained responders at 1 month. Headache days (N=266) decreased from 26.8±3.9 at baseline to 22.5±8.3 at the post-discharge office visit (p<0.001). Nausea and vomiting were the most common adverse drug effects and all were mild. CONCLUSION: Lidocaine infusions may be associated with short-term and medium-term pain relief in refractory chronic migraine. Prospective studies should confirm these results.

Beyond the Raskin Protocol: Ketamine, Lidocaine, and Other Therapies for Refractory Chronic Migraine.

PURPOSE OF REVIEW: The purpose of this review is to discuss the available evidence and therapeutic considerations for intravenous drug therapy for refractory chronic migraine. RECENT FINDINGS: In carefully monitored settings, the inpatient administration of intravenous lidocaine and ketamine can be successful in treating refractory chronic migraine. Many patients with refractory chronic migraine have experienced treatment failure with the Raskin protocol. The use of aggressive inpatient infusion therapy consisting of intravenous lidocaine or ketamine, along with other adjunctive medications, has become increasingly common for these patients when all other treatments have failed. There is a clear need for prospective studies in this population comprised of patients who have largely been excluded from other studies.

Ketamine for Refractory Chronic Migraine: An Observational Pilot Study and Metabolite Analysis.

Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia. In this prospective, observational pilot study of 6 patients, we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking. All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment ( P≤.05 ) but increased to 7.0 ± 1.4 by the postdischarge visit at 4 weeks (P > .05 vs baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization ( P≤.05 ) but increased to 7.2 ± 1.7 by the postdischarge visit at 6 weeks (P > .05 vs baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 vs -2.8; P≤.05 ), but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.

DHE-Induced Peripheral Arterial Vasospasm in Primary Raynaud Phenomenon: Case Report.

Dihydroergotamine (DHE) is primarily a serotonin 5HT1B and 5HT1D receptor agonist used for acute migraine treatment. It is associated with acute vasoconstriction mediated through the 5HT1B receptor and is contraindicated in patients with history of cardiac disease and peripheral vascular disease. We present a case of acute peripheral arterial vasospasm in a patient with primary Raynaud phenomenon while receiving inpatient treatment for status migrainosus with intravenous (IV) DHE. The patient is a 35-year-old female with a history of chronic migraine and primary Raynaud phenomenon. After 15 doses of IV DHE, the patient reported paresthesias of the right hand and was noted to have absent right radial and ulnar pulses to palpation. Portable arterial Doppler study demonstrated abnormal flat line pulse volume recordings (PVRs) in the right second, third, and fourth digits, with markedly dampened PVR in the right thumb and fifth finger along with no ulnar PVR detectable at the wrist. Duplex revealed bilateral severely diminished flow in the right ulnar and radial arteries without acute occlusions. Computed tomography angiogram of right upper extremity visualized arteries through the mid-forearm but not distally. Dihydroergotamine was discontinued, and the patient was started on oral amlodipine and aspirin. Repeat Doppler ultrasound 3 days later revealed normal arm and digital waveforms bilaterally consistent with resolution of vasospasm. This case highlights a potential complication of IV DHE therapy. Risk may be increased in patients with primary Raynaud phenomenon. We suggest cautious use of IV DHE in this population.

Rationale for electrical parameter determination in external trigeminal nerve stimulation (eTNS) for migraine: A narrative review.

BACKGROUND: Migraine is a primary headache disorder involving dysregulation of central and peripheral pain pathways. Medical treatment is often limited by drug side effects, comorbidities and poor compliance. This makes neuromodulation an ideal option for migraine treatment. Cefaly® is a transcutaneous electrical neurostimulator designed specifically for migraine treatment. It results in external trigeminal nerve stimulation of the supraorbital and supratrochlear nerves. External trigeminal nerve stimulation is effective for acute and preventive migraine treatment and may result in normalization of dysregulated pain pathways. OBJECTIVE: Our objective was to provide a narrative review of the neuroanatomical and pathophysiological basis of external trigeminal nerve stimulation for migraine treatment and to provide the rationale behind the choice of the electrical parameters used for external trigeminal nerve stimulation. METHODS: We reviewed external trigeminal nerve stimulation clinical trial publications, basic science neurostimulation literature, publications describing pathophysiological mechanisms in migraine, and documentation used in the application for the Food and Drug Administration approval of external trigeminal nerve stimulation. RESULTS: The electrical parameters used for external trigeminal nerve stimulation were chosen to maximize safety and efficacy. Critical parameters include generator characteristics, pulse shape, pulse duration, pulse frequency and session duration and frequency. We explain the rationale behind determination of each parameter. There is evidence of dysregulated central and peripheral pathways in migraine and evidence that external trigeminal nerve stimulation may normalize function of these pathways. CONCLUSION: External trigeminal nerve stimulation is a safe and effective Food and Drug Administration-approved option for the acute and preventive treatment of migraine. The electrical parameters were optimized specifically for external stimulation of the trigeminal nerve to maximum safety, comfort and efficacy.

Ketamine for Refractory Headache: A Retrospective Analysis.

BACKGROUND AND OBJECTIVES: The burden of chronic headache disorders in the United States is substantial. Some patients are treatment refractory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent analgesia in subanesthetic doses in chronic pain, and limited data suggest it may alleviate headache in some patients. METHODS: We performed a retrospective study of 61 patients admitted over 3 years for 5 days of intravenous therapy that included continuous ketamine to determine responder rate and patient and ketamine infusion characteristics. Pain ratings at 2 follow-up visits were recorded. An immediate responder was a patient with decrease of 2 points or greater in the numerical rating scale (0-10) from start to final pain in the hospital. Sustained response at office visits 1 and 2 was determined based on maintaining the 2-point improvement at those visits. Patients were assessed daily for pain and adverse events (AEs). RESULTS: Forty-eight (77%) of the 61 patients were immediate responders. There were no differences regarding demographics, opioid use, or fibromyalgia between immediate responders and nonresponders. Maximum improvement occurred 4.56 days (mean) into treatment. Sustained response occurred in 40% of patients at visit 1 (mean, 38.1 days) and 39% of patients at visit 2 (mean, 101.3 days). The mean maximum ketamine rate was 65.2 ± 2.8 mg/h (0.76 mg/kg per hour). Ketamine rates did not differ between groups. Adverse events occurred equally in responders and nonresponders and were mild. CONCLUSIONS: Ketamine was associated with short-term analgesia in many refractory headache patients with tolerable adverse events. A prospective study is warranted to confirm this and elucidate responder characteristics.

Current Treatment Options: Headache Related to Menopause-Diagnosis and Management.

PURPOSE OF REVIEW: Menopause is a life-changing event in numerous ways. Many women with migraine hold hope that the transition to the climacteric state will coincide with a cessation or improvement of migraine. This assumption is based mainly on common lay perceptions as well as assertions from many in the healthcare community. Unfortunately, evidence suggests this is far from the rule. Many women turn to a general practitioner or a headache specialist for prognosis and management. A natural instinct is to manipulate the offending agent, but in some cases, this approach backfires, or the concern for adverse events outweighs the desire for a therapeutic trial, and other strategies must be pursued. Our aim was to review the frequency and type of headache syndromes associated with menopause, to review the evidence for specific treatments for headache associated with menopause, and to provide management recommendations and prognostic guidance. RECENT FINDINGS: We reviewed both clinic- and population-based studies assessing headache associated with menopause. Headache in menopause is less common than headache at earlier ages but can present a unique challenge. Migraine phenotype predominates, but presentations can vary or be due to secondary causes. Other headache types, such as tension-type headache (TTH) and cluster headache (CH) may also be linked to or altered by hormonal changes. There is a lack of well-defined diagnostic criteria for headache syndromes associated with menopause. Women with surgical menopause often experience a worse course of disease status than those with natural menopause. Hormonal replacement therapy (HRT) often results in worsening of migraine and carries potential for increased cardiovascular and ischemic stroke risk. Estrogen replacement therapy (ERT) in patients with migraine with aura (MA) may increase the risk of ischemic stroke; however, the effect is likely dose-dependent. Some medications used in the prophylaxis of migraine may be useful in ameliorating the vasomotor and mood effects of menopause, including venlafaxine, escitalopram, paroxetine, and gabapentin. Other non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga may also be helpful in reducing headache and/or vasomotor symptoms associated with menopause. The frequency and type of headache associated with menopause is variable, though migraine and TTH are most common. Women may experience a worsening, an improvement, or no change in headache during the menopausal transition. Treatment may be limited by vascular risks or other medical and psychiatric factors. We recommend using medications with dual benefit for migraine and vasomotor symptoms including venlafaxine, escitalopram, paroxetine, and gabapentin, as well as non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga. If HRT is pursued, continuous (rather than cyclical) physiological doses should be used, transdermal route of administration is recommended, and the patient should be counseled on the potential for increased risk of adverse events (AEs). Concomitant use of a progestogen decreases the risk of endometrial hyperplasia with ERT. Biological mechanisms are incompletely understood, and there is a lack of consensus on how to define and classify headache in menopause. Further research to focus on pathophysiology and nuanced management is desired.

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress.

Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.

Current Treatment Options: Vestibular Migraine.

OPINION STATEMENT: Vestibular migraine (VM) is a disorder with a spectrum of clinical presentations and among the most common causes of chronic vestibular symptoms. Some present with attacks before or during typical migraine, but many others have fluctuating or daily symptoms. While the symptoms and pathogenesis of vestibular migraine may have elements of both central and peripheral disorders, hearing loss should be absent. VM typically worsens with activity and head movements in general, and encompasses symptoms of vertigo, disequilibrium, or imbalance. While it is possible to confuse other disorders such as Meniere's disease with migraine, it is worth making the diagnosis of vestibular migraine on clinical grounds after ruling out other possible causes. For acute attack treatment, migraine-specific medications such as triptans may be effective. In patients with frequent or disabling attacks, preventive treatment is essential. Vestibular rehabilitation may be helpful as well as medications used for migraine prevention such as including propranolol, venlafaxine, topiramate, and amitriptyline. For refractory patients, use of acetazolamide or lamotrigine may be reasonable.

Intravenous ketamine for subacute treatment of refractory chronic migraine: a case series.

BACKGROUND: Refractory migraine is a challenging condition with great impact on health related quality of life. Intravenous (IV) ketamine has been previously used to treat various refractory pain conditions. We present a series of patients with refractory migraine treated with intravenous ketamine in the hospital setting. METHODS: Based on retrospective chart review, we identified six patients with refractory migraine admitted from 2010 through 2014 for treatment with intravenous ketamine. Ketamine was administered using a standard protocol starting with a dose of 0.1 mg/kg/hr and increased by 0.1 mg/kg/hr every 3 to 4 h as tolerated until the target pain score of 3/10 was achieved and maintained for at least 8 h. Visual Analogue Scale (VAS) scores at time of hospital admission were obtained as well as average baseline VAS scores prior to ketamine infusion. A phone interview was conducted for follow-up of migraine response in the 3 to 6 months following ketamine infusion. RESULTS: The study sample had a median age of 36.5 years (range 29-54) and 83% were women. Pre-treatment pain scores ranged from 9 to 10. All patients achieved a target pain level of 3 or less for 8 h; the average ketamine infusion rate at target was 0.34 mg/kg/hour (range 0.12-0.42 mg/kg/hr). One patient reported a transient out-of-body hallucination following an increase in the infusion rate, which resolved after decreasing the rate. There were no other significant side effects. CONCLUSION: IV ketamine was safely administered in the hospital setting to patients with refractory chronic migraine. Treatment was associated with short term improvement in pain severity in 6 of 6 patients with refractory chronic migraine. Prospective placebo-controlled trials are needed to assess short term and long-term efficacy of IV ketamine in refractory chronic migraine.