Efficacy of Erenumab in the Treatment of Trigeminal Neuralgia: A Retrospective Case Series

Objective Trigeminal neuralgia (TN) is a chronic, often refractory, pain condition, which adversely affects the lives of patients. Current treatments are only mildly effective. Anti–calcitonin gene-related peptide (CGRP) monoclonal antibodies have been successfully studied in the treatment of migraines. CGRP plays a role in both TN and migraine. It is prudent to attempt CGRP monoclonal antibody therapy in TN. Erenumab, a human anti-CGRP monoclonal antibody medication, modulates CGRP, which is elevated in patients with TN. The primary objective of this study was to evaluate the efficacy of erenumab for patients with TN.

Retrospective analysis was performed on data collected from 10 patients diagnosed with TN and treated with erenumab for 6 months. Pain was tracked using a numeric pain rating scale (NPRS) from 0 to 10. The effect of erenumab on NPRS after 6 months' time was the primary end point. Secondary end points included side effects to therapy, improvement in headache frequency in those with comorbid migraine, evaluating mood following therapy, and global mood improvement using scale (worse, no change, improved).

Nine of 10 patients (90.0%) reported improvement in pain severity and in global mood improvement. Three patients reported resolution of anxiety and/or depression. Side effects were minimal, with 3 patients reporting constipation, injection site reactions, or both.

Based on these results, erenumab appears to be an efficacious treatment option for patients with refractory TN. Patients experienced improvement in pain, reduced frequency of headache, and improvement in mood. Treatment was well tolerated with only mild side effects reported. Classification of Evidence This study provides Class IV evidence that erenumab increases the probability of improved pain control in patients with medication-resistant TN. Trigeminal neuralgia (TN) is a chronic, often refractory condition leading to severe pain in the areas innervated by the sensory portion, typically V2, of the trigeminal nerve.1 TN usually occurs in people older than 50 years and is characterized by brief, usually unilateral, episodes of facial pain.2,3 TN tends to affect women more than men and has an annual incidence of 13 per 100,000.4,5 The International Classification of Headache Disorders (ICHD-3) diagnostic criteria for TN are pain, which lasts from a fraction of a second to 2 minutes, is severe in intensity, is electric shock-like, shooting, stabbing, or sharp in quality, is precipitated by innocuous stimuli within the affected trigeminal distribution, and is not better accounted for by other ICHD-3 diagnosis.3 TN can have a significant impact on quality of life and result in depression and other mental health afflictions in many sufferers.6 In addition, this condition tends to progress both in length of episodes, severity of pain, and frequency of episodes as patients age, leaving patients with little hope for relief.2 Thus, finding a treatment to reduce pain levels and improve quality of life is an important goal. Although some sufferers of TN get adequate relief with existing oral medications, others are refractory to multiple medications and interventional procedures. Furthermore, patients may be overburdened by medication side effects that traditional therapies often carry and may be unable to continue treatment. In a meta-analysis of traditional medical management in 639 TN patients, 44% reported adverse effects to the drug: vertigo, somnolence, nausea, and fatigue. In refractory cases or cases of severe side effects, patients are often referred to surgery.7 Patients of this nature would benefit greatly from an alternative pharmacologic approach with fewer side effects. According to the European Academy of Neurology's 2019 guideline for TN, carbamazepine or oxcarbazepine are recommended as first-line agents.8 Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen, and phenytoin can also be considered as add-on therapies or stand-alone therapies. If patients do not respond to these medications, microvascular decompression (MVD) is currently recommended in the 2019 European guidelines as first-line treatment for refractory TN.8,9 Although medication is the first-line treatment for TN, carbamazepine is the only FDA-approved medication. Carbamazepine is an anticonvulsant sodium channel blocker, which does have efficacy in treating TN but oftentimes does not work completely and carries many associated side effects: nausea, vomiting, dry mouth, fatigue, dizziness, and significant serious potential side effects including drug-induced agranulocytosis.10,11 In addition to this, carbamazepine also tends to become less effective over time. There are surgical treatment options, such as MVD. However, not all sufferers are candidates for this procedure, given their anatomy, or underlying comorbidities. Also, MVD is invasive and comes with risks associated with surgery.12 Of 5,149 patients treated with MVD, there was a mortality of 15 patients, 95 experienced hearing loss, 147 experienced facial hypesthesia, 211 had cranial nerve palsy, 101 developed CSF leak, 20 developed meningitis, and 16 developed hemorrhagic stroke.8,9 Calcitonin gene-related peptide (CGRP) is an important neuropeptide in the pathophysiology of orofacial pain. It was found that CGRP levels were increased in those with TN; similarly, CGRP infusion can induce headache in patients with migraine.13,14 CGRP sensitizes trigeminal primary afferent neurons, even without previous inflammation.15 In cats, CGRP is evenly distributed through the soma of ganglion cells during periods of pain further supporting its role in TN.16 CGRP is also elevated in patients with TN, supporting the idea that CGRP released from intraganglionic regions may mediate pain transmission, possibly through release of various cytokines.17,18 In rats, the intracisternal injection of CGRP sensitized the rats to sensory stimuli and enhanced withdrawal to pain. The enhancement of this response was inhibited by a CGRP antagonist.19 With the idea that CGRP has a role in TN and that CGRP antagonist blunted the pain caused by sensory stimulation of the head, it is a sound transition to attempt to treat TN with an anti-CGRP monoclonal antibody. Erenumab is the first CGRP monoclonal modulating antibody drug that is currently indicated for migraine headache prophylaxis.20 Its use comes as a result of studies detailing CGRP release from trigeminal neurons during episodes of migraine.20 Clinical trials have been initiated for treatment of TN with rimegepant and galcanezumab. However, there have been no established results, and no medications have received approval.21,22 There is currently limited research in the treatment of TN with erenumab or any other anti-CGRP medications. Thus, presented is a novel treatment trial, which investigates patients who received erenumab to treat TN and analyzes the data collected from their reports to determine effect on pain.

To determine whether erenumab improved pain control as well as affected mood (classification of evidence: IV) in patients with TN, data were gathered from 10 patients (n = 10) with a diagnosis of TN meeting ICHD-3 criteria and were retrospectively analyzed. All patients were either on or had failed at least 2 preventive medications for TN. Over a 6-month period, patients self-administered monthly subcutaneous injections of erenumab. Before initiation of therapy, patients were educated on the drug and advised of potential risks and adverse effects. The patients were followed up in person in the outpatient clinic or by phone by the treating physician. Any patient who reported depression was diagnosed based on DSM5 criteria for major depressive disorder by a licensed medical provider. All mood improvements were assessed via subjective reports from the study population. At baseline and at follow-up evaluation, patients were asked to report pain on a Numeric Pain Rating Scale (NPRS) of 1–10 designated as the primary end point. Secondary end points were also collected, including side effects to therapy, improvement in headache frequency in those with comorbid migraine, and global mood improvement assessment (worse/no change/improved) where patients noted their overall mood improvement. Patients were asked before starting treatment if they experienced either anxiety or depression. They were asked again at follow-up evaluations. Patients who reported a history of migraine headache were also asked to report their headache frequency during the evaluation period. Side effects of erenumab were tracked at each follow-up evaluation. All patients completed 6 months of therapy. Standard Protocol Approvals, Registrations, and Patient Consents All patients completed a written consent, and IRB approval was obtained from the Sheba Medical Center Helsinki Committee (#6647–19). Data Availability Anonymized data not published within this article will be made available by request from any qualified investigator.

An overview of all cases on presentation as well as patient information is reported in the table. Ten patients, 7 females and 3 males, whose ages ranged from 49 to 64 years came for treatment due to orofacial pain with a reported NPRS, which ranged from 7 to 10. All patients met the diagnostic ICHD-3 criteria for TN. Comorbidities of patients included anxiety, depression, endometriosis, hypertension, hyperlipidemia, hypothyroidism, multiple sclerosis, fibromyalgia, and cholecystectomy. Five of 10 patients reported migraine headaches as well. Migraineurs had a frequency of headaches days ranging from 3 to 25 headache days per month. All patients had tried and failed multiple oral therapies in the past and were currently on pharmacotherapy to manage their pain and any other conditions as detailed in the table. Table. Erenumab was tolerated well among all patients. Side effects were reported in 30% of patients, with 2 patients reporting mild constipation and 2 patients noting injection site reactions, also mild as shown in the table. Nine of 10 patients reported a significant decrease in pain as well as increase global improvement as shown in figure 1. Five of 10 patients reported pain freedom at 6-month follow-up with an NPRS of 0. On initial evaluation, 6 patients reported anxiety/depression; however, only 3 did at 6-month follow-up. Nine of 10 participants reported an improved mood. These findings were based on the patient population's subjective reports. For those having migraine headache, 4 of 5 had a significant reduction in their monthly headache frequency as well as shown in figure 2. Based on the results of the analysis of the data collected, it is clear that erenumab was considerably well tolerated and effective.

The 10 patients studied all had a diagnosis of TN based on ICHD-3 diagnostic criteria and were refractory based on failure of multiple medications and were not adequately controlled on their pharmacologic regimen at their initial visit. After being initiated on erenumab, based on the retrospective analysis of the data collected in this uncontrolled study, there was a dramatic improvement in pain and quality of life measured from a majority of the patients. Erenumab improved pain, global improvement, and mood with minimal side effects in our study population. Nine of 10 of the patients reported improvement in pain, and there was a 50% reduction in those reporting anxiety or depression. There are, however, limitations to this study. Primarily, our patient sample is small, and all data were self-reported. Other limitations of this study include a single population base, a single physician and center, no placebo comparison, and open-label design. The positive results of this study indicate a need for a larger controlled study, which incorporates more doctors, larger populations to determine whether pain reduction is maintained over time when compared against placebo. Despite these limitations, the data look very promising, and erenumab was indeed significantly effective in meeting all primary and secondary end points including reduced pain and improved mood. Patients did not report significant adverse effects, and the therapy was well tolerated by all study participants. On further investigation, it is possible that erenumab may be an effective pharmacologic therapy for TN due to its efficacy, favorable side effect profile, and convenient dosing schedule. TAKE-HOME POINTS → Erenumab substantially improves pain, mood, and quality of life in patients with trigeminal neuralgia. → Erenumab can be a safe and effective treatment for patients having refractory trigeminal neuralgia. Appendix. Authors Contributor Information Eliot Parascandolo, Email: [email protected]. Kelsey Levinson, Email: [email protected]. Paul Rizzoli, Email: [email protected]. Study Funding No targeted funding reported. Disclosure E. Parascandalo, K. Levinson, and P. Rizzoli have no financial interests to declare. R. Sharon has been a paid speaker or consultant for the following companies: Novartis Teva, AbbVie, Eli Lilly, Theranica, Neurolief, and Dexcel. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

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