Abstract
Trigeminal neuralgia is the most common form of craniofacial neuropathic pain with an incidence of 4 to 29 per 100,000 people per year. Acute trigeminal neuralgia pain crises are characterized by increased pain frequency and severity and can impact oral intake and sleep, as well as mood. The diagnosis of acute trigeminal neuralgia is clinical and supported by magnetic resonance imaging demonstrating morphological changes in the trigeminal neurovascular bundle on the ipsilateral side of the pain. Patients often present to the hospital seeking relief from acute exacerbations, making it essential for physicians to understand the management of an acute pain crisis, which differs from the chronic management, especially as there may be limited neurology or pain specialist support after hours. The need for improved knowledge of the treatment of acute trigeminal neuralgia is evidenced by opioids being the most prescribed analgesia despite little efficacy in treating it, a lack of evidence supporting their use and concerning side-effects. This article summarizes the evidence behind pharmacological therapy with fosphenytoin, phenytoin, and lidocaine as rescue medications in acute trigeminal neuralgia through the case of a male patient, age 58 years, who experienced complete resolution of pain following administration of phenytoin.
Trigeminal neuralgia is an extremely painful condition and is the most common form of craniofacial neuropathic pain. It has an incidence of 4 to 29 per 100,000 people per year.1 Trigeminal neuralgia is more prevalent in women and in those of increasing age, with a mean age of onset in the fifth decade.2
Trigeminal neuralgia is managed by medical and surgical specialists, making it essential for physicians to become familiar with both the acute and chronic management, especially the management of an acute pain crisis, when patients often present to the emergency room after hours during which time there is limited neurology or pain specialist support.
Trigeminal neuralgia is characterized as a unilateral sharp stabbing or electricity shock-like sensation affecting the face in the distribution of the trigeminal nerve.1,2 The pain is recurrent and abrupt in onset and termination and lasts seconds to minutes.1,2 The pain can be triggered by stimuli such as touch, tooth brushing, shaving, speech, or mastication.1 Patients with trigeminal neuralgia have increased anxiety, depression, and worsening of sleep, highlighting the impact of this condition on day-to-day life.3 Risk factors for trigeminal neuralgia include increasing age, female sex, neurological conditions, and facial-dental surgery.1 Up to half of patients with trigeminal neuralgia will experience a continuous dull-aching pain in the same region of their sharp intermittent pain.3 Thankfully, pain from trigeminal neuralgia alleviates with time and therapy, with results from a prospective Danish study demonstrating a pain reduction of over 50% in half of patients at 2 years.4
Trigeminal neuralgia is a clinical diagnosis and is made based on criteria determined by the International Classification of Headache Disorders (Table 1).5 The differential diagnosis for facial pain is broad, as outlined in Table 2, but it can be narrowed quickly by thorough history and examination.
Diagnostic criteria for trigeminal neuralgia, symptomatology must meet all criteria.
Differential diagnoses schema for facial pain.
Trigeminal neuralgia is separated into three sub-categories, classical, secondary, and idiopathic. Classical trigeminal neuralgia accounts for 75% of cases and is due to trigeminal nerve compression by nearby vascular structures, with magnetic resonance imaging (MRI) demonstrating morphological changes on the ipsilateral the side of the pain.1 Secondary trigeminal neuralgia accounts for 15% of cases and is not caused by neurovascular compression, but is instead caused by an alternative neurological disease, such as cerebellopontine angle tumor, arteriovenous malformation, or multiple sclerosis.1 Idiopathic trigeminal neuralgia accounts for 10% of cases and includes those who do not meet the criteria for classical or secondary type.1 Neurological examination in trigeminal neuralgia is typically normal, although some patients may experience hypoesthesia or facial muscle contraction during periods of pain.1 An abnormal neurological examination increases concern for secondary trigeminal neuralgia and should prompt additional investigations.3
The patho-physiology of trigeminal neuralgia is compression of the trigeminal sensory root near the brainstem by a blood vessel. This compression causes focal demyelination and remyelination at the area of transition from the peripheral Schwann cell myelin sheath to central myelin sheath. These changes in myelination lower the excitability threshold promoting the sensation of pain. After a few seconds the discharges spontaneously run out and are followed by a refractory period of inactivity and relief from the pain.1,2 There is additional evidence that abnormalities in voltage gated sodium channels may play a role in the pathogenesis, explaining the mechanism of benefit of anti-seizure medications.1,2
Acute trigeminal neuralgia is a crisis characterized by a high attack frequency and increased attack severity.6 Currently, it is unknown why patients experience acute trigeminal neuralgia crises, and there are no known triggers or risk factors that can identify the patients at highest risk for experiencing an acute pain crisis. Acute trigeminal neuralgia can lead to anorexia and dehydration, as eating and drinking can trigger pain and can impact sleep as well as mood. Patients with acute trigeminal neuralgia may warrant hospitalization for initiation of rescue therapies, and up titration of preventative medications and rehydration.3
Case Report
A gentleman, age 58 years, presented to the emergency department with 3 days of excruciating left sided facial pain, described as sharp and stabbing. The pain spontaneously occurred every few minutes, with speaking, eating, as well as touch simulation of the left check. The pain would last seconds before alleviating without intervention. Due to the frequency and severity of pain he was unable to sleep. He reported a past medical history of trigeminal neuralgia diagnosed 5 years prior, and he described this pain as being similar in character but of significantly increased frequency and severity. The pain was not alleviated by oxcarbamazepine 300mg by mouth twice a day started at the time of diagnosis of trigeminal neuralgia, which had previously provided relief. The acute pain prompting his presentation to the emergency department was not alleviated by his home medication of oxcarbamazepine or the oral hydromorphone and intravenous ketorolac he received in the emergency department.
Discussion
The mainstay treatment of trigeminal neuralgia is chronic therapy, which aims at secondary pain prevention, with evidence supporting the choice of carbamazepine as the first-line agent.1,2,6 Oxcarbamazepine is comparable to carbamazepine in reducing trigeminal neuralgia symptoms and is associated with fewer side-effects.1,2,7 Importantly, clinicians should know there is allergic cross-reactivity between carbamazepine and oxcarbamazepine, where patients allergic to one medication may have an allergy to the other. Carbamazepine and oxcarbamazepine should be slowly titrated to avoid side-effects. Second line agents for patients who have persistent symptoms or who experience adverse effects from carbamazepine and oxcarbamazepine include gabapentin, baclofen, lamotrigine, and botulinum type A toxin injection.6 While monotherapy is preferred due to cumulative adverse effects with additional agents, roughly one-third of patients will require poly-therapy for chronic management.1,2 Table 3 outlines the chronic pharmacological options in trigeminal neuralgia.
Chronic preventative pharmacological options in trigeminal neuralgia.
Since 1941, there has been evidence supporting phenytoin as analgesic therapy in trigeminal neuralgia.10 However, in 1959 J.R. Geigy patented carbamazepine, and in 1962 an open study of eleven patients with trigeminal neuralgia treated with carbamazepine concluded that the effect was probably better than phenytoin.11 This prompted a change in first line therapy from phenytoin to carbamazepine and may be due to effective marketing opposed to high-quality evidence.12 Despite this, phenytoin still has an important role as a rescue therapy in acute trigeminal neuralgia, and the majority of the published literature focuses on phenytoin or fosphenytoin.
While the chronic management of trigeminal neuralgia is well established, there is wide practice variation in treating acute trigeminal neuralgia owing to a paucity of evidence. Recommendations for rescue therapies in an acute trigeminal neuralgia pain crisis are based on clinical expertise, cross-sectional studies, case series, and cohort studies, with only one randomized control trial completed to date. Oral agents are typically not tolerated due to triggering pain. Infusions of fosphenytoin (the pro-drug to phenytoin) or phenytoin can provide rapid relief, but these require admission for telemetry and monitoring for hypotension.2,6,3 Lidocaine can be used as a topical agent, with local injection requiring procedural expertise or systemic infusion requiring cardiac monitoring.2,6,3 Opioids are commonly prescribed despite being generally ineffective for acute trigeminal neuralgia and should not be used.2,6,3,18 Surgical intervention with gamma knife or stereotactic radiosurgery as well as low level laser therapy and ozone injection procedures are reserved for those with debilitating pain refractory to pharmacological intervention and access to centers with surgical expertise.2 A summary of the published literature outlining the acute treatment of trigeminal neuralgia can be found in Table 4.
Summary of the evidence behind acute trigeminal neuralgia therapies.
Two new agents, eslicarbazepine and vixotrigine are in development for chronic preventative management of trigeminal neuralgia. Eslicarbazepine is an extended-release formulation of oxcarbamazepine and an open-label study of 15 patients demonstrated it is a safe and effective preventative therapy in trigeminal neuralgia.8 Vixotrigine is a selective sodium channel blocker currently undergoing a phase 3 placebo-controlled, double-blind, randomized trial (ClinicalTrials.gov, Identifier # NCT03070132) after a phase 2a study demonstrated tolerability at therapeutic doses.9
Conclusion
Trigeminal neuralgia is a common etiology of intermittent craniofacial pain that causes severe pain impacting the daily activities of patients. Acute exacerbations of trigeminal neuralgia with increased pain frequency and severity often prompt presentation to hospital, as patients seek relief and may require intravenous rehydration due to pain interfering with oral intake. Emergency and internal medicine consultation are frequently required to care for patients presenting with acute trigeminal neuralgia, as neurology may not be available in local centers or not available overnight.
Despite the lack of evidence and efficacy of opioids, these are still the most prescribed medications.18 Intravenous infusions of fosphenytoin or phenytoin 15 mg/kg, as described in our case, as well as infusions of lidocaine or lacosamide can provide rapid relief in acute trigeminal neuralgia, allowing for the up titration of oral preventative long-term medications.
Footnotes
Disclosures: None of the authors have declared any personal or financial competing interests. None of the authors have received funding for this manuscript or related work.
- Received July 10, 2024.
- Revision received November 11, 2024.
- Revision received November 21, 2024.
- Accepted November 22, 2024.
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