16.1 Introduction

Trigeminal neuralgia (TN), as defined by the International Association for the Study of Pain (IASP), is a unilateral facial pain disorder that is characterized by brief, paroxysmal, sharp lancinating pains that are recurrent, and limited to the distribution of one or more divisions of the trigeminal nerve. ¹ The prevalence of this disorder is approximately 1 in 25,000, and it is slightly more common in women than in men. It also affects middle-aged or older people more frequently. ²

In the latest classification of the International Headache Society, TN was divided into two distinct groups: classical TN and painful trigeminal neuropathy. Classical TN includes idiopathic cases in addition to those with vascular compression of the fifth cranial nerve; painful trigeminal neuropathy is diagnosed in cases where there is damage to the trigeminal nerve from another disorder, including herpes zoster, multiple sclerosis, trauma, and space occupying lesions, resulting in facial pain. ³ Classical TN can be further divided into purely paroxysmal or with concomitant persistent facial pain, with the paroxysmal variant being more common and amenable to treatment. The pain attacks are typically precipitated by innocuous cutaneous stimuli within specific “trigger zones,” but can also be spontaneous (although precipitated attacks are required for diagnosis). The attacks can leave some patients unable to eat, drink, brush their teeth, or shave. Attacks typically last a few seconds to 2 minutes, but can be more prolonged and severe as time goes on.

The peripheral neuropathic process is a result of damage to the trigeminal nerve, resulting in irritation and accumulation of nociceptive agents. The accumulation of pain modulators along with focal inflammation lowers the sensory threshold of peripheral nerve endings to nociceptive stimuli. Then peripheral sensitization increases arrival of the nociceptive signals into the spinal cord and sensitizes the sensory spinal cord neurons, leading to chronic pain. ⁴

Nerve damage can result from demyelination of the sensory fibers within the proximal nerve root of the trigeminal nerve. ⁵ Most cases of classical TN (80–90%) have an overlying blood vessel causing compression at the root entry zone. The offending vessel can be the superior cerebellar artery (75%), the anterior inferior cerebellar artery (10%), or a vein. ⁶ Focal demyelination within or near this area has been documented on histologic examination of specimens taken during microvascular decompression in the immediate vicinity of the indentation, with the demyelinated axons found to be in direct apposition. ⁷ The A-δ thinly myelinated nociceptive fibers may be particularly vulnerable to such changes. ⁸ This pathologic arrangement may lead to abnormal nonsynaptic ephaptic transmission to adjacent fibers. ⁹ Moreover, because fibers for light touch and pain are closest in proximity within the root entry zone, this theory provides a ready explanation for the paroxysmal pain provoked by cutaneous stimuli. ⁵

Many approaches have been employed to alleviate the pain and reduce the frequency of pain attacks in this disorder. Pharmacotherapy with anticonvulsive drugs remains the first-line therapy, in particular carbamazepine or oxcarbazepine. In patients with TN refractory to medical therapy, microvascular decompression, percutaneous approaches to the Gasserian ganglion, and stereotactic radiotherapy may also be considered, depending on surgeon experience and patient preference; however, these procedures carry additional morbidity. ¹⁰

Botulinum neurotoxin type A (BoNT-A) has been successfully utilized to several pain syndromes including migraine and occipital neuralgia as discussed in previous chapters in this book. The mechanism by which BoNT-A influences pain has been described through a number of in vitro and in vivo studies. In vitro, investigators have demonstrated that application of BoNT-A to cultured sensory neurons inhibits the release of calcitonin gene-related peptide (CGRP), glutamate, and other pain transmitters after cleaving the SNARE proteins. In animal studies, toxin has been demonstrated to travel to the spinal cord and inhibits the release of substance P from spinal neurons along with a reduction of c-Fos expression at the spinal cord level. ¹¹ The peripheral injection of BoNT prior to the application of a noxious stimuli has also been shown to reduce local accumulation of pain transmitters such as glutamate as well as improve behavioral manifestations of pain in an animal model. ^{11 ,​ 12}

These findings led to the application of BoNT-A in the treatment of classical TN as well as painful trigeminal neuropathy. In recent years, BoNT-A has gained popularity in treating patients with TN that is refractory to medical and occasionally surgical treatment given its low side-effect profile. ^{13 ,​ 14 ,​ 15 ,​ 16} BoNT-A has been shown to have significant benefit when compared with placebo in the reduction of paroxysmal attacks and visual analog scale (VAS) scores for pain in patients with classical TN as well as reduce VAS scores in patients with postherpetic painful trigeminal neuropathy. ^{4 ,​ 17} A recent review found that there is level A evidence (effective) for BoNT therapy in TN, with three double-blind and one prospective single-blind clinical trials having assessed the efficacy of BoNT treatment in TN. ¹⁸