Botulinum Toxin A for the Treatment of Greater Occipital Neuralgia and Trigeminal Neuralgia

Introduction

Greater occipital neuralgia (GON), facial pains and other focal sources of chronic pain are disorders that, on top of the significant impact they can cause (1, 2) are often perceived as making other primary headache syndromes (e.g. migraine) more refractory to treatment (3–5). GON has often been implicated in headache syndromes associated with tenderness in the suboccipital area (1, 6, 7). Injection of local anaesthetics and corticosteroids into the region of the occipital nerve (ON) are usually the treatment of choice for GON (8, 9). Neurosurgical procedures including nerve resection have been suggested as alternative therapies for the treatment of refractory GON (10, 11) Similarly, trigeminal neuralgia (TN) may also be associated with other primary headaches (cluster-tic and migraine-tic syndromes). It is possible that in migraine patients, neuralgias may contribute to headache chronification and to treatment refractoriness by virtue of sensitizing areas that are related to migraine pathophysiology (3, 4).

Although botulinum toxin type-A (BTX-A) is not approved by regulatory agencies for the treatment of headaches, some clinical studies suggest good efficacy and safety in migraine and other refractory headache types (12–14). However, a recent meta-analytic review showed that, to date, there is no evidence to support the use of BTX-A in the treatment of cluster headache, chronic paroxysmal hemicrania, TN or GON (15). Herein we report a patient with migraine and probable medication overuse headache presumably related to refractory GON as well as to TN, in whom treatment with BTX-A injection into the territory of the ON resulted in complete relief of pain with cessation of analgesic overuse. Similar results were verified after the treatment of TN. We are presenting this case because of the previous absence of successful reports with BTX-A therapy for the treatment of GON and TN, and to discuss possible mechanisms of action of BTX-A in focal pain.

Case report

This is a 44-year-old white male patient with a history of migraine with and without aura since the age of 12, characterized by unilateral throbbing pain, predominantly on the left side, of one-day duration. The pain usually interfered with activities. He did not have other associated symptoms. The initial headache frequency was less than three attacks per week of moderate intensity and one severe attack every 6 months.

Since the age of 22, temporally related to a dental procedure, the patient developed severe short-lasting (from 20 s to 2 min) episodes of stabbing pain over the left cheek, of variable frequency (from two per week to four per day), without autonomic symptoms or ipsilateral interictal sensory changes. Shaving, talking and local touch triggered the pain. Four years ago, the patient also developed unilateral pain in the left temporomandibular joint (TMJ), and was diagnosed with TMJ dysfunction (TMD). At that time, the patient began to overuse aspirin/acetaminophen/caffeine (AAP) (more than 5 pills per/day) and developed daily, diffuse headaches. After the daily headaches were established, the patient had his initial evaluation at our headache centre. The initial Migraine Disability Assessment Scale (MIDAS) was 19 (Grade III, moderate disability). The patient was detoxified from AAP overuse, and was given sumatriptan to treat his acute attacks of migraine, as well as gabapentin 1800 mg plus montelukast 10 mg as preventive medications. With this treatment, he returned to a pattern of manageable episodic migraine over a period of three months; the left V2 TN also improved, but not the pain related to the left TMD.

Two years ago, the patient suddenly developed severe, intermittent, stabbing, side-locked right occipital pain, which recurred five to 20 times per day. Duration was one to five minutes. There were no migrainous or autonomic symptoms, and the pain did not radiate. On physical examination he had significant tenderness in the territory of the right occipital nerve, as well as decreased range of movement of the neck. Based on the clinical features, absence of neck clinical or imaging abnormalities, and lack of pain abolition with blocks, GON was diagnosed and cervicogenic headache (CvH) was ruled out (Table 1) (16).

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TABLE 1

International Classification Headache Disorders Criteria for Greater Occipital Neuralgia and Cervicogenic Headache

13.8. Greater Occipital Neuralgia	111.2.1. Cervicogenic Headache
A. Paroxysmal stabbing pain with or without persistent aching between paroxysms in the distribution of the greater, lesser and/or third occipital nerves	A. Pain referred from a source in the neck and perceived in one or more regions of the head.
B. Tenderness over the affected area	B. Clinical, laboratory or imaging evidence of a disorder or pathology within the cervical spine or soft tissues of the neck, known to be or accepted as valid headache cause.
C. Pain is eased temporarily by local anaesthetic nerve block	C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of the following:
	1. Demonstration of clinical signs that implicate a source of pain in the neck
	2. Abolition of headache following diagnostic cervical or nerve blockade with placebo or other adequate controls.
	D. Resolution of pain 3 months after successful treatment of the causative disorder or lesion

Modified from ICHD-II (16).

The severity of the pain, as well as the duration of the GON gradually increased, up to 3–4 severe attacks per day of at least 1-h duration. The patient returned to AAP overuse, resuming a pattern of medication overuse headache.

One year later, the GON was treated with a right superficial cervical plexus block and had partial relief for several weeks; seven months later a nerve block was performed injecting 2% lidocaine plus 4 mg of dexamethasone with no more than partial pain relief for 2 months. Because of these partial responses, and taking into account a probable longer benefit from BTX-A treatment than from a steroid block, the patient was given a right ON injection of 15 units of BTX-A. The patient had a gradual decrease of pain in the first 10 days. In the two following months the patient experienced complete relief of pain in the right greater ON distribution. However, a few months later, because of persistent left V2 TN pain, he began to take AAP again, resulting in a third medication overuse period. The patient was given an additional 7.5 units of BTX-A into the left masseter and zygomatic muscles, which gave him excellent pain control (more than 90% relief) over the next 2 months with consequent analgesic overuse cessation. A new series of BTX-A injections were given to the patient at the end of the fourth month of follow-up, 6 units into the left masseter and zygomatic muscles, and 12 units over the right ON area, with complete relief of pain both from GON and left V2 TN in the last three months. A third series of BTX A was given recently. Currently, the patient has been followed for 10 months, with good results, without side-effects and no further medication overuse.

Discussion

The case reported herein has several particularities. Of particular note:

The term GON was first used in 1821 by Beruto y Lentijo and Ramos to describe a characteristic pain in the region innervated by the greater ON (16, 17). The term GON encompasses a collection of signs and symptoms that develop secondary to a variety of different diseases such as occipital osteolytic lesions, (18) upper cervical cavernous angioma, (19) cervical osteochondroma, (20) giant cell arteritis, (21) exuberant callus formation (22) and C1–C2 arthrosis syndrome (23). GON, apparently more frequent in women, manifests as a paroxysmal, sharp or electric-like pain, unilateral or bilateral in the distribution of the greater, lesser or third occipital nerves, that can be triggered by movement, specifically hyperextension, with or without pain between paroxysms (17, 24). Occasionally the pain radiates into the arms and shoulders (25). The physical examination is usually normal or may show cervical tenderness, limitation of motion and decreased sensation over the C2 dermatome (1, 17).

GON is common in migraine sufferers. In a study of 500 patients, GON was found in 48% of them, although other studies failed to report such a high prevalence (1). This comorbid association between GON and migraine could be explained by several factors. On the one hand, the ON contains fibers from the C2 and C3 dorsal root ramus that emerges through the trapezius and sternocleidomastoid muscles (26–28). The trigeminocervical complex neurones are the major relay neurones for nociceptive afferent input from the meninges and cervical structures from the level of the caudal trigeminal nucleus to at least the C2 segment, which allows for a synaptic convergence input from supratentorial dura mater, and ipsilateral, as well as contralateral GON (29, 30). Neuronal convergence with subsequent central sensitization also could partially explain the relationship between TN and migraine refractoriness.

An increased afferent input from primary nociceptive afferents, activating second-order neurones, may cause sensitization and hyperexcitability (31). This process is thought to involve the release of neuropeptides, including calcitonin gene-related peptide (CGRP), glutamate and substance P. The sensitization may also be the result of decreased local segmental spinal inhibition in response to afferent stimulation (31, 32). In addition to these factors, dysfunctional brainstem pain-modulatory structures could trigger the development of central sensitization. Clinically, this would explain the phenomenon of hypersensitivity, spread, and referred pain to and from trigeminal and cervical dermatomes, and worsening in the migraine pattern with the development of secondary medication overuse (29).

BTX-A is used to treat various neurological disorders associated with pathologically increased muscle tone. BTX-A inhibits the release of the neurotransmitter acetylcholine at the neuromuscular junction thereby inhibiting striatal muscle contractions. Besides the reduction in muscle tone, BTX-A tends to reduce pain in pain syndromes associated with muscle spasm through the release inhibition of nociceptive neuropeptides and/or postganglionic sympathetic neuropeptides (norepinephrine and ATP) (33). In addition, BTX-A has been proposed as an analgesic, suggesting alternative noncholinergic mechanisms of action (34–38). Indeed, a recent study found evidence that BTX-A can directly decrease the amount of CGRP released from trigeminal neurones (39). These findings were supported by an animal study, where intravesical BTX administration blocked acetic acid induced bladder pain responses and inhibited CGRP release from afferent nerve terminals (40). Additionally, a prior study had shown that BTX inhibited the release of substance P in a primary culture of embryonic rat dorsal root ganglia neurones that exhibited calcium-dependent substance P secretion when depolarized with elevated extracellular potassium (41). Finally, another animal study showed that pretreatment of rats with BTX-A significantly reduced formalin-evoked glutamate release (42).

In this case report we describe a patient with a history of migraine with and without aura and three episodes of chronification and medication overuse, probably related to poor control of GON and TN. The patient had good response to BTX-A. We discussed the possible mechanisms for BTX-A effect on GON and TN, and hypothesized that the development of poor primary headache control and medication overuse headache may have been caused by or exacerbated by central sensitization due to the poor control of GON and TN pain in the patient. This study expands our knowledge regarding the BTX A local analgesic effects and also highlights the importance of other chronic pain syndromes in the development of CDH. Nevertheless, because previous studies have found mixed results with BTX A in primary headache prevention, our results must be taken with caution (43, 44).