Botulinum Toxin Treatment of Chronic Facial Pain: Trigeminal Neuralgia, Temporomandibular Disorders, and Dental-Related Pain

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Botulinum Toxin Treatment Program, Yale School of Medicine, New Haven, CT, USA

Abstract

Chronic facial pain is physically and emotionally disabling. Trigeminal neuralgia, pain associated with temporomandibular disorders, and dental-related pain are some of the most common forms of chronic facial pain. Despite the advances in pharmacological therapy of these disorders, many patients with these ailments remain unsatisfied with the level of pain relief. This chapter begins with a review of clinical features, pathophysiology, and conventional treatment of these three forms of chronic facial pain. The literature in the efficacy of botulinum neurotoxins (BoNTs) in trigeminal neuralgia, pain related to temporomandibular disorders, and dental disorders is reviewed. Case reports from the author’s experience are provided in selected patients. A comment page, at the end of each section, critically reviews the technical and dosage issues and provides recommendations for the design of future studies.

Currently, a significant level of efficacy for local use of botulinum toxins can be ascribed only for trigeminal neuralgia (one class I study, level B, probably effective). In temporomandibular pain, data generated from retrospective studies and observation of experienced clinicians suggesting efficacy are encouraging, but solid blinded and controlled studies are lacking and very much needed. In chronic neuropathic pain following dental procedures, the positive data on the local use of BoNTs is limited to few anecdotal observations.

Keywords

Facial painTrigeminal neuralgiaTemporomandibular disorderTemporomandibular jointDental painBotulinum toxinBotulinum neurotoxinOnabotulinumtoxinAAbobotulinumtoxinA

Introduction

Management of facial pain is a major challenge in clinical medicine. Most facial pains reflect a form of neuropathic pain. The role of botulinum toxins in neuropathic pain (including trigeminal neuralgia) is of considerable interest (Brown et al. 2014). Facial pain is treated separately in this chapter since the pathophysiology of pain in a vast majority of cases pertains to the dysfunction of a single cranial nerve.

Trigeminal Neuralgia

Trigeminal neuralgia is one of the most painful of human afflictions. Its incidence in the USA is estimated at 4/100,000 individuals (Katusic et al. 1990). Women are more frequently affected. The peak age of onset is between 50 and 70 years (Yoshimasu et al. 1972).

The pain is severe and often described as jabbing, stabbing, and shock-like. It involves one side of the face and may affect any branch of the trigeminal nerve, but the ophthalmic and maxillary branches are more commonly affected. The pain usually lasts for seconds, but durations of up to 2 min are also observed. Bouts of pain may occur multiple times a day and disable the patient. Facial movements, eating, speaking, chewing, and shaving often exacerbate the pain. Many patients have local trigger points in the face that upon touching provoke severe pain. In the chronic state, a high proportion of the patients live in constant fear and anticipation of upcoming bouts of pain. Table 10.1 summarizes the clinical features of TN and provides a list of differential diagnoses.

Table 10.1

Diagnostic criteria of trigeminal neuralgia (TN) and how these compare with other entities in the differential diagnoses

Symptom	TN	Pulpitis	TMD	Neuropathic trigeminal pain	SUNA/SUNCT	Paroxysmal hemicrania
Character	Shooting, stabbing, sharp, electric	Sharp, aching, throbbing	Dull, aching, nagging, sharp at times	Aching, throbbing	Burning, stabbing, sharp	Throbbing, boring, stabbing
Site/radiation	Trigeminal distribution only, intraoral and extraoral, affects V(a) rarely	Around a tooth, intraoral	Preauricular, radiates down the mandible, temple area, may be postauricular or neck	Around tooth or area of trauma/dental surgery or facial trauma	Periorbital but can affect maxillary division	Orbit, temple
Severity	Moderate to severe	Mild to moderate	Mild to severe	Moderate	Severe	Severe
Duration	1e60 s refractory period	Rapid but no refractory period	Not refractory, lasts for hours, mainly continuous, can be episodic	Continuous soon after injury	Episodic 5e240 s	Episodic 2e30 min
Periodicity	Rapid onset and termination, complete periods of remission weeks to months	Unlikely to be more than 6 months	Tends to build up slowly and diminish slowly, lasts for years	Continuous	Numerous, can be periods of complete remission	1e40 a day, can be periods of complete remission
Provoking factors	Light touch, non-nociceptive	Hot/cold applied to teeth	Clenching teeth, prolonged chewing, yawning	Light touch	Light touch	Nil
Relieving factors	Keeping still, drugs	Avoid eating on that side	Rest, decrease mouth opening	Avoid touch	Nil	Indometacin
Associated factors	Local anesthetic placed in trigger area relieves pain	Decayed tooth, exposed dentine	Muscle pain in other parts of the body, limited opening	History of dental treatment or trauma in the area	Often restless	May have migrainous features

From Zakrzweska and Mc Millan (2011), reprinted with permission

SUNA short unilateral neuralgiform pain with autonomic symptoms, SUNCT short unilateral neuralgiform pain with conjunctival tearing, TMD temporomandibular disorder

Pharmacological approaches to therapy include antiepileptic drugs such as carbamazepine, oxcarbazepine, and gabapentin that specifically block pain mediators and GABAergic medications such as baclofen (30–60 mg) which enhances inhibitory mechanisms (Fromm et al. 1981). In one blinded study, combination of carbamazepine and baclofen proved more effective than either of the two alone (Fromm et al. 1984). Unfortunately, with passage of time, patients will require more analgesics and higher doses of medications to control pain with the risk of developing more side effects (particularly among elderly). Narcotic analgesics are not usually helpful.

In many cases, trigeminal neuralgia is caused by an anomalous artery or vein impinging against the trigeminal nerve at or close to its exit point from the brain stem. This compression causes focal demyelination in the nerve which, over time, leads to generation of ectopic discharges. Hence, in recalcitrant cases, surgical intervention may prove helpful. The anomalous vessel can be surgically lifted from the nerve during decompression surgery (Brown 2014). Gamma Knife surgery is also effective; the frequency of this approach is increasing (Baschnagel et al. 2014). Both approaches are not devoid of side effects which may be substantial and include permanent ataxia, brain stem damage, and cranial nerve palsies. It is currently believed that at least half of the patients with TN are not satisfied with their medical management. Therefore, a pharmacological agent with low incidence of side effects would be welcome in the management of TN.

Anatomy and Physiology of Trigeminal Sensory System

Sensations from the face, gums, inner part of the cheeks, and teeth are conveyed to the central nervous system via three branches of the trigeminal nerve, namely, the ophthalmic, maxillary, and mandibular. The ophthalmic branch innervates the skin of the forehead and top of the head and provides corneal sensation. The ophthalmic sensory branch to the cornea is the afferent arm of the corneal reflex, one of the most informative reflexes used in clinical medicine. The ophthalmic branch enters the cranium through the superior orbital fissure, travels with the maxillary branch in the cavernous sinus, and then along with the maxillary and mandibular branches converges into the trigeminal ganglion (Gasserian ganglion), located in the middle fossa.

The maxillary branch of the trigeminal nerve innervates the middle part of the face, cheek, upper teeth, and mucosa of the nasal cavity, soft and hard palates, and the pharynx. Innervation of the nasal mucosa is the basis for sternutatory reflex (unilateral grimacing after gently putting a Q-tip inside one nostril) that tests the integrity of the maxillary branch of the trigeminal nerve. The maxillary nerve leaves the face through the inferior orbital fissure and enters the skull via the foramen rotundum.

The sensory part of the mandibular nerve (third division of trigeminal nerve) carries information from the skin of the lower face, side of the face and head, lower teeth, anterior two thirds of the tongue, and mucosa of the mouth and cheeks. The mandibular nerve enters the skull via the foramen ovale and ends in the inferior part of the trigeminal ganglion.

Many major pain mediators, specific pain receptors, and pain-activating voltage-gated sodium channel are highly expressed in the neurons of trigeminal ganglia and trigeminal nerve endings. Cultured trigeminal neurons, within days, release large amounts of calcitonin gene-related peptide (CGRP), a major inflammatory pain mediator (Durham et al. 2004). Transient receptor potential vanilloid 1 (TRPV1), a cation channel, is recognized as a major contributor to nociception since its activation releases CGRP. TRPV1 is highly expressed in a large number (≥90 %) of trigeminal neurons (Meng et al. 2009). More recently, the role of endothelins (A and B) has been investigated as pro-nociceptives in the trigeminal system (Chichorro et al. 2010).

Botulinum Toxin Treatment of Trigeminal Neuralgia

Since 2002, a total of eight studies have reported on the efficacy of BoNT treatment in trigeminal neuralgia (Borodic and Acquadro 2002; Turk et al. 2005; Bohluli et al. 2011; Piovesan et al. 2005; Zuniga et al. 2008; Wu et al. 2012; Shehata et al. 2013; Wang et al. 2014). One study was prospective and double blind (class I) (Wu et al. 2012). Of the remaining seven, one was single blind and prospective (Shehata et al. 2013), while the six were retrospective. All used type A toxin and reported various degrees of pain relief with no serious side effects. In the retrospective studies, some did not mention the exact type of A toxin or the number of injections. The two blinded studies are described in some detail here.

Wu et al. (2012) enrolled 42 patients with trigeminal neuralgia in a 13-week, randomized, parallel design, double-blind, placebo-controlled study. Forty patients, 21 in the BoNT and 19 in the saline (placebo) group, completed the study. Botulinum toxin A (Chinese toxin from Lanzhou Institute) was diluted in 1 cc of normal saline and injected, using a 16 mm-long needle, either between the epidermis and dermis or submucosally in the areas affected by pain (Fig. 10.1). Subjects in the BoNT group received 25–75 units, and a comparable volume was administered to the subjects in the saline group. Patients remained on the same dose of their medications (carbamazepine, gabapentin, and pregabalin) during the study.

Fig. 10.1

The primary outcome was a significant change in pain frequency and intensity (VAS) compared to placebo. Secondary outcomes were patient global impression of change (PGIC) and proportion of responders defined as 50 % or more compared to baseline. Both primary outcomes and all the secondary outcomes improved significantly in the BoNT group compared to the placebo (p < 0.001). Side effects were noted in the subjects who received BoNT; seven developed mild facial asymmetry which disappeared after 7 weeks, and three developed local facial swelling which subsided in a week.

In the single blind study of Shehata et al. (2013), 20 subjects with TN were randomized into BoNT and placebo groups. In the BoNT group, the subjects received subcutaneous injections of 40–60 units of onabotulinumtoxinA into 8–12 points (five units per point) in the face. Primary outcome was a decrease in pain intensity at 12 weeks measured by VAS compared to the placebo. At 12 weeks, the onaA group demonstrated a reduction of 6.5 points in the VAS compared to three points in the placebo group (p = 0.0001). As a secondary outcome, quality of life also improved significantly, and more patients in the BoNT were able to reduce the number of their pain medications.

Case Report 10-1

A 41-year-old woman was referred to the Yale Botulinum Neurotoxin Treatment Clinic for consideration of BoNT therapy for a disabling trigeminal neuralgia. She began to have severe left-sided face pain and headaches following a car accident 20 years earlier. The pain was dull and deep at first but gradually transformed into bouts of sharp and jabbing pain lasting 15–20 s. Many factors provoked pain especially exposure to cold environment. She reported several trigger points close to the nose and corner of the mouth, making application of the makeup difficult. In “bad days,” pain affected the region around the left eye and made it “twitch.”

The patient had tried multiple medications for the pain including beta-blockers, antiepileptic drugs, calcium channel blockers, nonsteroidal anti-inflammatory drugs, oxycodone, and acupuncture. She had had three surgical procedures in the past: decompression surgery via retro-mastoid craniotomy for relieving pressure upon the trigeminal nerve, exploration for possible CP angle pathology (second surgery), and cortical stimulation for pain relief. None of the three procedures relieved her pain. Patient described constant daily background facial pain with superimposed bouts of sharp pain. Past medical, family, and social history disclosed no issues of concern.

On examination, several trigger points were identified on the left side of the face close to the nose and corner of the mouth. A total of 30 units of onaA was injected subcutaneously in 20 sites (1.5 units per site) into the V2 distribution. In addition, another 10 units (4 points) was injected into the left frontalis (2.5 units, 4 sites) and 5 units into the anterior temporal region (2.5 units, 2 points) (Fig. 10.2).

Fig. 10.2

Case report 10-1, trigeminal neuralgia. The dose is two units per site for injections in the V2 distribution and 2.5 units per site in V1 and other sites (Created by Tahereh Mousavi; published with kind permission from © Bahman Jabbari 2014. All Rights Reserved)

After 2 weeks, patient reported marked reduction in severity of pain (from level 9 in VAS to 2) and in the frequency of sharp pains (90 % less). This response lasted for 5 months at which time the severity of pain returned and required another injection that produced a similar effect. No side effects were reported. Patient described her experience as very satisfactory in patient global impression of change.

The Mechanism of Action of BoNT-A in Trigeminal Neuralgia (TN)

The data from cell culture and animal studies explains some of the mechanisms through which administration of BoNTs relieves pain in trigeminal neuralgia. Addition of onaA to the cultured trigeminal neurons results in marked reduction of CGRP release from stimulated trigeminal neurons (Durham et al. 2004). In acute infraorbital nerve injury that causes significant local allodynia in the rat, subcutaneous injection of onaA improved allodynia and reduced release of pain mediators from disconnected trigeminal neurons (Kitamuaraet al. 2009).

Addition of A/E chimera of botulinum toxin (which specifically targets sensory neurons) to the trigeminal cell culture inhibits the release of CGRP secondary to activation of TRPV1 (Meng et al. 2009). Furthermore, subcutaneous injection of 0.25 and 0.5 ng/kg of botulinum toxin A (onaA) into the rat’s face markedly reduces the expression of TRPV1 in the trigeminal neurons within 2 days (Shimizu et al. 2012).

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