Botulinum Neurotoxin Type-A for the Treatment of Atypical Odontalgia

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1 Pain Medicine 2016; 17: doi: /pm/pnw040 NEUROPATHIC PAIN SECTION Brief Research Report Botulinum Neurotoxin Type-A for the Treatment of Atypical Odontalgia Marıa-Luz Cuadrado, MD, PhD,*, Hector Garcıa-Moreno, MD,* Jose-Antonio Arias, MD, PhD and Juan A. Pareja, MD, PhD *Headache Unit, Neurology Department, Hospital Clınico San Carlos, Madrid, Spain; Medicine Department, School of Medicine, Universidad Complutense, Madrid, Spain; School of Medicine, Universidad Alfonso X El Sabio, Madrid, Spain; Neurology Department, Hospital Universitario Fundacion Alcorcon, Madrid, Spain Correspondence to: Marıa-Luz Cuadrado, MD, PhD, Neurology Department, Hospital Clınico San Carlos, Calle Prof. Martın Lagos, S/N, Madrid, Spain. Tel: þ ; Fax: ; mlcuadrado@med.ucm.es. Funding sources: This research received no financial support. Conflicts of Interest: The authors declare that they have no conflicts of interest. Abstract Objective. Atypical odontalgia (AO), a subform of persistent idiopathic facial pain, is defined as a continuous toothache in which a thorough examination reveals no dental pathology. AO is believed to be a neuropathic condition, given that some cases are preceded by dental procedures. Different topical and systemic medications have been used for the treatment of AO, but their effect is often unsatisfactory. The authors aimed to assess the effect and safety of botulinum neurotoxin type-a (BoNTA) in a series of patients with AO. Methods. Four patients with refractory AO (2 males and 2 females, aged 31 72) were treated with local injections of BoNTA to the painful area. BoNTA was injected at various sites into the gums, and two patients had additional injections in the hard palate or the upper lip. The total dose of BoNTA for each procedure was U, and the total number of injection points was The follow-up ranged from 6 to 20 months. Two patients received two cycles of BoNTA, while the remaining patients received three and five cycles each, respectively. Results. All patients obtained significant relief with complete or almost complete reduction of pain. The analgesic effect was apparent after a latency period of 3 14 days, and the effect persisted for 2 6 months. There were no adverse events reported from any of the interventions. Conclusions. The responses to BoNTA injections in this series agree with those previously observed in neuropathic pain. BoNTA injections may be a safe and effective option for the treatment of AO. Key Words. Atypical Odontalgia; Atypical Facial Pain; Persistent Idiopathic Facial Pain; Neuropathic Pain; Orofacial Pain; Botulinum Neurotoxin Type-A Introduction Orofacial pain may be caused by a massive assortment of diseases [1 3]. First, conditions such as traumatisms, infections, inflammatory diseases, or neoplasms affecting the different structures in the face (teeth and periodontal tissues, sinuses, eyes, ear, nose, blood vessels) account for a great number of cases; indeed, odontogenic pain is the leading cause of acute facial pain [1]. Second, musculoskeletal pain is also an important group since temporomandibular disorders are the most prevalent non-odontogenic cause of facial pain. In addition, neuropathic pain represents a crucial category, including cranial neuralgias and painful cranial neuropathies (trigeminal neuralgia, glossopharyngeal neuralgia, painful neuropathies of the terminal branches of the trigeminal nerve). Furthermore, some primary headaches with presumed central origin (e.g., migraine and trigeminal autonomic cephalalgias) can be referred as facial VC 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please journals.permissions@oup.com 1717

2 Cuadrado et al. pain. Finally, some conditions have a mixed or idiopathic etiology. An illustration of this might be persistent idiopathic facial pain (PIFP), originally known as atypical facial pain, which has been included in the group of painful cranial neuropathies and other facial pains in the third edition of the International Classification of Headache Disorders (ICHD-3, beta version) [4]. Atypical odontalgia (AO) is one of the rare sources of facial pain. This condition has been designated in different ways in the literature, namely phantom tooth pain [5], idiopathic toothache [6], chronic continuous dentoalveolar pain [7], and persistent dentoalveolar pain disorder [8]. AO is considered as part of the PIFP spectrum in some classifications [4], while others regard it as an independent category [9]. It is thought to have a neuropathic origin, given that some cases are preceded by dental procedures [10 13]; yet, vascular and psychological mechanisms have been also proposed [11,12]. AO is defined as a continuous and spontaneous pain in a tooth or several teeth, or a persistent pain in the place where a tooth has been extracted, in which a thorough examination reveals no dental pathology. Likewise, it commonly affects the jaws, and the pain can occasionally spread to other areas of the face. Though it is more frequently described with a continuous pattern, some patients present acute exacerbations. Regarding treatment, it is of the utmost importance to avoid additional dental procedures since they could worsen the pain [11 13]. Most of the reported cases have been treated using different drugs, with insufficient or momentary effects: tricyclic antidepressants, phenothiazines, gabapentin, clonazepam, baclofen, phentolamine, opioids, or local analgesics [11,12]. Local injected anesthetics and corticosteroids or nerve blocks have been also essayed with inconsistent results [11]. Onabotulinum toxin A (botulinum neurotoxin type-a, BoNTA) is one of the most offbeat treatments in clinical pain practice. Although the precise mechanism of action is not completely understood, BoNTA has proved to be effective in different pain conditions including chronic migraine, joint pain, and myofascial pain [14]. It has also revealed itself as an advantageous treatment in a number of painful neuropathic conditions, such as trigeminal neuralgia (TN), painful diabetic neuropathy, complex regional pain syndrome, and postherpetic neuralgia [14 21]. As far as we know, this study is the first to present the effect of local injections of BoNTA in patients with AO. Methods An open, non-controlled clinical study was performed in the Headache Unit of a University Hospital. All four patients referred for refractory OA over a period of 2 years (2 males and 2 females, aged 31 72) were consecutively recruited. Their main clinical and demographic characteristics are summarized in Table 1. One of the patients started to have the pain after an endodontic procedure followed by tooth extraction (Patient 1), while the remaining patients did not recall any precipitating event. All of the patients had a continuous pain in a particular dentoalveolar region without any clinical sign of dental pathology upon a thorough dental exam. Moreover, routine blood tests including erythrocyte sedimentation rate and dental imaging tests (X-ray exams, orthopantomography, and computed tomography of the oral and maxillofacial region) were obtained in all cases, with normal results. Before inclusion, all patients had been on drug treatment with antidepressants (amitryptiline, duloxetine, venlafaxine), antiepileptics (carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, valproic acid, zonisamide, lacosamide, clonazepam), and/or opioids (tramadol) for more than 1 year, with null or partial effect (see Table 1). BoNTA (BotoxVR ) diluted with normal saline at a concentration of 5 U/0.1 ml was injected at various sites into the gums with a sterile 30-gauge, 0.5-inch needle. Injection sites were evenly distributed over the symptomatic area, and the solution was injected as 0.05 ml (2.5 U) per each site. The needle was inserted into the facial papillae of the interdental gingiva, where the soft tissues were thick enough for the injections (Figure 1A). Two patients had additional injections in adjacent areas (mucous membrane of hard palate, Patient 1; subcutaneous tissue of upper lip, Patient 2), and one of them was also injected in the tooth socket left after dental extraction (Patient 1; Figure 1B). Two patients received two cycles of BoNTA, while the remaining patients received three and five cycles each, respectively. The total dose of BoNTA for each procedure ranged from 15 U to 30 U, and the total number of injection points was Both the clinical effect and safety were assessed after each intervention. The follow-up ranged from 6 to 20 months(table 1). All patients gave signed informed consent for the procedures. The study protocol was approved by the local Ethics Committee. Results One patient obtained complete relief after BoNTA injections (Patient 2), while the others were left with a mild discomfort or intermittent mild pain. Moreover, all patients experienced a decrease of the extent of the painful area from the first administration, with the pain being thereafter limited to the tooth region where it was previously centered. The analgesic effect was apparent after a latency period of 3-14 days, and the effect persisted for 2-6 months(table 1). Drug treatment with antidepressants and/or antiepileptics was maintained at the former doses, but Patients 1, 2, and 4 could stop opioid treatment through the duration of BoNTA effect. There were no adverse events reported from any of the interventions. Discussion The clinical management of AO is often disappointing. So far, different systemic and topical medications have been used with inconclusive results [11,12]. In fact, there is insufficient evidence-based data available to establish guidelines for the treatment of AO. As we 1718

3 Botulinum Neurotoxin Type-A for Atypical Odontalgia Table 1 Main clinical and demographic characteristics of patients included in this series Patient (P) P1 P2 P3 P4 Sex Male Female Female Male Age, years Age at onset, years Precipitating event First molar endodontic surgery None None None plus extraction Location Left upper dental arch and missing molar (phantom pain) Paramedian upper and lower dental arches Left lower dental arch and paramedian dental arch Right upper dental arch Spread of the pain Left lower dental arch (exacerbations) Upper lip (continuous) Chin (continuous) Right preauricular area (exacerbations) Temporal pattern Continuous with exacerbations Continuous Continuous with exacerbations Continuous with exacerbations Intensity Moderate to severe Moderate Mild to severe Mild to severe Character Stabbing/Piercing Burning Stabbing/Piercing Burning/Stabbing Previous drug treatments (no response) Current drug treatment (partial response) Injection sites* (no. of injection points) Amitryptiline, carbamazepine, oxcarbazepine, gabapentin, pregabalin, valproic acid, zonisamide, lacosamide Duloxetine and tramadol Venlafaxine, gabapentin, clonazepam and tramadol Tooth socket (1), upper (3) and lower (3) left gums, hard palate (3) - - Carbamazepine, oxcarbazepine, phenytoin, gabapentin Upper (4) and lower (4) anterior gums, upper lip (4) Amitryptiline, duloxetine and pregabalin Paramedian and left lower gums (8) Pregabalin and tramadol Upper right gums (6) Total no. of injection points 10 (1 þ 3þ3 þ 3) 12 (4 þ 4þ4) 8 6 Dose of botulinum toxin 25 U (2,5 U x 10) 30 U (2,5 U x 12) 20 U (2,5 U x 8) 15 U (2,5 U x 6) Latency for analgesic effect 3 days 10 days 14 days 7 days Follow-up 20 months 11 months 9 months 6 months Duration of analgesic effect 4 months 3 months 3/6 months 2 months No. of injection cycles Response Almost complete relief (mild discomfort) Complete relief Almost complete relief (intermittent mild pain) Almost complete relief (mild discomfort) *Gums were injected at the facial papillae over the symptomatic area. 1719

4 Cuadrado et al. Figure 1 (A) Injection of botulinum neurotoxin-a (BoNTA) into the facial papillae of the interdental gingiva (Patient 1). (B) Injection of BoNTA into a tooth socket left after dental extraction (Patient 1). mentioned above, AO is believed to have a neuropathic origin [10 13]. Because BoNTA has proved to be effective in various neuropathic conditions, we postulated that it might be effective in patients with AO. The responses observed in our patients suggest that BoNTA injections may be a new option for the treatment of AO, with strikingly promising outcomes. Our findings in patients with AO agree with those previously observed in TN. The analgesic effect of BoNTA for TN was first reported in 2002 [17]. Consequently, several open studies and two randomized controlled trials have demonstrated that BoNTA can significantly relieve the pain in patients with TN [18 20]. In most of the studies, the amount of BoNTA injected was U in the subcutaneous and/or submucosal trigger zones (range: U). The effect was usually achieved within 1-2 weeks and the maximum effect was reached within 4-6 weeks; the duration of the therapeutic effect was quite heterogeneous among studies, lasting 1-6 months [19]. Interestingly, BoNTA injections have shown to reduce not only pain intensity and pain frequency, but also the surface of the painful area in patients with TN [21]. The mechanism by which BoNTA acts in nociception remains unclear. The dominant opinion is that BoNTA acts by inhibiting the exocytosis of local nociceptive neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), and excitatory neurotransmitters such as glutamate. In addition, BoNTA can decrease the translocation of the transient receptor potential vanilloid 1 (TRPV1) to neuron cell membranes, thus reducing pain sensitivity. Through this process, BoNTA would decrease peripheral sensitization, which in turn would lower central sensitization and pain [14,16]. It has also been suggested that BoNTA might act centrally because of retrograde axonal transport, but this mechanism is highly controversial. Although a placebo effect cannot be totally excluded, it is important to keep in mind that both the latency and duration of the analgesic effect in our patients were in line with those previously reported in neuropathic pain [19]. Moreover, a similar pattern of response in the overall patients supports a direct effect of BoNTA on the sensory system and pain. Further studies with larger number of patients, particularly randomized control trials, are needed to elucidate the effect of BoNTA in AO. The effect of BoNTA should also be explored in other forms of facial pain. References 1 Zakrzewska JM. Differential diagnosis of facial pain and guidelines for management. Br J Anaesth 2013; 111: Shephard MK, MacGregor EA, Zakrzewska JM. Orofacial pain: A guide for the headache physician. Headache 2014;54: Balasubramaniam R, Klasser GD. Orofacial pain syndromes: Evaluation and management. Med Clin North Am 2014;98: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33: Marbach JJ. Phantom tooth pain. J Endod 1978;4: Graff-Radford SB, Solberg WK. Atypical odontalgia. J Craniomandib Disord 1992;6: Greene CS, Murray GM. Atypical odontalgia: An oral neuropathic pain phenomenon. J Am Dent Assoc 2011;142: Nixdorf DR, Drangsholt MT, Ettlin DA, et al. Classifying orofacial pains: A new proposal of 1720

5 Botulinum Neurotoxin Type-A for Atypical Odontalgia taxonomy based on ontology. J Oral Rehabil 2012; 39: The IASP Taxonomy Working Group. Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edition (revised). Washington, DC: IASP Press; Marbach JJ. Is phantom tooth pain a deafferentation (neuropathic) syndrome? Part I: Evidence derived from pathophysiology and treatment. Oral Surg Oral Med Oral Pathol 1993;75: Melis M, Lobo SL, Ceneviz C, et al. Atypical odontalgia: A review of the literature. Headache 2003;43: Baad-Hansen L. Atypical odontalgia Pathophysiology and clinical management. J Oral Rehabil 2008;35: Abiko Y, Matsuoka H, Chiba I, et al. Current evidence on atypical odontalgia: Diagnosis and clinical management. Int J Dent 2012; Guo BL, Zheng CX, Sui BD, et al. A closer look to botulinum neurotoxin type A-induced analgesia. Toxicon 2013;71: Fabregat G, De Andres J, Villanueva-Perez VL, et al. Subcutaneous and perineural botulinum toxin type A for neuropathic pain: A descriptive review. Clin J Pain 2013;29: Oh HM, Chung ME. Botulinum toxin for neuropathic pain: A review of the literature. Toxins 2015;7: Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type A for patients with painful tic convulsif. Clin Neuropharmacol 2002;25: Wu CJ, Lian YJ, Zheng YK, et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: Results from a randomized, double-blind, placebocontrolled trial. Cephalalgia 2012;32: Hu Y, Guan X, Fan L, et al. Therapeutic efficacy and safety of botulinum toxin type A in trigeminal neuralgia: A systematic review. J Headache Pain 2013;14:72 20 Zhang H, Lian Y, Ma Y, et al. Two doses of botulinum toxin type A for the treatment of trigeminal neuralgia: Observation of therapeutic effect from a randomized, double-blind, placebo-controlled trial. J Headache Pain 2014;15: Piovesan EJ, Teive HG, Kowacs PA, et al. An open study of botulinum-a toxin treatment of trigeminal neuralgia. Neurology 2005;65:

Atypical Odontalgia: Current Knowledge and Implications for Diagnosis and Managemen...

Page 1 of 5 TABLE OF CONTENTS Mar 2012-0 comments Atypical Odontalgia: Current Knowledge and Implications for Diagnosis and Management By: Pavel S. Cherkas, DMD, PhD, MMedSc and Barry J Sessle, MDS, PhD,