July 2008.indd ABSTRACT This report presents the results of treatment of two adults, at the Pain Center of Montreal General Hospital, Canada, with intravenous lidocaine for intractable orofacial pain. Repeated lidocaine infusions (mg/kg in a bolus, followed by 4mg/kg infused over  hour) resulted in satisfactory pain relief in both patients, and the drug was well tolerated. Intravenous lidocaine therapy may be considered for intractable orofacial pain; further research is warranted. Keywords: Facial pain; Lidocaine; Therapeutics; Humans; Review; Literature; Case reports; Canada Intravenous Lidocaine for Refractory Chronic Orofacial Pain Two case reports and a literature review Abdulaziz Almahrezi,1 Louise Lamb,2 Mark A Ware,2 Yoram Shir,2 *Ibrahim Al-Zakwani3 1Department of Family Medicine and Public Health, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman; 2McGill Uni- versity Health Centre, Pain Centre, Montreal General Hospital, Montreal, Quebec, Canada; 3Department of Pharmacy, Sultan Qaboos University Hospital, Muscat, Oman *To whom correspondence should be addressed. Email: ial_zakwani@yahoo.com واملستعصي املزمن يّ هِ جْ الوَ ي وِ مَ الفَ األلم لعالج الوريدي الليدوكني لألدبيات ومراجعة حالتني تقرير الزكواني إبراهيم شير، يورام وير، مارك.أ. المب، لويز احملرزي، العزيز عبد عالج مركز في الليدوكني الوريدي حقن طريق عن مستعصية آالم فموية وجهية من يعانيان بالغني مريضني عالج نتائج التقرير امللخص: يستعرض على كحقنة جرام كيلو لكل 4 مليجرام ثم واحدة كدفعة جرام كيلو لكل (1 مليجرام املتكررة الليدوكني حقن مونتريال العام. مستشفى األلم في مفيدا يكون رمبا الوريدي الليدوكني جانبية. آثار أي من منهما أي ولم يعاني ، املريضني لكال مقبولة بدرجة إلى تخفيف األلم أدت واحدة) ساعة مدار هذا اال. في من البحوث ملزيد حاجة هناك املستعصية. الوجهية الفموية اآلالم عالج في ، كندا. حالة تقرير ، أدبيات ، مراجعة ، البشر ، العالج ، الليدوكني ، الكلمات: آالم الوجه مفتاح SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL JULY 2008, VOLUME 8, ISSUE 2, P. 205-209 SULTAN QABOOS UNIVERSITY© SUBMITTED - 23RD FEBRUARY 2008 ACCEPTED - 4TH MAY 2008 CHRONIC OROFACIAL PAIN INCLUDES A group of disorders with diverse etiologies affecting approximately 10 % of the adult population and 50 % of the elderly1 of whom at least 50% seek medical treatment.2 Diagnosis is difficult due to lack of a clear diagnostic classification3 and routine treatment modalities are often not effective.4 Surgery may be considered in selected cases; however, current international guidelines recommend multi-modal ap- proaches for the management of orofacial pain. These include pharmacological, nerve blocks, physiotherapy and psychological therapies. 5, 6 Intravenous lidocaine has been used in a vari- ety of neuropathic pain syndromes such as diabetic neuropathy7 and post herpetic neuralgia.8 To date, few published reports exist on the therapeutic role for intravenous lidocaine in chronic orofacial pain.9 Here we describe two patients, who presented at the Pain Center, Montreal General Hospital, Canada with features of a mixed nociceptive-neuropathic pain syn- drome, but with a primarily nociceptive etiology. They both experienced long-term pain relief after repeated lidocaine infusions. C A S E 1 This 46-year old female presented with a long history of pain in the area of both temporomandibular joints (TMJ). The pain was constant and sharp in nature and woke the patient up to 2-3 times per night. The av- erage pain was 8 out of 10 on a visual analogue scale (VAS), a measure of pain intensity expressed on a zero to ten score. In addition, the patient described severe C A S E R E P O R T A B D U L A Z I Z A L M A H R E Z I , L O U I S E L A M B , M A R K A WA R E , YO R A M S H I R , A N D I B R A H I M A L - Z A K WA N I 206 attacks of intermittent ‘pulling-like’ pain, lasting for 30 to 60 minutes. The pain was provoked by chew- ing solid foods and exposure to humid weather. Mild pain relief was obtained with local ice packs and rest. She had undertaken five surgical procedures on both TMJs, including a prosthesis on the right and an oste- otomy on the left. Apart from a small area of dysaesthesia in the distribution of the mandibular division of the right trigeminal nerve, the rest of the neurological examina- tion yielded no pathologies. In particular, the patient had no evidence of facial muscles atrophy, weakness or allodynia. However, tenderness bilaterally over the TMJs was noted. The patient was diagnosed with a mixed nociceptive-neuropathic pain syndrome and she was treated with the following medications se- quentially: amitriptyline, 25mg/day, gabapentin, up to 900mg/day and sustained release oxycodone up to 20mg/day. Trials with each of these medications had to be abandoned prematurely due intolerable side ef- fects experienced by the patient despite a very slow and careful titration. In view of the patient’s poor tol- erance, further trials with other oral medications were not initiated. Nerve blocks were not offered. Further- more, a trial of physiotherapy which included transcu- taneous electrical nerve stimulation (TENS) did not yield any significant result. As an alternative, the patient was given a trial of in- travenous lidocaine, using 1 mg/kg in a bolus followed by an infusion of 4 mg/kg over 1 hour. Response to treatment was recorded using both the VAS and the Neuropathic Pain Scale (NPS)10: pre-infusion and at 1 hour, 4 days and 14 days post-infusion. During the in- fusion, and for 14 days thereafter, the patient’s pain de- creased by more than 70% [Figure 1]. She reported no pain while chewing, and was able to have a solid meal for the first time in years. The patient received four lidocaine infusions during a period of four months with ongoing pain relief. Since beginning lidocaine treatment the patient has not been taking any other pain medications. C A S E 2 This 51 year old female presented with chronic pain over the right mandible. The patient had a history of a benign right mandibular cyst for which she had man- dibular condyle and disc removal with graft recon- struction. The pain was refractory to botulinum toxin Figure 1: (Patient 1) Pain intensity scores recorded over two weeks following the first intravenous lidocaine infusion (0-no pain; 10-the most intense pain sensation imaginable). I N T R AV E N O U S L I D O C A I N E F O R R E F R A C T O R Y C H R O N I C O R O FA C I A L PA I N 207 injections, sympathetic ganglion blocks, and various oral medications including opioids and anti-convul- sants. The patient underwent replacement of the right TMJ; however, despite significant improvement in function, the pain persisted. The pain was described as constant, deep, with numbness and tingling at the painful area and was triggered by eating and speak- ing. On examination, she had difficulty opening her mouth and moving her chin from side to side. The pa- tient had no facial weakness or asymmetry. Tactile and cold hyperalgaesia was detected over the lower part of the right face. The remainder of the neurological assessment including cranial nerves, motor, sensory, and cerebellar examination was normal. At the time of referral, she was taking amitriptyline 75mg/day, gabapentin 1800mg/day, lorazepam 1.5mg/day, and ketorolac 10 mg as necessary. Further titration of the doses of both amitrpityline and gabapentin had previ- ously failed due to the development of intolerable side effects. Her average VAS daily pain score was 8 out of 10. The patient was diagnosed with a mixed nocic- eptive-neuropathic chronic post-surgical pain. A trial of low dose methadone had to be stopped due to an allergic reaction. The patient was given a trial of in- travenous lidocaine, 1 mg/kg in a bolus followed by an infusion of 4 mg/kg over 1 hour. One hour after the treatment the patient experienced total pain relief [Figure 1]. Pain levels increased during the ensuing two weeks, but remained low compared to the pre-in- fusion period. The patient subsequently received nine infusions in eight months, with ongoing pain relief and improved function, and has decreased her pain medi- cations by 20-30%. D I S C U S S I O N Lidocaine, an amide local anesthetic and an anti-ar- rhythmic agent, possesses analgesic properties when given systemically particularly in chronic neuropathic pain conditions,7, 8, 11, 12 cancer pain,13 fibromyalgia,14 and chronic daily headaches.15 Findings from experimental models of neuropath- ic pain suggest that lidocaine acts by suppression of abnormal ectopic discharges which are generated by damaged primary afferents or dorsal root ganglion neurons.16 Intravenous lidocaine was also shown to produce suppression of mechanical allodynia17, 18 and hyperalgaesia.16 The postulated mechanism of action was thought to be peripheral in origin; however, this view was later challenged with several lines of evidence suggesting that lidocaine may also have central effects. Some of these observations include: suppression of polysynaptic C-fibre evoked flexor responses with- out evidence of conduction block at the periphery;19 suppression of the activity of dorsal horn neurons evoked by ionophoretically administered glutamate;20 and selective inhibition of a nociceptive response in the isolated rat spinal cord.21 Clinical studies23, 24 and human experimental models25, 26 have reached similar conclusions as to the action of intravenous lidocaine on mechanical allodynia and hyperalgaesia. In one study on healthy volunteers using the heat/capsaicin sensitisation model, intravenous lidocaine (5 mg/kg) was shown to have a selective effect on secondary hyperalgaesia.25 Several well-designed studies have documented the effectiveness of intravenous lidocaine. A ran- domised double-blind cross-over study showed that intravenous lidocaine (5mg/kg over 30 minutes), but not saline, reduced symptoms of pain, dysaesthesia, paraesthesia and nightly pain exacerbation as well as sleep disturbance in patients with chronic painful dia- betic neuropathy for a period of 3-21 days.7 According to VAS, 11 out of 15 patients had a significant reduc- tion (a reduction of greater than 15 millimetres on the VAS) in pain for a period of 3 days and no reported side effects.7 Another similarly designed study inves- tigated the effect of two different doses (1 mg/kg and 5 mg/kg over 2 hours) of intravenous lidocaine on 24 patients of postherpetic neuralgia.11 The investigators reported a significant reduction in VAS for evoked pain and a decline in the area of allodynia for up to 120 minutes following treatment with intravenous lidocaine.11 Circumoral paraesthesia was the only side effect reported by patients who received the higher dose.11 In a similar study investigating the effects of intravenous lidocaine (5 mg/kg over 30 minutes) on neuropathic central pain, a significant reduction (VAS score decreased by 50% or more) in spontaneous pain was reported.12 This response was achieved by 10 out of 16 patients.12 The period of observation in this study was for 45 minutes after the infusion. Investigators, using quantitative sensory testing, also reported a re- duction in the intensity of mechanical allodynia and hyperalgaesia.12 Side effects were reported as moder- ate and consisted mainly of lightheadedness, somno- lence, nausea and dysarthia.12 Sorenson et al studied A B D U L A Z I Z A L M A H R E Z I , L O U I S E L A M B , M A R K A WA R E , YO R A M S H I R , A N D I B R A H I M A L - Z A K WA N I 208 11 fibromyalgia patients who were randomised to lidocaine (5 mg/kg over 30 minutes) and saline in a double-blind and crossed-over design trial.14 Four patients were reported as responders (a reduction of 16 millimetres or greater on the VAS). 14 Three of the responders had a reduction in pain for 4-7 days. Side effects were mild and included nausea, perioral numb- ness, drowsiness, dysarthia and tremor.14 In another study of postamputation pain, intravenous lidocaine (1 mg/kg bolus + 4 mg/kg over 40 minutes), but not the placebo (diphenhydramine) decreased stump pain until 30 minutes after the infusion.26 No side effects were reported. Both of our patients had reported nausea and light- headedness during the period of the infusion. This is consistent with previously mentioned studies which documented only mild and transient adverse effects; however, serious side effects such as arrhythmias and pulmonary edema can occur with high doses.27 Close monitoring of the patient while receiving the infusion is therefore recommended. This is usually performed by means of a continuous electrocardiogram (ECG) and a regular check-up of blood pressure and heart rate. Besides side effects, other problems associated with the use of intravenous lidocaine include: invasiveness and the inconvenience of the intravenous route. Possi- ble alternatives to intravenous lidocaine are transder- mal lidocaine and oral congeners such as mexilitine. A lidocaine patch has been shown to be effective in a ran- domised controlled trial in postherpetic neuralgia;28 however, patients may find it inconvenient to apply a patch on the face. Furthermore, it is not known if a good response to intravenous lidocaine would pre- dict a similar response to transdermal lidocaine since the concentration of plasma lidocaine would be much lower with local administration. Mexilitine has been suggested as an alternative particularly in patients who respond negatively to intravenous lidocaine;29 howev- er, the use of this drug is associated with frequent side effects which limit its usefulness.23 In randomised controlled trials of chronic pain, the doses of intravenous lidocaine used ranged between 1 to 5 mg/kg. However, we elected to use a total dose of 5 mg/kg since this dose seems to be the best docu- mented effective dose according to a systematic review of these trials.30 The significance of our case reports is twofold: first, they provide the first evidence of the usefulness of intravenous lidocaine as a therapeutic option in the management of chronic orofacial pain. Second, these reports raise the likelihood that intravenous lidocaine is not only effective in pure neuropathic pain syndromes, as the current literature suggests, but may also be effective in mixed nociceptive and neuro- pathic pain conditions that are primarily nociceptive in origin. The observations that lidocaine is effective in non-neuropathic pain conditions such as burns31 and fibromyalgia,14 together with the variable effect of lidocaine in peripheral or central neuropathic pain conditions32 and its effect beyond the pharmacological half-life, are all supportive of this latter conclusion. C O N C L U S I O N In summary, based on this experience, intravenous lidocaine was a powerful and successful treatment op- tion after several insufficient therapeutic attempts that included oral pharmacotherapy, nerve blocks and sur- gery. A trial of intravenous lidocaine should be consid- ered much earlier, even if a multimodal management approach is used. Moreover, intravenous lidocaine should also be tried in pain syndromes of nociceptive origin rather than reserving it only for patients with pure neuropathic pain conditions. However, further research is needed to determine the exact role of in- travenous lidocaine in the treatment of orofacial pain. R E F E R E N C E S 1. Shinal RM, Fillingim RB. Overview of orofacial pain: epidemiology and gender differences in orofacial pain. Dent Clin North Am 2007; 51:1-18. 2. Riley JL 3rd, Gilbert GH, Heft MW. Health care utili- zation by older adults in response to painful orofacial symptoms. Pain 1999; 81:67-75. 3. Sarlani E, Balciunas BA, Grace EG. Orofacial pain - Part I: Assessment and management of musculoskeletal and neuropathic causes. AACN Clin Issues 2005; 16:333- 346. 4. Wirz S, Wartenberg HC, Nadstawek J. Pain manage- ment procedures used by dental and maxillofacial sur- geons: an investigation with special regard to odontal- gia. Head Face Med 2005; 1:14. 5. Türp JC, Hugger A, Nilges P, Hugger S, Siegert J, Busche E et al. Recommendations for the standardized evalu- ation and classification of painful temporomandibular disorders: an update. Schmerz 2006; 20:481-489. 6. Okeson JP. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. 4th ed. Chicago: Quintes- sence Publishing, 1996. 7. Kastrup J, Angelo H, Petersen P, Dejgard A, Hilsted J. I N T R AV E N O U S L I D O C A I N E F O R R E F R A C T O R Y C H R O N I C O R O FA C I A L PA I N 209 Treatment of chronic painful diabetic neuropathy with intravenous lidocaine infusion. Br Med J 1986; 292:173. 8. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991; 41:1024-1028. 9. Scrivani SJ, Chaudry A, Maciewicz RJ, Keith DA. Chronic neurogenic facial pain: lack of response to in- travenous phentolamine. J Orofac Pain 1999; 13:89-96. 10. Galer BS, Jensen MP. Development and preliminary val- idation of a pain measure specific to neuropathic pain: The neuropathic pain scale. Neurology 1997; 48:332- 338. 11. Baranowski, AP, De Courcey J, Bonello E. A trial of in- travenous lidocaine on the pain and allodynia of post- herpetic neuralgia. J Pain Symptom Manage 1999; 17:429-433. 12. Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F. Intravenous lidocaine in central pain: A dou- ble-blind, placebo-controlled, psychophysical study. Neurology 2000; 54:564-74. 13. Brose WG, Cousins MJ. Subcutaneous lidocaine for treatment of neuropathic cancer pain. Pain 1991; 45:145-148. 14. Sorensen J, Bengtsson A, Ahlner J, Henriksson KG, Ek- selius L, Bengtsson M. Fibromyalgia - are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 1997; 24:1615-1621. 15. Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Aust 2000; 172:157-159. 16. Abram SE, Yaksh TL. Systemic lidocaine blocks nerve injury-induced hyperalgesia and nociceptor-driven spinal sensitization in the rat. Anesthesiology 1994; 80:383-391. 17. Abdi S, Lee DH, Chung JM. The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth Analg 1998; 87:1360-1366. 18. Chaplan SR, Bach FW, Shafer SL, Yaksh TL. Prolonged alleviation of tactile allodynia by intravenous lidocaine in neuropathic rats. Anesthesiology 1995; 83:775-785. 19. Woolf CJ, Wiesenfeld-Hallin Z. The systemic admin- istration of local anaesthetics produces a selective de- pression of C-afferent fibre evoked activity in the spinal cord. Pain 1985; 23:361-374. 20. Biella G, Sotgiu ML. Central effects of systemic lido- caine mediated by glycine spinal receptors: an ionto- phoretic study in the rat spinal cord. Brain Res 1993; 603:201-206. 21. Jaffe RA, Rowe MA. Subanesthetic concentrations of lidocaine selectively inhibit a nociceptive response in the isolated rat spinal cord. Pain 1995; 60:167-174. 22. Wallace MS, Dyck JB, Rossi SS, Yaksh TL. Computer- controlled lidocaine infusion for the evaluation of neu- ropathic pain after peripheral nerve injury. Pain 1996; 66:69-77. 23. Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 2004; 62:218-225. 24. Wallace MS, Laitin S, Licht D, Yaksh TL. Concentra- tion-effect relations for intravenous lidocaine infusions in human volunteers: effects on acute sensory thresh- olds and capsaicin-evoked hyperpathia. Anesthesiology 1997; 86:1262-1272. 25. Dirks J, Fabricius P, Petersen KL, Rowbotham MC, Dahl JB. The effect of systemic lidocaine on pain and second- ary hyperalgesia associated with the heat/capsaicin sen- sitization model in healthy volunteers. Anesth Analg 2000; 91:967-972. 26. Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wessel- mann U et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002; 96:841-8. 27. Raphael JH, Southall JL, Treharne GJ, Kitas GD. Efficacy and adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome. BMC Musculoskelet Disord 2002; 3:21. 28. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999; 80:533-538. 29. Galer BS, Harle J, Rowbotham MC. Response to intra- venous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study. J Pain Symptom Manage 1996; 12:161-167. 30. Kalso E, Tramer MR, McQuay HJ, Moore RA. Systemic local-anaesthetic-type drugs in chronic pain: a system- atic review. Eur J Pain 1998; 2:3-14. 31. Jonsson A, Cassuto J, Hanson B. Inhibition of burn pain by intravenous lignocaine infusion. Lancet 1991; 338:151-152. 32. Galer BS, Miller KV and Rowbotham MC. Response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury. Neurology 1993; 43:1233-1235.