4 rd Congress of the European Academy of Neurology Lisbon, Portugal, June 16-19, 2018 Teaching Course 15 The difficult to treat headache patient - Level 3 Refractory trigeminal neuralgia Giorgio Cruccu Rome, Italy Email: giorgio.cruccu@uniroma1.it
Disclosure: the Author, Professor Cruccu, received personal fees for consultancy by Alfa Sigma, Angelini and Biogen, and a research grant by Alfa Sigma. Background. Trigeminal Neuralgia (TN) is a unique neuropathic facial pain condition, characterized by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. Patients with atypical trigeminal neuralgia also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The most recent classifications (Cruccu et al. 2016; Headache Classification Committee of the International Headache Society 2018), which are going to be reflected in the imminent International Classification of Diseases 11 (ICD-11) distinguish three etiological categories of TN: classical TN (caused by neurovascular compression causing morpho-logical changes to the trigeminal root), idiopathic TN (no cause can be found), and secondary TN (caused by major neurological disease, e.g. multiple sclerosis or cerebellopontine angle tumours (Table). (From Cruccu et al. Neurology 2016; 87:220-8) 1
Pathophysiology. One aspect of pathophysiology is fully agreed, being supported by established neurophysiologic, neuroimaging, and histologic evidence (relevant references can be found in Cruccu 2017). Both in classic and secondary trigeminal neuralgia, the primary mechanism is focal demyelination of primary afferents near the entry (extraaxial or intraaxial) of the trigeminal root into the pons. Some investigators believe this area represents a locus minoris resistentiae (a site of lower resistance or higher susceptibility to damage) because it is the site where Schwann cells are substituted by oligodendroglia in providing the myelin sheath (Cruccu et al. 1990). A second pathophysiologic step, admittedly more debatable, is that the damaged primary afferents, in the area of focal demyelination, become a source of ectopic generation of impulses. Demyelinated axons become hyperexcitable. Spontaneously, or because of a local direct mechanical stimulus such as the artery pulsation, ectopic activity is generated. The concept of ephaptic transmission (cross talk) from close, healthy nerve fibers, and the generation of high frequency discharges, is supported by evidence in animal models of focal demyelination of the trigeminal root. Although secondary changes of excitability and grey matter thickness are induced in the central nervous system as in any other type of chronic pain they are by no means necessary to develop typical TN. 2
Standard treatment. Voltage-gated, frequency-dependent sodium channel blockers are the ideal candidates for dampening the highfrequency discharge that is perceived as an electric shock or stabbing pain. This is well documented by recordings from trigeminal ganglion neurons before and after vixotrigine (Figure 1). Indeed, according to main neurological guidelines (Cruccu et al. 2008) this class of drugs, in particular oxcarbazepine (OXC) and carbabamazepine (CBZ), are first line. The authors first choice is oxcarbazepine because of its better tolerability (Attal et al. 2010; Di Stefano et al. 2014). If the patient reaches the (from Zakrzewska et al. Lancet Neurology 2017) dosages adequate for most patients (1200 mg/d to 1500 mg/d) without achieving the desired pain relief (ie, she or he is one of the rare cases of a real nonresponder), no other drug will be enough. Hence surgery, being extremely efficacious in trigeminal neuralgia, should be proposed. 3
Refractory trigeminal neuralgia. A real non-responder to OXC/CBZ is so rare in classical TN, that finding one must pose the problem of a possible misdiagnosis and warrant neuroimaging, neurophysiological, and genetic investigations. Aside from responders and non-responders, however, a third type of patient exists who requires the due consideration (see Treatment Algorithm, page 7). Some patients cannot take either of the two choice drugs because of specific contraindications (most frequently cardiac conduction problems or severe arrhythmias). Some other patients encounter serious side effects and allergic dermatitis, which, unfortunately, tend to be cross-reactive (i.e., the patients who had the allergic reaction to one of the two drugs cannot be switched to the other) or, in the case of CBZ, a fall in blood elements (white cells, red cells, or platelets) rarely reaching aplastic anemia. Indeed, patients on CBZ must undergo a complete blood count every 3 to 4 months. Both drugs may cause sodium depletion. Both drugs, being antiepileptic drugs, induce central nervous system (CNS) depression, presenting as somnolence, confusion, or imbalance. These central side effects, which are far more frequent with CBZ than OXC (Figure 2) (Di Stefano et al. 2014), may prevent patients from maintaining adequate doses. Hence, in this third group of patients, who are neither responders nor non-responders, other drugs can be tried. In this case, the AAN/EFNS guidelines (2008) suggest trying other pharmacologic options as monotherapy or add-on medications. In particular, analysis of the evidence-based trials led to the following suggestions: lamotrigine, baclofen, and pimozide. Unfortunately, neither baclofen nor pimozide represent a valid alternative. Only lamotrigine, used as add-on, and thus allowing the reduction of 4
OXC/CBZ to dosages that the patient can bear, may help (Zakrzewska et al. 1997). Often, this third group of patients is eventually referred for surgery. Many patients, however, may not accept surgery that easily. We believe that in those patients who do not want to undergo any kind of surgical intervention, botulinum toxin injections of the trigger areas should be tried, particularly because a new drug, vixotrigine, will soon be available. Vixotrigine. A new voltage- and frequency-dependent sodium channel blocker, has been discovered that has selectivity for the sodium channel 1.7 (Nav1.7) subtype (Morriset et al. 2013). Nav1.7 is a major sodium receptor in the nociceptive system, but no Nav1.7 receptors exist in the brain. This absence of brain Nav1.7 receptors promises to prevent any side effects associated with depression of CNS excitability. Nav1.7 has been validated as a key pain target by human genetic linkage, as gain of function mutations are linked to a severe chronic pain syndrome, whereas loss of function mutations leads to the inability to feel pain. Furthermore, its efficacy and extreme tolerability has already been proved in patients in a phase-2 trial. Zakrzewska and colleagues (2017) have now demonstrated that vixotrigine can inhibit the firing of trigeminal neurons, adding further mechanistic support to the potential of this new molecule (Figure 1). Two big phase-3 trials are expected to begin in June 2018, one in Europe and one in the US. 5
Botulinum toxin. The amount of published evidence about the efficacy of botulinum toxin injections is growing day by day, and the safety profile is very high. Reportedly, the pain relief lasts several months, and the main side effect is a transient weakness of the facial muscles in the injected area. A systematic review (Morra 2016) identified 4 RCT, on 178 patients, testing the effect of BTX-A in patients with TN [Wu et al, 2012, Zhang et al, 2014; Zúñiga 2013; Shehata 2013]. The dosage used varies from 25 U to 100 U and the number of injections (subcutaneous or intradermal) from one to twenty. The overall effect favored BTX-A versus placebo in terms of proportion of responders; paroxysms frequency per day was significantly lower for BTX-A group. The duration of effect was relatively long (at least 3 months). Adverse events included transient facial weakness, edema and hematoma at the site of injection. Despite these encouraging findings, future studies assessing the optimal dose, duration of the therapeutic efficacy, adverse events, the time and indications for repeat injection are required. Naturally, botulinum toxin injections should be performed by neurologists experienced in botulinum toxin injections for other established indications. Trigeminal neuralgia with concomitant continuous pain. No clinical trials assessing pharmacological treatment of background pain in atypical TN have been conducted. Different studies clearly demonstrated that concomitant continuous pain is associated with poorer medical and surgical outcome, i.e. the number of non-responders is higher in this TN phenotype (Obermann et al, 2008; Sandell and Eide, 2008; Zhang et al, 2013). Recently, in a prospective study totalling 158 patients 6
with typical and atypical TN, the prevalence of responders to sodium channel blockers was lower in the group with also concomitant continuous pain (Maarbjerg 2014). On the basis of these data, constant pain is considered a predictor of poor treatment response. No study has assessed the drug effect in reducing constant and paroxysmal pain intensity separately. Because CBZ and OXC are extremely efficacious in increasing the refractory period of action potentials, they act on the high frequency discharges that characterize the paroxysms of TN. Naturally, in patients with also background pain mediated by other pathophysiological mechanisms, a monotherapy with sodium channel blockers may not be sufficient to control pain. Future RCTs assessing gabapentinoids and antidepressants as add-on treatment in patients with atypical TN are required. Although botulinum toxin A is expectedly efficacious on constant pain, no study has so far assessed its differential effect in a patient with typical (purely paroxysmal) and atypical TN (with concomitant continuous pain). 7
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References 1. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17(9):1113-e88. doi:10.1111/j.1468-1331.2010.02999.x. 2. Cruccu G, Finnerup NB, Jensen TS, Scholz J, Sindou M, Svensson P, Treede RD, Zakrzewska JM, Nurmikko T. Trigeminal neuralgia: New classification and diagnostic grading for practice and research. Neurology 2016 Jul 12; 87(2):220-8. doi: 10.1212/WNL.0000000000002840. 3. Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM; American Academy of Neurology Society; European Federation of Neurological Society. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008 Oct;15(10):1013-28. doi: 10.1111/j.1468-1331.2008.02185.x. 4. Cruccu G, Leandri M, Feliciani M, Manfredi M. Idiopathic and symptomatic trigeminal pain. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1034-42. 5. Cruccu G, Truini A. Refractory trigeminal neuralgia. Non-surgical treatment options. CNS Drugs. 2013 Feb;27(2):91-6. doi: 10.1007/s40263-012-0023-0. 6. Cruccu G. Trigeminal Neuralgia. Continuum (Minneap Minn). 2017; 23 (Selected Topics in Outpatient Neurology): 396-420. doi:10.1212/con.0000000000000451. 7. Di Stefano G, La Cesa S, Truini A, Cruccu G. Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. J Headache Pain 2014;15:34. doi:10.1186/1129-2377-15-34. 8. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38(1):1-211. doi: 10.1177/0333102417738202. 9. Maarbjerg S, Di Stefano G, Bendtsen L, Cruccu G. Trigeminal neuralgia - diagnosis and treatment. Cephalalgia. 2017 Jun;37(7):648-657. doi: 10.1177/0333102416687280. 10. Maarbjerg S, Gozalov A, Olesen J, et al. Concomitant persistent pain in classical trigeminal neuralgia evidence for different subtypes. Headache 2014; 54: 1173 1183. 11. Morisset V, Davis JB, Tate SN. Mechanism of action of anticonvulsants as analgesic drugs. Chapter 35. In: McMahon, SB, Koltzenburg M, Tracey I, Turk DC, editors. Wall and Melzack s textbook of pain. 6th ed. Elsevier, 2013;491-499. 12. Morra ME, Elgebaly A, Elmaraezy A, Khalil AM, Altibi AM, Vu TL, Mostafa MR, Huy NT, Hirayama K. Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials. J Headache Pain. 2016 Dec;17(1):63. 13. Obermann M, Yoon MS, Sensen K, et al. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalalgia. 2008;28:174-81. 9
14. Sandell T, Eide PK. Effect of microvascular decompression in trigeminal neuralgia patients with or without constant pain. Neurosurgery 2008;63(1):93-99. 15. Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain. 1997 Nov;73(2):223-30. 16. Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, Cruccu G, Bendtsen L, Estacion M, Derjean D, Waxman SG, Layton G, Gunn K, Tate S; study investigators. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017 Apr;16(4):291-300. doi:10.1016/s1474-4422(17)30005-4. 17. Zhang H, Lei D, You C, et al. The long-term outcome predictors of pure microvascular decompression for primary trigeminal neuralgia. World Neurosurg 2013;79(5Y6):756-762. 18. Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N, Wu C. 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;15:65. 10