4rd 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 Classifi-

cation 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 high-

frequency discharge that is perceived

as an electric shock or stabbing pain.

This is well documented by recordings

from trigeminal ganglion neurons be-

fore and after vixotrigine (Figure 1).

Indeed, according to main neuro-

logical guidelines (Cruccu et al. 2008)

this class of drugs, in particular

oxcarbazepine (OXC) and carbaba-

mazepine (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. Un-

fortunately, 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
8
 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