Part Two: Trigeminal Neuralgia: A Closer Look at This Enigmatic and Debilitating Disease
Trigeminal neuralgia (TN), also known as tic douloureux, is a relatively common neuropathic disorder that is characterized by sudden severe episodes of lancinating or electric pain along the distribution of cranial nerve V (CNV). With an annual incidence of approximately 4.5 per 100,000 people, TN remains one of the most frequent causes of facial pain worldwide.1 Part one of our two-part series discussed the etiology and differential diagnosis of TN.2 This installment will review the pharmaceutical and surgical options for pain management, which can help reduce the suffering from this condition.
You can read Part One of this article series in the September 2012 issue.
When deciding upon the proper treatment for a patient with TN, the physician must take into account various clinical factors. The International Headache Society has separated TN into two categories: classic and secondary. While both categories present with similar symptoms, they differ in respect to their causality. Classic TN includes neuralgia that is idiopathic or caused by compression of the trigeminal nerve from a nearby blood vessel. Secondary TN, on the other hand, accounts for cases triggered by other structural abnormalities.
Of primary concern is establishing whether the TN is idiopathic/vascular or secondary in origin since most secondary causes, such as tumors, are refractory to medical therapy. Additional attention should also be paid to the clinical presentation of the patient. By assessing the severity of pain the patient is experiencing, the physician can accurately judge how aggressive the treatment plan should be.
Several antiepileptic medications have been proven to be exceedingly effective in the treatment of TN. However, the precise mechanism by which these drugs benefit patients with TN is unknown. Moreover, instances where patients do not improve on first-line medications are not uncommon. There are numerous second-line drugs that have been shown to be beneficial; nevertheless, there are limited studies, which explicitly outline their efficacy. Opioids also have a limited role in the short-term management of TN, but they require high doses in order to achieve adequate pain control. Table 1 highlights the most common medications prescribed for TN, their placement in the treatment hierarchy, and the most prominent adverse effects associated with them.
Carbamazepine and Oxcarbazepine
Through analysis of several clinical trials, carbamazepine has emerged as the gold standard for the treatment of TN. Principally used as a broad-spectrum antiepileptic, carbamazepine’s mechanism of action appears to be inhibition of voltage-sensitive sodium channels leading to a marked decrease in neuronal action potentials. Carbamazepine has also been shown to be effective as a mood elevator, making this medication particularly useful with TN patients who develop depressive symptoms. Following analysis of several randomized controlled trials, Gronseth et al have determined that carbamazepine achieves satisfactory pain control in more than 60% of patients diagnosed with TN.3 However, these promising results should be reviewed alongside the adverse effects seen with this medication. Because carbamazepine is metabolized by cytochrome P450-3A4, it can alter the circulating levels of other medications that are metabolized through the same pathway. In addition, carbamazepine can cause vestibular toxicity resulting in nystagmus and ataxia. Other less common side effects include agranulocytosis and aplastic anemia, thus requiring continuous complete blood count monitoring. Women prescribed this medication should be aware that various birth defects have been associated with carbamazepine, ranging from neural-tube defects to congenital heart disease.
In order to avoid these complications, oxcarbazepine (Trileptal), a keto analogue of carbamazepine, was developed. This medication appears to achieve similar levels of pain control in the treatment of TN with a less distressing side-effect profile.3 While drug interactions and vestibular toxicity are less common, patients taking oxcarbazepine are prone to developing hyponatremia. Additionally, patients with certain genetic predispositions are at risk for developing Stevens-Johnson syndrome when taking either carbamazepine or oxcarbazepine.
Pimozide and Tocainide
Belonging to the phenylbutylpiperidine group of high-potency antipsychotics, pimozide (Orap) is chiefly used in the management of Tourette syndrome. However, in 1989 a double-blind crossover trial of 48 patients with TN was conducted comparing pimozide to carbamazepine. At its conclusion, pimozide achieved pain control in all 48 patients, while carbamazepine only reached a 56% success rate suggesting that pimozide could be more effective than carbamazepine in the treatment of TN.4 While displaying encouraging results, the use of pimozide has been avoided due to the extrapyramidal side effects produced by its properties as a dopamine antagonist.
Tocainide (Tonocard) is another medication that has been proposed to produce pain relief on par with carbamazepine. Acting as a class IB antiarrhythmic, tocainide causes mild sodium channel blockage, analogous to lidocaine (also class IB). The use of tocainide in TN has been hampered primarily by the lack of clinical trials demonstrating its efficiency.
Baclofen and Levetiracetam
When faced with patients who experience pain refractory to carbamazepine, a large number of medications have been proposed to be useful, although clinical evidence of their effectiveness has not been robust. Baclofen is a ɣ-aminobutyric acid (GABA) analogue that activates GABAB receptors resulting in spasmolytic properties. In a trial of 50 patients with TN refractory to carbamazepine, Fromm et al concluded that when baclofen was added to the patients’ treatment regimens, 74% achieved a decrease in the frequency of painful episodes. These findings were consistent after follow up 1 to 5 years later.5
An alternative medication that has been reported to be useful for lowering the number of daily attacks in refractory TN is levetiracetam (Keppra).6 Acting through an unknown mechanism, levetiracetam, a broad-spectrum antiepileptic, has been shown to be beneficial not only in the treatment of TN, but in bipolar disorder and for migraine prophylaxis as well.
Lamotrigine (Lamictal) is another option for refractory cases of TN. Lamotrigine is notable for having multiple mechanisms of action, including inhibition of voltage-gated sodium and calcium channels, to prevent partial seizures, and the seizures of Lennox-Gastaut syndrome. In a double-blinded placebo-controlled crossover trial with 14 refractory TN patients, 11 patients (79%) experienced improvement in pain control with lamotrigine as opposed to the placebo.7 Similar to carbamazepine, lamotrigine is associated with Stevens-Johnson syndrome and toxic epidermal necrolysis; however, this risk can be diminished with slow titration of the drug.