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13 Articles in Volume 12, Issue #9
PROMPT Challenges PROP’s Petition
PROP Answers Questions Raised About Opioid Label Changes
PROP vs PROMPT: Who Speaks for the Pain Doctor?
PROP’s Petition: PPM’s Editorial Board Weighs in
Assessment of Long-term Outcomes Of Opioid Treatment: How to Set Goals and Objectives
Extracorporeal Shock Wave Therapy: Applications in Pain Medicine—Part One
Neck Pain: Diagnosis And Management
Part Two: Trigeminal Neuralgia: A Closer Look at This Enigmatic and Debilitating Disease
Reducing Musculoskeletal Disorders Through Ergonomics
Risk Evaluation and Mitigation Strategy Compliance
Treating the Opioid-addicted Chronic Pain Patient: The Role of Suboxone
Electromagnetic Devices: A New Partner in Pain Management
Methadone Management in a Patient With Pain and History Of Addiction

Part Two: Trigeminal Neuralgia: A Closer Look at This Enigmatic and Debilitating Disease

Part two of this two-part series discusses the pharmaceutical and surgical treatment of trigeminal neuralgia.

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.

Pharmacotherapy
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
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.

Table 1. Pharmacotherapy.

Fosphenytoin
Given the abrupt onset of pain, medications that provide acute relief of painful crises have proven to be a necessity in the treatment of TN. One of the most prominent medications that fulfills this need is fosphenytoin, the water-soluble prodrug of phenytoin. Similar to carbamazepine, phenytoin achieves its antiepileptic effects by prolonging the refractory period of voltage-sensitive sodium channels. Well known for its use in partial and generalized tonic-clonic seizures, phenytoin’s inconsistent bioavailability when used intravenously lead to the development of fosphenytoin. When given during a pain crisis of TN, intravenous fosphenytoin has been found to provide a pain-free interval of 2 days in order for other long-term medications to take effect.8 Although typically used in the acute setting, physicians should be aware that fosphenytoin is associated with similar adverse effects as phenytoin including vestibular toxicity and cardiovascular instability.

Other options for patients requiring acute relief of pain in the setting of TN include injections of onabotulinum toxin A (Botox) and sumatriptan (Imitrex), although the latter should not be used in patients with coronary artery disease or those prone to hypertensive episodes. Intranasal lidocaine may also provide a window of pain relief for a few hours to those suffering from a paroxysm of pain.9

Gabapentin and Misoprostol
TN is classified as either classic or secondary to other systemic diseases, such as multiple sclerosis. Several medications have shown to be particularly effective when TN is secondary to multiple sclerosis, with gabapentin being most notable.10 Gabapentin was originally designed to be a GABA receptor agonist; however, it has been found to act primarily on presynaptic calcium channels of neurons to inhibit the release of excitatory neurotransmitters. Another proposed mechanism for its pain modulating effects is through its interference with substance P, a neuropeptide involved in nociception. Gabapentin is also remarkable for its favorable side-effect profile, with mild sedation and peripheral edema being most prominent.

Misoprostol (Cytotec), an analogue of prostaglandin E1, has also been demonstrated to relieve the symptoms of TN secondary to multiple sclerosis. Generally used for prevention of non-steroidal anti-inflammatory drug–induced gastric ulcers and as a uterine stimulant, researchers from the University of Chicago administered misoprostol to 7 patients with refractory TN secondary to multiple sclerosis. Of the 7 patients, 6 patients (86%) reported at least partial relief of symptoms.11

Clonazepam
Clinical trials studying the use of benzodiazepines in TN have been sparse, limiting these medications to second-line therapy. Of this class of drugs, only clonazepam, a long-acting benzodiazepine, has received attention. Acting on GABAA receptors, clonazepam increases the frequency of channel openings, which reduces neuronal excitability. In a trial of 25 patients with TN, most of which were refractory to carbamazepine, clonazepam was able to provide complete pain control in 40% of patients, while another 23% reported some pain relief.12 These results were marred by the presence of somnolence experienced by more than 80% of patients.

Surgical Interventions
The surgical options for patients with TN have broadened as our understanding of this disease has progressed. Patients whose facial pain does not adequately respond to medical therapy may consider several surgical alternatives that vary in regards to their invasiveness and adverse effects. The three fundamental surgical therapies include: microvascular decompression, rhizotomy, and gamma-knife radiosurgery. When advising patients experiencing refractory TN, clinicians must be mindful that the effectiveness of these surgical therapies depend not only on the specific subtype of TN, but the patients’ other comorbidities as well. Akin to medical treatments, these surgical techniques for the most part have not been examined in large-scale controlled trials detailing their degree of success and rate of recurrence. However, several small well-designed clinical trials have been conducted, which enable patients to have a reasonable appreciation of the risks and benefits of each surgical intervention.

Microvascular Decompression
With neurovascular compression being the most common cause of TN, it is no surprise that microvascular decompression (MVD) is the most popular surgical therapy used for cases of TN refractory to medical therapy. While this technique is generally reserved for the classic form, patients with TN secondary to multiple sclerosis may experience some degree of pain relief as well. Prior to performing MVD, surgeons frequently perform magnetic resonance imaging (MRI) angiography in order to better delineate the relationship between CNV and the compressing vessel. The trigeminal nerve is composed of three divisions that innervate distinct regions of the face: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3) (Figure 1).

The operation consists of a surgeon gaining access to the neurovasculature through a suboccipital craniotomy. After identifying and isolating CNV and the offending vessel, typically the superior cerebellar artery, a small sponge or pad is placed between the nerve and artery to prevent further demyelination and irritation of the trigeminal nerve. The operation is concluded with the surgeon cleaning the wound with saline solution and replacing the missing occipital bone with a small titanium plate.

While initial success rates following MVD have reached 90%, recurrence rates also increase gradually. In order to gauge the long-term effectiveness of MVD, Barker et al followed 1,155 patients who underwent this procedure over a 20-year period.13 After 10 years, roughly 70% of the patients were still free of symptoms. Of the 30% who experienced recurrences, the overwhelming majority occurred within 2 years of surgery. The most noteworthy indicator of recurrence was the presence of pain initially following surgery. Other risk factors included being female and length of symptoms prior to surgery (>8 years).13 While these results are promising, the procedure is not without its risks. With a mortality rate of >0.5%, numerous other complications are associated with MVD, including hearing loss, paralysis of the extraocular muscles, and self-limited meningismus.13 Other less common adverse effects include stroke, seizure, cerebrospinal fluid leakage, and double vision.

Figure 1. Distribution of the cranial nerve V: the ophthalmic nerve, the maxillary nerve, and the mandibular nerve

Rhizotomy
In order to avoid the invasiveness of MVD, physicians treating patients with refractory TN should consider rhizotomy as a surgical alternative. Rhizotomy refers to the destruction or severing of nerves that are functioning improperly. Generally initiated through a percutaneous approach, rhizotomy interrupts the signaling of hyperactive nerves through several methods including thermocoagulation, balloon compression, and chemical injection. While achieving immediate success rates that are comparable to MVD, rhizotomy is associated with higher rates of recurrence and a different array of side effects. When thermocoagulation is used, a needle is inserted through the patient’s face while they are under partial anesthesia, and is positioned adjacent to the trigeminal ganglion. An electrode follows the needle and uses thermal energy to selectively damage the trigeminal nerve under the direction of the patient, who tells the surgeon when his/her pain is alleviated. Balloon compression rhizotomy is performed in a similar manner except the trigeminal nerve is damaged through mechanical compression from an expandable balloon. Likewise, chemical rhizotomy uses glycerol to interrupt pain transmission from the trigeminal nerve. In the early postoperative period, these techniques can relieve pain in >95% of patients; however, long-term remission usually requires multiple operations. Moreover, various side effects accompany each technique, including sensory loss to the face, meningitis, and weakness of the muscles of mastication.14 Keratitis may also occur due to sensory loss of the cornea, although this risk is minimal with balloon compression rhizotomy.15 The most distinctive and dreaded complication of rhizotomy is anesthesia dolorosa, which is characterized by relentless burning pain in the face after surgery and is refractory to all treatments. In addition to a burning sensation, patients may experience shooting facial pain that parallels the pain felt in TN.14

Gamma-knife Radiosurgery
In recent years, the use of stereotactic radiosurgery has provided another noninvasive surgical option to combat TN. After stabilizing the patient with a head frame and providing local anesthesia, a gamma-knife unit can emit radiation using cobalt-60 sources. The radiation can then directly target the trigeminal nerve.16 The safety of this procedure is derived from the precise delivery of gamma radiation to the trigeminal nerve, whose distribution is usually mapped preoperatively with MRI. The mechanism by which radiosurgery inhibits pain transmission is not well understood; however, disruption of ephaptic transmission is thought to play a role.16

In order to determine the symptom response to this surgical intervention, Young et al followed 60 patients with TN (9 cases of which were tumor related) who had undergone stereotactic radiosurgery.17 Of the 51 patients without tumors, 38 patients (75%) experienced no pain within 4 months of surgery. Similarly, of the 9 patients with tumors, 8 patients (89%) reported some degree of pain relief.17 While this study demonstrated the immediate effects of radiosurgery, the mean follow up was only 16 months, leaving its long-term efficacy in doubt.

A more protracted study was conducted by Sheehan et al, who followed 151 patients treated with gamma-knife radiosurgery for 3 years. Although more than 90% of study patients experienced some pain relief initially, 27% reported a recurrence of pain after approximately 1 year.18 These results demonstrate that while radiosurgery is favorable for its lack of complications, its long-term effectiveness pales in comparison to MVD.

Summary
The severity of pain associated with TN and its devastating psychological effects make prompt diagnosis and treatment essential. Without a proper understanding of its clinical features and medical course, TN may go undiagnosed for years, creating an unacceptable quality of life for patients. After a diagnosis is established, clinicians must determine whether the cause of TN is secondary or idiopathic since the treatment regimens differ based upon the underlying etiology. With a proper diagnostic work up and early treatment, patients with this neuropathic disorder may achieve pain relief within weeks and resume a healthy and productive life.

Last updated on: November 5, 2012
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