Now, we are going to review the role of anticonvulsants for the treatment of neuropathic pain. And you might wonder who had this crazy idea about using a drug for seizures for the treatment of neuropathic pain. It actually goes back all the way to 1853 when Trousseau, a French neurologist, proposed that the paroxysmal episode of pain suffered by patients with TN were due to paroxysmal depolarization in the trigeminal pathways and were very reminiscent, in his own mind, to the paroxysmal cortical depolarization that occurred in patients with epilepsy.

He actually coined the term "neuralgic epilepsy" to describe that condition and he further suggested that drugs that would be effective for the treatment of seizures would perhaps be useful for the treatment of this condition. This then led another French neurologist, Bergouignan, to first test the efficacy of phenytoin (DPH) in the early 40s. And he found it to be slightly effective at high dosages in some of his patients.

But it wasn't until the early 60s that Blom, a Swedish neurologist, first evaluated the efficacy of carbamazepine (CBZ) in the treatment of this condition. And he found it to be highly effective in the majority of his patients.

These anecdotal reports were bolstered by animal data that showed that both DPH and CBZ depressed synaptic transmission following maxillary nerve stimulation in the spinal trigeminal nucleus.

Since that time a variety of antiepileptic drugs (AEDs) [have] been purported to have efficacy in the treatment of trigeminal neuralgia. This includes the standard AEDs such as carbamazepine, phenytoin, clonazepam, valproate, as well as the more recently introduced anticonvulsants felbamate, gabapentin, lamotrigine, and oxcarbazepine.

With carbamazepine, 3 clinical trials were done. The largest trial was done by Campbell back in 1966 whereby he took 70 patients, put them on carbamazepine at 400-800 mg/day and showed on a pain relief scale that there was a 58% improvement during the carbamazepine phase, as compared to 26% improvement during the placebo phase; this being a statistically significant difference.

A year later, a similar trial showed that on carbamazepine 400-800 mg/day, there was a 70% improvement and a minimal or absent response in all placebo-treated patients.

The trial by Nicol in 1969 replicated these results and showed that there was 75% improvement on CBZ compared to a 25% improvement on placebo.

And it is based on those 3 clinical trials that the FDA approved the use of CBZ for the treatment of trigeminal neuralgia and why CBZ remains today the drug of choice for this condition.

It is estimated that 70, 80 or up to 90% of patients have a good initial response to this drug. Actually, experts in this field suggest that, if you are considering this diagnosis and the patient doesn't respond to CBZ, you might want to rethink your diagnosis. This is how good the initial response is. You put somebody on 200 mg bid and within a day or two the pain is gone or significantly relieved. Once autoinduction takes place, you might have to increase the dose to 600, 800 or 1000 mg daily. But the initial response is virtually good in every patient.

There is a very nice correlation between efficacy and serum levels. The effective serum level range between 6-10 mg/cc, again, achieved on daily dosages between 400-1000 mg. So, the problem with CBZ is not with the initial response. If you were, however, to follow these patients for a long time there is about a 30 to 40% drop-out rate at 1 year, either because of the development of tolerance or because of the development of significant side effects. So down the line you are going to have to look for another agent or at least for an adjunctive therapy.

[These are] the results with oxcarbazepine. Oxcarbazepine is a new AED released on the US market a few months ago. It's new in the United States, but has been approved in more than 50 countries and there is more than 200,000 patient exposure on this drug. It's a drug that is approved for the treatment of seizures, both as monotherapy as well as add-on therapy. It is a keto-analog of carbamazepine. And oxcarbazepine is really a pro-drug. It's very rapidly reduced to the monohydroxy derivative (MHD), which is the [pharmacologically] active substance.

Now, it is reduced rather than oxidized. Carbamazepine is oxidized to the 10,11-epoxide, which contributes to the side effect profile of this drug. By virtue of the fact that oxcarbazepine is reduced, it doesn't form the 10,11-epoxide and, as you will see, this is probably why it has significantly less side effects.

In addition, it doesn't undergo autoinduction so the starting dose is an effective dose. You don't have to change the dose [because autoinduction does not take place]. And because of the fact that it is reduced and doesn't induce the hepatic enzymes [to the same extent as CBZ], it has a much lower propensity for drug-drug interactions. If somebody was to develop a rash on CBZ there is only a 27% cross-reactivity with oxcarbazepine. And when it was compared head-to-head in epilepsy trials with CBZ, it was found to have comparable efficacy, but it was significantly better tolerated predominantly because of a lower incidence of rash and a lower incidence of CNS side effects.

In trigeminal neuralgia, oxcarbazepine (OXC) was tested in a number of clinical trials. The one shown was published by Lindstrom and it was a comparative trial of OXC vs CBZ in a cross-over design. OXC was titrated to 900-2100 mg/day vs CBZ at 400-1200 mg/day. The efficacy was assessed on an 11-point scale and the data showed comparable analgesic effect in 12 patients, better efficacy on OXC for 2 patients and better efficacy for CBZ in 1 patient.

The author concluded that OXC offers an alternative to CBZ for the treatment of trigeminal neuralgia. As far as the dosing of OXC, if you want to give the equivalent of 1 mg of CBZ you have to give 1.5 mg of OXC, so 600 mg of CBZ would be [equivalent to] 900 mg of OXC.

Two other trials are shown. Fifteen patients with trigeminal neuralgia [were] treated with a mean daily [OXC] dose of 850 mg and followed for a period of close to a year. Seventy-three percent of patients [were] well-controlled and 27% [were] moderately-controlled. Another series of 6 patients [who were] refractory or intolerant to CBZ treated with 600-2400 mg/day of OXC achieved control of symptoms within 24 hours after initiation of treatment.

And finally, an open-label trial of 15 patients [who were] refractory to CBZ [were] converted to OXC monotherapy. Two-thirds of the patients were completely controlled on 900-1800 mg/day.

With the other anticonvulsants there are no double-blind trials. The data for phenytoin suggest that [at] high dosages and [at] high serum levels between 15-25 mg/cc a proportion of patients have a positive response to this drug. However, it's been mostly used as an adjuvant to CBZ [in] patients with only a partial response to this drug.

With clonazepam, 2 open-label series, one of 25 patients the other of 19 patients, and about two-thirds of the patients were reported to have a positive response. With valproate, a single open-label series of 20 patients, about half of the patients were reported to have a positive response.

As far the other newer anticonvulsants felbamate (FBM) was a drug which mechanistically should have been great for the treatment of neuropathic pain. It blocked NMDA receptors. It was a GABA-ergic drug and also was a modulator of the sodium channel. So, it would have worked both on peripheral as well as central sensitization. And actually, it was tested in 3 patients with refractory trigeminal neuralgia who had a good response to this drug. Unfortunately it's a drug that was associated with significant idiosyncratic reactions not only the aplastic anemia, but also [a fulminant] hepatic failure and it is quite unlikely that this drug is going to be further developed as an antineuralgic agent.

With gabapentin (GBP) there are a number of open-label series that suggested that at 900-1800 mg/day about two-thirds of the patients are refractory to CBZ develop a positive response to this drug. And with lomatrigine (LTG) 2 open-label series totaling 24 patients, the majority of whom responded very well to lamotrigine as monotherapy at 100-450 mg/day with a follow-up of close to a year. These are some of the alternative agents that you might use in addition to CBZ.