There are a variety of reasons for why there are so few trials in this area. The conditions are rare and so one centre will not be able to recruit enough patients for an adequately powered study. A recent trial of a new drug for trigeminal neuralgia needed 11 countries and 27 centres in order to recruit 30 to the full trial [43]. There are no biomarkers for any of these conditions and so diagnosis is based solely on history and examination and will be dependent on the expertise of the clinician and patients’ ability to recall details. The changes in the diagnostic criteria seen between different versions of the IHCH classification [2, 3], are ample evidence of the difficulties in agreeing on criteria. These need to be very precise in clinical trials. Patients with rare conditions are often reluctant to volunteer for RCTs as they are concerned that they will be allocated to placebo or the current best drug rather than the new one [22]. RCTs are often of short duration which may not provide sufficient time for the effects of the drug to be noted nor for their adverse effects to become evident. Many of these conditions are very severe and so designs with placebo controls cannot be used. An active control may not be possible due to drug interactions as is found in trials in trigeminal neuralgia (TN) [43]. Another major concern in trials in TN is that spontaneous remissions are common especially in the early stages of the disease. Thus, recruiting patients with a short duration of the disease may bias towards a favourable outcome as may have occurred in one study in the field of trigeminal neuralgia [25]. These factors have recently been considered by the NeupSig group and shown how significantly they can affect outcomes [13].

Patients with classical-type TN do not have any background pain whereas the patients with some background pain are described as classical trigeminal neuralgia with concomitant persistent facial pain. The background pain may be continuous or only be present for several hours [28]. None of the current trials are specific about this distinction and yet Maarbjerg et al. [28] suggest that those with background pain have a poorer response to anti-epileptic drugs (AEDs). There is also a general consensus that patients with multiple sclerosis (MS) have reduced efficacy and tolerability to AEDs when used to manage their TN.

The first drug to be shown to have a significant impact on TN was phenytoin in 1942 and then in 1962 the landmark paper by Blom established carbamazepine as a very effective drug [8]. Baclofen, valproate and clonazepam were the next series of drugs used and except for baclofen the reports were all case series. Subsequently numerous other drugs have been trailed, some in RCTs but others as open label. The most recent is CNV 1014802 [43] which shows promise. There has recently been published an update on trigeminal neuralgia in Clinical Evidence and this will be used for individual drug results [41, 42]. Although there are now a vast array of drugs available to manage TN, it is important to ensure that a neurosurgical opinion is sought early on so that if patients develop severe pain they know that there are options other than drugs available [41, 42].