Fig. 20.1
Diary of patient reporting severity of pain on a scale of 0–10 and drug dosage (lamotrigine) over time
Medications will only provide partial relief, so combining them with psychological strategies can lead to significant improvement in outcomes. Systematic reviews have shown that cognitive behaviour techniques for chronic pain can have a significant impact on quality of life and hence patients’ abilities to cope with their pain [31]. There is less evidence for their use in orofacial pain [1]. These are often delivered face to face but online ones are also available [29]. Allaying patients’ fears and changing beliefs about their pain will have a marked impact on their ability to respond to further management with both medications and psychology [6].
20.1.2 Clinical Trials in Trigeminal Neuropathies
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].
20.2 Trigeminal Neuralgia, Classical, with Concomitant Pain
Trigeminal Neuralgia
TN is defined by the Headache Classification Committee of the International Headache Society as “A disorder characterized by recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli. It may develop without apparent cause or be a result of another diagnosed disorder. There may or may not be, additionally, persistent background facial pain of moderate intensity” [2].
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].
Carbamazepine
The gold standard drug is carbamazepine and three RCTs, crossover design of poor quality in a total of 208 patients have been reported as well as a systematic review. The NNT is 2 with 95 % CI 1–2 [41, 42]. There is very little literature on effectiveness over time and one study suggests that over a 16-year period efficacy is reduced [37]. This however could also have been due to progression of the disorder itself. Although highly effective the side effects of carbamazepine are significant and there are reported deaths but it is not clear if carbamazepine was the direct cause. Allergies to carbamazepine occur and there is a risk of Stevens-Johnson syndrome in people with the allele HLA-B1502. Side effects are listed in Table 20.1 and recent review of side effects using a psychometrically tested questionnaire AEP shows that cognitive side effects are the most prominent [9]. Drug interactions are also common and this becomes a substantial problem in the elderly who are on polypharmacy. To reduce side effects the drug needs to be slowly escalated and equally slowly withdrawn. Due to its pharmacokinetics it is important to monitor haematinics, electrolytes, liver enzymes on a regular basis if high doses are used and especially at the start of therapy. NICE [33] suggests that vitamin D and calcium levels need to be checked if the drug is used long term. It remains the first-line drug of choice in the UK [34].
Table 20.1
Commonest drugs in use for trigeminal neuralgia to gain 50 % pain relief
Drug/therapy | Daily dose range | Efficacy | Side effects/comments |
---|---|---|---|
Evidence from RCT | |||
Baclofen | 50–80 mg used as four times a day | Good | Ataxia, lethargy, fatigue, nausea, vomiting, beware of rapid withdrawal, useful in MS |
Carbamazepine | 300–1000 mg used as four times a day | Excellent number needed to treat 2 | Drowsiness, ataxia, cognitive impairment, gastrointestinal, diplopia, rash, introduce slowly, drug interactions common, regular monitoring |
Lamotrigine | 200–400 mg used as twice a day | Good when added to other anti-epileptics | Dizziness, drowsiness, cognitive impairment, constipation, ataxia, diplopia, irritability, rapid dose escalation leads to rashes |
Gabapentin | 1800–3600 mg used as three times a day | Good | Drowsiness, cognitive impairment, ataxia, oedema, weight gain |
Oxcarbazepine | 300–1200 mg used as four times a day | Excellent | Fatigue, dizziness, cognitive impairment, nausea, hyponatraemia in high doses, no major drug interactions |
Case series only | |||
Phenytoin | 200–300 mg used as three times a day | Good | Drowsiness, ataxia, cognitive impairment, gastrointestinal, diplopia, easy to overdose |
Pregablin | 300–600 mg used as twice a day | Good | Drowsiness, cognitive impairment, ataxia, gastrointestinal, oedema |
Oxcarbazepine
This drug is closely related to carbamazepine but as it does not use the liver enzyme system for metabolism and has fewer drug interactions. RCTs have been done and compared to carbamazepine but the only data available is in poster presented at a conference and then quoted in Beydoun’s paper [5]. Its efficacy was the same as for carbamazepine but there are insufficient data to report an NNT. The data also suggest that tolerability of oxcarbazepine was better but no further details are provided. The drug reduces in efficacy over time [44], [11]. One of its major side effects is hyponatraemia which is dose-related [44]. There is general consensus among clinicians that oxcarbazepine is the preferred drug and in some countries it is the first-line drug [10].
Lamotrigine
This has only been used in combination with either carbamazepine or phenytoin in a small crossover RCT. It is therefore not possible to provide an NNT. It needs to be very slowly escalated due to its propensity to cause rashes when the dose is escalated too rapidly. It remains a useful drug when allergy to carbamazepine or oxcarbazepine occurs and it has been reported to be useful in SUNA (short unilateral neuralgiform pain with autonomic features) [23]. Otherwise, its side effect profile is similar to other AEDs.
Baclofen
As this is a drug often used in patients with MS to improve spasticity, many clinicians will use the drug in this group of patients. There is a reported RCT but its quality is too poor to make any recommendations or provide an NNT. It is probably better used in combination with carbamazepine rather than on its own. It can cause sedation and its withdrawal must be slow as it can result in hallucinations.
Gabapentin
A newer AED which has been used in a small RCT comparing its action to supplementation with injection of ropivicane into trigger zones [25]. Although an effective drug in other neuropathic pains, its effectiveness in this study was low.
Botulinum
Other RCTs
These have been very small trials of drugs in facial neuralgia, dextromethorphan [16] and topiramate [15]. There are older drugs such as pimozide, tizanidine, tocainide and proparacaine eye drops that have been reported in small poor quality RCTs which showed no positive efficacy and are not in use [40].
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