Abstract
Introduction
Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Pain occurs in paroxysms, which last from a few seconds to 2 minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day. Periods of remission can last for months to years, but tend to shorten over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with trigeminal neuralgia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: ablative neurosurgical techniques to the Gasserian ganglion; baclofen; carbamazepine; clonazepam; cryotherapy of peripheral nerves; gabapentin; lamotrigine; microvascular decompression; nerve block; oxcarbazepine; peripheral acupuncture; phenytoin; proparacaine eye drops; sodium valproate; stereotactic radiosurgery; tizanidine; and topiramate.
Key Points
Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. The diagnosis is made on the history alone, based on characteristic features of the pain.
Pain occurs in paroxysms, which last from a few seconds to 2 minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day.
Periods of remission can last for months to years, but tend to get shorter over time.
The annual incidence in the UK is 26.8/100,000.
Carbamazepine is considered the gold standard in treatment for symptoms of trigeminal neuralgia.
Carbamazepine has been shown to increase pain relief compared with placebo, but also increases adverse effects, such as drowsiness, dizziness, constipation, and ataxia.
There is consensus that oxcarbazepine is an effective treatment in people with trigeminal neuralgia, although there is a lack of RCT-based data to confirm this.
We found no sufficient evidence to judge the effectiveness of tizanidine, baclofen, or lamotrigine.
Lamotrigine is often used in people who cannot tolerate carbamazepine, but the dose must be increased slowly to avoid rashes, thus making it unsuitable for acute use.
There is consensus that baclofen may be useful for people with multiple sclerosis who develop trigeminal neuralgia.
We don't know the effectiveness of other antiepileptic drugs, such as phenytoin, clonazepam, sodium valproate, gabapentin, or topiramate, in people with trigeminal neuralgia.
Despite a lack of RCT data, observational evidence supports the use of microvascular decompression to relieve symptoms of trigeminal neuralgia.
Proparacaine eye drops (single application) do not relieve pain in people with trigeminal neuralgia, despite initial open-label use that suggested they were helpful.
We don't know whether peripheral nerve treatments such as acupuncture, cryotherapy, laser surgery, or nerve block are effective in people with trigeminal neuralgia.
We found no RCT evidence assessing stereotactic radiosurgery or ablative neurosurgery to the Gasserian ganglion. However, there is some observational data suggesting that radiofrequency thermocoagulation may offer higher rates of complete pain relief than glycerol rhizolysis and stereotactic radiosurgery, but is associated with the highest rate of complications. Typically, pain relief with radiosurgery is not immediate.
About this condition
Definition
Trigeminal neuralgia is a characteristic pain in the distribution of one or more branches of the fifth cranial nerve. The diagnosis is made on the history alone, based on characteristic features of the pain. It occurs in paroxysms, with each pain lasting from a few seconds to 2 minutes. The frequency of paroxysms is highly variable, ranging from hundreds of attacks a day to long periods of remission that can last years. Between paroxysms, the person is asymptomatic. The pain is severe and described as intense, sharp, superficial, stabbing, or shooting — often like an electric shock. In any individual, the pain has the same character in different attacks. It is triggered by light touch in a specific area or by eating, talking, washing the face, or cleaning the teeth. Other causes of facial pain may need to be excluded. In trigeminal neuralgia, the neurological examination is usually normal.
Incidence/ Prevalence
Most evidence about the incidence and prevalence of trigeminal neuralgia is from the USA. The annual incidence (age adjusted to the 1980 age distribution of the USA) is 5.9/100,000 women and 3.4/100,000 men. The incidence tends to be slightly higher in women at all ages, and increases with age. In men aged over 80 years, the incidence is 45.2/100,000. One questionnaire survey of neurological disease in a single French village found one person with trigeminal neuralgia among 993 people. A retrospective cohort study in UK primary care, which examined the histories of 6.8 million people, found that 8268 people had trigeminal neuralgia, giving it an incidence of 26.8/100,000 person-years.
Aetiology/ Risk factors
The cause of trigeminal neuralgia remains unclear. It is more common in people with multiple sclerosis (RR 20.0, 95% CI 4.1 to 59.0). Hypertension is a risk factor in women (RR 2.1, 95% CI 1.2 to 3.4), but the evidence is less clear for men (RR 1.53, 95% CI 0.30 to 4.50). One case control study in the USA found that people with trigeminal neuralgia smoked less, consumed less alcohol, had fewer tonsillectomies, and were less likely than matched controls to be Jewish or an immigrant.
Prognosis
One retrospective cohort study found no reduction in 10-year survival in people with trigeminal neuralgia. We found no evidence about the natural history of trigeminal neuralgia. The illness is characterised by recurrences and remissions. Many people have periods of remission with no pain for months or years. Anecdotal reports suggest that in many people it becomes more severe and less responsive to treatment with time. Most people with trigeminal neuralgia are initially managed medically, and a proportion eventually have a surgical procedure. We found no good evidence about the proportion of people who require surgical treatment for pain control. Anecdotal evidence indicates that pain relief is better after surgery than with medical treatment.
Aims of intervention
To relieve pain, with minimal adverse effects.
Outcomes
Pain relief: pain frequency and severity scores; psychological distress; ability to perform normal activities; adverse effects.
Methods
Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this review: Medline 1966 to September 2006, Embase 1980 to September 2007, and The Cochrane Database of Systematic Reviews 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE clinical guidelines. Abstracts of the studies retrieved were assessed independently by an information specialist using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 10 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all RCTs described as "open"’, "open label", or not blinded. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are continually added to the review as required. The contributor also included results from a 2005 search conducted whilst writing a guideline on the surgical management of trigeminal neuralgia. The search strategy for this guideline was designed to find RCTs and CCTs related to surgical options in trigeminal neuralgia in Medline, Embase, and Cochrane 1966 to 2005. Additionally, the contributors have used results from their own database collated from 1990 to September 2007, which includes case series reports. As Clinical Evidence was unable to perform a second appraisal of results retrieved by the contributor's search, we may have missed studies that could affect our overall assessment of the interventions in this review. As trigeminal neuralgia is a rare disease, and patents on many of the drugs have expired, it is highly unlikely that further trials comparing carbamazepine versus local anaesthetics (such as tizanidine or proparacaine) will be conducted. Trigeminal neuralgia is a very painful condition and, therefore, placebo-controlled trials are considered unethical. Trials using active controls have important limitations. The gold-standard drug for treating trigeminal neuralgia is carbamazepine, but it is difficult to be sure that its effects have been totally eliminated before crossover when compared with other drug treatments in crossover designs. This is because carbamazepine alters liver enzymes, and reversal of this takes about 3 weeks. The choice of active control is limited because few drugs have been subjected to high-quality trials. Different trial designs are needed. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Trigeminal neuralgia.
| Important outcomes | Ability to perform normal activities, Adverse effects, Pain relief, Psychological distress | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in people with trigeminal neuralgia? | |||||||||
| 3 (161) | Pain relief | Carbamazepine versus placebo | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and short follow-up. Directness points deducted for inclusion of different pain severities and uncertainties about diagnostic criteria and outcomes measured. Effect-size point added for OR 2 to 5 |
| 1 (143) | Pain relief | Long-term carbamazepine treatment versus stopping carbamazepine earlier | 2 | –1 | –1 | 0 | 0 | Very low | Quality point deducted for sparse data. Consistency point deducted for different results at different time points |
| 1 (48) | Pain relief | Oxcarbazepine versus carbamazepine | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and no direct comparison between groups |
| 1 (14) | Pain relief | Lamotrigine versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, crossover design with no pre-crossover results, and short period of treatment. Directness point deleted for concurrent use of other medication |
| 1 (17) | Pain relief | Baclofen versus carbamazepine | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, no intention-to-treat analysis, and poor follow-up |
| 1 (10) | Pain relief | Tizanidine versus placebo | 4 | –3 | 0 | –1 | +2 | Low | Quality points deducted for sparse data, short follow-up, and crossover design. Directness point deducted for different results at different time frames (pain relief not sustained). Effect-size points added for RR over 5 |
| 1 (12) | Pain relief | Tizanidine versus carbamazepine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and lack of intention-to-treat analysis. Directness point deducted for unclear measurement of outcome |
| 1 (47) | Pain relief | Proparacaine hydrochloride versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (37) | Pain relief | Streptomycin plus local anaesthetic versus local anaesthetic alone | 4 | –2 | –2 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency points deducted for conflicting results between RCTs and different results at different time points. Directness point deducted for selection bias in one RCT |
| 1 (87) | Pain relief | Stereotactic radiosurgery using one versus two isocentres | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of other interventions |
| 1 (87) | Adverse effects | Stereotactic radiosurgery using one versus two isocentres | 4 | –2 | 0 | 0 | 0 | Low | Quality points deleted for sparse data and incomplete reporting |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Microvascular decompression
Major neurosurgical procedure that involves access through the posterior fossa to the trigeminal nerve just at its point of entry into the brain. Any vessels distorting or in close contact with the nerve are moved out of the way with the aim of avoiding nerve damage and hence preserving function.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Joanna M Zakrzewska, Barts and the London Queen Mary's School of Medicine and Dentistry, London, UK.
Mark E Linskey, Department of Neurological Surgery, University of California, California, USA.
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