Medical management of trigeminal neuropathic pains

Figures & data

Figure 1. Key clinical features of trigeminal neuralgia.

Figure 2. The CONSORT flowchart (www.consort-statement.org).

Table 1. Drugs used in trigeminal neuralgia which have been evaluated in randomized controlled trials (RCTs).

Drug/therapy	Mechanism of action	Trial details	Daily dose range	Efficacy NNT	Side effects NNH	Comments on use
Baclofen	Muscle relaxant, GABAb receptor agonist	Fromm et al. 1984: R*, D-B, C-O baclofen-10 patients Fromm et al. 1987 R, D-B, C-O racemic vs l-baclofen, 15 patients Parekh et al. 1989: R, D-B, P baclofen vs CBZ vs combination, 30 patients	50 – 80 mg	Good but not possible to determine NNT	Ataxia, lethargy, fatigue, nausea, vomiting, loss of muscle tone Beware rapid withdrawal	May be useful in patients with multiple sclerosis or with allergies to CBZ
Carbamazepine (CBZ)	Acts on Na^+ channels and blocks l-type Ca^2+ channels	Campbell 1966: R, D-B, C-O, 70 patients Killian & Fromm 1968: R, D-B, initially C-O, followed by closed label extension, 24 patients Nicol 1969: R, D-B, modified C-O, followed by closed-label extension	300 – 1000 mg	NNT 1.9 (95% CI 1.4 – 2.8) but loses efficacy with time	Drowsiness, ataxia, headaches, nausea, vomiting, constipation, blurred vision, rash, introduce slowly, drug interactions NNH 3.7 (CI 2.4 – 7.8). For minor side effects	Needs careful monitoring especially if patients are on other drugs
Gabapentin (GBP) and ropivacain (ROP)	Gabapentin: Ca^2+ channel α2δ ligand, elevates GABA. ropivacain: blocks Na^+ channels	Lemos et al. 2008: R, single B, P, 36 patients, 12 GBP, 12 ROP, 12 GBP + ROP followed by open-label 12 months	GBP 300 – 900 mg ROP weekly in trigger area, max 4	Insufficient pain control on ROP alone GBP + ROP: NNT 2.4 (95% CI: 1.46 – 8.49) at 4 weeks	Sedation,ataxia, dizziness, oedema	Short trial, short duration of disease small. Open studies have needed to use much higher doses
Lamotrigine	Acts both on Na^+ and Ca^2+ channels, alters release of glutamate and aspartate	Zakrzewska et al. 1997: R, D-B, C-O, add on 14 patients	200 – 400 mg	Good when added to other AED NNT 2.1 (1.3 – 6.1)	Dizziness, drowsiness, constipation, ataxia, diplopia, irritability, rapid dose escalation leads to rashes	Short trial with no follow-up and no indication if effective as monotherapy. The need for slow escalation precludes it from acute use
Oxcarbazepine (OXC)	Keto derivative of CBZ so same action	Liebel 2001: R, D-B, PG 48 patients vs CBZ Beydoun et al. 2000, 2002: R, D-B, PG, 130 patients, included meta-analysis vs CBZ	300 – 1200 mg	Equal to CBZ	Improved tolerability when compared to CBZ Vertigo, fatigue, dizziness, nausea, hyponatraemia in high doses, no major drug interactions	Effective drug used as primary drug of choice in Scandinavian countries
Clomipramine		Carasso 1979: R*, single–B, P, 18 patients vs amitriptyline	20 – 75 mg	Some improvement	None stated	Very poor quality study, not used
Pimozide	Dopamine receptor antagonist	Lechin et al. 1989: R, D-B, C-O, 48 patients vs CBZ	4 – 12 g	Excellent	Severe side effects Extrapyramidal; tremor, rigidity, memory loss	Side effects limit its use
Proparacaine hydrochloride 0.5% eyedrops	Not entirely clear. May inhibit Na^+ ion fluxes	Kondziolka et al. 1994: R, D-B, C-O, 47 patients	2 drops of 0.5% solution for 20 min	Ineffective	Nil	No clinical use
Sumatriptan	Activation %-HT receptors	Kanai et al. 2006: R, D-B, C-O, 24 patients	3 mg subcutaneous		Transient rise in blood pressure, fatigue, nausea	Effects too short term to be of clinical use
Tocainide	Na^+ channel blocker	Lindstrom & Lindblom 1987: R, D-B, C-O- 12 patients vs CBZ	60 mg/kg	As effective as CBZ	Rash, nausea, paraesthesia, aplastic anemia	Its severe side effects preclude its routine use
Tizanidine	α-adrenoceptor agonist	Fromm 1993: R*, D-B, C-O, 11 patients Vilming et al. 1986: R*, D-B, P, 12 patients vs CBZ	6 – 18 mg	Ineffective	Drowsiness, dizziness, alters liver enzymes	No clinical use

*poor randomization.

AED: Anti-epileptic drug; C-O: Cross-over design; D-B: Double blind; NNH: Number needed to harm; NNT: Number needed to treat; P: Parallel groups, R: Randomized.

Table 2. Drugs used in case series only for trigeminal neuralgia.

Drug daily dosage	Outcome reported in each study	Side effects/withdrawals (no of side effects in reports)	Comments	Ref.
Capsaicin 3 g for 21 – 28 days	6/12 complete, 4/12 partial, 4/12 relapses, 1/5 partial, 4/5 nil or little	Burning sensation (NS)	Rub on the skin, temporary relief in majority, avoid contact with the eye	Fusco et al. 1992 Epstein et al. 1994
Clonazepam 2 – 8 mg	5/7 good result, 13/19 excellent or good, 10/25 excellent, 6/25 good, 64% complete/partial	Lethargy, fatigue, dizziness, personality change (5/5, 4/19, 22/25)	Drowsiness is very severe and dose related. Thromocytopenia can occur	Caccia 1975 Chandra 1976 Court & Kase 1976 Smirne & Scarlato 1997
Felbamate 800 – 1200 mg daily	3/3 improved	Nausea, insomnia, in epilepsy studies can cause aplastic anaemia	Due to potential severe side effects not of clinical use	Cheshire 1995
Leviteracetam 1000 – 4000 mg daily 10 weeks	4/10 good result using a variety of outcome measures	1 drowsy, 1 tiredness, 1 diarrhoea	Efficacy low in severe cases, very good tolerability compared to other AED	Jorns Zakrzewska 2009
Phenytoin 200 – 300 mg	4/4 excellent, 8/20 excellent, 6/20 partial, 4/5 excellent, 1/5 partial	Ataxia, lethargy, nausea, headache, behavioural changes (1/4, NS, NS)	Folate deficiency in prolonged use, gingival hypertrophy, can be used intravenously for immediate effect	Iannone et al. 1958 Braham & Saia 1960 Chinitz et al. 1966
Pregablin 150 – 600 mg daily for 1 year	39/53 had > 50% improvement, 14/53 no response, overall 59% response in 65	19% dizziness, 15% tiredness, 4% headaches, 2% peripheral oedema	Included patients with other facial pains who did less well. Results were not sustained and other AEDs were needed later in both studies.	Obermann et al. 2008 Perez et al. 2009
Valproic acid 600 – 2000 mg	9/20 excellent/good, 4/20 good if used with other drugs 3/20 no response, 4/10 excellent/good, 6/10 poor but if used as add on 10/10 good	Irritability, restlessness, tremor, confusion, nausea (1/20, NS)	Rash and with prolonged use alopecia, weight gain, increase efficacy with addition of baclofen	Peiris et al. 1980 Desai et al. 1991

AED: Anti-epileptic drugs; NS: Not stated.

Figure 3. Clinical features of trigeminal neuropathic pain.

Table 3. Summary of drugs used in neuropathic pain based on a review of the O'Conner and Dworkin guidelines, which could be used in trigeminal neuropathic pain.

Medication class	Daily dose- average -range	Use	Side effects	Comments
Tricyclic antidepressants: nortiptyline	50 mg (25 – 150 mg)	Minimum 6 – 8 weeks nocte	Sedation, dry mouth, weight gain	Improves depression, low cost, use with care in cardiac disease, glaucoma Can use lower doses with good response
SSNRIs: duloxetine	60 mg (30 – 120 mg)	4 weeks twice daily	Nausea	Improves depression, care in those with hepatic or renal problems, taking tramadol
SSNRI: velafaxine	225 mg (75 – 225 mg)	4 – 6 weeks daily	Nausea	Small RCT in atypical facial pain no benefit
Calcium channel blocker: gabapentin	3000 mg (600 – 3600 mg)	3 – 8 weeks three times a day	Sedation,ataxia, dizziness, oedema	Improves sleep, few drug interactions Care in renal dysfunction
Calcium channel blocker: pregablin	600 mg (300 – 600 mg)	4 weeks, twice daily	Dizziness, tiredness, headaches, peripheral oedema	Improves anxiety, sleep Care in renal dysfunction
Topical: 5% lidocaine patch	3 patches for maximum 12 h	12 h at any one time	Local erythema, rash	Only if extraoral pain and allodynia present

RCT: Randomized controlled trial.

Figure 4. Clinical features of burning mouth syndrome.

Table 4. Drugs used in burning mouth syndrome based on table in ref.[97].

Drug/therapy	Daily dose range	Use	Efficacy NNT	Side effects	Comments
Proven in RCTs
Antioxidant alphalipoic acid	200 – 600 mg	Daily for 3 months	In earlier trials NNT 1.6 – 3.3	Nil reported	Several studies from same centre, not all double blind and newer RCT shows no benefit
Clonazepam	1 – 3 mg topical 0.25 – 1 mg systemic	Topically suck for 3 min for 2 weeks Systemic nocte few weeks	Topical 10/16 still some benefit at 6/12 Limited benefit	Nil significant if topical but systemically drowsiness	Topical use reported as RCT for 14 days, open label follow up 6 months Systemic use case reports
Benzydamine topical	0.15% solution 15 ml	3 times daily	Not effective when used in RCT	Nil	High-quality RCT
Capsaicin systemic	0.25% capsule	3 times daily for 1 month	NNT 1 – 2	Gastric pain in 32% increase over time	Poor-quality trial,side effects limit its use
Trazodone	200 mg	Daily	No effect	Drowsiness and dizziness	High-quality RCT not used clinically
Amisulpride Paroxetine Sertraline	50 mg 20 mg 50 mg	Daily dosage for few weeks	All effective no NNT	Mild, non-specific	No placebo control, poor RCT, not used clinically
Commonly used but no RCT
Gabapentin	300 – 2400 mg	3 – 8 weeks 3 times a day	Limited	Ataxia, dizziness, drowsiness, nausea, headache, weight gain	Improves sleep, few drug interactions Care in renal dysfunction
Nortiptyline	20 – 50 mg	Nocte 6 – 8 weeks	May be effective	Sedation, dry mouth, weight gain	Improves depression, low cost, use with care in cardiac disease, glaucoma
Pregablin	100 – 300 mg	4 weeks, twice daily	May be effective	Dizziness, tiredness, headaches, weight gain	Improves anxiety, sleep Care in renal dysfunction

RCT: Randomized controlled trial.

Woda A, Grushka M. Burning mouth syndrome. In: Zakrzewska JM, editors, Orofacial Pain. 1st Edition. Oxford University Press, Oxford; 2009

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