Introduction     Tri-cyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and anti-epileptic drugs (AEDs) are the mainstays of adjuvant therapy for neuropathic pain. This Fast Fact reviews the evidence for the use of AEDs in the treatment of neuropathic pain. For a more in-depth look at gabapentin, pregabalin, and antidepressants for neuropathic pain see Fast Facts #49, 187, 288, and 299. Due to lack of head-to-head data, evidence is presented as numbers needed to treat (NNT) and numbers needed to harm (NNH). For instance, an NNT of 5 for 50% pain reduction means for every 5 patients treated with a drug, only 1 of them would achieve a 50% reduction in pain. All data presented and doses mentioned are for adults and based on investigations of patients with chronic pain. Given the paucity of research about the use of adjuvants for pain management in patients with life-limiting illnesses, many clinicians empirically extrapolate available data to palliative care patients.

Gabapentin is effective in treating central and peripheral neuropathic pain. According to a Cochrane review of the effect of gabapentin on chronic neuropathic conditions (including post-herpetic neuralgia, painful diabetic neuropathy, mixed neuropathic pain), the NNT is 5.8 (4.8-7.2) for moderate benefit. Adverse effects are frequent, but usually tolerable and include drowsiness, dizziness, and edema (1). Gabapentin should be dose adjusted for renal dysfunction and withdrawn gradually to avoid precipitating seizures. Maximum dose is 3,600 mg/day (2). It is being evaluated for migraine treatment and prevention.

Pregabalin is effective in treating peripheral and central neuropathic pain for many patients (3). Its effectiveness increases as the dose approaches 600 mg/day. At a dose of 600 mg/day, the NNT to decrease pain by 50% is: 3.9 (range 3.1-5.1) for post-herpetic neuralgia; 5.0 (range 4.0-6.6) for diabetic neuropathy; and 5.6 (range 3.5-14) for central neuropathic pain. There was no difference in incidence of side effects among participants taking pregabalin vs placebo and no indication of a dose response to side-effects (4). Dosing starts at 150 mg/day in divided doses either twice or three times daily (2).

Carbamazepine is effective for neuropathic pain, specifically trigeminal neuralgia.  A meta-analysis reported that carbamazepine reduced chronic neuropathic pain compared to placebo with NNT of 1.7. However, adverse events occur frequently: NNH = 2.6 (5).  Common side effects include leukocytosis, thrombocytopenia, dizziness, drowsiness, ataxia, nausea/vomiting and blurred vision. Additionally, there is a risk of agranulocytosis, aplastic anemia, and Stevens Johnson syndrome. Laboratory tests (BUN, complete blood count, sodium, liver function tests, urinalysis) and serum drug levels should be checked at baseline and during treatment. Dosing starts at 100-200 mg twice a day and is titrated by 200 mg/day every 3 – 5 days until pain relief is achieved.  Maximum dose is 1,200 mg/day (2).  In general, it is not first-line for general neuropathic pain, but many consider it as a first line agent for trigeminal neuralgia.

Oxcarbazepine is an analogue of carbemazepine which is equally effective at treating trigeminal neuralgia (6) but with fewer side effects (7). Oxcarbazepine can be started at 300 mg twice a day and titrated up by 300 mg/day every 3 days to therapeutic effect. Maximum dose is 2,400 mg/day (2).

Valproic acid was evaluated in a meta-analysis for the treatment of neuropathic pain. There were insufficient data for reliable pooled analysis, and the authors recommend against its use as first line therapy (8). Several small studies (n<60) showed benefit (maximum of 1200 mg/day in divided doses) over placebo in the treatment of diabetic neuropathy (9). However, other studies failed to find an effect (10). Adverse effects include liver function test abnormalities, dizziness, drowsiness, and nausea. Divalproex is a similar medication approved for migraine prevention (11).

Topiramate has not demonstrated convincing efficacy for painful diabetic neuropathy in three studies totaling more than 1200 participants (10).  A subsequent randomized controlled trial of 317 patients with diabetic neuropathy showed a benefit over placebo with a NNT of 6.9. Serious adverse events include convulsion, bradycardia, and syncope (12). Additional adverse effects include sedation, nausea, diarrhea, and metabolic acidosis (2). Dosing starts at 50 mg/day and can be titrated up to 400 mg/day (12). It is being evaluated for migraine prevention and treatment.  

Lacosamide has weak evidence supporting its use.  In a randomized, placebo-controlled study, patients treated with lacosamide (100-400 mg/day) for diabetic neuropathy showed a decrease in baseline pain by 2 or more points on an 11-point scale compared to controls, NNT 10.9 (13,14). Subsequent trials have failed to show similar effects except for a subgroup analysis of 400 mg/day (10).Dosing starts at 50 mg twice daily. Abrupt discontinuation can precipitate seizures (2).

Using other AEDs including phenytoin and levetiracetam to treat neuropathic pain is not supported by clinical research. Although, a single small study (n=92) demonstrated benefit for lamotrigine for HIV-related neuropathy at doses of 200-400 mg daily (14,15).

Summary      TCAs, SNRIs, and the AEDs gabapentin and pregabalin are the best adjuvant analgesics for neuropathic pain. For patients who are intolerant to or who have pain refractory to the above medications, one can consider therapy with carbamazepine, oxcarbazepine, valproic acid, topiramate or lacosamide, keeping in mind they are associated with more side effects and lower rates of efficacy.

References

1. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2011, Issue3, Art No.: CD007938. DOI: 10.1002/14651858.CD007938.pub2
2. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
3. Derry S, Bell RF, et al.  Pregabalin for neuropathic pain in adults.  Cochrane Database of Systematic Reviews 2019; 1: Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub3
4. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews.2009, Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2.
5. Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database of Systematic Reviews.  2011, Issue 1. Art. No.: CD005451. DOI: 10.1002/14651858.CD005451.pub2.
6. Zakrzewska J, Linskey M. Trigeminal Neuralgia. Clinical Evidence. 2009; 3(1207). Retrieved Nov 15, 2011 from http://clinicalevidence.bmj.com/ceweb/conditions/nud/1207/1207.jsp
7. Finnerup NB, et al. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain. 2005; 18:289-305.
8. Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults.Cochrane Database of Systematic Reviews. 2011, Issue 10. Art. No.: CD009183. DOI: 10.1002/14651858.CD009183.pub2.
9. Kochar DK, et al. Sodium valproate for painful diabetic neuropathy:  A randomized double-blind placebo-controlled study. Quarterly J Med. 2004; 97:33-8.
10. Finnerup NB, et al. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010; 150: 573-581.
11. Gallagher RM, Mueller L, Feitag FG.  Divalproex sodium in the treatment of migraine and cluster headaches.  J Am Osteopath Assoc 2002; 102(2):92-94.
12. Raskin P, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004; 63(5):865-73.
13. Rauck RL, et al. Lacosamide in painful diabetic peripheral neuropathy: A phase 2 double blind placebo-controlled study. Clin J Pain. 2007; 23:150-8.
14. Goodyear-Smith F, Halliwell J. Anticonvulsants for neuropathic Pain: gaps in the evidence. Clin J Pain. 2009; 25: 528-536.
15. Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database of Systematic Reviews. 2011, Issue 2. Art. No.: CD006044. DOI: 10.1002/14651858.CD006044.pub3.

Authors’ Affiliations: University of Pittsburgh Medical Center, Pittsburgh, PA.
Conflict of Interest Disclosure: the authors have disclosed no relevant conflicts of interest.
Version History:  First published September 2013. Re-copy-edited by Sean Marks in September 2015; edited again in June 2021 to reflect updates in the published literature.