Anticonvulsants for Analgesia

Family Practice Recertification, July 2015, Volume 33, Issue 7

This month, we will consider what is probably an underutilized class of medications – anticonvulsants – in treating many types of chronic pain syndromes.

In last month’s Pain Perspectives, the “art” of using antidepressants for analgesia in chronic pain was discussed. This month, we will consider what is probably an underutilized class of medications — anticonvulsants – in treating many types of chronic pain syndromes.

As early as the 1950s, reports on the use of medications with anticonvulsant properties for relief of pain began to appear in the literature(1). These medications, however, were more accurately classified as sedatives or tranquilizers, and had little in common with the anticonvulsants that are used today. Early “anticonvulsants” were barbiturates, until the discovery of phenytoin’s properties as a seizure-blocking agent in the 1930s (2). In the 1960s, investigators began to look at carbamazepine as an analgesic agent, particularly in the treatment of facial (3) and headache (4) pain.

The 1970s witnessed the emergence of valproate sodium as an anticonvulsant of interest, with early research indicating some efficacy in its treatment of post-herpetic pain (5). In the late 80s and early 90s, investigators found efficacy for valproate for headache prophylaxis (6), yet results of studies of its utility as a therapeutic agent for other types of pain have not been particularly encouraging (7-9). In comparison to valproate, equivalent efficacy and safety of a new anticonvulsant, topiramate, has been established (10). While widely used in psychiatry for mood stabilization, lamotrigine has been less commonly used for pain management, with a recent Cochrane Review (11) indicating a relative lack of efficacy for the drug as compared to antidepressants and certain other anticonvulsants.

Without a doubt, the anticonvulsants with the strongest evidence-basis for analgesia are gabapentin and pregabalin. Gabapentin has been available since the 1980s, with its efficacies established for treating numerous pain conditions commonly addressed in primary care practice. These conditions include postherpetic neuralgia (12), painful diabetic neuropathy (13), neuropathic pain syndromes considered widely (14), trigeminal neuralgia (15), CRPS (16), and fibromyalgia (17). As an adjunctive agent, the exciting news is that in animal models, gabapentin appears to mitigate opioid-induced hyperalgesia (18). Side effects of gabapentin, however, can be complicated to manage, and may include dizziness, somnolence, peripheral edema, and ataxia/gait disturbance (19).

Most physicians, unfortunately, misunderstand dosing gabapentin. The approach of “start low and go slow” is a prudent one, in that it allows patients to acclimate to some degree to the medication’s side effects. However, for neuropathic pain, the therapeutic goal range for most patients has been established to be in the 1800-3600 mg/day range (20). Far too often in my clinical practice I witness physicians initiating gabapentin therapy at 300 mg/day….and then failing to increase the dosage toward the therapeutic range. A 2013 retrospective study of postherpetic neuralgia patients treated with gabapentin, for example, found a mean daily dosage of only 826 mg (21). Patients may also complain about the necessity of three times daily dosing of gabapentin, although a relatively newly-released once daily form of the drug is now available, and enhanced bioavailability allows for lower dosing to achieve therapeutic effects (22).

Pregabalin has demonstrated empirical support for the treatment of postherpetic neuralgia (23), painful diabetic neuropathy (24), central neuropathic pain (25), fibromyalgia (26), and trigeminal neuralgia (27). Side effects are similar to those of gabapentin, including dizziness, somnolence, and peripheral edema (28). When directly compared to gabapentin, safety and efficacy were similar for both drugs in the treatment of painful diabetic neuropathy (29). Issues of appropriate dosing and pharmacogenomics need to be taken into consideration when comparing relative efficacies. And, of course, should it become necessary to discontinue an anticonvulsant, it should be done slowly — as abrupt cessation can result in seizures (30).

For additional hands-on training on using anticonvulsants to treat chronic pain, readers are encouraged to attend PAINWEEK — as this is a topic regularly covered by thought leaders in the field. Until next month, let’s continue to expand our primary care pain management armamentaria!


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2) Brodie MJ. Antiepileptic drug therapy: the story so far. Seizure 2010;19:650-655.

3) Kiluk KI, Knighton RS, Newman JD. The treatment of trigeminal neuralgia and other facial pain with carbamazepine. Mich Med. 1968;67:1066-1069.

4) Kienast HW, Boshes LD. Clinical trials of carbamazepine in suppressing pain. Headache 1968;8:1-5.

5) Raftery H. The management of post herpetic pain using sodium valproate and amitriptyline. Ir Med J. 1979;72:3:99-401.

6) Mathew NT, Ali S. Valproate in the treatment of persistent chronic daily headache. An open label study. Headache 1991;31:71-74.

7) Drewes AM, Andreasen A, Poulsen LH. Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study. Paraplegia 1994;32:565-569.

8) Martin C, Martin A, Rud C, Valli M. Comparative study of sodium valproate and ketoprofen in the treatment of postoperative pain. Ann Fr Anesth Reanim. 1988;7:387-392.

9) Hardy JR, Rees EA, Gwilliam B, Ling J, Broadley K, A'Hern R. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain Symptom Manage. 2001;21:204-209.

10) Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V. Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache 2006;46:642-648.

11) Wiffen PJ, Derry S, Moore RA. Lamotrigine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2013;12:CD006044.

12) Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837-1842.

13) Backonja MM. Gabapentin monotherapy for the symptomatic treatment of painful neuropathy: a multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus. Epilepsia 1999;40 Suppl 6:S57-59.

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15) Cheshire WP Jr. Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain. 2002;3:137-142.

16) Mellick GA, Mellick LB. Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil. 1997;78:98—105.

17) Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56:1336-1344.

18) Stoicea N, Russell D, Weidner G, et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharmacol. 2015;6:104.

19) Fan H, Yu W, Zhang Q, et al. Efficacy and safety of gabapentin 1800 mg treatment for post-herpetic neuralgia: a meta-analysis of randomized controlled trials. J Clin Pharm Ther. 2014;39:334-342.

20) Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25:81-104.

21) Johnson P, Becker L, Halpern R, Sweeney M. Real-world treatment of post-herpetic neuralgia with gabapentin or pregabalin. Clin Drug Investig. 2013;33:35-44.

22) Chen C, Cowles VE, Sweeney M. The intestinal absorption mechanism of gabapentin makes it appropriate for gastroretentive delivery. Curr Clin Pharmacol. 2013;8:67-72.

23) Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003;60:1274-1283.

24) Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004;63:2104-2110.

25) Vranken JH, Dijkgraaf MG, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 2008;136:150-157.

26) Owen RT. Pregabalin: its efficacy, safety and tolerability profile in fibromyalgia syndrome. Drugs Today (Barc). 2007;43:857-863.

27) Obermann M, Yoon MS, Sensen K, Maschke M, Diener HC, Katsarava Z. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalalgia 2008;28:174-181.

28) Zhang SS, Wu Z, Zhang LC, et al. Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. Acta Anaesthesiol Scand. 2015;59:147-159.

29) Devi P, Madhu K, Ganapathy B, Sarma G, John L, Kulkarni C. Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian J Pharmacol. 2012;44:51-56.

30) Barrueto F Jr, Green J, Howland MA, Hoffman RS, Nelson LS. Gabapentin withdrawal presenting as status epilepticus. J Toxicol Clin Toxicol. 2002;40:925-928.