Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2376
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4936-4945
Copyright © 2005 by The Endocrine Society
Use of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy
Aaron Vinik
Diabetes Research Institute, Norfolk, Virginia 23510
Address all correspondence and requests for reprints to: Dr. Aaron Vinik, Diabetes Research Institute, 855 West Brambleton Avenue, Norfolk, Virginia 23510. E-mail: vinikal{at}evmsmail.evms.edu.
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Abstract
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Context: Up to 25% of individuals with diabetes develop painful diabetic neuropathy, suffering spontaneous pain, allodynia, hyperalgesia, and other unpleasant symptoms. Decreased physical activity, increased fatigue, and mood and sleep problems may result.
Evidence Acquisition: A MEDLINE search was conducted, limiting searching to double-blind, randomized, controlled trials (1978 to present) of antiepileptic drugs (carbamazepine, gabapentin, pregabalin, topiramate, and lamotrigine) used in the treatment of chronic neuropathic pain.
Evidence Synthesis: The most important aspect of treatment is targeted at modification of the underlying disease. However, approaches to symptomatic pain control are essential and include multiple drug classes. Tricyclic antidepressants, including imipramine, nortriptyline, and amitriptyline, have been the mainstays of treatment, but anticholinergic effects, such as dry mouth, blurring of vision, constipation, orthostatic hypotension, and cardiac arrhythmias, as well as other adverse effects, often limit their use. Other treatments include capsaicin, clonidine, acupuncture, and electrical stimulation, suggesting that there is no single effective treatment. First-generation antiepileptic drugs have been shown to be effective in neuropathic pain. The evidence supporting the use of a new generation of antiepileptic drugs in painful diabetic neuropathy is reviewed.
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Introduction
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PAINFUL DIABETIC NEUROPATHY (PDN) is one of the most common forms of neuropathic pain (1), and pain is the most troublesome symptom of diabetic neuropathy (2). Of the more than 14 million people in the United States with diabetes mellitus, nearly a quarter suffer from PDN (1), and up to 50% develop peripheral neuropathies after 25 yr of follow-up (3). Risk factors for diabetic neuropathy itself have not yet been ascertained, but may include increased age, duration of diabetes, lipotoxicity and glucotoxicity, genetic susceptibility, inflammation, and oxidative stress (1, 4, 5).
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Clinical Symptoms
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The International Association for the Study of Pain defines neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction in the nervous system" (6). The diagnosis of neuropathic pain secondary to diabetic neuropathy requires a comprehensive history and physical and neurological examinations (7). Patients should be asked the quality (e.g. burning, shooting, or electric), intensity, and duration of spontaneous pain as well as its location (8). Pain typically occurs symmetrically in the feet and ankles (i.e. glove and stocking distribution) (9). Patients may also have dysesthesias and paresthesias, such as crawling, itching, numbness, and tingling (8). Sensory loss may also be reported.
Pain may also be induced by touch, and a careful neurological examination can map out regions of allodynia, hyperpathia, and hyperalgesia (8). Pain quality and intensity can be estimated with the Neuropathic Pain Scale, the Neuropathic Pain Questionnaire, and other scales (8). An assessment of global function, sleep, psychological comorbidity, and other issues should be undertaken to determine the effect of diabetic neuropathy on the patient’s quality of life, using a neuropathy-specific tool such as the Norfolk QOL-DN (10).
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Differential Diagnosis
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Diagnosis of PDN requires the presence of a neuropathy consistent with diabetes as well as the exclusion of other possible etiologies of neuropathy. The differential diagnosis is vast, including alcoholic, idiopathic, nutritional, and many other types of neuropathy (Table 1
). Nerve conduction studies and electromyography can assist in the description and objective confirmation of the neuropathy. Nerve conduction studies are, however, best suited to rule out the other causes of neuropathy or to identify additional neuropathies (4). Nerve biopsy, although usually not required, can reveal the involvement of unmyelinated fibers, which are not routinely evaluated by electrophysiological tests (11). More recently, neuropathy associated with changes in intraepidermal nerve fiber density and dendritic length has been demonstrated in patients with impaired glucose tolerance (12), diabetes for more than 5 yr (13), and the dysmetabolic syndrome (14).
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Classification of Diabetic Neuropathy
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Clinical types of diabetic neuropathy can be classified into groups, although patients may have more than one type (Fig. 1 and Table 2) (4). PDN may result from several varieties of diabetic neuropathy, the most common of which is distal sensory neuropathy. PDN can be further divided as acute or chronic and as stimulus independent or stimulus evoked (Table 3) (4).
The acute sensory neuropathy syndrome presents within the first 6 months of the diagnosis of diabetes. It can be sporadic, induced by periods of metabolic instability such as ketoacidosis, poor glycemic control, or fluctuating blood glucose levels, and also is commonly seen with the introduction of insulin to improve glycemic control. Although symptoms can be severe and are similar to those of the chronic variety, it nonetheless resolves spontaneously. In contrast, the chronic variety increases and decreases in intensity, but remains for years. The symptoms are for the most part patient specific, but some are common to all patients, such as hyperesthesia, burning pain, stabbing or shooting electric-type pains, and allodynia. All these symptoms are worse at night (4).
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Psychosocial Impact
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Diabetic neuropathy pain is a difficult to manage clinical problem (15). It is often associated with mood and sleep disturbances (16), and patients with PDN are more apt to seek medical attention than those with other types of diabetic neuropathy (17). Patients may also complain of decreased physical activity and mobility, increased fatigue, and negative effects on their social lives (1). In a recent double-blind, placebo-controlled study, it was found that gabapentin, in addition to providing significant pain relief, markedly improved quality of life measures, including sleep and vitality, in patients with PDN (18). More recently, it has been shown that pregabalin improved mean sleep interference scores, mood, and tension-anxiety components of the Profile of Mood States (POMS) while reducing pain, compared with placebo (19). These data support anecdotal reports that medications indicated for seizure treatment also have a role in pain relief as well as in the enhancement of quality of life.
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Pathophysiology
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The most common type of diabetic neuropathy is distal symmetric polyneuropathy, which may affect large and/or small fibers and may be either sensory or motor (4). The major neurotransmitter in small unmyelinated C fibers is substance P, and those of A
fibers, such as glutamate, act on Na+ channels. Thus, capsaicin, which depletes substance P, is usually effective for C fiber pain, whereas agents that correct Na+ channelopathy improve large fiber function (4). PDN is caused by the involvement of small nerve fibers, which may be affected without objective clinical findings, such as decreased peripheral reflexes or abnormalities, on routine electrophysiological studies (4). Small fiber neuropathies may manifest as a number of different clinical symptoms, including allodynia, burning pain, defective warm thermal sensation, and defective autonomic function, e.g. decreased sweating, dry skin, and impaired vasomotor control (4).
Peripheral neuropathic pain is differentiated from other types of pain by injury or loss of primary afferent nerve fibers (i.e. deafferentation). Allodynia, hyperalgesia, and spontaneous pain may be related to ectopic nerve impulses or abnormal expression of neurotransmitters and their receptors and ion channels (8). Multiple mechanisms related to hyperglycemia may contribute to the pathogenesis of diabetic neuropathy (Fig. 2) (4). All these mechanisms represent potential therapeutic targets for patients with PDN. In addition, insulin resistance is an atherogenic state, contributing to the development of neuropathy through microvascular insufficiency. During the early course of introduction, insulin itself can produce a self-limiting insulin neuritis that is painful, but intensive treatment of critically ill patients with insulin reduces the development of neuropathy (20, 21).
Repeated or strong exposure of nerve terminals to chemical substances released in somatic tissues by noxious stimuli may sensitize nociceptors. These chemical substances may include prostaglandins, bradykinin, serotonin, and histamine. Sensitized nociceptors become more responsive to previously effective stimuli. The response is an increase in discharge and a lower threshold. In addition, they may become responsive to new forms of stimulation.
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Treatment
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Treatment of PDN rests on a two-pronged approach: modification of the underlying disease and control of pain symptoms (15). Disease modification includes tight glycemic control, which in one study reduced the risk of development of clinical diabetic neuropathy in patients with insulin-dependent diabetes by as much as 62% (22). The maintenance of ideal body weight and normal lipid levels is also fundamental to the prevention of diabetic neuropathy. Experimental therapies such as aldose reductase inhibitors (23), 
-lipoic acid (24), cilostazol (25), 
-linolenic acid (26), prostaglandins I2 and E1 (25), N-methyl carnitine (25), and nerve growth factor (27) may also play a role in the prevention or treatment of diabetic neuropathy. Recognition of the clinical symptomatology produced by the various pathogenic mechanisms described above will ultimately provide a logical basis for treatment selection (4). Research suggests that there are defects in several control systems, which may warrant a multiple treatment strategy (28).
Evidence that the quality of pain is influenced by affective and cognitive processes and the acceptance of the Melzack Gate Control model of pain (29) have led to an increased role for psychological intervention in chronic pain management (30). Psychological treatments, such as biofeedback, cognitive-behavioral therapy, hypnosis, and operant behavioral interventions, may be considered in addition to medications, although clinical trials of psychological intervention in patients with diabetic neuropathy are lacking (30).
The wide variety of medical therapies used to treat PDN attests to the lack of an ideal treatment (15). Amitriptyline is prescribed for diabetic neuropathy (9), but it is associated with anticholinergic side effects, such as orthostatic hypotension and possible cardiac arrhythmias (15). Contraindications to amitriptyline and other tricyclic antidepressants (TCAs) include significant cardiac conduction disease, long QT syndrome, myocardial infarction within 6 months, and ventricular arrhythmias or frequent premature ventricular contractions (15). The elderly, often affected by diabetic neuropathy, are at particular risk of such adverse effects of TCAs as balance problems and cognitive impairment (8). Patients over 40 yr of age should have a screening electrocardiogram before starting these medications (8).
Other commonly used drug classes include analgesics (local, simple, and narcotic), antiarrhythmics, and narcotics (15). Based on positive results from randomized, controlled trials and the expert clinical opinion of members of the faculty of the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain, recommendations for first-line medications for neuropathic pain include gabapentin, 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, and TCAs (8).
Consideration of the safety and tolerability of different therapies is important in avoiding adverse events, a common result of treatment of neuropathic pain. Dosages must be titrated based on positive response, treatment adherence, and adverse events (8). A useful index is a low score (close to 1) of the NNT (number needed to treat for success) and a high score (>10) for the NNH (number needed to harm). A value of less than 1 for the NNT/NNH ratio suggests a good and safe drug. A valuable assessment tool for evaluating the response of patients with diabetic neuropathy to therapies is the Norfolk QOL Tool (31).
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Antiepileptic Drugs
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Antiepileptic drugs (AEDs) have a long history of effectiveness in the treatment of neuropathic pain, dating back to case studies of the treatment of trigeminal neuralgia with phenytoin in 1942 and carbamazepine in 1962 (32). Since 1993, nine new AEDs (felbamate, gabapentin, pregabalin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide) have received Food and Drug Administration (FDA) approval for the adjunctive treatment of partial seizures (33) (Table 4). Three of these drugs have also been approved for generalized seizures (felbamate, lamotrigine, and topiramate) and three for monotherapy (felbamate, lamotrigine, and oxcarbazepine) (33). Principal mechanisms of action include sodium channel blockade (felbamate, lamotrigine, oxcarbazepine, topiramate, and zonisamide), potentiation of -aminobutyric acid activity (tiagabine and topiramate), calcium channel blockade (felbamate, lamotrigine, topiramate, and zonisamide), antagonism of glutamate at N-methyl-D-aspartate receptors (felbamate), or -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (felbamate, topiramate) (Fig. 3) (33). Although the mechanisms of action of gabapentin, pregabalin, and levetiracetam remain to be fully determined, evidence suggests they act on subunits of voltage-gated calcium channels. An understanding of the mechanisms of action of the various drugs leads to the concept of rational polytherapy, where drugs with complementary mechanisms of action can be combined for synergistic effect. For example, one might choose a sodium channel blocker such as lamotrigine to be used with a glutamate antagonist such as felbamate. Furthermore, a single drug may possess multiple mechanisms of action, perhaps increasing its likelihood of success (e.g. topiramate). If pain is divided according to its derivation from different nerve fiber types (e.g. A vs. C fiber), spinal cord or cortical, then different types of pain should respond to different therapies (Fig. 3).
In addition to providing efficacy against epilepsy, these new AEDs may also be effective in neuropathic pain. For example, spontaneous activity in regenerating small-caliber primary afferent nerve fibers may be quelled by sodium channel blockade, and hyperexcitability in dorsal horn spinal neurons may be decreased by the inhibition of glutamate release, two mechanisms of action possessed by the AED lamotrigine (34, 35). In addition, the wind-up phenomenon caused by nerve injury and the kindling that occurs in hippocampal neurons in patients with mesial temporal sclerosis both enlist activation of N-methyl-D-aspartate receptors (36, 37), which can be affected by felbamate (33). The evidence supporting the use of AEDs for the treatment of PDN continues to evolve (37). Patients who have failed to respond to one AED may respond to another or to two or more drugs in combination (8).
Although it would be preferable to rely on FDA-approved medications for the treatment of PDN, no drugs have yet received an indication for this purpose. As shown in Table 5, only a few drugs, including two AEDs, have received FDA approval for the treatment of chronic neuropathic pain syndromes (8). Carbamazepine has FDA approval for the treatment of trigeminal neuralgia and is effective in controlling the lightning pain of PDN (38, 39), and both gabapentin and lidocaine (5%) patch are approved for postherpetic neuralgia (8).
Study design may also affect the results of clinical trials. For example, topiramate was effective in a recent, randomized, placebo-controlled trial of diabetic neuropathic pain, but was ineffective in three others (40, 41, 42).
The results of published AED trials for the treatment of painful diabetic neuropathy are summarized below and in Table 6.
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Carbamazepine
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Carbamazepine is FDA approved for trigeminal neuralgia and may also be appropriate for PDN (8, 38). In a double-blind, 6-wk, placebo-controlled, crossover trial of 30 patients (21 women and nine men; mean age, 54.2 yr), carbamazepine (daily dose, 
600 mg) relieved sensory symptoms in 28 of 30 patients (93%) with diabetic neuropathy, which was superior to the results with placebo (39). Sensory symptoms evaluated included muscular pains (26 patients), shooting pains (23 patients), burning (19 patients), numbness (19 patients), cutaneous hyperalgesia (15 patients), cramps (10 patients), and tingling (five patients). Two patients withdrew from the study because of rash (39).
In another early, double-blind, placebo-controlled, crossover trial, 40 patients (30 women and 10 men; mean age, 56.4 yr) received either carbamazepine (200 mg/d) or placebo for 1 wk and reported their pain using a 10-cm analog scale (43). Carbamazepine provided significant relief of diabetic peripheral neuropathy pain compared with placebo on d 10 and 14 (P < 0.05). Observers also noted a statistically significant decrease in pain in favor of carbamazepine. Adverse events occurred in 25 of the patients treated with carbamazepine compared with only two treated with placebo (43).
More recently, 200 mg carbamazepine (1.5 tablets/d for 2 wk and 3 tablets/d for 2 wk) was compared with 10 mg nortriptyline/0.5 mg fluphenazine (3 tablets/d for 2 wk and 6 tablets/d for 2 wk) in a double-blind, randomized, crossover, double-placebo trial involving 16 patients with diabetic peripheral neuropathy (11 men and five women; mean age, 43.1 yr in the nortriptyline group and 51.5 yr in the carbamazepine group) (44). One patient was excluded because of upper gastrointestinal bleeding due to alcoholic gastritis and another because of lack of adherence. Carbamazepine reduced pain by 28.7% in the first 2 wk and by 49% in the second 2 wk compared with baseline values (P < 0.001 at wk 4). Nortriptyline-fluphenazine reduced pain by 38.2% in the first 2 wk and by 66.6% in the second 2 wk compared with baseline values (P < 0.001). However, there was no statistically significant difference between treatments. Adverse events were more common with nortriptyline/fluphenazine than with carbamazepine (44).
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Gabapentin
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One hundred sixty-five patients with PDN participated in an 8-wk, multicenter, double-blind, randomized, placebo-controlled trial of gabapentin (900–3600 mg/d) (16). Gabapentin-treated patients had significantly lower mean daily pain scores (6.4 baseline/3.9 end point vs. 6.5 baseline/5.1 end point; P < 0.001) and significant improvement of all secondary efficacy parameters, which included mean sleep interference (P < 0.001); total score on the Short Form McGill Pain Questionnaire (SF-MPQ; P < 0.001); the Visual Analog Scale (VAS) component of the SF-MPQ (P < 0.001); the Present Pain Intensity component of the SF-MPQ (P < 0.001); SF-36 Quality of Life questionnaire components of bodily pain (P = 0.01), mental health (P = 0.03), and vitality (P = 0.001); as well as the POMS components of anger-hostility (P = 0.02), vigor/activity (P = 0.01), fatigue/inertia (P = 0.01), and total mood (P = 0.03) (16). Gabapentin was significantly superior to placebo in pain control, beginning at wk 2 and continuing through wk 8, and significantly reduced sleep interference, beginning at wk 1 and continuing through wk 8. The most common adverse events with gabapentin were dizziness and somnolence (16).
In another study of PDN, gabapentin was found to be equivalent to amitriptyline (9). The total number of patients experiencing any adverse effect was similar in the two groups (18 gabapentin patients and 17 amitriptyline patients). Weight gain was the only adverse effect that was statistically different between the two groups, occurring in six patients receiving amitriptyline and none of those receiving gabapentin (P = 0.01) (9).
Gabapentin has the additional benefit of improving sleep (16), which is often compromised in patients with chronic pain (8). However, one reservation regarding prescribing gabapentin for PDN is a case report that suggests that gabapentin may induce a sensory polyneuropathy (45). Over the long term, it is known to produce weight gain, which may complicate diabetes management (46).
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Pregabalin
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A randomized, double-blind, placebo-controlled, multicenter study evaluated the effectiveness of pregabalin in a fixed dose with an open-label extension in alleviating pain associated with PDN. One hundred forty-six patients were randomized to receive placebo (n = 70) or pregabalin (n = 76) in a fixed dose of 300 mg/d (19). Patients were required to have pain of 1- to 5-yr duration, a pain score on the SF-MPQ of more than 40 mm VAS, and an average daily pain score of more than 4 on an 11-point numerical scale. Pregabalin produced significant improvements for pain scores within 1 wk of treatment (P < 0.01), which persisted for the 8 wk of the study (P < 0.01). For the patient global impression of change, there was a 67% improvement vs. 39% in patients given placebo (P = 0.001). Furthermore, 40% of patients receiving pregabalin reported a 50% or greater reduction in pain compared with 14.5% of the placebo group (P = 0.001) (19).
Secondary measures that improved included a reduction in mean sleep interference scores on the SF-36 Bodily Pain subscale (P < 0.0001), total SF-MPQ score (P < 0.05), and total mood disturbance and tension-anxiety components of the POMS (P < 0.03) (19). In this respect, the data appear to be not unlike the early reports on gabapentin. Unfortunately, the study was limited to 8 wk, and there are no long-term data on the durability of the effect.
A 12-wk flexible- vs. fixed-dosage study of pregabalin included 249 patients with PDN (mean duration of diabetes, 13.5 yr, and of PDN, 4.7 yr) plus 89 patients with postherpetic neuralgia. Patients in the flexible-dosage group received 150 to 600 mg/d pregabalin, with an average dosage during the last 8 wk of 457 mg/d. Patients in the fixed-dosage group received 600 mg/d pregabalin. The responder rate (with response defined as 
50% pain relief) was 48.2% for the flexible-dosage group, 52.3% for the fixed-dosage group, and 24.2% for the placebo group (47).
Side effects in these two studies of pregabalin were those expected and included dizziness and somnolence, which were dose dependent, and peripheral edema. Other side effects included headache, infection, and dry mouth (19, 47).
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Lamotrigine
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In the first published study of lamotrigine for the treatment of PDN, 15 patients (eight men and seven women; mean age, 53 yr) received lamotrigine, titrated from 25–400 mg/d over 6 wk (48). Among the 13 patients taking 400 mg/d lamotrigine who completed the study, mean spontaneous pain, as measured on the VAS, decreased from 49 ± 8 to 20 ± 8.6 at the end of the study (P = 0.001). A significant decrease in mean pain intensity occurred during the second study week, when patients were taking 50 mg/d lamotrigine (P < 0.05) (48).
Additional data analysis revealed two patient populations; nine patients had a significant decrease in their numerical pain scale score (6.2 ± 0.4 to 2.4 ± 0.5; P < 0.0001), and four had no change in their numerical pain scale score (8.1 ± 0.7 to 8.4 ± 0.7). Two weeks after the end of the study, pain was still significantly reduced, suggesting a lasting effect of lamotrigine. Two patients discontinued the study because of adverse effects; one complained of dizziness and ataxia while taking 400 mg/d lamotrigine, and the other developed a rash after the first dose of lamotrigine. Symptoms resolved in both patients within 1 wk after discontinuing lamotrigine (48).
In an 8-wk, double-blind, randomized, placebo-controlled study of 59 patients with PDN, numerical pain scale scores decreased from baseline significantly more with 400 mg/d lamotrigine than with placebo (6.4 to 4.2 vs. 6.5 to 5.3, respectively; P < 0.001) (34). Significant pain reduction began at wk 6, when the patients were taking 200 mg/d lamotrigine (P < 0.001). Pain reduction persisted during the next 2 wk, when lamotrigine was increased to 300 mg/d and then to 400 mg/d. During the last 3 wk of treatment, 12 patients receiving lamotrigine, compared with only five placebo recipients, had a 50% reduction in pain (P = 0.05). When lamotrigine and placebo were discontinued at the end of the study, pain intensity was similar in the groups. Two patients receiving lamotrigine developed a rash that resolved after lamotrigine was discontinued. The number of patients reporting adverse events was similar in both groups (34).
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Phenytoin
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Forty outpatients (23 men and 17 women; mean age, 49.9 yr) with significant pain due to diabetic sensory motor neuropathy received either placebo or phenytoin (100 mg, three times daily) for 2 wk, followed by a 1-wk washout period before crossing over to the other treatment (49). All patients in both groups, those receiving phenytoin first and those receiving placebo first, had pain, and most had paresthesias. Thirty-eight patients (95%) completed the trial. In the first group, pain improved in 14 of 20 patients (70%) taking phenytoin compared with five of 20 patients (25%) receiving placebo (P < 0.02). In the second group, pain improved in 14 of 18 patients (78%) taking phenytoin, compared with five of 18 patients (28%) receiving placebo (P < 0.01). Nine patients (24%) obtained complete relief with phenytoin compared with one patient receiving placebo. Paresthesias were also significantly improved in the phenytoin groups (49).
In an open-label study of treatment with phenytoin (100 mg, three or four times a day) in 60 patients (38 men and 22 women) with PDN, 41 (68%) had an excellent response and 10 (17%) had a fair response within 48–96 h (49). Nine patients (15%) did not improve, and no patient had an increase in neuropathic symptoms. Neuropathy severity did not predict the response. All female patients responded to therapy. Two patients discontinued the drug because of rash (50).
A placebo-controlled, double-blind, randomized, crossover trial (3 wk on each drug) of 12 patients with insulin-dependent diabetes that evaluated pain, numbness, and "pins and needles" failed to show any benefit from phenytoin, even when pain was analyzed separately. Phenytoin also produced significantly elevated glucose levels (51).
The risk of peripheral neuropathy with phenytoin is well known and appears to be related to duration of use and increased serum levels. This potential adverse event may be an additional reason to avoid phenytoin in patients with peripheral neuropathy (52).
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Valproic acid
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A 4-wk, double-blind, randomized, placebo-controlled study of valproic acid (1200 mg/d) in 52 patients with diabetic neuropathy demonstrated significantly improved pain scores (P < 0.05), but showed no significant changes in electrophysiological measurements (17).
A double-blind, randomized, placebo-controlled, crossover study of 31 patients (15 with diabetic polyneuropathy and 16 with nondiabetic polyneuropathy) failed to demonstrate any statistical superiority of valproic acid over placebo on any outcome measure (53).
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Topiramate
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Using identical methods, three simultaneous, placebo-controlled studies of topiramate for PDN did not show significance (42). An independent, yet concurrent, study of the analgesic and metabolic effects was carried out as a double-blind, placebo-controlled, multicenter, randomized trial in 323 patients with PDN and pain scores of more than 40 mm on a VAS of no pain to worst possible pain. Over 12 wk, topiramate (n = 214) was titrated to 400 mg/d vs. placebo (n = 109). Short-acting analgesics were permitted only during the first 6 wk. Twelve weeks of topiramate therapy reduced pain scores from 68 to 46.2 mm, whereas scores for patients taking placebo went from 69.1 to 54 mm (P = 0.038). Fifty percent of patients taking topiramate vs. 34% taking placebo responded to treatment, defined as a more than 30% reduction in pain score (P < 0.004). Topiramate also reduced worst pain intensity vs. placebo (P < 0.003) as well as sleep disruption scores (P < 0.02) (41).
Side effects of topiramate included diarrhea, loss of appetite, and somnolence. Topiramate also reduced body weight (–2.6 vs. +0.2 kg for placebo; P < 0.001). This beneficial effect of topiramate on weight appears to be accompanied by other metabolic effects. However, dosing must be started low and increased slowly. The initial dose should be given at night, starting with 25 mg and escalating by 25 mg to 50 mg/d after 4 wk. Generally, not more than 100 mg is needed in the diabetic population (41). In a small within-subjects study, Vinik et al. (40) reported that topiramate relieves symptoms of PDN and improves conduction amplitudes as well as causes an increase in intraepidermal nerve fibers. This was in addition to the lowering of blood pressure, cholesterol, and hemoglobin A1c. Thus, of all the AEDs, it would seem that topiramate may be one of the few to show potential for altering the basic biological nerve dysfunction in diabetic neuropathy (40).
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NNT vs. NNH
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Physicians prescribing pain medication for patients with diabetic neuropathy should consider the following: 1) the number of patients needed to treat to obtain a beneficial result (NNT); and 2) the number of patients "needed" to treat before adverse events (harm) occur (NNH). These values have been calculated and are shown in Table 7. Studies of effectiveness in neuropathic pain, but not necessarily diabetic neuropathic pain, suggest that other antiepileptic drugs, such as oxcarbazepine (54), tiagabine (55), and zonisamide (56), may be effective for PDN.
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Conclusion
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PDN is a common cause of neuropathic pain and produces significant morbidity. Successful treatment can be difficult and relies on modification of the underlying disease with maintenance of euglycemia and normal body weight and lipid levels as well as a multitude of symptomatic therapies. TCAs remain the mainstay of therapy for many patients. Advances in our understanding of the pathophysiology of PDN are providing potential new avenues for prevention and treatment targeted at neuronal transmission (antiepileptics, capsaicin, and lidocaine), fatty acid production (-linolenic acid), inflammation (nonsteroidal antiinflammatory drugs and prostaglandins), antioxidants (-lipoic acid), the polyol pathway (aldose reductase inhibitors), ß2 protein kinase C, and others. The physician’s selection of pain medication must be individualized, with special attention to a particular patient’s susceptibility to side effects, hepatic and renal function, and potential drug-drug interactions. Double-blind, randomized, controlled trials reveal that certain antiepileptic drugs, such as carbamazepine, gabapentin, pregabalin, topiramate, and lamotrigine, measurably decrease symptoms and are well tolerated. Evidence from case reports and studies of chronic neuropathic pain suggest that a wide variety of antiepileptic drugs may also be effective in diabetic neuropathic pain. Multiple mechanisms of action, including sodium channel blockade, -aminobutyric acid potentiation, glutamate antagonism, calcium channel blockade, and others yet to be described, may be responsible for the antinociceptive properties of antiepileptic drugs. Continuing research into the underlying pathophysiology of PDN will ultimately lead to more effective and better-tolerated therapies.
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Footnotes
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This article was written with the assistance of IMPRINT Publication Science, which is supported by a grant from GlaxoSmithKline. The authors receive no honoraria, and GlaxoSmithKline is not privy to any review of the material before submission.
First Published Online May 17, 2005
Abbreviations: AED, Antiepileptic drug; NNH, number needed to harm; NNT, number needed to treat for success; PDN, painful diabetic neuropathy; POMS, Profile of Mood States; SF-MPQ, Short Form McGill Pain Questionnaire; TCA, tricyclic antidepressant; VAS, Visual Analog Scale.
Received December 6, 2004.
Accepted May 11, 2005.
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Abstract
Introduction
