Pain Management Forum Report
American Academy of Neurology
San Diego, California

New Treatment Options for the Management of Pain with the Use of Anticonvulsants

This report was reviewed for medical and scientific accuracy by Stephen D. Silberstein, MD , Professor of Neurology and Director, Jefferson Headache Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.


The 52nd Annual Meeting of the American Academy of Neurology

Stephen D. Silberstein, MD, FACP, Professor of Neurology, Jefferson Medical College of Thomas Jefferson University; Director, Jefferson Headache Center at Thomas Jefferson University, Philadelphia, Pennsylvania

Headache, pain syndromes, and their management received prominent attention among the 1,200 scientific presentations at the 52nd Annual Meeting of the American Academy of Neurology (AAN), April 29-May 6, 2000. These presentations coincided with the release of the multidisciplinary US Headache Consortium's Evidence-based Guidelines for Migraine, the result of combined efforts of the American Academy of Family Physicians, the American Academy of Neurology, the American Headache Society, the American College of Emergency Physicians, the American College of Physicians, the American Osteopathic Association, and the National Headache Foundation. The guidelines review migraine diagnosis, treatment, and prevention. The evidence-based guidelines are available at the AAN web site ( and the Neurology web site (

According to an editorial in Neurology (54th ed., 2000, p.1553) by Dr. Stephen Silberstein and Dr. Jay Rosenberg, migraine represents a significant public health problem, affecting 13 percent of the population, an estimated 28 million Americans (American Migraine Study II, National Headache Foundation, February 2000). Migraines affect 18 percent of women and six percent of men. Seventy percent of headache sufferers show hereditary influence. Headaches are responsible for over ten million physician visits a year, and account for over $13 billion a year in indirect costs due to decreased productivity and days lost from work. Many migraine sufferers never receive an accurate diagnosis or adequate care. There were multiple courses at the AAN on headache and pain related topics, four platform discussions, and six poster sessions.

Papers presented at the meeting1 discussed a wide variety of pain syndromes, including diabetic peripheral neuropathy, hemicrania continua, menstrually associated migraine, pain in amyotrophic lateral sclerosis, painful tics in Tourette's syndrome, trigeminal neuralgia, and complex regional pain syndrome. Pain types assessed in trials included migraine (acute and preventive), menstrually associated migraine, and painful diabetic neuropathy. Although less common than headache, diabetic neuropathy serves as a model for neuropathic pain syndromes. The International Association for the Study of Pain defines neuropathic pain as "initiated or caused by a primary lesion or dysfunction in the nervous system."

Clinicians have been using anticonvulsants for neuropathic pain-and to a lesser extent, headache-for more than 50 years. They are being increasingly recommended for migraine prevention and the treatment of neuropathic pain because of open-label and placebo-controlled, double-blind trials that show them to be effective.

The anticonvulsant activity of most antiepileptic drugs is thought to be due to a state-dependent blockade of voltage-dependent Na+ or Ca2+ channels, or an ability to enhance the activity of g-aminobutyrate (GABA) at GABAA receptors (Handbook of Epilepsy, Lippincott-Raven, Philadelphia, PA, 1997, p.188). Topiramate can also influence the activity of the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate subtype of glutamate receptors and inhibit some isoenzymes (CA-II and CA-IV) of carbonic anhydrase.

Carbamazepine has been used for the lancinating pain of trigeminal neuralgia; phenytoin (Dilantin®), gabapentin (Neurontin®), and topiramate (Topamax®) are also useful. With their widespread use for pain disorders and mania, some have suggested calling them neuromodulators. Two drugs classified as anticonvulsants-divalproex sodium extended release (Depakote® ER) and topiramate-were tested for migraine prophylaxis. Memantine, a NMDA receptor antagonist; pregabalin, an investigational anticonvulsant; and venlafaxine (Effexor®), an antidepressant, were evaluated for symptoms of painful diabetic neuropathy. Naratriptan (Amerge®) was studied for short-term prophylaxis for menstrually associated migraine; rizatriptan (Maxalt®), a 5-HT 1B/1D receptor agonist, was studied for multiple migraine attacks; almotriptan, another 5-HT 1B/1D receptor agonist, was researched for migraines occurring over a six month period; and LY334370, a novel selective serotonin 1F agonist, was studied for acute migraine.

1. See abstracts from AAN 2000 meeting. Abstracts are available in Abstract Book or on CD-ROM (distributed to registered AAN attendees).


James R. Storey, MD, Upstate Neurology Consultants, LLP, Albany, New York

Dr. James R. Storey and his colleagues compared topiramate (Topamax®) (up to 200 mg/day) to placebo in a double-blind study involving 40 patients with two or more migraines per month, with or without aura. Topiramate is a broad spectrum anticonvulsant, (Physicians' Desk Reference, 54th ed., 2000, p.329) effective as adjunctive treatment for partial onset and primary generalized tonic clonic seizures. Topiramate blocks sodium and calcium channels, antagonizes the ability of kainate to activate the kainate/AMPA subtype of the glutamate receptor, has a positive effect on GABA receptors, and inhibits certain isoenzymes (CA-II and CA-IV) of carbonic anhydrase. One or all of these actions may be responsible for its benefit in the prevention of migraine headaches.

Forty participants, ranging from 19 to 62 years old (39 women and one man), all had experienced migraine for at least one year. Patients had to have had at least two headaches a month to be eligible for the study and maintain this frequency during the four-week baseline period. An eight-week titration phase and eight weeks of maintenance treatment followed. Patients could continue other prophylactic migraine medication as long as the dose remained unchanged in the three months prior to enrollment and during the study. Patients with chronic tension-type headaches or more than three migraines per week were ineligible.

Thirty-five of the 40 patients completed the protocol. Three patients were noncompliant or withdrew consent, and two patients in the topiramate arm withdrew because of nausea or emotional liability.

The topiramate dose in the remaining 16 patients in the active study arm ranged from 25 to 200 mg/day, with an average dose of 125 mg/day. Adverse events noted more often in the topiramate group were paresthesias, taste alteration, weight loss, anorexia, memory impairment, dysarthria, abnormal vision, emotional lability, and urinary frequency. Although 68 percent of the patients had paresthesias, Dr. Storey noted that these symptoms "tended to go away and were dose dependent." When asked about sedation, Dr. Storey observed, "We really didn't see sedation as a major problem, as we were using fairly small doses in most of these people and increasing them fairly gradually. . . . The people who are going to respond tolerate it well, and usually at quite a low dose." Fifty-three percent experienced weight loss.

Upon completion, the median reduction in monthly headache rate was 33 percent in the topiramate group, versus eight percent in the placebo group (p = 0.0061). The mean decrease in headache rate was 1.83 for topiramate and only 0.55 for placebo (p = 0.0025). Dr. Storey concluded, "Topiramate is an effective addition to our list of medications [for migraine prophylaxis]."


Randal Von Seggern, MD, Headache Wellness Center of Greensboro, North Carolina

Dr. Randal Von Seggern and colleagues used a retrospective chart analysis to assess the efficacy of topiramate (Topamax®) in the prophylaxis of migraine headaches.

According to Dr. Von Seggern, topiramate has been previously reported to be effective in migraine prophylaxis in prospective, open-label studies and a placebo-controlled study (Potter, 2000, Neurology; Edwards, 1999, 18th Annual Scientific Meeting of the American Pain Society). In this study, the charts of 69 migraine patients treated prophylactically with topiramate over 28 days were analyzed. All patients met the International Headache Society diagnostic criteria for migraine, with or without aura. There were two patient groups: one group was treated with fewer than nine migraine medications, and one group was treated with greater than nine migraine medications.

There was a statistically significant reduction in the frequency (7.4 ± 7.7 versus 10.6 ± 8.4, p = 0.0004) of moderate and severe headaches at the end of the treatment period, compared to the beginning. This effect was seen both in patient groups that had failed on either fewer than or greater than nine previous migraine medications. There was a significant reduction in mild headaches in the subgroup who had failed with fewer than nine previous medications, but the frequency of mild headaches was not significantly reduced in either group overall. There was a 6.8 percent reduction in the 28-day frequency of mild migraine headaches (11.0 ± 10.0 at the end versus 11.8 ± 8.9 at the start of treatment, p value not significant).

The most common adverse effects participants experienced were paresthesias, drowsiness, diarrhea, weight loss, and decreased appetite. Treatment was associated with weight loss (ranging from one to 43 pounds) in 65 percent of patients.

These findings suggest the need for larger, prospective, controlled, efficacy studies. Even in patients considered refractory to treatment, a significant impact on prevention of moderate and severe headaches was found.


Fred Freitag, DO, Diamond Headache Clinic, Chicago, Illinois

Divalproex sodium extended release (Depakote® ER) is the conventional preparation of divalproex sodium, and it has already received approval by the Food and Drug Administration for the prophylaxis of migraine headaches, manic episodes associated with bipolar disorder, and complex partial and absence seizures (Physicians' Desk Reference, 54th ed., 2000, p. 428). Improved compliance and fewer side effects related to dosing peaks might be expected with an extended release preparation.

Dr. Fred Freitag presented the results of his double-blind, randomized, placebo-controlled, parallel study. Two hundred and thirty-seven patients with two or more migraine headaches during the four-week baseline period received a daily dose of either 1000 mg of divalproex sodium extended release or placebo. Patients who had been treated with other migraine therapy had a two-week washout period before entering the study.

One hundred and fifteen patients took placebo, while 122 received divalproex sodium extended release. These patients began with 500 mg/day for one week, then increased to 1000 mg/day. If they suffered side effects, they were allowed to return to the 500 mg/day dosage. At the end of the study, all patients decreased to 500 mg/day and discontinued after three months.

The similar number of dropouts due to adverse events in each group (8.2 percent in the treatment arm versus 8.7 percent in the placebo arm) suggested that the new preparation was well-tolerated.

The treatment arm demonstrated a mean reduction in headache rate "twice the reduction of the placebo" (1.2 versus 0.6, p = 0.006). In addition, headache days decreased by 2.5 times in the treatment group. According to Dr. Freitag, "Many patients showed a very positive response by the end of four weeks, and [the response] was quite significant by eight weeks for the majority of patients." The results of the 500 mg and 1000 mg dose were similar. Dr. Freitag noted, "Those patients who had the most frequent attacks at baseline. . .had the strongest positive response of reducing headache days."


Eleni Kavvadia, MD, Athens, Greece

The anticonvulsant medication valproate sodium was used to treat acute migraine headache attacks in a study performed by Dr. Eleni Kavvadia and her colleagues. Dr. Kavvadia reported the results of the study, which included a total of 54 patients (42 female and 12 male) who had previously been received at the emergency room with symptoms that fulfilled the International Headache Society criteria for acute migraine attack.

In this three-arm study, the patients, whose ages ranged from 21-67, were randomly chosen to receive intravenous normal saline solution alone (placebo), a single dose of 400 mg of an intravenous form of valproate sodium, or an 800 mg intravenous dose of valproate sodium.

In order to evaluate the effectiveness of valproate sodium in treating the migraine attacks, participants were evaluated at 30 and 60 minutes following treatment. They used a four-step self-assessment tool in which the patients rated the effectiveness of headache relief as complete, marked, moderate, or minimal. The results showed a dose response effect of the valproate sodium in which seven patients (39 percent) in the 800 mg dose group showed a complete or marked response, four patients (22 percent) in the 400 mg dose group showed a complete or marked response, and only one patient (5.5 percent) in the placebo group showed such a response. The proportion of high responders (those who exhibited either a complete or marked response) among the patients in the high dose (800 mg) valproate sodium group was significantly greater (p = 0.04) than in the placebo group.

It is thought that valproate sodium's effects in migraine prevention relate to its ability to stabilize a "state of hyperexcitability" in the brain of migraine patients. According to the authors, the mechanism of action in treating acute migraine is less clear as valproate sodium does not appear to have direct effects on cerebral blood vessels or analgesic properties.


Edward Chronicle, PhD, Associate Director of Mental Health & Neural Systems Research Unit, Lancaster University, United Kingdom

Investigators from the United Kingdom and the Netherlands reported on the results of their research on cortical excitability in migraine and the response to intervention with valproate sodium (Depacon®).

Dr. Edward Chronicle and his colleagues investigated cortical excitability in migraine patients with aura (MA), migraine patients without aura (MO), and age- and sex-matched, headache-free control subjects. They first recorded the stimulus thresholds at which subjects undergoing transcranial magnetic stimulation reported phosphenes. The migraine patients had significantly lower thresholds than the control subjects, but they found no significant differences between the thresholds found in the MA and MO subjects.

Each of the migraine patients included in these studies had at least two attacks per month prior to entry into the protocol. Following a month of treatment with valproate sodium (individualized doses), there was a significant reduction in headache frequency (p < 0.01). The response to valproate sodium in reducing phosphene thresholds was variable. When transcranial magnetic stimulation was performed using a circular coil, there was no significant threshold difference in MA or MO patients. With a figure-eight stimulating coil, the phosphene thresholds were significantly increased after treatment with valproate sodium. Using this technique, the baseline phosphene thresholds in MO patients were higher and did not change with treatment.

The authors concluded that their data support the "idea of cortical hyperexcitability as characteristic of migraine," and that it may be "modulated by appropriate GABA-agonists," such as valproate sodium.


Lawrence Newman, MD, Headache Institute at St. Luke's-Roosevelt Hospital Center, New York, New York

During his presentation, Dr. Lawrence Newman stated that approximately 66 percent of women with migraine have both menstrual migraines and sporadic attacks, and a smaller number-seven to 14 percent-has migraines only during the perimenstrual period. The day before menses begins and the next two days constitute the highest risk period for headache (A Pilot Study of Oral Sumatriptan as Intermitant Prophylaxis of Menstruation-Related Migraine. Neurology, Vol. 51, 1998, p. 307-309.).

Based on encouraging results from an open-label study (A Pilot Study of Oral Sumatriptan as Intermitant Prophylaxis of Menstruation-Related Migraine. Neurology, Vol. 51, 1998, p. 307-309.) of sumatriptan for menstrually associated migraine (MAM), the authors undertook a short term prophylaxis of MAM using naratriptan (Amerge®), a 5HT(1) agonist. Investigators compared two doses (1 mg and 2.5 mg) of oral naratriptan to placebo in a randomized, double-blind, parallel group study of women, 18 years or older, with at least a six-month history of MAM. Investigators defined MAM headaches as those occurring in the interval two days before and up to four days following the menstrual period. The investigators divided 206 women into three study groups, (1 mg = 70, 2.5 mg = 70, placebo = 66). Patients took naratriptan doses of 1 mg, 2.5 mg, or matching placebo tablets twice a day for five days, beginning two days before the predicted menstrual period. Researchers tallied the results for four menstrual cycles. Adverse effects were similar in incidence and severity in both the active treatment and placebo groups.

Surprisingly, only the 1 mg naratriptan dose proved effective. Women in this group experienced fewer MAM headaches compared with placebo (two versus four, p = 0.011). They also had a lower number of headache days (four versus seven, p = 0.001). Almost three times as many women in the 1 mg naratriptan group had no MAM headaches compared to the placebo group (23 percent versus eight percent). More women in the 1 mg naratriptan group also had a 50 percent or more reduction in MAMs compared with the placebo group (61 percent vs. 38 percent, p < 0.05). Headaches that did occur were similar in the three groups with respect to peak headache severity, work/activity productivity, percent effectiveness while doing work/activities with migraine symptoms, and migraine-related quality of life.

Dr. Newman could not explain why the 1 mg dose of naratriptan proved effective, while the 2.5 mg dose did not. "There are a number of possible reasons, none of which I'm convinced is true. . . . There's something unique, but I'm not sure what it is." Nonetheless, Dr. Newman noted that his was the "first placebo-controlled trial to document that a 5HT(1) agonist prevents migraines. . . . What we have here is another agent that is useful in our treatment strategies to treat women with menstrually associated migraine."


Praful Kelkar, MD, Assistant Professor of Neurology, Department of Neurology, University of Minnesota, Minneapolis

Distal, symmetric, predominantly small fiber sensory painful neuropathies (DPSPNs) plague many patients. Individuals with DPSPN suffer symptoms of painful distal dysesthesias and loss of pain and temperature sensation, while retaining normal or near normal reflexes and motor examination. The most common associated illness is diabetes. Dr. Praful Kelkar presented a poster summarizing his evaluation of 12 patients with cryptogenic polyneuropathy. All patients had common causes of polyneuropathy ruled out, such as diabetes, alcohol, uremia, Sjogren's syndrome, and Lyme disease. Dr. Kelkar retrospectively reviewed clinical characteristics, electrophysiologic findings, and sural nerve biopsies in ten females and two males with persistent burning feet. Their mean age was 55.5 years (34-75). Patients had well-established, progressive symptoms, with a mean duration of 76 months (36-120) and failure to respond to medications such as tricyclic antidepressants, carbamazepine (Carbatrol®, Tegretol®), and gabapentin (Neurontin®). Pain and temperature senses were reduced in the legs in all patients. Nine had diminished vibration sense in the toes. Five had reduced or absent ankle jerks. Three had mild motor weakness of toe extensors/flexors. Most of the patients had decreased sural nerve conduction velocities.

Review of the biopsies revealed no fibrinoid necrosis or transmural inflammation to suggest vasculitis. Axonal loss occurred in ten patients and was interpreted as moderate to severe in five. Two patients had normal fiber density and five had multifocal axon loss.

Common to all 12 sural nerve biopsies was the presence of epineural perivascular lymphocytes. Seven biopsies revealed perivascular collections of inflammatory cells or perivascular cuffing, and evidence of significant inflammation. Ten of the 12 patients had greater than ten lymphocytes and four of the ten patients had greater than 50 lymphocytes. Dr. Kelkar explained, "Less than ten cells is just an epiphenomenon and not a cause," but a greater number of lymphocytes raises the possibility of a primary inflammatory etiology. The authors found no correlation between the biopsy results and clinical features such as age of onset, illness duration, symptom severity, or type of pain.

Dr. Kelkar believes that the presence of inflammation seen in all 12 sural biopsies suggests that these patients have a "low-grade inflammatory neuropathy [that is] probably autoimmune [in etiology]." The strong female predominance of the sample (ten out of 12) supports the autoimmune hypothesis.

Dr. Kelkar tried intravenous immunoglobulin (IVIG) and methylprednisolone sodium succinate (Solu-Medrol®) in five patients. He administered methylprednisolone sodium succinate doses of 500 mg/day for two days every two weeks. One patient responded to IVIG with complete resolution of pain. Another patient responded to methylprednisolone sodium succinate. Three patients did not respond to the treatment. Based on the nerve biopsy results and the observed therapeutic response in two patients, the authors recommend that immune modulating treatment should be considered in patients who fit this profile.

In the future, Dr. Kelkar plans to evaluate a larger number of patients in a prospective study to learn more about the possible inflammatory nature of cryptogenic polyneuropathy.


Jann Stefano, MD, Assistant Professor of Neurology, Niguarda Hospital, Milan, Italy

At the AAN meeting Dr. Jann Stefano stated that cryptogenic polyneuropathy comprises up to approximately 70 percent of polyneuropathies. Neurologists make the diagnosis by exclusion of other etiologies. Dr. Stefano explained, "There is a cause, but we don't know it."

The authors evaluated patients with symptoms and signs of symmetric sensorimotor polyneuropathy with neurological examination, neurophysiologic studies, and laboratory tests to assess for known causes of polyneuropathy. Patients were seen every three months and neurophysiologic studies were repeated yearly. Laboratory tests were repeated twice a year for the first two years and yearly thereafter. Forty patients (27 males, 13 females) were identified. Neurophysiologic evaluation indicated that all patients had a chronic axonal polyneuropathy. Six patients had nerve biopsies that confirmed "chronic axonal neuropathy and no inflammatory reaction," said Dr. Stefano. Immunocytochemistry revealed an increase of HLA DR and p75 NTF expression (HLA is the logo for the human major histocompatibility gene complex). Patients exhibited a slowly progressive course during follow up.

The authors concluded, "Cryptogenic polyneuropathy is a chronic, axonal, sensorimotor polyneuropathy with a slowly progressive course." According to Dr. Stefano, "The management of pain is the main problem in these patients." In his experience, gabapentin has proved "very useful in these patients." However, the side effects and high cost of the drug can be limiting. "Somnolence and dizziness are the most important side effects [among many others, which tend to be] present at high doses."

At two years of follow up, none of the patients developed diabetes, cancer, or any other known cause of polyneuropathy. Dr. Stefano concluded that once these patients receive a thorough clinical and laboratory evaluation, it is not necessary to repeat these "expensive examinations." In order to qualify for this recommendation, patients must have had symptoms for greater than one year, normal laboratory findings, no relapsing or remitting course, no pes cavus or other features of a hereditary sensorimotor neuropathy, and no known etiology for their symptoms. In this group of patients, Dr. Stefano advised, "No extensive laboratory tests and neurophysiologic studies are necessary during the follow up."


Keith Edwards, MD, Western New England Headache Clinic, Bennington, Vermont

Dr. Keith Edwards reported that topiramate (Topamax®) significantly reduces pain in diabetic neuropathy; however, the FDA has not approved the drug for this use. Topiramate is only indicated as adjunct therapy in adults and pediatrics with seizures. Topiramate is a broad-spectrum anticonvulsant drug that inhibits voltage-gated sodium and calcium ion channels and has GABAergic and glutaminergic effects as well. Dr. Edwards' study had a randomized, double-blinded, placebo-controlled design to test for efficacy in the treatment of pain associated with diabetic neuropathy.

Twenty-seven patients were randomly allocated in a 2:1 fashion to receive either 200 mg of topiramate twice a day (or the maximum dose tolerated by the individual) or placebo for four weeks. In order to be included in the study, patients with either type-1 or type-2 diabetes had to have symptoms of painful diabetic neuropathy for at least six months. Pain was assessed at a baseline visit and at the final visit using the visual analogue scale (VAS) of the Short Form McGill Pain Questionnaire (SF-MPQ) and the Short Form McGill Questionnaire (SFMQ). Patients who required analgesics other than acetaminophen or who had evidence of unstable control of glucose levels were excluded from the study.

At the final visit, there was a statistically significant reduction (40.7+ 28.6 for patients on topiramate versus 70.4 + 25.4 for patients on placebo, p = 0.007) in the average pain scores using the VAS SF-MPQ (the study's primary outcome measure) in patients taking topiramate compared to those taking placebo. The reduction of pain in the topiramate group was also significant (p = 0.039) on the SFMQ. A patient global assessment of change showed a trend toward improvement in the topiramate group that did not reach statistical significance.

Twenty-eight percent of the patients in the topiramate group dropped out of the study, compared to 11 percent in the placebo group. The most common adverse effects were weight loss, asthenia, and confusion. Dr. Edwards commented that for those patients completing the study, topiramate was generally well-tolerated and all reached the target dose of 400 mg/day.


Michael Poole, MD, FACP, Senior Director and Neurology Therapy Head, and Don Iacobellis, PharmD, Senior Assistant Clinical Scientist of Clinical Research, Parke Davis, Ann Arbor, Michigan

In animal models, the experimental anticonvulsant, pregabalin [S-(+)-3-isobutyl-gamma-aminobutyric acid] was effective in neuropathic pain. A five-week, multicenter, clinical trial compared three different doses (75 mg/day, 300 mg/day, and 600 mg/day) of pregabalin to placebo in patients with chronic diabetic neuropathy. Forty-five centers in the US participated. Patients had to have experienced one to five years of painful diabetic neuropathy and attain a baseline pain score of at least four out of ten. Patients were excluded if they previously had taken gabapentin (Neurontin®) at a dose of 1200 mg/day or greater with no pain control improvement. Three hundred and thirty-seven patients entered the study. Eighty-two received 600 mg/day of pregabalin, 81 received 300 mg/day, and 77 received 75 mg/day. The remaining 97 patients received placebo. Patients rated their degree of pain on a zero to ten scale and kept pain and sleep diaries. Patients who took 75 mg/day of pregabalin had no benefit. However, patients in both the 300 and 600 mg/day arms had more responders (45.7 percent and 48.1 percent, respectively) compared to placebo (17.5 percent), and they showed a statistically significant mean difference of 1.26 and 1.45 in their endpoint mean pain score, p = 0.0001 and p = 0.0002, respectively, compared to placebo. Higher doses produced significant improvements in the weekly pain score; sleep interference score; Clinical and Patient Global Impressions of Change scores; and sensory, affective, total, visual analogue, and present pain intensity scales of the SFMQ scales. Dizziness (39 percent), somnolence (26.8 percent), and peripheral edema (13.4 percent) were the most common side effects. Peripheral edema appeared dose dependent. More patients on the 600 mg/day dose withdrew from the study (12.2 percent) than on 300 mg/day (3.7 percent) or placebo (3.1 percent). The withdrawal rate for patients on 300 mg/day was not statistically significant from the placebo group.

Patients did not experience cardiovascular, ophthalmologic, renal, or hepatic complications. No change in diabetic control was observed in any of the treatment groups. Orthostatic hypotension was not observed.

Mr. Iacobellis assisted in the presentation of the poster. He noted that 99 percent of pregabalin is renally excreted and exhibits no protein binding. In addition, the drug may have a "synergistic effect" with gabapentin. Dr. Michael Poole, the senior author of the study, found pregabalin to have "very, very robust efficacy. [If the drug is going to help,] within a week, you should see an effect." Patients experienced "dose dependent improvements in allodynia and hyperalgesia." Dr. Poole noted that pregabalin's mechanism of action remains unknown. Like gabapentin, it is a GABA analogue drug, but does not function as a GABA agonist. Brain GABA levels increase slightly, but less than with tiagabine or vigabatrin. Because pregabalin is so well-tolerated, patients "can begin an effective dose on the first day."

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