Painful diabetic peripheral neuropathy relieved with use of oral topiramate. (Case Report).

Abstract

Diabetic peripheral neuropathy affects 5 to 50% of people with diabetes in the United States. It is a progressive disorder that results in a gradual decrease in peripheral sensation and eventually complete loss of sensation. Patients with diabetic peripheral neuropathy are challenging to treat because of intolerable adverse medication effects and the development of tolerance to medical treatment. We present the case of a patient with peripheral neuropathy that was unresponsive to usual therapies. She experienced significant relief with the administration of topiramate. Topiramate is an anticonvulsant that is gaining recognition in the treatment of patients with neuropathic pain syndromes.

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Peripheral neuropathy affects 5 to 50% of people with diabetes in the United States. (1) Peripheral neuropathy typically affects the lower extremities of diabetic patients and is characterized by an initial bilateral tingling or burning sensation that spontaneously increases or decreases in intensity over time. Patients may describe the pain associated with peripheral neuropathies as dull, cold, burning, crushing, aching, cramping, or tingling. Patients with diabetic peripheral neuropathies may have a heightened sensitivity to stimuli such as touch, temperature changes, or application of external pressure that results in excruciating pain with the slightest changes. The pain associated with peripheral neuropathy usually is more intense at night than during the day. Diabetic peripheral neuropathy is a progressive disorder and results in a gradual decrease in peripheral sensation with eventual complete loss of sensations to heat, cold, pressure, or pain. (1,2)

Discussion

Treatment of diabetic peripheral neuropathy is targeted at improving nerve function, alleviating pain and decreasing paresthesia symptoms. (1) Optimal blood glucose control will significantly delay the onset and progression of peripheral neuropathies in diabetic patients. (3,4) Other treatment options are aimed at controlling the patient's pain and paresthesias. Numerous therapies have been utilized over the years to treat peripheral neuropathies. Tricyclic antidepressants, selective serotonin reuptake inhibitors, antiepileptic medications, and capsaicin have been effective in relieving the pain associated with peripheral neuropathies. (1,5) Gabapentin has been the most recent medication to gain approval from the FDA for the treatment of neuropathic pain. Despite being effective agents, some have intolerable adverse effects or fail to be effective for prolonged durations of therapy. There is a need for medications that are effective and tolerable for prolonged durations.

Topiramate is an anticonvulsant that is gaining acknowledgment in the treatment of neuropathic pain syndromes. The exact mechanism of topiramate, like other anticonvulsants, in the treatment of painful neuropathies is unknown. It is theorized that topiramate may act on the central pain pathway or may slow neuronal firing both via the inhibition of GABAergic pathways as well as blocking [alpha]-amino-3-hydroxy-5methyl-4-isoxazoleproprionic acid (AMIPA)/ glutamate pathways. (6) Topiramate potentiates [gamma]-aminobutyric acid (GABA) activity thus increasing inhibitory neurotransmission, modulates voltage dependent sodium conduction to block sustained, repetitive firing of action potentials and blocks kainate evoked currents via an antagonistic effect on the AMPA pathway but not the N-methyl-D-aspartate (NMDA) pathway. (7,8)

There have been few data published to date on the use of topiramate for the treatment of diabetic peripheral neuropathy. However, there is a small amount of data available on the use of topiramate in the treatment of neuropathic pain (Table 2).

In a double-blind, randomized, placebo-controlled study by Edwards et al, topiramate was evaluated in 27 patients with Type 1 or Type 2 diabetes with painful diabetic neuropathies for greater than 6 months. Topiramate was titrated over 9 weeks to a total daily dose of 400 mg or the highest tolerated dose and continued at that dose for 4 weeks. Patients in the topiramate group (n = 18) had significantly less pain (P = 0.007) than those in the placebo group (n = 9). The most commonly reported adverse effects were asthenia, weight loss >10% and confusion. Five of 18 in the treatment group and 1 of in the placebo group withdrew from the study due to intolerable adverse effects. This is the only abstract found to date that looks at the use of topiramate in the treatment of painful diabetic neuropathies. (13)

Topiramate is typically well tolerated; however, if the dose is titrated too quickly agitation, anxiety, nervousness, and word finding difficulties are more pronounced. (7) The most common adverse effect reported in the literature is psychomotor slowing resulting in difficulty with concentration, speech hesitancy and word finding as well as somnolence and fatigue. Psychomotor slowing is a dose-related phenomenon and escalates as the dose increases. Somnolence is not a dose-related effect and typically will occur with initiation of topiramate. Other adverse effects that may occur with topiramate include dizziness, confusion, memory problems, weight loss of 2 to 7 kg, and increased risk of renal calculi formation. (7)

Topiramate is not metabolized to a significant extent and is primarily eliminated renally. The dose should be adjusted in patients with renal dysfunction. (7,8) Because 50 to 80% of topiramate is not metabolized, it has minimal drug interactions, which is advantageous. Topiramate is known to interact with carbamazepine, phenytoin, and ethinyl estradiol, which may require dose adjustments with concomitant use. (7'8)

There are no published, large, randomized controlled studies on the use of topiramate in the treatment of diabetic peripheral neuropathies to assist with recommending an appropriate dose of topiramate. However, it has been well reported that topiramate must be titrated slowly to minimize adverse effects. (7'8) The patient should be maintained on the lowest dose possible to control symptoms.

Conclusions

Diabetic peripheral neuropathies are difficult to treat. Patients may fail to tolerate certain therapies due to adverse effects or therapies may fail to work over time. Topiramate may be effective in the treatment of diabetic peripheral neuropathies, but randomized controlled trials will be needed. It has been shown that if topiramate is utilized, it should be started at a low dose and titrated slowly to a dose that is effective in controlling pain. Patients should be counseled on possible adverse effects such as difficulty concentrating, word finding difficulties, memory problems, and weight loss. (7) In this patient there was a corresponding drop in blood glucose values and hemoglobin AlC as the topiramate dose was increased and the effects have been maintained for the entire year of treatment with topiramate. Based on our observations with this patient, we recommend counseling diabetic patients who take topiramate on the signs and symptoms of hypoglycemia and effective ways to manage a hypoglycemic episod e.

Table 1

Overview of HgbA1C and Diabetic Medication Adjustments after Topiramate
Intification

Date        HgbA1C  Medications     Changes

October     7.7     Metformin
 2000                1,000 mg bid

                    Glimepiride
                     4 mg bid

December            Metformin       Added rosiglitazone
 2000                1,000 mg bid

                    Rosiglitazone   Stopped glimepiride
                    4 mg bid

January             Metformin       Added Glipizide XL
  2001               1,000 mg bid

                    Rosiglitazone
                     4 mg bid

                    Glipizide XL
                     5 mg qd

February            Metformin       Increased Glipizide XL
  2001               1,000 mg bid

                    Rosiglitazone
                     4 mg bid

                    Glipizide XL
                     10 mg AM,
                     5 mg PM

March 2001  5.2     Topiramate      No change in diabetic
                     started         medications

April 2001          Metformin       Stopped rosiglitazone
                     1,000 mg bid   Stopped Glipizide XL

May 2001            Metformin       Added rosiglitazone
                      1,000 mg bid

                    Rosiglitazone
                     4 mg qd

June 2001   5.1     No change       No change

October             Metformin       Increased rosiglitazone
  2001               1,000 mg bid

                    Rosiglitazone
                     4 mg bid

September   5.1     No change       No change
  2001

December    5.4     No change       No change
  2001

February    5.4     No change       No change
  2002

May 2002    5.2     No change       No change

Table 2

Overview of studies and case reports on the use of topiramate in the
treatment of patients with neuropathic pain

                          No. of
Series (ref. no.)        patients  Condition

Potter et al,              14      Painful nondiabetic
   1998 (10)                        peripheral neuropathies




Bajwa et al,                1      Refractory intercostal
  1999 (6)                          neuralgia
Zvartau-Hind et             6      Refractory trigeminal
   al, 2000 (9)                     neuralgia





Misha-Mirolslav,           43      Neuropathic pain
   2001 (12)                        syndromes








Jenson et al, 2002 (11)     61     Neuropathic pain
                                    syndromes did not
                                    respond to gabapentin
                                    or carbamazepine





Series (ref. no.)        Adverse effects

Potter et al,
   1998 (10)




Bajwa et al,             No intolerable AEs
  1999 (6)
Zvartau-Hind et
   al, 2000 (9)





Misha-Mirolslav,         Most were mild to
   2001 (12)              moderate and resolved
                          with time; 11 patients
                          discontinued topiramate
                          due to AEs





Jenson et al, 2002 (11)  18 patients discontinued
                          topiramate due to mild
                          to moderate AEs






Series (ref. no.)        Results

Potter et al,            Pain was significantly decreased
   1998 (10)              (P < 0.0001)
                         First sign of pain relief occurred
                          with an average dose of 214 mg/d
                          (range, 50-600 mg/d)
                         Average treatment period, 3.3 months
Bajwa et al,             Effective pain relief
  1999 (6)                maintained for >6 months
Zvartau-Hind et          5 of 6 patients had complete
   al, 2000 (9)           resolution with topiramate
                          therapy alone
                         I patient had complete resolution
                          with 300 mg/d titrated over 6
                          weeks plus carbamazepine
                         Effect was maintained for 6 months
Misha-Mirolslav,         51% improved
   2001 (12)             28% showed no improvement
                         21% worsened
                         4 patients discontinued topiramate
                          due to perceived lack of efficacy
                         Average daily dose of topiramate
                           129 mg (range, 15-800 mg)
                         Average weight loss in patients
                          taking 150 mg topiramate daily
                          was 9.7 pounds
Jenson et al, 2002 (11)  14.6% had excellent results
                         42.7% had good results
                         30.5% had fair results
                         12.2% had poor results
                         Primary reason for discontinuation
                          of topiramate was perceived
                          lack of efficacy

Accepted November 21, 2002.

References

(1.) Calissi PT, Jaber LA. Peripheral diabetic neuropathy: Current concepts in treatment. Ann Pharmacother 1995;29:769-777.

(2.) Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: Mechanisms of action and place in therapy. Drugs 2000;60:1029-1052.

(3.) The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.

(4.) The Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neural 1995;38:869-880.

(5.) Vaillancourt PD, Langevin HM. Painful peripheral neuropathies. Med Clin North Am 1999;83:627-642.

(6.) Bajwa ZH. Sami N, Warfield CA, Wootton J. Topiramate relieves refractory intercostal neuralgia. Neurology 1999;52:1917.

(7.) Rosenfeld WE. Topiramate: A review of preclinical, pharmacokinetic, and clinical data. Clin Ther 1997;19:1294-1308.

(8.) Schneiderman JH. Topiramate: Pharmacokinetics and pharmacodynamics. Can J Neural Sci 1998;25:S3-S5.

(9.) Zvartau-Hind M, Din MU, Gilani A, Lisak RP, Khan QA. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology 2000;55:1587-1588.

(10.) Potter D, Edwards R, Bennington VT. Potential role of topiramate in relief of neuropathic pain. Neuralagy 1998;50:A255 (abstract).

(11.) Jenson MG, Royal MA, Ward S, Movva V, Bhakta B, Gunyca I. Topiramate for the treatment of neuropathic and chronic pain syndromes: An open label trial. AJPM Am J Pain Manage 2002;12:12-16.

(12.) Misha-Miroslav B. Topiramate in the treatment of chronic neuropathic pain: A retrospective chart review. Ann Neural 2001;1:S63-S64 (abstract).

(13.) Edwards KR, Glantz MJ, Button J, Norton JA, Whittaker T, Cross N, et al. Efficacy and safety of topiramate in the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled study. Neuralagy 2000;54:A81 (abstract).

RELATED ARTICLE: Key Points

* Painful diabetic peripheral neuropathies are difficult to treat because of adverse medication effects and the development of tolerance to medications.

* Anticonvulsant medications are often used to treat patients with peripheral neuropathy. Topiramate is one such drug that is showing promising results.

* Topiramate is most tolerable when it is started in low doses and gradually increased.

* More studies evaluating topiramate's effects on decreasing blood glucose may be needed in the future.

Case Report

The patient was a 47-year-old, nonsmoking, obese white woman with asthma, hypertension, paroxysmal atrial fibrillation and hypercholesterolemia who was diagnosed with diabetes mellitus Type 2 six years earlier and subsequently developed severe peripheral neuropathy two years after diagnosis and poor glucose control. She had no associated retinopathy or nephropathy. An EMG revealed diffuse peripheral neuropathy consistent with diabetes and without lumbar nerve impairment. The patient had been tried on gabapentin 1,200 mg per day and ibuprofen 800 mg TID without improvement of her symptoms. She said her first symptom was an inability to keep her feet warm even during the summer. She then developed numbness, tingling and heaviness in both of her feet with an occasional burning sensation. She stated that she would get severe muscle cramps and could see her feet jump and cramp. She noticed little to no change in her symptoms while on the gabapentin and ibuprofen. She denied any progression of the symptoms into he r legs though at times her ankles would be affected. She was also started on amitriptyline but was unable to tolerate the medication secondary to the side effects. The patient had fair control of her blood sugar on extended release glipizide 10 mg in the morning and 5 mg in the evening, rosiglitazone 4 mg BTD, and metformin 1,000 mg BID. Her hemoglobin A1Cs ranged from 7 to 8%. The patient was seen by a podiatrist in consultation for her peripheral neuropathy who could offer no further suggestions. She eventually started using a walker because of the pain and difficulty ambulating secondary to the neuropathy. On physical examination the patient had evidence of stasis dermatitis on both lower extremities. The dorsalis pedis and posterior tibial pulses were +2 to +3/4, bilaterally. Capillary responses were less than 3 seconds, bilaterally. The Semmes-Weinstein monofilament examination revealed decreased sensation from the midfoot distally on both feet. There was no evidence of erythema, edema, or any wounds on either foot. She had tenderness to light touch on both feet. Lab results revealed hemoglobin, hematocrit, red blood cell count and MCV all were within normal limits not prompting further investigation of a B12 deficiency.

The patient was seen by a neurologist, who stopped her gabapentin and ibuprofen and started her on topiramate 25 mg BID for her neuropathy. She had gradual improvement of her symptoms, the first of which was the severe muscle cramps of her feet. Initially she was increased to 100 mg BID but was unable to tolerate this increase secondary to jitteriness, nervousness and a feeling that she was "coming unglued." She also experienced sleep difficulties. She was taken back down to 25 mg BID and gradually increased over several months to the 100 mg BID. She experienced improvement of the cold sensation, the shooting pains, and the numbness. After the patient was started on the topiramate, she began experiencing severe hypoglycemic reactions with blood sugars in the 60s. She was taken off the extended release glipizide and the rosiglitazone was decreased to 4 mg po QD. Her hemoglobin A1Cs have remained less than 6% since she has been on the topiramate. After approximately six months of being on the topiramate, the r osiglitazone was increased to 4 mg BID because her blood glucose was increasing (Table 1). The patient has tolerated topiramate well other than difficulty sleeping if she takes the medicine after six o'clock in the evening. Her physical examination has remained stable and her neuropathy has not progressed.

From the Department of Family Medicine, College of Medicine, and the College of Pharmacy, University of Oklahoma-Tulsa, Tulsa, OK.

Reprint requests to Kristina M. Kline, MD, Department of Family Medicine, College of Medicine, and the College of Pharmacy, University of Oklahoma-Tulsa, 9920 E. 21st Street, Tulsa, OK 74129. Email: [e-mail]

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