Diabetic Peripheral Neuropathy - Diabetic Autonomic Neu...

Diabetic Peripheral Neuropathy

Diabetic Peripheral Neuropathy
11/15/02
Dennis Russell, Pharm.D.
Julie Stading, Pharm.D.
U.S. Pharmacist

Diabetes mellitus affects nearly 16 million people--5.9% of the population within the United States--and about 800,000 new cases are diagnosed each year. Of all diabetes patients, type 2 diabetes is the most prevalent type, affecting nearly 15 million Americans. Type 2 diabetes, which is usually diagnosed after 45 years of age, often goes unrecognized until symptoms become severe or individuals seek treatment for its complications.1 Diabetes complications can result in blindness, renal disease, heart disease, stroke, and nerve disorders--which in severe cases may result in amputations.

Diabetic nerve disease, or "peripheral neuropathy," is the most common complication of diabetes mellitus, affecting up to 62% of Americans with diabetes.2 Many times diabetic peripheral neuropathy is the "forgotten complication" of diabetes, overshadowed by other complications of the disease. The purpose of this article is to create an awareness of diabetic neuropathy by recognizing symptoms and identifying treatment options for neuropathic pain associated with diabetes.

Etiology
A number of factors have been outlined as potential causes of diabetic nerve disease or diabetic peripheral neuropathy. Although the exact origin is not fully understood, most experts feel it is multifactorial.3 Microvascular abnormalities can lead to neural ischemia, and sorbitol-induced myo-inositol deficiency can impair normal intracellular metabolism. In addition, neurotrophic factors involved in development, maintenance, and regeneration of the nervous system are impaired during diabetic peripheral neuropathy.4 There are contributing factors, most of which center around hyperglycemia and insulin deficiency.3,4 The Diabetes Control and Complications Trial (DCCT) convincingly demonstrated that intensive insulin therapy, which lowers the mean blood glucose level from 230 mg/dL to 155 mg/dL, reduced the risk of developing clinically detectable diabetic neuropathy by 60% over a 5 year-period.4

Clinical Presentation
Diabetic peripheral neuropathy can manifest in a variety of ways. Some diabetes patients experience painful diabetic neuropathy (PDN), while others experience an asymptomatic, progressive loss of peripheral nerve function.3 Diabetic peripheral neuropathy can affect both the autonomic and the somatic nervous systems. Autonomic symptoms can include sexual dysfunction, bladder abnormalities, gastroparesis, orthostatic hypotension, and diabetic diarrhea. However, diabetic peripheral neuropathy most commonly affects the somatic, or sensorimotor, system. The sensorimotor system commonly exhibits peripheral symptoms in a distal symmetric pattern.5 These symptoms can be very painful and even disabling.6 They commonly present as burning, shooting, tingling, and allodynia (super-sensitivity to normal stimuli).5 The diabetes patient may describe the symptoms as "a pain in the bones," "walking on broken stones," "a toothache in the feet," or "feet on fire." Patients may also display muscle weakness, incoordination, and ataxia from their nerve disorder.6 Diabetic peripheral neuropathy presents as a "glove and stocking" distribution, with symptoms usually beginning in the lower extremities, first affecting the toes and then progressing upward. Involvement of the upper extremities starts distally with the fingertips, then subsequently moves proximally up the hands and arms. Patients may lose their ability to detect pain and temperature sensations or may complain of paresthesias or dysesthesias. Loss of sensation predisposes the patient to the development of diabetic foot ulcers and infection. Resulting infections may lead to serious sequalae of cellulitis, osteomyelitis, or gangrene, with amputation as the only possible cure in some instances.7 The best way to manage diabetic neuropathy is to minimize its development and manage early symptoms of pain.

Prevention and Treatment
Prevention: Minimizing the progression and severity of diabetic peripheral neuropathy involves reducing a number of risk factors. Elevated cholesterol, hypertension, tobacco use, and excessive alcohol intake will accelerate its progression. Eliminating these risk factors, coupled with controlling blood glucose and weight, will slow its progression and impact.6,8 Ironically, improved blood glucose control may initially worsen neuropathic pain, but this effect usually subsides with continued blood glucose control. Diabetes patients should be encouraged to maintain their improved blood glucose levels. Good foot care and annual neurological exams by a physician will identify early-stage neuropathy, at which point preventive measures can be implemented, or treatment for pain started.8 However, after years of diabetes, patients may develop PDN, and treatment may become necessary for chronic conditions of pain.

Treatment: Control of pain is one of the most difficult management issues in diabetic neuropathy. Often it requires a trial-and-error approach utilizing a variety of different medications until a satisfactory regimen is established. Traditional analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) are rarely effective in the treatment of PDN. NSAIDs may have some use on a short-term basis with joint or musculoskeletal pain, but should be used cautiously, since they may cause an increased risk of nephrotoxicity in diabetic nephropathy cases. Narcotic analgesics are not a first-line choice, as they can cause physiological dependence with chronic use, and can induce constipation, which exacerbates features of autonomic neuropathy.9 Thus, co-analgesics such as tricyclic antidepressants are often the first-line choice of treatment for chronic pain associated with diabetic neuropathy.

Antidepressant Medications
Tricyclic Antidepressants: The tricyclic antidepressants (TCAs) are considered first-line systemic therapy for many neuropathic pain syndromes, including diabetic neuropathy.10 There are two classes of TCAs: secondary amines (nortriptyline, desipramine) and tertiary amines (amitriptyline, imipramine, and doxepin).11 A literature review of TCAs for diabetic neuropathy showed no difference in the effectiveness of the different TCAs.10 Generally, the secondary amines exhibit fewer anticholinergic effects (e.g., constipation, dry mouth, blurred vision, cognitive changes, tachycardia, urinary hesitation) and sedation than do the tertiary amines. Elderly patients generally experience a higher frequency of adverse effects with TCAs, and slower dosage titration is recommended. Therefore, when using TCAs, the secondary amines may be more desirable in the elderly population.10

TCAs can cause difficulties if used by people with certain medical conditions. They should be used with caution in patients with angle-closure glaucoma, benign prostatic hypertrophy, urinary retention, constipation, cardiovascular disease, and impaired liver function. TCA use should be avoided in patients with second-degree or third-degree heart block, arrhythmias, prolonged QT interval on the electrocardiogram, severe liver disease, and in patients who have had a recent acute myocardial infarction.10

Neuropathic pain generally responds more quickly (3-10 days) than depression (2-4 weeks) to tricyclic antidepressants, and often with one-third to one-half the dosage administered for depression. This is not universal, however, since there is no accepted therapeutic drug range for TCA analgesia. TABLE 1 lists medications and dosages for pain of diabetic peripheral neuropathy. Higher doses of TCAs (e.g., as typically used for depression) and several weeks of treatment may be necessary for efficacy. However, starting TCAs at inappropriately high dosages or titrating too rapidly may produce unacceptable side effects, resulting in treatment failure. Starting with 10-mg doses of a secondary amine at bedtime, especially in elderly patients, and titrating the dose upwards at 10-25 mg weekly will help reduce side effects. Failure with one TCA, however, does not preclude success with a different TCA. A trial of two or three TCAs may be considered before one resorts to another class of therapeutic medication.10

When discontinuing TCAs, they should be tapered over two to four weeks (depending upon the dosage) to avoid a withdrawal syndrome. Abrupt withdrawal may result in the following symptoms: malaise, insomnia, drowsiness, anorexia, muscle aches, apathy, headache, mania, profuse sweating, irritability, abdominal pains, diarrhea, nausea, vivid and terrifying dreams, and movement disorders.10

Originally, the major mechanism of the analgesic effect of TCAs was believed to be related to serotonin reuptake inhibition. However, the selective serotonin reuptake inhibitor (SSRI) antidepressants (e.g., fluoxetine, paroxetine, citalopram) have not demonstrated substantial effectiveness in relieving neuropathic pain.10 Some studies show SSRIs to be useful in treating depressed patients with pain, but not as beneficial for treating non-depressed patients with pain.11

Animal models of peripheral neuropathic pain have shown that TCAs act as sodium channel blockers, similar to local anesthetic and antiarrhythmic agents.10 This mechanism of action may explain the difference in effectiveness for neuropathic pain between TCAs and SSRIs. Further studies are needed to verify this difference.

Venlafaxine: Venlafaxine, a chemically novel antidepressant, has demonstrated effectiveness in the treatment of pain associated with diabetic peripheral neuropathy in several case reports. Adverse effects from carbamazepine and amitriptyline prompted a trial of venlafaxine in eight patients. Dramatic relief was reported 2 to 8 days after initiating 75 mg of venlafaxine. Nausea was experienced by two patients, but resolved with continued treatment. No serious side effects were observed. Venlafaxine appears to have a favorable drug interaction profile and warrants further study in treating pain associated with diabetic peripheral neuropathy.12 Likewise, interest in other types of medications, particularly anticonvulsants, has been shown in treating pain associated with diabetic peripheral neuropathy.

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