Choosing Medications For Painful Diabetic Neuropathy

Pages: 16 - 18
By Matt Rampetsreiter, DPM, and Raymond Abdo, DPM

Diabetic peripheral neuropathy is very common sequelae of diabetes mellitus. Patients often complain of burning, tingling, numbness and even sharp stabbing pain. These symptoms can cause sleep disturbances as well as problems with daily activities. Many primary care physicians and podiatrists overlook these symptoms which, in most cases, have been going on for years. Many people are unaware of the medications that can help relieve the discomfort. At our facility, we are very aggressive in treating diabetic neuropathy and feel that it is very important in our treatment regimen. With this in mind, let’s take a closer look at the most common medications, contraindications, adverse effects and our experience in using these medications. Carbamazepine (tegretol) is an anti-epileptic drug that inhibits Ad and C pain fibers without interfering with normal nerve conduction. It is most frequently used in trigeminal neuralgia and diabetic neuropathy. According to Ahmad, et. al., carbamazepine is more effective against the paroxysmal shooting and lancinating pain and less effective against the constant burning pain experienced by patients with painful neuropathy.1 The most common side effects of carbamazepine include dizziness, somnolence and gait disturbances. In elderly patients, carbamazepine has been associated with an increased frequency of hyponatremia and cardiac conduction defects, which may lead to inappropriate antidiuretic hormone (ADH) secretion. Serum levels between 6 to 10 mg/L were found to be therapeutic and this corresponded to a dosage range of 400 to 1,000 mg/day.1 One study showed that 600 mg/day of carbamazepine was more effective than placebo.2 Leukopenia and thrombocytopenia occur in less than 10 percent of patients, which may be a concern in the elderly population. Therefore, you should obtain a complete blood count and liver function tests before initiating therapy and repeat this testing every six months. Should You Consider Tricyclic Antidepressants? Tricyclic antidepressants (TCAs) have been used for decades to treat neuropathic pain. These agents inhibit the reuptake of serotonin and norepinephrine into presynaptic terminals. There have been many studies that have proven the TCAs to be not only beneficial in diabetic neuropathy but in treating other neuropathic diseases as well. The problem lies in the fact that these drugs also inhibit many other types of receptors, which leads to a high incidence of side effects. The elderly are prone to these effects, which include heart block, orthostatic hypotension, dry mouth, urinary retention and constipation. The most commonly used TCAs are amitriptyline, nortriptyline, imipramine and clomipramine. Using TCAs in patients with heart block, narrow angle glaucoma and prostatism is probably contraindicated.1 If sedation is a problem, then using a small dose at bedtime may be beneficial. The analgesic dosages are smaller than the antidepressant dose. If these adverse effects are problematic, then consider the secondary amine compounds (nortriptyline or desipramine) as they have fewer anticholinergic effects.3 We have found that most patients who have tried these agents in the past are reluctant to use them again. Therefore, we are using these agents less than some of the newer drugs. Key Insights On Gabapentin Gabapentin, which was originally used in treating seizures, has become a very popular drug in relieving neuropathic pain. It does not have any direct effect on GABA-ergic receptors nor does it affect GABA uptake or metabolism. Although the mechanism of action is unknown, gabapentin (Neurontin) does bind with subunits of calcium channels. In one study, gabapentin has significant pain relief scores compared to placebo. The dosages range from 300 to 3,600 mg/day but most patients achieved pain relief beyond the dosage of 1,800 mg/day. A very common mistake we see is physicians routinely underdosing their patients. When using gabapentin, you should initiate treatment with a test dose of 100 mg for elderly patients and gradually increase the dosage by 100 to 300 mg every three to five days. The median effective daily dose ranges between 900 to 1,200 mg but some patients may require a higher dosage. However, one should reduce the dose and frequency for patients with impaired renal function since the medication is eliminated unchanged through the kidneys.4 The most common adverse effects include dizziness, somnolence, fatigue and nystagmus. These side effects usually only last for the initial two to three weeks of therapy. Gabapentin is a very effective drug with minimal propensity to interact with other drugs. We have found this agent to be of benefit in amputees complaining of phantom pain, especially after they have undergone transmetatarsal amputations. A Closer Look At The Potential Of Foltx, Folgard And Tramadol Foltx is a combination of three co-factors: folic acid, cobalamin (vitamin B12) and pyridoxine (vitamin B6). Folgard is a very similar agent but with different amounts of the co-factors. We are very excited about these medications and have increasingly prescribed them as our first drugs of choice. Foltx was originally made to treat elevated homocysteine levels in patients who are at increased risk for heart disease. Factors causing increased homocysteine levels include smoking, chronic high alcohol consumption, post-myocardial infarction, post-stroke and increasing age. It is also indicated for homocystinuria, dialysis, ESRF, peripheral vascular disease (PVD) and coronary artery disease (CAD). There are relatively few side effects or drug interactions with Foltx. However, one should avoid giving pyridoxine to patients receiving levodopa as pyridoxine antagonizes this drug. Also keep in mind that concurrent use of phenytoin and folic acid may result in decreased phenytoin efficacy. We have had very good results in treating diabetic neuropathy with Foltx. Patients usually start feeling positive effects in about six weeks. If patients are unable to afford the medication, we put them on a vitamin B complex pill. Tramadol (Ultram) is a central-acting, non-narcotic analgesic that inhibits noradrenaline and serotonin uptake. Tramadol was evaluated in a multicenter clinical trial of 131 patients with painful diabetic neuropathy.8 The patients who received a daily dose of 210 mg had significant pain relief compared to the placebo. Side effects included dizziness, nausea, headache and somnolence. When using Tramadol, one should initiate treatment at 50 mg/day and increase it by 50 mg a day.1 There does not appear to be an upper ceiling on dosage and reports of higher dose levels increasing efficacy are still pending. Only Consider These Drugs When Other Medications Fail Mexiletine is an antiarrhythmic drug that has been evaluated in three clinical trials for patients with painful diabetic neuropathy. In one study, patients who received the highest dosage of mexiletine (675 mg/day) garnered significant nighttime pain relief.5 The other two clinical trials did not show any significant improvement between the placebo and mexiletine.6,7 However, the patients with predominantly stabbing or burning pain had a better response to mexiletine. The effective daily dosages range between 450 to 675 mg/day. Common side effects include gastrointestinal disturbances, dizziness, tremors, palpitations, chest pain and headache. Given these potential side effects, obtaining a baseline EKG is required before initiating therapy. One should reserve this drug for patients who do not respond to therapy with safer profile drugs. In regard to opioid therapy, neuropathic pain is not particularly responsive to it and there have been no definitive studies advocating opioids for diabetic neuropathy. However, many physicians place their patients on opioids for chronic longstanding pain. Be advised that chronic usage may cause constipation, nausea and sedation in elderly patients. In one study, oxycodone was evaluated for post-herpetic neuralgia.9 Compared to the placebo, oxycodone resulted in reductions of persistent pain, allodynia and paroxysmal pain. However, when it comes to treating chronic pain, one should first utilize other drugs with safer profiles. A Guide To Topical Medications Capsaicin is an alkaloid that depletes substance P from the terminals of unmyelinated C fibers, causing an initial burning and then analgesia. There have various studies with conflicting data about the benefits of capsaicin for diabetic neuropathy. Although it may help in the short term, long-term results have not been promising. Most authors feel that oral agents are likely to be more effective. You would need to apply capsaicin cream (.025-.075%) three to five times daily, which can cause transient burning and erythema at the site of application.1 Topical lidocaine has become an ever increasingly popular treatment for neuropathic pain. Lidocaine gel and the 5% patch have been a very effective modality in treating pain associated with amputations, ulcers, scars and other neuritic conditions. A recent study showed some good results when the 5% patch was administered to patients with neuropathic pain.12 Isosorbide dinitrite (ISDN) is a vasodilator and a nitric oxide (NO) donor. Many researchers believe that low levels of nitric oxide may be a contributing factor in diabetic neuropathy. Yuen, et. al., tested 22 diabetic patients with either ISDN spray or placebo spray for four weeks.13 The patients sprayed their feet once before bedtime with 30 mg. The researchers concluded that the ISDN spray helped overall neuropathic pain and burning sensation but had no effect on tingling, numbness, hyperesthesia or jabbing-like sensations. We have had no experience using this medication or any other sprays. In Conclusion Painful diabetic neuropathy is often overlooked by many physicians as a minor problem. This cause serious disturbances with daily life activities and sleep. Treating podiatrists should be aware of the potential adverse effects and proper effective dosing regimens. At Forest Park Hospital, we are strong proponents in addressing the pain of the neuropathic patient. Although the TCAs and epileptic agents have been used for decades, we have found that the newer agents like Foltx and Folgard can be just as effective and safer. All of the aforementioned agents may be used to treat not only diabetic neuropathy but also neuropathic pain associated with amputations, CRPS, painful malleolar ulcers and symptomatic scars. Dr. Rampetsreiter and Dr. Abdo are surgical residents at Forest Park Hospital in St. Louis under the direction of Allen M. Jacobs, DPM, FACFAS. Dr. Steinberg (pictured) is an Assistant Professor in the Department of Orthopaedics/Podiatry Service at the University of Texas Health Science Center. Editor’s Note: For a related article, see “Expert Insights On Painful Diabetic Neuropathy” in the March 2003 issue.



References 1. Ahmed M, Goucke CR. Management Strategies for the Treatment of Neuropathic Pain in the Elderly. Drugs Aging 2002; 12: 929-945. 2. Rull JA, Quibrera R, Gonzales-Millan H, et al. Symptomatic treament of peripheral neuropathy with carbamazepine (Tegretol): double blind crossover trial. Diabetologia 1969; 4: 215-218. 3. Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic uses in chronic pain states. Drugs Aging 1996; 6: 459-476. 4. Perruca E. The clinical pharmocokinetics of the new antiepileptic drugs. Epilepsia 1999; 40: S7-S13. 5. Wright JM, Oki JC, Graves IIIL. Mexiletine in the symptomatic treatment of painful diabetic neuropathy. Ann Pharmacother 1997; 31: 29-34. 6. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine Study Group. Diabetes Care 1997; 20: 1594-7. 7. Stracke H, Meyer UE, Schumacher HE, et al. Mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care 1992; 15: 1550-5. 8. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50: 1842-6. 9. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998; 50: 1837-41. 10. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of buproprion SR for the treatment of neuropathic pain. Neurology 2001; 57: 1583-1588. 11. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful neuropathy: a randomized, controlled study. Neurology 2001; 57: 505-9. 12. Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open label study. Clin J Pain 2000; 16: 205-8. 13. Yuen K, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. Diabetes Care 2002; 25: 1699-1703. Additional References 14. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002; 59: S14-S17. 15. Simmons Z, Feldman EL. Update of diabetic neuropathy. Curr Opin Neurol 2002; 15: 595-603. 16. Mendell JR, Sahenk Z. Painful Sensory Neuropathy. N Eng J Med 2003; 348: 1243-55.



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