Innovations in Treating Neuropathic Pain: Off-label Pharmaceuticals, Novel Orthotics, and Other New Approaches

March 22, 2005

Management of diabetic peripheral neuropathy (DPN) centers on proper footcare, offloading, and various orthotic devices to prevent the development of ulcers. Management trends, however, show that off-label use of some pharmaceutical agents is common and that these agents are proving beneficial in relieving the pain that can accompany DPN in up to 35% of patients. In addition, innovations in orthotic devices and new technologies for patient monitoring are being rolled out.

Management of diabetic peripheral neuropathy (DPN) centers on proper footcare, offloading, and various orthotic devices to prevent the development of ulcers. Management trends, however, show that off-label use of some pharmaceutical agents is common and that these agents are proving beneficial in relieving the pain that can accompany DPN in up to 35% of patients. In addition, innovations in orthotic devices and new technologies for patient monitoring are being rolled out.GOING OFF-LABEL IN SEARCH OF PAIN CONTROLThe FDA only recently approved the use of pregabalin (Lyrica, Pfizer) for treatment of neuropathic pain associated with DPN and for treatment of postherpetic neuralgia. No other drug has been approved by the FDA specifically for analgesic relief of painful neuropathy, according to Peter Sheehan, MD, director of the Diabetes Foot and Ankle Center at the Hospital for Joint Diseases and an associate professor of medicine at New York University. As a result, physicians are writing off-label prescriptions for drugs approved for other indications, because some data show that they also are effective for painful neuropathy. Several anticonvulsants, for example, are regularly prescribed to alleviate neuropathic pain. Gabapentin (Neurontin, Pfizer) is now widely used for this indication, according to practitioners interviewed for this article and studies in the literature.1-6 The drug has been shown to be effective in large doses for relieving painful DPN with a minimum of side effects."The opiates don't seem to be of that much help," Sheehan said. Tramadol (Ultram, Ortho-McNeil) was shown in one trial to be effective, he said.7 "Among the anticonvulsants, Neurontin is used frequently," he said. "An older anticonvulsant, carbamazepine [Tegretol, Novartis], has some efficacy, but it also has some adverse safety issues, so many clinicians are reluctant to use it."Oxcarbazepine (Trileptal, Novartis), a second-generation analog of carbamazepine, appears in preliminary studies to offer analgesic benefits without the side effects of its predecessor, which include nausea and fatigue. In a 30-patient, 9-week trial led by Ahmad Beydoun, MD,8 an associate professor of neurology at the University of Michigan, mean visual analog scale scores dropped from 66.3 during the screening phase to 34.3 by the end of the trial, a mean reduction of 48.3%."Antidepressants have shown some efficacy," Sheehan said, "especially amitriptyline, better known as Elavil [AstraZeneca]. But they do have sedative effects, which makes them less popular with patients. That's why the anticonvulsants have superseded these drugs. Their safety profile is better."ORTHOTIC INSOLE FOR DIABETIC FOOTThe immediate goal of treatment for patients with diabetic foot ulcers is offloading pressure from the wound to allow healing. At the testing stage is an insole designed to be a shear-reducing orthosis. The insole, developed by Ammanath Peethambaran, CO, of the University of Michigan Orthotics and Prosthetics Center, is intended to help prevent ulcers and promote faster healing."Traditional orthoses address only the vertical force," Peethambaran said, "but not the horizontal force, or shear friction, that happens underneath the foot." The insole is designed to be a friction-reducing and shear-reducing interface between the foot and the orthosis and to provide a rolling and sliding motion in the front section of the device, according to Peethambaran. "The foot remains in one place but the orthosis moves, reducing the friction and shear," he said.Peethambaran says his insole, which can fit into any shoe, is made of Poron (PPT) and Plastazote. "I didn't utilize any different material," he said. "I just changed the configuration. So it's more of an engineering innovation."Although Peethambaran has engaged in only small, preliminary, unpublished studies, he's looking for funding, and perhaps manufacturer input, to establish larger trials. "The pilot study [unpublished] indicates there is at least a 50% reduction in the time that it takes ulcers to heal and that calluses are reduced tremendously compared to standard insoles," Peethambaran said. He's looking to study use of the insole in about 300 patients, because a larger pool of subjects will give him more reliable results.HOME MONITORING DEVICE: DERMAL THERMOMETERAnother example of a device that is almost ready for market is a dermal thermometer developed by Lawrence Lavery, DPM, associate professor of surgery at Texas A&M Health Science Center College of Medicine. Small and flexible, the tool is designed to warn patients with peripheral neuropathy when they are at particular risk for ulcer development. The technology is based on the concept that temperature increases accompany inflammation that can predispose the foot to injury. Promising findings were reported last year by Lavery and colleagues in the November issue of Diabetes Care (see "Home monitoring of foot skin temperatures to prevent ulceration," pages 2642-2647).The thermometer, which was developed by a team of engineers at the University of Texas Health Science Center in San Antonio, "kind of looks like a flashlight at the end of a moveable gooseneck," Lavery said. "At the end of that is a sensor. So if you have arthritis in your knee or hip, or you're too obese to put your foot up so you can see it, you can position the gooseneck so you can touch the sensor to the bottom of your foot. It has an LCD screen, so even people who have retinopathy or other visual impairments can see their readings." If patients see elevated heat levels in their feet, they know they have to decrease their activity or take particular care for a few days. If temperatures stay high, the patient knows a trip to the physician is in order, said Lavery.In addition to the trial for which findings were published in Diabetes Care last November, Lavery also has conducted a 50-participant, 6-month phase 1 trial, which has been submitted for publication. The incidence of ulcers dropped dramatically in both trials, he said. "There was a 9- or 10-fold reduction in ulcers for people using the thermometer in the first study and around a 3-fold reduction in the study of longer duration," Lavery said. "If there's a 3-fold decrease in ulcers, and an ulcer costs $40,000 to treat, you don't have to prevent very many ulcers to see a benefit."The thermometer, which will be marketed as the TempTouch by San Antonio-based Xilas Medical, will sell for $100 to $150, Lavery estimated.PERENNIAL CHALLENGE: MAINTAINING GLYCEMIC CONTROLResearchers, practitioners, pharmaceutical companies, and orthosis manufacturers are constantly hunting for answers to the complex puzzle posed by DPN and for better means of pain relief and ulcer prevention. But at least for the foreseeable future, it seems that the bottom line for delaying the onset of DPN and slowing its progress will continue to be the old standbys: proper diet and aggressive glycemic control."If you can control glucose and the swings in glucose over the short term and the long term, you can definitely alter both the immediate pain and the long-term damage that occurs with neuropathy," said David G. Armstrong, DPM, director of podiatry research in the Department of Surgery at Southern Arizona Veterans Affairs Medical Center in Tucson. "But that involves asking someone who's been living one way for 50 years to change his or her life and diet. It involves more than just education. It involves continually trying to alter behavior. It's really hard."To that end, manufacturers and researchers have been investigating the extent to which pharmaceuti-cal agents can help facilitate glycemic control. Aldosereductase inhibitors, antioxidants, protein kinase C (PKC) inhibitors, and angiotensin-converting enzyme inhibitors are some of the agents that have been studied, with varying degrees of promise."Whenever you see dozens of different types of therapies and treatments trying to treat a single disease, then I suppose your antennae should go up," Armstrong said. "That should tell you that there's no single silver bullet that's going to eliminate painful or painless diabetic neuropathy." The cause of DPN is multifactorial, he said. "Problems of peripheral microcirculation, oxidative stress, metabolic problems, and many other factors-to say one specific agent is going to eliminate this condition is probably not wise," he said. "The investigations that make the most sense are treatments that may somehow improve microcirculation and reduce the amount of oxidative stress on the nerve."According to Armstrong and several other sources, the most promising agent to date is the PKC inhibitor ruboxistaurin, developed by Eli Lilly. PKC is an enzyme thought to be associated with the microvascular damage that leads to complications in patients with diabetes. Ruboxistaurin was associated with improvement specifically in clinical global impression scale ratings in a large, randomized, double-blind, phase 2 study conducted by Lilly and reported at the 63rd annual meeting of the American Diabetes Association in June 2003. Lilly is currently recruiting patients for an international phase 3 trial of ruboxistaurin. For information about the trial and enrollment, visit the Web site at www.clinicaltrials.gov/ct/show/NCT00090519.ROLE FOR ANTIOXIDANTSBased on evidence that oxidative stress plays a significant role in the origins of neuropathy, researchers are exploring the role antioxidants might play in relieving the symptoms of diabetic neuropathy or even delaying or preventing its onset. Several tests of the antioxidant a-lipoic acid (ALA) are showing promise. In the randomized, double-blind symptomatic diabetic neuropathy (SYDNEY) trial, 60 patients with diabetic sensorimotor polyneuropathy received 600 mg of intravenous ALA infused once daily, 5 days a week, for a total of 14 treatments.9 Using the Total Symptoms Score, which encompassed presence, severity, and duration of pain, prickling, and numbness, the researchers reported significant improvements in all response categories, compared with the 60 patients in the placebo group. In addition, 80% of the patients receiving ALA judged overall efficacy following treatment as very good or good, compared with only 8.3% of those in the placebo group.However, there are drawbacks to ALA, according to Charlotte Grayson, MD, senior medical editor for WebMD Health. "Studies have shown that you can get significant relief of numbness as well as pain from the treatment," Grayson said. "The problem is the injected intravenous versions that had to be given in 30-minute [infusions] every day. They put a needle into your vein and leave it there for 30 minutes. That's not going to be practical in the long run."Herbal supplement manufacturers are promoting ALA supplements that can be taken orally, she said, but none has been studied in any sort of clinical trial. "It's kind of suspect that oral ALA treatments would ever work," Grayson said. "ALA taken orally has a [short] half-life, meaning it breaks down in the body within about 5 minutes. So we've never been able to move past the intravenous version of this drug. But researchers are looking into how to make it more stable." nEditor's Note: A previous version of this article was published in the October 2004 issue of BioMechanics. It has been updated and revised for Applied Neurology.REFERENCES1. Backonja MM, Serra J. Pharmacologic management part 1: better-studied neuropathic pain diseases. Pain Med. 2004;5(suppl 1):S28-S47.2. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836.3. Gorson KC, Schott C, Herman R, et al. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial.J Neurol Neurosurg Psychiatry. 1999;66:251-252.4. Morello CM, Leckband SG, Stoner CP, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159:1931-1937.5. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001;57:505-509.6. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458-1486.7. Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications. 2000;14:65-70.8. Beydoun A, Kobetz SA, Carrazana EJ. Efficacy of oxcarbazepine in the treatment of painful diabetic neuropathy. Clin J Pain. 2004;20:174-178.9. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. Diabetes Care. 2003;26:770-776.JERRY KARP is a freelance writer based in San Francisco.