Metabolic Neuropathy Treatment & Management

The best medical care for patients with metabolic neuropathy is control of the underlying metabolic condition, which results in better control of the neuropathy.

Diabetic neuropathy

No pharmacologic treatment exists for moderately severe to severe diabetic peripheral neuropathy or other metabolic neuropathies. Only symptomatic treatments exist for pain and other conditions such as gastroparesis. However, control of hyperglycemia has been demonstrated to decrease progression of diabetic neuropathy. ^[28] This section discusses recent and ongoing studies, followed by a discussion of symptomatic treatment.

• Insulin pump: Continuous infusion of insulin has been demonstrated to improve results of NCS. This treatment seems to benefit only patients with mild peripheral neuropathy associated with diabetes. Exercise caution to prevent severe hypoglycemic episodes.

• Aldose reductase inhibitors: A meta-analysis of randomized controlled trials of aldose reductase inhibitors indicates that benefits of treatment have not been demonstrated conclusively in diabetic neuropathy.

• Neurotrophic factors: Neurotrophic factors have been tested in animal models of diabetic neuropathy. Insulin growth factor (IGF) and NGF have yielded encouraging results in animal studies. However, in humans, only recombinant NGF has been tested in phase II clinical trials, and the initial results did not demonstrate major benefits.

• Gangliosides: Gangliosides have been shown to promote improvement in sensation without changes in NCVs. A moratorium has been placed on their development because of significant adverse effects.

• Linoleic acid: In patients with diabetes, conversion of linolic acid or its metabolite gamma linoleic acid (GLA) is impaired. A recent multicenter study using GLA for 1 year demonstrated clinical and neurophysiologic improvement.

• Advanced glycosylation end products (AGE): AGE inhibitors have shown some value in treatment of peripheral neuropathy in rats. Human trials are pending.

• Human intravenous immunoglobulin: Small open-label studies have demonstrated improvement in diabetic peripheral neuropathy, especially in neuropathies with asymmetric involvement (eg, diabetic lumbosacral radiculoplexopathy) with intravenous immunoglobulin. Further studies are necessary to draw definitive conclusions.

Symptomatic treatment of diabetic neuropathy

See the list below:

• Gastroparesis: The first step is to attempt multiple small feedings. The amount of dietary fat should be decreased. Metoclopramide, which sensitizes tissue to the action of acetylcholine, stimulates the motility of the upper gastrointestinal tract. Cisapride, a prokinetic drug, is effective in some patients. If medications fail, jejunostomy may help.

• Enteropathy: Stasis of bowel contents with bacterial overgrowth may contribute to diarrhea. Treatment with broad-spectrum antibiotics such as ampicillin or tetracycline is the initial therapy. Metronidazole may also be given. Anticholinergics may help in controlling diarrhea. Patients with poor digestion may benefit from a gluten-free diet.

• Cystopathy: Patients with neurogenic bladder may not perceive when the bladder is full. Manual downward pressure of the bladder can help. Parasympathomimetic agents such as bethanechol also may be of help.

• Treatment of painful neuropathy: The AAN guideline for treatment of painful diabetic neuropathy (PDN) from 2011 established pregabaline as effective treatment (Level A Evidence). ^[29] Venalafaxine, duloxetine, amitriptline, capsaicin, gabapentin, valproate, opioids (morphine sulfate, tramadol and oxycodone controlled release) are probably effective for treatment of PDN (Level B Evidence). The FDA has approved duloxetine hydrochloride, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), pregabalin, and capsaicin patches for the treatment of diabetic peripheral neuropathic pain. A recent study concerning neuropathic pain using the NNT approach (number of patients needed to treat to get a beneficial response) was published recently by Sindrup and Jensen. ^[30] This section reviews the drugs most often used to treat pain in peripheral neuropathies based on their approach.

  • Tricyclic antidepressants: Tricyclic antidepressants have been shown to be effective in treating painful diabetic neuropathy. Tricyclics act on the central nervous system, preventing the reuptake of norepinephrine and serotonin at synapses involved in pain inhibition. Benefits are unrelated to relief of depression. Amitriptyline and nortriptyline are used most commonly.

  • Selective antidepressants: Selective serotonin reuptake inhibitors (SSRIs) specifically inhibit presynaptic reuptake of serotonin but not noradrenaline. Paroxetine has been effective in painful diabetic neuropathy.

  • Ion channel blockers

    • Lidocaine: Lidocaine is a nonspecific sodium channel blocker. It relieves painful diabetic neuropathy in severe cases but is not convenient to administer since no oral form is available.

    • Mexiletine: Mexiletine is an oral analogue of lidocaine. It has been used at a dosage of 10 mg/kg, but clinical trials so far have shown equivocal results.

    • Phenytoin: Phenytoin blocks sodium channels nonspecifically and therefore reduces neuronal excitability in sensitized C-nociceptors. It has been demonstrated to be effective in neuropathic pain, but it suppresses insulin secretion and may precipitate hyperosmolar coma in patients with diabetes.

    • Carbamazepine: Carbamazepine is another nonspecific sodium channel blocker that has been effective in the treatment of painful diabetic neuropathy, but it is more useful in trigeminal neuralgia.

    • Pregabalin: Pregabalin binds to calcium channels and modulates calcium influx at nerve terminals. A randomized, double-blind, placebo-controlled, parallel group, multicenter trial done in 2004 showed that pregabalin produced significant improvement in pain score and sleep. The pain relief and sleep improvement began in week 1 of the study and effect remained significant through the study length. It was also effective in improving mood and quality of life. There was greater incidence of dizziness and somnolence as compared to placebo, but the adverse effects were mild to moderate and did not result in withdrawal from study. ^[31] Another randomized, double-blind clinical trial compared pregabalin and amitriptyline. There was no significant difference in improvement in both groups and improvement was seen from the first week. There were more reported adverse effects with amitriptyline (65.4%) as compared to pregabalin (25%). ^[32]

    • Gabapentin: Gabapentin is a novel anticonvulsant with an unknown mechanism of action, but it is believed to antagonize glutamate excitotoxicity. It has demonstrated effectiveness in neuropathic pain, but doses in clinical trials were as high as 3600 mg. Freeman et al performed a meta-analysis of 7 randomized, placebo-controlled trials that evaluated the efficacy and safety of pregabalin treatment of painful diabetic peripheral neuropathy. ^[33] Daily doses included 150, 300, and 600 mg/d, with dosing intervals of 2 or 3 times per day. Pregabalin was found to be effective for painful diabetic peripheral neuropathy at all doses and intervals, with the greatest and most rapid pain reduction seen in patients receiving pregabalin 600 mg/d divided into 2 or 3 doses.

    • Lamotrigine: Lamotrigine is a new anticonvulsant acting as a stabilizer in the slow inactivated conformation of a subtype of sodium channels, indirectly suppressing the neuronal release of glutamate. Studies in trigeminal neuralgia favor its use, but no studies have been reported in other neuropathic pain syndromes.

  • N -methyl-D-aspartate (NMDA) antagonists: Aspartate, an excitatory neurotransmitter, has been shown to play a role in the development of neuropathic pain. Its receptor is NMDA. NMDA antagonists have shown effectiveness when given intravenously for neuropathic pain (eg, ketamine). Other studies with another NMDA antagonist, dextromethorphan, have shown efficacy for neuropathic pain.

  • Opioids: Until recently, high controversy surrounded opioid use in neuropathic pain. However, recent studies have demonstrated its efficacy in different types of neuropathic pain. Tramadol is an analgesic drug probably acting over both monoaminergic and opioid mechanisms. The monoaminergic effect is shared with tricyclic antidepressants. Tolerance and dependence appear to be uncommon. Doses of 100-400 mg have been shown to be effective in diabetic neuropathic pain. Oxycodone and morphine have been tried in other neuropathic pain syndromes with good results. Risk of dependence remains an issue to consider, and these agents should not be given to individuals at risk of addiction.

  • Levodopa: Dopamine agonists inhibit noxious input to the spinal cord. Levodopa also has actions over noradrenergic receptors. One recent study showed benefit in polyneuropathic pain with 300 mg/d of levodopa.

  • Capsaicin: Capsaicin is an alkaloid substance derived from chilies. It depletes substance P from sensory nerves, causing chemodenervation. It has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain as well. It must be applied topically every 4 hours over the entire pain area. It causes a burning sensation, and applying it with gloves is advisable.

  • Miscellaneous: Several still unproven medical treatments are proposed for mitochondrial respiratory chain disorders, including drugs such as coenzyme Q10, menadione, vitamin E, ascorbic acid, N -acetylcysteine, riboflavin, succinate, L-carnitine, and dichloroacetate.

    • The SYDNEY-2 trial provided evidence that oral treatment with alpha lipoic acid for 5 weeks improved symptoms in patients with distal sensory polyneuropathy. A daily oral dose of 600 mg was found to have optimum risk-benefit ratio. ^[34]

    • A systematic review conducted in 2013 to determine role of acupuncture in management of diabetic peripheral neuropathy showed that manual acupuncture had better effect on global symptom improvement as compared to mecobalamin, Vitamin B1, Vitamin B12 and no treatment. The combination of manual acupuncture and mecobalamin had better effects on global symptom improvement than mecobalamin alone. Assymetric funnel plot suggested publication bias so more high-quality studies are needed for effects of acupuncture. ^[35]

  • Kiviniemi et al., based on their study, conclude that low cardiorespiratory fitness (CRF) was a more important determinant of cardiac autonomic function than moderate-to-vigorous physical activity (MVPA) and body fat. Furthermore, MVPA but not body fat was independently associated with cardiac autonomicfunction in both men and women. ^[36]

See the list below:

• Surgical release of entrapment neuropathy (CTS, ulnar neuropathy at the elbow, TTS)

• Specialized surgical care of diabetic foot and foot ulcers, including vascular and plastic surgery evaluation

• Jejunostomy for severe gastroparesis

• Pancreatic islet transplants have been reported to improve diabetic neuropathy and pancreas-kidney transplantation in patients with diabetes and renal failure

• Liver transplantation (may improve familial amyloid neuropathy)

• Renal transplantation (may improve uremic neuropathy)

See the list below:

• Nutrition or genetics consults, especially for patients with diabetes or metabolic neuropathies in childhood

• General surgery for patients in whom transplant is considered

• Plastic or vascular surgery for patients with diabetic foot ulceration or necrosis

See the list below:

• Low-calorie diet in patients with diabetes

• Modified lipid-intake diets for inherited conditions associated with alteration in lipid metabolism

• Low-protein intake in chronic renal failure and in hepatic failure

No restrictions in activity are recommended for most of the metabolic neuropathies. However, some neuropathies in childhood can be triggered by exercise.