Diabetic Neuropathy

Diabetic neuropathy affects around 50% of people who have had diabetes for 15-20 years, and is related to poor blood-sugar control.  The first symptom the person may notice is tingling or pins and needles, which can progress to intense pain.  They may also get numbness and can hurt themselves because they can no longer detect things that can cause harm, such as hot water or tight shoes.  This can mean damage goes undetected and, in extreme cases, amputation of the injured limb or digit may be necessary.

I haven't done a thorough study of this issue, but the articles below that I have collected give some treatments that have been researched.  Thiamine looks good and cheap.  I like the carnitines since the carnitines have a total of 63 positive studies for human illness.  Lipoic acid looks good, too, but it is much less researched for human disease.  I don't like valproate due to its high cost and considerable weight gain.  Nortriptyline is a good anti-depressant without weight gain, although if the patient is not depressed, I would try one of the other above strategies first.  SSRIs also appear to help.  All of the anticonvulsants would rank lowest on my list, but still worth trying.  Carbamazepine is the only inexpensive anticonvulsant on the Joslin list, but topiramate has the advantage of helping with weight loss although it has side-effects in many patients and is much more expensive.

There is ongoing research on monthly injections of a gene which increases vascular endothelial growth factor production which in turn counteracts the neuropathy.  However, this is a long way from being available (BBC News 7/30/05).

Morphine is being pushed for this mild-to-moderate chronic pain condition.  I can think of nothing more irresponsible, especially since 25% of all heroin addicts first get started by being given an unsolicited prescription for an opiate by a physician to treat a non-life-threatening pain condition. 

Acetyl-L-Carnitine Helps in Large Study: In a large English 333-patient 1-year DB PC study 2000 mg/d of ALCAR, peripheral nerve function improved and leg pain diminished. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. De Grandis D, Minardi C. Drugs R D. 2002;3(4):223-31. Ed: ALCAR costs $8 a month if a 500 day supply is purchased in powdered bulk (1 kg. for $133 from dextersports.com).  Patients might want to buy a month's supply in capsules from iHerb.com for about $35 to try it out. For more, see the Carnitines.

Acetyl-l-Carnitine: In two 52-week DB PC studies of 1,257 diabetics with peripheral neuropathy using acetyl-l-carnitine (ALC): 500 and 1,000 mg/day three times a day, significant improvements in sural nerve fiber numbers and regenerating nerve fiber clusters occurred with active treatment. Nerve conduction velocities and amplitudes did not improve, but vibration perception improved in both studies. Pain as the most bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg ALC. Acetyl-L-Carnitine Improves Pain, Nerve Regeneration, and Vibratory Perception in Patients With Chronic Diabetic Neuropathy: An analysis of two randomized placebo-controlled trials. Sima AA, Calvani M, et al, Wayne State University Diabetes Care. 2005 Jan;28(1):89-94

Lipoic Acid Helps Polyneuropathy: DB German study of 25 type II found decreases in pain, numbness, burning from 600 mg three times a day without significant side-effects. Also called antioxidant thioctic acid. Diabet Med 1999 Dec;16(12):1040-3. Benefit also found after 24 months for type I and II with 1200 mg/d better than 600. Free Radic Res 1999 Sep;31(3):171-9

Lipoic Acid Helps Cardiac Autonomic Neuropathy: 73 Type 2 diabetic patients in a DB German study with cardiac autonomic neuropathy, assessed by heart rate variability for 4 months at 800 mg/d found lipoic acid helpful. Diabetes Care 1997 Mar;20(3):369-73. Ed: 600 mg/day would cost $24/month, 800 mg $32, and 1,200 mg/day $48 from iHerb.com (10/04).

Morphine and Gabapentin Studied in Mild-Moderate Neuropathy Pain: In a poorly designed and small 5-week each DB crossover study of 57 patients with either painful diabetic neuropathy or postherpetic neuralgia, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine. Only 41 completed the trial. Mean daily pain at a maximal tolerated doses was as follows: 5.72 at baseline, 4.49 with lorazepam, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Morphine, gabapentin, or their combination for neuropathic pain. Gilron I, et al. Queen's University, Kingston, Ont, Canada. . N Engl J Med. 2005 Mar 31;352(13):1324-34. Ed: These patients had only mild to moderate pain, i.e. 14 points of pain on a 45 point scale. Mixing two totally different causes of pain seems unwise.  Why anyone would want to use a highly addictive narcotic for chronic mild to moderate pain in conditions that are likely to last for many years, like diabetic neuropathy, or for short-term conditions like PHN, I simply can't understand.  There are many better non-narcotic treatments for diabetic neuropathy than expensive gabapentin or highly addictive morphine.

Nortriptyline then Anti-Convulsant Joslin Clinic Recommendation: The Joslin Diabetic Clinic recommends nortriptyline at low doses as an inexpensive well-tolerated medication that is effective. Gabapentin is an excellent choice when nortriptyline is ineffective or not tolerated. Other anticonvulsants, such as lamotrigine, carbamazepine, oxycarbazepine, and topiramate, may also provide benefit. Clin Podiatr Med Surg. 2003 Oct;20(4):671-88

 Pregabalin (Lyrica-Phizer) Helped Diabetic Neuropathy:  Pregabalin, an alpha2-delta ligand with analgesic, anxiolytic, and anticonvulsant activity, was used in a 5-week DB PC study at 75, 300, or 600 mg/day vs. placebo in 338 patients with diabetic peripheral neuropathy (DPN). The 300- and 600-mg/day groups did much better than placebo (p = 0.0001). Responders (patients with > or =50% reduction in pain compared to baseline) were 46% (300 mg/day), 48% (600 mg/day), and 18% (placebo). Most common side-effects were dizziness and sleepiness. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Lesser H, Sharma U, et al. University of Rochester. Neurology. 2004 Dec 14;63(11):2104-10

Pregabalin (Lyrica-Phizer) Helped Diabetic Neuropathy eua: Pregabalin binds with high affinity to the alpha(2)-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. In a 12-week 338-patient DB PC study of chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN) using a flexible schedule of 150, 300, 450, and 600mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300mg/day for 1 week followed by 600mg/day for 11 weeks (n=132), both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common side-effects were dizziness, peripheral edema, weight gain (not affecting diabetes control), and somnolence. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Freynhagen R, Strojek K, et al. Universitatsklinikum Dusseldorf, Germany. Pain. 2005 Jun;115(3):254-63.

Sertraline Helps Diabetic Neuropathy: Both SSRIs and tricyclics found to help in past. Sertraline also helps with compliance and glycosylated Hb. Non-depressed patients did well on just 50 mg/d with major decrease in parathesias, pain, and numbness. Mendoza, U Miami, APA 5/30/98 Toronto.

Valproate Helps DM Neuropathy Pain: 52 DM II DB PC. Benefit noted by 4^th week. p<0.05. Sodium valproate in the management of painful neuropathy in type 2 diabetes - a randomized placebo controlled study. Kochar DK, Jain N, Agarwal RP, Srivastava T, Agarwal P, Gupta S.

Vitamin B-1 Thiamine Better than B-6 Pyridoxine in Tanzania for Diabetic Neuropathy: In a 200-patient DB study of thiamine 25 mg/day vs. pyridoxine 50 mg/day, 88% of thiamine vs. 30% of pyridoxine patients improved at four weeks. Evaluation of the efficacy of thiamine and pyridoxine in the treatment of symptomatic diabetic peripheral neuropathy. Abbas ZG, Swai AB. East Afr Med J. 1997 Dec;74(12):803-8; Similar results in a German DB PC with thiamine, B-6, and B-12. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6

Diabetic Retinopathy May Be Helped by Vitamin C, N-Acetyl-l-Cysteine: Diabetic retinopathy is a leading cause of blindness. One of the hallmarks of early diabetic retinopathy is death of pericytes. Glycated albumin (GA) was found to produce a progressive cytotoxic effect in a near time and dose dependent manner. Among the antioxidant pretreatments, l-ascorbic acid, Trolox, produced a reduction of GA-induced cytototoxicity. N-Acetyl-l-cysteine showed partial effect but taurine had no effect on the GA-toxicity. Pericytes and the prevention of diabetic retinopathy. Kim J., Chung-Ang University Hospital, Seoul, South Korea. Diabetes Res Clin Pract. 2004 Dec;66 Suppl 1:S49-51

Thomas E. Radecki, M.D., J.D.

 modern-psychiatry.com