Abstract & Commentary
Commentary by Michael Rubin, MD, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.
Synopsis: Painful diabetic neuropathy appears to respond to 1000 mg t.i.d. of ALC, but larger, longer trials, initiated early in the course of diabetic neuropathy, are warranted to confirm these results.
Source: Sima AAF, et al. Acetyl-L-carnitine Improves Pain, Nerve Regeneration, and Vibratory Perception in Patients With Chronic Diabetic Neuropathy. Diabetes Care. 2005; 28:96-101.
Two multicenter, double-blind, placebo-controlled, year-long trials were undertaken to assess the efficacy and safety of acetyl-L-carnitine (ALC), 500 or 1000 mg thrice daily (t.i.d.), in diabetic neuropathy. The frozen databases of these studies were evaluated to determine the findings. Both type 1 and type 2 diabetics were included, comprising 1346 men and women, ages 18-70 years, with at least 1 year of diabetes and no other causes for neuropathy. Exclusionary factors included alcohol or drug abuse, cardiac or liver disease, malignancy or pregnancy. All patients underwent neurological examination, nerve conduction studies, and vibratory detection threshold testing. Efficacy end points included morphometric analysis of sural nerve biopsy at baseline and follow-up, median, peroneal, and sural nerve conduction velocity and amplitude combined in an O’Brien average rank score, as well as index finger and great toe vibratory detection threshold combined in the same fashion. Clinical symptom score was measured by Sima and colleagues on a 0 (no symptoms) to 3 (incapacitating symptoms) scale and a visual analogue score was assessed by the patient. Statistical analysis was undertaken using rank-transformed data in an ANOVA model, O’Brien’s average rank scores, and a mixture of linear models to account for heterogeneity in response data.
Although no improvement was demonstrated for any nerve in either conduction velocity or amplitude in patients taking 500 mg or 1000 mg ALC t.i.d., vibratory detection threshold improved significantly and, in biopsied patients, numbers of sural nerve fibers and regenerating clusters increased (P = 0.049 and 0.033, respectively). Clinical symptom score demonstrated no significant improvement in treated patients compared to placebo. Among 27% of the patients who reported pain as their primary symptom, significant improvement in the visual analog pain score was seen at the 1000 mg-treatment level in 1 study and in the pooled cohorts of both studies at 26 (P = 0.031) and 52 (P = 0.025) weeks. Pain improvement also correlated with significant improvement, in the 1000 mg group, in the O’Brien rank score for biopsy parameters including myelinated fiber regeneration, occupancy, and fiber size. ALC was safe with pain, paresthesiae, and hyperesthesia the most common adverse events. Painful diabetic neuropathy appears to respond to 1000 mg t.i.d. of ALC, but larger, longer trials initiated early in the course of diabetic neuropathy are warranted to confirm these results.
Another option for refractory painful neuropathy is methadone, a potent µ agonist and schedule II opioid known best as the staple for the treatment of withdrawal in the drug-addicted. Subsequent to a successful lawsuit brought by the American Pharmaceutical Association in 1976, its analgesic usage has increased, with small clinical trials showing efficacy, more so in patients with peripheral neuropathic, rather than central, pain syndromes. Its use in diabetic neuropathy, despite the absence of adequate clinical trials, is being advocated (Hays L et al. Diabetes Care. 2005;28;485-487).
Convincing points may be raised arguing that it is the opioid of choice for persistent neuropathic pain. Apart from its very low cost and ease of administration, unique properties that set it apart from other opioids include its activity as an N-methyl-D-aspartate (NMDA) receptor antagonist, its inhibition of norepinephrine and serotonin reuptake, its trimodal mode of metabolism and excretion encompassing the liver, fecal, and renal routes, precluding the need for dosage adjustment in renal failure, the absence of psychoactive metabolites, and excellent bioavailability due to its lipophilic nature.
If antidepressants or anticonvulsants fail to manage painful diabetic neuropathy, methadone may be an alternative, starting with 0.5-1 mg every 8 h in the elderly, or 2.5-5 mg every 8 h in younger diabetics. Titrate upward weekly with breakthrough doses as needed; the latter will usually encompass not less than 10-20% of the total dose. Side effects, including nausea, vomiting, sweating, pruritus and, rarely, respiratory depression, may warrant lowering the dose by 25% but constipation, the most frequent side effect, requires aggressive attention. Methadone discontinuation, as with any long-acting opioid, should be done slowly.