Controlling Diabetic Neuropathic Pain
Abstract & Commentary
By Michael Rubin, MD. Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Three common medications amitriptyline, duloxetine, and pregabalin all appear equally efficacious in treating neuropathic pain from diabetic neuropathy.
Source: Boyle J, et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain. Diabetes Care 2012; Sept 18 (Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/22991449).
Among the 246 million diabetics worldwide, approximately 20-30 mil-lion are at risk for polyneuropathy. More than 80% of patients with diabetic polyneuropathy have the distal, symmetric form, which is painful in 16%, unreported in 12.5%, and untreated in 39%. Relief is desperately sought. Which agent works best?
Type 1 and type 2 diabetics who were ≥ 18 years of age and had neuropathic pain manifested by lower extremity allodynia, dysesthesiae, hyperalgesia, and burning or lancinating pain were recruited to participate in a double-blind, randomized, placebo-controlled, parallel group trial of low-dose, followed by higher-dose, pregabalin, amitriptyline, and duloxetine. Low doses comprised amitriptyline 25 mg bid, duloxetine 60 mg qd, and pregabalin 150 mg bid, whereas high doses comprised amitriptyline 25 mg qAM and 50 mg qhs, duloxetine 60 mg bid, and pregabalin 300 mg bid. Diagnosis of painful neuropathy was confirmed with a score of > 12 on the Leeds Assessment of Neuropathic Symptoms and Signs, and exclusionary criteria included drug abuse, pregnancy, breastfeeding, recent cardiac or cerebral ischemic events, recurrent hypoglycemic episodes requiring third-party assistance, or end-stage disease of a major organ system. Subjective pain, assessed by the Brief Pain Inventory, was the primary outcome measure. Secondary outcomes measures, including quality of life, measured by the short-form, 36-item general health survey, and subjective sleep, mood, and daytime sleepiness, assessed by the Leeds Sleep Evaluation Questionnaire, the Linear Analog Rating Scale, and the Karolinska Sleepiness Scale. Daytime functioning was evaluated during a 2-day inpatient period using a psychometric test battery including continuous tracking, choice reaction time, central nervous system arousal and information processing, Stroop task, digit symbol substitution testing, and working and explicit memory tasks. Statistical analysis comprised a preplanned statistical analysis plan, with statistical significance set at P < 0.05.
Among 83 patients enrolled and randomized between February 2007 and March 2009, 65 completed all treatment periods, with 27 randomized to pregabalin and 28 each to amitriptyline and duloxetine. No significant difference between treatment groups was found for the primary outcome of subjective pain. Pregabalin facilitated falling asleep and improved sleep continuity, but no significant differences between treatments were appreciated for any of the sleep components. Duloxetine significantly reduced sleep time and increased wake time, but nevertheless enhanced central nervous system (CNS) arousal and performance on sensory motor tasks. Duloxetine (60 and 120 mg) was associated with a small but significant decrease in nocturnal blood glucose, whereas pregabalin (600 mg only) was associated with a small but significant increase in nocturnal blood glucose. No serious adverse events were felt to be due to the study medication. Pregabalin, amitriptyline, and duloxetine are equally efficacious in reducing diabetic neuropathic pain, but sleep is improved with pregabalin.
Commentary
Microgliosis denotes the process whereby microglia, the CNS macrophages, respond to pathogens or injury by proliferating and altering their surface proteins, gene expression, and morphology. When peripheral nerves are injured, microgliosis occurs within the dorsal and ventral horns of the spinal cord, where these nerves terminate, as well as in the thalamus, hypothalamus, rostral ventromedial medulla, and periaqueductal grey. Mediators such as neuregulin-1, MMP-9, CCL2, and fractalkine induce this microglia transformation, as may tissue injury products including ATP, misfolded proteins or nuclear factors, complement components, and reactive oxygen species. These mechanisms, in part, explain chronic pain as a consequence of peripheral nerve injury, and blocking the microglial response can prevent injury-induced hypersensitivity in animal models. However, not all models of peripheral neuropathic pain evoke such a significant immune response in the CNS, and the extent to which CNS inflammation occurs in human peripheral neuropathic pain remains to be elucidated.1
Reference
1. Calvo M, et al. The role of the immune system in the generation of neuropathic pain. Lancet Neurology 2012;11:629-642.
Three common medications amitriptyline, duloxetine, and pregabalin all appear equally efficacious in treating neuropathic pain from diabetic neuropathy.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content