Diabetes mellitus is a syndrome with disordered metabolism and hyperglycemia due to inappropriate insulin secretion characterized by chronic complications affecting nervous system, kidney, eye and foot besides acute complications. Diabetic neuropathy has a prevalence of more than 50% among diabetics of more than 25 years duration.

Diabetic neuropathy has been classified in to generalized symmetric polyneuropathies as well as focal and multiple neuropathies. Generalized symmetric polyneuropathies are divided in to acute sensory, chronic sensorimotor and autonomic neuropathies. Focal and multifocal neuropathies are classified in to cranial, truncal, focal limb, proximal motor and coexisting chronic inflammatory demyelinating polyneuropathy.

Though exact pathogenesis of diabetic neuropathy is unknown, different mechanisms have been suggested. Polyol pathway hyperactivity, non-enzymatic glycation, oxidative stress, neurotrophic factor deficiency, protein kinase-C activation and microvascular compromise are the mechanisms suggested for the occurrence of diabetic neuropathy.

Clinically, sensorimotor neuropathy is characterized by affection of sensory and motor nervous systems. Sensory fibers first affected are the small non-myelinated nerve fibers followed by larger ones. It usually affects the distal lower limb and upper limb first, the reason being postulated to be due to the longer length of these neurons. Most patients are asymptomatic or have only mild symptoms initially.

The diagnosis is often overlooked. Paresthesia, dysesthesias, neuropathic pain which may be burning, stabbing or aching types, loss of vibration and proprioception senses, sensory ataxia, predisposition to foot injury and foot ulceration and slowing of nerve conduction are the common features. Motor involvement is usually minor and is restricted to the distal extremities.

It can cause foot deformity leading to callus and ulcer formation. Reflexes may also be altered. In acute painful diabetic neuropathy, patients complain of severe pain which is worse at night. They feel intense pain when bed sheet or clothing touches their foot which is termed allodynia.

There might be negligible other sensory or motor symptoms and signs. This can occur when the sugar control is poor and is seen in new diabetics, during metabolic disruption following ketoacidosis or eating disorders. This may be associated with weight loss and may improve over 6 to 24 months. Such pain occasionally is seen with improved diabetes control too.

Painful diabetic neuropathy is diagnosed by detailed history and symptom assessment. Vibration perception threshold (VPT) alteration,  monofilament test, electrophysiology, nerve biopsy, skin punch biopsy, quantitative sensory testing, peripheral nerve imaging and composite measures though can be advocated for early diagnosis of diabetic neuropathy, none of them are fully confirmatory. They help in prognostic assessment of diabetic neuropathy. But in the case of painful diabetic neuropathy detailed history along with assessment of signs and symptoms is the most reliable method since all the above tests may be normal.

Painful neuropathic symptoms are present in up to 53% of patients who suffer from diabetic neuropathy. The present management of painful diabetic neuropathy include control of sugar level followed by drugs for control of pain. It is currently thought that pharmacologic therapy for PDN is most effective when it targets mechanisms that contribute to neuropathic pain signals. Neuropathic pain may result from hyperexcitability of peripheral and central pain pathways, including changes in the type, degree of expression, or function of sodium and calcium channels. Aberrant peripheral nerve activity also may drive alterations in central pain processing via the excitatory neurotransmitter glutamate and reduced γ-aminobutyric acid (GABA) inhibitory control. Drugs belonging to the group of antidepressants, anticonvulsants, membrane stabilizing agents, electrical stimulation and capsaicin are the agents that have been tried for treatment in painful diabetic neuropathy and different mechanisms for their benefit in the condition are described.

Though amitriptyline is considered the first choice, it causes sedation in considerable number of patients. Anti-cholinergic side effects of amitriptyline can further worsens the situation if diabetes is associated with autonomic neuropathy.

Naltrexone hydrochloride is a potential novel treatment for chronic pain. The drug is a competitive antagonist of opioid receptors, and has been used clinically for over 30 years mainly for the treatment of opioid addiction. However, when naltrexone is given at a lower dose, equal to or less than 5 mg/day [low-dose naltrexone (LDN)], its opiate antagonist activity turns into an agonist one so as to trigger a prolonged release of endogenous opioids such as β-endorphins (BE). Naltrexone has also been found to attenuate the production of pro-inflammatory cytokines and neurotoxic superoxides via suppressive effects on central nervous system microglia cells. Naltrexone has also been proposed to exert neuroprotective effects via modulation of mitochondrial apoptotic pathways.

More recently, the drug has been used in dosages ranging from 3 mg to 4.5 mg per day to treat chronic pain and autoimmune disorders Naltrexone used in this dosage range is typically referred to as low-dose naltrexone (LDN). Pilot trials for LDN in Crohn’s disease, multiple sclerosis, cancer related pain and fibromyalgia have recently been conducted.

Given the  naltrexone’s demonstrated efficacy in suppressing effect on centrally produced proinflammatory cytokine activity and the overlap in symptoms between painful diabetic neuropathy and above mentioned conditions, we hypothesized that LDN would successfully reduce the symptoms of PDN. To test these hypotheses, we plan to conduct a clinical trial of LDN for the treatment of painful diabetic neuropathy, using a placebo-controlled, double-blind, cross-over design with amitriptyline as active comparator.