Off-Label, Low-Dose Naltrexone for Refractory Painful Diabetic Neuropathy

Dear Editor,

Naltrexone is a long-acting, potent, competitive opioid antagonist approved for the treatment of alcohol and opioid dependence at a dose of 50 mg/day [ 1 ]. Recently, naltrexone in 1–5 mg OD, typically referred to as low-dose naltrexone (LDN) [ 2 ], has been reported to treat chronic pain and autoimmune disorders. Pilot trials of LDN in Crohn’s disease, multiple sclerosis, cancer-related pain, and fibromyalgia have recently been conducted with success [ 3 ].

Here, we report a case in which off-label LDN was used for the treatment of painful diabetic neuropathic pain refractory to most available therapy.

In April 2012, a 76-year-old male with a 30-year history of type-2 diabetes and 7 years of diabetic neuropathic symptoms presented in the endocrinology clinic with complaints of burning pain in both legs below the mid-calf level. He described that the pain began insidiously, occurring off and on and associated with certain degree of numbness. Subsequently, both the frequency of occurrence and intensity of pain were increased disturbing his night-time sleep. The pain was partially relieved by walking, massage, hot fomentation, or paracetamol.

In July 2010, for the first time the patient sought treatment for neuropathic pain. He received Amitriptyline, Pregabalin, Duloxetine, Lamotrigine, and nonsteroidal anti-inflammatory drugs (NSAIDs) in varying doses and combinations. All drugs and combinations were tried for at least 1–2 months. Subsequently, he underwent a lumbar paravertebral nerve block (L2-L4) and had near complete pain relief afterward but the pain reappeared in a few weeks. He also received injectable vitamin B-complex and vitamin-D in therapeutic doses without any benefit. Opiates, transdermal patches of capsaicin, or lidocaine were not used.

On examination of the lower limbs, the skin over the dorsum of both the feet was shiny without any ulcer suggesting good foot care. The touch perception was decreased bilaterally below the knees and there was hyperalgesia, but no allodynia. The temperature sensation was normal in both legs. There was decreased vibration perception on both feet. The joint position sensation was lost in all joints on both feet but preserved in knees and above. The patient rated his pain to be 90% (0–100 points), 8, and 8 on a visual analog scale (VAS), short form McGill pain questionnaire, and 11-point Likert pain scale, respectively. The neuropathy symptom score was 9 out of 9. The deep tendon reflexes were absent in both ankles, 1+ in both knees, and 2+ in the joints of the upper limbs. Muscle power was normal in all limbs. Nerve conduction studies showed bilateral sensory motor polyneuropathy. The patient had adequate glycaemic control (HbA1c, 6.4%) and was on metformin (2 g/day), pioglitazone (30 mg/day), and insulin (20 units/day; 30% soluble and 70% isophane) with good compliance. Workup for other causes of neuropathy was non-contributory. MRI of lumbar spine showed degenerative changes without any neural involvement.

Based upon earlier reports [ 4 ], it was planned to administer oral naltrexone in graded doses (1, 2, and 4 mg HS for 2 weeks each). The 1 mg dose did not show any appreciable response. However, with the 2 mg dose, the patient reported a partial improvement in the burning pain. The 4 mg dose for 2 weeks produced a much greater pain relief. He rated his pain to be 5% on VAS as compared to 90% before therapy. On the Likert scale for pain and short-form McGill pain questionnaire the scores reduced to 1 and 2, respectively. Sleep was good after the treatment. On examination, there was no hyperalgesia, but the sensory loss was not improved. Following naltrexone therapy, initially he experienced mild diarrhea, nausea, and somnolence, which subsided spontaneously in a few days without any intervention. At every follow up the patient was satisfied with LDN (4 mg HS) and was continuing the same dose until October 2014 (last follow up) without experiencing any significant side effect.

The proposed mechanisms of pain relief with LDN include opioid receptor blockade causing compensatory release of endogenous opioids, and antagonism of Toll-like receptor-4 on microglia, which produces a variety of inflammatory factors such as pro-inflammatory cytokines, substance-P, nitric oxide, and excitatory amino acids [ 5,6 ]. Other proposed targets include astrocytes [ 7 ] NADPH oxidase-2 [ 8 ], and opioid growth factor receptor (OGFr) [ 9 ]. So far, very little information is available on the mechanism of pain relief by LDN and its long-term safety.

To our knowledge, this is the first report demonstrating the efficacy of LDN in relieving the pain of diabetic neuropathy. Based upon the present findings, we feel the need for further research to elucidate the possible mechanism(s) of LDN focussing on the roles of endogenous opioids and neuroinflammation, and to conduct large randomized, double-blind, clinical trials to establish the possible mechanism, efficacy, and safety of LDN in painful diabetic neuropathy and other chronic painful conditions.

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