Low dose naltrexone in foot pain of diabetes
- Conditions
- Type 2 diabetes mellitus with neurological complications,
- Registration Number
- CTRI/2013/06/003735
- Brief Summary
Diabetes mellitus is a syndrome with disordered metabolismand hyperglycemia due to inappropriate insulin secretion characterized bychronic complications affecting nervous system, kidney, eye and foot besidesacute 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 generalizedsymmetric polyneuropathies as well as focal and multiple neuropathies.Generalized symmetric polyneuropathies are divided in to acute sensory, chronicsensorimotor and autonomic neuropathies. Focal and multifocal neuropathies areclassified in to cranial, truncal, focal limb, proximal motor and coexistingchronic 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 suggestedfor the occurrence of diabetic neuropathy.
Clinically, sensorimotor neuropathy is characterized byaffection of sensory and motor nervous systems. Sensory fibers first affectedare the small non-myelinated nerve fibers followed by larger ones. It usuallyaffects the distal lower limb and upper limb first, the reason being postulatedto be due to the longer length of these neurons. Most patients are asymptomaticor 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 tofoot injury and foot ulceration and slowing of nerve conduction are the commonfeatures. Motor involvement is usually minor and is restricted to the distalextremities.
It can cause foot deformity leading to callus and ulcerformation. Reflexes may also be altered. In acute painful diabetic neuropathy,patients complain of severe pain which is worse at night. They feel intensepain when bed sheet or clothing touches their foot which is termed allodynia.
There might be negligible other sensory or motor symptomsand signs. This can occur when the sugar control is poor and is seen in newdiabetics, during metabolic disruption following ketoacidosis or eatingdisorders. This may be associated with weight loss and may improve over 6 to 24months. Such pain occasionally is seen with improved diabetes control too.
Painful diabetic neuropathy is diagnosed by detailed historyand symptom assessment. Vibration perception threshold (VPT) alteration, monofilament test, electrophysiology, nervebiopsy, skin punch biopsy, quantitative sensory testing, peripheral nerveimaging and composite measures though can be advocated for early diagnosis ofdiabetic neuropathy, none of them are fully confirmatory. They help inprognostic assessment of diabetic neuropathy. But in the case of painfuldiabetic neuropathy detailed history along with assessment of signs andsymptoms is the most reliable method since all the above tests may be normal.
Painful neuropathic symptoms are present in up to 53% ofpatients who suffer from diabetic neuropathy. The present management of painfuldiabetic neuropathy include control of sugar level followed by drugs forcontrol of pain. It is currently thought that pharmacologic therapy for PDN ismost effective when it targets mechanisms that contribute to neuropathic painsignals. Neuropathic pain may result from hyperexcitability of peripheral andcentral pain pathways, including changes in the type, degree of expression, orfunction of sodium and calcium channels. Aberrant peripheral nerve activityalso may drive alterations in central pain processing via the excitatoryneurotransmitter glutamate and reduced γ-aminobutyric acid (GABA) inhibitorycontrol. Drugs belonging to the group of antidepressants, anticonvulsants,membrane stabilizing agents, electrical stimulation and capsaicin are theagents that have been tried for treatment in painful diabetic neuropathy anddifferent mechanisms for their benefit in the condition are described.
Though amitriptyline is considered the first choice, itcauses sedation in considerable number of patients. Anti-cholinergic sideeffects of amitriptyline can further worsens the situation if diabetes isassociated with autonomic neuropathy.
Naltrexone hydrochloride is a potential novel treatment forchronic pain. The drug is a competitive antagonist of opioid receptors, and hasbeen used clinically for over 30 years mainly for the treatment of opioidaddiction. However, when naltrexone is given at a lower dose, equal to or lessthan 5 mg/day [low-dose naltrexone (LDN)], its opiate antagonist activity turnsinto an agonist one so as to trigger a prolonged release of endogenous opioidssuch as β-endorphins (BE). Naltrexone has also been found to attenuate theproduction of pro-inflammatory cytokines and neurotoxic superoxides viasuppressive effects on central nervous system microglia cells. Naltrexone hasalso been proposed to exert neuroprotective effects via modulation ofmitochondrial apoptotic pathways.
More recently, the drug has been used in dosages rangingfrom 3 mg to 4.5 mg per day to treat chronic pain and autoimmune disordersNaltrexone used in this dosage range is typically referred to as low-dosenaltrexone (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 centrallyproduced proinflammatory cytokine activity and the overlap in symptoms betweenpainful diabetic neuropathy and above mentioned conditions, we hypothesizedthat LDN would successfully reduce the symptoms of PDN. To test thesehypotheses, we plan to conduct a clinical trial of LDN for the treatment ofpainful diabetic neuropathy, using a placebo-controlled, double-blind,cross-over design with amitriptyline as active comparator.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Closed to Recruitment of Participants
- Sex
- All
- Target Recruitment
- 60
- Presence of type 2 diabetes mellitus.
- No change in anti-diabetic medication for the last 1 month.
- Evidence of diabetic neuropathy by.
- Diabetic Neuropathy Symptom Score >1 point.
- Diabetic Neuropathy Examination Score >4 point.
- Vibration perception test and monofilament test.
- Mean pain intensity of more than 50% by patient assessment by VAS.
- Age below 18 or above 75 years.
- Evidence of renal disease (S. creatinine > 1.5).
- Evidence of liver disease (deranged LFT with clinical evidence).
- Pregnant and lactating mothers and women intending pregnancy.
- Evidence of other causes for neuropathy and painful conditions.
- Epilepsy, psychiatric and cardiac diseases, hypertensives not on treatment, peripheral vascular disease and substance abuse.
- Intake of anticonvulsants, antidepressants, membrane stabilizers and opioids.
- Participation in any other clinical trial with in the last 30 days.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method VAS scoring of diabetic neuropathic pain Every 2 weeks from 2 to 16 weeks
- Secondary Outcome Measures
Name Time Method Improvement on Likert scale, PGIC and neuropathy score every 2 weeks from 2 to 16 weeks
Trial Locations
- Locations (1)
Postgraduate Institute of Medical Education and Research, Chandigarh
🇮🇳Chandigarh, CHANDIGARH, India
Postgraduate Institute of Medical Education and Research, Chandigarh🇮🇳Chandigarh, CHANDIGARH, IndiaDrDebasish HotaPrincipal investigator01722744401debhota@gmail.com