Peripheral nerve damage can result in neuronal hyperexcitability, resulting in neuropathic pain. Localized neuropathic pain is confined to a specific area not larger than a letter-size piece of paper. Topical analgesics are increasingly popular for the treatment of localized neuropathic pain because systemic agents for managing neuropathic pain often produce undesirable and intolerable side effects. Commonly used agents for topical use are amitriptyline, baclofen, ketamine and lidocaine; however, these agents do not always give the desired analgesic effect in some patients. We report for the first time a patient with chronic idiopathic axonal polyneuropathy and intractable localized neuropathic pain treated successfully with loperamide 5% cream. After application of loperamide 5% cream, the patient reported a complete reduction of pain within 30 mins, lasting for 2.5 hrs. Subsequently, the patient was able to reduce his daily intake of oxycodone, while using topical loperamide for pain relief. Loperamide is a nonprescription opioid agonist, commonly used against diarrhea. As a topical formulation, it is preferable over other opioids due to its low systemic bioavailability and low risk of crossing the blood-brain barrier. Peripheral upregulation and sensitization of opioid receptors at peripheral nerve endings and perhaps at other cell populations in the epidermis might be targets of topical loperamide.