Gordon Sloan, Uazman Alam, Dinesh Selvarajah and Solomon Tesfaye*
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact, resulting in a low quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, there are currently no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful-DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful-DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. Weak opioids (e.g., tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants, such as amitriptyline and α2δ ligand gabapentin, are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol) should be prescribed with caution in view of the lack of definitive data surrounding efficacy and concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g., botulinum toxin, intravenous lidocaine,, and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practice. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy, and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies, such as novel compounds and stratification of patients according to individual characteristics, (e.g., pain phenotype, neuroimaging, and genotype) to improve treatment responses.
Painful-DPN, Ligand pregabalin, Ligand mirogabalin, Opioids, Pathogenetic treatments, Novel therapeutic agents
Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, Department of Cardiovascular & Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital NHS Foundation Trust, Liverpool, Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield