Painful Diabetic Neuropathy: Why Treatment Response Stays Poor and What Patients Actually Report
DOI:
https://doi.org/10.5281/zenodo.22260618Keywords:
Painful diabetic neuropathy, Neuropathic pain, Duloxetine, Pregabalin, Number needed to treatAbstract
Roughly a quarter of people with diabetes experience painful neuropathy, and the drugs recommended for it have not changed
materially in twenty years. A multicentre randomised crossover trial compared three first-line pathways in 130 patients across 13
centres and found them equivalent: mean pain fell from 6.6 to 3.3 on an eleven-point scale in all three, with a difference between
pathways of -0.1 (98.3% CI -0.5 to 0.3). Pooled analyses put the number needed to treat for meaningful pain relief at about 5 for
both duloxetine and pregabalin, against a number needed to harm of 15 for withdrawal due to adverse effects. The trial team
stated the ceiling plainly: the best achievable with any monotherapy is 50 per cent pain relief in 50 per cent of patients, with side
effects in 10 to 20 per cent depending on dose. This review sets out why the choice between first-line drugs matters less than it is
usually made to, and what the trial data say about what patients experience.
References
Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. "Diabetic neuropathy: a position statement by the American Diabetes Association". Diabetes Care 40(2017):136-154.
Selvarajah D, Kar D, Khunti K, Davies MJ, Scott AR, Walker J, et al. "Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention". Lancet Diabetes Endocrinol 7(2019):938-948.
Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah D, Orengo C, et al. "The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy". Pain 157(2016):1132-1145.
National Institute for Health and Care Excellence. "Neuropathic pain in adults: pharmacological management in non-specialist settings, clinical guideline CG173". NICE, London (2013, updated 2020).
Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. "Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis". Lancet Neurol 14(2015):162-173.
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. "Pregabalin for acute and chronic pain in adults". Cochrane Database Syst Rev (2009):CD007076.
Lunn MPT, Hughes RAC, Wiffen PJ. "Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia". Cochrane Database Syst Rev (2014):CD007115.
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. "Amitriptyline for neuropathic pain in adults". Cochrane Database Syst Rev (2015):CD008242.
Waldfogel JM, Nesbit SA, Dy SM, Sharma R, Zhang A, Wilson LM, et al. "Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review". Neurology 88(2017):1958-1967.
Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, et al. "Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial". Lancet 400(2022):680-690.
Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Young T, et al. "Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT". Health Technol Assess 26(2022):1-100.
Barry HC. "Amitriptyline, duloxetine, and pregabalin each effective in decreasing pain from diabetic peripheral neuropathy; combinations even better". Am Fam Physician 107(2023):319.
Quilici S, Chancellor J, Lothgren M, Simon D, Said G, Le TK, et al. "Meta-analysis of duloxetine vs pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain". BMC Neurol 9(2009):6.
Sultan A, Gaskell H, Derry S, Moore RA. "Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials". BMC Neurol 8(2008):29.
Arezzo JC, Rosenstock J, LaMoreaux L, Pauer L. "Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial". BMC Neurol 8(2008):33.
Callaghan BC, Little AA, Feldman EL, Hughes RAC. "Enhanced glucose control for preventing and treating diabetic neuropathy". Cochrane Database Syst Rev (2012):CD007543.
BLOSSOM investigators. "Efficacy of pregabalin and duloxetine in patients with painful diabetic peripheral neuropathy: a multi-centre phase IV clinical trial". Pharmaceuticals 16(2023):1011.
Petersen EA, Stauss TG, Scowcroft JA, Brooks ES, White JL, Sills SM, et al. "Effect of high-frequency spinal cord stimulation on painful diabetic neuropathy: a randomized clinical trial". JAMA Neurol 78(2021):687-698.
Ziegler D, Fonseca V. "From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy". J Diabetes Complications 29(2015):146-156.
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. "Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations". J Pain 9(2008):105-121.
Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole RM. "Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale". Pain 94(2001):149-158.
Boulton AJM, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. "Diabetic neuropathies: a statement by the American Diabetes Association". Diabetes Care 28(2005):956-962.
Tesfaye S, Boulton AJM, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. "Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments". Diabetes Care 33(2010):2285-2293.
Vinik AI, Nevoret ML, Casellini C, Parson H. "Diabetic neuropathy". Endocrinol Metab Clin North Am 42(2013):747-787.
Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, et al. "EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision". Eur J Neurol 17(2010):1113-1123.
Griebeler ML, Morey-Vargas OL, Brito JP, Tsapas A, Wang Z, Carranza Leon BG, et al. "Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis". Ann Intern Med 161(2014):639-649.
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. "Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial". Pain 110(2004):628-638.
Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. "Duloxetine vs placebo in patients with painful diabetic neuropathy". Pain 116(2005):109-118.
Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. "Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy". N Engl J Med 326(1992):1250-1256.
Selvarajah D, Cash T, Sankar A, Thomas L, Davies J, Cachia E, et al. "The contributors of emotional distress in painful diabetic neuropathy". Diab Vasc Dis Res 11(2014):218-225.
Alleman CJ, Westerhout KY, Hensen M, Chambers C, Stoker M, Long S, et al. "Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: a review of the literature". Diabetes Res Clin Pract 109(2015):215-225.
Davies M, Brophy S, Williams R, Taylor A. "The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes". Diabetes Care 29(2006):1518-1522.
Ziegler D, Papanas N, Schnell O, Nguyen BDT, Nguyen KT, Kulkantrakorn K, et al. "Current concepts in the management of diabetic polyneuropathy". J Diabetes Investig 12(2021):464-475.
