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Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs

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A Letter to the Editor to this article was published on 04 July 2020

Abstract

There is a high prevalence of painful diabetic polyneuropathy (pDPN) with around one-third of all patients with diabetes suffering from pDPN. pDPN has debilitating consequences, with a major impact on morbidity and quality of life. Unfortunately, there is no globally licenced pharmacotherapy that modulates the underlying disease mechanisms to prevent or halt the progression of diabetic neuropathy. The cornerstone of treatment therefore remains optimising glycaemic control and cardiovascular risk factors, and symptom control. Evidence from placebo-controlled studies has shown that antidepressants and anticonvulsants are effective for alleviating pDPN. Current clinical guidelines recommend the treatment of pDPN through the use of amitriptyline (tricyclic antidepressant), duloxetine (serotonin norepinephrine reuptake inhibitor), gabapentin and pregabalin (α2-δ ligands), tramadol and tapentadol (μ receptor agonists and norepinephrine reuptake inhibitors) and topical agents such as capsaicin (transient receptor potential V1 receptor desensitizer), although the latter is known to cause degeneration of small nerve fibers. pDPN can be difficult to treat, which frustrates healthcare providers, patients and caregivers. There is an additional need for clinical trials of novel therapeutic agents and optimal combinations for the management of pDPN. This article reviews the pharmacological management of pDPN, emerging therapies, the difficulties of placebo response in clinical trials and novel proposed biomarkers of treatment response.

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References

  1. IDF. IDF diabetes atlas. 8th Edition ed: Web; 2017.

  2. Diabetes UK. Diabetes: facts and stats. In: Diabetes UK, editor. Web; 2017.

  3. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin N Am. 2013;42(4):747–87.

    Google Scholar 

  4. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care. 2003;26(6):1790–5.

    PubMed  Google Scholar 

  5. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518–22.

    PubMed  Google Scholar 

  6. Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med (Malden, Mass). 2008;9(6):660–74.

    Google Scholar 

  7. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34(10):2220–4.

  8. Zelman DC, Brandenburg NA, Gore M. Sleep impairment in patients with painful diabetic peripheral neuropathy. Clin J Pain. 2006;22(8):681–5.

    PubMed  Google Scholar 

  9. Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag. 2005;30(4):374–85.

    Google Scholar 

  10. Tolle T, Xu X, Sadosky AB. Painful diabetic neuropathy: a cross-sectional survey of health state impairment and treatment patterns. J Diabetes Complic. 2006;20(1):26–33.

    Google Scholar 

  11. Gore M, Brandenburg NA, Hoffman DL, Tai KS, Stacey B. Burden of illness in painful diabetic peripheral neuropathy: the patients’ perspectives. J Pain. 2006;7(12):892–900.

    PubMed  Google Scholar 

  12. Iqbal Z, Azmi S, Yadav R, Ferdousi M, Kumar M, Cuthbertson DJ, et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Therap. 2018.

  13. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part) (author’s transl). Diabete Metab. 1977;3(4):245–56.

    CAS  PubMed  Google Scholar 

  14. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993;36(2):150–4.

    CAS  PubMed  Google Scholar 

  15. Kayaniyil S, Retnakaran R, Harris SB, Vieth R, Knight JA, Gerstein HC, et al. Prospective associations of vitamin D with beta-cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study. Diabetes. 2011;60(11):2947–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee CC, Perkins BA, Kayaniyil S, Harris SB, Retnakaran R, Gerstein HC, et al. Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: the PROMISE cohort. Diabetes Care. 2015;38(5):793–800.

    PubMed  Google Scholar 

  17. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86.

    CAS  PubMed  Google Scholar 

  18. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33(5):1090–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352(4):341–50.

    CAS  PubMed  Google Scholar 

  20. Hamman RFBR, Dabelea D, D’Agostino RB Jr, Dolan L, Imperatore G, Lawrence JM, Linder B, Marcovina SM, Mayer-Davis EJ, Pihoker C, Rodriguez BL, Saydah S. The SEARCH for diabetes in youth study: rationale, findings, and future directions. Diabetes Care. 2014;37:3336–44.

    PubMed  PubMed Central  Google Scholar 

  21. Jaiswal M, Divers J, Dabelea D, Isom S, Bell RA, Martin CL, et al. Prevalence of and risk factors for diabetic peripheral neuropathy in youth with type 1 and type 2 diabetes: SEARCH for diabetes in youth study. Diabetes Care. 2017;40(9):1226–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ziegler D. Painful diabetic neuropathy: treatment and future aspects. Diabetes/Metab Res Rev. 2008;24(Suppl 1):S52–7.

    Google Scholar 

  23. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain. 2002;18(6):350–4.

    PubMed  Google Scholar 

  24. Torrance N, Elliott AM, Lee AJ, Smith BH. Severe chronic pain is associated with increased 10 year mortality. A cohort record linkage study. Eur J Pain (London, England). 2010;14(4):380–6.

  25. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabetic Med. 2004;21(9):976–82.

    CAS  PubMed  Google Scholar 

  26. Sadosky A, Hopper J, Parsons B. Painful diabetic peripheral neuropathy: results of a survey characterizing the perspectives and misperceptions of patients and healthcare practitioners. Patient. 2014;7(1):107–14.

    PubMed  Google Scholar 

  27. Kennedy R, Abd-Elsayed A. The International Association for the Study of Pain (IASP) classification of chronic pain syndromes. In: Abd-Elsayed A, editor. Pain: a review guide. Cham: Springer; 2019. p. 1101–3.

    Google Scholar 

  28. Pavy FW. Introductory address to the discussion on the clinical aspect of glycosuria. Lancet. 1885;126(3250):1085–7.

    Google Scholar 

  29. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Syst Rev. 2007(4).

  30. (NICE) NICE. Neuropathic pain in adults: pharmacological management in non-specialist settings. NICE 2018.

  31. Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–54.

    CAS  PubMed  Google Scholar 

  32. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015;21(Suppl 1):1–87.

    PubMed  PubMed Central  Google Scholar 

  33. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113–1188.

    CAS  PubMed  Google Scholar 

  35. Oates PJ. Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets. 2008;9(1):14–36.

    CAS  PubMed  Google Scholar 

  36. Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007(4):CD004572.

  37. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.

    CAS  PubMed  Google Scholar 

  38. Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167(4):465–71.

    CAS  PubMed  Google Scholar 

  39. Javed S, Alam U, Malik RA. Mirogabalin and emerging therapies for diabetic neuropathy. J Pain Res. 2018;11:1559–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Taylor CP. Mechanisms of analgesia by gabapentin and pregabalin–calcium channel alpha2-delta [Cavalpha2-delta] ligands. Pain. 2009;142(1–2):13–6.

    CAS  PubMed  Google Scholar 

  41. Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28(2):75–82.

    CAS  PubMed  Google Scholar 

  42. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57(5):451–62.

    CAS  PubMed  Google Scholar 

  43. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–9.

    CAS  PubMed  Google Scholar 

  44. Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathic pain. Palliat Med. 2004;18(1):5–11.

    PubMed  Google Scholar 

  45. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25(1):81–104.

    CAS  PubMed  Google Scholar 

  46. Inc. P-DDoP. [

  47. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831–6.

    CAS  PubMed  Google Scholar 

  48. Pérez HE, Sánchez GF. Gabapentin therapy for diabetic neuropathic pain. Am J Med. 2000;108(8):689.

    PubMed  Google Scholar 

  49. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis. 2001;3(2):53–62.

    CAS  PubMed  Google Scholar 

  50. Gorson KC, Schott C, Herman R, Ropper AH, Rand WM. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999;66(2):251–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159(16):1931–7.

    CAS  PubMed  Google Scholar 

  52. Dallocchio C, Buffa C, Mazzarello P, Chiroli S. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manag. 2000;20(4):280–5.

  53. Rauck R, Makumi CW, Schwartz S, Graff O, Meno-Tetang G, Bell CF, et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485–96.

    PubMed  Google Scholar 

  54. Wiffen PJ, Derry S, Bell RF, Rice AS, Tölle TR, Phillips T, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD007938.

  55. 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. 2015;14(2):162–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Rudroju N, Bansal D, Talakokkula ST, Gudala K, Hota D, Bhansali A, et al. Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis. Pain Phys. 2013;16(6):E705–14.

    Google Scholar 

  57. Frampton JE, Scott LJ. Pregabalin: in the treatment of painful diabetic peripheral neuropathy. Drugs. 2004;64(24):2813-20; discussion 21.

  58. Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs. 2003;12(4):663–72.

    CAS  PubMed  Google Scholar 

  59. Juhn MS, Parsons B, Varvara R, Sadosky A. Pregabalin for painful diabetic peripheral neuropathy: strategies for dosing, monotherapy vs. combination therapy, treatment-refractory patients, and adverse events. Curr Med Res Opin. 2015;31(5):1017–26.

  60. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;110(3):628–38.

    CAS  PubMed  Google Scholar 

  61. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63(11):2104–10.

    CAS  PubMed  Google Scholar 

  62. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005;115(3):254–63.

    CAS  PubMed  Google Scholar 

  63. Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6(4):253–60.

    CAS  PubMed  Google Scholar 

  64. Tölle T, Freynhagen R, Versavel M, Trostmann U, Young JP. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12(2):203–13.

    PubMed  Google Scholar 

  65. 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. 2008;8:33.

    PubMed  PubMed Central  Google Scholar 

  66. Satoh J, Yagihashi S, Baba M, Suzuki M, Arakawa A, Yoshiyama T, et al. Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med. 2011;28(1):109–16.

    CAS  PubMed  Google Scholar 

  67. Raskin P, Huffman C, Toth C, Asmus MJ, Messig M, Sanchez RJ, et al. Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: a randomized withdrawal trial. Clin J Pain. 2014;30(5):379–90.

    PubMed  Google Scholar 

  68. Raskin P, Huffman C, Yurkewicz L, Pauer L, Scavone JM, Yang R, et al. Pregabalin in patients with painful diabetic peripheral neuropathy using an NSAID for other pain conditions: a double-blind crossover study. Clin J Pain. 2016;32(3):203–10.

    PubMed  Google Scholar 

  69. Huffman C, Stacey BR, Tuchman M, Burbridge C, Li C, Parsons B, et al. Efficacy and safety of pregabalin in the treatment of patients with painful diabetic peripheral neuropathy and pain on walking. Clin J Pain. 2015;31(11):946–58.

    PubMed  Google Scholar 

  70. Mu Y, Liu X, Li Q, Chen K, Liu Y, Lv X, et al. Efficacy and safety of pregabalin for painful diabetic peripheral neuropathy in a population of Chinese patients: a randomized placebo-controlled trial. J Diabetes. 2018;10(3):256–65.

    CAS  PubMed  Google Scholar 

  71. Smith T, DiBernardo A, Shi Y, Todd MJ, Brashear HR, Ford LM. Efficacy and safety of carisbamate in patients with diabetic neuropathy or postherpetic neuralgia: results from 3 randomized, double-blind placebo-controlled trials. Pain Pract. 2014;14(4):332–42.

    PubMed  Google Scholar 

  72. Ziegler D, Duan WR, An G, Thomas JW, Nothaft W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain. 2015;156(10):2013–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bansal D, Bhansali A, Hota D, Chakrabarti A, Dutta P. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009;26(10):1019–26.

  74. Boyle J, Eriksson ME, Gribble L, Gouni R, Johnsen S, Coppini DV, et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care. 2012;35(12):2451–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study. Curr Med Res Opin. 2009;25(7):1663–76.

    CAS  PubMed  Google Scholar 

  76. Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”—a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain. 2013;154(12):2616–25.

    CAS  PubMed  Google Scholar 

  77. Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1:CD007076.

  78. Zhang SS, Wu Z, Zhang LC, Zhang Z, Chen RP, Huang YH, et al. Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. Acta Anaesthesiol Scand. 2015;59(2):147–59.

    CAS  PubMed  Google Scholar 

  79. Parsons B, Li C. The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy. Curr Med Res Opin. 2016;32(5):929–37.

    CAS  PubMed  Google Scholar 

  80. Hurley RW, Lesley MR, Adams MC, Brummett CM, Wu CL. Pregabalin as a treatment for painful diabetic peripheral neuropathy: a meta-analysis. Reg Anesth Pain Med. 2008;33(5):389–94.

    CAS  PubMed  Google Scholar 

  81. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008;31(7):1448–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Serpell M, Latymer M, Almas M, Ortiz M, Parsons B, Prieto R. Neuropathic pain responds better to increased doses of pregabalin: an in-depth analysis of flexible-dose clinical trials. J Pain Res. 2017;10:1769–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Snedecor SJ, Sudharshan L, Cappelleri JC, Sadosky A, Mehta S, Botteman M. Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy. Pain Pract. 2014;14(2):167–84.

    PubMed  Google Scholar 

  84. Roth T, van Seventer R, Murphy TK. The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: a review of nine clinical trials. Curr Med Res Opin. 2010;26(10):2411–9.

    CAS  PubMed  Google Scholar 

  85. Lampl C, Schweiger C, Haider B, Lechner A. Pregabalin as mono- or add-on therapy for patients with refractory chronic neuropathic pain: a post-marketing prescription-event monitoring study. J Neurol. 2010;257(8):1265–73.

    PubMed  Google Scholar 

  86. Vinik A, Emir B, Parsons B, Cheung R. Prediction of pregabalin-mediated pain response by severity of sleep disturbance in patients with painful diabetic neuropathy and post-herpetic neuralgia. Pain Med. 2014;15(4):661–70.

    PubMed  Google Scholar 

  87. Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2011;52(4):826–36.

    CAS  PubMed  Google Scholar 

  88. Freynhagen R, Serpell M, Emir B, Whalen E, Parsons B, Clair A, et al. A comprehensive drug safety evaluation of pregabalin in peripheral neuropathic pain. Pain Pract. 2015;15(1):47–57.

    PubMed  Google Scholar 

  89. Parsons B, Emir B. Glycemic and serum lipid control in patients with painful diabetic peripheral neuropathy treated with pregabalin. J Diabetes Complic. 2017;31(2):489–93.

    Google Scholar 

  90. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77(4):403–26.

    CAS  PubMed  Google Scholar 

  91. England N. Rescheduling of gabapentin and pregabalin as schedule 3 controlled drugs. https://www.england.nhs.uk/wp-content/uploads/2019/03/pregabalin-and-gabapentin-guidance-v1.pdf2019

  92. K D. Handling of gabapentin and pregabalin as schedule 3 controlled drugs in health and justice commissioned services. https://www.england.nhs.uk/publication/handling-of-gabapentin-and-pregabalin-as-schedule-3-controlled-drugs-in-health-and-justice-commissioned-services/. NHS, England; 2019

  93. Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28(6):491–6.

    CAS  PubMed  Google Scholar 

  94. Bonnet U, Richter EL, Isbruch K, Scherbaum N. On the addictive power of gabapentinoids: a mini-review. Psychiatr Danub. 2018;30(2):142–9.

    CAS  PubMed  Google Scholar 

  95. Deeks ED. Mirogabalin: first global approval. Drugs. 2019;79(4):463–8.

    CAS  PubMed  Google Scholar 

  96. Field MJ, Li Z, Schwarz JB. Ca2+ channel alpha2-delta ligands for the treatment of neuropathic pain. J Med Chem. 2007;50(11):2569–75.

    CAS  PubMed  Google Scholar 

  97. Baba M, Matsui N, Kuroha M, Wasaki Y, Ohwada S. Mirogabalin for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase III study in Asian patients. J Diabetes Investig. 2019.

  98. Vinik A, Rosenstock J, Sharma U, Feins K, Hsu C, Merante D, et al. Efficacy and safety of mirogabalin (DS-5565) for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo- and active comparator-controlled, adaptive proof-of-concept phase 2 study. Diabetes Care. 2014;37(12):3253–61.

    CAS  PubMed  Google Scholar 

  99. Lawson K. A brief review of the pharmacology of amitriptyline and clinical outcomes in treating fibromyalgia. Biomedicines. 2017;5(2).

  100. Chong MS, Hester J. Diabetic painful neuropathy: current and future treatment options. Drugs. 2007;67(4):569–85.

    CAS  PubMed  Google Scholar 

  101. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005;96(6):399–409.

    CAS  PubMed  Google Scholar 

  102. Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states. Drugs Aging. 1996;8(6):459–76.

  103. 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. 1992;326(19):1250–6.

    CAS  PubMed  Google Scholar 

  104. Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smoller B, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37(4):589–96.

    CAS  PubMed  Google Scholar 

  105. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH. A comparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997;13(4):313–23.

    CAS  PubMed  Google Scholar 

  106. Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009;24(2):178–88.

    PubMed  Google Scholar 

  107. Biesbroeck R, Bril V, Hollander P, Kabadi U, Schwartz S, Singh SP, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther. 1995;12(2):111–20.

    CAS  PubMed  Google Scholar 

  108. Jose VM, Bhansali A, Hota D, Pandhi P. Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. Diabetes Med. 2007;24(4):377–83.

    CAS  Google Scholar 

  109. Kaur H, Hota D, Bhansali A, Dutta P, Bansal D, Chakrabarti A. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34(4):818–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 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. 2014;161(9):639–49.

    PubMed  Google Scholar 

  111. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015(7):CD008242.

  112. Max MB, Kishore-Kumar R, Schafer SC, Meister B, Gracely RH, Smoller B, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45(1):3–9 (discussion 1–2).

  113. Sindrup SH, Gram LF, Skjold T, Grodum E, Brøsen K, Beck-Nielsen H. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study. Br J Clin Pharmacol. 1990;30(5):683–91.

  114. Kvinesdal B, Molin J, Frøland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984;251(13):1727–30.

    CAS  PubMed  Google Scholar 

  115. Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209.

  116. Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014(9):CD011003.

  117. Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014(5):CD010769.

  118. Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS, Sindrup SH. Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial. Pain. 2015;156(5):958–66.

    CAS  PubMed  Google Scholar 

  119. Leucht C, Huhn M, Leucht S. Amitriptyline versus placebo for major depressive disorder. Cochrane Database Syst Rev. 2012;12:CD009138.

  120. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014;11(3–4):37–42.

    PubMed  PubMed Central  Google Scholar 

  121. Hunziker ME, Suehs BT, Bettinger TL, Crismon ML. Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder. Clin Ther. 2005;27(8):1126–43.

    CAS  PubMed  Google Scholar 

  122. Marks DM, Shah MJ, Patkar AA, Masand PS, Park GY, Pae CU. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol. 2009;7(4):331–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2011;50(5):281–94.

    CAS  PubMed  Google Scholar 

  124. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1–2):109–18.

  125. Raskin J, Pritchett YL, Wang F, D’Souza DN, Waninger AL, Iyengar S, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6(5):346–56.

    PubMed  Google Scholar 

  126. Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Iyengar S, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67(8):1411–20.

    CAS  PubMed  Google Scholar 

  127. Raskin J, Smith TR, Wong K, Pritchett YL, D’Souza DN, Iyengar S, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med. 2006;9(1):29–40.

    PubMed  Google Scholar 

  128. Wernicke JF, Raskin J, Rosen A, Pritchett YL, D’Souza DN, Iyengar S, et al. Duloxetine in the long-term management of diabetic peripheral neuropathic pain: an open-label, 52-week extension of a randomized controlled clinical trial. Curr Ther Res Clin Exp. 2006;67(5):283–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Wernicke JF, Wang F, Pritchett YL, Smith TR, Raskin J, D’Souza DN, et al. An open-label 52-week clinical extension comparing duloxetine with routine care in patients with diabetic peripheral neuropathic pain. Pain Med. 2007;8(6):503–13.

    PubMed  Google Scholar 

  130. Tanenberg RJ, Clemow DB, Giaconia JM, Risser RC. Duloxetine compared with pregabalin for diabetic peripheral neuropathic pain management in patients with suboptimal pain response to gabapentin and treated with or without antidepressants: a post hoc analysis. Pain Pract. 2014;14(7):640–8.

    PubMed  Google Scholar 

  131. Enomoto H, Yasuda H, Nishiyori A, Fujikoshi S, Furukawa M, Ishida M, et al. Duloxetine in patients with diabetic peripheral neuropathic pain in Japan: a randomized, doubleblind, noninferiority comparative study with pregabalin. J Pain Res. 2018;11:1857–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Quilici S, Chancellor J, Löthgren 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. 2009;9:6.

  133. Gao Y, Ning G, Jia WP, Zhou ZG, Xu ZR, Liu ZM, et al. Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China. Chin Med J (Engl). 2010;123(22):3184–92.

    CAS  PubMed  Google Scholar 

  134. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014(1):CD007115.

  135. Brunton S, Wang F, Edwards SB, Crucitti AS, Ossanna MJ, Walker DJ, et al. Profile of adverse events with duloxetine treatment: a pooled analysis of placebo-controlled studies. Drug Saf. 2010;33(5):393–407.

    CAS  PubMed  Google Scholar 

  136. Gahimer J, Wernicke J, Yalcin I, Ossanna MJ, Wulster-Radcliffe M, Viktrup L. A retrospective pooled analysis of duloxetine safety in 23,983 subjects. Curr Med Res Opin. 2007;23(1):175–84.

    CAS  PubMed  Google Scholar 

  137. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110(3):697–706.

    CAS  PubMed  Google Scholar 

  138. NICE. Neuropathic pain in adults: pharmacological management in non-specialist settings [CG173]. 2013. https://www.nice.org.uk/guidance/cg173.

  139. Aiyer R, Barkin RL, Bhatia A. Treatment of neuropathic pain with venlafaxine: a systematic review. Pain Med. 2017;18(10):1999–2012.

    PubMed  Google Scholar 

  140. Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015(8):CD011091.

  141. Trouvin AP, Perrot S, Lloret-Linares C. Efficacy of venlafaxine in neuropathic pain: a narrative review of optimized treatment. Clin Ther. 2017;39(6):1104–22.

    CAS  PubMed  Google Scholar 

  142. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352(13):1324–34.

    CAS  PubMed  Google Scholar 

  143. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374(9697):1252–61.

    CAS  PubMed  Google Scholar 

  144. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12(6):804–13.

    CAS  PubMed  Google Scholar 

  145. Gilron I, Tu D, Holden RR, Jackson AC, DuMerton-Shore D. Combination of morphine with nortriptyline for neuropathic pain. Pain. 2015;156(8):1440–8.

    CAS  PubMed  Google Scholar 

  146. Tanenberg RJ, Irving GA, Risser RC, Ahl J, Robinson MJ, Skljarevski V, et al. Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc. 2011;86(7):615–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Zin CS, Nissen LM, O’Callaghan JP, Duffull SB, Smith MT, Moore BJ. A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin. J Pain. 2010;11(5):462–71.

    CAS  PubMed  Google Scholar 

  148. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005;103(1):140–6.

    CAS  PubMed  Google Scholar 

  149. Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012(7):CD008943.

  150. Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6.

  151. Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017(6).

  152. Kurien T, Arendt-Nielsen L, Petersen KK, Graven-Nielsen T, Scammell BE. Preoperative neuropathic pain-like symptoms and central pain mechanisms in knee osteoarthritis predicts poor outcome 6 months after total knee replacement surgery. J Pain. 2018;19(11):1329–41.

    PubMed  Google Scholar 

  153. Vinik AI, Shapiro DY, Rauschkolb C, Lange B, Karcher K, Pennett D, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care. 2014;37(8):2302–9.

    CAS  PubMed  Google Scholar 

  154. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth. 2014;113(1):148–56.

    CAS  PubMed  Google Scholar 

  155. Vadivelu N, Kai A, Maslin B, Kodumudi G, Legler A, Berger JM. Tapentadol extended release in the management of peripheral diabetic neuropathic pain. Ther Clin Risk Manag. 2015;11:95–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151–62.

    CAS  PubMed  Google Scholar 

  157. Chou R, Fanciullo, G.J., Fine, P.G., et al. American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain; 2009:113–30.

  158. Nenke MA, Haylock CL, Rankin W, Inder WJ, Gagliardi L, Eldridge C, et al. Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. Psychoneuroendocrinology. 2015;56:157–67.

  159. Iqbal Z, Azmi S, Yadav R, Ferdousi M, Kumar M, Cuthbertson DJ, et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40(6):828–49.

    PubMed  Google Scholar 

  160. Kozma CM, Benson C, Slaton TL, Kim MS, Vorsanger GJ. Opioids before and after initiation of pregabalin in patients with diabetic peripheral neuropathy. Curr Med Res Opin. 2012;28(9):1485–96.

    CAS  PubMed  Google Scholar 

  161. Patil PR, Wolfe J, Said Q, Thomas J, Martin BC. Opioid use in the management of diabetic peripheral neuropathy (DPN) in a large commercially insured population. Clin J Pain. 2015;31(5):414–24.

    PubMed  PubMed Central  Google Scholar 

  162. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60(6):927–34.

    CAS  PubMed  Google Scholar 

  163. Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1–2):71–8.

    CAS  PubMed  Google Scholar 

  164. Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial sample size on treatment effect estimates: meta-epidemiological study. BMJ (Clinical Research Ed). 2013;346:f2304-f.

  165. McNicol ED, Midbari, A., Eisenberg, E. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2013;8.

  166. McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2013(8).

  167. Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016(7).

  168. Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, et al. Fentanyl for neuropathic pain in adults. Cochrane Database Syst Rev. 2016(10).

  169. Stannard C, Gaskell H, Derry S, Aldington D, Cole P, Cooper TE, et al. Hydromorphone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016(5).

  170. Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice ASC, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia—an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013(11).

  171. Agrawal RP, Goswami J, Jain S, Kochar DK. Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study. Diabetes Res Clin Pract. 2009;83(3):371–8.

    CAS  PubMed  Google Scholar 

  172. Kochar DK, Rawat N, Agrawal RP, Vyas A, Beniwal R, Kochar SK, et al. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. QJM. 2004;97(1):33–8.

    CAS  PubMed  Google Scholar 

  173. Wadhawan S, Pant S, Golhar R, Kirov S, Thompson J, Jacobsen L, et al. NaV channel variants in patients with painful and nonpainful peripheral neuropathy. Neurol Genet. 2017;3(6):e207.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Hoeijmakers JG, Faber CG, Merkies IS, Waxman SG. Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point? Trends Mol Med. 2014;20(10):544–50.

    CAS  PubMed  Google Scholar 

  175. Wolff RF, Bala MM, Westwood M, Kessels AG, Kleijnen J. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): a systematic review. Swiss Med Wkly. 2010;140:297–306.

    CAS  PubMed  Google Scholar 

  176. Krumova EK, Zeller M, Westermann A, Maier C. Lidocaine patch (5%) produces a selective, but incomplete block of Adelta and C fibers. Pain. 2012;153(2):273–80.

    CAS  PubMed  Google Scholar 

  177. Barbano RL, Herrmann DN, Hart-Gouleau S, Pennella-Vaughan J, Lodewick PA, Dworkin RH. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol. 2004;61(6):914–8.

    PubMed  Google Scholar 

  178. Wolff RF, Bala MM, Westwood M, Kessels AG, Kleijnen J. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): a systematic review. Swiss Med Wkly. 2010;140(21–22):297–306.

    CAS  PubMed  Google Scholar 

  179. Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ. 2014;348:g1799.

    PubMed  Google Scholar 

  180. Cizkova D, Lukacova N, Marsala M, Marsala J. Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Res Bull. 2002;58(2):161–71.

    CAS  PubMed  Google Scholar 

  181. Yuen KC, Baker, N.R., Rayman, G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled cross-over study. . Diabetes Care. 2002;25:1699–703.

  182. Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care. 2003;26:2697–8.

    PubMed  Google Scholar 

  183. Markovits E, Gilhar A. Capsaicin—an effective topical treatment in pain. Int J Dermatol. 1997;36:401–4.

    CAS  PubMed  Google Scholar 

  184. Cortright DN, Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur J Biochem. 2004;271:1814–9.

    CAS  PubMed  Google Scholar 

  185. The Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical Capsaicin A multicenter, double-blind, vehicle-controlled study. Arch Intern Med. 1991;151(11):2225–9.

  186. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med. 1991;151(11):2225–9.

  187. Kulkantrakorn K, Lorsuwansiri C, Meesawatsom P. 0.025% capsaicin gel for the treatment of painful diabetic neuropathy: a randomized, double-blind, crossover, placebo-controlled trial. Pain Pract. 2013;13(6):497–503.

  188. Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fiber regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127(Pt 7):1606–15.

    PubMed  Google Scholar 

  189. Burness CB, McCormack PL. Capsaicin 8% patch: a review in peripheral neuropathic pain. Drugs. 2016;76(1):123–34.

    CAS  PubMed  Google Scholar 

  190. Vinik AI, Perrot S, Vinik EJ, Pazdera L, Jacobs H, Stoker M, et al. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC Neurol. 2016;16(1):251.

    PubMed  PubMed Central  Google Scholar 

  191. Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain. 2012;153(9):1815–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Ho KY, Huh BK, White WD, Yeh CC, Miller EJ. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain. 2008;24(1):51–5.

    PubMed  Google Scholar 

  193. Gordon RA. Intravenous novocaine for analgesia in burns: (a preliminary report). Can Med Assoc J. 1943;49(6):478–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Viola V, Newnham HH, Simpson RW. Treatment of intractable painful diabetic neuropathy with intravenous lignocaine. J Diabetes Complic. 2006;20(1):34–9.

    Google Scholar 

  195. Rogers M, Tang L, Madge DJ, Stevens EB. The role of sodium channels in neuropathic pain. Semin Cell Dev Biol. 2006;17:571–81.

    CAS  PubMed  Google Scholar 

  196. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000;93:858–75.

    CAS  PubMed  Google Scholar 

  197. Hu P, McLachlan EM. Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience. 2002;112:23–38.

    CAS  PubMed  Google Scholar 

  198. Moulin DE, Morley-Forster PK, Pirani Z, Rohfritsch C, Stitt L. Intravenous lidocaine in the management of chronic peripheral neuropathic pain: a randomized-controlled trial. Can J Anaesth. 2019;66(7):820–7.

  199. Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB, et al. Diabetes in older adults: a consensus report. J Am Geriatr Soc. 2012;60(12):2342–56.

    PubMed  PubMed Central  Google Scholar 

  200. Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic neuropathy in older adults. Clin Geriatr Med. 2008;24(3):407–35 (v).

  201. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther. 2004;75(3):234–41.

    CAS  PubMed  Google Scholar 

  202. Yekehtaz H, Farokhnia M, Akhondzadeh S. Cardiovascular considerations in antidepressant therapy: an evidence-based review. J Tehran Heart Cent. 2013;8(4):169–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Toth C. Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain. Ther Adv Drug Saf. 2014;5(1):38–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Alsaloum M, Estacion M, Almomani R, Gerrits MM, Bonhof GJ, Ziegler D, et al. A gain-of-function sodium channel beta2-subunit mutation in painful diabetic neuropathy. Mol Pain. 2019;15:1744806919849802.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Lauria G, Ziegler D, Malik R, Merkies IS, Waxman SG, Faber CG. The role of sodium channels in painful diabetic and idiopathic neuropathy. Curr Diab Rep. 2014;14(10):538.

    PubMed  Google Scholar 

  206. Calandre EP, Morillas-Arques P, Molina-Barea R, Rodriguez-Lopez CM, Rico-Villademoros F. Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study. BMC Musculoskelet Disord. 2011;12(1):95.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord. 2007;8:27.

    PubMed  PubMed Central  Google Scholar 

  208. Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469–76.

    CAS  PubMed  Google Scholar 

  209. Keppel Hesselink JM, Schatman ME. EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain. J Pain Res. 2017;10:439–43.

    PubMed  PubMed Central  Google Scholar 

  210. Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, et al. Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. Eur J Pain (London, England). 2013;17(7):1012–26.

    CAS  Google Scholar 

  211. Chio CC, Chang YH, Hsu YW, Chi KH, Lin WW. PKA-dependent activation of PKC, p38 MAPK and IKK in macrophage: implication in the induction of inducible nitric oxide synthase and interleukin-6 by dibutyryl cAMP. Cell Signal. 2004;16(5):565–75.

    CAS  PubMed  Google Scholar 

  212. Rice ASC, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet (London, England). 2014;383(9929):1637–47.

    CAS  Google Scholar 

  213. Tesfaye S. PL37: a new hope in the treatment of painful diabetic neuropathy? Pain Manag. 2016;6(2):129–32.

    PubMed  Google Scholar 

  214. Thibault K, Elisabeth B, Sophie D, Claude FZ, Bernard R, Bernard C. Antinociceptive and anti-allodynic effects of oral PL37, a complete inhibitor of enkephalin-catabolizing enzymes, in a rat model of peripheral neuropathic pain induced by vincristine. Eur J Pharmacol. 2008;600(1–3):71–7.

    CAS  PubMed  Google Scholar 

  215. Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015;20:658–66.

    PubMed  PubMed Central  Google Scholar 

  216. Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts L, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci. 2017;58(6):Bio52–Bio60.

  217. Thisted RA, Klaff L, Schwartz SL, Wymer JP, Culligan NW, Gerard G, et al. Dextromethorphan and quinidine in adult patients with uncontrolled painful diabetic peripheral neuropathy: a 29-day, multicenter, open-label, dose-escalation study. Clin Ther. 2006;28(10):1607–18.

    CAS  PubMed  Google Scholar 

  218. Shaibani AI, Pope LE, Thisted R, Hepner A. Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study. Pain Med. 2012;13(2):243–54.

    PubMed  Google Scholar 

  219. Basit A, Basit KA, Fawwad A, Shaheen F, Fatima N, Petropoulos IN, et al. Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Res Care. 2016;4(1).

  220. Bell DS. Reversal of the symptoms of diabetic neuropathy through correction of vitamin D deficiency in a type 1 diabetic patient. Case Rep Endocrinol. 2012;2012:165056.

    PubMed  PubMed Central  Google Scholar 

  221. Shehab D, Al-Jarallah K, Abdella N, Mojiminiyi OA, Al Mohamedy H. Prospective evaluation of the effect of short-term oral vitamin d supplementation on peripheral neuropathy in type 2 diabetes mellitus. Med Princ Pract. 2015;24(3):250–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Ghadiri-Anari A, Mozafari Z, Gholami S, Khodaei SA, Aboutorabi-Zarchi M, Sepehri F, et al. Dose vitamin D supplementations improve peripheral diabetic neuropathy? A before-after clinical trial. Diabetes Metab Syndrome. 2019;13(1):890–3.

    Google Scholar 

  223. Lee P, Chen R. Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Arch Intern Med. 2008;168(7):771–2.

    PubMed  Google Scholar 

  224. Valensi P, Le Devehat C, Richard JL, Farez C, Khodabandehlou T, Rosenbloom RA, et al. A multicenter, double-blind, safety study of QR-333 for the treatment of symptomatic diabetic peripheral neuropathy. A preliminary report. J Diabetes Complic. 2005;19(5):247–53.

    Google Scholar 

  225. Shillo P, Selvarajah D, Greig M, Gandhi R, Rao G, Wilkinson ID, et al. Reduced vitamin D levels in painful diabetic peripheral neuropathy. Diabetic Med. 2019;36(1):44–51.

    CAS  PubMed  Google Scholar 

  226. Soderstrom LH, Johnson SP, Diaz VA, Mainous AG 3rd. Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001-2004 NHANES. Diabetic Med. 2012;29(1):50–5.

    CAS  PubMed  Google Scholar 

  227. Basit A, Basit KA, Fawwad A, Shaheen F, Fatima N, Petropoulos IN, et al. Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Res Care. 2016;4(1):e000148.

    PubMed  PubMed Central  Google Scholar 

  228. Alam U, Fawwad A, Shaheen F, Tahir B, Basit A, Malik RA. Improvement in neuropathy specific quality of life in patients with diabetes after vitamin D supplementation. J Diabetes Res. 2017;2017:7928083.

    PubMed  PubMed Central  Google Scholar 

  229. Dworkin RH, Turk DC, Peirce-Sandner S, McDermott MP, Farrar JT, Hertz S, et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain. 2010;150(1):12–6.

  230. Thienel U, Neto W, Schwabe SK, Vijapurkar U. Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials. Acta Neurol Scand. 2004;110(4):221–31.

    CAS  PubMed  Google Scholar 

  231. Silver M, Blum D, Grainger J, Hammer AE, Quessy S. Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. J Pain Symptom Manag. 2007;34(4):446–54.

    CAS  Google Scholar 

  232. Vinik AI, Tuchman M, Safirstein B, Corder C, Kirby L, Wilks K, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain. 2007;128(1–2):169–79.

    CAS  PubMed  Google Scholar 

  233. Hauser W, Bartram-Wunn E, Bartram C, Reinecke H, Tolle T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain. 2011;152(8):1709–17.

    PubMed  Google Scholar 

  234. Irving G. The placebo response: relationship to outcomes in trials of postherpetic neuralgia. Clin Drug Investig. 2010;30(11):739–48.

    CAS  PubMed  Google Scholar 

  235. Katz J, Finnerup NB, Dworkin RH. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology. 2008;70(4):263–72.

    PubMed  Google Scholar 

  236. Dworkin RH, Turk DC, Peirce-Sandner S, Burke LB, Farrar JT, Gilron I, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain. 2012;153(6):1148–58.

    CAS  PubMed  Google Scholar 

  237. Freeman R, Emir B, Parsons B. Predictors of placebo response in peripheral neuropathic pain: insights from pregabalin clinical trials. J Pain Res. 2015;8:257–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Wiffen PJ, Derry S, Moore RA. Lamotrigine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2013(12).

  239. Irizarry MC, Webb DJ, Ali Z, Chizh BA, Gold M, Kinrade FJ, et al. Predictors of placebo response in pooled lamotrigine neuropathic pain clinical trials. Clin J Pain. 2009;25(6):469–76.

    PubMed  Google Scholar 

  240. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care. 2010;33(1):128–30.

    PubMed  Google Scholar 

  241. Quessy SN, Rowbotham MC. Placebo response in neuropathic pain trials. Pain. 2008;138(3):479–83.

    PubMed  Google Scholar 

  242. Tavakoli M, Asghar O, Alam U, Petropoulos IN, Fadavi H, Malik RA. Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy. Ther Adv Endocrinol Metab. 2010;1(2):69–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Dworkin RH, Katz J, Gitlin MJ. Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain. Neurology. 2005;65(12 Suppl 4):S7–19.

    PubMed  Google Scholar 

  244. H.J. M. Placebo and control event rate. In: McQuay H.J., editor. Systematic reviews in pain research: methodology redefined. IASP Press, Seattle; 2008. pp. 51–6.

  245. Mackey S, Greely HT, Martucci KT. Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine. Pain Rep. 2019;4(4):e762.

    PubMed  PubMed Central  Google Scholar 

  246. Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain. 1983;17(1):45–56.

    CAS  PubMed  Google Scholar 

  247. Fillingim RB. Individual differences in pain: understanding the mosaic that makes pain personal. Pain. 2017;158(Suppl 1):S11–S18.

    PubMed  PubMed Central  Google Scholar 

  248. Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice AS, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia—an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013(11):CD010567.

  249. Selvarajah D, Heiberg-Gibbons F, Wilkinson ID, Gandhi R, Tesfaye S. A magnetic resonance imaging volumetry study of regional brain atrophy in diabetic peripheral neuropathy. Diabetes. 2018;67(Supplement 1):550-P.

  250. Selvarajah D, Awadh M, Gandhi R, Wilkinson ID, Tesfaye S. Alterations in somatomotor network functional connectivity in painful diabetic neuropathy—a resting state functional magnetic resonance imaging study. Diabetes. 2018;67(Supplement 1):61-OR.

  251. Segerdahl AR, Themistocleous AC, Fido D, Bennett DL, Tracey I. A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy. Brain. 2018;141(2):357–64.

    PubMed  PubMed Central  Google Scholar 

  252. Wanigasekera V, Mezue M, Andersson J, Kong Y, Tracey I. Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development. Anesthesiology. 2016;124(1):159–68.

    CAS  PubMed  Google Scholar 

  253. Bouhassira D, Wilhelm S, Schacht A, Perrot S, Kosek E, Cruccu G, et al. Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind. COMBO-DN study. Pain. 2014;155(10):2171–9.

    PubMed  Google Scholar 

  254. Rolim LC, Koga da Silva EM, De Sá JR, Dib SA. A systematic review of treatment of painful diabetic neuropathy by pain phenotype versus treatment based on medical comorbidities. Front Neurol. 2017;8(285).

  255. Vadivelu N, et al. Patient considerations in the use of tapentadol for moderate to severe pain. Drug Healthc Patient Saf. 2013;5:151–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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There was no financial support for the production of this article. No other individuals were involved in the production of the manuscript. All authors contributed equally to the production of the manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

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UA. has received honoraria for educational meetings from Sanofi, Napp, Boerhringer Ingelheim, Pfizer and Eli Lilly, and is currently a local investigator for BIIB074 (Vixotrigine) (Biogen: NCT03339336). G.S. has none to declare. S.T. reports grants from Impeto Medical; personal fees from Neurometrix, Pfizer, Miro, Worwag Pharma, Mundipharma, Merck and Mitsubishi Pharma; and personal fees and other from Novo Nordisk.

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Alam, U., Sloan, G. & Tesfaye, S. Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs. Drugs 80, 363–384 (2020). https://doi.org/10.1007/s40265-020-01259-2

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