Generic placeholder image

CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Pharmacological Treatment of Diabetic Peripheral Neuropathy: An Update

Author(s): Mohamed Rafiullah* and Khalid Siddiqui

Volume 21, Issue 10, 2022

Published on: 03 March, 2021

Page: [884 - 900] Pages: 17

DOI: 10.2174/1871527320666210303111939

Price: $65


Neuropathy is the most common complication of diabetes. 50% of adults with diabetes will develop neuropathy in their lifetime. Diabetic peripheral neuropathy (DPN) is the major form of neuropathy found in 75% of diabetic neuropathy incidences. Pharmacological treatments are recommended for pain management in DPN. Anticonvulsants like pregabalin and gabapentin are the preferred first-line treatment, followed by amitriptyline, duloxetine, and venlafaxine. Topical agents like capsaicin and isosorbide dinitrate are also useful in treating the DPN and may be considered for the second or third-line treatment. Opioids and related drugs are suggested for short-term use during the acute exacerbation of pain. Combination therapy may be beneficial in patients who do not respond to monotherapy. However, currently, there is no compelling evidence to suggest any specific combination of agents. Disease-modifying agents such as alpha-lipoic acid and epalrestat appear to improve the disease state but are not recommended by any guideline. This review discusses the available pharmacological therapy for treating DPN. Also, we highlight the recommendations from different guidelines about the pharmacological treatment of DPN.

Keywords: Diabetic peripheral neuropathy, diabetes, neuropathic pain, pharmacological treatment, diabetic complication, pain.

WHO. The top 10 causes of death. Fact Sheets 2018.
Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep 2019; 19(10): 86.
[] [PMID: 31456118]
Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012; 11(6): 521-34.
[] [PMID: 22608666]
Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012; 28(Suppl. 1): 8-14.
[] [PMID: 22271716]
Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 2017; 40(1): 136-54.
[] [PMID: 27999003]
Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep 2014; 14(8): 473.
[] [PMID: 24954624]
Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000 Res 2016; 5: 5.
[] [PMID: 27158461]
Microvascular Complications and Foot Care: <em>Standards of Medical Care in Diabetes—2019</em>. Diabetes Care 2019; 42(Supplement 1): 124-38. content/42/Supplement_1/S124
Khdour MR. Treatment of diabetic peripheral neuropathy: a review. J Pharm Pharmacol 2020; 72(7): 863-72.
[] [PMID: 32067247]
Ardeleanu V, Toma A, Pafili K, et al. Current pharmacological treatment of painful diabetic neuropathy: A narrative review. Medicina (Kaunas) 2020; 56(1): 1-10.
[PMID: 31936646]
Arora N, Niraj G. Management of painful peripheral diabetic neuropathy. Br J Med Pract 2013; 6(1): a606.
Singh R, Rao HK, Singh TG. Neuropathic pain in diabetes mellitus: Challenges and future trends. Obes Med 2020; 18: 100215.
Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev 2019; 1(1): CD007076.
[PMID: 30673120]
Zhang S-S, Wu Z, Zhang L-C, et al. Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. Acta Anaesthesiol Scand 2015; 59(2): 147-59.
[] [PMID: 25328117]
Onakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ Open 2019; 9(1): e023600.
[] [PMID: 30670513]
Bonnet U, Scherbaum N. On the risk of dependence on gabapentinoids. Fortschr Neurol Psychiatr 2018; 86(2): 82-105.
[PMID: 29179227]
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.
[] [PMID: 20818832]
Backonja M, Beydoun A, Edwards KR, 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.
[] [PMID: 9846777]
Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017; 6(6): CD007938.
[] [PMID: 28597471]
Sandercock D, Cramer M, Wu J, Chiang Y-K, Biton V, Heritier M. Gabapentin Extended Release for the Treatment of Painful Diabetic Peripheral Neuropathy. Diabetes Care 2009; 32(2): 20-0.
Treatments P. AAN summary of evidence-based guideline for clinicians treatment of painful diabetic neuropathy. 2011.
Narain T, Adcock L. Gabapentin for Adults with Neuropathic Pain: A Review of the Clinical Effectiveness. Gabapentin Adults with Neuropathic Pain A Rev Clin Eff 2018
Sekar P, Punnagai K, David DC. Comparative study of safety and efficacy of gabapentin versus amitriptyline in patients with painful diabetic peripheral neuropathy, a randomized open label parallel group study. Biomed Pharmacol J 2017; 10(3): 1259-65.
Wiffen PJ, Derry S, Moore RA, Kalso EA. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014; 2014(4): CD005451.
[] [PMID: 24719027]
Cohen K, Shinkazh N, Frank J, Israel I, Fellner C. Pharmacological treatment of diabetic peripheral neuropathy. P&T 2015; 40(6): 372-88.
[PMID: 26045647]
Zhou M, Chen N, He L, Yang M, Zhu C, Wu F. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2013; CD007963(3): CD007963.
[PMID: 23543558]
Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011; 2011(10): CD009183.
[PMID: 21975791]
Vinik AI, Tuchman M, Safirstein B, 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. article/pii/S0304395906005252
[] [PMID: 17161535]
Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy. Neurology 2001; 57(3): 505-9.
Wiffen PJ, Derry S, Moore RA. Lamotrigine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013; 2013(12): CD006044-.
[] [PMID: 24297457]
Beyreuther BK, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007; 13(1): 21-42.
[] [PMID: 17461888]
Ziegler D, Hidvégi T, Gurieva I, et al. Efficacy and safety of lacosamide in painful diabetic neuropathy. Diabetes Care 2010; 33(4): 839-41.
[] [PMID: 20067958]
Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012; CD009318(2): CD009318.
[] [PMID: 22336864]
Carroll DG, Kline KM, Malnar KF. Role of topiramate for the treatment of painful diabetic peripheral neuropathy. Pharmacotherapy 2004; 24(9): 1186-93.
[] [PMID: 15460179]
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.
[] [PMID: 15355485]
Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013; 2013(8): CD008314.
Nazarbaghi S, Amiri-Nikpour MR, Eghbal AF, Valizadeh R. Comparison of the effect of topiramate versus gabapentin on neuropathic pain in patients with polyneuropathy: A randomized clinical trial. Electron Physician 2017; 9(10): 5617-22.
[] [PMID: 29238506]
Lawson K. A Brief Review of the Pharmacology of Amitriptyline and Clinical Outcomes in Treating Fibromyalgia. Biomedicines 2017; 5(2): E24.
[] [PMID: 28536367]
Baltenberger EP, Buterbaugh WM, Martin BS, Thomas CJ. Review of antidepressants in the treatment of neuropathic pain. Ment Heal Clin 2015; 5(3): 123-33.
Lee Y-C, Chen P-P. A review of SSRIs and SNRIs in neuropathic pain. Expert Opin Pharmacother 2010; 11(17): 2813-25.
[] [PMID: 20642317]
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.
[] [PMID: 21355098]
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.
[] [PMID: 10493324]
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.
[] [PMID: 19900234]
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015; 2015(7): CD008242.
[PMID: 26146793]
Schulz P, Turner-Tamiyasu K, Smith G, Giacomini KM, Blaschke TF. Amitriptyline disposition in young and elderly normal men. Clin Pharmacol Ther 1983; 33(3): 360-6.
[] [PMID: 6825390]
Boulton AJM. Management of Diabetic Peripheral Neuropathy. Clin Diabetes 2005; 23(1): 9-15.
Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain 1991; 45(1): 3-9.
[] [PMID: 1861872]
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.
[] [PMID: 1560801]
Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; 2014(9): CD011003.
[PMID: 25246131]
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.
[] [PMID: 2271367]
Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; 2014(5): CD010769.
[PMID: 24838845]
Snyder MJ, Gibbs LM, Lindsay TJ. Treating painful diabetic peripheral neuropathy: An update. Am Fam Physician 2016; 94(3): 227-34.
[PMID: 27479625]
Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015; 1(1): CD011209.
[PMID: 25569864]
Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci 2014; 11(3-4): 37-42.
[PMID: 24800132]
Minami K, Tamano R, Kasai E, et al. Effects of duloxetine on pain and walking distance in neuropathic pain models via modulation of the spinal monoamine system. Eur J Pain 2018; 22(2): 355-69.
[] [PMID: 28952182]
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.
[] [PMID: 15927394]
Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006; 67(8): 1411-20.
[] [PMID: 17060567]
Raskin J, Pritchett YL, Wang F, 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.
[] [PMID: 16266355]
Raskin J, Smith TR, Wong K, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med 2006; 9(1): 29-40.
[] [PMID: 16430342]
Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014; CD007115(1): CD007115.
[] [PMID: 24385423]
Boyle J, Eriksson MEV, Gribble L, 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.
[] [PMID: 22991449]
Tanenberg RJ, Irving GA, Risser RC, 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.
[] [PMID: 21719618]
Wasan AD, Ossanna MJ, Raskin J, et al. Safety and efficacy of duloxetine in the treatment of diabetic peripheral neuropathic pain in older patients. Curr Drug Saf 2009; 4(1): 22-9.
[] [PMID: 19149522]
Chappell AS, Littlejohn G, Kajdasz DK, Scheinberg M, D’Souza DN, Moldofsky H. A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia. Clin J Pain 2009; 25(5): 365-75.
[] [PMID: 19454869]
Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJM. Does Treatment With Duloxetine for Neuropathic Pain Impact Glycemic Control? Diabetes Care 2007; 30(1): 21-6.
Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2011; 50(5): 281-94.
[] [PMID: 21366359]
Cegielska-Perun K, Bujalska-Zadrożny M, Tatarkiewicz J, Gąsińska E, Makulska-Nowak HE. Venlafaxine and neuropathic pain. Pharmacology 2013; 91(1-2): 69-76.
[] [PMID: 23183148]
Aiyer R, Barkin RL, Bhatia A. Treatment of Neuropathic Pain with Venlafaxine: A Systematic Review. Pain Med 2017; 18(10): 1999-2012.
[] [PMID: 27837032]
Trouvin A-P, Perrot S, Lloret-Linares C. Efficacy of Venlafaxine in Neuropathic Pain: A Narrative Review of Optimized Treatment. Clin Ther 2017; 39(6): 1104-22.
[] [PMID: 28554532]
Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications 2008; 22(4): 241-5.
[] [PMID: 18413214]
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.
[] [PMID: 15288411]
Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev 2015; 2015(8): CD011091.
[PMID: 26298465]
Jia HY, Li QF, Song DP, et al. Effects of venlafaxine and carbamazepine for painful peripheral diabetic neuropathy: A randomized, double-blind and double-dummy, controlled multi-center trial. Chinese J Evidence-Based Med 2006; 6(5): 321-8.
Razazian N, Baziyar M, Moradian N, Afshari D, Bostani A, Mahmoodi M. Evaluation of the efficacy and safety of pregabalin, venlafaxine, and carbamazepine in patients with painful diabetic peripheral neuropathy. A randomized, double-blind trial. Neurosciences (Riyadh) 2014; 19(3): 192-8.
[PMID: 24983280]
St Onge EL, Miller SA. Pain associated with diabetic peripheral neuropathy: a review of available treatments. P&T 2008; 33(3): 166-76.
[PMID: 19750158]
Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis 2001; 3(2): 53-62.
[] [PMID: 19078655]
Magalhães P, Alves G, Llerena A, Falcão A. Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers. Drug Metabol Drug Interact 2014; 29(3): 129-41.
[] [PMID: 24607919]
Troy SM, Schultz RW, Parker VD, Chiang ST, Blum RA. The effect of renal disease on the disposition of venlafaxine. Clin Pharmacol Ther 1994; 56(1): 14-21.
[] [PMID: 8033490]
Allen R, Sharma U, Barlas S. Clinical experience with desvenlafaxine in treatment of pain associated with diabetic peripheral neuropathy. J Pain Res 2014; 7: 339-51.
[] [PMID: 25018648]
Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia. Med Clin North Am 2007; 91(2): 199-211.
[] [PMID: 17321281]
Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50(6): 1842-6.
[] [PMID: 9633738]
Ko S, Kwon H, Yu J, et al. Original Article : Treatment Comparison of the efficacy and safety of tramadol / acetaminophen combination therapy and gabapentin in the treatment of painful diabetic neuropathy. 2010; 1033-40.
Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications 2000; 14(2): 65-70.
[] [PMID: 10959067]
Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev 2017; 6(6): CD003726.
[PMID: 28616956]
Boostani R, Derakhshan S. Tramadol induced seizure: A 3-year study. Caspian J Intern Med 2012; 3(3): 484-7.
[PMID: 24009919]
Vazzana M, Andreani T, Fangueiro J, et al. Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother 2015; 70: 234-8.
[] [PMID: 25776506]
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.
[] [PMID: 21162697]
Vinik AI, Shapiro DY, Rauschkolb C, 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.
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.
[] [PMID: 24713310]
Jain D, Basniwal PK. Tapentadol, a novel analgesic: Review of recent trends in synthesis, related substances, analytical methods, pharmacodynamics and pharmacokinetics. Bull Fac Pharm Cairo Univ 2013; 51(2): 283-9. article/pii/S1110093113000239
Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003; 60(6): 927-34.
[] [PMID: 12654955]
Watson CPN, 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.
[] [PMID: 14499422]
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.
[] [PMID: 18262450]
Gatti A, Sabato AF, Occhioni R, Colini Baldeschi G, Reale C. Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: results of a multicenter Italian study. Eur Neurol 2009; 61(3): 129-37.
[] [PMID: 19092248]
Yao P, Meng L-X, Ma J-M, et al. Sustained-release oxycodone tablets for moderate to severe painful diabetic peripheral neuropathy: a multicenter, open-labeled, postmarketing clinical observation. Pain Med 2012; 13(1): 107-14.
[] [PMID: 22082200]
Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 2016; 7(7): CD010692-.
[PMID: 27465317]
Huddart R, Clarke M, Altman RB, Klein TE. PharmGKB summary: oxycodone pathway, pharmacokinetics. Pharmacogenet Genomics 2018; 28(10): 230-7.
[PMID: 30222708]
Thisted RA, Klaff L, Schwartz SL, 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.
[] [PMID: 17157116]
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.
[] [PMID: 22314263]
Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002; 96(5): 1053-61.
[] [PMID: 11981142]
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.
[] [PMID: 15800228]
Cooper TE, Chen J, Wiffen PJ, et al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017; 5(5): CD011669.
[] [PMID: 28530786]
Fattori V, Hohmann MSN, Rossaneis AC, Pinho-Ribeiro FA, Verri WA. Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses. Molecules 2016; 21(7): E844.
[] [PMID: 27367653]
Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Arch Intern Med 1991; 151(11): 2225-9.
[] [PMID: 1953227]
Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992; 15(2): 159-65.
[] [PMID: 1547671]
Tandan R, Lewis GA, Krusinski PB, Badger GB, Fries TJ. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992; 15(1): 8-14.
[] [PMID: 1737545]
Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O’Brien PC. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain 1995; 62(2): 163-8.
[] [PMID: 8545141]
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.
[] [PMID: 23228119]
Biesbroeck R, Bril V, Hollander P, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995; 12(2): 111-20.
[PMID: 10150323]
Mou J, Paillard F, Turnbull B, Trudeau J, Stoker M, Katz NP. Qutenza (capsaicin) 8% patch onset and duration of response and effects of multiple treatments in neuropathic pain patients. Clin J Pain 2014; 30(4): 286-94.
[] [PMID: 23765045]
Simpson DM, Robinson-Papp J, Van J, et al. Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. J Pain 2017; 18(1): 42-53.
[] [PMID: 27746370]
Vinik AI, Perrot S, Vinik EJ, 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.
[] [PMID: 27919222]
Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2009; CD007393(4): CD007393.
[] [PMID: 19821411]
van Nooten F, Treur M, Pantiri K, Stoker M, Charokopou M. Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis. Clin Ther 2017; 39(4): 787-803.e18.
[] [PMID: 28365034]
Yang X-D, Fang P-F, Xiang D-X, Yang Y-Y. Topical treatments for diabetic neuropathic pain. Exp Ther Med 2019; 17(3): 1963-76.
[PMID: 30783472]
Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin 2004; 20(Suppl. 2): S21-8.
[] [PMID: 15563743]
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.
[] [PMID: 15210530]
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.
[] [PMID: 19485723]
Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 2009; 25(7): 1677-87.
[] [PMID: 19480610]
Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; 2014(7): CD010958.
[] [PMID: 25058164]
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.
[PMID: 20458651]
Yuen KCJ, Baker NR, Rayman G. Treatment of Chronic Painful Diabetic Neuropathy With Isosorbide Dinitrate Spray. Diabetes Care 2002; 25(10): 1703. content/25/10/1699
Agrawal RP, Choudhary R, Sharma P, et al. Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study. Diabetes Res Clin Pract 2007; 77(2): 161-7.
[] [PMID: 17316865]
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.
[] [PMID: 19208440]
Bril V, Breiner A, Perkins BA, Zochodne D. Clinical Practice Guidelines: Neuropathy. Diabetes Canada Clin Pract Guidel Expert Comm 2018; 42: 5.
Flores MP, Castro AP, Nascimento J dos S. Topical analgesics. Rev Bras Anestesiol 2012; 62(2): 244-52.
[] [PMID: 22440379]
Kiani J, Ahmad Nasrollahi S, Esna-Ashari F, Fallah P, Sajedi F. Amitriptyline 2% cream vs. capsaicin 0.75% cream in the treatment of painful diabetic neuropathy (Double blind, randomized clinical trial of efficacy and safety). Iran J Pharm Res 2015; 14(4): 1263-8.
[PMID: 26664395]
Ho K-Y, Huh BK, White WD, Yeh C-C, Miller EJ. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain 2008; 24(1): 51-5.
[] [PMID: 18180637]
Kopsky DJ, Hesselink JMK. High doses of topical amitriptyline in neuropathic pain: two cases and literature review. Pain Pract 2012; 12(2): 148-53.
[] [PMID: 21676162]
Campbell C, Campbell J, Schmidt W, Brady K, Stouch B. Topical clonidine gel reduces pain caused by diabetic neuropathy: Results of a multicenter, placebo-controlled clinical trial. J Pain 2009; 10(4)(Suppl.): S55. pii/S1526590009003411
Campbell CM, Kipnes MS, Stouch BC, et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 2012; 153(9): 1815-23.
[] [PMID: 22683276]
Wrzosek A, Woron J, Dobrogowski J, Jakowicka-Wordliczek J, Wordliczek J. Topical clonidine for neuropathic pain. Cochrane Database Syst Rev 2015; 8(9): CD010967.
[PMID: 26329307]
Park J, Park HJ. Botulinum Toxin for the Treatment of Neuropathic Pain. Toxins (Basel) 2017; 9(9): E260.
[] [PMID: 28837075]
Lakhan SE, Velasco DN, Tepper D. Botulinum Toxin-A for Painful Diabetic Neuropathy: A Meta-Analysis. Pain Med 2015; 16(9): 1773-80.
[] [PMID: 25800040]
Ghasemi M, Ansari M, Basiri K, Shaigannejad V. The effects of intradermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathy. J Res Med Sci 2014; 19(2): 106-11.
[PMID: 24778662]
Gomaa M, Egila H. Botulinum Toxin Type A in Severe Diabetic Neuropathy (P6.272). Neurology 2016.
Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag 2003; 8(3): 149-54.
[] [PMID: 14657982]
Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med 2003; 17(7): 576-87.
[] [PMID: 14594148]
McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev 2017; 5(5): CD012499.
[PMID: 28514508]
Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018; 3(3): CD012182.
[] [PMID: 29513392]
Albers JW, Herman WH, Pop-Busui R, 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.
[] [PMID: 20150297]
Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012; 6(6): CD007543.
[] [PMID: 22696371]
Rochette L, Ghibu S, Muresan A, Vergely C. Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Can J Physiol Pharmacol 2015; 93(12): 1021-7.
[] [PMID: 26406389]
Khanna S, Roy S, Packer L, Sen CK. Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Am J Physiol 1999; 276(5): R1327-33.
[PMID: 10233023]
Ametov AS, Barinov A, Dyck PJ, et al. The Sensory Symptoms of Diabetic Polyneuropathy Are Improved With α-Lipoic Acid. Diabetes Care 2003.
Ziegler D, Ametov A, Barinov A, et al. Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy. Diabetes Care 2006. 29/11/2365
Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 2004; 21(2): 114-21.
[] [PMID: 14984445]
Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJG. Alpha Lipoic Acid for Symptomatic Peripheral Neuropathy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Trials. Int J Endocrinol 2012; 456279.
Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol 2012; 167(4): 465-71.
[] [PMID: 22837391]
Brave M. Alpha Lipoic Acid Office of New Drugs Alpha Lipoic Acid Review Team. Available at:
Oates PJ. Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets 2008; 9(1): 14-36.
[] [PMID: 18220710]
Ramirez MA, Borja NL. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 2008; 28(5): 646-55.
[] [PMID: 18447661]
Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev 2007.
Kawai T, Takei I, Tokui M, et al. Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(ɛ)-carboxymethyl lysine. J Diabetes Complications 2010; 24(6): 424-32.
[] [PMID: 19716319]
Hu X, Li S, Yang G, Liu H, Boden G, Li L. Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis. PLoS One 2014; 9(2): e87096.
[] [PMID: 24533052]
Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung 1999; 49(3): 220-4.
[PMID: 10219465]
Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy-a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther 2005; 43(2): 71-7.
[] [PMID: 15726875]
Fraser DA, Diep LM, Hovden IA, et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24- month, double-blind, randomized, placebo-controlled trial. Diabetes Care 2012; 35(5): 1095-7.
[] [PMID: 22446172]
Ruggenenti P, Lauria G, Iliev IP, et al. Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial. Hypertens (Dallas, Tex 1979) 2011; 58(5): 776-83.
Didangelos T, Tziomalos K, Margaritidis C, et al. Efficacy of Administration of an Angiotensin Converting Enzyme Inhibitor for Two Years on Autonomic and Peripheral Neuropathy in Patients with Diabetes Mellitus. J Diabetes Res 2017; 6719239.
Ekberg K, Brismar T, Johansson B-L, et al. C-Peptide Replacement Therapy and Sensory Nerve Function in Type 1 Diabetic Neuropathy. Diabetes Care 2007.
Wahren J, Foyt H, Daniels M, Arezzo JC. Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial. Diabetes Care 2016. content/39/4/596
Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede R-D. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna) 2020; 127(4): 589-624.
[] [PMID: 32036431]
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14(2): 162-73.
[] [PMID: 25575710]
Rudroju N, Bansal D, Talakokkula ST, et al. Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis. Pain Physician 2013; 16(6): E705-14.
[PMID: 24284851]
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007; CD005454(4): CD005454.
[PMID: 17943857]
Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev 2012.
Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17(9): 1113-e88.
[] [PMID: 20402746]
Sumitani M, Sakai T, Matsuda Y, et al. Executive summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: second edition by the Japanese Society of Pain Clinicians. J Anesth 2018; 32(3): 463-78.
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.
[] [PMID: 28676788]
NICE. National Institute for Health and Care Excellence. Neuropathic pain-pharmacological management The pharmacological management of neuropathic pain in adults in non-specialist. Available at:
Husein R, Depkes RI, Soelistijo SA, et al. Global Guideline for Type 2 Diabetes.
Zochodne DW, Toth C. Diabetes and the Nervous System. Michael J. Aminoff, S. Andrew Josephson. Eds. Aminoff's Neurology and General Medicine (Fifth Edition), Academic Press, 2014; Pages 351-368.
Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis 2015; 6(1): 15-28.
[] [PMID: 25553239]
Bates D, Schultheis BC, Hanes MC, et al. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Med 2019; 20(Suppl. 1): S2-S12.
[] [PMID: 31152178]
Lindsay TJ, Rodgers BC, Savath V, Hettinger K. Treating diabetic peripheral neuropathic pain. Am Fam Physician 2010; 82(2): 151-8.
[PMID: 20642268]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy