Combination Therapy in Painful Diabetic Neuropathy: A Scoping Review

Authors

  • Jimmy Fransisco Abadinta Barus Atma Jaya Catholic University of Indonesia
  • Harvey Sudharta Atma Jaya Catholic University of Indonesia
  • Yetty Octavia Hutahaean Mulawarman University
  • Rizaldi Taslim Pinzon Duta Wacana Christian University
  • I Putu Eka Widyadharma Udayana University

DOI:

https://doi.org/10.31351/vol35iss3pp1-18

Keywords:

Painful diabetic neuropathies, Combination , Drug therapy, Treatment outcome, Treatment efficacy, Adverse effects

Abstract

Diabetic neuropathy is the most common microvascular complication of Diabetes Mellitus. Approximately one-third of patients with Diabetic Neuropathy experience clinical features that fit the Painful Diabetic Neuropathy spectrum. Many studies have discussed the effectiveness of monotherapy in PDN. Recommendations indicate that if pain is not resolved with monotherapy then drug combination therapy can be considered. This scoping review follows the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) statement guideline and the PCC (Population-Concept-Context) framework. We conducted a structured literature search in PubMed, ScienceDirect, EBSCOhost, and ProQuest from the beginning until August 2023 to identify all published articles on the efficacy and safety of combination therapy. The Mixed Methods Appraisal Tool (MMAT) was used to evaluate the quality of evidence in each included article. We gathered 15 relevant publications including 20 studies in the present scoping review. Three outcomes were evaluated, clinical effectiveness, clinical safety, and cost-effectiveness. Common clinical effectiveness outcomes observed included significant pain relief, nerve function improvement, and sleep improvement in combination therapy over monotherapy. Pain improvement in combination was mostly observed by using Pregabalin. Nerve function improvement was mostly observed using Methylcobalamin. More studies showed no difference in clinical safety between combination and monotherapy. The overall cost of monotherapy and combination therapy also did not differ significantly. In conclusion, combination therapy potentially showed better results in terms of clinical outcomes and safety profile but not in cost-effectiveness compared to monotherapy in the management of PDN.

How to Cite

1.
Barus JFA, Sudharta H, Hutahaean YO, Pinzon RT, Widyadharma IPE. Combination Therapy in Painful Diabetic Neuropathy: A Scoping Review. Iraqi Journal of Pharmaceutical Sciences [Internet]. 2026 Sep. 28 [cited 2026 Sep. 29];35(3):1-18. Available from: https://www.bijps.uobaghdad.edu.iq/index.php/bijps/article/view/4867

Publication Dates

Received

2026-09-18

Revised

2025-09-20

Accepted

2026-02-04

Published Online First

2026-09-28

References

Girach A, Julian TH, Varrassi G, Paladini A, Vadalouka A, Zis P. Quality of Life in Painful Peripheral Neuropathies: A Systematic Review. Pain Res Manag. 2019;2019:2091960.

Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.

Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019;19(10):86.

Preston FG, Riley DR, Azmi S, Alam U. Painful Diabetic Peripheral Neuropathy: Practical Guidance and Challenges for Clinical Management. Diabetes Metab Syndr Obes. 2023;16:1595–612.

Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–54.

Davoudi M, Rezaei P, Rajaeiramsheh F, Ahmadi SM, Taheri AA. Predicting the quality of life based on pain dimensions and psychiatric symptoms in patients with Painful diabetic neuropathy: a cross-sectional prevalence study in Iranian patients. Health Qual Life Outcomes. 2021;19(1):49.

Ziegler D, Papanas N, Schnell O, Nguyen BDT, Nguyen KT, Kulkantrakorn K, et al. Current concepts in the management of diabetic polyneuropathy. J Diabetes Investig. 2021;12(4):464–75.

Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis. 2015;6(1):15–28.

Sun W, Sanderson P, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today. 2016;21(7):1189–95.

Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Inj J Soc Res Methodol. 2005;8(1):19–32.

Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, et al. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol. 2023;14:1301093.

Hong QN, Fàbregues S, Bartlett G, Boardman F, Cargo M, Dagenais P, et al. The Mixed Methods Appraisal Tool (MMAT) version 2018 for information professionals and researchers. Education for Information. Edu Info. 2018;34(4):285–91.

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

Freeman R, Raskin P, Hewitt DJ, Vorsanger GJ, Jordan DM, CAPSS-237 Study Group, et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy. Curr Med Res Opin. 2007;23(1):147–61.

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.

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.

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.

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.

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.

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.

Irving G, Tanenberg RJ, Raskin J, Risser RC, Malcolm S. Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain. Int J Clin Pract. 2014;68(9):1130–40.

Vasudevan D, Naik MM, Mukaddam QI. Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol. 2014;17(1):19–24.

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.

Alvarado AM, Navarro SA. Clinical Trial Assessing the Efficacy of Gabapentin Plus B Complex (B1/B12) versus Pregabalin for Treating Painful Diabetic Neuropathy. J Diabetes Res. 2016;2016:4078695.

Kuo K-L, Brixner D, Lipman AG, Goodman M, Hung M, Oderda GM. Single- Versus Multiple-Drug Pharmacotherapy in the Management of Diabetic Painful Neuropathy. J Pain Palliat Care Pharmacother. 2016;30(3):184–94.

Didangelos T, Karlafti E, Kotzakioulafi E, Kontoninas Z, Margaritidis C, Giannoulaki P, et al. Efficacy and Safety of the Combination of Superoxide Dismutase, Alpha Lipoic Acid, Vitamin B12, and Carnitine for 12 Months in Patients with Diabetic Neuropathy. Nutrients. 2020;12(11):3254.

Sharma C, Kaur I, Singh H, Grover IS, Singh J. A randomized comparative study of methylcobalamin, methylcobalamin plus pregabalin and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy. Indian J Pharmacol. 2021; 53(5) : 358 – 63.

Shokri M, Sajedi F, Mohammadi Y, Mehrpooya M. Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial. Eur J Clin Pharmacol. 2021; 77(11) :1649–63.

Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. The Lancet. 2022;400(10353):680–90.

Ardeleanu V, Toma A, Pafili K, Papanas N, Motofei I, Diaconu CC, et al. Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review. Medicina (Kaunas). 2020;56(1):25.

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-e88.

Bril V, England J, Franklin GM, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy [RETIRED]: 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.

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.

National Institute for Health and Care Excellence. Neuropathic pain in adults: pharmacological management in non-specialist settings (CG173). NICE. 2013.

Price R, Smith D, Franklin G, Gronseth G, Pignone M, David WS, et al. Oral and Topical Treatment of Painful Diabetic Polyneuropathy: Practice Guideline Update Summary. Neurology. 2022;98(1):31–43.

Jk G, Sana QS. Potential Benefits of Methylcobalamin: A Review. Austin J Pharmacol Ther. 2015;3(3).1076.

Baldacara L. Duloxetine: An Update. Res Soc Dev. 2024;13(3):e7313345331

Pereira CdS, Cruz JN, Ferreira MKM, Baia-da-Silva DC, Fontes-Junior EA, Lima RR. Global Research Trends and Hotspots Analysis of the Scientific Production of Amitriptyline: A Bibliometric Approach. Pharmaceuticals. 2023;16(7):1047.

Haryalchi K, Olangian-Tehrani S, Kasmaei P, Eghbal SB, Heidarzadeh A, Mehrabian F, et al. The Importance of Intravenous Perioperative Lidocaine as an Adjuvant to Acute Postoperative Pain Control: A Narrative Review Article. Arch Anesthesiol Crit Care. 2025;11(4):567-572.

Mi W, Wang S, You Z, Lim G, McCabe MF, Kim H, et al. Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System. Anesth Analg. 2017;125(3):1032-1041.

Ajayi AF, Borisade MS, Oyedokun P, Akano OP, Ajayi LO, Oluwole DT, et al. Melatonin protect against pregabalin-induced gonadotoxicity via anti-oxidative, anti-inflammatory, anti-apoptotic, enzymatic and hormonal regulatory mechanisms in rats. BMC Pharmacol Toxicol. 2025;26(1):30.

Li Y, Tian H, Wu T. Prostaglandin E1 for diabetic neuropathy. Cochrane Database Syst Rev. 2017;2017(1):CD006051.

Hosseini A, Samadi M, Baeeri M, Rahimifard M, Haghi-Aminjan H. The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies. Front Pharmacol. 2022;13:984499.

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Published

2026-09-28