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Background:
Review

Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review

by
Valeriu Ardeleanu
1,2,3,†,
Alexandra Toma
1,4,*,
Kalliopi Pafili
5,†,
Nikolaos Papanas
5,†,
Ion Motofei
6,
Camelia Cristina Diaconu
7,
Manfredi Rizzo
8,9 and
Anca Pantea Stoian
10,*
1
Department of Surgery, University “Dunarea de Jos”, 800008 Galati, Romania
2
Department of Surgery, University “Ovidius’’, 900470 Constanta, Romania
3
Arestetic Clinic, 800098 Galati, Romania
4
Department of Surgery, Emergency County Clinical Hospital “Sf. Apostol Andrei”, 800578 Galati, Romania
5
Second Department of Internal Medicine, Diabetes Centre-Diabetic Foot Clinic, Democritus University of Thrace, University Hospital of Alexandroupolis, 681 00 Alexandroupolis, Greece
6
Department of Surgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
7
Internal Medicine Department, Clinical Emergency Hospital of Bucharest, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
8
Biomedical Department of Internal Medicine and Medical Specialties School of Medicine, University of Palermo, 90133 Palermo, Italy
9
Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine Columbia, Columbia, SC 29209, USA
10
Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
*
Authors to whom correspondence should be addressed.
†
These authors have contributed equally to the present work.
Medicina 2020, 56(1), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina56010025
Submission received: 29 December 2019 / Revised: 3 January 2020 / Accepted: 6 January 2020 / Published: 9 January 2020
(This article belongs to the Special Issue Chronic Pain Management)
Review Reports Versions Notes

Abstract

:
Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms “distal symmetrical polyneuropathy”, “neuropathic pain treatment”, “diabetic neuropathy”, “diabetes complications”, ”glycaemic control”, “antidepressants”, “opioids”, and “anticonvulsants”. Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.

1. Introduction

Diabetic neuropathy is one of the most common chronic complications of diabetes mellitus [1]. It is defined as the presence of signs and/or symptoms of nerve dysfunction in patients with diabetes mellitus after exclusion of other causes [1,2]. The most frequent clinical manifestation is distal symmetrical polyneuropathy (DSPN), with a prevalence of 20–30% [2]. The precise pathophysiology of DSPN is multifactorial and complicated. Its main risk factors include diabetes duration, patient age, and vascular risk factors [3].
DSPN has an insidious course, characterized by chronic sensory loss with stocking and glove distribution [1]. However, it may also lead to chronic neuropathic pain [1]. DSPN treatment is complex, including both an optimal glycemic status, as well as the treatment of pain. Pain management in DSPN does not yet include specific medication to prevent or limit the reversibility of DSPN. Most often, clinical guidelines recommend symptomatic therapy, with the primary goal of pain reduction.
The present narrative review summarizes the current pharmacological treatment of painful DSPN. It includes brief references to emerging concepts and concerns such as opioid dependency and pathogenesis-oriented therapy (mainly α-lipoic acid), which are generally overlooked in many publications and guidelines.

2. Materials and Methods

We performed a review of the literature starting from 1990 by searching PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases for all observational studies, randomized clinical trials, and meta-analyses including the terms “distal symmetrical polyneuropathy”, “neuropathic pain treatment”, “diabetic neuropathy”, “diabetes complications”, ”glycaemic control”, “antidepressants”, “opioids”, and “anticonvulsants”, as well as their combinations regarding DSPN. All currently available original studies, abstracts, and review articles including systematic reviews and meta-analyses were examined. Case reports and letters to the editor were excluded. Publications in English were studied in full, whereas those in other languages only in abstract form.

3. Results and Discussion

3.1. Pharmacotherapy of Diabetic Neuropathy

There are several guidelines on the optimal pharmacological treatment of painful DSPN [4,5,6]. There is currently a general agreement on first-line drugs and other options.

3.2. Glycemic Control

An optimal early glycemic control may delay or even prevent DSPN in type 1 diabetes mellitus and prediabetes [7,8,9,10,11]. In type 2 diabetes mellitus, this is less effective [12,13,14,15]. Interestingly, specific glucose-lowering strategies may have different effects. In a post-hoc analysis of the BARI 2D clinical trial (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes), subjects treated with insulin sensitizers exhibited a reduced incidence of DSPN at 4 years, as compared with those receiving insulin or sulphonylureas [16].

3.3. Antidepressants

Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor. It is used with a dose of 60–120 mg daily [5,17,18,19]. Duloxetine appears to improve the quality of life of patients with painful DSPN [20]. Its main metabolic adverse events include modest increases of fasting plasma glucose in both short- (12 weeks) and long-term (52 weeks) treatment, a modest increase in glycated hemoglobin A1c, and small non-significant weight gain in extension studies (52 weeks) [21]. Other common side effects include dry mouth, decreased appetite, sleepiness, sweating, and gastrointestinal problems [22]. Duloxetine was approved by the US Food and Drug Administration (FDA) for painful DSPN [23].
Tricyclic antidepressants may be used as well, especially amitriptyline. Amitriptyline appears to relieve pain in comparison to placebo in patients with DSPN [24] and seems non-inferior to pregabalin [25], gabapentin [26], and duloxetine [27]. Its precise mechanism of action remains to be clarified. Nonetheless, two hypotheses have been proposed: (1) inhibition of serotonin and norepinephrine reuptake [28] and (2) antagonism of N-methyl-d-aspartate receptors, which mediate hyperalgesia and allodynia [29,30]. Amitriptyline may be considered for DSPN at a single dose of 25 to 100 mg [31], although a dosage range of 25 to 150 mg per day has been suggested [28]. Amitriptyline has FDA approval only for the treatment of depression [32,33]. The side effects include dry mouth, water retention, constipation, and vertigo. Furthermore, clinicians should assess the QTc interval, to avoid the risk of torsades de pointes, especially among subjects with additional cardiovascular risk factors [33].
Although not formally approved, venlafaxine has been used as well [5], with evidence of effectiveness for the short-term management of painful DSPN [17]. It is a potent serotonin and norepinephrine reuptake inhibitor [32]. The proposed off-label dosage ranges between 75 and 225 mg per day in patients with DSPN [31]. Common side effects include sleepiness, dizziness, and mild gastrointestinal problems [34]. Patients should be regularly assessed for QTc prolongation [35].

3.4. Anticonvulsants

The leading agent of this class is pregabalin, a calcium channel subunit α2-δ binder. It has been approved by the US Food and Drug Administration (FDA) for painful DSPN [36]. The dosage ranges from 150 to 300 mg daily [36]. Many studies have reported favorable outcomes with more than 30–50% pain improvement [5,17,18,37,38,39]. However, not all pregabalin-related studies had positive results [5,17,19,39,40]. Untoward effects include water retention, visual disturbances, drowsiness, ataxia, euphoria, and vertigo [41].
Gabapentin also belongs to this class of agents [42]. It has the same therapeutic target as pregabalin [39]. Gabapentin has been reported to relieve pain among DSPN subjects [26,42,43,44,45], and combination with venlafaxine seems to provide additional benefit [46]. Although not formally indicated [47], guidelines of the American Academy of Neurology suggest the use of gabapentin for the treatment of DSPN as a second-line therapy after pregabalin [31]. The recommended off-label daily dosage for DSPN subjects ranges between 900 and 3600 mg [31]. In patients with chronic kidney disease, the doses of gabapentin and pregabalin need to be adjusted: the renal clearance (CrCl ≤ 30 mL/min) requires dose adjustment, with a recommended dose of gabapentin of 300 mg daily and pregabalin of 75 mg daily [48]. Gabapentin has been associated with sleepiness, dizziness, suicidal behaviour, withdrawal-precipitated seizure frequency, multi-organ hypersensitivity, systemic symptoms, and drug reaction with eosinophilia [47].
Other anticonvulsants have been used as well (carbamazepine, lamotrigine, lacosamide, etc.), with variable results [5,17,48,49,50].

3.5. Opioids

Tapentadol is a centrally acting opioid analgesic that exerts its analgesic effects by inhibiting the μ-opioid receptor and noradrenaline uptake [51]. The FDA approved prolonged-release tapentadol for painful DSPN, based on data from two clinical trials in which patients titrated with an optimal dose of tapentadol were arbitrarily requested to continue with that dose or to change it with placebo [52,53]. However, both studies used an enriched design for patients who responded to tapentadol, and therefore the results obtained are not generalizable. Importantly, a recent systematic review and meta-analysis by the Special Interest Group on Neuropathic Pain within the International Pain Study Association found that evidence supporting the effectiveness of tapentadol in reducing neuropathic pain is inconclusive [5]. Finally, addiction is a serious concern with long-term opioid use [32].

3.6. Topical Treatment

Capsaicin is a natural alkaloid [54]. This is thought to desensitize afferent Aδ and C fibers [55]. Two forms of capsaicin are available for the treatment of painful DSPN: a low-dose cream (0.075%) [31] and a high-dose (8%) patch (Qutenza, Acorda Therapeutics, Ardsley, NY, USA) [56]. A series of studies have provided evidence of pain relief among subjects who received capsaicin cream in comparison to the vehicle [57,58,59,60], although results were inconsistent [61,62,63]. An older study even provided evidence of equal efficacy of capsaicin cream (0.075%) to oral amitriptyline for painful DSPN [64]. In agreement with the guidelines of the American Academy of Neurology [31], a dosage of 0.075% four times daily is recommended for the treatment of painful DSPN. A notable disadvantage is local adverse effects— mainly stinging, burning, and erythema [65].
Patches with capsaicin 8% have also been studied in painful DSPN, with conflicting results [66]. Nonetheless, some evidence points to superiority in comparison with oral pregabalin, duloxetine, and gabapentin for pain relief among DSPN patients [67]. Although not formally approved [68], a single application of this patch may provide up to 12 weeks of pain relief [69]. This should be performed under specialist supervision, with appropriate local anesthesia and monitoring for blood pressure increase, especially during the first hour following application [69].
The 5% lidocaine plaster is licensed for postherpetic neuralgia in approximately 50 countries around the world and for localized neuropathic pain in 11 Latin American countries [70]. The lidocaine molecule is a voltage-gated sodium channel inhibitor which blocks abnormally functioning neuronal sodium channels (in the dermal A-δ and C fibers) [71]. Studies have provided evidence of pain relief in DSPN patients comparable to pregabalin [72,73], amitriptyline, capsaicin, and gabapentin [73]. A maximum of three lidocaine patches 5% can be applied to intact skin once for 12 h within a 24-h period [70]. Adverse events include mild and transient application-site reactions—mainly erythema, edema, and a burning sensation [74].
Finally, topical clonidine, a presynaptic α-2 adrenergic receptor agonist with antinociceptive activity, was associated with pain relief in DSPN in a small number of studies of low-to-moderate quality [75]. Clonidine gel 0.1% may be administered in single doses of 0.65 g of gel (0.65 mg of clonidine), three times daily so that the total daily dose should not exceed 3.9 mg for both feet. The administration is associated with only mild skin-site reactions [76].

3.7. Pathogenesis-Oriented Treatment

α-Lipoic acid is a natural thiol with potent antioxidant properties, and is used as a dietary supplement. In studies evaluating this indication, it has been administered orally at doses between 600 and 1800 mg and intravenously at 600 mg per day for 3 weeks, excluding weekends [77,78,79,80,81,82]. Both formulas have been recently characterized by the FDA as safe and effective treatment options for painful DSPN [83]. The efficacy of the daily administration of a 600 mg intravenous formula for 3 weeks was investigated in a meta-analysis of four randomized, placebo-controlled trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) comprising 1258 participants with painful DSPN [82]. It was shown that α-lipoic acid improved positive neuropathic symptoms (24.1% in favor of α-lipoic acid versus placebo), but failed to alter the neuropathy impairment score significantly [82,83].
Finally, actovegin is a deproteinated, pyrogen- and antigen-free ultrafiltrate obtained from calf blood. It appears to ameliorate oxidative stress and to exhibit antiapoptotic properties [79]. In a study conducted by Ziegler et al., 567 patients were treated with actovegin (n = 281) versus placebo (n = 286). After 6 months, compared with placebo, actovegin was associated with better improvement of neuropathic symptoms, but not pain specifically (OR [95% CI] of 1.73 [1.21–2.48] for patients treated with actovegin and 1.94 [1.33–2.84] for patients placebo treated). Actovegin treatment (20 daily intravenous infusions of 2000 mg/day followed by three actovegin tablets of 600 mg each for 140 days) was associated with a clinically significant response in neuropathic symptoms and vibration perception threshold in patients with symptomatic DSPN, with a good safety profile [84]. Further studies are needed to demonstrate the efficacy of α-lipoic acid and actovegin in painful DSPN. Current pharmacological agents for painful DSPN are summarized in Table 1.

4. Conclusions

DSPN is a burden both from diagnostic and treatment perspectives. It is still under-diagnosed and undertreated.
As summarized in this narrative review, first-line treatment options include pregabalin and duloxetine, with gabapentin seeming a reasonable alternative to pregabalin treatment. Second- and third-line drugs include opioids and topical analgesics. Indeed, opioids are an effective alternative in the treatment of neuropathic pain; however adverse reactions and addiction concerns limit their widespread use. More recently, research has extended beyond symptom alleviation. Pathogenesis-oriented treatments, including α-lipoic acid and actovegin, appear promising, but results need to be confirmed in more extensive trials.

Author Contributions

V.A. conceived the original draft preparation. V.A., A.T., A.P.S., K.P., and N.P. were responsible for conception and design of the review. A.T., N.P., K.P., A.P.S., C.C.D., and M.R. were responsible for the data acquisition. A.T., K.P., V.A., N.P., A.P.S., and I.M. were responsible for the collection and assembly of the articles/published data, and their inclusion and interpretation in this review. V.A., A.T., K.P., N.P., and A.P.S. contributed equally to the present work. All authors contributed to the critical revision of the manuscript for valuable intellectual content. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received.

Conflicts of Interest

A.P.S. was on advisory boards and received honoraria as a speaker for Astra Zeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi. She is currently Vice President of the Romanian National Committee of Diabetes, Nutrition and Metabolic Diseases. M.R. was on advisory boards for Astra Zeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi. He is currently the Director of Clinical Medicine and Regulatory Affairs at Novo Nordisk Europe East and South. N.P. has been an Advisory Board Member of TrigoCare International, Abbott, AstraZeneca, Elpen, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, and Takeda. He has participated in sponsored studies by Eli Lilly, MSD, Novo Nordisk, Novartis, and Sanofi-Aventis. He has received honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elpen, Galenica, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda, and Vianex. He has attended conferences sponsored by TrigoCare International, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis. The other authors declare no conflict of interest.

References

  1. Pop-Busui, R.; Boulton, A.J.M.; Feldman, E.L.; Bril, V.; Freeman, R.; Malik, R.A.; Sosenko, J.M.; Ziegler, D. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017, 40, 136–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Ziegler, D.; Papanas, N.; Vinik, A.I.; Shaw, J.E. Epidemiology of polyneuropathy in diabetes and prediabetes. In Handbook of Clinical Neurology; Elsevier BV: Amsterdam, The Netherlands, 2014; Volume 126, pp. 3–22. [Google Scholar]
  3. Papanas, N.; Ziegler, D. Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev. Diabet. Stud. 2015, 12, 48–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Deng, Y.; Luo, L.; Hu, Y.; Fang, K.; Liu, J. Clinical practice guidelines for the management of neuropathic pain: A systematic review. BMC Anesthesiol. 2016, 16, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Finnerup, N.B.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpää, M.; Hansson, P.; Jensen, T.S.; et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015, 14, 162–173. [Google Scholar] [CrossRef] [Green Version]
  6. Dowell, D.; Haegerich, T.M.; Chou, R. CDC guideline for prescribing opioids for chronic pain—United States. MMWR 2016, 65, 1–49. [Google Scholar] [PubMed]
  7. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann. Neurol. 1995, 38, 869–880. [Google Scholar] [CrossRef] [PubMed]
  8. CDC Study Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998, 41, 416–423. [Google Scholar] [CrossRef] [Green Version]
  9. Albers, J.W.; Herman, W.H.; Pop-Busui, R.; Feldman, E.L.; Martin, C.L.; Cleary, P.A.; Waberski, B.H.; Lachin, J.M.; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. 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, 1090–1096. [Google Scholar] [CrossRef] [Green Version]
  10. Pop-Busui, R.; Low, P.A.; Waberski, B.H.; Martin, C.L.; Albers, J.W.; Feldman, E.L.; Sommer, C.; Cleary, P.A.; Lachin, J.M.; Herman, W.H.; et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus:the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 2009, 19, 2886–2893. [Google Scholar] [CrossRef] [Green Version]
  11. Martin, C.L.; Albers, J.W.; Pop-Busui, R.; DCCT/EDIC Research Group. Neuropathy and related findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Diabetes Care 2014, 37, 31–38. [Google Scholar] [CrossRef] [Green Version]
  12. Ismail-Beigi, F.; Craven, T.; Banerji, M.A.; Basile, J.; Calles, J.; Cohen, R.M.; Cuddihy, R.; Cushman, W.C.; Genuth, S.; Grimm, R.H., Jr.; et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: An analysis of the ACCORD randomised trial. Lancet 2010, 376, 419–430. [Google Scholar] [CrossRef] [Green Version]
  13. Callaghan, B.C.; Little, A.A.; Feldman, E.L.; Hughes, R.A.C. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst. Rev. 2012, 6. [Google Scholar] [CrossRef] [PubMed]
  14. Ang, L.; Jaiswal, M.; Martin, C.; Pop-Busui, R. Glucose control and diabetic neuropathy: Lessons from recent large clinical trials. Curr. Diabetes Rep. 2014, 14, 528. [Google Scholar] [CrossRef] [PubMed]
  15. Zoungas, S.; Arima, H.; Gerstein, H.C.; Holman, R.R.; Woodward, M.; Reaven, P.; Hayward, R.A.; Craven, T.; Coleman, R.L.; Chalmers, J. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: A meta-analysis of individual participant data from randomized controlled trials. Lancet Diabetes Endocrinol. 2017, 5, 431–437. [Google Scholar] [CrossRef]
  16. Pop-Busui, R.; Lu, J.; Brooks, M.M.; Albert, S.; Althouse, A.D.; Escobedo, J.; Green, J.; Palumbo, P.; Perkins, B.A.; Whitehouse, F.; et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) cohort. Diabetes Care 2013, 36, 3208–3215. [Google Scholar] [CrossRef] [Green Version]
  17. Griebeler, M.L.; Morey-Vargas, O.L.; Brito, J.P.; Tsapas, A.; Wang, Z.; Leon, B.G.C.; Phung, O.J.; Montori, V.M.; Murad, M.H. Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis. Ann. Intern. Med. 2014, 161, 639–649. [Google Scholar] [CrossRef]
  18. Tesfaye, S.; Wilhelm, S.; Lledo, A.; Schacht, A.; Tölle, T.; Bouhassira, D.; Cruccu, G.; Skljarevski, V.; Freynhagen, R. 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, 2616–2625. [Google Scholar] [CrossRef] [Green Version]
  19. Quilici, S.; Chancellor, J.; Lothgren, M.; Simon, D.; Said, G.; Le, T.K.; Garcia-Cebrian, A.; Monz, B. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 2009, 9, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Wernicke, J.F.; Pritchett, Y.L.; D’Souza, D.N.; Waninger, A.; Tran, P.; Iyengar, S.; Raskin, J. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006, 67, 1411–1420. [Google Scholar] [CrossRef]
  21. Hardy, T.; Sachson, R.; Shen, S.; Armbruster, M.; Boulton, A.J.M. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes Care 2007, 30, 21–26. [Google Scholar] [CrossRef] [Green Version]
  22. Goldstein, D.J.; Lu, Y.; Detke, M.J.; Lee, T.C.; Iyengar, S. Duloxetine vs. Placebo in patients with painful diabetic neuropathy. PAIN 2005, 116, 109–118. [Google Scholar] [CrossRef] [PubMed]
  23. Vinik, A.; Casellini, C.; Nevoret, M.L. Diabetic Neuropathies. In Endotext [Internet]; Feingold, K.R., Anawalt, B., Boyce, A., Eds.; Table 7, Drugs Approved by the FDA for Treatment of Neuropathic Pain Syndromes; MDText.com, Inc.: South Dartmouth, MA, USA, 2000. [Google Scholar]
  24. Max, M.B. Endogenous monoamine analgesic systems: Amitriptyline in painful diabetic neuropathy. Anesth. Prog. 1987, 34, 113–127. [Google Scholar] [PubMed]
  25. 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, 1019–1026. [Google Scholar] [CrossRef] [PubMed]
  26. Morello, C.M.; Leckband, S.G.; Stoner, C.P.; Moorhouse, D.F.; Sahagian, G.A. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch. Intern. Med. 1999, 159, 1931–1937. [Google Scholar] [CrossRef]
  27. 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, 818–822. [Google Scholar] [CrossRef] [Green Version]
  28. Boulton, A.J.M. Management of diabetic peripheral neuropathy. Clin. Diabetes 2005, 23, 9–15. [Google Scholar] [CrossRef] [Green Version]
  29. Max, M.B.; Lynch, S.A.; Muir, J.; Shoaf, S.E.; Smoller, B.; Dubner, R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N. Engl. J. Med. 1992, 326, 1250–1256. [Google Scholar] [CrossRef]
  30. Ulugol, A.; Karadag, H.C.; Tamer, M.; Firat, Z.; Aslantas, A.; Dokmeci, I. Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci. Lett. 2002, 328, 129–132. [Google Scholar] [CrossRef]
  31. American Academy of Neurology AAN Summary of Evidence-Based Guidelines for Clinicians: Treatment of Painful Diabetic Neuropathy. 2011. Available online: https://www.aan.com/Guidelines/home/GetGuidelineContent/480 (accessed on 6 August 2019).
  32. Cohen, K.; Shinkazh, N.; Frank, J.; Israel, I.; Fellner, C. Pharmacological treatment of diabetic peripheral neuropathy. Pharm. Ther. 2015, 40, 372–388. [Google Scholar]
  33. Thour, A.; Marwaha, R. Amitriptyline. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2019. [Google Scholar]
  34. Gallagher, H.C.; Gallagher, R.M.; Butler, M.; Buggy, D.J.; Henman, M.C. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst. Rev. 2015, 8. [Google Scholar] [CrossRef]
  35. Rowbotham, M.C.; Goli, V.; Kunz, N.R.; Lei, D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: A double-blind, placebo-controlled study. PAIN 2004, 110, 697–706. [Google Scholar] [CrossRef] [PubMed]
  36. Cross, A.L.; Sherman, A.L. Pregabalin. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2019. [Google Scholar]
  37. 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, 1448–1454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Moore, R.A.; Straube, S.; Wiffen, P.J.; Derry, S.; McQuay, H.J. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst. Rev. 2009, 3. [Google Scholar] [CrossRef] [PubMed]
  39. Raskin, P.; Huffman, C.; Toth, C.; Asmus, M.J.; Messig, M.; Sanchez, R.J.; Pauer, L. Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: A randomized withdrawal trial. Clin. J. Pain 2014, 30, 379–390. [Google Scholar] [CrossRef]
  40. Ziegler, D.; Duan, W.R.; An, G.; Thomas, J.W.; 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, 56, 2013–2020. [Google Scholar] [CrossRef]
  41. Dworkin, R.H.; Jensen, M.P.; Gammaitoni, A.R.; Olaleye, D.O.; Galer, B.S. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J. Pain 2007, 8, 118–126. [Google Scholar] [CrossRef]
  42. Wiffen, P.J.; Derry, S.; Bell, R.F.; Rice, A.S.; Tölle, T.R.; Phillips, T.; Moore, R.A. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2017, 6. [Google Scholar] [CrossRef] [Green Version]
  43. Backonja, M.; Beydoun, A.; Edwards, K.R.; Schwartz, S.L.; Fonseca, V.; Hes, M.; LaMoreaux, L.; Garofalo, E.; Gabapentin Diabetic Neuropathy Study Group. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 1998, 280, 1831–1836. [Google Scholar] [CrossRef] [Green Version]
  44. Moore, R.A.; Wiffen, P.J.; Derry, S.; Toelle, T.; Rice, A.S. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 2014, 4. [Google Scholar] [CrossRef] [Green Version]
  45. 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, 280–285. [Google Scholar] [CrossRef]
  46. Simpson, D.A. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J. Clin. Neuromuscul. Dis. 2001, 3, 53–62. [Google Scholar] [CrossRef]
  47. Neurontin (Gabapentin) Prescribing Information; Pfizer, Inc.: New York, NY, USA, 2014.
  48. Ziegler, D.; Fonseca, V. From guideline to patient: A review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J. Diabetes Complicat. 2015, 29, 146–156. [Google Scholar] [CrossRef] [PubMed]
  49. Waldfogel, J.M.; Nesbit, S.A.; Dy, S.M.; Sharma, R.; Zhang, A.; Wilson, L.M.; Bennett, W.L.; Yeh, H.C.; Chelladurai, Y.; Feldman, D.; et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017, 88, 1958–1967. [Google Scholar] [CrossRef] [PubMed]
  50. Papanas, N.; Ziegler, D. Emerging drugs for diabetic peripheral neuropathy and neuropathic pain. Expert Opin. Emerg. Drugs 2016, 21, 393–407. [Google Scholar] [CrossRef] [PubMed]
  51. Vadivelu, N.; Huang, Y.; Mirante, B.; Jacoby, M.; Braveman, F.R.; Hines, R.L.; Sinatra, R. Patient considerations in the use of tapentadol for moderate to severe pain. Drug Healthc. Patient Saf. 2013, 5, 151–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Schwartz, S.; Etropolski, M.; Shapiro, D.Y.; Okamoto, A.; Lange, R.; Haeussler, J.; Rauschkolb, C. 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, 151–162. [Google Scholar] [CrossRef] [PubMed]
  53. Vinik, A.I.; Shapiro, D.Y.; Rauschkolb, C.; Lange, B.; Karcher, K.; Pennett, D.; Etropolski, M.S. 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, 2302–2309. [Google Scholar] [CrossRef] [Green Version]
  54. Chong, M.S.; Hester, J. Diabetic painful neuropathy: Current and future treatment options. Drugs 2007, 67, 569–585. [Google Scholar] [CrossRef]
  55. Snyder, M.J.; Gibbs, L.M.; Lindsay, T.J. Treating painful diabetic peripheral neuropathy: An update. Am. Fam. Phys. 2016, 94, 227–234. [Google Scholar]
  56. Anonymous. What role for capsaicin in diabetic peripheral neuropathy? Drug Ther. Bull. 2016, 54, 90–93. [Google Scholar] [CrossRef]
  57. Donofrio, P.; Walker, F.; Hunt, V.; Lewis, G.; Mireles, J.A.; Hoffman, J.; Scheffler, N.; Sheitel, P.; Campbell, S.; Wendt, J.; et al. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Arch. Intern. Med. 1991, 151, 2225–2229. [Google Scholar]
  58. Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992, 15, 159–165. [Google Scholar] [CrossRef] [PubMed]
  59. Tandan, R.; Lewis, G.A.; Badger, G.B.; Fries, T.J. Topical capsaicin in painful diabetic neuropathy. Effect on sensory function. Diabetes Care 1992, 15, 15–18. [Google Scholar] [CrossRef] [PubMed]
  60. Tandan, R.; Lewis, G.A.; Krusinski, P.B.; Badger, G.B.; Fries, T.J. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992, 15, 8–14. [Google Scholar] [CrossRef]
  61. Low, P.A.; Opfer-Gehrking, T.L.; Dyck, P.J.; Litchy, W.J.; O’Brien, P.C. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. PAIN 1995, 62, 163–168. [Google Scholar] [CrossRef]
  62. Chad, D.A.; Aronin, N.; Lundstrom, R.; McKeon, P.; Ross, D.; Molitch, M.; Schipper, H.M.; Stall, G.; Dyess, E.; Tarsy, D. Does capsaicin relieve the pain of diabetic neuropathy? PAIN 1990, 42, 387–388. [Google Scholar] [CrossRef]
  63. Kulkantrakorn, K.; Chomjit, A.; Sithinamsuwan, P.; Tharavanij, T.; Suwankanoknark, J.; Napunnaphat, P. 0.075% capsaicin lotion for the treatment of painful diabetic neuropathy: A randomized, double-blind, crossover, placebo-controlled trial. J. Clin. Neurosci. 2019, 62, 174–179. [Google Scholar] [CrossRef]
  64. Biesbroek, R.; Bril, V.; Hollander, P.; Kabadi, U.; Schwartz, S.; Singh, S.P.; Ward, W.K.; Bernstein, J.E. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv. Ther. 1995, 12, 111–120. [Google Scholar]
  65. Zin, C.S.; Nissen, L.M.; Smith, M.T.; O’Callaghan, J.P.; Moore, B.J. An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy. CNS Drugs 2008, 22, 417–442. [Google Scholar] [CrossRef]
  66. Derry, S.; Rice, A.S.; Cole, P.; Tan, T.; Moore, R.A. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2017, 1. [Google Scholar] [CrossRef] [Green Version]
  67. 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, 787–803. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Baranidharan, G.; Das, S.; Bhaskar, A. A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain. Ther. Adv. Neurol. Disord. 2013, 6, 287–297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Mou, J.; Paillard, F.; Turnbull, B.; Trudeau, J.; Stoker, M.; Katz, N.P. Qutenza (capsaicin) 8% patch onset and duration of response and effects of multiple treatments in neuropathic pain patients. Clin. J. Pain 2014, 30, 286–294. [Google Scholar] [CrossRef] [PubMed]
  70. Mick, G.; Correa-Illanes, G. Topical pain management with the 5% lidocaine medicated plaster-a review. Curr. Med. Res. Opin. 2012, 28, 937–951. [Google Scholar] [CrossRef] [PubMed]
  71. Krumova, E.K.; Zeller, M.; Westermann, A.; Maier, C. Lidocaine patch (5%) produces a selective, but incomplete block of Aδ and C fibers. PAIN 2012, 153, 273–280. [Google Scholar] [CrossRef]
  72. 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, 1663–1676. [Google Scholar] [CrossRef]
  73. Wolff, R.F.; Bala, M.M.; Westwood, M.; Kessels, A.G.; Kleijnen, J. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): A systematic review. Swiss Med. Wkly. 2010, 140, 297–306. [Google Scholar]
  74. Navez, M.L.; Monella, C.; Bösl, I.; Sommer, D.; Delorme, C. 5% lidocaine medicated plaster for the treatment of postherpetic neuralgia: A review of the clinical safety and tolerability. Pain Ther. 2015, 4, 1–15. [Google Scholar] [CrossRef] [Green Version]
  75. Wrzosek, A.; Woron, J.; Dobrogowski, J.; Jakowicka-Wordliczek, J.; Wordliczek, J. Topical clonidine for neuropathic pain. Cochrane Database Syst. Rev. 2015, 8. [Google Scholar] [CrossRef]
  76. Campbell, C.M.; Kipnes, M.S.; Stouch, B.C.; Brady, K.L.; Kelly, M.; Schmidt, W.K.; Petersen, K.L.; Rowbotham, M.C.; Campbell, J.N. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. PAIN 2012, 153, 1815–1823. [Google Scholar] [CrossRef] [Green Version]
  77. Papanas, N.; Ziegler, D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin. Pharmacother. 2014, 15, 2721–2731. [Google Scholar] [CrossRef] [PubMed]
  78. Leppert, W.; Malec–Milewska, M.; Zajaczkowska, R.; Wordliczek, J. Transdermal and Topical Drug Administration in the Treatment of Pain. Molecules 2018, 23, 681. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Bönhof, G.J.; Herder, C.; Strom, A.; Papanas, N.; Roden, M.; Ziegler, D. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr. Rev. 2019, 40, 153–192. [Google Scholar] [CrossRef] [PubMed]
  80. Ziegler, D.; Low, P.A.; Litchy, W.J.; Boulton, A.J.; Vinik, A.I.; Freeman, R.; Samigullin, R.; Tritschler, H.; Munzel, U.; Maus, J.; et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 trial. Diabetes Care 2011, 34, 2054–2060. [Google Scholar] [CrossRef] [Green Version]
  81. Papanas, N.; Maltezos, E. A-Lipoic acid, diabetic neuropathy, and Nathan’s prophecy. Angiology 2012, 63, 81–83. [Google Scholar] [CrossRef]
  82. Ziegler, D.; Nowak, H.; Kempler, P.; Vargha, P.; Low, P.A. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A meta-analysis. Diabet. Med. 2014, 21, 114–121. [Google Scholar] [CrossRef]
  83. Alpha Lipoic Acid Pharmacy Compounding Advisory Committee Meeting 12 September 2018. Available online: https://www.fda.gov/media/116311/download (accessed on 12 August 2019).
  84. Ziegler, D.; Edmundson, S.; Gurieva, I.; Mankovsky, B.; Papanas, N.; Strokov, I. Predictors of response to treatment with actovegin for 6 months in patients with type 2 diabetes and symptomatic polyneuropathy. J. Diabetes Complicat. 2017, 31, 1181–1187. [Google Scholar] [CrossRef]
Table
Table 1. Current pharmacological agents for painful distal symmetrical polyneuropathy (DSPN) [5,6].
Table 1. Current pharmacological agents for painful distal symmetrical polyneuropathy (DSPN) [5,6].
PharmacotherapyFDA Approval for DSPNDaily DosageUntoward EffectsComments
Antidepressants
DuloxetineYes [23]60–120 mg/d [5,17,18,19]Xerostomia, decreased appetite, somnolence, sweating, gastrointestinal discomfort [22]Appears to improve the quality of life of patients with painful DSPN [20]
AmitriptylineNo [33]25–100 mg/d [31]Xerostomia, water retention, increased appetite, weight gain, constipation, vertigo [33]Appears non-inferior to pregabalin [25], gabapentin, [26] and duloxetin [27] in painful DSPN; monitor QTc interval [33]
VenlafaxineNo [31]75–225 mg/d [31]Somnolence, dizziness, mild gastrointestinal problems [34]Evidence of effectiveness for short-term management of painful DSPN [17]; monitor QTc interval [35]
Anticonvulsants
PregabalinYes [36]150–300 mg/d [36]Water retention, visual disturbances, somnolence, ataxia, euphoria, vertigo [41]DSPN-related pain improvement of >30%–50% has been reported [5,17,18,37,38,39]
GabapentinNo [47]900–3600 mg/d [31]Somnolence, dizziness, suicidal behaviour, withdrawal-precipitated seizure frequency, multi-organ hypersensitivity [47]DSPN-related pain relief has been repeatedly reported [26,42,43,44,45,46]
Opioids
Tapentadol extended releaseYes [52,53]100–500 mg/d [51]Dizziness, somnolence, headache, fatigue, gastrointestinal problems [51]Inconclusive pain reduction [5]; addiction concern [32]
Topical treatment
Capsaicin creamNo [32]0.075% four times/d [31]Skin-site reactions [63]Equal efficacy to amitriptyline [62]
Capsaicin 8% patchNo [68]One application every 3 months [66]Skin-site reactions [66]Conflicting results in DSPN [66]; application can be painful [66]; monitor for transient blood pressure increase for at least one hour following application [66]
5% lidocaine plasterNo [70]Maximum 3 lidocaine plasters 5% can be applied to intact skin once daily for a period of 12 h [70]Skin-site reactions [74]Comparable efficacy to pregabalin, amitriptyline, capsaicin, and gabapentin [72,73]
Clonidine gel 0.1%No [75]Single doses of 0.65 g of gel, three times daily [76]Skin-site reactions [76]Pain relief in a small number of studies of low-to-moderate quality [75]
Pathogenesis-oriented treatment
α-Lipoic acidNo [77]600–1800 mg orally or 600 mg/d intravenously for 3 weeks, excluding weekends [77,78,79,80,81]Nausea, vomiting, abdominal discomfort, diarrhea [77]FDA statement: safe and effective treatment option for painful DSPN [82]
Legend: FDA: Food and Drug Administration.

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Ardeleanu, V.; Toma, A.; Pafili, K.; Papanas, N.; Motofei, I.; Diaconu, C.C.; Rizzo, M.; Pantea Stoian, A. Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review. Medicina 2020, 56, 25. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina56010025

AMA Style

Ardeleanu V, Toma A, Pafili K, Papanas N, Motofei I, Diaconu CC, Rizzo M, Pantea Stoian A. Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review. Medicina. 2020; 56(1):25. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina56010025

Chicago/Turabian Style

Ardeleanu, Valeriu, Alexandra Toma, Kalliopi Pafili, Nikolaos Papanas, Ion Motofei, Camelia Cristina Diaconu, Manfredi Rizzo, and Anca Pantea Stoian. 2020. "Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review" Medicina 56, no. 1: 25. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina56010025

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