Issues and challenges in diabetic neuropathy management: A narrative review

Table 1 Management strategies from the previous literature to prevent progression of diabetic neuropathy in patients

Strategies	Description/indication	Intervention/strategies	Ref.
Glucose level monitoring	Prevents distal symmetric polyneuropathy and cardiovascular autonomic neuropathy developments in patients with T1DM, and delays the progression of distal symmetric polyneuropathy in T2DM patients	Treatments (insulin, anti-diabetic medications, electrical stimulation, and percutaneous nerve stimulation; non-treatments (lifestyle modifications such as glucose-dietary control, exercises, and physiotherapy); pancreas transplant; bariatric surgery	[6,4,132]
Lifestyle modifications	Reduce risk of DN and cardiometabolic causes	Glucose-dietary control; counselling; supervised training programs including physiotherapy/rehabilitation	[4]
Diabetic foot care	Delays or lowers the risk of amputations	Five key elements for prevention of DFUs: (1) Recognition of the at-risk foot; (2) consistent check and examination of the at-risk foot; (3) education of patients, their family, and healthcare providers; (4) routine of wearing suitable footwear; and (5) management of pre-ulceration signs	[47]
Pharmacologic therapeutics	Manage diabetes and neuropathy and treat symptomatic pain	Three suggested phases can be useful: Step 1: Treatment with first-line therapy of TCAs (e.g., amitriptyline), SNRIs (e.g., duloxetine), pregabalin, and gabapentin; step 2: Treatment with second-line therapy including tramadol (weak opioids and SNRIs); step 3: Treatment with last line therapy including strong opioids, cannabinoids, and anticonvulsants	[89,90,133]
		Alternatives (anti-oxidant supplementations): α-lipoic acid; acetyl-L-carnitine vitamin B12

T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; TCAs: Tricyclic antidepressants; SNRIs: Serotonin-norepinephrine reuptake inhibitors; DN: Diabetic neuropathy; DFUs: Diabetic foot ulcers.

Table 2 Available therapeutic medications for management of diabetic neuropathy

Management strategy	Therapeutic approach	Description	Contraindications/issues
Pharmacological	Anti-convulsants: Gabapentin; pregabalin	First line medication for painful DN[4,51]; gold standard for pain management[50,51]	Reports on misuse and increased death rate in patients[54]
	SSRI and SNRIs: Duloxetine; venlafaxine	First- and second-line therapy for painful DN[56,57]	Low evidence on venlafaxine effectiveness for painful DN treatment[58]
	TCAs: Amitriptyline; desapramine	First and second-line therapy for painful DN	Associated with constipation, dry mouth, sleep disturbance, sexual dysfunction, somnolence, headaches, arrhythmias, constipation, sleep disturbances, and postural hypotension[4,63]
	Opioids: Tramadol; trapentadol	Opted as acute salvage treatment or as a part of drug combination for painful DN treatment	Strong opioids are frequently associated with therapeutic abuse and misuse[68]; use of tramadol is more preferred due to reduced risk of abuse or misuse[68]
	Sympathetic blocking agents (α-adrenergic antagonists): Clonidine; regitine; phenoxybenzamine	One of the opted therapies for complex regional pain syndrome treatment[72]	Limited evidence in RCT testing the drug’s efficacy in painful DN patients; efficiency of clonidine depends on relative functionality of nociceptors in painful DN patients, however no statistical significance is achieved although the trends of efficacy is shown[70]
Non-pharmacological	Sympathetic nerves blockade: Lumbar sympathetic nerves blockade; combined strategies of lumbar sympathetic pulsed radiofrequency and continuous epidural infusion; combined treatment of continuous sympathetic block and neurolysis with alcohol	Recommended for severe painful DN patients who failed to any pharmacological treatments	Patients demonstrated improved life expectancy, greater DN symptom improvement, satisfactory safety, rapid recovery, and rapid relief of pain[73-76]; associated with several limitations of additional diagnostic tools, small size population, short period of follow-up, and issue regarding combined treatment duration[75,76]
	Capsaicin	Recommended for patients with intolerable oral therapeutic consumption[4]	Low to moderate level of evidence for topical capsaicin efficacy[82,83]; associated with small nerve fibers injury and disturbed nociceptive signaling[84]
	Neuromodulation devices: FREMS; SCS, NMES; TENS	Studies on their efficacy in painful DN is still on-going	Not yet approved for clinical guidelines for painful DN treatment due to very low evidence of efficacy[4,85,86]
	Nutraceuticals: ALA; ALC; vitamin B12	ALA improves numbness and paraesthesia with reduced side effects[89]; vitamin B12 is recommended to T2DM patients with metformin prescription[90]	There is a lack of standardization in quality and manufacturing of nutraceuticals[91,92]; low safety level due to less evidence of high-quality studies[87,93]

TCAs: Tricyclic antidepressants; FREMS: Frequency-modulated electromagnetic neural stimulation; SCS: Spinal cord stimulation; NMES: Neuromuscular electrical stimulation; TENS: Transcutaneous electrical nerve stimulation; ALA: α-lipoic acid; ALC: Acetyl-L-carnitine; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus.