Table 2.

Summary of serotonin/norepinephrine-reuptake inhibitors as potential treatment options for diabetic peripheral neuropathy [63–65, 69, 70]

Treatment	Mechanism of action	Advantages	Disadvantages	NNT (95 % CI)	NNH (95 % CI)
SNRIs				5.0 (3.9–6.8)	13.1 (9.6–21)
Duloxetine	Inhibition of reuptake of the neurotransmitters serotonin and norepinephrine	• FDA-approved for pDPN • Efficacious in reducing pain scores for up to 1 year (efficacy beyond 12 weeks has not been systematically studied) • Improved tolerability vs TCAs • Beneficial for patients with comorbid depression • Simple dosing; effective dose is starting dose • Once-a-day dosing • First-line agent	• Tapering schedule necessary on discontinuation • Side effects include nausea, vomiting, dry mouth, constipation, somnolence, dizziness, decreased appetite, hyperhidrosis, sexual dysfunction • Potential for interactions due to metabolism via hepatic CYP1A2 and CYP2D6 enzymes • Contraindicated for use with MAOIs • May worsen glycemic control in patients with diabetes • Discontinuation rates of 15 %–20 % • Rare cases of hepatotoxicity
Venlafaxine	As for duloxetine, but with a relatively reduced effect on norepinephrine at lower doses	• Efficacious in pDPN • May be added to gabapentin to improve response • Improves QoL measures • No dosage adjustment necessary if co-administered with a CYP2D6 inhibitor	• Not FDA-approved for pDPN • Requires titration schedule and tapering on discontinuation • Most common side effects include asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision, and sexual dysfunction • ECG changes during treatment – should be prescribed with caution for patients with cardiac disease • Dose-dependent sustained blood pressure increases in some patients • Potential for drug–drug interactions with CYP3A4 inhibitors

CI confidence interval, CYP cytochrome P450, ECG electrocardiogram, FDA Food and Drug Administration, MAOI monoamine oxidase inhibitor, NNH the number of patients needed to harm for one drop-out due to adverse events, NNT estimated number of patients with painful polyneuropathy needed to treat to achieve one patient with a 50 % reduction in pain, pDPN painful diabetic peripheral neuropathy, QoL quality of life, SNRI serotonin/norepinephrine-reuptake inhibitor, TCA tricyclic antidepressant