Table 4.

Summary of opioid agents as potential treatment options for diabetic peripheral neuropathy [63–65, 69, 70, 81–83]

Treatment	Mechanism of action	Advantages	Disadvantages	NNT (95 % CI)	NNH (95 % CI)
Opioids			• Long-term use can result in tolerance, constipation, and rebound headaches	2.6 (1.7–6.0)	17.1 (9.9–66)
Tramadol	Weak opioid μ-receptor agonist Inhibits reuptake of serotonin and norepinephrine	• Efficacious in several neuropathic pain conditions including pDPN • Relatively rapid pain relief • Once-daily formulation • Generics available • Lower potential for abuse than other opioids • Combination treatment with acetaminophen appears better tolerated	• Not FDA-approved for pDPN • Limited efficacy • Side effects include constipation, sedation, and nausea • Lower threshold for seizures than other opioids • Used with caution in elderly patients due to risk of confusion • Not recommended for concomitant use with drugs acting on serotonin uptake (e.g., SSRIs)	4.9 (3.5–8.0)	13.3 (8.8–27)
Tapentadol ER	Weak opioid μ-receptor agonist Inhibits reuptake of norepinephrine	• FDA-approved for pDPN • Significant improvement in pain intensity in patients with diabetic peripheral neuropathy in large clinical studies • Clinically relevant CYP interactions unlikely to occur	• Late-line treatment agent • Twice-daily formulation • Danger of overdose if tablets not swallowed whole • Requires individual titration • Tapering schedule necessary on discontinuation • Side effects include constipation, nausea, dizziness, headache, and somnolence • Close monitoring of patients for respiratory depression • Caution needed with concomitant use of serotonergic drugs • Contraindicated for use with MAOIs

CI confidence interval, CYP cytochrome P450, ER extended release, 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, SSRI selective serotonin-reuptake inhibitor