Table 2.

Advantages and disadvantages of pharmacotherapies for painful diabetic neuropathy. DN, diabetic neuropathy; IV, intravenous; SNRIs, serotonin and norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; UK, United Kingdom; USA, United States.

Pain Management Strategy	Level of Evidence	Advantages	Disadvantages
Anticonvulsants—pregabalin and gabapentin	Moderate-quality [127,128]	-Anticonvulsants significantly reduce pain in DN [127,128] -Pregabalin is approved for painful DN in the USA and UK [129,130]	-In the USA gabapentin is not approved for painful DN -In the UK there have been recent cases of misuse [131] -Anticonvulsants are associated with tachyphylaxis -Anticonvulsants have a range of side effects (e.g., drowsiness, dizziness, headache, diarrhea and nausea) [130,132] -Pregabalin is linked to infrequent reports of severe respiratory depression [133]
Serotonin and norepinephrine reuptake inhibitors (SNRIs)—duloxetine and venlafaxine	Moderate-quality (duloxetine) [134,135,136,137,138,139,140,141]; Low-quality (venlafaxine) [142]	-Duloxetine significantly reduces pain in DN [134,135,136,137,138,139,140,141] -Duloxetine is approved for painful DN in the USA and UK [129,143]	-SNRIs have similar side effects to anticonvulsants -Sexual dysfunction and sleep problems may be more noticeable [4,143] -Venlafaxine is not approved for painful DN
Tricyclic antidepressants (TCAs) –amitriptyline	Low-quality [144]	-Amitriptyline has benefitted thousands of people with painful DN over the years [144] -Amitriptyline is approved in the UK for neuropathic pain [145]	-Amitriptyline has a range of side effects (e.g., sleep disorders, constipation, sexual dysfunction, arrythmias and postural hypotension) [145] -Amitriptyline is not approved in the USA
Opioids—tramadol and tapentadol	Low-quality [146,147]	-Tramadol significantly reduces pain in DN [148,149] -Tramadol is approved in the USA and UK for moderate to severe pain [129,150] -Tramadol may have a decreased risk for abuse [151] -Tapentadol is approved for neuropathic pain in the USA [129]	-Opioids are linked to problems with misuse and abuse [152] -Opioids have a range of side effects (e.g., dizziness, drowsiness, headache, nausea and constipation) [150] -Tramadol should not be taken in combination with SNRIs/SSRIs [99] -Tapentadol is not approved for neuropathic pain in the UK [153]
Topical analgesics—topical capsaicin	Moderate-quality (8% capsaicin) [154,155]; Low-quality (0.075% capsaicin) [156,157]	-8% capsaicin significantly reduces pain in DN [154,155] -8% capsaicin may be more beneficial than anticonvulsants and may have a similar efficacy to duloxetine [154] -0.075% capsaicin significantly reduces pain in DN [156]	-Some patients may require two to three applications of 8% capsaicin before achieving a treatment response [155] -Topical capsaicin may disturb nociceptive signaling [158] -Topical analgesics only relieve pain in localized areas
Intravenous (IV) medications—IV lidocaine and IV ketamine	Low-quality [159,160,161]	-IV medications significantly reduce pain in DN [159,161]	-IV medications are not currently recommended by clinical guidelines for DN -IV lidocaine may not have long-term effectiveness [159] -IV medications are limited to inpatient use -IV medications have a range of side effects (e.g., sleep disorders, dizziness and nausea) [152,160]