Tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine) are recommended as the first-line agents for peripheral neuropathic pain, especially for painful polyneuropathy, the other first-line options being gabapentinoids and topical lidocaine. Tricyclic antidepressants became a mainstay in the management of neuropathic pain before their mechanisms were elucidated and before the advent of systematic ways to evaluate their efficacy. Venlafaxine and duloxetine should be used with caution in patients with a history of mania, seizures, or bleeding tendency. Due to risk of excessive serotoninergic effect, they should be used with caution in patients receiving concomitant selective serotonin reuptake inhibitor (SSRI) or tramadol treatment. When selecting the treatment for an individual patient, comorbid conditions and their medications need to be taken into account. More detailed information of the effects of pharmacological agents on various symptoms of neuropathic pain and sensory profiles may guide drug selection in the future.