The first serotonin–norepinephrine reuptake inhibitor (SNRI) , venlafaxine (Effexor), was introduced in 1994. Since then multiple other medications including duloxetine (Cymbalta) have been introduced. They all share the same mechanism of action as they selectively block the reuptake of serotonin and norepinephrine. They are used for a variety of ailments including depression, anxiety, obsessive–compulsive disorder, and fibromyalgia. The descending pathways in the spinal cord are moderated by serotonin and norepinephrine and inhibit the sense of pain. SNRI medications increase serotonin and norepinephrine and thus decrease the experience of pain.

There is extensive research in using duloxetine for analgesia. It currently has FDA approval for diabetic neuropathy, fibromyalgia, osteoarthritis, and musculoskeletal back pain. Dosing for duloxetine ranges from 30 to 120 mg daily. Evidence shows analgesic response at doses of 60–120 mg daily. Duloxetine is generally well tolerated, with nausea being a common side effect which is usually self-limited or can be alleviated by lowering the dose. Although the half-life of duloxetine is 12 h, it is often used as a once daily medication.

Venlafaxine does not currently have FDA approval for any pain indications, but there is substantial evidence for its efficacy for analgesia. Doses greater than 150 mg are necessary for analgesia as venlafaxine acts as a SSRI below 150 mg. Venlafaxine is available in an XR and IR formulation. The XR formulation is more readily prescribed as it is dosed once daily and less likely to cause hypertension compared to the IR formulation. The XR is usually started at 37.5 mg and slowly titrated up to 450 mg. It is typically prescribed in the morning as it is activating and will otherwise cause insomnia. Abrupt discontinuation of venlafaxine is associated with withdrawal (flu-like symptoms, nausea, anxiety, dizziness) and thus a slow taper is required upon discontinuation.

After first-pass metabolism , venlafaxine is metabolized into its active metabolite desvenlafaxine (Pristiq), which is currently used to treat depression and menopause. Currently there is limited evidence available for its use in analgesia, however as it is a metabolite of venlafaxine, evidence is anticipated to be forthcoming in the near future supporting its use in pain.

Milnacipran (Savella) was the first drug approved by the FDA for fibromyalgia. It is currently not FDA approved for depression. The starting dose of milnacipran is 12.5 mg which is then titrated up to 50 mg twice a day. Dose can eventually be titrated up to 100 mg twice daily.

The first selective serotonin reuptake inhibitor fluoxetine (Prozac) was introduced in 1987, and since then several medications in this class have been released and have become the mainstay in treatment for depression. Since 1987, SSRIs have had FDA approval for treatment of anxiety disorders, obsessive–compulsive disorder, and bulimia nervosa. They are also commonly used in treating post-traumatic stress disorder, premature ejaculation, premenstrual dysphoric disorder, irritable bowel syndrome, migraines, and attention-deficit hyperactivity disorder. Compared to TCAs, SSRIs are better tolerated and much safer in the event of an overdose scenario and have thus become first line in treating mood disorders. There have been a number of studies which have demonstrated SSRIs to provide clinically significant analgesia, although their effect is not as pronounced as the relief provided by TCAs.