Nontricyclic antidepressant analgesics and pain: are serotonin norepinephrine reuptake inhibitors (SNRIs) any better?

Almost 50 years of clinical investigation has resulted in a large amount of literature regarding pain and antidepressants, one of the first categories of drugs found effective for chronic noncancer pain (CNCP) by randomized controlled trials (RCTs). These RCTs first examined tricyclic antidepressants (TCAs) based on published observational data and the rationale that their actions potentiated descending pain-inhibitory brainstem mechanisms involving serotonin andnoradrenaline [5]. Attention turned tomore selective antidepressants as they were developed because of limitations in efficacy and concern about adverse effects. These were initially the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine and congeners) and the more noradrenergic agents (the tetracyclic antidepressant maprotiline and the TCAs nortriptyline and desipramine, which are themetabolites of amitriptyline and imipramine). The results of these investigationswere generally disappointing regarding any superiority (except for nortriptyline) [54]. Recent pain treatment research has explored the dual serotonin noradrenaline reuptake inhibitor antidepressants (SNRIs), particularly venlafaxine, duloxetine, and milnacipran. Like the TCA amitriptyline, these have a more balanced effect on both serotonin and noradrenaline reuptake, but potentially have fewer adverse effects because of fewer receptor interactions. Recent RCTs have been primarily placebocontrolled trials of single agents, and there are few head-to-head trials comparing efficacy and side effects [54]. This reviewwill focus on the SNRIs and RCTs in neuropathic pain (NP) and fibromyalgia (FM). There is a need to address whether these drugs represent an advance in efficacy and safety over older antidepressants and other analgesics. Of importance to the clinician are the following: (1) the clinical meaningfulness of the results of a reportedly positive RCT; (2) how antidepressants compare directly in head-to-head RCTs [54]; and (3) the role of indirect comparisons of SNRIs with each other and with other drugs (older TCAs, gabapentinoids, opioids, cannabinoids) using number needed to treat (NNT) and number needed to harm (NNH) as estimates of efficacy and tolerability [12]. Also critical for the practitioner is an appreciation of how generalizable RCT results are to clinical practice (external validity) [51]