According to the findings of a comprehensive review and Network Meta-Analysis (NMA), Duloxetine stands out as an antidepressant with proven efficacy for chronic pain, while the effectiveness of other antidepressants remains uncertain. Researchers conducted this study to compare the effectiveness and safety of antidepressants for adults suffering from chronic pain, excluding headaches. This research involved searching various databases such as PsycINFO, AMED, LILACS, CENTRAL, MEDLINE, Embase, and CINAHL, as well as clinical trials registries, for randomized controlled trials (RCTs) conducted in January 2022 that focused on the use of antidepressants for chronic pain conditions.

Those RCTs examining the use of antidepressants for chronic pain compared to any other treatment option were included. For the study to be double-blind, it was necessary for the comparator to be either a placebo, another medication, a distinct antidepressant, or the same antidepressant administered at varying doses. RCTs with active comparators that couldn't be double-blinded (such as psychotherapy) were included but considered to have a high risk of bias. RCTs with a follow-up period of less than 2 weeks and those with fewer than ten subjects in each group were excluded.

For data collection and analysis, two of the review authors conducted a thorough examination of the studies, extracting pertinent information and evaluating bias risks independently. The data was then synthesized for each outcome with the aid of pairwise meta-analyses and Bayesian NMA. With respect to efficacy, the antidepressants were ranked via surface under the cumulative ranking curve (SUCRA). To assess the certainty of the evidence, primary evaluations were carried out using Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) and Confidence in Meta-Analysis (CINeMA). In cases where CINeMA and ROB-MEN couldn't be applied due to complex networks, the GRADE approach was relied upon to assess the certainty of the evidence.

The study focused on several key outcomes, including significant (50%) pain mitigation, severity of pain, mood, and side effects. Additionally, several secondary endpoints were considered, such as serious adverse events, withdrawal, moderate pain mitigation (30%), physical function, quality of sleep, quality of life, and Patient Global Impression of Change (PGIC). A total of 176 studies involving 28,664 participants were analyzed. The majority of these studies (83) were placebo-controlled, and the majority followed a parallel-arm design (141). Musculoskeletal pain (n=40 studies), neuropathic pain (n=49 studies), and fibromyalgia (n=59 studies) were the most commonly studied pain conditions. The average duration of RCTs included was 10 weeks. However, seven studies did not provide usable data and were therefore excluded from the NMA. The majority of the studies primarily focused on short-term outcomes and did not encompass individuals with low mood or other mental health conditions.

When examining efficacy outcomes, Duloxetine consistently ranked as the most effective antidepressant, supported by moderate-to-high certainty evidence. In studies involving Duloxetine, the standard dose was found to be equally effective as the high dose for the majority of outcomes. Milnacipran frequently ranked as the second most effective antidepressant; however, the certainty of the evidence for its efficacy was lower compared to Duloxetine. For other antidepressants used in the treatment of chronic pain, there was a dearth of evidence to draw firm conclusions regarding their usefulness.

 

Primary endpoint

The standard dosage of Duloxetine (60 mg) demonstrated a moderate effect in providing remarkable pain relief (odds ratio [OR] 1.91; 16 studies, 4490 subjects; moderate-certainty evidence) and reducing continuous pain intensity (standardized mean difference [SMD] -0.31, 4959 subjects; moderate-certainty evidence). Milnacipran at the standard dosage (100 mg) also exhibited a small effect on pain intensity (SMD -0.22; 4 studies, 1866 subjects; moderate-certainty evidence).

Regarding mood, Mirtazapine (30 mg) illustrated a moderate effect (SMD -0.5; 1 study, 406 subjects; low-certainty evidence), while Duloxetine exhibited a small effect (SMD -0.16; 26 studies, 7952 subjects; moderate-certainty evidence). The majority of the studies eliminated subjects suffering from mental health illness, resulting in average anxiety and depression scores falling within the "subclinical" or  "normal" ranges at the baseline.

 

Secondary endpoint

In terms of moderate pain relief, PGIC, quality of life, physical function, and sleep quality, Duloxetine and Milnacipran were ranked highest among the antidepressant agents with moderate-certainty evidence. However, the effects observed were small. Both Duloxetine and Milnacipran illustrated comparable effectiveness between standard and high doses.

 

Safety

Safety parameters, including withdrawal, severe adverse events, and adverse events exhibited very low-certainty evidence across all antidepressant agents. Therefore, reliable conclusions regarding these outcomes cannot be drawn from the NMA.

This study yielded important findings regarding the effectiveness of various antidepressants in treating chronic pain. Among the 25 different antidepressants investigated, Duloxetine is the only one for which a high level of certainty in its efficacy was noted. Duloxetine demonstrated moderate effectiveness across all outcomes when administered at the standard dose. Although there is promising evidence for Milnacipran, further rigorous research is necessary to establish its efficacy with confidence.

The evidence for the effectiveness of all other antidepressants is of low certainty. It is worth noting that the exclusion of individuals with low mood in the RCTs hindered the ability to determine the effects of antidepressants in people with both chronic pain and depression. Consequently, there was a paucity of reliable evidence on the long-term efficacy of any antidepressant for chronic pain, as well as the safety of antidepressant use at any point in time.