Many Chronic Pain Studies Omit Patients With Depression

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Of the randomized controlled trials identified, only 41% involved patients with depression.

The majority of randomized controlled trials (RCTs) evaluated excluded patients without significant depressive symptoms at baseline, according to an analysis published in Sage Journals.1 Therefore, the results of these reviews and subsequent guidelines are less applicable to patients with significant depression. Further, systemic biases regarding psychological conditions, as well as gender, may play an important in evaluating depression in fibromyalgia compared with other conditions like arthritis.

“In recent years, there has been an increase in the number of chronic pain RCTs that collect depression outcomes, but it is unknown how often these trials include people with depression or significant depressive symptoms,” wrote Darren K Cheng, MSc, associated with the Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada, and colleagues. “If trials do not include participants representative of real-world populations, evidence and guidance generated from these trials risk being inapplicable for large proportions of the target population, or worse, risk harm.”

Chronic pain currently affects 20% of North American adults and is commonly associated with a variety of mental illness comorbidities, including depression. Those with chronic pain report comorbid major depressive disorder ranging from 27% to 85%, compared with 8 to 10% of the general population. Patients with comorbid depression experience lower mental and physical quality of life, increased intensity of pain, and a reduction in pain tolerance.2

To identify strategies to improve clinical trials, investigators aimed to analyze the proportion of RCTs evaluating chronic pain and depression outcomes including patients with significant depressive symptoms. They also determined the variability of inclusion proportions based on gender, country, intervention type, pain type, and publication year.

Data extraction and RCT screening were completed in duplicate. Trials with ≥50% adult participants and validated depression scales were eligible for inclusion. RCTs including populations with mean scores at or above depression thresholds at baseline were categorized as including patients with depression.

Ultimately, 346 RCTs were identified, of which 142 (41%) involved patients with depression. The studies were published between 1981 and 2018. Investigators identified 8 pain-type groups, such as fibromyalgia and axial pain, and 9 intervention types, including psychological, pharmacological, and exercise.

The highest proportion of patients with depression were reported in RCTs evaluating fibromyalgia and mixed chronic pain (57.1% and 61.1%, respectively). The lowest proportion of depression was observed in studies involving arthritis and axial pain (18.6% and 26.9%, respectively).

RCTs from the United States (US) had significantly lower proportions of inclusion when compared with studies outside of the US, particularly for studies on arthritis. An increase in inclusion by publication year was directly linked to an increase in fibromyalgia studies.

Investigators noted examining depression over a period of 4 decades across various pain types, intervention types, gender, and country of origin strengthened the study and allowed for the comparison of inclusion proportions across multiple categories. However, as the inclusion of RCTs were dependent on their inclusion in systematic reviews, there is a possibility some relevant studies were excluded from the analysis. Further, as analyses were restricted to trial-level as opposed to participant level, smaller RCTs may have had a disproportionate impact on the described inclusion proportions.

“This study highlights opportunities to improve the conduct of chronic pain clinical trials,” investigators concluded. “Given the high prevalence of comorbid chronic pain and depression, future RCTs investigating interventions for people with chronic pain must work to include participants with depression, or at the very least, significant depressive symptoms.”


  1. Cheng DK, Ullah MH, Gage H, Moineddin R, Sud A. Chronic pain trials often exclude people with comorbid depressive symptoms: A secondary analysis of 346 randomized controlled trials [published online ahead of print, 2023 Jun 22]. Clin Trials. 2023;17407745231182010. doi:10.1177/17407745231182010
  2. Yang SE, Park YG, Han K, et al. Association between dental pain and depression in Korean adults using the Korean National Health and Nutrition Examination Survey. J Oral Rehabil 2016; 43(1): 51–58.