We are delighted to present the Emerging Trends in Clinical Trialling 2021 article collection. This collection showcases the high-quality work of internationally recognized researchers in the early to mid stages of their research careers. These rising star researchers have been recognized by the Frontiers in Pain Research Editors for their potential to influence the future directions in their respective fields. The work presented here highlights the diversity of research performed across the entire breadth of clinical trialling and presents advances in theory, experimental techniques and methodology along with their application. New articles will be added to this collection as they are published.

University of Pennsylvania

INSERM U987 Physiopathologie et Pharmacologie Clinique de la Douleur (LPPD)

School of Medicine, Tufts University

Queen's University

University of Pittsburgh Medical Center

Frontiers in Pain Research

Clinical Trials, Methods, and Evidence Synthesis

Emerging Trends in Clinical Trials, Methods, and Evidence Synthesis

During the last decades, the emergence of Bibliometrics and the progress in Pain research have led to a proliferation of bibliometric studies on the medical and scientific literature of pain (B/P). This study charts the evolution of the B/P literature published during the last 30 years. Using various searching techniques, 189 B/P studies published from 1993 to August 2022 were collected for analysis—half were published since 2018. Most of the selected B/P publications use classic bibliometric analysis of Pain in toto, while some focus on specific types of Pain with Headache/Migraine, Low Back Pain, Chronic Pain, and Cancer Pain dominating. Each study is characterized by the origin (geographical, economical, institutional, …) and the medical/scientific context over a specified time span to provide a detailed landscape of the Pain research literature. Some B/P studies have been developed to pinpoint difficulties in appropriately identifying the Pain literature or to highlight some general publishing pitfalls. Having observed that most of the recent B/P studies have integrated newly emergent software visualization tools (SVTs), we found an increase of anomalies and suggest that readers exercise caution when interpreting results in the B/P literature details.

During the last decades, the emergence of Bibliometrics and the progress in Pain research have led to a proliferation of bibliometric studies on the medical and scientific literature of pain (B/P). This study charts the evolution of the B/P literature published during the last 30 years. Using various searching techniques, 189 B/P studies published from 1993 to August 2022 were collected for analysis—half were published since 2018. Most of the selected B/P publications use classic bibliometric analysis of Pain in toto, while some focus on specific types of Pain with Headache/Migraine, Low Back Pain, Chronic Pain, and Cancer Pain dominating. Each study is characterized by the origin (geographical, economical, institutional, …) and the medical/scientific context over a specified time span to provide a detailed landscape of the Pain research literature. Some B/P studies have been developed to pinpoint difficulties in appropriately identifying the Pain literature or to highlight some general publishing pitfalls. Having observed that most of the recent B/P studies have integrated newly emergent software visualization tools (SVTs), we found an increase of anomalies and suggest that readers exercise caution when interpreting results in the B/P literature details.

Thirty-year survey of bibliometrics used in the research literature of pain: Analysis, evolution, and pitfalls

ObjectiveTo evaluate the reporting quality of randomized controlled trials (RCTs) of acupuncture for labor pain, and to explore relevant factors for facilitating reporting transparency and integrity for future RCTs.</sec>MethodEight Chinese and English databases were systematically searched from their inception until August 31, 2021. General characteristics and methodological quality of the included reports were evaluated based on the CONSORT statement and the STRICTA guidelines. Descriptive statistical analysis was performed. Cohen's κ-statistics were calculated to assess the agreement of all items between two reviewers.</sec>ResultsA total of 84 RCTs were included. Based on the CONSORT statement, a positive reporting rate (greater than 80%) was evident for the items “trial design” “participants” “intervention” “outcomes” “numbers analyzed” and “generalizability”. The quality of reporting for the items “randomized in the title or abstract” “sample size” “allocation concealment” “implementation” “blinding” “recruitment” “ancillary analyses” “harms” “interpretation” “registration” and “protocol” was poor with positive rates less than 10%. Based on the STRICTA guidelines, the items “extent to which treatment varied” “number of needle insertions per subject per session” and “control or comparator interventions” had poor reporting quality with positive rates of less than 10%. Substantial agreement was observed for most items and excellent agreement for some items.</sec>ConclusionThe reporting quality of RCTs of acupuncture for labor pain is suboptimal generally. Rigorous adherence to the CONSORT statement and the STRICTA guidelines should be emphasized in future studies to improve the quality of acupuncture RCT reports.</sec>

Objective: To evaluate the reporting quality of randomized controlled trials (RCTs) of acupuncture for labor pain, and to explore relevant factors for facilitating reporting transparency and integrity for future RCTs.Method: Eight Chinese and English databases were systematically searched from their inception until August 31, 2021. General characteristics and methodological quality of the included reports were evaluated based on the CONSORT statement and the STRICTA guidelines. Descriptive statistical analysis was performed. Cohen's κ-statistics were calculated to assess the agreement of all items between two reviewers.Results: A total of 84 RCTs were included. Based on the CONSORT statement, a positive reporting rate (greater than 80%) was evident for the items “trial design” “participants” “intervention” “outcomes” “numbers analyzed” and “generalizability”. The quality of reporting for the items “randomized in the title or abstract” “sample size” “allocation concealment” “implementation” “blinding” “recruitment” “ancillary analyses” “harms” “interpretation” “registration” and “protocol” was poor with positive rates less than 10%. Based on the STRICTA guidelines, the items “extent to which treatment varied” “number of needle insertions per subject per session” and “control or comparator interventions” had poor reporting quality with positive rates of less than 10%. Substantial agreement was observed for most items and excellent agreement for some items.Conclusion: The reporting quality of RCTs of acupuncture for labor pain is suboptimal generally. Rigorous adherence to the CONSORT statement and the STRICTA guidelines should be emphasized in future studies to improve the quality of acupuncture RCT reports.

Assessment of reporting quality in randomized controlled trials of acupuncture for labor pain

Pain and depression frequently co-occur. Due to its antidepressant and analgesic properties, ketamine has been used for the management of treatment-resistant depression and pain. This systematic review examined the literature on the efficacy of sub-anesthetic doses of ketamine in individuals experiencing comorbid depression and chronic pain (CDCP), as well as comorbid depression and acute pain (CDAP). A secondary objective was to provide an assessment of dosage, route, and adverse effects of ketamine treatment for CDCP and CDAP. A literature search was conducted on MEDLINE, PsycINFO, and Embase databases, coupled with a manual screening of the bibliography sections of included articles. In addition, registered ongoing and planned trials were searched on Clinicaltrials.gov. The end date of the search was April 9th, 2022. Included studies assessed changes in depression and pain in patients receiving at least one sub-anesthetic dose of ketamine. Assessment of quality was conducted using the GRADE checklist. Of the 7 CDCP clinical trials, 3 reported a reduction in depression and pain, 3 reported a reduction in depression or pain only, and 1 reported no improvement in either comorbidity. Among the 7 CDAP clinical trials, 4 studies found improvements in depression and pain while the remaining 3 reported improvements in only one parameter. Ten of the 12 case studies and 2 of the 3 observational studies assessing CDCP and CDAP found improvements in pain and depression scores post-treatment with effects of variable duration. The planned methodologies of the registered clinical trials are in line with those of the published research. Preliminary evidence supports the efficacy of ketamine in treating CDCP and CDAP. However, the current review identified a small number of heterogeneous studies with mixed results, preventing comprehensive conclusions. More longitudinal placebo-controlled studies are needed to identify the effects of ketamine for patients with CDCP and CDAP.

Pain and depression frequently co-occur. Due to its antidepressant and analgesic properties, ketamine has been used for the management of treatment-resistant depression and pain. This systematic review examined the literature on the efficacy of sub-anesthetic doses of ketamine in individuals experiencing comorbid depression and chronic pain (CDCP), as well as comorbid depression and acute pain (CDAP). A secondary objective was to provide an assessment of dosage, route, and adverse effects of ketamine treatment for CDCP and CDAP. A literature search was conducted on MEDLINE, PsycINFO, and Embase databases, coupled with a manual screening of the bibliography sections of included articles. In addition, registered ongoing and planned trials were searched on Clinicaltrials.gov. The end date of the search was April 9th, 2022. Included studies assessed changes in depression and pain in patients receiving at least one sub-anesthetic dose of ketamine. Assessment of quality was conducted using the GRADE checklist. Of the 7 CDCP clinical trials, 3 reported a reduction in depression and pain, 3 reported a reduction in depression or pain only, and 1 reported no improvement in either comorbidity. Among the 7 CDAP clinical trials, 4 studies found improvements in depression and pain while the remaining 3 reported improvements in only one parameter. Ten of the 12 case studies and 2 of the 3 observational studies assessing CDCP and CDAP found improvements in pain and depression scores post-treatment with effects of variable duration. The planned methodologies of the registered clinical trials are in line with those of the published research. Preliminary evidence supports the efficacy of ketamine in treating CDCP and CDAP. However, the current review identified a small number of heterogeneous studies with mixed results, preventing comprehensive conclusions. More longitudinal placebo-controlled studies are needed to identify the effects of ketamine for patients with CDCP and CDAP.

Efficacy of ketamine for comorbid depression and acute or chronic pain: A systematic review

Previous research reports suggest greater baseline variability is associated with greater pain relief in those who receive a placebo. However, studies that evidence this association do not control for confounding effects from regression to the mean and natural history. In this report, we analyzed data from two randomized clinical trials (Placebo I and Placebo II, total N = 139) while adjusting for the effects of natural history and regression to the mean via a no treatment group. Results agree between the two placebo groups in each study: both placebo groups showed negligible semi-partial correlations between baseline variability and adjusted response [rsp (CI95%) = 0.22 (0.03, 0.42) and 0 (−0.07, 0.07) for Placebo I and II, respectively]. The no treatment group in Placebo I showed a negative correlation [−0.22 (−0.43, −0.02)], but the no treatment and drug groups in Placebo II's correlations were negligible [−0.02 (−0.08, 0.02) and 0.00 (−0.10, 0.12) for the no treatment and drug groups, respectively]. When modeled as a linear covariate, baseline pain variability accounted for <1% of the variance in post-intervention pain across both studies. Even after adjusting for baseline pain and natural history, the inability of baseline pain variability to account for substantial variance in pain response highlights that previous results concerning pain variability and treatment response may be inconsistent. Indeed, the relationship appears to be neither consistently specific nor sensitive to improvements in the placebo group. More work is needed to understand and establish the prognostic value of baseline pain variability—especially its placebo specificity and generalizability across patient populations.

Previous research reports suggest greater baseline variability is associated with greater pain relief in those who receive a placebo. However, studies that evidence this association do not control for confounding effects from regression to the mean and natural history. In this report, we analyzed data from two randomized clinical trials (Placebo I and Placebo II, total N = 139) while adjusting for the effects of natural history and regression to the mean via a no treatment group. Results agree between the two placebo groups in each study: both placebo groups showed negligible semi-partial correlations between baseline variability and adjusted response [rsp (CI95%) = 0.22 (0.03, 0.42) and 0 (−0.07, 0.07) for Placebo I and II, respectively]. The no treatment group in Placebo I showed a negative correlation [−0.22 (−0.43, −0.02)], but the no treatment and drug groups in Placebo II's correlations were negligible [−0.02 (−0.08, 0.02) and 0.00 (−0.10, 0.12) for the no treatment and drug groups, respectively]. When modeled as a linear covariate, baseline pain variability accounted for &lt;1% of the variance in post-intervention pain across both studies. Even after adjusting for baseline pain and natural history, the inability of baseline pain variability to account for substantial variance in pain response highlights that previous results concerning pain variability and treatment response may be inconsistent. Indeed, the relationship appears to be neither consistently specific nor sensitive to improvements in the placebo group. More work is needed to understand and establish the prognostic value of baseline pain variability—especially its placebo specificity and generalizability across patient populations.