Johny Marice
Far more people work very early morning shifts than overnight schedules, yet many struggle with severe fatigue linked to shift work disorder. This condition can interfere with concentration, job performance, and safety. A new clinical trial led by researchers at Mass General Brigham found that the wake-promoting drug solriamfetol (Sunosi) helped early morning shift workers stay more alert. The findings were published in NEJM Evidence.
Addressing a Critical Gap in Shift Work Disorder Treatment
"Until now, no clinical trial had tested a treatment for shift work disorder in early-morning shift workers, even though this is the most common type of shift schedule," stated senior author Charles A. Czeisler, PhD, MD, chief and senior physician of the Division of Sleep and Circadian Medicine in the Mass General Brigham Department of Medicine. "This study addresses a major gap by focusing on the workers who start their day when most people are still asleep."
This research marks a significant advancement in understanding and treating a prevalent but often overlooked form of shift work disorder. Historically, much of the clinical focus and subsequent treatment development for shift work disorder has been directed towards individuals working overnight shifts. However, the reality for a substantial portion of the workforce is the necessity of commencing their duties in the pre-dawn hours. This study’s deliberate focus on this demographic aims to rectify a long-standing disparity in research and therapeutic intervention.
The Biological Challenge of Early Morning Shifts
Roughly one in four workers operates outside the standard 9 a.m. to 5 p.m. schedule, a category that includes a vast number of individuals who begin their workday in the very early morning. Many of these workers do not self-identify as "shift workers," often viewing their schedule as simply an earlier start to the day rather than a deviation from typical societal norms. Despite this self-perception, they can be at a high risk for developing shift work disorder, a condition characterized by disrupted sleep patterns and persistent daytime sleepiness.
The core of the problem lies in the inherent biological programming of the human circadian rhythm. "People who start work between 3 a.m. and 7 a.m. are waking up at a time when the brain is biologically programmed to sleep," explained first author Kirsi-Marja Zitting, PhD, an investigator with the Division of Sleep and Circadian Medicine at Mass General Brigham. "That makes staying alert extraordinarily difficult, even when they are highly motivated." This biological imperative to sleep during these hours creates a significant challenge for maintaining wakefulness and cognitive function.
The consequences of this misalignment are profound. Workers in these early shifts often face a "double burden": experiencing excessive sleepiness during their working hours, which impairs performance and increases safety risks, and concurrently struggling to obtain adequate restorative sleep when they are off duty. This difficulty in sleeping can stem from the body’s natural inclination to sleep during the day, which is often perceived as a period of wakefulness, and can lead to chronic sleep deprivation.
Health and Safety Implications of Shift Work Disorder
The ramifications of untreated shift work disorder extend beyond mere inconvenience, encompassing a spectrum of serious health and safety concerns. These include a demonstrable reduction in mental acuity, leading to decreased productivity and an increased likelihood of errors in judgment. Furthermore, the impaired alertness associated with the disorder significantly elevates the risk of accidents, both on the road during commutes and within the workplace. Statistics from various occupational safety and health organizations consistently highlight shift workers as a demographic with a higher incidence of workplace injuries. For instance, studies on transportation workers, a sector heavily reliant on early shifts, have shown a correlation between sleep disorders and accident rates.
While medications like modafinil have been employed to promote wakefulness, their application in shift work disorder has predominantly been studied in overnight workers. Moreover, these wake-promoting agents can sometimes interfere with the ability to fall asleep later, creating a cyclical problem for individuals trying to manage their sleep schedule.
Solriamfetol, the drug investigated in this groundbreaking study, is already established and approved for treating excessive sleepiness in individuals diagnosed with obstructive sleep apnea and narcolepsy. Its mechanism of action, which promotes alertness for extended periods without significantly disrupting subsequent sleep, made it a promising candidate for addressing the unique challenges faced by early morning shift workers. This characteristic is particularly crucial, as interventions for shift work disorder must not exacerbate existing sleep difficulties.
Clinical Trial Design and Findings
The efficacy of solriamfetol in early morning shift workers was rigorously assessed in a clinical trial conducted by Mass General Brigham researchers. The study enrolled 78 participants who had been diagnosed with shift work disorder and worked early morning shifts. The participants were randomly assigned to one of two groups: one group received solriamfetol, while the other received a placebo. This double-blind, placebo-controlled design is the gold standard for clinical research, ensuring that neither the participants nor the researchers knew who was receiving the active drug, thereby minimizing bias.
The trial spanned a four-week period, during which participants took their assigned medication on workdays. A key component of the assessment involved a controlled laboratory setting designed to simulate low-stimulation environments, mimicking the conditions that can exacerbate sleepiness during work hours. Researchers monitored participants’ ability to remain awake during periods that corresponded with their typical work schedule. In addition to objective sleepiness assessments, participants also provided subjective reports on their daily functioning and met regularly with clinicians to track their progress and any adverse effects.
The results of the trial provided compelling evidence of solriamfetol’s effectiveness. After the four-week intervention, individuals who received solriamfetol demonstrated statistically significant improvements in their ability to stay awake and alert. They experienced reduced levels of sleepiness and were able to maintain wakefulness for longer durations during the simulated work periods. Crucially, these improvements translated into tangible benefits in daily life. Both participants and their prescribing clinicians reported enhanced overall functioning, better work performance, and a greater capacity to manage their daily responsibilities.
"The improvement we saw is clinically meaningful," Dr. Czeisler emphasized. "These workers were able to stay awake and alert throughout a full eight-hour shift, which has real implications for performance, safety, and quality of life." He further highlighted the societal importance of this group: "Shift workers are essential to how our society functions, yet they often pay a hidden biological cost. This study shows we can do better for them." The findings suggest that solriamfetol could offer a viable solution for many individuals who previously had limited effective treatment options.
Broader Impact and Future Directions
The implications of this study are far-reaching, potentially impacting millions of workers across various industries, including healthcare, transportation, manufacturing, and service sectors. By providing a targeted treatment for early morning shift workers, solriamfetol could help mitigate the health risks associated with shift work disorder, improve workplace safety, and enhance the overall well-being and productivity of this essential segment of the workforce. The ability to maintain alertness during crucial working hours can reduce errors, prevent accidents, and improve the quality of patient care in healthcare settings, for example.
However, the researchers are keen to emphasize that further research is necessary. The current trial, while promising, had a relatively short duration of four weeks and included participants who were otherwise healthy adults. "Early morning shift workers have not been widely studied, and the current trial lasted only four weeks and included otherwise healthy adults," the authors noted. Therefore, more extensive research is required to fully understand the long-term effects of solriamfetol in this population, including its safety profile and sustained efficacy over extended periods.
To that end, the research team is already embarking on the next phase of their work. They are actively enrolling participants for a follow-up clinical trial that will investigate the effects of solriamfetol in overnight shift workers. This subsequent study aims to gather more comprehensive data that could potentially support broader approval for the drug’s use in treating shift work disorder across all shift types. Such an expansion of approved indications would significantly increase access to this therapeutic option for a wider range of affected individuals.
The study’s funding sources, including Jazz Pharmaceuticals and Axsome Therapeutics, underscore the pharmaceutical industry’s growing interest in developing treatments for sleep disorders, particularly those related to occupational schedules. The collaborative effort between academic institutions like Mass General Brigham and pharmaceutical companies is crucial for translating scientific discoveries into tangible clinical benefits for patients.
A Timeline of Research and Development
The journey leading to this publication represents a culmination of years of research into circadian rhythms, sleep disorders, and pharmacological interventions. While the specific timeline for the solriamfetol clinical trial is detailed in its NCT number (NCT04788953, initiated around March 9, 2021), the foundational understanding of shift work disorder and the development of wake-promoting agents have evolved over decades.
Early Research (Pre-2000s): Initial recognition of shift work disorder as a distinct medical condition and its association with sleep disturbances and health problems. Early attempts at management often focused on behavioral interventions and sleep hygiene.
Development of Wake-Promoting Agents (Late 1990s – Early 2000s): The emergence of drugs like modafinil, initially developed for narcolepsy, began to be explored for their potential in treating excessive sleepiness associated with shift work disorder, primarily in overnight workers.
Focus on Circadian Rhythms (2000s – 2010s): Deeper scientific understanding of the complex mechanisms governing the body’s internal clock and how shift work disrupts these natural rhythms. This period saw advancements in chronobiology and its application to sleep medicine.
Targeted Drug Development (2010s – Present): Pharmaceutical companies began developing drugs specifically designed to target the neurobiological pathways involved in wakefulness and alertness, with a growing recognition of the need for treatments that are effective and well-tolerated. Solriamfetol, with its unique mechanism of action, emerged during this phase.
Current Study (2021-Present): The Mass General Brigham trial focused on the underserved population of early morning shift workers, culminating in the NEJM Evidence publication. This study represents a significant step in extending the therapeutic benefits of solriamfetol to a broader patient group.
Future Research: Ongoing and planned clinical trials, including the study in overnight shift workers, will continue to refine our understanding and treatment strategies for shift work disorder.
The authors of the study, including Kirsi-Marja Zitting, Charles A. Czeisler, Katherine R. Gilmore, Brandon J. Lockyer, Wei Wang, Nicolas C. Issa, Stuart F. Quan, Jonathan S. Williams, Jeanne F. Duffy, and Eileen B. Leary, represent a collaborative effort from Mass General Brigham and other institutions, highlighting the interdisciplinary nature of this research. Their continued work promises to bring further advancements in managing this pervasive occupational health challenge.
