As a leading cause of disability in countries worldwide, chronic pain is a significant health crisis. Aside from its economic burden totaling hundreds of billions of dollars each year, chronic pain is exacerbated by a range of adverse effects impacting both health and quality of life at the individual, familial, and societal level.
To complicate things further, the range of available pharmacological and non-pharmacological treatments for people living with chronic pain often has limited effectiveness. Indeed, several studies report up to three in four people with chronic pain experience inadequate pain management (Geneen et al., 2017; Gregori et al., 2018; Williams et al., 2020). Many of these people with lived experience are prescribed opioids that – in addition to often having low levels of efficacy for pain relief – can be associated with the development of opioid use disorder and overdose deaths in certain instances.
To help address the global challenge of chronic pain, the United States’ National Institutes of Health (NIH) recently launched the Acute to Chronic Pain Signatures (A2CPS) research consortium. The A2CPS program is funded by the NIH Common Fund within the Office of the Director and is the result of a decade’s work exploring pain, largely driven by the United States government.
“Linda Porter [director of the Office of Pain Policy and Planning], together with Nora Volkow [director of the National Institute on Drug Abuse] and Walter Koroshetz [director of the National Institute of Neurological Disorders and Stroke] put together a proposal with the Common Fund, an initiative for high-risk, high-reward research that could make transformative changes in science,” explained the University of Iowa’s (USA) Kathleen Sluka, a principal investigator of the A2CPS Clinical Coordination Center.
The A2CPS program is structured around evaluating biomarkers involved in pain chronification from a range of fields, including neuroimaging, psychology, genomics, and proteomics, to name a few. The need to focus on biomarkers for pain chronification (Price et al., 2018) became apparent to the NIH through a workshop (see related PRF news story) designed to inform the Helping to End Addiction Long-Term (HEAL) initiative, launched by the NIH in 2018 to address the opioid crisis through a focus on pain and addiction research.
The A2CPS research consortium comprises several hubs selected by the NIH after a competitive application process. They include the Clinical Coordination Center at the University of Iowa, two multisite Clinical Centers in Chicago and Michigan (where patient recruitment and testing occur), a Data Integration and Resource Center (led by Tor Wager of Dartmouth College, New Hampshire, USA, and Martin Lindquist of Johns Hopkins University, Maryland, USA), and the “Omics” Data Generation Centers, located at Wake Forest University (North Carolina, USA), the Pacific Northwest National Laboratory (Washington, USA), and the University of California, San Diego (USA).
Sluka and her colleagues from the University of Iowa were quick to throw their hats into the A2CPS ring, excited by the opportunity to be involved in such an interesting study.
“My colleague Laura Frey Law has a lot of experience working with large multisite studies, so she knew a lot about coordination. Another thing we had on our side was a clinical trials statistics and data management center at our institute, run by Christopher Coffey, a biostatistician,” offered Sluka.
“We partnered with them because we felt we could make the strongest application and do really well with the regulatory side of things, as well as all the other bits and pieces that come along with running a Clinical Coordination Center.”
Wager and Lindquist also jumped at the opportunity to be a part of the A2CPS consortium, as they felt it would be the perfect opportunity to put some of their ideas about data processing and analysis – something they are both passionate about – into practice on a large scale.
“Tor and I had previously developed brain-based biomarkers for physical pain, and this felt like a natural next step in the process. We were intrigued by the potential of such a rich and unique dataset, and wanted the chance to use it to better understand pain,” said Lindquist (Wager et al., 2013).
“I love thinking about how we can improve our data workflows and quality control, and how we can invent new ways to answer neuroscientific questions using data. There are so many unanswered questions about pain, because a longitudinal neuroimaging study of the transition to chronic pain has never been conducted with this sample size,” said Wager excitedly.
Bringing together such a large and diverse group – more than 200 staff in total, including 100 researchers – has made the study stronger, according to Sluka. Also, utilizing the “non-pain” expertise of certain members – particularly those in the omics space – has been invaluable.
“When they decided one of their outcomes would be across multiple omics fields, they wanted to get really good omics people who do this for a living – rather than just have me running cytokine assays or metabolomics,” said Sluka.
“Working with the omics specialists has been fantastic. They come to us for our pain expertise, and we go to them for everything else related to omics. They’ve been an incredibly valuable resource in making sure the omics are done at such a high level. The quality of our science will be so much better with them than it would have been without them. And ultimately, we want the highest quality science.”
The extent of the shared knowledge and expertise of the A2CPS research program is on display in their first publication, Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures, which reviews and summarizes existing literature to identify what is – and isn’t – known, and how the consortium plans to address the gaps in the literature. The review was published on 15 June 2023 in PAIN.
“The review shows there’s good evidence for the psychosocial and pain variables that we measure, but it also highlights how little we know about the biological components,” Sluka explained.
The consortium is focusing on susceptibility/risk biomarkers, which indicate how likely an individual is to develop a disease in the future, and prognostic biomarkers, which describe the risk of disease recurrence or progression. A2CPS includes psychosocial measures such as depression and fatigue in their broader definition of a biomarker, as these measures are indirect indicators of complex biological processes.
The publication serves as an important milestone for the consortium.
“It shows how far we have come as a group. Most of us had never worked together before the consortium was put together, and many of us come from different disciplines. It takes time to learn how to ‘speak the same language,’ and the paper provides a summary of the countless hours of passionate discussion we have had as a consortium,” Lindquist explained.
“It [also] marks a transition from the planning and fine-tuning stage of the study towards making plans for analyzing the data and ultimately making it publicly available,” he continued.
Sharing the goals and findings of the consortium is the most exciting aspect of the project for Stephani Sutherland, the A2CPS communications director based at Johns Hopkins University, who leads the Scientific Outreach and Communications arm of the program.
“When I start telling people that we’ll have thousands of people with blood draws, omics data, brain imaging data, patient-reported outcomes, QST data… their eyes get a little wider, and sometimes there’s a twinkle,” Sutherland said with a laugh and a smile.
“The mission is not only to collect and analyze the data, but to share it with the scientific pain community. It will be a few years before the data is available, but I think a lot of the researchers in the consortium are excited. We’re going to have this tremendously comprehensive dataset that we can turn loose on the pain community – it’s going to be fun to see what other researchers can mine from the data.”
Wager foresees a wide range of uses for the A2CPS dataset being made available to the public, citing that the large, multifaceted nature of the dataset will appeal to different areas of basic and clinical science.
“These range from understanding antecedents and potential causes of pain in the brain and immune systems – a goal very close to the consortium’s mission – to the ability to pioneer new ways of analyzing brain tractography, functional MRI of clinical pain, connections between the brain and immune system, and many more.”
Sluka shares Sutherland’s and Wager’s enthusiasm about the A2CPS dataset being made available to the public.
“We hope people will come up with unique and novel questions, which is important. It’s going to be a wonderful database for the research community to jump into and use, much like the UK Biobank.”
Lincoln Tracy is a researcher and journalist based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.
Sluka et al. Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures. PAIN. 2023; 164(9):1912-1926.
Geneen et al. Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017; 4:CD011279.
Gregori et al. Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. JAMA. 2018; 320(24):2564-2579.
Williams et al. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2020; 8:CD007407.
Price et al. Transition to chronic pain: opportunities for novel therapeutics. Nature Reviews Neuroscience. 2018; (19):383-384.
Wager et al. An fMRI-based neurologic signature of physical pain. New England Journal of Medicine. 2013; (368):1388-1397.