NIH – Mechanisms Underlying the Contribution of Sleep Disturbances to Pain (R01, R21 Clinical Trial Optional)

March 12, 2019 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

In 2014, The National Center for Complementary and Integrative Health (NCCIH) led a trans-NIH workshop on “Contribution of Sleep Disturbances to Chronic Pain” ( Workshop participants concluded that evidence exists for an interaction between sleep and pain, but little is known about the mechanisms that underlie this interaction. To support research on this topic, in 2016, NCCIH, NIDA, NINDS, NINR, and NIAMS issued an FOA for Administrative Supplements for Research on Sleep Disturbances and Impact on Chronic Pain ( The purpose of this FOA is to further encourage additional mechanistic research to investigate the impact of sleep, and sleep disturbance on acute and chronic pain, and the transition from acute to chronic pain.

Chronic pain, in particular, is a major public health concern. It impacts over one third of the U.S. population, consumes substantial health care resources, and significantly reduces work productivity. The management of chronic pain has relied on opioids, which have significant risks for adverse events, and misuse. Sleep disorders commonly co-occur with chronic pain. There is not only substantial evidence that chronic pain states can disrupt sleep but, also, a growing evidence that sleep disturbances contribute to pain, and treatments of sleep disturbances can reduce pain. There is evidence suggesting sleep disturbances may increase acute pain sensitivity and, conversely, increased sleep time can reduce acute pain sensitivity. In addition, emerging evidence indicates that the presence of sleep disturbances may be one of several factors that predict the transition from acute to chronic pain. Furthermore, a meta – analysis of a few pilot studies of nonpharmacologic treatments of insomnia among chronic pain populations reported a small overall effect of reduced pain in the treatment groups relative to the control groups. But, more work is needed to validate these clinical findings. Successful management of pain, therefore, requires a better understanding of how sleep disturbances and their associated biological mechanism, contribute to the chronic pain, including its transition from acute pain.

Given the paucity of research on the mechanisms on how sleep may impact pain, and how modulation of sleep mechanisms influences pain, through this FOA, researchers are encouraged to address this unmet need.  Topics of interest relevant to this FAO include, but are not limited, to the following:

  • The mechanisms by which changes in sleep may impact nociception
  • The mechanisms by which hypothalamic neurons or other mechanisms involved in sleep regulation may affect nociceptive pathways
  • The mechanisms by which brain regions associated with sleep dysregulation may contribute to pain
  • The mechanisms by which deficient sleep or circadian dysregulation may impact central pain-modulatory processes
  • Neural/glial mechanisms underlying the effect of sleep on the transition from acute to chronic pain
  • The relationship between sleep and microbiome impacting pain and analgesia
  • The mechanisms by which pharmacologic interventions for sleep may impact chronic pain
  • The mechanisms by which nonpharmacologic or complementary and integrative health approaches for sleep regulation may impact chronic pain
  • The mechanisms underlying comorbidity of sleep disturbances, pain, and psychiatric disorders such as depression, posttraumatic stress disorders, and other conditions
  • The mechanisms by which complementary approaches, alone or in combination with medications, interact with sleep to increase or mitigate pain
  • The impact of chronotype (“morningness” versus “eveningness”) on perception of pain
  • The impact of circadian misalignment (“social jet lag”) on perception of pain
  • The effect of comorbid conditions with sleep on pain
  • The relationship between glymphatic function and pain

This FOA supports research in appropriate model organisms or human subjects. This FOA may support studies that are mechanistic clinical trials, which means that such studies meet the NIH definition of a clinical trial but are mechanistic in nature.  Applications submitted should not include any specific aims that propose to measure the efficacy or effectiveness of any intervention. Investigators who wish to conduct studies with clinical endpoints as the primary outcomes should consider other NIH-issued FOAs specifically designed for efficacy or effectiveness studies. Applications proposing to study the impact of pain on sleep will be considered low priority and are unlikely to be funded under this FOA.

Applicants are strongly encouraged to contact the Scientific/Research Contacts from various NIH Institutes and Centers (ICs) listed in Section VII prior to submission to discuss IC program relevance.

Specific Areas of Research Interest

Below are the areas of research interest from the participating NIH ICs of this FOA:

National Center for Complementary and Integrative Health (NCCIH):

NCCIH supports research on the science and clinical applications of complementary and integrative health approaches in pain management and their contributions to reduce the current opioid epidemic.  NCCIH is interested in applications that explore the mechanisms by which natural products (including botanicals, probiotics, dietary supplements, and special diets) and mind and body approaches (such as acupuncture, meditation, spinal manipulation, yoga, massage, hypnosis) modulate sleep in association with the regulation of pain perception and treatment responses.

National Cancer Institute (NCI):

Poor sleep is a known problem in cancer patients all along the cancer trajectory from diagnosis to end of life. A limited body of research suggests that sleep disturbances, primarily insomnia, can increase cancer patients’ sensitivity to pain. Patients often report significantly disrupted sleep even when their pain is well controlled by opioids. NCI is interested in the broad topics (both pre-clinical and clinical) listed in this FOA within the context of cancer, and with a particular interest in the following cancer-specific pain conditions:

  • Chemotherapy-induced peripheral neuropathy
  • Aromatase inhibitor arthralgias
  • Metastatic bone pain
  • Radiation-induced pain syndromes.

In addition, NCI is interested in the population of patients undergoing curative therapies, particularly those receiving neurotoxic agents and/or undergoing radiation therapy, and how these therapies impact the onset and duration of sleep disturbances and subsequent development of treatment-induced pain conditions.

National Institute on Drug Abuse (NIDA):

NIDA is interested in research in the following areas:

  • The mechanisms by which opioids may affect sleep
  • The mechanisms by which potential substances of abuse (e.g., nicotine, caffeine, cocaine) interact with sleep to increase or mitigate pain
  • The impact of sleep on opioid use and misuse in people with chronic pain
  • The opioid-sparing effects of improved sleep in people with chronic pain.

National Institute of Neurological Disorders and Stroke (NINDS):

NINDS is interested in research related to the neural mechanisms underlying the contribution of sleep disturbances to chronic pain. For applications submitted to this FOA that propose clinical trials, NINDS will support applications that propose human mechanistic trials/studies that meet NIH’s definition of a clinical trial and that fall within the NINDS research priorities. Clinical trials designed to answer specific questions about the safety, tolerability, efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions will only be supported by NINDS if submitted to an NINDS clinical trials-specific FOA. A current list of active NINDS clinical trials FOAs is available at

National Institute of Nursing Research (NINR):

NINR is interested in the biological underpinnings by which sleep disturbances can exacerbate chronic pain. Areas of interest include, but are not limited to, the following:

  • Genetic variations that alter sleep homeostasis in individuals suffering from chronic pain
  • Mechanisms of lifestyle factors (e.g., diet, inactivity, sociocultural) that contribute to impaired sleep in individuals with pain
  • How different forms of sleep disturbance (e.g., increased sleep latency) prolonged awakenings, are associated with pain.

National Institute of Dental and Craniofacial Research (NIDCR):

NIDCR is interested in mechanisms and processes underlying the contribution of sleep disturbances to orofacial chronic pain development and maintenance in temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, and other conditions. Clinical trials designed to answer specific questions about the safety, tolerability, efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device interventions will only be supported by NIDCR if submitted to an NIDCR clinical trials-specific FOA ( Awardees will be required to comply with the NIDCR Clinical Terms of Award for activities that involve human subjects.

Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

National Institute on Aging (NIA):

NIA encourages applications that investigate the mechanisms underlying the contribution of sleep disturbances to pain in midlife or older age, particularly in older adults with neurodegenerative diseases or multiple morbidities.

National Institute on Alcohol Abuse and Alcoholism (NIAAA):

Humans and animal models have shown considerable evidences that acute and chronic alcohol consumption disrupts patterns of sleep. Studies revealed many reciprocal interactions between alcohol and sleep and chronic alcohol abuse leading to sleep disruptions, which lead to alcohol dependence. These sleep changes may persist for months or even years of abstinence, suggesting that alcohol abuse may have enduring effects on circadian and/or homeostatic sleep processes. Similarly, alcohol initially produces analgesia while chronic, escalating use increases pain sensitivity. The influence of alcohol use on sleep or pain has been studied to some extent. However, how alcohol use could regulate the interactions between sleep and pain have not been investigated. This is highly important as chronic pain and sleep problems largely coexist and alcohol use can influence both pathophysiological states. Therefore, NIAAA interest in this FOA includes, but is not limited to, the following research questions:

  • Determination of the effects of sleep quality on pain and how alcohol use impacts these effects
  • Understanding the mechanisms of alcohol-mediated sleep disorders and how pain impacts the effects of alcohol
  • Investigations on persistent sleep problems on pain sensitivity in abstinence from alcohol use and as additional risk factor for relapse
  • Identification of factors, including genetic variability and epigenetic modifications that may predispose to sleep problems affecting pain sensitivity, and how alcohol use might influence these genetic factors
  • Investigations on these interactions across the lifespan, especially during prenatal and adolescence exposure and in an aging population where pain and sleep problems could be significantly influenced by alcohol use.

The National Heart, Lung, and Blood Institute (NHLBI):

NHLBI encourages applications elucidating the mechanistic relationship of sleep disturbances and circadian misalignment to comorbid pain in the context of heart, lung, blood, and sleep disorders.

Potential examples of research topics well-coupled to the NHLBI mission include, but are not limited to the following:

  • Identify pain mechanisms and pathways closely-coupled to sleep disordered breathing (SDB) pathobiology; elucidate mechanisms through which SDB-induced pathobiology increase pain sensitivity or significantly influence the effectiveness of pharmacotherapeutic interventions for acute pain and chronic pain. What mechanisms mediate changes in cognitive perception of pain through sleep fragmentation, sleep deprivation, or circadian disturbances associated with SDB?
  • Identify mechanisms through which sleep and breathing disturbances closely coupled to Sickle Cell Disease (SCD) increase the frequency of chest pain crises and interfere with management of pain in this and other blood disorders
  • Elucidate sleep and circadian mechanisms that contribute to the severity of pain in heart, lung, and blood diseases such as SCD and COPD.  Does sleep duration, quality, or timing contribute to the severity of acute and chronic hyper-reactive inflammation?
  • Identify specific cellular mechanisms through which sleep and circadian disturbances diminish physiological resilience to pain in heart, lung, blood, and sleep disorders.

Applicants are strongly encouraged to discuss their anticipated research plans with the NHLBI Scientific/Research contact listed in this announcement well in advance of the anticipated submission date.  NHLBI will not fund studies designed for the purpose of determining the efficacy or effectiveness of an intervention, including NIH defined clinical trials, under this funding opportunity announcement. Applicants interested in these types of studies are encouraged to apply to the NHLBI clinical trial specific funding opportunities: (single-site) or and for multi-site clinical trials.

Office of Behavioral and Social Sciences Research (OBSSR): 

OBSSR is interested in research that would investigate the behavioral and/or sociocultural mechanisms or modulators that regulate sleep (quality, quantity, etc.) and the effects on chronic pain. These can include but are not limited to lifestyle factors, e.g., diet, inactivity, sociocultural, socioeconomic, sleep hygiene, etc. Additionally, research that focuses on behavioral interventions for sleep deficiencies in the context of improving pain would also be of interest.

Office of Research on Women’s Health (ORWH):

Women have a higher prevalence of pain disorders and a greater sensitivity to pain, and therefore there is a crucial need to recruit women into pain-related clinical research in sufficient numbers to determine sex-specific responses as well as sex differences. Research also shows that women are more susceptible to sleep deficiency and sleep disorders than men based on biological differences and the societal and social expectations of women in the workplace and the home. ORWH therefore is interested in supporting research to address sex influences in basic, translational, interdisciplinary, behavioral, clinical, and/or health services research on pain and sleep neurobiology and pathology and how they might interact. As appropriate, projects will use both sexes to better understand the influence of sex as a variable in accordance with NIH policies on Consideration of Sex as a Biological Variable in NIH-funded Research and Enhancing Reproducibility through Rigor and Transparency.

Deadlines: standard dates apply


Filed Under: Funding Opportunities