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Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Chronic Pain and Palliative Care

Many chronic diseases are associated with pain that can be chronic and severe. Pain often is difficult to treat and can significantly erode patients’ quality of life. As discussed in the Neuroscience section, NIH supports a spectrum of pain research that includes basic science to understand the mechanisms of pain and pain relief, as well as clinical research to evaluate pharmacological, surgical, and alternative strategies for pain management. Palliative care, which includes pain management, focuses on alleviating disease symptoms and improving patients’ quality of life. Optimizing end-of-life care is an important topic within the field of palliative care research, particularly with respect to understanding the needs of dying children with chronic diseases and their families. Researchers also are studying the many cultural, spiritual, age-related, and disease-specific factors that affect the end of life. Because each person’s experience at the end of life is unique, NIH has developed an initiative to support research on interventions for end-of-life and palliative care that can be applied in a variety of settings, illnesses, and cultural contexts.

Chronic pain is a debilitating symptom of many long-term disease states such as cancer or arthritis. It may also manifest as a persistent pain state that outlasts an acute injury or illness, or arises in the absence of an identified causative mechanism. Persistent pain is widely considered to be a distinct disease state in itself. The transition from acute pain to a persistent and intractable condition involves improper functioning of neuronal pain circuits, in which parts of the nervous system become hypersensitized for long or indefinite periods of time. It is unclear why some but not all people develop chronic pain after an acute insult has resolved. Common chronic pain conditions include migraine and other headaches, low back pain, cancer pain, arthritis pain, and neuropathic pain such as in diabetic neuropathy (pain resulting from damage to the peripheral nerves or to the central nervous system).

Many chronic pain conditions are co-morbid or overlapping in nature with two or more conditions occurring simultaneously in the same patient. It is likely that some of these overlapping disorders share common mechanisms including genetic susceptibility. Overlapping pain conditions may include migraine, chronic fatigue syndrome, endometriosis, fibromyalgia, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, temporomandibular joint disorders (TMJD), and vulvodynia. Chronic pain conditions can be exacerbated by environmental or psychosocial factors.

NIH funds a broad portfolio of chronic pain research activities ranging from basic research into the molecular, genetic, and bio-behavioral basis of chronic pain to large-scale clinical studies of potential treatments. NIH has leveraged various award mechanisms such as the Common Fund-sponsored Transformative Research Award Program, ARRA-funded NIH Challenge grants and Grand Opportunity grants as well collaborative funding through the NIH Blueprint for Neuroscience Research to fund cutting-edge pain research.

Pain research activities at NIH are coordinated in large part by the NIH Pain Consortium—a joint undertaking across 25 Institutes and offices that identifies and facilitates implementation of key opportunities in collaborative pain research. In 2010–2011, the Consortium was proactive in coordinating a number of pain research initiatives and activities at NIH which included identifying key opportunities in pain research and education, convening conferences and workshops to highlight recent advances and needs in the field, and building collaborations with other federal agencies, such as the FDA, and academic institutions involved in pain research. For example, members of the Pain Consortium currently participate in an advisory committee for the Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) initiative, a public-private partnership program sponsored by FDA to streamline the discovery and development of analgesics. In 2011, Pain Consortium members established working groups for overlapping chronic pain conditions as well as chronic lower back pain. Led by NIDA and in collaboration with members of the Consortium 12 health professional schools in May 2012 were designated and funded as “Centers of Excellence for Pain Education” to develop, evaluate, and distribute pain management curriculum resources for medical, dental, nursing and pharmacy schools to advance the assessment, diagnosis, and safe treatment of pain while minimizing risks of addiction and diversion.123

In addition to Trans-NIH efforts, NIH ICs fund chronic pain research aligned with their missions through joint funding opportunity announcements (FOA), workshops, and conferences. For example, NINDS focuses on headache and neuropathic pain research. The Institute recently released a headache planning meeting report124 detailing the opportunities, priorities, and recommendations for headache research. NINDS is funding a ten-year study on overlapping pain conditions that disproportionately affect women, including episodic migraines and is also funding a comparative effectiveness trial of drugs used to prevent pediatric migraine. Results are expected to have a significant effect on clinical practice and could help to establish clinical practice guidelines for headache management in children and adolescents.

In 2011, NEI created a new program for ocular pain and funded new projects to examine the neurons and pathways involved in corneal pain. NINR sponsors numerous training opportunities to develop improved research capacity in the science of pain, such as its intramural Methodologies Boot Camp. Also in 2011, NINR released a FOA to stimulate research that will link basic genomic discovery to the prevention and alleviation of symptoms in patients suffering from chronic disorders, while its intramural program is focused on studying the molecular-genetic mechanisms of pain and analgesia at the level of the individual. NCCAM recently funded two Centers of Excellence for Research on Complementary and Alternative Medicine to understand neural processing of chronic low-back pain using neuroimaging to elucidate how mind-and-body interventions affect these processes.

To coordinate, complement, and inform pain research goals and follow recommendations from the Institute of Medicine,125 NIH has designated NINDS as the lead Institute for coordinating pain research efforts across the organization; selected a cadre of 11 Centers of Excellence for Pain Education; begun to develop new informational material for the public and medical professionals on pain conditions; and instituted more frequent meetings of the NIH Pain Consortium. NIH convened a number of conferences, workshops, and strategic planning efforts on chronic pain conditions in 2011–2012. For example, in April 2011, ORWH and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group held a State of the Knowledge Workshop on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research. Also in April 2011, the Pain Consortium’s 6th Annual Symposium on Advances in Pain Research was held on the NIH campus, entitled Mechanisms and Management of Overlapping Chronic Pain and Associated Conditions. In June 2011, NIDCR and other ICs sponsored the Sixth Scientific Meeting of the TMJ Association titled Comorbid Chronic Pain Conditions – Mechanisms, Diagnosis and Treatments. In September 2011, ORWH held a seminar and panel discussion on Sex Differences and Pain Research.

Understanding and managing chronic pain is hampered by the neurobiological and psychosocial complexity of the conditions and by the individual variation in susceptibility to chronic pain, perception of pain, and response to pain therapies. Challenges include basic research outcomes on chronic pain that poorly predict clinical applications of the research findings and pose as barriers to therapy development. Current animal models do not reflect the complexity of pain disorders, and assays for pain in animals and humans are not well matched. Priorities for advancing pain research include understanding how acute pain transitions to chronic pain, identifying biological pain signals, determining the risks and predictors of who will develop one or more chronic pain conditions, who will respond to certain therapies, as well as developing alternative pain medications with reduced abuse liability. For instance, NCCAM’s Third Strategic Plan (2011–2015)126 highlights its commitment to advancing understanding of pain and pain relief through complementary and integrative health approaches. NIDCR plans to invest in understanding the genomics of chronic orofacial pain, which often co-occurs with other chronic pain disorders, to better inform prevention, diagnosis, and treatment of pain disorders.

NIH’s significant investment in pain research has recently provided important advances in our basic understanding of pain and our ability to treat it. For example, a gene variant discovered by NIH researchers protects some people from chronic pain after back surgery due to variations in signaling pathways. The team is now clinically testing an analgesic drug to target these signaling pathways.127 NIH-funded research has identified a family of so-called Piezo proteins that are ion channel proteins essential to the sensation of painful touch and new therapeutic targets for the treatment of pain128 and another study demonstrated that variations in the gene that encodes receptors for the hormone vasopressin are associated with pain sensitivity in a stress- and sex-specific manner in both mice and men.129 NIH supported scientists have shown that transplantation of neuron precursors into adult spinal cord can reduce injury-induced neuropathic pain.130 Finally, research has demonstrated that massage therapy helps reduce pain and improve function more rapidly than usual medical care in people with chronic low-back pain, according to a NIH-funded study published in the Annals of Internal Medicine.131

As mentioned above, NINDS has been designated as the lead IC for pain research at NIH. In this role, the NINDS director, a longtime member of the Pain Consortium Executive Committee, has been appointed as the Chair of the committee, and will work to catalyze and coordinate enhanced trans-NIH research efforts on pain. As a reflection of this enhanced activity level, the Pain Consortium moved to a more frequent quarterly meeting schedule. The Interagency Pain Research Coordinating Committee was recently created under the Patient Protection and Affordable Care Act to enhance pain research efforts and promote collaboration across the government, advance fundamental understanding of pain, and improve pain-related treatment strategies.

123For more information, see https://painconsortium.nih.gov/CoEPES.html.
124For more information, see https://painconsortium.nih.gov/Headache-Research-Opp.pdf.
125For more information, see https://iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx.

126 For more information, see https://nccam.nih.gov/about/plans/2011.
127 For more information, see http://www.sciencedirect.com/science/article/pii/S1471489211002013 Exit Disclaimer
128 For more information, see http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10812.html Exit Disclaimer
129 Mogil JS, et al. Nat Neurosci. 2011;14(12):1569–73. PMID: 22019732.
130 For more information, see http://www.cell.com/neuron/abstract/S0896-6273%2812%2900270-X?switch=standard Exit Disclaimer
131 Cherkin DC, et al. Ann Intern Med. 2011;155(1):1–9. PMID: 21727288.

Chronic Pelvic Pain

Chronic pelvic pain is a general term that health care providers use to describe pain that occurs mostly or only in the lower abdominal area. It may be steady pain, or recurrent. It includes conditions affecting and/or originating in the genitourinary and GI tracts. Common health conditions associated with chronic pelvic pain include:

NIH supports a wide range of basic, clinical, and translational research to better understand the causes of chronic pelvic pain conditions and to find ways to diagnose, prevent, treat, and possibly cure these conditions. IC/PBS, CP/CPPS, vulvodynia, and IBS are especially challenging pain conditions because their cause(s) are unknown, and fully effective treatments remain elusive.
NIDDK supports studies to address chronic pelvic pain of urologic and GI origin, including the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.This NIDDK-led network includes multiple centers to conduct innovative, collaborative studies of IC/PBS and CP/CPPS that include searching “beyond the bladder/prostate” to find the causes of these conditions and includes studies of the possible relationships between these conditions and other chronic pain disorders (such as IBS and fibromyalgia).132

Co-funded by ORWH, NIDDK leads the Interdisciplinary Research on Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) initiativeto support interdisciplinary research teams to address critical research questions focused on IC/PBS, with translational or clinical relevance. One team is exploring the possible role of the GI and/or reproductive tract microbiomes in IC/PBS,133 the other is studying whether women with IC/PBS have global pain hypersensitivity.134

The Women’s Health and Functional Visceral Disorders Center is studying the interplay between gut and brain pathways in IC/PBS and IBS, focusing on sex differences in the development, clinical manifestation, and treatment response in these pain syndromes. This interdisciplinary Specialized Center of Research-(SCOR) on Sex and Gender Factors Affecting Women’s Health was established through an ORWH program and is co-funded by NIDDK and ORWH.135NIDDK is supporting the Rand IC Epidemiology (RICE) study and other large studies to answer fundamental questions about prevalence, potential causes, and risk factors of IC/PBS, and to learn more about the broader impact of this condition on health and quality of life.136 The RICE study found through a nationwide telephone-based survey that 2.7 to 6.7 percent of adult women in the U.S. have symptoms consistent with IC/PBS.137 The RICE study has also revealed a very high prevalence of sexual dysfunction among women with IC/PBS symptoms,138 as well as high rates of depressive symptoms and panic disorder.139 In addition to helping establish the public health burden, this information is important to the design of future clinical trials and epidemiological studies that can benefit people with IC/PBS.

NIDDK supports fundamental studies of the bladder and prostate in health and disease, including studies of structure, function, and innervation, as well as studies of the possible role of infectious agents in triggering urologic pain. NIDDK also supports fundamental studies of GI innervation, motility, and bacterial complement that could provide insight into why and how IBS develops.
TheNICHD-led Pelvic Floor Disorders Network (PFDN) isa highly productive clinical trials network that conducts research on how to improve the care and daily lives of women with pelvic organ prolapse and bladder and bowel control problems.
A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response, co-funded by NICHD and ORWH, addresses the efficacy of the drug gabapentin in vulvodynia treatment, and seeks to identify clinical features associated with successful treatment response.

NICHD funds the Prostaglandin E2 Signaling in Growth and Pains of Endometriosis study, co-funded by ORWH, aims to develop a new non-steroidal treatment for endometriosis, by examining the mechanisms by which inhibitors of specific prostaglandin receptors relieve endometriosis pain and prevent disease progression.

NIH also sponsors conferences to stimulate innovative research and encourage collaboration on pelvic pain disorders. On July 11–12, 2011, NICHD and ORWH co-sponsored the conference Vulvodynia: A Chronic Pain Condition—Setting a Research Agenda in Potomac, Maryland.140 In November 2010, NICHD, ORWH, other NIH Institutes and Centers, and other federal Agencies sponsored Advances in Uterine Leiomyoma Research: Third NIH International Congress.

132 For more information, see https://rt5.cceb.upenn.edu/mapp_web/MAPP_About.html Exit Disclaimer.
133 For more information, see https://projectreporter.nih.gov/project_info_description.cfm?aid=8257609&icde=10793568&ddparam=&ddvalue=&ddsub.
134 For more information, see https://projectreporter.nih.gov/project_info_description.cfm?aid=8257614&icde=10793568&ddparam=&ddvalue=&ddsub.
135 For more information, see https://www.cns.med.ucla.edu/CenterAbout.htm Exit Disclaimer.
136 Berry SH, et al. J Urol. 2011;186(2):540–4. PMID: 21683389.
137 Berry SH, et al. J Urol. 2011;186(2):540–4. PMID: 21683389.
138 Bogart LM, et al. Urology. 2011;77(3):576–80. PMID: 21215432.
139 Watkins KE, et al. Gen Hosp Psychiatry. 2011;33(2):143–9. PMID: 21596207.
140For more information, see https://www.nichd.nih.gov/publications/pubs/upload/NIH_Vulvodynia_Plan_April2012.pdf

Brain function and anatomy in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) was revealed through fMRI.Results of this study show an association between functional and anatomical changes in the brains of men with CP/CPPS compared to those without this condition. Future studies will determine whether the observed brain changes are a result of chronic pelvic pain or represent risk factors for the development of CP/CPPS.141

Research on pelvic pain associated with UTIs has implicated bacterial LPS142in inciting pain through a novel mechanism involving host TLR4 receptors. This line of research is being explored by chronic urologic pelvic pain researchers as it also suggests that there may be an infectious origin in the persistent, chronic pain experienced by people with IC/PBS and CP/CPPS, and could yield new therapeutic strategies.143

 A recent study in over 100 participants found that a cognitive behavioral therapy protocol for the treatment of IBS which directly targets visceral sensations may be particularly effective for this condition, compared to other CBT approaches not specifically focused on these sensations.144

Endometriosis occurs when tissues that usually grow inside the uterus instead grow on the outside, such as on the surfaces of organs in the pelvis or abdomen. Endometriosis may cause infertility or pelvic pain and affects an estimated 8–10 percent of reproductive age women. The pain of endometriosis can be chronic or cyclical. Researchers surveyed women enrolled in an endometriosis research program registry in Puerto Rico to study the burden of disease from a patient perspective. The majority of survey respondents indicated that their pain interfered with daily activities, such as household chores, sexual relations, sleep, exercise, and social activities. About 66 percent reported that their pain interfered with work. Most perceived a decrease in the quality of their work when suffering from endometriosis-related pain, and almost 20 percent reported being unable to work due to pain. Respondents who missed work due to pain were absent an average of 2.8 days per month. Among all respondents, endometriosis resulted in an average of 19.3 days of work missed per year. Thus, for women with moderate to severe cases, the burden of endometriosis significantly impacts quality of life across home, work, and social domains. It can interfere with work performance and lead to significant absenteeism. These effects are costly to not only the patients, but also to the medical system and employers.145

Uterine fibroids, also called leiomyomas, are non-cancerous growths that occur in the wall of the uterus. They may cause painful menstrual periods, heavy bleeding, pain during sexual intercourse, infertility, anemia, and fatigue. One study estimated that one of four American women—and up to three of four African-American women—have uterine fibroids that cause problematic symptoms. Although scientists know that the female hormones estrogen and progesterone play a role in the growth of fibroids, they have been unable to determine what causes uterine fibroids to develop. Treatment options are limited to hormone therapy and surgery. However, hormone therapies used to treat fibroid tumors do not always produce much improvement and only temporarily relieve symptoms. Even if fibroids are surgically removed, they may return, or their removal may result in the formation of painful scar tissue. The only sure way to prevent fibroids from returning is to remove the uterus, which is not an option for women who want to have children in the future.

Researchers are investigating new treatments for fibroids with the hope of finding an option that will provide long-term relief without compromising fertility. One possibility is a form of gene therapy that affects estrogen receptors. A recent study examined the safety and efficacy of this gene therapy in rats with uterine fibroids. Researchers randomized the rats to a fibroid gene therapy condition, an alternate gene therapy unrelated to fibroids, and a no treatment condition. Results revealed that the fibroid gene therapy shrunk fibroids by 45 percent at day 8 following the treatment and 80 percent at day 15. Treatment effects remained significant at day 30, with a 77 percent decrease in fibroid size compared to pretreatment size. In contrast, the two control groups saw fibroids double in size over the course of 30 days.

The gene therapy treatment was not only effective, it was safe. Tests revealed no damage to uterine tissue surrounding the fibroids or changes in liver function that might suggest toxicity. In most cases, the gene therapy did not appear to spread beyond the uterus, although some of the treated rats did show faint traces in the liver. This study provides preclinical data to support the development of gene therapy as an alternative to surgical and hormonal treatments of uterine fibroids.146 NINR also developed a palliative care brochure, "Palliative Care: The Relief You Need When You're Experiencing the Symptoms of Serious Illness," to increase awareness of the many benefits of this comprehensive treatment among patient and caregiving populations, the general public, the media, and health care providers. The brochure was recently translated into Spanish, has been featured on the NIH website, and has been downloaded over 1,700,000 times from the NINR website since its release in September 2009.147

NIH will continue to pursue research avenues to alleviate the burden of chronic pelvic pain. NIDDK will maintain multidisciplinary research efforts to uncover the causes and contributors to IC/PBS, CP/CPPS, and IBS, and to develop prevention and treatment strategies. Current efforts should provide a foundation for improved methods to determine prevalence and identify affected individuals, and for the development and testing of new therapeutic strategies. The Institute will continue to collaborate and consult on new opportunities with NICHD and ORWH, and with members of the NIH Pain Consortium.

141Farmer MA, et al. J Urol. 2011;186(1):117–24. PMID: 21571326.
142Lipopolysaccharides (LPS) are found on the outer membrane of certain bacteria and elicit strong immune responses in animals.
143Rudick CN, et al. J Infect Dis. 2010;201(8):1240–9. PMID: 20225955.
144Craske MG, et al. Behav Res Ther. 2011;49(6-7):413–21. PMID: 21565328.
145Fourquet J, et al. Fertil Steril. 2010;93(7):2424–8. PMID: 19926084.
146Hassan MH, et al. Fertil Steril. 2010;93(1):239–50. PMID: 19144333.\
147For more information, see https://www.ninr.nih.gov/sites/www.ninr.nih.gov/files/palliative-care-brochure.pdf.