Full Text DE-97-003 SEX AND GENDER-RELATED DIFFERENCES IN PAIN AND ANALGESIC RESPONSE NIH GUIDE, Volume 26, Number 23, July 18, 1997 RFA: DE-97-003 P.T. 34 Keywords: Pain National Institute of Dental Research National Institute for Nursing Research National Institute on Drug Abuse National Cancer Institute Office of Research on Women's Health Letter of Intent Receipt Date: August 25, 1997 Application Receipt Date: September 25, 1997 PURPOSE The National Institute of Dental Research (NIDR), National Institute of Nursing Research (NINR), National Institute on Drug Abuse (NIDA), National Cancer Institute (NCI), and the Office of Research on Women's Health (ORWH) invite research grant applications to identify significant sex- or gender- related differences in analgesic response and to characterize fundamental biological or biobehavioral mechanisms underlying male/female differences in response to nociceptive stimuli or clinical pain. Both animal and human studies are encouraged. This initiative is expected to yield new insights which may ultimately lead to more targeted, effective, and safe approaches for treating acute or chronic clinical pain and preventing pain-related disability in both men and women. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA is related to the priority areas of chronic disabling conditions and oral health, as well as the cross-cutting issue of women's health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Governing Printing Office, Washington, DC 20402-9325 (telephone 202- 512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by either domestic or foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal Government. Awards in connection with this RFA will be made to foreign institutions only for research of exceptional merit, scientific promise, or need, in accordance with PHS policy governing such awards. Foreign institutions are not eligible to apply for First Independent Research Support and Transition (FIRST) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms of support utilized will be the individual research project (R01) and the FIRST (R29) award. Responsibility for the planning, direction and execution of the proposed project remains solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. Typically, a maximum of three years of support will be provided for R01 applications. This RFA is a one-time solicitation for new and competing renewal awards. Future competitive renewal applications will compete with all investigator-initiated applications and will be reviewed according to customary referral and review procedures. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA will be $2,400,000. The NIDR, NINR, NIDA, NCI, and the ORWH each plan to support or contribute toward the support of projects. Pending receipt of a sufficient number of applications of high scientific merit, the agencies intend to fund a total of approximately eight to ten grants in response to this RFA in FY98. Applications may not request more than three percent annual increases for inflation over subsequent years. Usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIDR, NINR, NIDA, NCI, and the ORWH, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and the availability of funds. RESEARCH OBJECTIVES Background The terminology used throughout this RFA encompasses both solely biological factors influencing differential pain or analgesic responses observed in male and female animals or humans (i.e., sex-related differences) and the interactions between biological factors and differential cultural expectancies, socialization, or experiential factors influencing pain or analgesic response in men and women (gender-related differences). Recent reviews of sex and gender differences related to pain highlight important questions that need additional study (Unruh, 1996; Fillingim and Maixner, 1995; Berkely, 1996; Miaskowski, 1996). In general, the existing research literature on experimentally-induced pain suggests that women tend to show lower pain thresholds, assign higher ratings of pain intensity to the same stimulus, and to discontinue pain- inducing tasks earlier (i.e., show lower pain tolerance) than do men. However, gender-related differences observed in response to experimentally-induced cutaneous pain are relatively small and are most reliably observed in response to mechanical or electrical (but not thermal) nociceptive stimuli. Animal studies also suggest that female rats, as compared with males, show enhanced discrimination of nociceptive stimuli, and are more likely to show persisting pain behaviors after experiencing procedures which can lead to neuropathic pain. Several recent studies indicate that gonadectomy in both males and females decreases nociceptive thresholds, and that the administration of testosterone to gonadectomized males, as well as females, increases the antinociceptive effects of morphine. Other studies indicate sex-related differences in the underlying neurochemical mediation of stress-induced analgesia, the development of which is sensitive to the hormonal environment during early post-natal development. Several studies suggest that cyclical or pregnancy-related hormonal variations, as well as the use of exogenous hormones, influence pain. For example, data from both animal and human studies indicate marked endorphin-mediated increases in pain thresholds in pregnant females during the final days of gestation. Findings from a recent epidemiological study using a large, longitudinal data set obtained from a health maintenance organization indicated that post-menopausal estrogen use was associated with a 77% increase in the odds of referral for treatment of temporomandibular disorder (jaw) pain, even when patients' overall patterns of health care utilization had been controlled for statistically. Use of oral contraceptives was also significantly, though less strongly, associated with an increased probability of referral for treatment of temporomandibular disorder pain. Clinically, gender differences have been noted in the prevalence of a number of pain syndromes. Women, for example, show a higher prevalence of fibromyalgia, temporomandibular joint disorders, and rheumatoid arthritis, while cluster headaches, duodenal ulcers, and ankylosing spondylitis are more prevalent in men. In general, given the same diagnosis, women report greater pain intensity, indicate higher numbers of painful sites, and are more likely to use over-the-counter pain medications. In contrast, studies focusing on patterns of health care delivery suggest that health care professionals managing post-operative and cancer pain tend to provide less potent analgesic coverage for women as compared with men. In adolescence and early adulthood, women report higher levels of recurrent pain than do men. It has not been determined whether sex- related differences in natural occurring experiences which generate pain (e.g., menstruation, pregnancy, parturition) may favor the development of biological or behavioral changes altering pain sensitivity or analgesic response. Also, many questions remain regarding the mechanisms through which hormonal variations influence pain behaviors and response to analgesics. Few studies have focused on sex-specific differences in analgesic response. However, a recent study indicates that drugs activating kappa opioid receptors produce more powerful, persisting post-operative pain relief in females as compared with males. This and related work suggests the possibility that fundamental differences may exist in pain modulatory systems, or in interactions between sex hormones and pharmacological agents impacting upon pain and analgesic response. Scope of Research Sought This initiative focuses upon expanding our understanding of biologically significant differences between males and females in response to experimentally-induced or clinical pain or analgesics and the underlying mechanisms through which such differences occur. It is recognized that pain is a multidimensional phenomenon, including physiological, behavioral, sensory, cognitive, affective, and sociocultural factors. While this initiative emphasizes biological determinants of differential pain and analgesic responses, studies which integrate biological and environmental or sociobehavioral factors are specifically encouraged. Examples of some pertinent areas and research topics are listed below. This list is intended to be illustrative, not exhaustive. Topics are not presented in a priority order: o animal or human studies which characterize relationships between hormonal function and analgesic or pain response; o studies to improve methodologies for studying hormonal and other sex-related biological variables impacting on nociceptive or analgesic response; o studies characterizing mechanisms underlying male/female differences in analgesic or nociceptive response, including studies at the molecular or genetic level; o studies evaluating male/female differences in pain modulatory systems or elucidating the role of cyclical hormonal variations in pain modulatory systems or analgesic response; o studies to clarify biobehavioral mechanisms underlying differences between men and women in pain thresholds, pain ratings, and pain tolerance; o studies evaluating sex or gender-related differences in malignant or non-malignant visceral pain, responses to analgesic regimens, or mechanisms underlying visceral pain; o studies clarifying gender-related differences in "break-through" pain associated with malignant or non-malignant chronic pain conditions. Studies to develop or test new analgesics or epidemiological studies evaluating gender-related differences in the prevalence of various clinical disorders, pain symptoms, or health care utilization are considered outside the scope of this RFA and will be returned without review. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). Investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts of Vol. 23, No. 11, March 28, 1994. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent on or before August 25, 1997. The letter should include a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA to which the application responds. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it provides will assist in planning for the timely review of applications. Receipt of such letters will allow Institute staff to estimate the potential review workload and make review plans which will avoid possible conflict of interest. The letter of intent should be addressed to Dr. Patricia Bryant at the address and telephone number listed under INQUIRIES and will be distributed promptly to co-sponsoring agencies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Individuals must also comply with the 1994 NIH Guidelines for FIRST awards and the Just-in-Time procedures announced in the NIH Guide on March 29, 1996. The RFA label available in the PHS 398 application form kit must be affixed to the bottom of the face page of the original and the original must be placed on top of the entire package. Failure to use this label or failure to follow the mailing instructions outlined below could result in delayed processing of the application such that it may not reach the review committee in time for review. In order to identify the application as a response to this RFA, the RFA title "SEX AND GENDER-RELATED DIFFERENCES IN PAIN AND ANALGESIC RESPONSE" and number DE-97-003 must be typed in item 2 of the face page of the application form and the YES box must be checked. Specific attention should be given to efforts to contain costs and ensure cost-competitive implementation of the project's research goals. Investigators are also encouraged to examine the potential for securing supplementary funds for the project from non-NIH sources, such as foundations or industry. If additional financial support from non-NIH sources is planned to complement or expand the research proposed for support by the NIH, the applicant should explain how such activities will further the goals of the project and make it more cost-effective. Awardees will be expected to update this information on an annual basis. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Dr. H. George Hausch Chief, Scientific Review Branch Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN-44F 45 Center Drive MSC 6402 Bethesda, MD 20892-6402 Applications must be received by September 25, 1997. All applications received after that date will be returned to the applicant without review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by relevant program and review staff. Incomplete and/or unresponsive applications will be returned without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by a special emphasis panel convened by the Scientific Review Branch, NIDR. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non- competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and assigned a priority score. Applications deemed non- competitive will be withdrawn from further consideration; the principal investigator/program director and the official signing for the applicant organization will be notified. Factors to be considered in the evaluation of the scientific merit of applications will be similar to those used in the review of traditional research project grant applications and will include: the novelty, originality, and feasibility of the approach; the training, experience, and research competence of the investigator(s); the adequacy of experimental design; the accessibility and appropriateness of study populations and facilities. Secondary review of the applications will be conducted by advisory boards or councils of sponsoring NIH institutes. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program priorities, and the availability of funds. Applicants should also be aware that, in addition to scientific merit, program priorities and program balance, the total cost of the research proposed will be considered by program staff and the relevant advisory board or council in making funding recommendations. When applications have similar scientific merit, but vary in cost- competitiveness, program staff may select the more cost-competitive application for funding. INQUIRIES Staff welcomes requests for this RFA and welcomes opportunities to answer questions applicants have. Please direct inquiries regarding programmatic issues to: Patricia S. Bryant, Ph. D. Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN 18A 45 Center Drive MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-2095 FAX: (301) 480-8318 e-mail: BryantP@de45.nidr.nih.gov Mary D. Leveck, Ph. D., RN Scientific Program Administrator National Institute of Nursing Research Building 45, Rm 3AN-12 MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-5963 FAX: (301) 480-8260 email: mleveck@ep.ninr.nih.gov David A. Thomas, Ph. D. Division of Basic Research Behavioral Neurobiology Research Branch National Institute on Drug Abuse 5600 Fishers Lane, Rm 10A-10 Rockville, MD 20857 Telephone: (301) 443-6975 FAX: (301)594-6043 email:dt78k@nih.gov Claudette Varricchio, D.S.N., R.N. Division of Cancer Prevention and Control National Cancer Institute 6130 Executive Plaza N. - Rm 300 Rockville, MD 20892-7340 Telephone: (301) 496-8541 FAX: (301) 496-8667 email:cv9h@nih.gov Joyce Rudick Office of Research on Women's Health National Institutes of Health Bldg 1, Rm 201 Telephone: (301) 402-1770 FAX: (301) 402-1798 email:RudickJ@od1tm1.od.nih.gov Direct inquiries regarding fiscal issues to: Mr. Martin R. Rubinstein Grants Management Office National Institute of Dental Research Natcher Building, Room 4AN-44A 45 Center Drive MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 email: Rubinstein@DE45.nidr.nih.gov Mr. Jeff Carow Grants Management Office National Institute of Nursing Research Building 45 Rm 3AN12 - MSC 6301 Bethesda, MD 20892-6301 Telephone: (301) 594-5974 FAX: (301) 480-8256 email: jcarow@ep.ninr.nih.gov Dr. Gary Fleming Chief, Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Rm 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 FAX: 30`-594-6847 email:gf6@nih.gov Mr. Robert E. Hawkins Team Leader, Grants Administration Branch National Cancer Institute Executive Plaza S - Rm 243 6130 Executive Blvd Bethesda, MD 20892 Telephone 301-496-7800 FAX: 301-496-8601 email: rh60d@nih.gov SCHEDULE Letter of Intent Receipt Date: August 25, 1997 Application Receipt Date: September 25, 1997 Scientific Review Date: January/February, 1998 Advisory Council Date: May, 1998 Earliest Possible Award Date: July 1, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES Berkley, K.J. Sex differences in pain Behav. Brain Sci. (in press) Gear, R. W. Miaskowski, C, Gordon, N., Paul, S, Heller, P, & Levine, J. Kappa opioids produce significantly greater analgesia in women than in men Nature 1996 2 1248-1250. Fillingim, R. B. & Maixner, W. Gender differences in the responses to noxious stimuli Pain Forum 1995 4 209-221. Islam, A.K. Cooper, M. L.& Bodnar, R.M. Interactions among aging, gender, and gonadectomy effects upon morphine antinociception in rats Physio. Behav.1993 54 45-53 LeResche, L. Saunders, K, VonKorff, M., Barlow, W, and Dworkin, S. Use of exogenous hormones and risk of temporomandibular disorders Pain 1997 69 153-160. Unruh, A M. Gender variations in clinical pain experience Pain 1996 65 123-167. .
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