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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