Copyright
by
Nicole Powell-Dunford
2008
The Capstone Committee for Nicole C. Powell-Dunford Certifies that this is the
approved version of the following dissertation capstone:
DYSMENORRHEA: An Aeromedical Clinical Practice Guideline
Committee
Robert Johnson, MD, MPH, MBA,
Supervisor
Richard Jennings, MD, MS
James Vanderploeg, MD
Janice Smith, MD
__________________
Dean, Graduate School
DYSMENORRHEA: An Aeromedical Clinical Practice Guideline
by
Nicole C. Powell-Dunford, MD
Capstone
Presented to the Faculty of the Graduate School of
The University of Texas Medical Branch
in Partial Fulfillment
of the Requirements
for the Degree of
Master of Public Health
The University of Texas Medical Branch
August, 2008
Dedication
This Capstone is dedicated to my brothers and sisters in Army Aviation
Acknowledgements
I would like to give sincere thanks to all the UTMB and Army RAM faculty for their
support in this research, particularly Dr. Johnson, Dr. Jennings, Colonel Boneta and
Colonel Albano. I am also especially grateful for the support of my husband Mike and
my children Julia and Joshua.
DYSMENORRHEA: An Aeromedical Clinical Practice Guideline
Publication No._____________
Nicole Powell-Dunford, MPH
The University of Texas Medical Branch, 2008
Supervisor: Robert Johnson
This capstone proposes a clinical practice guideline on the management of
dysmenorrhea, with attention to the occupational aspects of disease and treatment within
the aviation community. This evidence based clinical practice guideline was developed
through a systematic review of the literature with consideration of the physiological and
operational aspects of the flight environment. Dysmenorrhea can have a significant
impact on United States civil and military flight crews. A standardized aeromedical
guideline can benefit flight crew members as well as the aeromedical community who
cares for them.
Table of Contents
CHAPTER 1: INTRODUCTION
A. Historical Context .....................................................................................1
B. Aeromedical Concerns .............................................................................2
C. Background and Literature Review..........................................................2
CHAPTER 2: DYSMENORREA .........................................................................4
A. Impact of Disease ......................................................................................4
B. Etiology…….............................................................................................4
C. Clinical Presentation & Diagnosis……………………………………….5
D. Epidemiologic Principles ..........................................................................5
E. Evidence Based Medicine & Strength of Recommendation Theory……..5
F. Clinical Practice Guidelines……………………………………………...7
CHAPTER 3: TREATMENT
A. NSAIDS…………………………………………………………………..9
B OCPs……………………………………………………………………....9
C. Other Hormonal Treatments……………………………………………....9
Danazol………………………………………………………………..10
Depo Medroxy-Progesterone Acetate (Depo-Provera)……………....10
Gonadotropin Releasing Hormone Agonists……………………….....10
Levonorgestrel Releasing Intrauterine System………………………..11
Novel Hormonal Therapies…………………………………………...11
D. Surgery…………………………………………………………………....12
E. Non Traditional Therapies……………………………………………….12
Acupuncture/TENS………………………………………………….12
Lifestyle Modification……………………………………………….12
Fish Oil………………………………………………………………13
Herbs………………………………………………………………...13
Spinal Manipulation…………………………………………………13
Topical Heat Application……………………………………………13
Vasoactive Medications…………………………………………….14
Vitamins/Supplements……………………………………………...14
Magnesium…………………………………………………..14
Thiamine……………………………………………………..14
Vitamin E…………………………………………………….14
Zinc………………………………………………………….14
CHAPTER 4: AEROMEDICAL CONCERNS OF
TREATMENT……………………………………………………………………16
A. NSAIDS……………………………………………………………….....16
B OCPs……………………………………………………………………...16
C. Other Hormonal Treatments……………………………………………...18
Danazol………………………………………………………………18
Depo Medroxy-Progesterone Acetate (Depo-Provera)……………..18
Gonadotropin Releasing Hormone Agonists………………………...19
Levonorgestrel Releasing Intrauterine System……………………....19
Novel Hormonal Therapies…………………………………………..19
D. Surgery……………………………………………………………………19
E. Non Traditional Therapies………………………………………………...20
Acupuncture/TENS………………………………………………...…20
Lifestyle Modification……………………………………………...…20
Fish Oil……………………………………………………………..…20
Herbs……………………………………………………………..…...20
Spinal Manipulation……………………………………………..……21
Topical Heat Application………………………………………..……21
Vasoactive Medications……………………………………….……..21
Vitamins/Supplements……………………………………………….21
Magnesium……………………………………………………21
Thiamine……………………………………………………...21
Vitamin E…………………………………………………..…22
Zinc……………………………………………………….….22
CHAPTER 5: DISCUSSION & CONCLUSION…………………………..…..23
A. Gap Analysis……………………………………………………….…….23
B. Study Types & Statistical Methods………………………………………23
C. Outcome……………………………………………………………….…23
Appendix A Aeromedical Clinical Practice Guideline…………………………...24
References…………………………………………………………………………27
Vita ………………………………………………………………………………..33
CHAPTER 1: INTRODUCTION
Women have made remarkable progress in integration into the aviation
community. Previously blocked from flight during the menstrual cycle due to unfounded
beliefs that menstruation would contribute towards fatal mishaps, women now participate
in every facet of modern aviation to include combat operations and international space
station missions. Despite this, a shortage of aeromedical guidance exists with respect to a
common gynecological condition in the civil aeromedical literature. Previous
aeromedical guidance restricting flight during the normal physiologic condition of
menstruation has been cast aside. Guidelines with respect to pilots with the common
condition of dysmenorrhea are now proposed. Dysmenorrhea, painful menstruation that is
sometimes associated with abnormal deposits of endometrial tissue in abnormal
anatomical positions, may cause work limitations in a small percentage of women.
Appropriate aeromedical management of this group is important.
A. HISTORICAL CONTEXT
Women have gained slow but steady progress in integration with aviation. Due to
financial necessity and national defense, women entered aviation service in significant
numbers during WWII, playing a critical support role as women Air Force service pilots.
Yet the menstrual cycle was misconstrued as a safety of flight factor. In the 1935 Civil
Aeronautics Handbook for Medical Examiners, the medical officer of the Aeronautics
branch of the U.S. Dept of Commerce formally cautioned against flight during the
menstrual cycle as well as 3 days prior and following the menstrual cycle due to an
unsubstantiated link between menstruation and fatal accidents (Whitehead, 1935). The
1942 U.S. Army Fit to Fly handbook also cautioned against flight during the menstrual
cycle due to the perception that accidents would ensue (Grow, 1942).
Concerns about the menstrual cycle as a safety of flight factor were raised in the
same decade. After interviewing many female endurance and racing pilots of the era, the
assistant chief flight surgeon of the Connecticut Department of Aeronautics observed that
the majority of women flew without significant symptoms during the menstrual cycle and
that many noteworthy flight accomplishments occurred during the menstrual cycle
(Holtz, 1941). In an analysis of U.S. Air Force training dropout and accident rates, the
menstrual cycle was not found to be correlated with either (Monrerud, 1988). In fact,
male pilots were found to have higher accidents rates when compared to female pilots
(Lyons, 1992, Vail and Ekman, 1986).
Although barred from combat flight under Title 10 U.S. Code 8549 of the
Women’s Armed Services Integration Act of 1948 (Murnane, 2007), female pilots were
finally authorized to perform combat flight duties on Congressional repeal of the
Prohibition act in 1991. They have since not only served in combat, but as shuttle and
space station commanders in civil aviation. Although outdated regulations in regards to
menstrual cycle flight restrictions have been cast aside, little aeromedical guidance exists
in modern regulations with regards to menstrual disorders, specifically dysmenorrhea.
1
B. AEROMEDICAL CONCERNS
Prevalence of dysmenorrhea varies between 45 – 95%, making it the most
common gynecological condition in the world (Proctor and Farquhar, 2006) with an
estimated 10%-15% suffering from 1-3 days of incapacitating or work limiting symptoms
every month (Ferri 2007, Dawood, 2006). This potentially translates to a significant
number of the over 36,000 private and commercial women pilots today, 58 of which are
captains on a single major U.S. carrier airline (American Airlines, 2007, FAA, 2007).
Untreated severe dysmenorrhea can cause significant pain and loss of concentration,
although likely contributing more to missed flight time ‘sick days’ than to sudden
incapacitation due to gradual onset and predictable nature of the condition. Rarely
associated with dysmenorrhea is the condition of spontaneous pneumothorax in areas of
endometrial deposition, which is a special concern for crewmembers subject to altitude.
Although first line medications are potentially compatible with flight duty, some second
line therapies and herbal remedies are not compatible or are of unknown aeromedical
safety. Lastly, aeromedical examiners may not be aware of newer therapies or guidelines
for dysmenorrhea. A clinical guideline can serve to ensure aeromedically sound
therapeutics, with appropriate flight restrictions when warranted.
C. BACKGROUND & LITERATURE REVIEW
The literature search for this capstone encompasses literature from peer-reviewed
preventive medicine, aeromedical, gynecological and primary care sources as well as
historical aeromedical publications. Other than references used for historical context and
the limited information regarding non-traditional treatments, material previous to 2003
with respect to therapeutics was excluded from analysis in order to ascertain current
medical knowledge of the past 5 years. Resources for literature review included the
UTMB electronic medical library to include OVID, the Cochrane library, PubMed , and
MdConsult. Additional data was found at the on-line AAFP (American Association of
Family Physicians) and ACOG (American College of Obstetricians Gynecologists)
medical repositories as well as the National Guideline Clearinghouse website which
consolidates the clinical guidelines of major medical organizations. Aeromedical
guidance was found at the AsMA (Aerospace Medical Association) and ASAM
(American Society of Aerospace Medical Specialists) websites. The NTSB (National
Transportation Safety Board) database was searched in order to determine incidence of
medical condition involvement in aircraft accidents. Furthermore, the U.S. Department of
Health and Human Services website was accessed for current U.S. preventative
recommendations. Federal Aviation Administration (FAA) aeromedical clinical
guidance was reviewed on-line at the official FAA website. Aeromedical Department of
Defense (DoD) guidance was reviewed within the U.S. Army Aeromedical Resource Online (AERO, 2007) and the on-line U.S. Air Force aeromedical waiver guide, obtained
through a secure Air Force knowledge exchange site. Search terms used included
2
‘dysmenorrhea,’ ‘cyclic pelvic pain,’ as well as each of the individual names of therapies
which will discussed for the treatment of dysmenorrhea. ‘Clot’ ‘DVT’, ‘deep venous
thrombosis,’ PE’ and ‘pulmonary embolism’ were also used in an NTSB database search
with regards to aviation mishaps related to complications from the treatments for
dysmenorrhea. Data on traditional therapeutics prior to 2003 was excluded.
3
CHAPTER 2: DYSMENORRHEA
A. IMPACT OF DISEASE
Although no formal studies have analyzed the prevalence of dysmenorrhea in
aviators, dysmenorrhea affects a significant percentage of the childbearing population in
various degrees. Higher rates of dysmenorrhea are found in smokers, menorrhagic,
nulliparous and younger women, with up to 15% experiencing work-limiting symptoms
(Ferri 2007, Dawood, 2006). With close to 8,000 commercial female pilots today, this
disease burden could translate to 7,000 pilots experiencing some degree of dysmenorrhea,
with work implications for as many as 800 who experience incapacitating symptoms
(FAA 2007). Due to gradual onset and predictable nature of symptoms of dysmenorrhea
however, there have been no documented accidents or aviation mishaps from 1970 until
present attributable to dysmenorrhea, with a lower overall mishap rate established for
female pilots (NTSB, 2007, Lyons, 1992).
B. ETIOLOGY
Dysmenorrhea has been definitively linked with Prostaglandin F2α (PG F2)
(Ferri, 2007), which causes uterine contractions and stimulates vasopressin release.
Associated symptoms of severe dysmenorrhea, which may include nausea, vomiting,
headaches, anxiety, fatigue, diarrhea, fainting, and abdominal bloating are mediated
through prostaglandin (Ferri, 2007). Endometriosis, or abnormal deposition of uterine
lining in extra-uterine locations, may also be associated with dysmenorrhea. Although
asymptomatic subjects are just as likely to demonstrate endometrial deposits as women
with symptomatic endometriosis on pathological specimen, extent of endometrial
deposition correlates with symptom severity in symptomatic populations (French, 2005).
Associated conditions, which have not been established as causal but consistently linked
with dysmenorrhea, include smoking, depression/anxiety attempts to lose weight, heavy
menstrual flow, nulliparity and social disruption (French, 2005). Whereas smoking could
be proposed to lead to abnormal vascular changes that could contribute towards
dysmenorrhea, psychosocial factors may affect pain perception and tolerance.
Menorrhagia, or excessive menstrual bleeding in simple terms, is a predictor of
dysmenorrhea and may exist independent of this condition (French, 2005).
Whereas primary dysmenorrhea occurs in the setting of normal anatomy and
physiology, secondary dysmenorrhea is cyclic menstrual pain from a pathological
condition. Typical etiologies include endometriosis, adenomyosis, leiomyomas and, less
commonly, chronic salpingitis, IUD use, congenital or acquired outflow tract obstruction,
including cervical stenosis (Ferri, 2007).
4
C. CLINICAL PRESENTATION & DIAGNOSTICS
Dysmenorrhea can vary from mild pain to severe incapacitation. Duration of
symptoms varies between 1-3 days, with symptoms rarely exceeding 3 days. Iron
deficient anemia, with risk for hypoxia-induced performance decrements, can result from
menorrhagia. but is not linked independently with dysmenorrhea. Catamenial
pneumothorax, occurring secondary to endometrial deposition, is an extremely rare
condition and has never been linked with a mishap to date, but is a special aeromedical
concern. Described in sporadic case reports and small case series (Hazelrigg, 2003,
Mauer, 1958), this condition frequently manifests as sudden onset dyspnea, typically
manifests right hemi-diaphram involvement and may require surgical treatment.
Diagnosis of primary dysmenorrhea is typically straightforward with cramping
pain occurring predictably at the time of menstruation in the setting of a normal physical
examination. In most settings, no further diagnostic work up is required. Dysmenorrhea
refractory to first line medications, with unusual history, abnormal physical exam or of
longstanding nature is initially investigated through ultrasound, with surgical exploration
reserved for severe cases and/or dysmenorrhea in the setting of abnormal diagnostic
work- up. Ultrasonography is capable of visualizing cysts, fibroids and stage 3-4
endometriosis, with a 84% concordance rate with surgically staged endometriosis
(Exacoustos et al., 2003). Saline infusion of the uterus or sonovagiograhy, is helpful in
establishing rectovaginal endometriosis, frequently implicated in dysmenorrhea (Dessole
et al., 2003). MRI has limited diagnostic utility, is more expensive and time intensive to
obtain than ultrasonograhy and is not within the current standard of care (French, 2005,
Stratton et al., 2003).
D. EPIDEMIOLOGIC PRINCIPLES
Dysmenorrhea is predominantly a disease of young women. Smokers and
nulliparous women as well as women with depression and ongoing life stressors may
benefit most from formalization of clinical practice guidelines due to increased
prevalence in these populations. Aviators are a special epidemiological population with
high levels of motivation and health consciousness. However as a group, they are prone
to under-reporting. Strict treatment protocols that mandate grounding for any condition
will decrease self-referral and treatment rates. Clinical guidelines including treatment
options that permit continuation of flight status will likely increase diagnosis and
treatment rates.
E. EVIDENCE BASED MEDICINE & STRENGTH OF RECOMMENDATION
THEORY
With an expansion of medical literature, it has grown increasingly important to
isolate clinically important and high quality medical data for diagnostic and treatment
guidance. Malpractice coverage, Joint Commission on the Accreditation of Healthcare
Organizations inspection and insurance reimbursement increasingly demand evidencebased medical practices. The Cochrane review database is explicitly dedicated to the
5
evaluation of the medical literature in order to establish the degree to which evidence
supports specific medical practices.
A number of family medicine and primary care organizations, including the
American Association of Family Physicians (AAFP), have adopted formal stratification
of clinical recommendations in the SORT or ‘Strength of recommendation taxonomy.’
system. Recommendations are rated with respect to quality, quantity, and consistency of
evidence. ‘A’ level recommendations are based on ‘consistent, good quality, patientoriented evidence’, which would include high quality systematic reviews, randomized
control trials (RCTs) and prospective cohort studies with good follow up. ‘B’
recommendations are based on ‘inconsistent or limited quality patient-oriented evidence,’
which includes lower-quality systematic reviews and RCTs, cohort studies with
inconsistent results and/or poor follow-up, as well as case-control studies and prognostic
case series. ‘C’ recommendations are based on ‘consensus, disease rather than patientoriented evidence, usual practice, opinion and/or non prognostic case series’ (AFP, 2007,
Ebell et al., 2005). SORT class ‘B’ recommendations are further stratified as ‘probably
effective’ and ’possibly effective’ whereas SORT class ‘C’ recommendations are further
stratified into ‘uncertain effectiveness’ and ‘ineffective.’
The American College of Obstetric and Gynecology (ACOG ) uses a similar
format for stratification of recommendations in which an ‘A’ recommendations are based
on ‘good and consistent scientific evidence’. ‘B’ recommendations are based on ‘limited
or inconsistent scientific evidence’ and ‘C’ recommendations are based primarily on
‘consensus and expert opinion’ (NGC/ACOG, 2004).
Clinical Evidence Concise, a publication of the British Medical Journal,
substantiates primary care medical interventions as ‘Beneficial’,
‘Likely to be beneficial,’ ‘Likely to be ineffective or harmful’ and ‘Unknown
effectiveness.’ The U.S. Preventative Services Task Force (USPSTF, 2007) maintains
another large repository of evidence-based recommendations, which are rated as ‘A’
through ‘D’ based on quality of evidence as well as magnitude of net benefit (benefit
minus harms) with an ‘I’ designation for interventions that demonstrate insufficient
evidence for application.
Although the USPSTF currently has no formal recommendations for
dysmenorrhea, the American College of Obstetric and Gynecology (ACOG) and
American Association of Family Physicians (AAFP) have established guidelines for
management of menstrual disorders which utilize ‘A’ through ‘C’ stratification systems.
AGOC guidelines utilize an additional stratification system for ranking of evidence,
which follows.
I-Evidence obtained from at least one properly designed randomized controlled
trial
II-1 Evidence obtained from well-designed controlled trials without
randomization
II-2 Evidence obtained from well-designed cohort or case-control analytic studies,
preferably from more than one center or research group
II-3 Evidence obtained from multiple time series with or without the intervention
or dramatic results in uncontrolled experiments.
6
III. Opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert committees (NGC/ACOG, 2004).
Walkover comparison between SORT and other rating systems such as those of the
British Medical Journal have been proposed. SORT ‘A’ recommendations are the
equivalent of the Center for Evidence Based Medicine’s ‘consistent level I’ or the
Clinical Evidence Concise and British Medical Journal’s ‘Beneficial’ ratings. SORT ‘C’
recommendations are equivalent to ‘Inconsistent’ or ‘Unknown Effectiveness’
interventions of these organizations respectively. SORT B recommendations are
equivalent to ratings intermediate to these extremes (Ebell et al., 2004).
Formal guidelines on management of dysmenorrhea have been established by the
AAFP using the SORT criteria and guidelines on management of endometriosis have
been established by the AGOC using both recommendation and quality of evidence
stratification systems. Therefore, SORT recommendation levels for dysmenorrhea will be
predominantly referenced in discussion of medical treatments in this paper. The ACOG’s
stratification system will be referenced when pertinent as relating to the diagnosis of
endometriosis.
The National Guideline Clearinghouse (NGC) is “an initiative of the Agency for
Healthcare Research and Quality, U.S. Department of Health and Human Services…
originally (created) in partnership with the American Medical Association and the
American Association of Health Plans (National Clearinghouse, 2007).” NGC is a
databank of the clinical guidelines of major medical organizations, including over 250
guidelines currently in development. Guidelines for dysmenorrhea include a 2003 nursing
guideline on management of cyclic pelvic pain as well as the 2004 ACOG guideline for
management of endometriosis.
F. CLINICAL PRACTICE GUIDELINES
In order to streamline and summarize best evidence practices for the busy
clinician, many professional societies such as the Aerospace Medical Association have
embraced clinical practice guidelines, which formulate evidence-based recommendations.
Guidelines differ from protocols in that they are more flexible and present multiple
acceptable treatment options. Due to outcries against wide variation in medical practices
throughout the 1970s, clinical practice guidelines evolved as a means of standardizing
care (Wennberg and Gittelsohn, 1973).
Standardized guidelines for treatment within a clinic, hospital or professional
body have tremendous benefits. Medical providers are spared the task of analyzing
conflicting data of unknown quality and can give clinical recommendations with
confidence. Standardized clinical practice guidelines help to ensure that patients receive
ideal management of a condition independent of variables such as ethnic origin,
geographic location or insurer.
On-line Clinical Practice Guidelines have the additional benefit of easy access,
with capability of real-time updates as clinical developments occur. The American
Society of Aeromedical Specialists, the U.S. Army and U.S. Air Force have on-line
repositories and are models for this practice. U.S. Army has specific policy letter
guidance on endometriosis (AERO, 2006, U.S. Army Aeromedical Policy Letters, 2006).
7
The U.S. Air Force has guidelines on both endometriosis as well as dysmenorrhea.
Although the on-line American Society of Aeromedical Specialists clinical guideline
repository includes a 2007 guideline on endometriosis, the Federal Aviation
Administration (FAA) Guide for Aviation Medical Examiners deals with dysmenorrhea
in a non- specific way, stating that “disorders such as sterility and menstrual irregularity
are not usually of importance in qualification for medical certification” and that
diagnostic evaluation is best left to a gynecologist (Guide for Aviation Medical
Examiners, 2006).
From a financial perspective, clinical guidelines prevent wastage of limited
medical resources that may occur through application of ineffective therapies. Validation
of clinical guidelines often occurs through peer review. For example ACOG’s final
guidelines are evaluated by practicing obstetrician-gynecologists to include generalists
and sub-specialists as well as the ACOG executive board (NGC/ACOG, 2004).
8
CHAPTER 3: TREATMENT
A. NSAIDs
Non-steroidal anti-inflammatories (NSAIDs) are a first line treatment for
dysmenorrhea, a level A SORT recommendation (French, 2005). Importantly, NSAIDs
not only alleviate pain but also inhibit prostaglandin. Although individual variation may
exist, different NSAIDs are of similar or equal efficacy. A 2003 analysis of Cochrane
Menstrual Disorders and Subfertility Group trials register determined that NSAIDs were
significantly more effective for pain relief than placebo (OR 7.91, 95% CI 5.65 to 11.09),
though overall adverse effects were also significantly more common (OR 1.52 95% CI
1.09 to 2.12) and that there was little evidence of the superiority of any individual
NSAID with regard to either efficacy or safety (Marjoribanks et al., 2003). The NSAIDs
studied in this analysis were high dose regimens and included ibuprofen (Motrin) 800mg
three times daily, diclofenac (Voltaren) 50mg three times a day, mefenamic acid
(Ponstel) 500mg loading dose followed by 250mg four times daily and naproxen
(Naprosyn) 500-550mg twice daily. Patients taking lower doses, including typical over
the counter doses, may not achieve effective symptom control (French, 2005).
B. OCPs
Oral contraceptive pills (OCPs) act as a treatment for dysmenorrhea through
relative suppression of menstruation and can furthermore be prescribed for continuous
use for complete menstrual suppression. Continuous use regimens are now available
commercially; off-label use of continuous oral contraceptives for management of
dysmenorrhea has been utilized for decades. A recent study with regards to continuous
OCPs analyzed computerized databases (Cochrane Central Register of Controlled Trials,
MEDLINE, EMBASE, POPLINE, LILACS) for trials using continuous or extended
OCPs during the years 1966 to 2005. In the 6 studies reviewed, “The extended cycle
group fared better in terms of headaches, genital irritation, tiredness, bloating, and
menstrual pain. Five out of the six studies found that bleeding patterns were either
equivalent between groups or improved with continuous-dosing regimens…. (with)
similar contraceptive efficacy (i.e., pregnancy rates) and safety profiles (Edelman et al.,
2005).” AAFP’s and ACOG’s most recent ratings of OCPs determine them to be a class
‘B’ intervention for dysmenorrhea and endometriosis respectively. AAFP further
stratifies continuous OCP use to be ‘probably effective’ with standard oral and
intravaginal OCP use as ‘possibly effective’ (French, 2005, NGC/ACOG, 2004). These
classifications however must be taken in context with only limited data available for
newer brands of extended cycle OCPs.
C. OTHER HORMONAL TREATMENTS
Approximately 10% of women with primary dysmenorrhea do not respond to
treatment with either NSAIDs or oral contraceptives (Nasir and Bope, 2004, Proctor and
Farquhar, 2006). Further hormonal treatments indicated for endometriosis-related
9
dysmenorrhea include danazol, depo-medroxyprogesterone acetate (Depo-Provera),
Gonadotropin-releasing hormone agonists (GnRHAs) such as leuprolide acetate (Lupron)
and the levonorgestrel releasing intrauterine system (Mirena), which have all received a
SORT B ‘probably effective’ classification (French, 2005). New contraceptives such as
the estrogen patch (Ortho Evra), injectable estrogen (Lunelle) and the vaginal ring
(NuvaRing) also offer promise. These novel therapies do not appear in the Cochrane
database as analyzed pools of clinical studies and have been assigned no formal SORT
categories. Other hormonal based contraceptives demonstrate variable efficacy in the
treatment of dysmenorrhea.
Danazol
Treatment of endometriosis-related dysmenorrhea with danazol for at least 6
months appears effective in most patients and is a class ‘A’ recommendation of ACOG
(NGC/ACOG, 2004). Regardless of surgical confirmation, treatment of dysmenorrhea is
rated as a SORT class ‘B’ ‘probably effective’ recommendation by the AAFP (French,
2005). Danazol in doses of 600 to 800 mg per day is as effective as 3 months of
treatment with gonadotropin-releasing hormone agonsists (GnRHAs) for pain relief, but
is associated with a significantly greater incidence of side effects (NGC/ACOG, 2004).
Typical treatment is with 200—400 mg/day PO in two divided doses, with maximum
800mg/day for severe endometriosis and with therapy not to exceed 9 months, with 3-6
months typically required for benefit. The cost of treatment with danazol is about one
third less than treatment with a GnRHA, but nearly twice as costly as treatment with oral
contraceptives and oral depot medroxyprogesterone acetate (NGC/ACOG, 2004).
Depo Medroxy-Progesterone Acetate (Depo-Provera)
An intramuscular injection of 150mg depo medroxy-progesterone acetate (DepoProvera) once every three months is a convenient, off-label hormonal method of
endometrial involution with a class ‘B’ ‘probably effective’ rating and class ‘B’ with
‘limited or inconsistent scientific evidence’ by AAFP and ACOG for the treatment of
endometriosis and dysmenorrhea respectively. Associated with amenorrhea in over 75%
of users after 1 year of use, it may be very efficacious in the treatment of dysmenorrhea
for those taking this contraceptive. 104 mg Depo Sub-Q was subsequently specifically
FDA approved for management of endometriosis, with the same bone density precautions
as the 150mg IM Depo Provera injection (Gold Standard, 2007).
Gonadotropin Releasing Hormone Agonists
Treatment of biopsy proven endometriosis with the gonadotropin-releasing
hormone agonists (GnRHAs), such as intramuscular leuprolide (Lupron), for at least 3
months is a class ‘A’ recommendation of the ACOG (NGC/ACOG, 2004). Treatment of
chronic pelvic pain without surgical confirmation of endometriosis is a class ‘B’
10
recommendation of ACOG while treatment of dysmenorrhea with lupron is an AAFP
class ‘B’ ‘probably effective’ recommendation (French, 2005, NGC/ACOG, 2004).
GnRHAs also include goserelin acetate (Zoladex), which is subcutaneous, and naferelin
(Synarel), which is a nasal spray (Mahutte and Arici, 2003). All are associated with
reduced bone density and vasomotor symptoms. However, when pain relief supports
continued therapy, the addition of add-back therapy (progestins alone, bisphosphonates,
progestins and estrogens, pulsatile parathyroid hormone and/or nasal calcitonin) reduces
or eliminates GnRHA-induced bone mineral loss without reducing the efficacy of pain
relief. Leuprolide (Lupron) is administered as an injection 3.75 mg IM once monthly or
alternatively, 11.25 mg IM once every 3 months, for a maximum of 6 months. Either
leuprolide dosage may be co-administered with norethindrone acetate (5 mg PO daily)
(NGC/ACOG, 2004).
Levonorgestrel Releasing Intrauterine System
The levonorgestrel releasing intrauterine system (Mirena Intra-Uterine Device)
releases levonorgestrel (20 µ/day) over the course of five years, causing up to 50% of
women using it to achieve amenorrhea after 12 months. A reduction in dysmenorrhea,
spontaneously reported in clinical trials, was also observed in a one-year random
controlled trial of women with endometriosis (Proctor and Farquhar, 2006). The device
has demonstrated good long-term acceptability (Baldaszti, 2003) and is a SORT class ‘B’
‘possibly effective’ intervention for dysmenorrhea (French, 2005). Complications such as
misplacement or infection requiring early removal are rare.
Novel Hormonal Therapies
The estrogen patch requires weekly application but is not currently FDA approved
for dysmenorrhea. The patch is a small (2 cm2) adhesive square that releases 150 g of
the progestin norelgestromin and 20 g of the estrogen ethinyl estradiol daily.
Transdermal application once weekly may improve compliance and afford greater
medication tolerability in some patients. Lunelle is a once-a-month injectable
contraceptive containing 25 mg medroxyprogesterone acetate and 5 mg estradiol
cypionate. It has not been formally studied in the treatment of dysmenorrhea.
The vaginal ring (NuvaRing: etonogestrel and ethinyl estradiol) is a lightweight, small
single-size contraceptive vaginal ring that releases 15 g of ethinyl estradiol and 120 g
of etonogestrel daily; It is removed every three weeks for a single week. Although it is
specifically cited as non-FDA approved for dysmenorrhea, it may afford a more
convenient method of hormonal delivery for this syndrome. NuvaRing may need to be
used for 6-9 months in order to be effective in the involution of endometrial deposits
(Gold Standard, 2007).
11
D. SURGERY
Surgical treatments for endometriosis-related dysmenorrheal include excision,
endocoagulation, electrocautery, laser vaporization and hysterectomy with or without
bilateral salpingoophrectomy as outlined in the ACOG clinical guideline on management
of endometriosis (NGC/ACOG, 2004). Compared to laparotomy, operative laparoscopy
for surgical treatment of pelvic pain related to endometriosis is associated with more
rapid recovery, the potential to decrease postoperative adhesion formation, and lower
complication rates (NGC/ACOG, 2004). The benefits of surgical interruption of the
pelvic nerve pathways are still not fully developed and are considered a SORT class ‘C’
‘uncertain effectiveness’ recommendation (French, 2005, Proctor et al., 2004).
Hysterectomy is a SORT class ‘B’ ‘probably effective’ treatment recommendation of the
AAFP (French, 2005).
E. NON-TRADITIONAL THERAPIES
Potentially beneficial non-traditional therapies that have undergone scientific
review include acupuncture, behavioral modification, fish oil, herb and vitamin
supplementation, as well as topical heat application, spinal manipulation and the use of
off label vasoactive medications.
Acupuncture/TENS (Transcutaneous Electric Nerve Stimulation)
Both these treatment modalities were studied through a Cochrane systemic review
and were found to be potentially beneficial in a number of small trials, resulting in a
SORT ‘B’ ‘possibly effective’ treatment recommendation for acupuncture, acupressure
and TENS (French, 2005, Proctor et al., 2002).
Lifestyle Modification
Although frequently recommended, exercise and behavioral intervention have not
demonstrated clear effectiveness and are considered to be class ‘C’ SORT
recommendations (French, 2005). Adherence to a low fat vegetarian diet, is a SORT class
‘B’ ‘possibly effective’ recommendation. A more recent 2007 Cochrane analysis of the
medical literature reveal only mixed results for trials involving use of relaxation
techniques (Proctor et al., 2007). Tobacco cessation, although not formally studied, may
be a promising intervention. Responsible for the vast majority of all lung cancer, which is
now the number one cause of cancer deaths in women, smoking has been established as a
risk factor for dysmenorrhea. Although full cessation is difficult, even limited cessation
around time of impending menses may offer benefit and is part of a recommended
clinical guideline for nurse practitioners (NGC/Nurses Professional Association, 2003).
12
Fish Oil
Fish oil supplementation has been determined to be a SORT class ‘B’ ‘possibly
effective’ recommendation of the AAFP (French, 2005). A small RCT found that 2 g of
fish oil (omega-3 polyunsaturated fatty acids) daily significantly reduced pain in 21
adolescent patients compared to 21 controls using the Cox Menstrual Symptom Scale
with a mean change from 69.9 to 44.0 ( p < 0.0004) on this rating scale (Harel, 1996).
High intake of marine n-3 fatty acids correlated with milder menstrual symptoms in 181
Danish women in an observational study (Deutch, 1995). Omacor, a fish oil pill with
primary indication for hypertriglyceridemia, contains 4 mg (6 IU) of vitamin E as well as
1 gram of omega-3 fatty acids.
Herbs
Angelica (Dong Quai, Dang Gui, Tang Kuei) and Rose Tea (Toki-shakuyaku-san)
are herbs that have been used in the treatment of dysmenorrhea. Angelica has been
recommended for a multitude of generic gynecological complaints ranging from atrophic
vaginitis to menopause to dysmenorrhea, but has not been rigorously studied for
dysmenorrhea. The ACOG clinical guidelines do not cite angelica among the limited
number of botanicals demonstrating even limited evidence of efficacy and furthermore
strongly counsels against this therapy due to the non-regulated nature of botanical use
(NGC/ACOG, 2006). Rose tea has been determined to be a class ‘B’ ‘possibly effective’
intervention by the AAFP (French, 2005). In 70 adolescents, rose tea was found to be
efficacious compared to controls in management of dysmenorrhea at 1, 3 and 6 months
(Taiwan, 2005).
Spinal Manipulation
Cochrane analysis has determined there to be insufficient evidence for
recommendation of spinal manipulation in the treatment of dysmenorrhea. Four trials of
high velocity low amplitude manipulation did not establish significant differences
between sham and actual treatment; a small study involving the Toftness technique
suggested some difference between sham treatment, but this study was found to be
methologically flawed (Proctor et al. 2004). AAFP specifically recommends against this
therapy, with a class ‘C’ ‘ineffective’ categorization (French, 2005).
Topical Heat Application
AAFP currently cites topical heat application as a SORT class ‘B’ ‘possibly
effective’ treatment modality, which has few adverse effects (French, 2005, Proctor and
Farquhar, 2002).
13
Vasoactive Medications
Glyceryl trinitrate, nifedipine and terbutaline were briefly explored for the
management of dysmenorrhea in the 1970s. Although demonstrating potential utility,
these medications have never become established treatments; Nifedipine and terbutaline
are referenced by AAFP as SORT class ‘C’ therapies of ‘uncertain effectiveness’
(French, 2005). Glycerine trinitrite has been studied more recently (Facchinetti et al.,
2002) but had significant limitation in utility due to its association with headaches.
Vitamins/Supplements
Magnesium, Thiamine, Vitamin E and Zinc have been used in the treatment of
dysmenorrhea.
Magnesium
Several small clinical trials, involving 20-50 women revealed that magnesium
may be beneficial in reducing symptoms of dysmenorrhea. Magnesium was taken for a
maximum of six months in various doses and regimens in these trials (Proctor et al.,
2001). Magnesium salicylate is currently cited as an off- label treatment for
dysmenorrhea with a recommended dosage of 600 mg every 4 hours with a maximum 4.8
g daily, with therapeutic effects through salicylate effects. It may serve as a useful
adjuvant therapy to those unable to tolerate NSAIDs but has not been studied as part of
major Cochrane analyses and has not been given a SORT rating.
Thiamine
Thiamine received an AAFP SORT rating of B, ‘possibly effective’, with positive
systematic reviews and one study showing that 100 mg of thiamine (vitamin B-1) taken
daily cured 87% of patients for up to two months after treatment (Proctor and Murphy,
2001).
Vitamin E
Treatment with 2500 IU of Vitamin E was proven useful in a single small trial.
Daily use for 5 days beginning 2 days prior to menses may be effective in treatment of
dysmenorrhea, a SORT ‘B’ ‘possibly effective’ intervention according to AAFP
guidelines (French, 2005).
Zinc
A small case series has demonstrated zinc, “in 1–3 30-mg doses given daily for
one to four days prior to onset of menses, prevents essentially all warning of menses and
all menstrual cramping” (Eby, 2007). A previous study also revealed a positive impact of
zinc on menstrual cramping (Eby et al., 1984). Menstrual cramping occurred at 15 mg but
not 30mg of supplementation in patients treated with zinc (Goei, 1982) and effects were
seen with zinc gluconate specifically. Lozenger delivery of zinc appeared to deliver
quicker results (Prasad, 2000). Zinc oxide does not have physiologic utility and should
14
not be used. Although the mechanism by which zinc would improve menstrual cramping
is not understood, relative deficiency may play a role.
“The United States recommended daily allowance (RDA) for zinc has been 15 mg
for many years, but it has recently been lowered to 8 mg per day for women,
while the median intake of zinc from food in the United States has been found to
be 9 mg per day for women…therapeutic doses of 30mg a daily for 3-5 days
appear safe and do not interfere with copper metabolism (Eby, 2007).”
Zinc supplementation has not received a SORT rating.
15
CHAPTER 4: AEROMEDICAL CONCERNS OF TREATMENT
In this section, aeromedical concerns of first line medical therapies as well as
those of non-traditional medical therapy for dysmenorrhea are discussed. In both military
and civil aviation, aeromedical guidance about medications such as NSAIDs and
hormonal therapies has been previously outlined. Non-traditional medication and
supplements may have varying doses and are not regulated by the FDA (Food and Drug
Administration). For this reason, all but 4 are explicitly grounding for use in U.S. Army
aviation, none of which are indicated for dysmenorrhea (AERO, 2006). At the other
extreme, little written guidance or specific prohibition exists in civil aviation medicine
with regards to non-traditional therapies. Side effects and medication interaction potential
in traditional as well as non-traditional treatments for dysmenorrhea are discussed here in
an aeromedical context.
A. NSAIDs
Aeromedical concerns of NSAIDs include risk for gastric/duodenal bleeding and
perforation, with potential for chronic anemia, incapacitating pain and/or acute blood
loss. These risks are elevated in patients taking high dose regimens, and also increase
with age. Overall risk of GI bleeding with high dose NSAIDs is low, with less than 1% of
Motrin users experiencing ‘serious GI events’ which include ulcer with or without
bleeding (Gold Standard, 2007). Anecdotally, acetaminophen has been selected over
NSAIDs in combat aviation for minor menstrual pain when fully responsive to this
medication due to lower risk for excessive trauma and/or forward surgical related
bleeding.
An on-line Aeromedical Examiner Guidebook reference cites upset GI tract,
itching, dizziness and water retention as concerns for ibuprofen use (Guide for Aviation
Medical Examiners tutorial, 2006). Caution must be used with high-dose NSAIDs,
especially when combined with non-disclosed over the counter medications containing
NSAIDs. Over the counter use of medication should be regulated in order to ensure high
dose NSAIDs with differing brand names are not used simultaneously. Duration of use
should be limited to just prior to symptom onset until normal day of resolution of
symptoms. ASAMs cites NSAIDs as a waiverable class of medication in the management
of endometriosis (ASAMS, 2007). The U.S. Army Policy Letters cites NSAIDs and
analgesic equivalents as ‘not requiring a waiver’ (AERO, 2006).
B. OCPs
Aeromedical concerns for oral contraceptives include risk for DVT (deep venous
thrombosis), which is four times higher in users of low-dose estrogen preparations
containing older progesterone agents (levonorgestrel, lynoestrenol, and norethisterone)
than the risk is for non users of OCPs (Hoffman, 2005). However, overall myocardial
infarction and stroke risk is reduced in OCP users, likely because of estrogen's favorable
influence on lipid profile (Hoffman, 2005). OCPs formulated with newer progestins
16
(desogestrel, gestodene, and norgestimate) are associated with a higher risk of DVT when
compared to traditional OCPs (Hoffman, 2005). OCPs users who are pro-thrombotic face
even higher than average risk with OCP use; carriers of Factor V Leiden deficiency
mutation are at 35-fold increased risk. (Hoffman, 2005). Carriers of prothrombin gene
(PT G20210A), which appears in 1-6% of Caucasian women but is uncommon in other
ethnicities, have a 16-fold risk of DVT (Press et al., 2002).
To present these risks in context, it is helpful to realize the overall small
prevalence of a first time occurrence of a DVT – the incidence in the general population
being 0.008 episodes per 100 person-years, with OCP users still having an overall low
incidence of 0.03 episodes per 100 person-years and OCP users with the factor V Leiden
mutation 0.285 episodes per 100 person-years (Hoffman, 2005). DVT has not been
associated with any in-flight fatalities on a NTBS search dating from 1970 to present.
OCPs are preventative against several medical conditions that present significant risk for
in-flight incapacitation such as ovarian torsion, symptomatic hemorrhagic cyst and
ruptured ectopic pregnancy.
In terms of longitudinal health of the individual OCP user, it must also be
remembered that pregnancy itself carries a much higher risk of PE/ DVT than OCPs.
Pregnancy at some point will almost always temporarily preclude flight duties and may
be the very least concern in the event of an unintended gestation.
OCP users with hypertension may experience increase in blood pressure. Acne
and headaches may worsen or improve in patients with either condition. New OCP users
may also experience bloating, nausea and menstrual irregularities; these are frequently
transient and resolve within 3 months of initial use. In terms of ocular risk, users of
hormonal contraception experience slightly increased risk of optic neuritis, diplopia, loss
of vision and retinal thrombosis with estrogens being specifically related to keratoconus.
Pilots who begin new hormonal therapy should be advised to seek evaluation for any
change in vision. Headaches and emotional changes may occur in some women, but
significant gastrointestinal side effects are rare. Given potential for side effects that might
have aeromedical implications, a brief period of initial flight restriction is appropriate in
new OCP users in order to ensure lack of flight interference. U.S. Army policy letters
conservatively advise at least 24 hours of grounding for the first time use of most
medications (AERO, 2006). Intravaginal oral contraceptive application of 30mcg ethinyl
estradiol and 150mg levonorgestrel may afford greater side effect tolerability as
demonstrated in a RCT of 143 women (Ziaei, 2002) and may be a useful means of
treating dysmenorrhea in women with persistent side effects from oral contraceptives.
Oral contraceptives use for endometriosis is cited as waiverable in ASAMS clinical
guidelines (ASAMS, 2007). Progestins, to include combination oral contraceptives, are
cited as potentially waiverable in the U.S. Army Aeromedical Policy letters (AERO,
2006).
17
C. OTHER HORMONAL TREATMENTS
Danazol
Danazol is noteworthy for the induction of androgenic and anabolic side effects as
well as a pseudomenopausal state. Diaphoresis, flushing, headache, nausea/vomiting,
photosensitivity, pruritis and visual changes may occur, along with increased risk for
stroke, thromboembolism, Guillain Barre syndrome and Stevens Johnson syndrome
(Gold Standard, 2007). U.S. Army aviators who are prescribed this medication for
endometriosis may be granted a waiver once symptoms have stabilized (AERO, 2006).
Danazol is also cited as a waiver-requiring medication by the ASAMS (ASAMS, 2007).
Refractory symptoms or side effects that interfere with flight mandate at least temporary
grounding.
Depo Medroxy-Progesterone Acetate (Depo-Provera)
Although not associated with thrombo-embolic events that would immediately
impact flight safety, Depo Provera may be associated with long-term risk for bone loss.
In November 2004, Pfizer Pharmaceuticals added a black box warning that “women who
use Depo-Provera Contraceptive Injection may lose significant bone mineral density.
Bone loss is greater with increasing duration of use and may not be completely
reversible…. (Depo-Provera) should be used as a long-term birth control method (e.g.
longer than 2 years) only if other birth control methods are inadequate” (Nicoletti and
Tonelli, 2005). In the setting of conflicting data on reversibility of bone demineralization,
some clinicians discount demineralization as an insignificant risk of Depo-Provera use
(Nicoletti and Tonelli, 2005). However the potential long-term risk is an important
consideration for military pilots, who must maintain excellent fitness and weight bearing
capacity, as well as astronauts who assume the additional bone reduction risk of
microgravity. Additionally, transient breakthrough bleeding occurs in 38% to 47% of
patients (Olive, 2007). Depo-Provera is listed as waiverable for the treatment of
endometriosis by ASAMS and the U.S. Army Policy Letters (AERO, 2006, ASAMS,
2007).
Gonadotropin Releasing Hormone Agonists
With significant side effects of hot flushes, vaginal dryness, and insomnia being
common, GnRHA use is frequently incompatible with flight. Moreover, a 5-6% decrease
in bone mineral density has been established in GnRHA users, presenting readiness and
long-term health issues to military pilots and astronauts. Utilization of add-back therapy
can prevent bone loss for up to 1 year and may be helpful in side effect alleviation;
GnRHA use of even short duration should be coupled with add-back therapy in this
population (Mahutte and Arici, 2003, Olive, 2007). U.S. Army aviators who are
prescribed this medication for endometriosis may be granted a waiver once symptoms
18
have stabilized (AERO, 2006). ASAMS also considers this medication to have potential
for waiver action when used in the treatment of endometriosis (ASAMS, 2007).
Levonorgestrel Releasing Intrauterine System
Side effects of hormonal based IUDs include potentially aeromedically significant
“dizziness, headaches, breast tenderness, nausea, vomiting (Shulman et al., 2004).”
However risk for most of these side effects is relatively small, with 23% experiencing
some nausea, 5% experiencing vomiting and approximately 11% experiencing other
symptoms with initial use (Gold Standard, 2007). Like other progestins, this therapy is
cited as potentially waiverable by in the U.S. Army Policy Letters (AERO, 2007).
Novel Hormonal Therapies
The estrogen patch, injectable estrogen and vaginal ring have unique aeromedical
concerns. In the case of the estrogen patch, two case-control studies compared DVT rates
between patch and OCP users using insurance and medical record data. Although one
study found no difference in rates, the unpublished “Ingenix study” found a twofold
increased risk of thromboembolism in patch vs. OCP users (odds ratio, 2.2; CI, 1.3–3.8)
(Jick et al., 2006, Orthoevra.com, 2006, Swica, 2007). The Ingenix study has not been
published in a peer-reviewed journal and many clinicians feel that the FDA black box
warning which the Ingenix study generated is unwarranted (Swica, 2007). None the less,
until true DVT risk is further established, pilots at risk for DVT through genetics or
frequent long duration flight are not ideal candidates for the estrogen patch in the
management of dysmenorrhea.
Injectable estrogen (Lunelle) is a once-a-month injectable contraceptive
containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate
(E2C) (MPA/E2C: Lunelle; Pfizer, Inc.) and presents similar aeromedical concerns with
respect to estrogen effects. The Vaginal Ring (NuvaRing) (etonogestrel and ethinyl
estradiol) is classified as low estrogen, and is cited as having similar risk profile to
standard OCPs, with additional small risk of toxic shock like syndrome. Risk for
dislodgement with flight has not been analyzed but rates of non-specific ‘device related
events’, which include dyspareunia as well as dislodgement, are approximately 4%
(Swica, 2007). The NuvaRing outer diameter is 5.4 cm with a cross-sectional diameter of
0.4 cm. Pilots with acrobatic, negative G and other highly demanding flight profiles
should consider a trial of relatively level flight with initial use if fit is uncertain.
D. SURGERY
Following appropriate post-operative recovery and stabilized symptomatology,
return to flight duties is appropriate. Surgical treatment of endometriosis in particular is
fully endorsed as a waiverable condition in the U.S. Army Aeromedical policy letters
(AERO, 2006).
19
E. NON-TRADITIONAL THERAPIES
Acupuncture/TENS (Transcutaneous Electric Nerve Stimulation)
Acupuncture, when controlling symptoms, may afford ideal pain management due
to extremely low side effect profile. Although no FAA restrictions apply, acupuncture use
must be reported on interval flight physicals in civil aviation. The Civil Aerospace
Medical Institute stresses the importance of ensuring that the underlying condition is fully
explored and reported (Mohler, 2002).
Lifestyle Modification
Tobacco cessation may be associated with irritability as well as increased rates of
sore throat, cough, hearing difficulty, and mouth ulcers in the first 6 weeks of cessation,
presenting potential distraction from flight (Ussher at al., 2003). However sustained
tobacco cessation affords significant increases in overall lifetime survival and may reduce
the self-imposed stress of hypoxia in pilots (Edwards, 2004). A well-balanced low fat
vegetarian diet with adequate protein supplementation should pose no aeromedical
concern; furthermore aviators who do not exceed BMI may have greater tolerance for
physiologic stresses of flight. Although not clearly indicated for treatment of
dysmenorrhea, exercise affords multiple health benefits. Weight training rather than
excessive jogging is traditionally preferred for pilots subject to high G environments
secondary to G-lock considerations (Burton and Whinnery, 2002).
Fish oil
N-3 fatty acids (FAs) from fish or fish-oil supplements such as Omacor have
demonstrated ability to reduce rates of cardiac, sudden and all-cause mortality with
further potential for stroke reduction and little adverse risk (Wang et al., 2006). Omacor’s
only major adverse effect is burping and fishy taste (Bays, 2006), which would not
preclude flight duties unless burping is distracting from flight.
Herbs
The use of angelica (Dong Quai, Dang Gui, Tang Kuei) and rose tea (Tokishakuyaku-san) have aeromedical sifnificance. The FAA advises that aeromedical
examiners (AMEs) use caution with use of angelica during pregnancy and breast-feeding
(Guide for Medical Examiners tutorial. 2006). No other non-traditional treatment of
dysmenorrhea is discussed in the AME Guidebook, although guidance is given to the
AME to evaluate the underlying condition and to caution aviators against the ‘more is
better’ approach to self-medication. Herbal products are notorious for inconsistent
labeling of concentrations and non- disclosure of full contents. Without reliability in
deliverance, presence of evidence based research and safety regulations, herbal products
cannot be recommended for aeromedical use. Aside from a limited number of products,
which can be only used under the supervision of a flight surgeon, the U.S. Army Aviation
Policy Letters categorizes virtually all herbal supplements as grounding (AERO, 2006).
20
Spinal manipulation
Although no adverse events compared to sham therapy were determined in small
studies involving treatment of dysmenorrhea, a lack of effectiveness of this therapy along
with the potential for iatrogenic musculoskeletal disturbance exists. Therefore spinal
manipulation cannot be recommended for aviators for dysmenorrhea.
Topical Heat Application
Although potentially useful in symptom alleviation, undertaking flight with
reliance on this method to resolve distracting symptoms is problematic. Application of
heat during flight may be burdensome and less effective with temperature declinations
associated with flight.
Vasoactive Medications
Glyceryl trinitrate ,nifedipine and terbutaline have completely unacceptable risk
profiles for flight given sympathomimetic and vasodilatory actions (Gold Standard,
2007), leading to high risk for incapacitation.
Vitamins/Supplements
Magnesium
Magnesium salicylate’s major limitations are GI side effects, which may affect up
to 30% of individuals (Gold Standard, 2007). Long term and high dose use of salicylates
are also associated with tinnitus and hearing loss, important aeromedical considerations.
Magnesium oxide and magnesium sulfate both have laxative effects that could be
problematic for flight. Ensuring daily intake of 310-320 mg of magnesium, the
recommended daily allowances of magnesium, may be prudent in women with
dysmenorrhea. However additional supplementation beyond this amount may pose
aeromedical risk. Salicylate use in the combat aviation setting may confer unacceptable
risk of bleeding in the event of trauma and/or forward surgical operative requirement.
Thiamine
Hypersensitivity involving thiamine is rare, however hyperthyroid like symptoms
of irritability, restlessness, headache, tremor, palpitations, anorexia and nausea/vomiting
can occur with chronic large oral doses of thiamine, resolving when supplementation is
stopped (Gold Standard, 2007). Recommended daily allowance is only 1.1 mg daily, far
below the 100 mg doses used for treatment of dysmenorrhea and insufficient data exists
on upper limits permissible in healthy subjects. Thiamine supplementation with 100 mg
daily for dysmenorrhea appeared to be safe in studies involving 500 East Indian women
21
of unknown baseline serum thiamine levels (Proctor and Furquhar, 2002), but high dose
supplementation should be studied further before being considered a safe therapy for
general aeromedical use.
Vitamin E
Vitamin E and all fat-soluble vitamins are not considered appropriate for flight
under army aeromedical policy due to potential for long term over accumulation.
Prolonged use of large doses of vitamin E (400-800 Units daily) has caused
nausea/vomiting; diarrhea; breast enlargement; fatigue; intestinal cramps; weakness;
blurred vision; headache; and rash. Higher doses exceeding 800 Units per day can impact
thyroid, pituitary, and adrenal hormone metabolism as well as bleeding time (Gold
Standard, 2007). Lower doses, such as those included in Omacor, are safe for use in
aviation. The 5-day treatment with 2,500 IU of Vitamin E, although effective in symptom
reduction, may allow potential for side effects with long-term use and cannot be
recommended for individuals on a flight status.
Zinc
Zinc supplementation should not exceed the upper tolerable limits of 40mg/day
for adults (Gold Standard, 2004). The most common side effects with high dose zinc
supplementation include nausea, abdominal pain and dyspepsia. Sideroblastic anemia
may occur secondary to zinc induced copper deficiency (Gold Standard, 2007) and is a
significant aeromedical concern with long-term use of high dose zinc supplementation.
22
CHAPTER 5: DISCUSSION & CONCLUSION
A. GAP ANALYSIS
Despite increasing participation of women in aviation, a gap exists in civilian
aeromedical clinical guidelines for dysmenorrhea, a common condition. Military
aeromedical guidelines, such as the Army aeromedical policy letters, contain guidelines
for endometriosis but not primary dysmenorrhea.
B. DATA & METHODS
The clinical guideline was developed using literature search as previously
discussed, in conjunction with senior aeromedical and obstetrical staff review.
Aeromedical concerns were based upon typical side effects and potential adverse
outcomes of therapies as delineated in 2007 Gold Standard pharmaceutical reference as
well as those cited with previous DoD and civilian aeromedical references.
This capstone has resulted in a clinical guideline for primary dysmenorrhea as a
waiverable medical condition for flight when symptoms are controlled through
appropriate therapeutics as outlined fully in capstone appendix.
C. STUDY TYPES & STATISTICAL METHODS
Data substantiating standard medical and surgical treatment recommendations
were derived from randomized controlled trials. Guidance on non-traditional modalities
as well as innovative new modalities was derived from existing knowledge from case
reports, typical medical practice and historical data. To a limited degree, evidence for
some nutritional supplementation such as thiamine and magnesium were also
substantiated on 2001 Cochrane analysis.
D. OUTCOME
This capstone was developed with the intention of expanding clinical and
aeromedical knowledge with respect to women in aviation. The attached Clinical
guideline will be submitted to ASAM (American Society of Aerospace Medical
Specialists) as well as to U.S. Army aeromedical authority, with potential for on line
publication and access.
23
APPENDIX A: PROPOSED AEROMEDICAL
CLINICAL PRACTICE GUIDELINE
Overview: Dysmenorrhea occurs when prostaglandin F2α (PG F2α) causes menstrual
cramping, with or without associated symptoms of nausea headaches, anxiety, fatigue,
diarrhea, and bloating. In varying degrees, it affects 45-95% of reproductive aged
women, causing 3 days of incapacitating symptoms and/or up to 3 lost duty days per
month in 10-15% of women with untreated dysmenorrhea. Dysmenorrhea occurs most
commonly in young nulliparous women. Smoking and psychological stress are additional
risk factors. The physical exam in primary dysmenorrhea is normal; abnormal
examination may indicate secondary dysmenorrhea from ovarian cyst, adenomyosis,
leiomyomas and, less commonly, chronic salpingitis, copper IUD use, or acquired
outflow tract obstruction. First line management includes the use of non-steroidal antiinflammatory drugs (NSAIDs) and combination oral contraceptives pills (OCPs), with
acetaminophen acceptable when controlling mild symptoms. OCPs may be used
continuously for menstrual suppression. Estrogen-progesterone delivery is also available
through the vaginal ring (NuvaRing®) and the estrogen patch (OrthoEvra®) for
individuals who prefer more convenient dosing. Medroxyprogesterone acetate (DepoProvera) and progesterone containing IUDs such as the levonorgestrel IUD (Mirena®)
may afford pain relief through cessation of menstruation.
Other medications such as danazol, (Danocrine ®) and medroxyprogesterone
acetate (Depo- Provera ®) as well as gonadotropin releasing hormone (GnRH) agonists
such as leuprolide (Lupron ®) and goserelin (Zoladex ®) are available and effective in
treating the symptoms of endometriosis. GnRH antagonists are not currently approved for
dysmenorrhea but may have therapeutic potential. NSAIDS/NSAID equivalent
medications such as acetaminophen, OCPs, progesterone containing IUDs and
medroxyprogesterone acetate (Depo-Provera) are more frequently waiverable. However
other treatments such as danazol (Danocrine ®) or GnRH agonists/antagonists may be
considered for waiver if well tolerated and, in the case of GnRH agonists/antagonists,
used in conjunction with low-dose estrogen and progesterone continuous ‘add back’
therapy.
Non-traditional interventions that may be beneficial include thiamine, vitamin E
and fish oil supplementation, low fat vegetarian diet, acupuncture/acupressure and TENs.
(transcutaneous electric nerve stimulation) Other multi-vitamin formulations and spinal
manipulation have not been proven and cannot be recommended. Rose tea may be
effective, but lack of FDA oversight makes this a potentially unreliable therapy. Although
not studied rigorously, tobacco cessation eliminates a risk factor for dysmenorrhea as
well as a self-imposed stress for flight. Surgical therapy is the preferred treatment for
patients with endometriosis related infertility. More definitive surgery, such as
24
hysterectomy and bilateral salpingo-oophorectomy, may be also effective.
Aeromedical Concerns: Dysmenorrhea usually begins as low grade discomfort and may
progress over hours or days to severe discomfort that is distracting. It is not normally
acutely incapacitating. Menorrhagia may be associated with dysmenorrhea and can cause
a gradual onset anemia. Medical therapy should consist of medications that are
aeromedically acceptable, such as NSAIDs and OCPs. Due to low impact on clotting
mechanisms, acetaminophen for control of mild symptoms is especially acceptable in
pilots operating high-risk environments such as acrobatic instruction, urban law
enforcement, search and rescue operations and extreme environmental monitoring. Oral
contraceptive pills afford additional benefits in terms of pregnancy prevention,
prevention of incapacitating emergencies such as ovarian torsion and ectopic pregnancy,
preservation of hemoglobin and potential for menstrual suppression, However, OCPs
predispose towards clot formation, especially in long duration flights and in individuals
with hereditary thromophilias. Due to risk for bone density loss, medroxyprogesterone
acetate and GnRH agonists/antagonists must be used with caution in pilots subject to
microgravity or who have other risk factors for bone loss. GnRH agonists/antagonists
should be used only in conjunction with ‘add back’ therapy. Although
medroxyprogesterone acetate is convenient and reliable, it is associated with weight gain
and irregular menstrual bleeding. The estrogen-progesterone patch may be associated
with higher rates of thrombosis than OCPs and is not ideal for pilots with risk factors
such as hereditary thrombophilas or prolonged duration flights. Potassium sparing OCPs
require potassium monitoring in order to prevent electrolyte imbalance.
Medical Work-up: The following consults and tests are required for proper medical
evaluation leading to an aeromedical disposition:
A) History of symptoms
B) Gynecological evaluation report
c) Report of previous treatments used
d) Report of any current medications or ongoing treatments
e) Hemoglobin/Hematocrit
.
References:
ASAMS:Endometriosis. Obtained on 31 Dec 2007 from
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32
VITA
Nicole Powell-Dunford was born on 19 February 1975 in Albany New York to
Richard and Danielle Powell. She attended Albany High School and the State University
of New York at Albany. earning a B.A. in English and Biology. Nicole subsequently
graduated from the Uniformed Services University of the Health Sciences and completed
a family medicine residency at Tripler Army Medical Center. She has served as a Combat
Aviation Brigade Surgeon in the 25th Infantry Division, an Aviation Medicine Clinic
Chief as well as a Task Force flight surgeon in Iraq and Afghanistan. She is married to
Mike Dunford and is the proud parent of Julia and Joshua Dunford.
33