Menopausal Symptoms and Higher Risk Opioid Prescribing in a National Sample of Women Veterans with Chronic Pain

  • Carolyn J. GibsonEmail author
  • Yongmei Li
  • Alison J. Huang
  • Tessa Rife
  • Karen H. Seal
Original Research



The greatest increases in long-term opioid use and opioid-related overdose mortality in recent years have been among women in midlife. Common menopausal symptoms broadly affect health and health care utilization in midlife, but their contribution to chronic pain management during this period is unknown.


To examine relationships between menopausal symptoms and long-term opioid prescription patterns among midlife women with chronic pain.


Cross-sectional analysis of national Veterans Health Administration medical and pharmacy records (2014–2015).


Women Veterans aged 45–64 with ≥ 1 outpatient visit and chronic pain diagnoses spanning ≥ 90 days.

Main Measures

Long-term opioids (prescribed oral opioids for ≥ 90 days), high-dose long-term opioids (> 50 mg average morphine equivalent daily dose), and long-term opioids co-prescribed with central nervous system depressants (benzodiazepine and non-benzodiazepine sedative-hypnotics, gabapentin/pregabalin, muscle relaxants). Multivariable logistic regression models were used to examine associations between outcomes and menopausal symptoms (menopausal symptom–related diagnoses (i.e., “symptomatic menopausal states”) on ≥ 2 encounters and/or menopausal hormone therapy, adjusting for race, age, body mass index, and mental health and substance use disorder diagnoses.

Key Results

In this national sample of 104,984 midlife women Veterans with chronic pain (mean age 54.5, SD 5.4 years), 17% had evidence of menopausal symptoms, 51% were prescribed long-term opioids, 13% were prescribed high-dose long-term opioids, and 35% were co-prescribed long-term opioids and central nervous system depressants. In multivariable analyses, women with menopausal symptoms had increased odds of long-term opioids (OR 1.21, 95% CI 1.18–1.26), high-dose long-term opioids (OR 1.08, 95% CI 1.02–1.13), and long-term opioids co-prescribed with central nervous system depressants (sedative-hypnotics OR 1.25, 95% CI 1.22–1.30; gabapentin/pregabalin OR 1.23, 95% CI 1.20–1.27; muscle relaxants OR 1.24, 95% CI 1.20–1.28).


Among midlife women Veterans with chronic pain, evidence of menopausal symptoms was associated with potentially risky long-term opioid prescription patterns, independent of known risk factors.


women’s health menopause opioids chronic pain Veterans 



CJG and KHS were responsible for the study concept and design. KHS obtained funding and supervised the study. YL conducted the statistical analysis. All authors were involved in the interpretation of data. CJG drafted the manuscript, and all authors critically revised it for important intellectual content and approved the final version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. CJG is the guarantor and accepts overall responsibility for the accuracy of the data, its analysis, and this report.

Data Sharing

No additional data are available owing to a data use agreement with the Department of Veterans Affairs.


This research was supported, in part, by the U.S. Department of Veterans Affairs Quality Enhancement Research Initiative (VA QUERI), “Evaluation of the Implementation of the Integrated Pain Team Clinic” (KHS, YL); CJG was supported by the VA Advanced Fellowship Program in Women’s Health at the San Francisco VA Health Care System and VA Health Services Research & Delivery CDA IK2 HX002402 during the conduct of this study.

Compliance with Ethical Standards

The study was approved by the institutional review boards of the University of California, San Francisco, and the Research and Development Committee of the San Francisco VA Health Care System.

Conflict of Interest

AH has received research grants from Pfizer Inc. and Astellas through the University of California, San Francisco to conduct research unrelated to this manuscript. All remaining authors declare that they do not have a conflict of interest.


The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; or the decision to submit the manuscript for publication. The views expressed herein are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs or the University of California, San Francisco.

Supplementary material

11606_2019_5242_MOESM1_ESM.docx (13 kb)
Online Appendix (DOCX 13 kb)


  1. 1.
    Campbell CI, Weisner C, Leresche L, et al. Age and gender trends in long-term opioid analgesic use for noncancer pain. Am J Public Health. 2010;100(12):2541–2547.CrossRefGoogle Scholar
  2. 2.
    Bohnert AS, Ilgen MA, Trafton JA, et al. Trends and regional variation in opioid overdose mortality among Veterans Health Administration patients, fiscal year 2001 to 2009. The Clinical journal of pain. 2014;30(7):605–612.Google Scholar
  3. 3.
    Higgins DM, Kerns RD, Brandt CA, et al. Persistent pain and comorbidity among Operation Enduring Freedom/Operation Iraqi Freedom/operation New Dawn veterans. Pain Med. 2014;15(5):782–790.CrossRefGoogle Scholar
  4. 4.
    Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL, 3rd. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–485.Google Scholar
  5. 5.
    Kroll-Desrosiers AR, Skanderson M, Bastian LA, et al. Receipt of prescription opioids in a national sample of pregnant veterans receiving Veterans Health Administration care. Women’s Health Issues. 2016;26(2):240–246.CrossRefGoogle Scholar
  6. 6.
    Mosher H, Krebs E, Carrel M, Kaboli P, Vander Weg M, Lund B. Trends in prevalent and incident opioid receipt: an observational study in veterans health administration 2004–2012. Journal of general internal medicine. 2015;30(5):597–604.CrossRefGoogle Scholar
  7. 7.
    Darnall BD, Stacey BR. Sex differences in long-term opioid use: cautionary notes for prescribing in women. Arch Intern Med. 2012;172(5):431–432.CrossRefGoogle Scholar
  8. 8.
    CDC. Prescription Painkiller Overdoses: A Growing Epidemic, Especially Among Women. Published 2017. Accessed June 21, 2019.
  9. 9.
    Calcaterra S, Glanz J, Binswanger IA. National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999-2009. Drug Alcohol Depend. 2013;131(3):263–270.CrossRefGoogle Scholar
  10. 10.
    Magliano M. Menopausal arthralgia: Fact or fiction. Maturitas. 2010;67(1):29–33.CrossRefGoogle Scholar
  11. 11.
    Craft RM. Modulation of pain by estrogens. Pain. 2007;132 Suppl 1:S3–12.CrossRefGoogle Scholar
  12. 12.
    Meriggiola MC, Nanni M, Bachiocco V, Vodo S, Aloisi AM. Menopause affects pain depending on pain type and characteristics. Menopause. 2012;19(5):517–523.CrossRefGoogle Scholar
  13. 13.
    Attarian H, Hachul H, Guttuso T, Phillips B. Treatment of chronic insomnia disorder in menopause: evaluation of literature. Menopause. 2015;22(6):674–684.CrossRefGoogle Scholar
  14. 14.
    Berlin RK, Butler PM, Perloff MD. Gabapentin Therapy in Psychiatric Disorders: A Systematic Review. Prim Care Companion CNS Disord. 2015;17(5).Google Scholar
  15. 15.
    Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;22(11):1155–1172; quiz 1173–1154.Google Scholar
  16. 16.
    Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017;17(1):230.CrossRefGoogle Scholar
  17. 17.
    Frayne SM, Phibbs, C.S., Saecho, F., Maisel, N.C., Friedman, S.A., Finlay, A., Berg, E., Balasubramanian, V., Dally, S.K., Ananth, L., Romodan, Y., Lee, J., Iqbal, S., Hayes, P.M., Zephyrin, L., Whitehead, A., Torgal, A., Katon, J.G., Haskell, S. . Soucebook: Women Veterans in the Veterans Health Administration. Vol Volume 3. Sociodemographics, Utilization, Costs of Care, and Health Profile. Washington, D.C.: Women’s Health Evaluation Initiative, Women’s Health Services, Veterans Health Administration, Department of Veterans Affairs.; February 2014.Google Scholar
  18. 18.
    Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women’s health across the nation. Am J Public Health. 2006;96(7):1226–1235.CrossRefGoogle Scholar
  19. 19.
    Seal KH, Bertenthal D, Barnes DE, et al. Association of Traumatic Brain Injury With Chronic Pain in Iraq and Afghanistan Veterans: Effect of Comorbid Mental Health Conditions. Arch Phys Med Rehabil. 2017;98(8):1636–1645.CrossRefGoogle Scholar
  20. 20.
    Oliva EM, Midboe AM, Lewis ET, et al. Sex differences in chronic pain management practices for patients receiving opioids from the Veterans Health Administration. Pain Med. 2015;16(1):112–118.CrossRefGoogle Scholar
  21. 21.
    VA/DoD Opioid Therapy for Chronic Pain Work Group. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain, Vol. 3. Published 2017. Accessed June 21, 2019.
  22. 22.
    Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309(7):657–659.CrossRefGoogle Scholar
  23. 23.
    Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160–1174.CrossRefGoogle Scholar
  24. 24.
    Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017;77(4):403–426.CrossRefGoogle Scholar
  25. 25.
    Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017;14(10):e1002396.CrossRefGoogle Scholar
  26. 26.
    Abrahamsson T, Berge J, Ojehagen A, Hakansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug Alcohol Depend. 2017;174:58–64.CrossRefGoogle Scholar
  27. 27.
    Slavova S, Miller A, Bunn TL, et al. Prevalence of gabapentin in drug overdose postmortem toxicology testing results. Drug Alcohol Depend. 2018;186:80–85.CrossRefGoogle Scholar
  28. 28.
    Burgess DJ, Nelson DB, Gravely AA, et al. Racial differences in prescription of opioid analgesics for chronic noncancer pain in a national sample of veterans. J Pain. 2014;15(4):447–455.CrossRefGoogle Scholar
  29. 29.
    Seal KH, Shi Y, Cohen G, et al. Association of mental health disorders with prescription opioids and high-risk opioid use in US veterans of Iraq and Afghanistan. JAMA. 2012;307(9):940–947.CrossRefGoogle Scholar
  30. 30.
    Pamuk ON, Cakir N. The variation in chronic widespread pain and other symptoms in fibromyalgia patients. The effects of menses and menopause. Clin Exp Rheumatol. 2005;23(6):778–782.Google Scholar
  31. 31.
    Martinez-Jauand M, Sitges C, Femenia J, et al. Age-of-onset of menopause is associated with enhanced painful and non-painful sensitivity in fibromyalgia. Clin Rheumatol. 2013;32(7):975–981.CrossRefGoogle Scholar
  32. 32.
    Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain perception and treatment. Pain Med. 2009;10(2):289–299.CrossRefGoogle Scholar
  33. 33.
    Thurston RC, Bromberger JT, Joffe H, et al. Beyond frequency: who is most bothered by vasomotor symptoms? Menopause. 2008;15(5):841–847.CrossRefGoogle Scholar
  34. 34.
    Maki PM, Freeman EW, Greendale GA, et al. Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition. Menopause. 2010;17(4):815–822.CrossRefGoogle Scholar
  35. 35.
    Huang AJ, Moore EE, Boyko EJ, et al. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause. 2010;17(1):121–126.CrossRefGoogle Scholar
  36. 36.
    Elavsky S, Gonzales JU, Proctor DN, Williams N, Henderson VW. Effects of physical activity on vasomotor symptoms: examination using objective and subjective measures. Menopause. 2012;19(10):1095–1103.CrossRefGoogle Scholar
  37. 37.
    Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path forward. J Pain. 2013;14(12):1539–1552.CrossRefGoogle Scholar
  38. 38.
    Patel KV, Cochrane BB, Turk DC, et al. Association of Pain With Physical Function, Depressive Symptoms, Fatigue, and Sleep Quality Among Veteran and non-Veteran Postmenopausal Women. Gerontologist. 2016;56 Suppl 1:S91–101.CrossRefGoogle Scholar
  39. 39.
    Sullivan MD, Edlund MJ, Zhang L, Unutzer J, Wells KB. Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med. 2006;166(19):2087–2093.CrossRefGoogle Scholar
  40. 40.
    Gorka SM, Fitzgerald DA, de Wit H, Angstadt M, Phan KL. Opioid modulation of resting-state anterior cingulate cortex functional connectivity. J Psychopharmacol. 2014;28(12):1115–1124.CrossRefGoogle Scholar
  41. 41.
    Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions. Am J Ther. 2005;12(2):151–171.CrossRefGoogle Scholar
  42. 42.
    Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry. 2015;72(2):136–142.CrossRefGoogle Scholar
  43. 43.
    Cooper TE, Derry S, Wiffen PJ, Moore RA. Gabapentin for fibromyalgia pain in adults. Cochrane Database Syst Rev. 2017;1:CD012188.Google Scholar
  44. 44.
    Guttuso T, Jr. Effective and clinically meaningful non-hormonal hot flash therapies. Maturitas. 2012;72(1):6–12.Google Scholar
  45. 45.
    Peckham AM, Fairman KA, Sclar DA. All-Cause and Drug-Related Medical Events Associated with Overuse of Gabapentin and/or Opioid Medications: A Retrospective Cohort Analysis of a Commercially Insured US Population. Drug Saf. 2018;41(2):213–228.CrossRefGoogle Scholar
  46. 46.
    Jann M, Kennedy WK, Lopez G. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Pract. 2014;27(1):5–16.CrossRefGoogle Scholar
  47. 47.
    Campbell G, Nielsen S, Larance B, et al. Pharmaceutical Opioid Use and Dependence among People Living with Chronic Pain: Associations Observed within the Pain and Opioids in Treatment (POINT) Cohort. Pain Med. 2015;16(9):1745–1758.CrossRefGoogle Scholar
  48. 48.
    Edlund MJ, Martin BC, Fan MY, Devries A, Braden JB, Sullivan MD. Risks for opioid abuse and dependence among recipients of chronic opioid therapy: results from the TROUP study. Drug Alcohol Depend. 2010;112(1–2):90–98.CrossRefGoogle Scholar
  49. 49.
    Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med. 2015;49(4):493–501.CrossRefGoogle Scholar
  50. 50.
    Darnall BD, Stacey BR, Chou R. Medical and psychological risks and consequences of long-term opioid therapy in women. Pain Med. 2012;13(9):1181–1211.CrossRefGoogle Scholar
  51. 51.
    Guina J, Rossetter SR, De RB, Nahhas RW, Welton RS. Benzodiazepines for PTSD: A Systematic Review and Meta-Analysis. J Psychiatr Pract. 2015;21(4):281–303.CrossRefGoogle Scholar
  52. 52.
    Nielsen S, Lintzeris N, Bruno R, et al. Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization. Pain Med. 2015;16(2):356–366.CrossRefGoogle Scholar
  53. 53.
    Dominick KL, Bosworth HB, Dudley TK, Waters SJ, Campbell LC, Keefe FJ. Patterns of opioid analgesic prescription among patients with osteoarthritis. J Pain Palliat Care Pharmacother. 2004;18(1):31–46.CrossRefGoogle Scholar
  54. 54.
    Meghani SH, Byun E, Gallagher RM. Time to take stock: a meta-analysis and systematic review of analgesic treatment disparities for pain in the United States. Pain Med. 2012;13(2):150–174.CrossRefGoogle Scholar
  55. 55.
    Hadlandsmyth K, Mosher H, Vander Weg MW, Lund BC. Decline in Prescription Opioids Attributable to Decreases in Long-Term Use: A Retrospective Study in the Veterans Health Administration 2010-2016. J Gen Intern Med. 2018;33(6):818–824.CrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine (This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply) 2019

Authors and Affiliations

  • Carolyn J. Gibson
    • 1
    • 2
    Email author
  • Yongmei Li
    • 1
  • Alison J. Huang
    • 2
  • Tessa Rife
    • 1
    • 2
  • Karen H. Seal
    • 1
    • 2
  1. 1.San Francisco VA Health Care SystemSan FranciscoUSA
  2. 2.University of California, San FranciscoSan FranciscoUSA

Personalised recommendations