Comprehensive systematic review of long-term opioids in women with chronic noncancer pain and associated reproductive dysfunction (hypothalamic–pituitary–gonadal axis disruption)

A comprehensive systematic literature review of reproductive side effects in women aged 18 to 55 years treated with opioids for 1 month or longer for chronic noncancer pain. A search of 7 databases including EMBASE and Medline was undertaken (October 2014 and a limited rerun April 2016). The search contained key words for opioids (generic and specific drug names) and side effects (generic and specific reproductive). Titles were screened using predefined criteria by a single reviewer and abstracts and full texts by 2 independent reviewers. A total of 10,684 articles were identified and 12 full texts (cohort [n = 1], case–control [n = 4], cross-sectional [n = 4], case series [n = 1], and case report [n = 2] with a maximum of 41 cases in 1 article) were included covering 3 different modes of administration: oral (n = 6), intrathecal (n = 5), and transdermal (n = 1). Amenorrhoea occurred in 23% to 71% of those receiving oral or intrathecal opioids. Decreased libido was seen in 61% to 100%. Of the 10 studies that undertook hormonal assays, only 2 studies showed a statistically significant decrease in hormone levels. This review supports the view that there is a potential relationship between the use of long-term opioids in women and reproductive side effects. The evidence is however weak and the mode of administration, duration, type, and dose of opioid might influence associations. Although hormone levels were statistically significant in only 2 studies, women exhibited clinically important symptoms (decreased libido and altered menstrual cycle). Further investigation is required with larger cohorts and analysis of different delivery methods.