Stella Iacovides

Reduced quality of life when experiencing menstrual pain in women with primary dysmenorrhea

Primary dysmenorrhea is the most common gynecological condition among women of reproductive age. Although dysmenorrhea has been reported to affect the ability of women to carry out daily activities, the impact of primary dysmenorrheic pain specifically on quality of life (QoL), has yet to be elucidated. We investigated whether QoL varies between women with and without severe primary dysmenorrhea, and whether QoL is impaired only during menstruation or also during pain‐free phases of the menstrual cycle. Twelve women with severe primary dysmenorrhea and nine control women completed the quality of life enjoyment and satisfaction questionnaire (Q‐LES‐Q‐SF) during menstruation and during the late follicular phase. Women with dysmenorrhea had a significant reduction in Q‐LES‐Q‐SF scores (mean ± SD: 54 ± 18%, percentage of the total maximum possible score) when they were experiencing severe menstrual pain compared with their own pain‐free follicular phase (80 ± 14%, p < 0.0001) and compared with controls during menstruation (81 ± 10%, p < 0.0001). They also rated their overall life satisfaction and contentment as poorer during menstruation. Severe menstrual pain associated with primary dysmenorrhea, therefore, impacts health‐related of QoL.

Does pain vary across the menstrual cycle? A review.

Reproductive hormones are implicated in moderating pain. Animal studies support both pronociceptive and antinociceptive actions of oestradiol and progesterone suggesting that the net effect of these hormones on pain is complex and likely depends on the interaction between hormones and the extent of fluctuation rather than absolute hormone levels. Several clinical pain conditions show variation in symptom severity across the menstrual cycle. Though, there is still no consensus on whether the menstrual cycle influences experimental pain sensitivity in healthy individuals. Comprehensive literature searches on clinical and experimental pain across the menstrual cycle, as well as gonadal hormones and pain were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full‐text manuscripts were reviewed for relevancy and reference lists were cross‐checked for additional relevant studies. Most of the more recent, well‐controlled studies show that menstrual cycle phase has no effect on the perception of pain in healthy, pain‐free women. Although recent studies investigating pain‐related brain activation have shown differential activation patterns across the menstrual cycle in regions involved with cognitive and motor function, even in the absence of a behavioural pain response, suggesting that cognitive pain and bodily awareness systems are sensitive to menstrual cycle phase. The interaction between the gonadal hormones and pain perception is intricate and not entirely understood. We suggest further investigations on the association between female reproductive hormones and pain sensitivity by exploring the interaction between clinical and experimental pain and the hormone changes that characterize puberty, post‐partum and the menopause transition.

Women with dysmenorrhea are hypersensitive to experimental deep muscle pain across the menstrual cycle.

UNLABELLED Primary dysmenorrhea is a common painful condition in women that recurs every month across the reproductive years. The recurrent nociceptive input into the central nervous system that occurs during menstruation each month in women with dysmenorrhea is hypothesized to lead to increased sensitivity to painful stimuli. We investigated whether women with primary dysmenorrhea are hyperalgesic to deep muscle pain induced by a cleanly nociceptive method of hypertonic saline injection. Pain stimulation was applied both within an area of referred menstrual pain (lower back) and at a remote site outside of referred menstrual pain (forearm) in 12 healthy women with severe dysmenorrhea and 9 healthy women without dysmenorrhea, at 3 phases of the menstrual cycle: menstruation and follicular and luteal phases. Women rated their pain severity on a 100-mm visual analog scale every 30 seconds after injection until the pain subsided. In both groups of women, menstrual cycle phase had no effect on the reported intensity and duration of muscle pain. However, women with dysmenorrhea had increased sensitivity to experimental muscle pain both at the site of referred pain and at a remote nonpainful site, as assessed by peak pain severity visual analog scale rating, area under the visual analog scale curve, and pain duration, compared to women without dysmenorrhea. These data show that women with severe primary dysmenorrhea, who experience monthly menstrual pain, are hyperalgesic to deep muscle pain compared to women without dysmenorrhea. PERSPECTIVE Our findings that dysmenorrheic women are hyperalgesic to a clinically relevant, deep muscle pain in areas within and outside of referred menstrual pain indicates lasting changes in pain sensitivity outside of the painful period during menstruation.

Women with dysmenorrhoea are hypersensitive to experimentally induced forearm ischaemia during painful menstruation and during the pain-free follicular phase.

Monthly primary dysmenorrhoeic pain is associated with increased sensitivity to painful stimuli, particularly in deep tissue. We investigated whether women with dysmenorrhoea, compared with controls, have increased sensitivity to experimentally induced deep‐tissue muscle ischaemia in a body area distant from that of referred menstrual pain.

Sleep Fragmentation Hypersensitizes Healthy Young Women to Deep and Superficial Experimental Pain

The effect of sleep deprivation on pain sensitivity has typically been studied using total and partial sleep deprivation protocols. These protocols do not mimic the fragmented pattern of sleep disruption usually observed in individuals with clinical pain conditions. Therefore, we conducted a controlled experiment to investigate the effect of sleep fragmentation on pain perception (deep pain: forearm muscle ischemia, and superficial pain: graded pin pricks applied to the skin) in 11 healthy young women after 2 consecutive nights of sleep fragmentation, compared with a normal night of sleep. Compared with normal sleep, sleep fragmentation resulted in significantly poorer sleep quality, morning vigilance, and global mood. Pin prick threshold decreased significantly (increased sensitivity), as did habituation to ischemic muscle pain (increased sensitivity), over the course of the 2 nights of sleep fragmentation compared with the night of normal sleep. Sleep fragmentation did not increase the maximum pain intensity reported during muscle ischemia (no increase in gain), and nor did it increase the number of spontaneous pains reported by participants. Our data show that sleep fragmentation in healthy, young, pain-free women increases pain sensitivity in superficial and deep tissues, indicating a role for sleep disruption, through sleep fragmentation, in modulating pain perception. PERSPECTIVE Our findings that pain-free, young women develop hyperalgesia to superficial and deep muscle pain after short-term sleep disruption highlight the need for effective sleep management strategies in patients with pain. Findings also suggest the possibility that short-term sleep disruption associated with recurrent acute pain could contribute to increased risk for future chronic pain conditions.

Sleep in Women with Chronic Pain and Autoimmune Conditions: A Narrative Review

Chronic pain and sleep disturbances are intricately intertwined. This narrative review provides comments on observations related to pain, stress-immunity, and sleep. Sleep evidence is reviewed from studies of select conditions involving pain (ie, functional somatic syndromes and autoimmune) that are predominant in women. Chronic pain and poor sleep encompass persistent stress-immune activation with systemic inflammation, cellular oxidative stress, and sick behavior indicators that increase morbidity and threaten quality of life. In painful conditions, sleep impairments are nearly ubiquitous, and exaggerated combined effects should not be underestimated or ignored, nor should crucial implications for clinical practice and research.

Reply: LNG-IUDs in treating dysmenorrhea

Sir, We appreciate Dr Wildemeersch’s interest in our review and comments about the potential effectiveness of hormonal intrauterine technology in treating primary and secondary dysmenorrhea. Non-steroidal antiinflammatory drugs (NSAIDs) are the most common treatment for dysmenorrhea and are given more extensive coverage in our review (Iacovides et al., 2015). We would like to take this opportunity to extend Dr Wildemeersch’s discussion about the use of intrauterine devices (IUDs) as a treatment strategy for dysmenorrhea. The levonorgestrel-releasing IUD (LNG-IUD) is an effective contraceptive option in women and usage rates are increasing, although usage is still relatively low in women under the age of 20 years (Ott et al., 2014); the age-group in which primary dysmenorrhea is common. More recently, smaller framed (28 × 30 mm) LNG-IUDs (LNG 13.5 mg) have become available (http://www.medicines.org.uk/ emc/medicine/28672/SPC/Jaydess+13.5+mg+intrauterine+delivery+ system. Accessed on 5/10/2015), thereby creating the opportunity for increased use of intrauterine technology in nulliparous women and adolescents. Insertion of a smaller IUD may be easier for these groups of women, who have smaller uterine dimensions compared with parous women. The frameless LNG-IUDs are promising for similar reasons, as highlighted by Dr Wildemeersch. However, it should be noted that recent published data showed that most insertions of a standard-size framed IUD(LNG52 mg, size 32 × 32 mm) were uneventful innulliparous adult women with small uterine measures (Kaislasuo et al., 2014) and a smaller uterine cavity size predicted less bleeding and pain during use compared with adult women with larger uterine cavity measurements (Kaislasuo et al., 2015). The LNG-IUD has well-established non-contraceptive benefits, including reduction of severe dysmenorrhea and/or heavy menstrual bleeding associated with endometriosis, adenomyosis, and chronic pelvic pain (Bahamondes et al., 2007). The reduction in menstrual pain is thought to be due to the effects of LNG on the endometrium leading to oligomenorrhea and amenorrhea, as well as inhibition of inflammatory mediators present in the peritoneum (Bahamondes et al., 2007). However, the pain-reducing benefit of the LNG-IUD may not be immediately evident, and is influenced by dysmenorrheic pain severity at baseline: women with dysmenorrhea are more likely to experience greater pain when inserting (Kaislasuo et al., 2014) and when using a LNG-IUD during the first 3 months of use (Kaislasuo et al., 2015). Given the evidence that women with dysmenorrhea are hypersensitive to experimental pain (Iacovides et al., 2015), they may also be hypersensitive to the pain of IUD insertion and the initial uterine irritation. Lack of immediate relief of menstrual pain in some women may also explain why pre-existing dysmenorrhea predicts removal of an IUD 1 year later (Maguire et al., 2015). Self-reported bleeding and cramping are associated with lower user satisfaction with the LNG-IUD, however, the majority of women (.90%) are satisfied with their device at 6 months (Diedrich et al., 2015). Further study is needed to follow up on associations between dysmenorrhea and IUD use so that women can be adequately counseled on what to expect. As with any treatment, side effects need to be considered; LNG-IUD use in women is associated with increased risk of acne, headache, migraine and mental side effects (http://www.medicines.org.uk/emc/ medicine/28672/SPC/Jaydess+13.5+mg+intrauterine+delivery+system. Accessed on 5/10/2015). For women who are seeking contraception in addition to menstrual pain relief, intrauterine devices as well as oral contraceptives, are good options. Short-term use (i.e. only during painful menstruation) of NSAIDs should not be excluded as an effective means of pain relief, particularly for nulliparous women not seeking contraception, and particularly since gastrointestinal side effects associated with NSAID use are of less concern with acute, rather than chronic, use (Iacovides et al., 2015). As commented by Dr Wildemeersch, current research on the effectiveness of intrauterine technology in alleviating dysmenorrhea is promising although we await collection of further data to confirm the efficacy of the new smaller framed and frameless LNG-IUDs in the long-term alleviation of dysmenorrhea in different populations, including adolescents, considering primary versus secondary dysmenorrhea. Finally, looking ahead to potential alternative treatments that are currently under development, we note the recent publication showing, for the first time, efficacy of PDC31 (prostaglandin F2a receptor inhibitor) in decreasing uterine activity and alleviating pain in primary dysmenorrhea (Böttcher et al., 2014). Having more options available to women for treating dysmenorrhea is optimal and will improve management of this very common gynecological disorder.