Management
The treatment of CPP should be patient orientated and individualized for each patient.
Medical treatment
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase (COX-1 and COX-2) and impeding the production of prostaglandins and thromboxane, which are involved in the pain pathway.
NSAIDs have been proven to be effective in randomized control trials for treatment of primary dysmenorrhea (32). NSAIDs are widely used by many physicians as the first-line treatment for CPP.Oral contraceptive pills
Combined oral contraceptive pills (OCPs) work by inhibiting ovulation by suppressing the release of gonadotrophins. Many studies have shown that they are effective in the treatment of dysmenorrhea. However, there is limited evidence to suggest that it is effective in treating CPP. So far, there is only one RCT which reported on the efficacy of a low-dose OCP for CPP and endometriosis (33). In this study, a 6-month trial of low-dose OCPs was compared with gonadotrophin-releasing hormone (GnRH) agonists in treating women with laparoscopically proven endometriosis. OCPs were shown to be of similar efficacy in relieving dyspareunia and non- menstrual pain as a GnRH agonist but was less effective in reducing dysmenorrhea.
A prospective observational trial showed that continuous low- dose OCPs were more effective than cyclical low-dose OCPs in controlling endometriosis symptoms in patients after surgical treatment for endometriosis but further studies are required to confirm this finding (34). In general, OCP is the first- line hormonal treatment for women with cyclical CPP, given that the OCP has a low-risk profile, is relatively inexpensive, and is widely available.
Danazol
Danazol is a synthetic androgen which inhibits ovarian steroidogenesis and release of pituitary gonadotrophins.
A Cochrane review showed that danazol was more effective than placebo in providing pain relief in patients with laparoscopic-confirmed endometriosis and in patients who had not undergone surgery (35). A daily dose of 40O-8OO mg is effective in treating CPP but it should be given for a minimum of 3 months. However, patients should be warned about the common hyperandrogenic side effects including hirsutism, acne, weight gain, and deepening of the voice (36).Progestogens
Progestogens such as medroxyprogesterone acetate (MPA) are useful in those with endometriosis. A previous study showed that MPA depot (150 mg every 3 months) had effects comparable to GnRH agonists in a 12-month trial. Although the benefit was not sustained, MPA in an oral dosage of 50 mg daily was found to be effective in reducing pain scores at the end of the therapy (37). Dienogest (2 mg daily) has also been shown to improve the sexual function and quality of life of patients with endometriosis-related pelvic pain (38).
Mirena, the levonorgestrel-releasing intrauterine system (LNG- IUD), is another commonly used option in treating endometriosis. A Cochrane review in 2013 of three RCTs concluded that there was limited but consistent evidence showing that postoperative LNG- IUD use reduces the recurrence of painful periods in women with endometriosis but further well-designed RCTs are needed to confirm these findings (39).
Gonadotrophin-releasing hormone agonists
GnRH agonists such as goserelin, leuprolide, buserelin, and triptorelin create a hormonal milieu similar to a postmenopausal state by downregulating the pituitary-ovarian axis with subsequent hypo-oestrogenism. It can be administrated as a nasal spray, by injection of a short-acting formulation, or by injection of a depot formulation every 1-3 months. Suppression has been found to be more profound and constant with a monthly depot preparation. Again, most evidence available for GnRH agonists is mostly for endometriosis-related pelvic pain and with comparison to danazol, progestogens, or OCPs.
Empirical use of a GnRH agonist was evaluated by a RCT in 100 women with noncyclical pelvic pain and clinically suspected endometriosis. After 12 weeks of therapy with depot leuprolide acetate (3.75 mg/month), significant reductions in dysmenorrhea, pelvic pain, and tenderness were noted in the treatment group. Endometriosis was visualized at subsequent laparoscopy in 78% of the leuprolide-treated and 87% of the placebo group. Even those patients with no visualized endometriosis responded favourably to treatment with a GnRH agonist (32, 40).A Cochrane review also confirmed that GnRH agonists were more effective than no treatment or placebo in pain relief. There was no difference in pain relief between GnRH agonists and danazol or between GnRH agonist and levonorgestrel. However, there were more adverse effects in the GnRH agonist group when compared with danazol (35). Due to the hypo-oestrogenic state caused by GnRH agonists, side effects including hot flushes, vaginal dryness, decreased libido, mood swings, headaches, and osteoporosis are often reported and may ultimately affect compliance of the treatment.
Add-back therapies with steroidal and non-steroidal agents have been used together with a GnRH agonist to suppress the vasomotor symptoms completely and protect against decreasing bone density without affecting its efficacy in controlling pain relief. Add-back therapy is often considered when prolonged use of GnRH agonists is considered beyond 6 months. A number of RCTs have shown the efficacy of add-back regimens with various GnRH agonists for treatment of endometriosis during 6-month courses. A prospective randomized trial showed that long-term use of a GnRH agonist plus immediate add-back HRT is a safe and acceptable approach to the management of intractable cyclical pelvic pain (41). In this study, women given Zoladex 10.8 mg over 18 months were randomized to receive HRT (tibolone 2.5 mg) either immediately or after 6 months and they were followed up 12 months after treatment.
Bone mineral density at 6 months, the end of treatment (18 months), and 12 months later, pain, and quality of life were measured. Women treated with immediate HRT add-back therapy showed less bone mineral density loss at 6 months and less vasomotor symptoms compared with those who had delayed HRT add-back treatment. Longterm follow-up showed that both groups experienced the same bone mineral density loss. Pain and quality of life also showed improvement in both groups and there was evidence of return to baseline levels after ending treatment.Others
The role of antibiotics is of limited clinical value and they should not be used unless there is good evidence of infection. Antidepressants such as tricyclic antidepressants have been shown to be useful in women with CPP with negative laparoscopy as in the case of other chronic pain syndromes.
Surgery
Adhesions
The role of adhesiolysis in women with CPP associated with adhesions remains controversial. An earlier RCT conducted by Peters et al. suggested adhesiolysis was of benefit (42) while a subsequent RCT by Swank et al. found laparoscopic adhesiolysis was no better than diagnostic laparoscopy (43). In a recently published doubleblinded RCT, which was unfortunately was stopped before a statistically powered sample size was reached, Cheong et al. reported that adhesiolysis performed in women with CPP appeared beneficial in terms of improvement of pain and quality of life (7). Overall, current data suggests that women with CPP and adhesions should be offered surgery to remove the adhesions.
Endometriosis
A Cochrane meta-analysis showed that the improvement of pain after laparoscopic treatment of endometriosis was significantly better in those who only underwent diagnostic laparoscopy. Pain relief was significantly higher in patients with moderate and mild endometriosis than those in minimal diseases (44).
Medical treatment of the endometriomas may lead to a temporary reduction in size of the cysts but not complete resolution and thus surgery is the definitive treatment for large symptomatic endometriomas.
Laparoscopic ovarian cystectomy with the stripping method has been shown to be more effective than fenestration and ablation alone. Laparoscopic ovarian cystectomy with the stripping method was also shown to be associated with greater improvement in dysmenorrhea, deep dyspareunia, and non-menstrual pain. However, the procedure is associated with a significant risk of damaging the ovarian reserve (45). In women who wish to preserve their fertility, haemostasis with the use of FloSeal, a gelatin haemostatic matrix, rather than haemostasis with the use diathermy should be considered (46).Pain transmission
The Lee-Frankenhauser sensory nerve plexuses and parasympathetic ganglia in the uterosacral ligaments carry pain from the uterus
(47). It is believed that laparoscopic Uterosacral nerve ablation (LUNA) can reduce uterine pain by disrupting the efferent nerve fibres in the uterosacral ligament. Daniels et al. performed an individual patient data meta-analysis of randomized trials to assess the effectiveness of LUNA in treating CPP (48). Raw data were available from 862 women in 5 randomized trials. Pain scores were calibrated to a 10-point scale and were analysed using a multilevel model allowing for repeated measures. They found no significant difference in outcome between those who had and those who had not undergone the LUNA procedure. It seems that current evidence does not support the use of the LUNA procedure in women with CPP. However, the international LUNA IPD Meta-analysis Collaborative Group is collecting further raw individual patient data from randomized trials to reassess its effectiveness (47).
Presacral neurectomy (PSN) disrupts the sympathetic pathways from the uterus. Comparison between LUNA and laparoscopic PSN for primary dysmenorrhea showed no difference in pain relief in the short term. However, long-term laparoscopic PSN was shown to be significantly more effective than LUNA. PSN combined with endometriosis treatment appeared to produce better pain relief than endometriosis treatment alone, although data suggested that this may be specific to laparoscopy and for midline abdominal pain only.
In addition, the procedure is not without risks, including haemorrhage from accidental laceration of the middle sacral vein, visceral injury, and disturbance of bladder and bowel function. PSN should not be recommended outside the context of a clinical trial (49).Hysterectomy and oophorectomy
Hysterectomy with or without oophorectomy is sometimes considered in women who have completed childbearing and who experience debilitating painful symptoms. Hysterectomy without oophorectomy is usually less effective, with higher recurrence and subsequent reoperation rates, than hysterectomy and oophorectomy. However, the implications of oophorectomy need to be fully discussed with the patient and the decision should take into consideration the consequences of surgical menopause. A trial of a GnRH agonist may be considered before a final decision is made. Women who respond to GnRH agonist therapy are more likely to benefit from hysterectomy and oophorectomy.
Others
Pelvic venous congestion
MPA at a dose of 50 mg per day has been shown to produce significant pain relief during 4 months of treatment with 73% ofthe women reporting at least 50% benefits. The pain reduction was better if MPA treatment was given along with psychotherapy, which also produced longer-lasting benefit (50). In case medical treatment has failed, surgical treatment with ligation, embolization, or sclerotherapy of the pelvic vessels may be considered.
Psychological
Relaxation therapies, behavioural modification, and cognitive behavioural therapies sometimes improve a patient's perception of pain, coping ability, and promote overall wellness, improving a patient's response to pain management. However, a recent systemic analysis failed to confirm the beneficial role of psychological interventions on self-reported pain scores among women with CPP (51).
Alternative treatment options
When medical or surgical treatment fails, women often seek complementary or alternative treatment options, which may include a wide range of treatment methods such as acupuncture, herbal medicine, hypnotherapy, physiotherapy, osteopathy, or chiropractic.
Chinese herbal medication and acupuncture is popular in the Chinese and Asian populations but there is no evidence to confirm that it is effective.
Chinese herbal medication includes the use of an herbal formula containing several different herbs, consumed in the form of herbal soups, powder, or pills. A Cochrane review showed it had comparable benefits to antiprogestogen gestrione as a postoperative adjuvant therapy after surgery for endometriosis but was associated with less adverse effects. The use of herbal medication was also found to produce significantly greater reduction in dysmenorrhea compared with danazol (52).
Acupuncture involves the insertion of fine needles to specific defined (needle) points over the body surface. The exact mechanism of how it may work is still unknown, although it is likely to act by altering the processing of pain in the brain and spinal cord, promoting release of vascular or immune modulatory factors, releasing adenosine, which help reduce sensitivity to painful stimuli and improve microcirculation, leading to reduction in muscle stiffness and tension. There is preliminary evidence that acupuncture is effective in reducing severity of dysmenorrhea when compared to an untreated group (53). Two small trials included in a Cochrane review suggested that acupuncture was superior to standard NSAIDs in the reduction of menstrual symptoms (54).
However, due to a lack of good-quality clinical trials involving these various complementary alternative medicine treatments, it is not possible to make recommendations other than to consider these treatment options as empirical measures.
Multidisciplinary approach
In women with persistent, unexplained CPP refractory to conventional therapy, a multidisciplinary team approach should be adopted. There is good evidence of benefit in integrating psychological interventions into management of chronic pain syndromes. A multidisciplinary team approach has been shown to be more effective than a single treatment modality for CPP (55, 56). The team, which may be formed ad hoc, may involve a gynaecologist, a surgeon, a radiologist, an anaesthetist, a psychologist, a physiotherapist, and a specialist nurse. In this way, it will hasten the treatment process, improve the patient's confidence, compliance, and in some cases, acceptance at the end that there may not be any miraculous cure for the condition.