Nociceptive pelvic pain

Nociceptive pain occurs in response to a noxious stimulus that initiates the nociceptive pathway. The clinical characteristics of visceral pelvic pain include that it is not always linked to injury and thus may be functional; it frequently results in somatic referral of pain, possibly because of central convergence of visceral and somatic afferents; it tends to be diffuse or poorly localised, probably because of the low concentration of nociceptive afferents within viscera⁽Reference Cervero and Laird¹⁴⁾.

Many nociceptors in viscera are silent nociceptors that do not normally respond to intense mechanical or thermal stimuli, but when there is inflammation of the surrounding tissue they become sensitised and respond to several stimuli⁽Reference Gebhart¹⁵⁾. Moreover, the severity of visceral pain does not always reflect the severity of the pain-generating condition, in acute and also chronic visceral pelvic pain⁽Reference Gebhart¹⁵⁾.

The nerves that function as nociceptors are primarily C and Aδ fibres⁽Reference Howard¹³⁾.

There is clear evidence that mechanisms of nociceptive pain are implied in CPP and that peripheral and central sensitisation leads to abnormal perception of both painful and non-painful stimuli contributing to visceral hyperalgesia and allodynia⁽Reference Howard¹³⁾. Temporal and spatial summation of pain stimuli is also thought to be important in the development of hyperalgesia at the site of an irritated organ that develops as a result of enhanced excitability of respective neuronal soma within the dorsal root ganglia⁽Reference Buéno, Fioramonti and Garcia-Villar¹⁶⁾.

The major evidence for nociceptive pelvic pain as a trigger mechanism for CPP is represented by endometriosis and comes from clinical trials of laparoscopic surgical ablation or excision of endometriotic lesions⁽Reference Abbott, Hawe and Hunter¹⁷⁾. In this context it is important to recognise that there was incomplete relief of pain after surgical treatment of endometriosis and that many women continued to have some degree of pelvic pain⁽Reference Howard¹³⁾.

Inflammatory pelvic pain

Inflammatory pain is due to the response to tissue injury and the resulting inflammatory process; it may be a normal pain, but in some cases it becomes chronic or persistent and represents a pathological pain mechanism⁽Reference Howard¹³⁾. The most frequent pelvic cause of the CPP-related inflammatory process is endometriosis⁽Reference Whiteside and Falcone¹⁸⁾.

Some research has confirmed that endometriotic implants develop a sensory and sympathetic nerve supply both in rats and in humans⁽Reference Sharpe-Timms^19, Reference Berkley, Rapkin and Papka²⁰⁾. The nerve invasion by means of perineural and endoneural invasion, as well as the presence of degranulating mast cells near nerve structures, could be responsible for the inflammatory pain and hyperalgesia⁽Reference Kyama, Mihalyi and Simsa²¹⁾. After tissue damage, a variety of immune mediators are released, which exert algesic actions by acting directly on nociceptors, or indirectly via the release of other mediators, most notably prostanoids⁽Reference Thacker, Clark and Marchand²²⁾.

There is increasing knowledge of the intracellular cascades that are activated in nociceptors by mediators such as TNF-α, IL-1β, IL-6, NO, nerve growth factor (NGF) and cyclo-oxygenase (COX)-2, which ultimately either activate or sensitise these neurons⁽Reference Thacker, Clark and Marchand²²⁾.

Mast cells, residing in the nerve, are the first cells to be activated and contribute to the recruitment of neutrophils and macrophages. In the setting of inflammation, mast cells degranulate and release their inflammatory mediators and may activate or sensitise primary nociceptive neurons⁽Reference Thacker, Clark and Marchand²²⁾. These initial events promote the recruitment of T-cells, which reinforce and maintain inflammatory reactions.

Deregulation of neural transmission appears be produced by neurotransmitters, neuromodulators, neuropeptide hormones or paracrine regulators including the neuroendocrine system cells stained with specific immunohistochemical markers such as neuron-specific enolase, synaptophysin, chromogranin A and cytokeratin⁽Reference Lai, Lü and Xing²³⁾.

In modulation of acute inflammation, monocyte chemotactic protein 1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) appears to be at least one of the factors responsible for this increase of activated macrophages, stimulating macrophages to secrete growth factors and cytokines, increasing levels of many inflammatory cytokines⁽Reference Arici, Oral and Attar²⁴⁾.

After peripheral nerve injury, the site of damage is typified by the activation of resident immune cells, and recruitment and proliferation of non-neuronal elements, which release factors (for example, TNF-α, IL-1, IL-6, C-chemokine ligand 2, histamine, PGE₂ and NGF) that initiate and maintain sensory abnormalities after injury. These factors may either induce activity in axons or are transported retrogradely to cell bodies in the dorsal root ganglia, where they may alter gene expression of the neurons⁽Reference Thacker, Clark and Marchand²²⁾.

TNF-α is a cytokine that has an essential role in inflammatory process and in CPP. As well documented, TNF-α stimulates the expression of PG synthase-2, which in turn increases the production of PGE₂ and PGF_2α, an indirect mechanism by which TNF-α may cause inflammatory pain⁽Reference Sommer and Kress²⁵⁾.

Between them, IL-1, IL-6 and IL-8 have many biological functions such as inducing the synthesis of inflammatory prostaglandins and promoting fibroblast proliferation, collagen deposition and fibrinogen formation, which can contribute to the pathophysiology of chronic painful symptoms⁽Reference Wu and Ho²⁶⁾.

Recent evidence has revealed that NGF, a cytokine produced by Schwann cells, keratinocytes, fibroblasts, T lymphocytes and macrophages, regulated by oestrogen and progesterone, involved in the extension and maintenance of sympathetic and primary sensory nerves, is greater expressed in pelvic symptomatic endometriotic lesions⁽Reference Anaf, Simon and El Nakadi²⁷⁾. NGF promotes sprouting of nociceptors, increases the number of sensory neurons, and is known to contribute to persistent inflammatory and also neuropathic pain. NGF induces the expression of substance P and calcitonin gene-related peptide, which are neuropeptides involved in the modulation of central pain transmission⁽Reference Anaf, Simon and El Nakadi²⁷⁾.

In the peritoneal fluid of women with CPP elevated levels of prostaglandins have been found, especially PGE₂ and PGF_2α. These prostaglandins are mediators of inflammation, as well as direct generators of pain, activating nerve endings to pain, and trigger the release of other algesic mediators, such as serotonin and histamine from other cells and afferent nerves⁽Reference Matsuzaki, Canis and Pouly²⁸⁾.

The increase of PGE₂ is due to the up-regulation of COX-2. This is the rate-limiting enzyme that catalyses the initial step in the formation of prostaglandins from arachidonic acid. COX-2 expression is induced by a number of inflammatory, mitogenic and physical stimuli and is stimulated by oestradiol⁽Reference Lousse, Defrère and Colette²⁹⁾. So, a positive feedback loop appears to be present in women with endometriosis-related painful symptoms that supports the continuous formation of oestradiol and PGE₂.

Neuropathic pelvic pain

Neuropathic pain is usually accompanied by nerve injury or prolonged neuronal pressure but, additionally, the activation of cells involved in the immune response may contribute indirectly to the development of CPP and frequently leads to a chronic pain state by neural plasticity and central sensitisation⁽Reference Howard³⁰⁾. Also, visceral cross-sensitisation is believed to be due to increased, persistent nociceptive input from inflamed reproductive system organs that sensitise neurons, that receive input not only from the inflamed reproductive organs, but also from unaffected visceral organs by a phenomenon called convergent input⁽Reference Rudick, Chen and Mongiu³¹⁾.

Moreover, the nociceptive memory manifests itself most prominently as post-injury sensitisation; that is, after tissue damage, pain that results from subsequent stimulation is exaggerated and prolonged and can be initiated by low-intensity stimuli.

Atwal et al. studied nerve fibre concentration, microneuroma formation and perivascular nerve proliferation within the lower segment of the uterus and found that changes observed in innervation of the endometrium were much more prominent in uteri from women with endometriosis and with CPP than from women without either⁽Reference Atwal, du Plessis and Armstrong³²⁾.

Chronic pelvic pain and oxidative stress

Reactive oxygen species are a double-edged sword; they serve as key signal molecules in physiological processes, but also they have a role in pathological processes involving the reproductive tract⁽Reference Agarwal, Gupta and Sharma³³⁾.

Given the limited data and complex environment of the peritoneal cavity, it is unclear when and why oxidative stress may occur in relation to CPP. In addition, circulating levels of oxidative stress due to other causes such as persistent organic compounds and exposure to environmental toxicants, for example, 2,3,7,8-tetrachlorodibenzo-p-dioxin and heavy metals, may further induce symptomatic pelvic diseases.

It has been suggested that in women with endometriosis-related CPP there is an increased peritoneal level of lipid peroxidation markers and their by-products in a macrophage-rich inflammatory milieu. This finding is associated with an altered expression of pro-oxidants and a drop in antioxidant levels, with alterations in free radical detoxification pathways, consequentially⁽Reference Szczepanska, Kozlik and Skrzypczak³⁴⁾.

As a potential inducer of NF-κB, which activates genes involved in cell adhesion, secretion of inflammatory cytokines, and recruitment of macrophages, oxidative stress may help to trigger the chain of events that leads to the development of symptomatic pelvic diseases⁽Reference King, Critchley and Kelly³⁵⁾.

Oxidative stress induces a cytotoxic effect by peroxidation of membrane phospholipids, increased cell membrane permeability, loss of membrane integrity, enzyme activation, structural damage to DNA and cell death⁽Reference Evans, Dizdaroglu and Cooke³⁶⁾. The presence of activated macrophages and LDL together may lead to oxidation. Increased number and activity of polymorphonuclear leucocytes and oxidative stress-induced macrophages lead to an increased production of reactive oxygen species with higher levels of lipid peroxide accompanied by the release of more cytokines and other immune mediators, such as NO⁽Reference Giudice and Kao³⁷⁾.

Various cytokines released by abnormal immune responses might stimulate macrophages and/or endometrial cells to persistently produce a large amount of NO⁽Reference Ota, Igarashi and Hatazawa³⁸⁾.

Peritoneal macrophages express higher levels of the inducible NO synthase isoform, persistently marked throughout the menstrual cycle, in contrast to cyclic variations in healthy subjects, and produce more NO in response to immune stimulation in vitro ⁽Reference Osborn, Haney and Misukonis³⁹⁾. NO is a free radical initially implicated in low-grade inflammation, while elevated peritoneal NO levels are consistent with the increased number and activity of macrophages⁽Reference Dong, Shi and Cheng⁴⁰⁾.

Elevated levels of the marker of lipid peroxidation lysophophatidyl choline, a potent chemotactic factor for monocytes/T-lymphocytes, were seen in the peritoneal fluid of women with endometriosis⁽Reference Matsuzaki, Canis and Pouly²⁸⁾. Non-terminal oxidation may have a role in the pathophysiology of endometriosis. Minimally oxidised LDL is present in the peritoneal fluid of women with endometriosis in place of the terminally oxidised LDL⁽Reference Shanti, Santanam and Morales^41, Reference Foyouzi, Berkkanoglu and Arici⁴²⁾. The ratio of lysophosphatidyl choline, a breakdown product of oxidised-LDL, to phosphatidyl choline suggests minimally oxidised LDL rather than oxidised LDL.

Retrograde menstruation is likely to carry highly pro-oxidant factors into the peritoneal cavity. In addition, it is likely that damaged blood cells releasing metal ions as well as haeme and Fe, cell debris transplanted into the peritoneal cavity by menstrual reflux, and apoptotic endometrial cells would provide an ideal target for the recruitment of peritoneal fluid monocytes⁽Reference Kobayashi, Yamada and Kanayama⁴³⁾.

On the other hand, expression of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase) and non-enzymic antioxidants (taurine, vitamin C, vitamin E) appears to be reduced in the peritoneal fluid of patients with developing CPP compared with fertile symptom-free control women⁽Reference Matsuzaki, Canis and Pouly²⁸⁾. These enzymes play an important role in converting reactive oxygen species to water to prevent overproduction of reactive oxygen species, and in the breakdown of free radicals. Thereby, antioxidants might prevent the pathological effects of oxidative stress that are exerted by various mechanisms.

Conventional treatments

Given the complexity and not well-understood aetiology of CPP, its treatment is often unsatisfactory and limited to partial symptom relief.

Currently, the main approaches to treatment include counselling supported by reassuring ultrasound scanning or psychotherapy, attempting to provide reassurance using laparoscopy to exclude serious pelvic pathology, hormonal therapy, and neuroablative treatment to interrupt nerve pathways⁽Reference Gambone, Mittman and Munro⁴⁴⁾.

The treatment of CPP can focus on treating with medical or surgical interventions the underlying disease that might be a cause or a contributor to CPP, or on treating the pain itself, or on both⁽Reference Howard⁴⁵⁾.

Different pharmacological profiles and mechanisms to interrupt or decrease the transmission of pain information might be beneficial to decrease pain.

Clinical experience suggests that non-narcotic analgesics, including acetaminophen, acetylsalicylic acid and non-steroidal anti-inflammatory drugs are the first-line therapy for pain relief treating neural and biochemical pathways of CPP⁽Reference Gambone, Mittman and Munro⁴⁴⁾. The potential of side effects with analgesic drugs, especially with chronic use, are significant, and careful observation is important.

Only after all other reasonable attempts at pain control have failed and when persistent pain is the major impediment to improved function, tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, and, as a last resort, opioids for CPP should be considered⁽Reference Howard⁴⁵⁾. Opioids are the major category of analgesics with central activity used for chronic pain, whereas their use is controversial.

However, in a Cochrane analysis of treatments for CPP, only progestogen therapy such as medroxyprogesterone acetate (50 mg once daily) and lysis of severe deep adhesions were found to be associated with an improved outcome⁽Reference Stones and Mountfield⁴⁶⁾.

Finally, a recent pilot study proposed the combination of palmitoylethanolamide and polydatin as a support for medical therapies to treat CPP associated with endometriosis to obtain pain relief and a reduction in the analgesic drugs usually employed for the control of pain⁽Reference Indraccolo and Barbieri⁴⁷⁾. It has been reported that palmitoylethanolamide and its derivates play a role in controlling inflammation associated with mast cell activation, whereas polydatin is a resveratrol with well-known antioxidant and anti-chemotactic activities, as well as a regulator of aspecific leucocyte activation⁽Reference Facci, Dal Toso and Romanello^48, Reference Zhao, Jin and Huang⁴⁹⁾.

Dietary therapy

On account that potential benefit of medical therapy must be balanced against potential risk, dietary supplementation has been suggested to treat chronic medical illnesses that are poorly responsive to prescription drugs or in which therapeutic options are limited, costly or carry a high side effect profile⁽Reference Herbert⁵⁰⁾.

Over the past decade, many studies have provided evidence that higher intakes of fruit and vegetables, rich in antioxidants, among other micronutrients, improve the function of the immune system and fight free radical damage⁽Reference Parazzini, Chiaffarino and Surace⁵¹⁾.

In the USA, dietary supplements are currently governed by the Food and Drug Administration under the Dietary Supplement Health and Education Act. The act defines a supplement as ‘a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following: a vitamin, mineral, herb or other botanical, amino acid, a dietary substance used by man to supplement the diet by increasing the total dietary intake or a concentrate, metabolite, constituent, extract or combination of any of the ingredients described above’⁽⁵²⁾. Unfortunately, there is a deficit of well-designed, randomised, controlled trials to evaluate the efficacy and safety of complementary dietary therapy to manage CPP.

There is clear evidence for the effectiveness of n-3 fatty acids, vitamin E, vitamin B₁, vitamin B₃ and Mg in pain relief and the need for less additional medication in cyclic pelvic pain by a decreased release of prostaglandins, primarily PGE₂ and PGF_2α, which cause inflammation, pain and spastic uterine contractions⁽Reference Proctor and Murphy^53, Reference Barnard, Scialli and Hurlock⁵⁴⁾.

Inhibitors of COX enzyme function, such as vitamins and n-3 fatty acids, can block prostaglandins and thromboxane A₂ biosynthesis released from plasma membrane phospholipids by phospholipase A₂ and subsequent downstream events⁽Reference Ziaei, Zakeri and Kazemnejad⁵⁵⁾. Moreover, oestrogen and progesterone withdrawal leads to the stimulation of PGF_2α production via reactive oxygen species-induced NF-κB activation⁽Reference King, Critchley and Kelly³⁵⁾.

So, manipulation of dietary PUFA composition demonstrably affects the pro-inflammatory activities of many cell types involved in the immune response and inflammatory reactions⁽Reference Kidd⁵⁶⁾.

PUFA supplementation has important effects on the synthesis and biological activity of prostaglandins and cytokines such as IL-1, IL-2, IL-6, TNF and interferon, and might be useful in the management of chronic painful symptoms by reducing the inflammatory response and modulating cytokine network⁽Reference Halliwell and Gutteridge⁵⁷⁾.

In the dynamic structures of the cell membrane, the intrinsic structural synergy via ester bonds of fatty acids such as DHA and EPA, phospholipids and antioxidants in the ‘triple cell membrane synergy’ steadies and increases membrane fluidity, improving its biochemical performance⁽Reference Alberts, Johnson and Lewis⁵⁸⁾.

Healthy, non-inflammatory eicosanoid balance is maintained throughout the body by way of a homeostatic balance between n-3 and n-6 fatty acids in cell membranes. Table 1 shows n-6:n-3 fatty acid ratios in food.

Table 1 Food n-3:n-6 fatty acid ratios

In the presence of high n-6:n-3 PUFA ratios of dietary intake, biosynthesis of their metabolites steadies a prominent production of 2-series prostaglandins (PGE₂, PGF_2α), thromboxane A₂ and 4-series leucotrienes, which also are involved in the pathogenesis of pelvic pain, in contrast to high n-3:n-6 PUFA ratios⁽Reference Kidd⁵⁶⁾.

In addition, PGE₂ is thought to be a potent inducer of aromatase activity in endometriotic stromal cells. Of note, peritoneal macrophages from women with CPP release significantly more prostaglandins.

Likewise, Mg inhibits the biosynthesis of PGF_2α, as well as having a role in myometrial relaxation and vasodilatation, and vitamin B₆ is involved in the production of PGE₂.

Moreover, a diet based on vitamin B, vegetables, fibres and antioxidants decreases oestrogenic state-related body fat excess implicated in the oestrogen-dependent growth of endometriotic tissue⁽Reference Kidd⁵⁶⁾.

In actual fact, dietary supplementation induces enzymes of oestradiol metabolism such as the up-regulation of 17-β-hydroxysteroid dehydrogenase (types 1 and 7) and sulfatase; the subsequent defective formation and metabolism of steroid hormones are responsible for the promotion and development of endometriosis⁽Reference Harel, Biro and Kottenhahn⁵⁹⁾.

It may be supposed that nutritional intake has significant influence whenever there is an imbalance between the production of reactive oxygen species and aberrant expression of antioxidant systems, improving painful symptoms, without undesired effects and any important metabolic changes associated with hormonal therapy⁽Reference Barnard, Scialli and Hurlock^54–Reference Harel, Biro and Kottenhahn⁵⁹⁾.

In this context, α-tocopherol is considered to be the most important vitamin which prevents the peroxidation of PUFA⁽Reference Dennehy⁶⁰⁾. The mechanism of vitamin E involves endogenous arachidonic acid release and its conversion to prostaglandins by affecting phospholipase A₂ and COX. Activation of phospholipase A₂ is considered to be regulated by protein kinase C and the increase in the concentration of intracellular Ca. Vitamin E was found to inhibit protein kinase C in the bovine brain⁽Reference Dennehy⁶⁰⁾. It should be used cautiously in women who are on anticoagulants because vitamin E can have antiplatelet properties and daily intake should be limited to 400 IU or less⁽Reference Dennehy^60, Reference Ziaei, Faghihzadeh and Sohrabvand⁶¹⁾. Vitamin E is available as a synthetic (d-I-α-tocopherol, also referred to as α-tocopherol or SRR-tocopherol) formulation. The natural formulation is more bioavailable and, thus, greater in potency by a ratio of 1·36 to 2:1⁽Reference Ford, Ajani and Mokdad⁶²⁾. Moreover, 400 IU of natural vitamin E is not equivalent to 400 IU of synthetic vitamin E.

At present, only one randomised controlled trial has been designed to evaluate the effectiveness for the outcomes of chronic painful symptoms and quality of life of dietary therapy compared with hormonal suppression treatment or placebo after conservative surgery for symptomatic endometriosis stage III–IV (Revised American Fertility Society (r-AFS) classification)⁽Reference Sesti, Pietropolli and Capozzolo⁶³⁾. A total of 222 consecutive women who underwent conservative pelvic surgery were initially randomised to receive a placebo, treatment only as a control, or a post-operative adjunctive hormonal therapy with gonadotrophin-releasing hormone analogue (GnRH-a) or with continuous low-dose monophasic oral contraceptive or dietary therapy for 6 months. Dietary therapy was a protocol consisting of nutritional intake in addition to vitamins (vitamins B₆, A, C, E), mineral salts (Ca, Mg, Se, Zn, Fe), VSL3 lactic ferments (a compound containing Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. casei, L. bulgaricus and Steptococcus thermophilus), and fish oil, giving an energy intake between 1600 and 2000 kcal (6690 and 8370 kJ). The post-operative hormonal suppression therapy and nutritional supplementation groups had less CPP than the control group at 12 months' follow-up (P < 0·001). As to the outcome of control pain in the patients treated with dietary supplementation, compared with post-operative hormonal therapy, both therapies were similarly effective in reducing painful symptoms.

So, agents with antioxidant activity are able to improve endometriosis-related symptoms, without undesired prolonged hypo-oestrogenism state effects and any important metabolic change of hormonal suppression therapy.

Moreover, a recent study suggests that specific types of dietary fat such as trans-unsaturated fat are associated with the incidence of laparoscopically confirmed endometriosis, and that these relationships may indicate modifiable risk⁽Reference Missmer, Chavarro and Malspeis⁶⁴⁾. This evidence additionally provides another disease association that supports efforts to remove trans-fat from hydrogenated oils from the food supply.

Sesti et al. provide evidence that post-operative hormonal and dietary therapies were the most effective treatment, not only in terms of painful symptoms control, but also in terms of general health perception and vitality, when compared with post-operative placebo administration⁽Reference Sesti, Pietropolli and Capozzolo⁶³⁾. Conversely, the same authors showed that a 6-month course of dietary therapy or hormonal suppression treatment after laparoscopic cystectomy had no significant effect on the recurrence rate of ovarian endometriosis when compared with surgery plus placebo⁽Reference Sesti, Capozzolo and Pietropolli⁶⁵⁾. Further randomised trials with larger series and long-term follow-up to confirm these observations are needed.