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Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

1 Mechanisms of pain in endometriosis

2 Q1 Matteo Morottia,b,* , Katy Vincenta,c, Christian M. Beckera,c
3 a
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
4 b
Hypoxia and Angiogenesis Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford,
5 John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom
6 c
Endometriosis CaRe Centre Oxford, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom

A R T I C L E I N F O A B S T R A C T

Article history:
Received 5 February 2016 Pain is the central symptom in endometriosis and often persists despite treatment of the disease.
Received in revised form 18 June 2016 Multiple mechanisms underlie endometriosis-associated pain including nociception, inflammation, and
Accepted 25 July 2016 alterations in peripheral and central nervous system pain processing. As also occuring in other chronic
Available online xxx conditions, pain in endometriosis is often associated with psychological distress and fatigue, both of
which may amplify pain. It is hoped that in the future methods of phenotyping women on the basis of the
Keywords: underlying pain mechanisms will be developed, likely combining a critical evaluation of clinical
Central nervous system symptoms and signs with laboratory and imaging tests. Optimal pain relief for an individual is more likely
Endometriosis
if her specific contributory pain mechanisms are identified and appropriately addressed. Such methods
Neuroangiogenesis
may also improve the selection of patients for clinical trials, potentially increasing the probability of
Neuroimaging
Pain identifying novel treatments for the many women with endometriosis for whom acceptable analgesia is
not achieved.
ã 2016 Elsevier Ireland Ltd. All rights reserved.

7 Introduction and various coping mechanisms are known to influence pain 24

perception [6]. However, it is plausible that in an individual one 25

8 Endometriosis is an estrogen-dependent inflammatory disease particular pain mechanism may predominate, possibly due to a 26
9 estimated to affect approximately 10% of women of reproductive particular pathogenesis or disease entity and therefore symptoms 27
10 age [1]. Pain is one of its predominant clinical features. Women may only be responsive to certain treatments [7] (Fig. 1). 28
11 with endometriosis experience a variety of pain symptoms, most The experience of pain, no matter what the underlying disease, 29
12 commonly dysmenorrhea, noncyclical pelvic pain, dyspareunia, involves several different mechanisms and interactions between 30
13 and dyschezia [1]. These symptoms can have significant personal, the periphery and the central nervous system (CNS) [8]. Recent 31
14 social and economic effects on affected patients, their partners and work has shown alterations in both the peripheral and central 32
15 families [2]. Endometriosis-associated pain is as complex as the nervous systems of women with endometriosis-associated pain, in 33
16 disease itself and it is well accepted that no correlation exists addition to demonstrating direct innervation of endometriotic 34
17 between the extent of endometriosis as classified by the commonly deposits [9,10]. In this review, we will highlight the relevant 35
18 applied rAFS/ASRM system [3] and the degree of pain symptoms terminology and discuss existing data and theories on possible 36
19 Q2 [4]. peripheral and central mechanisms by which endometriosis 37
20 Pain may be nociceptive (including inflammatory), neuropathic engages and modulates different parts of the nervous system to 38
21 Q3 or a combination of these (see Box 1) and it is likely that generate and perpetuate pain. 39
22 endometriosis gives rise to all three types of pain [5]. Moreover,
23 factors such as psychological and physical stress, hormone status Terminology and assessment of pain 40

Pain is “an unpleasant sensory and emotional experience 41

associated with actual or potential tissue damage, or described in 42

* Corresponding author at: Hypoxia and Angiogenesis Group, Cancer Research terms of such damage” [11]. Establishing a uniform pain 43
UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, 44
University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United
terminology has been an objective of the International Association
of Study of Pain (IASP) since its inception and we believe it might 45
Kingdom.
E-mail address: matteo.morotti@oncology.ox.ac.uk (M. Morotti). be an important area to improve in basic and clinical endometriosis 46

http://dx.doi.org/10.1016/j.ejogrb.2016.07.497
0301-2115/ã 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: M. Morotti, et al., Mechanisms of pain in endometriosis, Eur J Obstet Gynecol (2016), http://dx.doi.org/
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Fig. 1. This figure illustrates the different factors, which are important in the generation of endometriosis-associated pain, both at the level of peripheral and central nervous
system. In the lower box endometriotic lesions are highlighted in red (they can be in the peritoneum, ovary, rectovaginal septum, etc.). These implants are usually surrounded
by nerve fibres (sensory and sympathetic fibres). These new fibres are commonly surrounded by new blood vessels (neuroangiogenesis). The extent of sensitisation is
dynamically modulated by estradiol and cytokines. Several immune mediators like cytokines but also interleukins and growth factors (NGF, VEGF, BDNF) are up-regulated in
peritoneal fluid of women with endometriosis. All these molecules can be secreted by different immune cells and mediate the release of each other, thus maintaining a vicious
circle. NGF and these molecules also sensitise (lower the threshold) or excite the terminals of sensory nerve fibres, thus generating or modulating the pain stimuli. Nerve fibres
from the endometriotic implants can reach the spinal cord and enter in the same DRG of nerves coming from other pelvic organs. This cross-sensitisation, which also can
happen in the periphery might be a partial explanation of the comorbidity between endometriosis and other diseases, such as irritable bowel syndrome. Normally, multiple
intersegmental spinal connections exist and they can be cause of cross-sensitisation at spinal levels as well. Moreover, activation of spinal microglia can maintain and
perpetuate the pain stimuli. Normally, spinal cord engages neurons throughout the brain that themselves are interconnected via complex ascending and descending
inhibitory/excitatory synapses at the level of CNS. Many factors influence how the brain processes pain (psychological, cortisol, etc.), so the pain experience varies both within
and between individuals. Recent advances in neuroimaging showed that modifications (volumetric increase or decrease) in specific CNS regions are statistically related to the
presence of pain or endometriosis, such as PAG. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Q5

47 research to better communicate our results to colleagues and For these reasons, we believe that it is of paramount importance 75
48 patients. In Table 1 we tried to summarise the more used pain to correctly standardise the terminology of pain and data collection 76
49 terms and their relationship to endometriosis. On the other hand, protocols in all future endometriosis studies and clinical trials [12]. 77
50 in Table 2 we tried to summarise a variety of validated patient This will minimize systematic differences across centres and will 78
51 report questionnaires; those recommended [5,12] or most hopefully allow correlation between symptoms and biological pain 79
52 commonly used in endometriosis research. Such measurement generating mechanisms in endometriosis-associated pain (e.g. 80
53 tools can assess multiple characteristics of pain: (1) the severity; neuroangiogenesis, inflammation, central sensitization, etc.). We 81
54 (2) the quality (e.g. burning, stabbing etc.; potentially reflecting the hope such strategies might open the way to more personalised 82
55 underlying mechanism); and (3) the interference with physical or medicine in the endometriosis setting, focussing as much on the 83
56 emotional function or quality of life in general. Thus, the use of an pain phenotype as on the surgical or radiological findings. 84
57 appropriate combination of such tools can give a much more
58 clinically meaningful assessment of the pain experience than a Peripheral mechanisms of endometriosis-associated pain 85
59 single descriptor of pain severity. Although it is relatively unusual
60 for any pain to be constantly at the same level of severity, Peripheral mechanisms in endometriosis-associated pain are 86
61 endometriosis is perhaps unique in the heterogeneity of the numerous with interplay between endometriotic lesions, immune 87
62 temporal pattern of pains experienced by affected women. An system, peripheral nerve fibres in both the lesions and adjacent 88
63 individual woman may experience a combination of constant non- peritoneum and peripheral neurons [13]. Changes in the peritoneal 89
64 cyclical chronic pelvic pain (CPP) with only minor fluctuations in fluid (PF) in women with endometriosis can activate or sensitise 90
65 severity, unpredictable episodic flares, or clear menstrual cycle peripheral nociceptors [14]. Numerous algogens (pain-producing 91
66 exacerbations; severe dysmenorrhoea (clearly cyclical); and pain agents) have been identified in the PF of women with endometri- 92
67 that is purely related to a specific function e.g. defecation osis, which can directly evoke excitatory inward currents or modify 93
68 (dyschezia), urination (dysuria) or sexual activity (dyspareunia). the function of ion channels, for example the transient receptor 94
69 It is likely that different mechanisms underlie pain exacerbated by/ potential vanilloid channel 1 (TRPV1) [15]. Furthermore, cytokines 95
70 associated with menstruation, CPP and functional pain. For (such as IL-1b, IL-6, and TNFa), growth factors (such as b-nerve 96
71 example, cyclical pain may be more associated with activation growth factor and vascular endothelial growth factor), and several 97
72 of mechanoreceptors, flares of inflammatory disease and local chemokines, such as CCL2 (also known as monocyte chemotactic 98
73 prostaglandins, whilst a major role of a sensitised nervous system protein-1), which are secreted by immune cells, are also present at 99
74 in generating non-cyclical pain would be expected [6]. increased levels in PF of endometriosis patients. They can directly 100

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Table 1
Definitions of relevant terms in endometriosis setting. Q6

Term Definition Endometriosis setting Diagnosis and treatment

Allodynia Pain due to a stimulus that does not
normally provoke pain.
Central Increased responsiveness of nociceptive
sensitisation neurons in the central nervous system to
their normal or sub-threshold afferent
input.
Hyperalgesia Increased pain sensation from a stimulus
that normally provokes pain.
Inflammatory Pain associated with active inflammation.
pain It falls in the category of nociceptive pain.
Neuropathic Pain caused by a lesion or disease of the
pain somatosensory nervous system.
Neuropathic pain is a clinical description
and not a diagnosis which requires a
demonstrable lesion or a disease that
satisfies established neurological
diagnostic criteria.
Nociceptive pain Pain that arises from damage to non-neural
tissue. It is due to the activation of
nociceptors (sensory receptor of the
peripheral nervous system capable of
transducing noxious stimuli). Nociceptive
pain can be divided into visceral and
superficial depending on the location.
Pain threshold The minimum intensity of a stimulus that
is perceived as painful.
Peripheral Increased responsiveness and reduced
sensitisation threshold of nociceptive neurons in the
periphery to the stimulation of their
receptive fields.
Regional allodynia is detected more often and
in more sites in women with pain in general
than in healthy controls. In women with CPP
allodynia was similarly common, regardless of
the presence of EM [54].
Due to high prevalence of regional allodynia Future fMRI brain imaging studies should
and hyperalgesia, EM patients are more likely aim to identify clinical correlates of central
to have clinical evidence of central sensitisation in EM patients in order to
sensitisation compared to healthy controls appropriately target these patients with
[54]. early pain treatment in the absence of
macroscopic pathology or adjuvant
treatment after surgical removal.
Regional hyperalgesia has been observed most
commonly in women with current, biopsy-
proven EM compared with those with pain
only. It was significantly higher in both groups
compared with healthy controls [54].
Increased behavioural responses to noxious
stimuly at a distant site have been
demonstrated in women with CPP and EM
likely reflecting plastic changes in the CNS
(long-term disease).
Endometriotic implants cause a local Inflammatory pain responds best to Non-
inflammatory reaction, which irritates nerve Steroidal Anti-inflammatory drugs
endings. Nerve fibres also play an active role in (NSAIDS). COX2 drugs are newer and have
the mechanism of inflammatory pain by a different safety profile.
secreting proinflammatory neuromediators.
This is called neurogenic inflammation.
Recent work suggests that a small proportion Although there is no evidence in
of women with endometriosis-associated endometriosis specifically, neuropathic
pelvic pain have definite neuropathic pain, pain responds to adjunctive analgesics
however more than half may have a mixed including amitriptyline, gabapentin,
nocieceptive-neuropathic picture [55]. pregabalin and duloxetine.
Visceral nociceptive C-fibres activated by Nociceptive pain can be treated with
noxious stimuli from cells in target organs standard analgesic drugs. Opiates should
have been implicated as mediators of noxious be avoided except for acute flares of pain.
stimulus intensity. Visceral pain may be harder to treat than
somatic.
Pain threshold throughout the body may be
lower in women with EM compared to
controls due to peripheral and central
sensitisation mechanisms [8,9,33].
Both sympathetic and sensory nerve fibres
may maintain a proinflammatory milieu,
which become independent of the presence of
EM itself [10].

Definitions of all terms are from the International Association for the Study of Pain1 (IASP) Taxonomy. EM: endometriosis.

101 sensitise peripheral nerves through specific cell-surface receptors endometriotic implants and has raised the question whether these 106
102 or evoke complex feedback loops, which amplify the microenvi- nerve fibres might contribute to the generation of endometriosis- 107
103 ronmental inflammatory response and the generation of pain [16]. related pain [13]. The PF of women with endometriosis contains 108
104 Moreover, an increasing body of literature demonstrates the high levels of nerve growth factor (NGF), a key player in nerve 109
105 presence of new nerve fibres (neuroangiogenesis) in different development as well as other neurotrophins, such as brain-derived 110

Table 2
Dimensions of pain examined in questionnaires used in endometriosis research.

Sensory Emotional Quality Periodicity Functional interference Psychological wellbeing Quality of life
EHP No Yes No No Yes No Yes
SF-36 Yes Yes No No Yes No Yes
EQ-5D Yes No No No No No Yes
McGill pain questionnaire Yes Yes Yes No No No No
Brief pain inventory Yes No Yes (long form only) No Yes No No
VAS Yes No No No No No No
WHYMPI Yes Yes No No Yes Yes No
painDETECT Yes No Yes Yes No No Yes

Abbreviations: EQ-5D, European Quality of Life—5 dimensions; SF-36, short-form 36; VAS, visual analogue scale; WHYMPI, West Haven–Yale Multidimensional Pain
Inventory.

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111 neurotrophic factor (BDNF) or neurotrophin 4 and 5 (NT4/5) Pain itself also modifies central nervous system structure and 175
112 suggesting a role for these neurotrophins in the modulation of function, frequently leading to “central sensitisation”, whereby a 176
113 endometriosis-associated innervation and related pain [17–19]. patient becomes more sensitive to peripheral stimuli [37]. Such 177
114 However, a clinical correlation between high NGF or BDNF levels central sensitisation is likely an important mechanism in 178
115 and pain severity has not yet been demonstrated [17], suggesting endometriosis-associated pain and CPP. Central sensitisation 179
116 more complex mechanisms and/or the involvement of other may become independent of peripheral stimuli via neural 180
117 mediators of pain modulation. Interestingly, deep infiltrating mechanisms similar to those underlying the generation of memory 181
118 endometriosis (DIE) and bowel endometriosis, in which the [38] and for this reason its development can lead to the generation 182
119 anatomical distribution is generally more closely related to pelvic of pain without a peripheral noxious input. This may be a reason 183
120 pain symptoms, present a higher nerve fibres density compared to why pain can persist despite treatment of all identified peripheral 184
121 other sites [20–23], however no correlations between nerve fibres pathology [39]. In recent years neuroimaging techniques, such as 185
122 and measures of pain severity has been demonstrated in humans functional magnetic resonance imaging (fMRI) and positron- 186
123 so far [24]. In eutopic endometrium of patients with endometri- emission tomography (PET), have been used to identify the 187
124 osis, a positive correlation between high numbers of nerve fibres pathways by which acute pain is processed and increasingly used 188
125 and severity of pain has been demonstrated [25]. However this to understand the mechanisms by which noxious stimuli become 189
126 finding seems to be pain-dependent but endometriosis-indepen- amplified in individuals with chronic pain [40]. Insights into pain 190
127 dent, thus suggesting that the innervation of the functional layer of amplification in conditions associated with CPP have been 191
128 the endometrium is most likely to be a “common association” of reviewed recently [9,41]. Hence, here we will only consider the 192
129 many gynaecologic conditions rather than pathognomonic of limited studies specifically relevant to endometriosis. 193
130 endometriosis [26]. Dysmenorrhoea, with or without an underlying pathology 194
131 Interestingly, as seen in other chronic diseases, a peripheral diagnosed, has been investigated in a number of studies. Perhaps 195
132 autonomic nervous system deregulation has also been demon- unsurprisingly, Tu et al. showed that brain metabolism during 196
133 strated in endometriosis (a loss of sympathetic nerve fibres close to menstruation was different in women experiencing dysmenor- 197
134 the lesions and an increased presence in distant regions) [27,28]. rhoea compared with those whose periods were not painful [42]. 198
135 Some authors have postulated that this qualitative imbalance of However, Vincent et al. demonstrated that even when not 199
136 nerve fibres seen in chronic inflamed tissues, i.e. a local increase of experiencing pain, women with dysmenorrhoea were more 200
137 sensory nerve fibres and a concomitant loss of sympathetic nerve sensitive to noxious stimuli, probably due to increased activation 201
138 fibres, might be important in maintaining a local proinflammatory of particular CNS regions (e.g. the entorhinal cortex) [43]. Similarly, 202
139 milieu surrounding the deposits [29]. Interestingly, estrogens, structural alterations in other pain processing regions of the brain 203
140 which play a key role in endometriosis pathogenesis, can also have been shown in women with dysmenorrhoea compared to 204
141 directly or indirectly affect the peripheral nerve fibres. Estrogens control women outside of menstruation. However, as seen in other 205
142 can up-regulate NGF, VEGF and BDNF, supporting a direct link chronic diseases, the volume of specific brain regions correlated 206
143 between estrogens and neuroangiogenesis but also can modulate with the duration of the symptom suggesting that these 207
144 the expressions of some subclasses of semaphorins, which are volumetric changes are possibly a consequence rather than a 208
145 important for the sympathetic nerve fibres regulation (for reviews, cause of the pain [44]. However, more research is needed to better 209
146 see Morotti et al. [10]). understand this association. 210
147 Another role for the peripheral nervous system in modulating To date, only one group has specifically investigated brain 211
148 endometriosis-related pain is the so-called pelvic-lower abdomi- structure and function in women with endometriosis, however, 212
149 nal cross-organ sensitisation between the gastrointestinal, urinary their seminal work supports the idea that endometriosis- 213
150 and gynaecological viscera [30]. This mechanism may partially be associated pain is similar to other chronic pain conditions in its 214
151 explained by so-called dichotomising fibres (sensory endings of a engagement and alteration of the CNS. In their first study, As-Sanie 215
152 single neuron innervating two different tissues). Although the et al. [45] investigated women with CPP with and without 216
153 number of dichotomising sensory neurons in DRG is heteroge- laparoscopically proven endometriosis, in addition to women in 217
154 neous in humans (from 0.1% to 21% of all traced neurons) [31], their whom endometriosis had been found but who did not suffer with 218
155 identification suggests an anatomical and physiological basis for CPP and compared each group to healthy pain-free controls. 219
156 the occurrence of referred pain and may be a partial explanation Similar to other chronic conditions, women with CPP (whether or 220
157 for CPP in women with endometriosis and its common comorbid- not there was endometriosis present) had several volumetric 221
158 ities such as interstitial cystitis/painful bladder syndrome or modifications in specific brain areas (thalamus, insula, putamen, 222
159 irritable bowel syndrome [32,33]. etc.) compared to pain-free women. Perhaps most interestingly, 223

women with endometriosis but without CPP had an increase in the 224
160 Central mechanism in endometriosis-associated pain volume of their periaqueductal grey (PAG), a key region in the 225

descending pain modulatory pathways [46]. It is plausible 226

161 Although pain is usually perceived in a specific anatomical therefore, that women with endometriosis who do not suffer pain 227
162 area, the conscious experience of pain emerges from the brain as a still generate the peripheral noxious stimuli associated with the 228
163 result of co-ordinated activity within the central nervous system condition but have such good descending pain inhibitory activity 229
164 (CNS) [34]. Moreover, it is well accepted that the CNS contributes that they do not experience pain. This could also explain why some 230
165 to the modulation of pain in women with CPP [9] and it is likely to women only begin to experience pain from endometriosis later in 231
166 contribute to endometriosis-association pain [7]. Furthermore, their reproductive life, potentially after another insult (e.g. a severe 232
167 CPP is often associated with negative cognitive, behavioural, urinary tract infection, renal calculus or somatic injury) reduces 233
168 sexual and emotional consequences, potentially further exacer- their ability to engage descending inhibition. Clearly these 234
169 bating the pain experience [35]. It is important to remember, hypotheses remain to be tested formally however. 235
170 however, that whilst psychological distress may modulate pain it More recently the same group showed that women with 236
171 can also be a consequence of the pain (for reviews, see Blackburn- endometriosis-associated CPP demonstrated increased concen- 237
172 Munro and Blackburn-Munro [36]) and thus if identified trations of excitatory neurotransmitters in the anterior insula and 238
173 should be appropriately treated, but not assumed to be the sole had greater intrinsic connectivity of the same anterior insula 239
174 cause. region to the medial prefrontal cortex [47]. These insights into the 240

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241 function of the CNS in women with endometriosis-associated pain with greater efficacy and lower propensity for adverse reactions 305
242 and the similarities with other chronic pain conditions support the are urgently needed. 306
243 use of therapies targeting the CNS as opposed to (or in combination
244 with) those focussing on peripheral endometriotic lesions [48].
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