The Neurobiology of Pain

Background and Review-

Pain and Central Sensitisation-

The effect of the element of Pain could be better ascertained from the demonstrated standpoint of International Association for the study of pain in the manner of an experience which is associated with the emotional as well as sensory perceptions of the human body and this experience is unpleasant to the complete extent. This sensory experience is primarily associated with the actual or potential damage which could be caused to the tissues and the context of such a study of pain is integral to such damage which could be caused(The taxonomy of pain,2015). This could be primarily considered to be specifically symptomatic regarding the pathological conditions of the subject and the purpose of existence of the sensation of Pain could be rationalised in the manner of providing the impetus to the individual who could be undergoing such a sensation to extricate himself or herself from any detrimental situation so that the pathological structure of the body be protected from any furtherance of such sensation of Pain and for the objective of preclusion of any continuation of the normal functioning of the human physiology and during this period, the physical recovery could take place as well (Neurobiology of Pain, 1983). The continuation of the sensation of Pain could be sustained till to the removal of the noxious stimulus or the any damage to the pathological condition which could have been caused from external as well as internal elements, could be repaired as well. In this regard, the recurrence of Pain at regular intervals could be considered to be chronic in nature since such pain could persist for durations of over several months or for years also. The perception of Pain, which could be considered as nociceptive in nature, could be identified to get generated from the stimulation of the peripheral nociceptors, including those of the somatic or visceral ones. The neurons belonging to the somatic nociceptive category are generally differentiated for the purpose of undertaking generation of responses to the particularly high input threshold such as intensity of pressure or heat extremities. With the acquisition of this specific threshold by the external stimuli, the nociceptive neurons which are first in order generally transmit the nerve signals to the neurons which are second in order through the dorsal horn of the human spinal cord. Then onwards, the Pain signals are mostly relayed to the multiplicity of regions which are associated with those of the thalamus and neocortex of the human physic and this also is performed in the format of specific transmission (Woolf, 2011). The conventional concepts and comprehensions regarding Pain generally considered the system of afferent nerve fibres to be able to only perform the relaying of nociceptive signals and this denoted the supposition that the system did not have the ability of modulating the signals. This form of scientific perception had persisted with considerable prevalence upto 1960 (Woolf, 2011). Melzack and Wall (1965) had proposed the Spinal Gate theory after the year 1960 and this theoretical construct first brought forward the explicit demonstration of the scientific observation that this system of nerve signal relay could as well be modulated through undertaking inhibition of the spinal cord. The furtherance of the research in this direction that the entire system of signals generation to convey the sensation of pain could be modulated through a process of significant interaction and complication involving both the central as well as the peripheral nervous systems(Willis, 1985). This brings in the understanding that the experience of pain could be considered to be both stimulated and inhibited at the same time. In this context, the extensive and heightened response, which the human physic could generate and sustain as a definite pathological state of being, to highlight the external stimulus of pain, could be outlined in the format of “sensitisation”. The purpose of sensitisation is comprehended to be, after the injury could have taken place, to assist in the process of preventing the external stimuli of pain to aggravate the impact of injury and to lead to the situation where the process of recovery from the injury could be expedited. Notwithstanding this observation, it has to be acknowledged that in a range of different clinical syndromes, pain could never be considered to be a mechanism of protective preclusion against injury or externally imparted harm to the body of the subject. In such cases, the element of pain could spontaneously take place out of stimuli which could be innocuous as well as insipid in nature (allodynia) out of the causality of the convergence of the processes of sensory mechanisms. The convergence process is reflective of the central sensitisation procedure and could be considered to occur at the spinal cord region and within the networks of pain which is directly controlled by the human brain(Woolf, 2011). On the other hand, the element of Pain is also considered to be a response which could be prolonged and exaggerated to a great extent involving the noxious stimuli (hyperalgesia). This could get expanded much farther than the actual site where the injury could have occurred(secondary hyperalgesia) and this could be an outcome of the transmission of the pain signals at a much lower input threshold.The dual categories of sensitisation could be considered to be central and peripheral in terms of nomenclature and nature of occurrence. In case of the peripheral sensitisation, the nociceptor peripheral terminals could be sensitised at post injury occurrence stages where the threshold could be reduced to a great extent and the stimuli could be considered to be that of heat effects. This occurs at the location of the injury where the exposure of the terminals to the modulators which are inflammatory in nature could take place (Bishop T 2010, Campbell JN 1988). On the other hand, the process of central sensitisation, the inputs related to the nociceptive pathways could effectively involve the signals which generally could not be responsible for driving the sensitisation pathways and the examples of such could be determined in the format of extensive low-threshold mechanoreceptor myelinated fibres. The process of central sensitisation brings forth the outcomes in the form of changes which could occur in the nature and characteristics of the neurons which compose the central nervous system (CNS) and this could result in the incurrence of production of hypersensitivity of pain within the tissues which are non-inflamed in terms of characteristics through the alterations of the sensory responses which, in turn, are prompted by the inputs which are primarily normal. This also elicits the increased sensitivity to pain even if a long duration of the time could have occurred as a definite interval after the cause of initiation of the pain could have ceased completely. This also occurs while no peripheral pathology could be in existence at all(Alban, Wolf 2009).Various mechanisms, which have high potentiality, are considered to be included in the process. These could be identified as the NMDA receptor activation, the expression of the altered genecould be observed at the neurons of the dorsal horn as the process microglial activation( Weseler-Frank J et al 2005), considerably curtailed the procedure of inhibition as well as the changes which occur at the thalamic and somatosensory levels( Guilbaud G et al 1992). A variety of nociceptors could be responsible for the triggering of the perception of the Pain. These could be considered to be the sensory receptors which are considerably specialised for the detection of the stimuli which are noxious as well as non-pleasant. The stimuli, which are noxious in nature, could be transfigured into electro-chemical signals which could be transmitted through the central nervous system. Nociceptors could be considered to be nerve endings which are completely free and are associated with the primary afferent Aα and C fibres and these are disseminated throughout the length and breadth of the physical structure of the subject such as into the organs such as skin, viscera, muscles, joints and meninges etc. These nociceptors can be stimulated through the utilisation of the stimuli which are mechanical, thermal and even chemical ones. The stimuli, non-noxious in nature, are transmitted through primary afferent Aα fibres. Aβ fibres are responsible for transmitting of non- noxious stimuliand these fibres also generate the response to lightly received touch.Aδ fibres generate the responses to both thermal as well as mechanical stimuli in the form of transmission of very intense and immediate sensation of pain. C fibres are responsible for generation of responses to the stimuli which are generated through mechanical, chemical as well as thermal factors. The activation of C fibre could engender the sensation of not much intense, however, steady pain generated by the effect of incineration or burning. This sensation of pain associated with burning could then be transmitted to thalamus, hypothalamus, and the limbic system and then to the cortex associated with somatosensory activities by the Postsynaptic spinal cord fibres. The activation of the C fibres could lead to the release of a host of neurotransmitters and neuromodulators within the afferent terminals which are situated at the dorsal horn region. The resultant changes in the processes of somatosensory activities could be considered to be the direct outcomes of such observed stimuli and the effects generated by such neurosensory activities could be identified as the enhancement in the excitability of the membrane and, in a simultaneous manner, the inhibitory influences get significantly reduced and this triggers the central sensitisation.Functional Somatic Syndromes or Medically unexplained symptoms ( MUS) orFunctional Somatic Syndrome (FSS) could be understood to be the ailments which could never be explained or provided a definition concerning the organic disease analysis processes. These are also completely bereft of any structural lesion which could be definitely demonstrated or any associated change which is biochemical in nature(Lipkin 1969, Smith 1991). In this context, the expressions of historic observations could be utilised in the form of hysteria, imagined illness (hypochondriasis) or psychogenesis (Sharpe et al 1995). The novelty in terms of the newer descriptions which are generally utilised for the FSS could be identified in the measure of Medically Unexplained Symptoms (MUS) and, apart from this, the expression which has been developed at the more recent time period is the Body distress syndromes ( AnnBudtz Lilly 2015). Furthermore, the newly developed expressions which could be utilised for the FSS are closely associated with those of the Conditions in terms of Irritable Bowel Syndrome (IBS), Chronic Fatigue Syndrome (CFS), Fibromyalgia, Temporomandibular Disorder (TMD), and Chronic Pelvic Pain (CPP). These are to be considered to be the FSS expressions which are the most common ones. These are mostly explained in the manner of symptoms associated with the somatic processes whereas the conditions of depression and anxiety could outline the procedures of psychological responses to such physio-pathological conditions (Mayou& Farmer 2002 (BMJ). Out of every one of the 6 consultations which are associated with the primary care processes could include the Medically Unexplained Symptoms (Steinbrecher 2011).Barsky and Borus (1999)has opined that FSS could be quintessentially the explicit demonstration of the process of somatization. It had been as well determined that the patients who could be suffering from FSS, could demonstrate the extensive rates of psychiatric comorbidities. This involves specifically the elements of depression and anxiety. In spite of the observations, it could be determined that it is inherently difficult to outline the exactitude of the causes and the outcomes of such aspects (Fiedler N 1996). This could be further outlined that most of the patients who have FSS as ailments, do not generally exhibit the structural transformation or pathological changes in the actual regions where the symptoms could be reported. Thus, it could be observed that there could be no explicit or determinable structural deviation of normalcy, which could be better perceived at biomarkers, for IBS, CFS or fibromyalgia. This is a definite fact despite the observation that these patients could be affected by symptoms, fatigue and musculoskeletal pain in a respective manner. (Locker 2004; Branco 2010; Clauw , 2014; Morris &Maes, 2013; Soares, 2014). The aetiology of the FSS could be considered to be a matter of continuing debate and there are various theoretical suggestiveness with the supposition that the anomalies have extensive possibilities concerning both the central and peripheral nervous systems and these could not be evaluated or analysed in a direct or deliberate manner.The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) could outline that the terminology of Somatic Symptom Disorder (SSD) could be utilised to either augment or replaced the previously undertaken diagnoses in this regard and this makes such a process not at all in requirement of such symptoms which could not be associated with any form of medical assessment regarding the performance of the diagnosis. Looking for further insights on Overview of Huangchao Liqi Tushi? Click here.

Prevalence and Burden

The ascertainment of the extent to which FSSs could spread is difficult. However, as per the conducted studies, the rate of occurrence of IBS could be identified to be 11% (Canavan et al 2014), CPP could be understood to have the range in between 5.7%-26.6% (Ahangari 2014) CFS could be understood to be 9% (Skapinakis et al 2003) and fibromyalgia has been demonstrating the variability between 0,2% and 6.6% (AP Marques 2017) within all of the communities which have been selected as samples. Another aspect which could be determined in terms of such observations is that considerate measures of symptoms overlap with each other amongst the patients under consideration. The effect of Fibromyalgia and medically unexplained symptoms (MUS) is to be understood to be the deterioration of the psychosocial conditions which could be demonstrated by these patients. Other effects are disability in terms of working conditions and a propensity to utilise healthcare facilities to a greater extent by such patients (Kevin 2015). As an example the case could be observed where the patients suffering from mild, moderate, and severe fibromyalgia, the incurrence of annual costs regarding the healthcare service utilisation through availing the direct resources could be evaluated to be $4,854, $5,662, and $9,318 per patient, in a respective manner. The annual mean of the costs which are indirectly incurred and which could be inclusive of the prevalent rate of absence, the rate of unemployment, the incidences of undertaking premature retirement and disability concerning the patients suffering from mild, moderate, and severe fibromyalgia had been evaluated to be $4,428, $14,664, and $29,996 in a respective manner (Chandran 2012). Apart from these, the conditional functions, which could be separately observed could as well be comprehended to be related to the substantial financial cost incurrence which has to be shouldered by the patient, the process of healthcare and the society as well. One example could be ascertained in the manner of the deduced annual cost for the UK populace to avail the treatment of IBS has been £45.6 -£200 million (Wells 1997, Akehurst RL 2002). In a similar manner, the direct cost incurrence, which could be estimated on an annual basis regarding the availing of the treatment of CPP could be understood to be approximately $7000 (Clemens, Markossian, & Calhoun, 2009). FSS could represent the conditions where the reduction of the quality of life (QOL) could become an eventuality. When the comparative analysis of FSS and that of Healthy Controls (HC), female patients with CFS generally demonstrate physical functioning which could be much worse than that generated by other ailments, such as greater physical pain, dearth of vivacity and work ardour, reduction in any form of work productivity, deterioration in the conditions of general health as well as that of the capabilities associated with social functioning. These, in a cumulative manner, could have influence the prospects of employment considerably (Collin S 2011; Anderson JS 1997; Dickson 2009). Identical patterns of QOL generated complications are demonstrated by patients suffering from IBS (Monnikes H et al 2011) in similar conditions with those of the patients who could be affected by fibromyalgia (Hoffman D 2008; Martinez JE 1995). Regarding the functioning related limitations which are associated with the FSS, the previously undertaken studies could outline the fact that these limitations are mostly severe enough to be compared with those of the pathological disorders in spite of the fact that the any significant organic pathology could be not in existence in this regard (Monica L 2015). To this effect, it could be analysed that FSS exhibit the fact that the suffering extent emanating from this disease is considerably great for not only for the affected patients but also for their kith and kin and for the prevalent healthcare systems and for the society in general within the larger context.

Are FSSs discrete entities?

Previous studies have outlined the fact that FSSs could be considered to be completely discrete as specific syndromes (Kanaan RA 2007). Wessely et al (1999) had researched that significant overlap of the resultant symptoms from FSSs could occur and these could be identified in the manner of bloating or abdominal distension in 8 conditions, headache in 6 and abdominal pain in 6 and fatigue in 6. Aaron LA (2000) also outlined the fact that in a similar pattern with all of the patients with Chronic Fatigue Syndrome (CFS) who exhibit the incidence of fatigue, 86% of the patients who could be suffering from fibromyalgia (FM) also do the same. In a converse manner, most of the FM patients generally exhibit complications regarding the Arthralgia in tandem with those of the 88% of the patients suffering from Chronic Fatigue (CFS). Aron & Buchwald had provided the reviews of 53 different studies which had focused upon the assessment of the patients with one FSS through the formalised criteria of diagnosis which could have been associated with the diagnosis process involving other forms of FSS. As per their findings, it could be observed that in between 35 - 70% of the various patients who could be suffering from CFS met the criteria for FM, 58-92% fulfilled the criteria meant for IBS and 53-67% exhibited multiple chemical sensitivities. In a similar manner, 75% of the patients suffering from the FM fulfilled the criteria which have been developed for the diagnosis of the temporomandibular disorder, 32-80% fulfilled the criteria for IBS as well as the 55% of the patients demonstrated several modes of chemical sensitivities. Furthermore, various other studies also brought forth the fact that IBS has been observed within the extent of 39% of patients who have been suffering from CPP (Nickel et al., 2010). Considerable risk element is present regarding the development of the new FSS treatment regime in the near future on part of the possibility of presence of FSS within any individual patient. Warren et al (2013), had discovered that possession of the FSS could be directly associated with 2.4 greater odds (95% CI, 1.3-4.7) regarding the development of new FSS within the next year. (Warren, Langenberg, & Clauw, 2013). Thus, it could be determined from the previous studies that FSSs generally have multiple commonalities regarding psychosocial and demographic correlates. Previous considerations have as well perceived these in the forming of linking these with those of the patient histories of maltreatment and manhandling. Para et al 2009, had researched about a specific meta-analysis of 23 different studies which involved 4640 subjects who demonstrated a prolonged history of sexual abuse and the study outlined the fact that each of the patients was prone to a considerately significant odds regarding the contracting or developing of gastrointestinal disorders (OR 2.43, 95% CI, 1.36-4.31) as well as that of the CPP (OR 2.73, 95% CI 1.73-4.30). In this context, it could be understood that a specific and comparatively recent meta-analysis of 71 different studies which involved the evaluation of multiplicity of formats of psychological trauma involving the emotional, physical, and sexual abuse. This meta-analysis of the studies brought in the confirmation that the incidence of having to be exposed to any form of trauma could be deliberately associated the incurrence of 2.7 greater odds (95% CI, 2.27-3.10) of fulfilment of the criteria for a FSS (Afari et al., 2014).The commonality between various patients with similar extent of FSSs could be identified as disorders of moods as well as the incidence of both anxiety and depression. These are much more in their presence within such patients suffering from FSSs in comparison to the patients affected by organic diseases and also in comparison to the groups with healthy physical conditions (Henningsen, Zimmermann, & Sattel, 2003). Other factors, such as those with environmental and genetic implications could as well be considered to impart considerable impact on the constitution of FSSs (Vehof, Zavos, Lachance, Hammond, & Williams, 2014). MUSs and FSSs could as well be discovered to be of greater commonality regarding incurrence in women in comparison to that of men (Kroenke & Price, 1993). When the probability of heightened rates of psychiatric comorbidity could come true, the temptation of providing the suggestion that such symptoms could be the outcomes of catastrophizing, somatization or negative effect could be definitely serious one. Notwithstanding this, mediation modelling approaches (a procedural approach which could be utilised for the purpose of understanding the mutual influence between the dependent and independent variables through the utilisation of a mediator variable), could outline that both environmental as well as psychological factors (e.g. neuroticism, history of abuse, previous events in the personal lives, anxiety, somatization and catastrophizing) could amount for only a mere 36% of the variations in the measures of severity of the IBS and for another 42% regarding the variation of the pain related effects which are generally experienced by fibromyalgia patients ( van Tilburg, Palsson, & Whitehead, 2013). Such observations could attest for the fact that extensive variation regarding the FSSs symptoms could be attributed to only the factors which are psychological in nature.

FSS or Central sensitivity syndrome

Previous research has been able to indicate the fact that the sensation of pain which could not be explained medically could be one of the elemental constituents of the entire range of different constituents of FSSs. One example could be outlined in the format of characterisation of IBS through pain which could occur at either the entire or at the lower abdomen region and the this could be a case with the pain which is associated with irregular movements of the bowel (Drossman & Dumitrascu, 2006). Fibromyalgia could be better ascertained through the extensive existence of severe pain at the region of the back, shoulders and extremities (Wolfe et al., 2010) and CFS has the characteristic of inducing extensive headache, muscle pain and pain in the joints where any bulging or swelling could not be observed (Fukuda et al., 1994), TMD could be better identified in the form of extreme pain at the region of the jaw of the patient, earache, headache, facial pain (Robert L Gauer et al 2015). The ailment of CPP could be characterised in the form of considerable pain at the pelvic regions and myofascial pain (Jane P Daniel’s 2010). Pain could be understood to be one of the most frequently occurring complaint which has prompted the patients suffering from FSSs to avail medical assistance in this regard . (Hungin, Chang, Locke, Dennis, & Barghout, 2005).The prevalent suggestion that such multiplicity of pain disorders could be interconnected through comparable procedures of pathological mechanisms involving dysregulated nociception which is mediated centrally and this is generally alluded to as “central sensitization”( Lindsay L Kindler 2011). Apart from the mechanisms of pain which are commonalities, such complications and disorders could as well occur in tandem with each other (occur (Aggarwal, McBeth, Zakrzewska, Lunt, & Macfarlane, 2006). These could be considered to be the catalytic impetus for the advancement of such factors (Diatchenko, Nackley, Slade, Fillingim, & Maixner, 2006) and may likewise exhibit transformation from pain factors which could be localised to extensive disorders involving high rate of pain (Holm, Carroll, Cassidy, Skillgate, & Ahlbom, 2007). Most of such complications and pain disorders could generally commence from an incidentally interceded pain which could be mediated peripherally delivering instruments (aggravation or potentially mucosal or neural disturbance). In any case, the persistence of nociceptive signals can prompt alterations in the centralised nociceptive framework and the process of induction of centralised nociceptive framework mechanism as well as the central sensitisation, severity associated with painful sensations can emerge autonomously of the nociceptive information which could be peripheral in nature (Latremoliere & Woolf, 2009). Concerning the potentiality of the mechanisms of pathophysiology which could be shared the outlined complications and disorders could be termed, in a collective manner, by various research specialists as “central sensitivity syndromes” (CSS) (Yunus, 2008). Such associative connection could be effective in providing assistance to the researchers with the understanding the necessary improvement of extensive hyperalgesia in a few patients and in addition could furnish the logical perspective regarding the the rationale of affectability of central sensitivity syndromes and the frequency of overlapping of these with each other. The vital conclusion of the diagnosis in this regard is generally reliant on the patient's principle and highlighted complaint and furthermore the subspecialty region of the patient (Aaron 2001).

Different manifestations of symptoms which could put forward the proposition that proximity to CSS could be a definite perspective could be considered as: Abdominal bloating, abdominal pain, anxiety, depression, chronic fatigue, non -specific chest pain, atypical facial pain, burning mouth syndrome, chronic low backache, chronic pain, migraine, non- specific light headedness, chronic pelvic pain, hyperventilation, IBS, joint pains, symptoms of premenstrual syndrome, symptoms of posttraumatic disorder, panic attacks, myofascial pain, tinnitus and so forth. Nonetheless, the Etiology which has been proposed for these is progressively bolstered because of a procedure of central sensitization (Fleming 2015). The evaluated and mentioned literature above could be able to furnish the general guidelines and overviews regarding the adversities and the resultant effects which could be caused by therapeutically unexplained manifestations of different symptoms and furthermore on the developed defining elements regarding the Central Sensitivity Syndromes as a specific collection of different disorders which share symptoms in the most common manner so that their effects often overlap with pain being the most fundamental component and there could be no organic pathology which could be found in this regard which could underscore the causality of such symptoms. Bio-psycho-social model has been utilized to comprehend the pathophysiology as well as the various management procedures concerning the symptoms of CSS. In this context, one has to be cognizant of the fact that such variables could be primarily vital regarding the singular conditional perpetuity and are not congruent to the particularities of CSS(Leah M 2015). The complications with the various terminological definitions of FSS could be considered that in spite of having the capacity to integrate all the non -organic complaints there is irregularity in the utilisation of these. For instance, Fibromyalgia has been so far perceived to be individual Somatiform based disorder which could be assessed through particular tools of evaluation. On the other hand, the concept of the CSS idea can be utilized for greater variations of related disorders and symptoms with central sensitisation as the fundamental causality. Subsequently, it is imperative to comprehend the component of central sensitisation and its appraisal.

Mechanism of central sensitisation and its assessment

Central sensitisation process could be identified as transformation in the state of the functioning of neurons and nociceptive pathways which are engendered through the membrane excitability increment and synaptic efficiency and through the curtailment of the inhibition regarding this specific system (Wolf 1983). Multiplicity of differential phenomena, which are involved could be considered to be the activation of Wide Dynamic Range Neurons (WDR). These could be considered to be able to initiate to be responsive to nociceptive and previously non- nociceptive stimuli. The characteristic of consistent increment of such responses are mostly invoked through an entire range of standardised series of repeated stimuli (temporal windup which can be homosynaptic or heterosynaptic); enhancement of the spatial extension stimulus and ultimately the triggering of the changes which could be sustained for far longer periods than that of the stimulus which could be observed at the initial levels (Latinmore, Woolf 2009). LaMotte et al could have been the first study which considered the undertaking of the first delineations concerning the features of central sensitisation while performing a study session on the secondary cutaneous hyperalgesia engendered by intradermal capsaicin injection (which could have the effect of activating the TRPV1 receptor) (LaMotte RH 1991). The study also attested for the fact that secondary mechanical hyperalgesia generally has to be require a consistent sensory inflow to attain access to the central nervous system (CNS). The above mentioned scholars also provided appropriate demonstration of the fact that central sensitization which could be dependent upon specific activities, could as well be responsible for the emergence of tactile allodynia and secondary hyperalgesia within the human physio-pathological system(Torebjork HE et al 1992). Further experimentation also provided the evidence that capsaicin as well as nociception which could be related to heat, are mostly transmitted through the C fibres and the transmission of the mechanical allodynia is completely undertaken by the myelinated fibers which are of low threshold(Wolf 2011). Electrical stimulation related to the singular Aβ mechano-receptive fibers could be acknowledged to generate extensive pain whenever the receptive field if the fibres could be subjected within the region of influence of secondary mechanical hyperalgesia. The pain could be caused by the changes which are reversible in the central processing mechanism of mechanoreceptive inputs from myelinated fibers and these fibres are observed to generally induce tactile sensations which do not cause any pain (Torebjork HE et al 1992). Koltzenburg and Torebjork had brought forth findings which had been similar in nature to that of the previously expounded ones, through the utilisation of mustard oil (as this could activate TRPA1 receptors) (Koltzenburg M et al 1994). When the manifestation of such demonstration of central sensitization had been completed, changes which were similar in nature, had been also propounded through a range of diversified and differentiated studies in laminae I and V of spinal dorsal horn neurons (Cook AJ 1986); this had been the case regarding spinal nucleus, pars caudalis (Burstein R 1998); thalamus (Dostrovsky jo 1990) amygdala (Neugebauer V 2003) and at the cingulated area of anterior cortex (Wel F 2001).The enhancement in the exactitude of neurons within the somatosensory cortex could be adduced by the Ab stimulation involving the low threshold within the capsaicin-induced zone of secondary hyperalgesia and this had been brought forward through the Magnetic source imaging [Baron R 2000], and during this phase of study, various alterations within the procedures of the cerebral processing had been consistently identified through the magnetoencephalography [ Maihofner C 2010].Studies related to the MRI based examinations also brought forward the transformative changes in the brainstem which could be particular to the process of central sensitization, apart from the alterations within the primary somatosensory cortex which could be considered to be associated with the severity of the pain [Lee MC 2008). Central sensitization process is generally inclusive of the various changes in the procedures of neuronal activity which could be considered to be indicative of the neuronal plasticity and could be ascertained to be either temporary or permanent. Such aspects and changes are mostly initiated through the dorsal horn neuron based activities which is generated through the responses to the nociceptor stimuli which are present in C fibers, such as thermal stimuli above 49ºC, repeated stimuli electric C fibers stimulation (1 Hz for 10 to 20 seconds) (Bliddal H 2007) and chemical stimulation through the initiation of the activation process of nociceptors through the utilisation of the irritating compounds the prime example of which could be determined as allyl-isothiocyanate (mustard oil) and formalin ( Jordt SE 2004, McNamara CR 2007). The process of central sensitization could be primarily initiated after intense, repeated and sustained nociceptive stimuli. The utilisation of multiplicity of the fibres is a prerequisite regarding the extension of the same over an extensive period since the singular stimulus, for an instance a prick, could be considered to be not effective in triggering the entire procedure (Hazem Adel Ashmaw 2016). CS could be identified to be marked in a much clarified manner regarding the effect of the injuries caused by surgical treatment or by traumatic experiences. In an interesting manner, the conditioning of the muscles and joint afferents could be considered to be the most effective in bringing forward the central sensitization process in comparison with the conditions of the human skin [Wall PD 1984]. Central sensitization process could be further considered to be an occurrence which could be observed to be associated with the molecular level. The various explanations, which had been conceived previously and at an early stage, involved a proposition concerning both the maintenance and induction of central sensitization which has been dependent on acute activity related NMDA receptors, (Woolf CJ 1991). This leads to the revelation of the levels of most significant involvement of the glutamate and its receptors. This could thus be more effectively understood that the entire process of Central Sensitization could be comprised of two phases which are temporal in nature. These could be identified in the manner of the following: 1. The essential phase dependent upon phosphorylation and independent of transcription could prompt the result which could be related with fundamentally accilerated adjustments regarding the properties in glutamate receptor and concerning the perspectives of the ion channels (Woolf CJ 2000) 2.The process of central sensitisation is formulated through the synthesis of the relatively newer proteins which are primarily stimulated by the transcription dependent phases and are thus able to last longer (Woolf CJ 2000).

Receptors and Neurotransmitters responsible for central sensitisation

1. Glutamate, a neurotransmitter of primary afferent neurons, binds to several postsynaptic receptors on spinal dorsal horn, including ionophores such as amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPAR), N-methyl D-aspartate (NMDAR), kainate (KA), metabotropic receptors (coupled to G protein) and other subtypes of glutamate receptors (mGluR). AMPAR and NMDAR are present in almost all synapses in dorsal horn superficial laminae and are disposed in mosaic shape, while mGluRs are located in the extremities of the post-synaptic density zone (SDZ). Activation of NMDAR is important in both initiating and maintaining activity-dependent potentiation as its blockade by non-competitive (MK801) or competitive (D-CPP) NMDAR antagonists prevent and reverse the hyperexcitability of nociceptive neurons induced by nociceptor conditioning inputs. In normal conditions, NMDAR ionophore is blocked by magnesium ion (Mg2+). Sustained release by glutamate nociceptors, neuropeptides, substance P (SP) and gene related peptide calcitonin (CGPR) leads to enough depolarization of plasma membrane, forcing MG2+ ion to leave NMDA receptor pore. This then allows glutamate binding to the receptor generating an internal current and CA2+ inflow. The extensive measure of calcium ions inflow lead to the activation of the multiplicity of intracellular pathways which, in turn contributes in both the development as well as the maintenance of central sensitization.(Mayer ML 1984, Wolf CJ 1991). The activation of group I mGluRs by glutamate also does appear to be important for the development of central sensitization.

2.Another neurotransmitter playing a part in central sensitisation is Substance P, co-released with glutamate by unmyelinated nociceptors (C fibres) (Afrah AW 2002, Khasabov SG 2002). Substance P binds to neurokinin receptor -1(NK1) resulting in long-lasting membrane depolarization.

3 Calcitonin gene related peptide (CGRP), synthesised by small neurons also participate in central sensitisation due to activation of protein kinase A and C by CGRP1 postsynaptic receptors. There is also an increase in brain derived neurotrophic factor (BDNF) release from trigeminal nociceptors by CGRP, which is a synaptic modulator and released in the spinal cord. (Sun RQ 2003).

4.Bradykinin a pro-inflammatory substance activating and sensitizing the primary afferent, is produced in the spinal cord in response to intense peripheral noxious stimuli and acts by means of its B2 receptor, which is expressed by dorsal horn neurons.

This increases synaptic efficiency by activating protein kinase A (PKA), protein kinase C (PKC) and kinases regulated by extracellular stimuli (ERK). ERK may also be activated by the serotoninergic descending pathway (5-HT) involving receptor 5-HT3 and possibly receptor 5-HT7. (Woolf 2011).

5. Calcium Increased intracellular Ca2+ seems to be a primary trigger for the development of central sensitization. Increased intracellular calcium promotes AMPAR and NMDAR receptors to be phosphorylated by PKA/PKC changing the activity of receptors to plasma membrane. . AMPAR and NMDAR receptors phosphorylation during central sensitization increases density and activity of such receptors leading to post-synaptic hyperexcitability. AMPAR and NMDAR stimulation participates in the activation of intracellular pathways which support central sensitization and include phospholipase C pathway (PLC) and PKC, phosphatidylinositol-3-kinase pathway (PI3K) and protein kinase system pathway activated by mitogen/kinase and regulated by extracellular signal (MAPK/ERK). ERK phosphorylation is considered a marker of neuronal dysfunction occurring in central sensitization.

6.Protein Kinase C activation decreases NMDAR Mg++ block and making it easier for the NMDAR activated state ( Chen L 1992). Activated PKC also decreases inhibitory transmission by decreasing gamma-aminobutyric acid (GABA) levels of tonic glycin inhibition, of descending inhibition conducted by periaqueductal gray matter PAG ( Lin Q 1996).

Disinhibition could be considered to be another of the multiple mechanisms concerning the outcomes of the increment of susceptibility by the fibres to the excitatory stimuli and this could assist in the maintenance of the procedure of the central sensitisation.

Summary of mechanism of central sensitisation-

The element of Central sensitisation could be considered as a phenomenon based at the central nervous system which exhibits the characteristics of pain which is chronic in nature. According to The International Association for Study of Pain( IASP), central sensitisation is “ Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” ( Loeser JD 2008).

There is a condition of heightened dorsal horn sensitivity because of expanded peripheral nociceptor action. Reduced threshold limits for the actuation of dorsal horn neurons and in addition receptive field enhancement and increment of the responses of dorsal horns could be observed in terms of stimuli of pain. A portion of the potential mechanism which could be observed to be included could be assessed to be the initiation of NMDA receptor altered gene expression in dorsal horn neurons, microglial activation (Weseler-Frank et al 2005), decreased inhibition and thalamic and somatosensory cortex changes ( Guilbaud et al 1992). Initiation of the C fibres discharge different neurotransmitters and neuromodulators within the afferent terminals in the dorsal horn. These incorporate substance P, glutamate and nerve development factors which spur various receptors into action including NK1, NMDA, AMPA , glutamate metabotropic receptor and tyrosine kinase). Activation of NMDA receptors is responsible to initiate and maintain sensitisation. Normally, these receptor channels is blocked by Mg++ ions however, sustained release of glutamate, substance P and CGRP by nociceptors leads to membrane depolarisation forcing Mg++ out. This enhance the synaptic efficacy allowing Ca++ influx in the neuron. This activates the intracellular pathway and hence maintain central sensitisation. Fig 1 and Fig 2 depicts possible mechanism of CS.

Pain Sensitivity Questionnaire (PSQ) and the FCentral Sensitivity Index (CSI), have been formulated (Ruscheweyh et al., 2009; Mayer et al., 2012; Nijs et al., 2014) to evaluate different aspects of the received clinical pain. Considerable correlations could be observed in between the PSQ scores and ratings of pain intensity (Ruscheweyh et al., 2009; Sellers et al., 2013).

The CSI was originally designed to capture patient’s multiple somatic and emotional symptoms related to central sensitization (Mayer et al ;2012). Part A of the CSI assesses 25 symptoms common to central sensitivity syndromes( CSS )with a Likert scale from 0 (never) to 4 (always). Total score ranges from 0 to 100, and higher scores indicate a greater degree of symptomology related to CSS (Neblett et al ;2013). Part B of the CSI asks if subjects have previously been diagnosed with one or more specific CSS diagnoses. CSI score>40 is significant and provide high sensitivity and specificity for presence of underlying CSS and the following severity ranges have been recommended: Subclinical = 0 to 29; Mild = 30 to 39; Moderate = 40 to 49; Severe = 50 to 59; and Extreme = 60 to 100.(Neblett R 2016)

A systematic review on measurement properties of the CSI suggest that the tool produces reliable and valid data which can quantify the severity of several symptoms of CSS( Thomas Scerbo BS 2018). CSI is currently widely used as a tool to report symptoms of CSS however, its use as an alternative to Quantitative sensory testing is still challenged (Rogello A 2018). So, do we need more specific tool which can eliminate the need of quantitative sensory testing ?.One way is to undertake similar studies using fibromyalgia score . A number of other questionnaires have been developed such as pain DETECT questionnaire for assessing neuropathic components in chronic musculoskeletal pain, such as chronic low back pain (LBP) ( Freynhagen et al., 2006) and Osteoarthritis(OA) (Hochman et al., 2013) and mechanism-based classification questionnaire for LBP to screen symptoms and signs linked with a clinical classification of CS in patients with low back (leg) pain (Smart et al., 2012). However, to have a clear understanding about the spreading pattern of increased central involvement, it is useful to undertake clinical mapping of pain areas, referred pain areas, or areas with sensory hypo-/hypersensitivity which can be followed quantitatively over time. Area expansions and perceptual changes into a more diffuse character of the pain is observed in patients developing additional painful comorbidities (Thompson et al., 2010). Specific quantitative experimental tools for assessing CS have been discussed in several studies based on this proposed pathophysiology of CS-

1. Clinical Quantitative Sensory Testing (QST) studies have shown wide-spread sensitisation not only in case of neuronal injuries, but also found in conditions like migraine and chronic tension-type headache (Fernandez-de- Las-Penas et al., 2010). Similarly, contralateral and extra segmental wide-spread pressure pain hyperalgesia is found in, e.g. patients with painful knee OA (Arendt-Nielsen et al., 2015a) and chronic visceral pain conditions (Bouwense et al., 2013).

Clinical Quantitative Tangible Testing (QST) contemplates have demonstrated across the board sensitisation if there should be an occurrence of neuronal wounds, as well as found in conditions like headache and endless pressure compose cerebral pain (Fernandez-de-Las-Penas et al., 2010). So also, contralateral and additional segmental across the board weight torment hyperalgesia is found in, e.g. patients with excruciating knee OA (Arendt-Nielsen et al., 2015a) and endless instinctive agony conditions (Bouwense et al., 2013).

2.The element of temporal summation is a considerably capable procedure concerning the overall central sensitisation and its assistance is viewed as a proportion of expanded centralised advancement of pain stimuli. Temporal summation is considerably difficult regarding curtailment with customary analgesics or sedative systems (Petersen-Felix et al., 1996).Such an effect can be initiated through the utilisation of electrical, mechanical or modalities of thermal stimulation and can be initiated from the skin, musculoskeletal structures and viscera (Arendt-Nielsen, 1997; Arendt-Nielsen and Yarnitsky, 2009). This can be accomplished by either straightforward tapping the skin with a nylon fiber (Nikolajsen et al, 1996) or through the utilisation of institutionalized standardised automated user-independent methods, for example, thermal (Kong et al., 2013),or pressure (Nie et al., 2009).

3) Nociceptive stimuli generally coordinate the temporal integration as well as spatial integration (Quevedo and Coghill, 2007). Spatial integration also is dependent upon the central sensitisation process and the general sensitisation status (Bouhassira et al., 1995). In human beings, spatial summation can be evaluated in various ways through the application of stimulus to regional dimensions by, e.g. thermodes (Nielsen and Arendt-Nielsen, 1997), pressure probes (Nie et al., 2009), or cuffs (Polianskis et al., 2002).

4) It is by and large acknowledged that impaired descending pain modulatory pathways and activating of the facilitatory pathways may add to advancement and maintenance of CS (Wang et al., 2013; Ossipov et al., 2014; Bannister and Dickenson, 2016).

The process of pain control mechanism could be demonstrated to be prone to the influence of descending inhibitory noradrenergic pathway. This could further be considered to be accompanied in the form of e.g. a gain in the descending 5HT3 receptor-mediated facilitations (Bannister and Dickenson, 2016).Within the human populace, the evaluation as well as the resultant assessment of the descending pathways could be acknowledged as Conditioning Pain Modulation (CPM) (Yarnitsky et al., 2010). The CPM technique for the most part demonstrates a vast variation in the populace of healthy volunteers and in addition in patients as well and within patients who might be delegated as reducers of CPM (pain inhibition) or CPM increasers (pain facilitation) (L. Arendt-Nielsen 2018). It could be theorized that those patients who could be situated at in the lower quartile could be more prone to get affected regarding the pain stimuli which could be chronic in nature than those in the upper quartile who may on the other hand have a more defensive CPM framework (Skovbjerg et al., 2016). CPM viability decreases with age (Grashorn et al., 2013) and is affected by the gender identity as well (Martel et al., 2013) and conditions such as disorders of depression and psychosocial factors ( Nahman-Averbuch et al., 2016) This may clarify why psychiatric and psychological disorders may hint at sensitisation with absence of any specific peripheral catalyst in this regard.

In spite of the fact that multiplicity of questionnaires and quantitative investigation have been undertaken regarding the topic under consideration, the disappointment concerning the dearth of any proper understanding regarding the outcome of the responses of the phenotype with treatment (pharmacological, non-pharmacological, surgical) processes concerning the contextual manner of pain incurrence. The consequential development of other and more variegated tools could be deemed to be necessary regarding the effective performance of improvement of the factors such as sensitivity and specificity associated with those of the predictors (L. Arendt-Nielsen 2018). Notwithstanding the process that intensive research has been undertaken regarding the assessment of the concept under consideration along with the evaluation of the mechanisms of the factor of central sensitisation, the utilisation of the same within the clinical domain could be considered to be the object of much incurrence of adverse criticism( Hansson P 2014).

Pelvic organ Prolapse and central sensitisation

Pelvic Organ Prolapse could be identified as herniation of pelvic organs (uterus, cervix, bladder, rectum) which generally takes place within the or through the vagina of the patient on part of the causality of loss of pelvic floor support (Levator ani muscle, ligaments). This location of the pelvic floor could outline the neuromuscular unitwhich could provide the mechanism of support as well as the functional ability to impart control for pelvic viscera. Pelvic floor dysfunction generally involves the outcomes of weakness and generally leads to the complications of physiology in the form of pelvic organ prolapse.

Pelvic organ prolapse (POP) is a frequent indication for hysterectomy and pelvic surgery in women, with an annual age-related (surgical) in the range of 10 to 30 per 10,000 women confirmed in several large surgical database studies. According to the National Health Service England Hospital episode statistics (HES), the number of admissions for prolapse surgery is 1/1000 women (Dhinagar Subramanian 2009). Around one in 12 women reports symptoms of prolapse (Cooper J 2015). Lifetime risk of surgery for POP is 12-19% (Wu JM 1997, Smith FJ 2010). These numbers will increase in the current climate of increasing ageing population and rising obesity ( desamLazaro S et al 2016) The population prevalence for POP beyond the hymen (>stage 2) is probably between 3 and 6 % however loss of uterine support or vaginal support is seen in 30-76% women populations seeking gynaecological care. (Ellerkmann RM 2001, Swift SE 2000, Trowbridge ER 2008). The prevalence of POP increases with age. There are suggestions that prevalence increases by 40% with each decade of life (Swift S 2005). The risk factors for pelvic organ prolapse are higher parity ( Mant J 1997), vaginal child birth ( Lukacz ES 2006), advancing age( Swift S 2005), obesity, forceps delivery(Moali PA 2003), chronic constipation, occupations involving heavy lifting, connective tissue disorders such as those associated with variation of collagen type1 gene ( COL1A1) (Cartwright R 2015). The principal symptom manifested in prolapse is the feeling of bulge within the vagina that can be seen or felt (Barber MD 2009). A noteworthy extent of the proportion of female patients could put forward the complaint regarding a lingering sensation of pain or the pressure on the pelvis (Barber MD 2005).Different side effects could be identified in the manner of sensation of pressure on pelvis or vagina urinary incontinence, overactive bladder, weak or prolonged stream, Position change to start or complete voiding, incontinence of flatus or stool (liquid or solid) feeling of emptying being incomplete,experiencing of hard strains in defecation, faecal urgency, dyspareunia, decreased sensation, pain in vagina, bladder or rectum. Female patients could outline singular or combination of such symptoms. Apart from the bulge at the vagina, none of the indications are particular for POP and significant overlapping exist with other disorders regarding the pelvic floor (Barber MD 2006). Examination of the Pelvis is required to be characterized in the degree of prolapse and furthermore to distinguish the segments of the affected vagina. The pelvic organ Prolapse Quantification System (POPQ) is the evaluating framework for prolapse with most astounding reliable quality and is the most generally utilized framework. This research process is indicative of the methodical nature regarding the measures of anterior, posterior, and apical segment prolapse in centimetres in respect to a settled anatomical structure—the vaginal hymen (Bump RC 1996). Additional evaluations and tests are required whenever related bladder or bowel symptoms could become available. These are in type of urodynamics, defecating proctogram, anal manometry and Ultrasound Scan and MRI are utilized when side effects are not clarified by the prevalent testing process. The treatment for prolapse is offered when female patients develop different symptoms because of prolapse that they could find troublesome. The choices and options of treatment for the POP incorporate both preservationist and surgical intervention. The preservationist treatment interventions techniques are Pelvic Floor Muscle Training (PFMT) and inclusion of pessary alongside the advised methods of living with respect to getting more fit and keeping away from ailments such as constipation. Regulated Pelvic Floor Muscle Training is encouraged to be attempted in any event for 12-16 weeks ( Hagen S 2014, Wiegersma M 2014) to evaluate the result. Pessaries could be considered to be the mechanical devices which could be inserted within the vagina for the purpose of reduction of prolapse. Such instruments could be identified to be of different categories (e. g Gell horn, ring , shelf) and of different dimensions as well( Cundiff GW 2007). The objective of such treatment based surgery could be contended to be the restoration of anatomy as well as the improvement of bowel, bladder and sexual function. Invasive surgical medical procedure is typically offered to female patients with stage 2 or beyond POP through conducting the tests on the patients who could complain about vexatious indications in terms of symptoms with impact on their personal living qualities. The dangers related with invasive medical procedures are haemorrhage, recurrence, trauma to bladder, bowel, internal organs and considerable pain incurrence during intercourse. It is thus vital along these lines to evaluate the side effects of POP precisely with the end goal to accomplish more prominent fulfilment and evasion of damage by forestalling surgical intervention which could be not necessary at all. However, in clinical setting it has been seen that considerable extent of female patients bring forth the effect of lingering and heaviness concerning the sensation without a physically affirmed bulge on examination. It is realized that abnormalities exist between the pathology i.e. prolapse and level of lingering sensation. The suggested mechanism in this regard could be identified to be, includes the augmentation of pain transmission which could be an optional approach to a procedure portrayed before as central sensitization (CS) which likewise is observed to be a pathophysiological phenomenon for syndromes such as central sensitivity disorders like Fibromyalgia and chronic fatigue syndrome. There are certain symptoms which could be recognised in the manner of the sources of most significance concerning the under recognition of the critical symptoms such associated with the conditionalities involving FM and complex regional pain syndrome (Aries P Suhnan 2017). One such example could be outlined in the manner of hyperacusis which could be identified in the manner of enhancement of the sensitivities regarding the sounds which could contain particular volume extents and frequencies. One of the other acute symptoms of the FM or CSSs conditioning could be considered to be the sensation of being dragged. These are generally not specific completely to the process of prolapse. However, the current literature of research in this direction is not readily available in this regard. Levator myalgia, is additionally identified to be the contributor in a significant manner to pelvic floor dysfunction and issues pertaining to the sexual complications. Levator myalgia is a predominant health related condition which could be considered to be prevalent in 24% of female patients regarding the urogynaecologists practice (Adams K 2013). Levator myalgia might be considered as another conceivable appearance of central sensitisation, while considering indications of pain as well as the pelvic pressure based complications and symptoms, vaginal bulge, and urinary and defecatory dysfunction. (Kerrie Adams 2014). Previously undertaken studies have additionally exhibited that female patients with fibromyalgia(FM) are of the probability to have their hysterectomy compared with other members of their community, yet hysterectomy may not enhance the recovery from consistent pelvic torment in female patients with FM (Pamuk, Donmez, & Cakir, 2009; Santoro, Cronan, Adams, & Kothari, 2012). Likewise, patients with Chronic Pelvic Pain (CPP) could be contrasted with those without CPP and the results which could be observed could be of increasing danger of either not recovering at all or even worsening of the conditions after the patients could experience the transvaginal mesh revision (Danford, Osborn, Reynolds, Biller, and Dmochowski, 2015).The data of retrospective survey could provide the attestation to the identification of the existence of the somatic syndromes which could be functional in nature and these are generally independent as well as separate factors of risks regarding the hysterectomy within the female patients with bladder pain/interstitial cystitis(Williams and Clauw 2009). Female patients with the FM could be acknowledged to have reported considerably severe symptoms of pelvic floor complications and the extremities have been greater than the female patients who could have undergone aurogynaecology practices in spite of the fact that they had been in the similar age group as well (Kim Jones 2015) and form this specific reason it could be considered to be possible that sensory processing which could be enhanced could raise the level of awareness amongst female patients regarding the symptoms of organ prolapse in comparison with the female patients who could have no complications regarding FM. The evidence regarding the observation that sensation could be enhanced through the utilisation of multiplicity of pathways of dysfunctional pain could be abundant in nature (Julien, Goffaux, Arsenault, & Marchand, 2005) and these could explain the rationale of the patients being so much exhibitive of such symptoms. The available literature in this regard is indicative of the necessity for clinicians and physicians to receive proper training regarding the management of female patients who could be exhibitive of differential results regarding the FM conditionalities concerning the disorders related to pelvic floor in comparison with those female patients who could not be suffering from FM (Kim Jones 2015).

Summary and Purpose of the study

The performed review which has been observed so far could be observed as the following:

a) Both theFSSs or CSSs could be considered to be extremely dominant and thus sources of considerably burden for the patients and for the care service providers as well. This conclusive observation could be derived from the increased estimation of the prevalent FSSs within the selected sample of the community under consideration. Other factors such as the consistent and considerable curtailment in the QOL which could be reported by the affected patients suffering from the FSSs and the cost structures, both direct as well as indirect in nature, are considerably large which impede the proper patient care impartation concerning the effects of the FSSs. The element of central sensitisation is to be comprehended as the mechanism which could be proposed regarding the determination of pain levels within the physiology of the patients. b) POP could be identified as the dysfunction of the pelvic floor. This is to be ascertained as the indication, which is a common one, regarding the conditions of hysterectomy in postmenopausal women. This could have the capability to impart a considerable detrimental effect on the living quality and this could be contended to be identifiable within the extent of 30-70% of gynaecological consultation. The most predominant symptom which could indicate the occurrence of prolapse, could be identified in the form of a bulge. A considerable extent of numerical volume being composed by women patients could demonstrate the sensation of dragging or pressure effects at the pelvic area where the existence of the bulge could not be discoverable.

c) Levator myalgia known to be present in 24% of gynaecological patients represents another form of central sensitisation and contribute significantly in pelvic floor dysfunction. It may present as dragging sensation and pelvic pressure. d) Women with CSSs or FSSs have high symptom bother with their prolapses than women without CSSs These conclusions support that women presenting predominantly with dragging sensation, pelvic pressure and not the pelvic bulge may have underlying FSS or CSS contributing to their symptoms. Surgical therapy for prolapse is generally considered after conservative management has failed and when the degree of bother or symptoms of the prolapse are perceived to be greater than the risks of surgery. Owing to increased bother, women with evidence of central sensitisation or CSS may prefer treatment for prolapse at a stage of descent that would typically be considered less significant. Studies demonstrated that if a patient carries a diagnosis of fibromyalgia, 35 % of women reporting a bulge will have the leading edge of the prolapse within the hymen (Kerrie Adams 2014). Available surgical options may not improve the bulge sensation in these patients and may lead to a mismatch between patient and physician expectations and the patient with evidence of central sensitisation may anticipate unattainable results from prolapse interventions if her underlying condition is poorly understood or left untreated. The patients may end up in additional surgical procedure if they develop chronic postoperative pain. However, this may be critical as the pain system may already be in a facilitated stage. (Petersen et al., 2015b). Those patients with pain after revision surgery have continued enhanced temporal summation as compared with patients without pain (Skou et al., 2013) and develop more prominent spreading sensitisation than before the revision surgery (Skou et al., 2014a).

The current state of understanding has raised several questions including:

1. What is the role of CSSs in the development of chronic postoperative pain? 2. What is the role of CSSs in success of surgical treatment for prolapse? 3. How should the management strategies be optimised according to the profile of CSSs? 4. Does understanding CS/CSS help patients to get over their disappointments? 5. Does dragging sensation is one of symptoms seen in patients with CSSs? 6. Does identifying CS/CSSs preoperatively prepare patients from disappointment?. 7. Is CS a biomedical construct to blame for not getting better? 8. Is there a downregulatory cascade?

This value of this study is to enable us to find answers to some of these questions. The study consists of four parts/papers. The first paper aimed to capture the awareness of central sensitisation and CSS amongst gynaecologists and allied health professionals dealing with pelvic organ prolapse. The second paper aimed to identify the proportion of women having evidence of central sensitization presenting with various gynaecological disorders. The third paper aimed to compare the outcome of pelvic organ prolapse surgery in women with and without evidence of central sensitization. Finally, the last stage involved a qualitative study of patients with CS subjected to poor outcome following surgery. The purpose of the interviews will be to explore patient’s perception of the effectiveness of surgery for this condition and their understanding of their medically unexplained symptoms. We deployed the CSI in this study to identify appropriate women.

Chapter 1 – A survey on “Awareness of Central sensitisation and Central Sensitivity Syndrome amongst gynaecologists and health professionals dealing with pelvic Organ prolapse.”

Introduction:

Pelvic organ prolapse(POP) can profoundly affect a woman’s quality of life. Around 1 in 12 women living in UK report symptoms of pelvic organ prolapse (cooper 2015). However, quite often clinicians come across a clinical situation where symptoms are out of proportion of objective prolapse. As mentioned earlier this discrepancy can be due to variation in the processing of sensory stimuli. The suggested mechanism, involves the augmentation of pain transmission secondary to a process known as central sensitization (CS) which has been also found to be a contributor to many unexplained medical symptoms as in functional somatic disorders or central sensitivity syndromes(CSS) (Woolf 2011). The possibility of existence of central sensitization can be totally missed by the clinicians due to lack of awareness about this phenomenon (Kaur P 2015) This can make the management of these patients quite challenging leading to frustration and dissatisfaction amongst both clinicians and patients. Although, there is growing recognition of central sensitisation, variation exists in knowledge and understanding about this phenomenon among different specialities of medicine hence, we thought of conducting this survey amongst health professionals dealing with Pelvic organ prolapse. The purpose of this study is to capture the awareness of the concept of central sensitisation and CSS amongst health professionals dealing with pelvic floor dysfunction including general gynaecologists, urogynaecologists, incontinence nurse specialists, general practitioners and physiotherapists. We hypothesise that there is 1. little or no awareness about existence of central sensitisation amongst this group of health professionals. 2. Little awareness of increased bother with the symptoms of pelvic organ prolapse in patients with Central Sensitivity Syndrome.

Method –

This was a single point on line survey of understanding about CS/CSS amongst health professionals dealing with pelvic floor dysfunction. The survey was sent to urogynaecologists, gynaecologists(UK), to members of South Wales Incontinence group and General practitioners (Wales) by a single electronic mailing of the questionnaire. Ethical review was not sought as this was a survey of professionals and did not include any patient information. Closed questions were used to have better response (Stephen O’Brien 2016). The questions were designed by a group of sub-specialists urogynaecologists with the help of psychologist and covered domains in which it was felt that there is lack of understanding of the proposed condition i.e. central sensitisation. For example: Whether they have heard about central sensitisation and what are the common conditions contributing to the term central sensitivity syndrome. 2) whether they see patients with symptoms of prolapse out of proportion to the objective prolapse. The responses were in either yes /no or in form of rarely, occasionally, frequently and always respectively. Before rolling out the survey, pilot was undertaken in the local department to six health professionals including 2 gynaecology consultant, 2 physiotherapist, 1 incontinence nurse specialist, 1 obstetrics and gynaecology trainee. This was done to check the related categories have been covered and to check for the understanding of the survey. Minor amendments were done to the final survey based on the responses. Survey monkey was used to analyse the responses to the questionnaire. All questions and responses are listed in Table 1-7. The result was analysed on complete dataset following closure at 12 weeks after initial circulation. Two reminders were sent at 4 and 8 weeks after the initial circulation to all potential respondents. P value was calculated using one sample t test. XLSTAT was used for statistical analysis.

Result-

The initial invitation went to 200 professionals. A total of 70/200 (35%) responded to the survey. Of those 31% responded after initial circulation, 44% after first reminder and 25% after second reminder. The survey covered responses from both primary and secondary care. Out of 70 responses 48 were gynaecologist with 22 being urogynaecologists, 13 were GP, 7 were physiotherapists and 2 were incontinence nurse specialist(table 1). Thirty-three (47%) out of 70 responded that they encounter patients where the predominant complaint for prolapse is dragging sensation rather than bulge which was statistically significant(table 2). Twenty-eight (40%) felt that they frequently see patients where symptoms are out of proportion of the objective prolapse(table 3). Thirty -four (48%) do not believe that there is an element of central sensitisation where the symptoms are out of proportion to the objective prolapse findings and 10(14%) do not know(table 4). Significant number (32/70 -45%) of health professionals are unaware that patients with fibromyalgia or CFS or vaginal pain have higher bother with their symptoms (table 5). Similarly, significant number of health professionals have not heard the term central sensitisation or Central sensitivity syndrome (CSS) (48.5%).(table 6)

Table 1 showing response to Q1- Describe your role -

Table 2 showing response to Q2-How often do you see patients with pelvic organ prolapse complaining of dragging sensation rather than bulge?

Table 3 showing response to Q3- In your practice how often do you see patients whose symptoms of prolapse are out of proportion to/ with degree of prolapse?

Table 4 showing response to Q4- Do you believe that there is an element of central sensitisation in women where their symptoms are out of proportion to the objective prolapse?

Table 5 showing response to Q5- Do you believe that women with Fibromyalgia, chronic fatigue syndrome, ME or some vaginal pain have worse symptoms than women who do not have these conditions?

Table 6-part A showing response to - Have you heard the term central sensitisation or Central sensitivity syndrome?

Table 6-part b showing response to -Please circle the following conditions that can contribute to central sensitisation syndrome

Discussion –

Our survey demonstrated that statistically significant number of health professionals dealing with pelvic organ prolapse encounter women where their symptoms of prolapse is out of proportion to the objective prolapse. Significant proportion of them either do not believe or do not know that women with conditions like fibromyalgia, CFS, vaginal pain may have increased bother with their symptoms of pelvic organ prolapse and nearly half of them are unaware of the term Central sensitisation or CSS. We all know that professional assessment, communication and treatment are based on understanding of the disease patterns and in absence of this, the symptoms and distress of the patients persist. This may significantly put negative impact on patient well-being as well as patient doctor relationship. (Marianne Rosendal 2017). It has already been established that women with fibromyalgia, CFS, (CSS) seek interventions at the stage which is clinically less significant due to increased bother with their symptoms. (Kerrie Adams 2014). In these women, ignorance of underlying central sensitisation can lead to misdiagnosis/ misdirection of the symptoms and patients riding a merry-go-round of expensive and ineffective therapies including unnecessary surgeries. For example- women with pelvic pain can have pain in other parts of the body such as the bladder, bowel, and pelvic floor muscles with or without endometriosis and end up with multiple laparoscopies and even hysterectomy. Managing patients and their expectations where symptoms are inconsistent with the observable pathological findings can be challenging. Awareness of CS phenomenon may help to focus on treatment strategies which focus on the central nervous system such as medication, exercise, mindfulness, and cognitive behavioural therapy and avoid unnecessary surgical intervention (Kenneth Barron) with improved patient satisfaction. The educational aspects of central sensitisation and CSS should be broadened up to include not only pain specialists but also other relevant clinical disciplines including surgery, ,gynaecology). This is important as chronic pain patients often cannot understand why a limited trauma or even lack of a known/visible trauma can result in such disabling pain. Explaining that the pain system is not static but dynamic and undergoes changes helps the patients to better understand and accept their current situation ( L.Arendt-Nielson 2018). This can also help the clinician to offer them appropriate treatment strategies before embarking on any surgical intervention which will hopefully improve subjective outcome. The strength of our survey is that this is the first survey (to our knowledge) to explore the understanding of CS among Gynaecologists. The weakness of this survey is that the numbers are less.

Conclusion-

Our survey identified the gap in knowledge about CS among health professionals dealing with pelvic organ prolapse. It is clear that there is growing need for more understanding of central sensitisation and its relevance to patient’s symptoms as it may affect the outcome of the treatment. Understanding more about this condition should allow us to develop different strategies to manage these patients and improve patient satisfaction and minimise unnecessary surgical intervention. The survey helped us to establish the research project to answer this question

Chapter 2- The proportion of women with central sensitivity syndrome in Gynaecology Outpatient Clinics (GOPD)

Introduction:

Patients presenting in gynaecological outpatient departments frequently have symptoms which are not consistent with observable biomedical pathology. Some will have persistent pain presentations which are disproportionate to the pelvic pathological changes noted and on more thorough evaluation, will also have other more generalised symptomology such as fatigue, poor sleep pattern and perceptual sensitivities. This requires clinical vigilance particularly when patients are keen on definitive symptom relief despite modest clinical findings. Patients will often be distressed during the consultation, highlighting impaired function which they feel needs to be addressed by more aggressive management. Whilst it is common in primary care to manage patients having no clear diagnosis there has been little evaluation of the prevalence of this problem in secondary care. Historic evidence (Ninham C 2001) suggests that over 50% of those attending secondary care clinics also have a lack of a clear diagnosis resulting in suboptimal explanation of their presentation and so potentially ineffective management. Patients will find themselves being referred to more specialist gynaecological centres particularly if there have been previous unsuccessful attempts at surgical resolution. There has been little elucidation of the magnitude of this problem within the gynaecological arena. The patients described may or may not have a pre-existing diagnosis of a functional disorder. These include more widespread disorders such as fibromyalgia, chronic fatigue syndrome (CFS) or myalgia encephalitis (ME), medically unexplained symptoms (MUS), Central sensitivity syndromes or more regionally based diagnoses such as irritable bowel syndrome and interstitial cystitis. These are overlapping diagnoses, which are inconsistently used and there is continued debate about the aetiology and conceptualization of these various functional disorders. One diagnostic label which appears to be acceptable to both clinicians and patients is central sensitivity syndrome (CSS). (Yunus MB 2008) Recent research studies have shown that surgical intervention is less effective in those with a central sensitivity syndrome and potentially may exacerbate the problem in some( Gwilym SE 2011). Thus, accurate assessment and awareness of this problem may help avoid unnecessary invasive intervention and facilitate more appropriate customized conservative management. There is currently little evidence clarifying the prevalence of a central sensitivity syndrome among women presenting to a gynaecological outpatient’s department. This study was therefore, designed to estimate the proportion of women who might have symptoms suggesting the presence of a central sensitivity syndrome attending gynaecology out-patient clinics with general gynaecological disorder and in women with pelvic organ prolapse Method: This was a prospective study conducted at a tertiary teaching hospital and was approved by the West of Scotland Research Ethics Committee. The study was conducted from March 2014 to June 2014. All women attending gynaecology out- patient clinics and were above the age of 18 were included in the study. Women who were not able or willing to consent were excluded. The patient information leaflet was sent to all women before the clinic appointment. All women were asked to complete a validated Central Sensitisation Inventory (CSI) whilst they were in the Gynaecology clinic awaiting their appointment. The CSI was originally designed to capture patient’s multiple somatic and emotional symptoms related to central sensitization (Mayer TG 2012). Part A of the CSI assesses 25 symptoms common to CSS with a Likert scale from 0 (never) to 4 (always). Total score ranges from 0 to 100, and higher scores indicate a greater degree of symptomology related to CSSs. Part B of the CSI asks if subjects have previously been diagnosed with one or more specific CSS diagnoses. The CSI is presented in Appendices A and B. For screening purpose, a single cut-off score of 40 of the CSI was used to identify the group of women who may have syndrome of central sensitisation. ( Randy Neblett 2013). Proportions and confidence intervals were calculated using SPSS version 17. Fisher’s exact test was used to calculate p value. The CSI scores for pelvic organ prolapse (POP) patients were then compared to those with other general gynaecological diagnoses (such as Menorrhagia, pelvic pain, ovarian cyst, requesting sterilization, Overactive bladder symptoms, intermenstrual bleeding, Postmenopausal bleeding, cervical polyp, endometriosis). The comparison of CSI scores was performed between POP group and other general Gynae conditions to understand whether dragging sensation (one of the symptom of prolapse) is attributed to presence or absence of CSS and to identify proportion of CSS seen in POP group to be able to compare the outcomes of surgical treatment of prolapse. Two sample Kolmogrov-Smirnov test/Two tailed test was used to compare the distribution of CSI scores in women with evidence of CSS and pelvic organ prolapse and in women with evidence of CSS and other gynaecological conditions using XLSTAT. Results: About 480 women attended gynaecological clinics during this period. Three hundred and twenty-six women participated in the study. Overall 123 (37%) women achieved a score above 40. This could be interpreted as at an increased risk of underlying central sensitisation. Out of these, 43 had earlier confirmed diagnosis of migraine, 55 (44%) had depression, 39(31.7%) had anxiety, 11 had FM, 34 had confirmed diagnosis of IBS and 16 had CFS/ME. These conditions were picked up with the help of CSI and were found to be in combination of 2-3 in women with CSI scores between 40-60). Women (25%) with high CSI scores (60-91) were found to have a combination of 4-5 conditions. This may suggest that higher scores may reflect the presence of more conditions coming under the umbrella of CSS and hence giving more symptoms to patients. Out of 326 women, the main complaint of 86 women that attended the outpatient clinic was pelvic organ prolapse, while 240 women attended with other gynaecological concerns. The evidence of central sensitivity syndrome was established in 27 women (32%) with pelvic organ prolapse and 96 women (40%) with other gynaecological conditions (table7). The other general gynaecological conditions referred were Menorrhagia, pelvic pain, ovarian cyst, requesting sterilization, Overactive bladder symptoms, intermenstrual bleeding, Postmenopausal bleeding, cervical polyp, endometriosis, Fibroid, lichen sclerosis, women for Fenton’s, women referred for management of menopausal symptoms. The CS score for the general gynaecological conditions excluding pelvic pain were in range of (18-54). The CS scores for pelvic or vaginal pain were in the range of (32-91). There were 2 cases of known endometriosis and the scores were 59,60.

Mean CS scores for pelvic organ prolapse group and other gynaecological conditions were 33.9(SD 15.2) and 37.2 (SD 15.8) respectively. There was no statistical difference in overall mean central sensitisation scores between women with pelvic organ prolapse and other general gynaecological conditions (table 8). However, women presenting with pelvic or vaginal pain were found to have higher central sensitization scores (table 8).

The mean CSI score in women with POP with established evidence of CSS was 51.81(SD-9.11) and mean CSI score in other gynaecological conditions with evidence of CSS was 52.7(SD-10.43). (Table 9). The distribution of CSI scores in patients with evidence of CSS in both groups is shown in graph1 and graph 2 respectively. Two sample Kolmogrov-Smirnov test/Two tailed test used to compare the distribution, demonstrate that both groups follow very similar distributions (p value 0.999).

Discussion:

Clinicians will often assess patients who experience somatic symptomology which does not fit easily within existing biomedical diagnostic criteria. Some of these patients will have a clinical label of functional disorder. with the bodily symptoms, not demonstrably due to a specific underlying disease process (Engel GL1977). Research indicates that the widespread symptomology may be due to a dysfunction in central processing and possibly peripheral processing. (Bourke JH 2015). Central sensitization is a plausible theoretical explanation for persistence of such symptoms. Previously the term Medically Unexplained Symptoms (MUS) was used but was often felt to be unhelpful to both patients and clinicians. This could result in fractious consultations and disengagement by the patient with perceptions that the clinician thought that “the symptoms were all in their head”. (Sharpe M 2013) A potentially more acceptable umbrella term that is being increasingly adopted is central sensitivity syndrome (CSS). CSS includes conditions such as fibromyalgia, IBS, Temporomandibular joint disease (TMJ), chronic fatigue syndrome, tension headache/ migraines, restless leg syndrome, multiple chemical sensitivities, interstitial cystitis, myofascial pain syndrome, post-traumatic stress disorder (PTSD) and neck injuries such as whiplash. (Yunus MB 2007). The patients suffering from this syndrome have higher symptom bother due at least in part to underlying central sensitization (Kerrie Adams 2014,Shin Hyung Kim 2015). The development of this syndrome can also result in considerable psychosocial impairment, work disability, and increased utilization of health care resources (Creed FH 2012, Barsky AJ 2001, Shraim M 2013). The clinical challenge is to recognize, diagnose and manage this syndrome since it can be detrimental to the patient-doctor relationship as well as put patients at risk of iatrogenic harm from unnecessary diagnostic and surgical interventions (Fink P 1992, Warren JW 2014,Flynn TW 2011). Patients can potentially lose trust in the medical system as they perceive medical disbelief in their presentations while clinicians will unwittingly develop negative attitude towards them. Historically these patients have often been labelled “heart-sink” patients. It is therefore, imperative to identify patients with evidence of central sensitivity syndrome during the clinical decision making and ensuring appropriate interventions. This study explores the extent of this presentation within the gynaecological arena. Our study demonstrated that around 37% of patients attending our general gynaecological outpatient clinics (32% with POP and 40% with other Gynae disorders) could be considered as having a central sensitivity syndrome when using a validated CSS instrument. The CSI scores in both groups followed very similar distributions. The study indicated that women with pelvic pain and vaginal pain had higher scores on the CSI. This supports the potential pathophysiological role of central sensitization in chronic pelvic pain, irritable bowel and bladder disorder where the symptom complex is out of keeping with the clinical presentation as suggested by other authors. ( Randy Neblett 2013) The patients with CSS have higher bother with their symptoms and may well need the input of the multidisciplinary team involving pain team, physiotherapist and psychologist (if needed) rather than unnecessary diagnostic or surgical interventions. The strength of our study is that this is the first study in our knowledge so far to identify number of women having evidence of central sensitivity syndrome presenting with pelvic organ prolapse and general gynaecological conditions. This is also an attempt to identify possible hidden factors, which can be responsible for the poor outcome of surgical intervention in terms of improvement of patient’s symptoms as reported by Gwilym S and his team (Gwilym SE 2011). The weakness of this study is that there is no objective test utilized to identify CSS and so an independent measure cannot currently be used. The presence of a central sensitivity syndrome is based on a questionnaire; however; the questionnaire had been validated and tested for its reliability in diagnosing CSS (Mayer TG 2012,Kregel 2015, Yunhee choi 2013) There is very little in the literature to assess the role of central sensitisation for the outcomes of treatment. Following this study, a prospective study wasconducted to assess the outcome of pelvic organ prolapse surgery in women with evidence of CSS.

Conclusion:

Managing patients and their expectations in gynaecological outpatient departments, when symptoms are inconsistent with observable pathological findings, is challenging. This is further complicated when patients have a concomitant Central Sensitivity Syndrome which can also influence surgical outcome. Further research is required to elucidate the way this syndrome is best understood and managed in the gynaecological arena.

Chapter 3- A prospective cohort study to compare the outcomes of prolapse surgery between women with evidence of Central Sensitivity Syndrome (CSS) and women without evidence of CSS.

Introduction-

Pelvic organ prolapse (POP) is a frequent indication for hysterectomy and pelvic surgery in and accounts for 15-18% of hysterectomies and is the most common indication of hysterectomy in postmenopausal women.( Whiteman MK 2008).Pelvic organ prolapse is a complex condition as it has both functional and physical component to manage (Vitale SG 2016) and therefore can have a significant impact on quality of life and psychological well-being of the affected women.( Hefni M 2013, Varuso s 2010) According to the National Health Service England Hospital episode statistics (HES), the number of admissions for prolapse surgery is 1/1000 women ( Dhinagar Subramanian 2009)) and around one in 12 women reports symptoms of prolapse (Cooper J 2015).( cross reference- page 24 ( paragraph 2,3);page 25 (paragraph 1)) The principal symptom manifested in prolapse is the perception of a bulge within the vagina. (Barber MD 2009). A significant proportion of women however may also complain of a dragging sensation or pelvic pressure (Barber MD 2005). Women with pelvic pressure or dragging sensation may not have significant objective prolapse on examination. A possible explanation for this discrepancy is presence of underlying central sensitivity syndrome or central sensitisation. As earlier mentioned CSS includes conditions such as fibromyalgia, IBS, Temporomandibular joint disease (TMJ), chronic fatigue syndrome, tension headache/ migraines, restless leg syndrome, multiple chemical sensitivities, interstitial cystitis, myofascial pain syndrome, post-traumatic stress disorder (PTSD) and neck injuries such as whiplash. Recent research studies have demonstrated that the patients suffering from this syndrome have higher symptom bother from their prolapse [Kerrie Adams 2014] and surgical intervention is less effective in those with a central sensitivity syndrome and patients may well have worse outcome following surgical intervention as seen following decompression in impingement syndrome.(Gwilym SE 2011) It is currently unclear whether women who complain of a disproportionate dragging sensation to the objective pelvic organ prolapse or who have evidence of CSS/CS benefit as much from an operative approach as women with no evidence of CSS/CS .There are no studies to date to compare the outcome of prolapse surgery in these group of women. The aim of our study is to compare the outcomes of pelvic organ prolapse surgery between women with evidence of CSS and women without evidence of CSS

Method- This was a multicentre prospective cohort study . The study was approved by the West of Scotland Research Ethics Committee(13/WS/0319). Patients-Women for pelvic organ prolapse surgery ( as agreed by patient and surgeon), Inclusion criteria- Women for POP surgery who were willing to participate, can give informed consent and are able and willing to comply with all study requirements were included in the study.Exclusion criteria-Women who could not give informed consent, who needed concomitant urinary or faecal incontinence surgery, with previous prolapse surgery in the same compartment and severe vaginal pain were excluded from the study. Intervention- surgical treatment for pelvic organ prolapse. Outpatient/ Telephone follow ups to assess the subjective and objective outcome of surgery. Comparison – The outcome of pelvic organ prolapse surgery was compared between women with evidence of central sensitivity syndrome and women without central sensitivity syndrome. Outcomes – Both subjective and objective outcomes were compared as per the IUGA/ICS POP outcomes (Toozs-Hobson 2012) The primary outcome was to evaluate and compare the prolapse symptomology using the validated Pelvic Organ Prolapse Symptom Scale (POP-SS) between two groups at 3 months after surgery . The secondary outcomes were to comparePatient global impression of improvement- PGI-I , to assess and compare the objective residual, prolapse stage at original site by POPQ ,to assess and compare and measure pain quality by using McGill’s short pain Questionnaire for somatic pain and to assess Satisfaction with surgery by using the acronym EGGS (E- Expectations, G-goal setting, G-goal achievement, S-satisfaction between the two groups . Following study questionnaires and forms were used in the study Central sensitisation inventory (CSI) – See paper 2 /chapter 2 PGI-I – The PGI-I has been validated and consists of a single item that asks the participant to rate improvement of her condition using a seven-point scale with the following anchors: very much better, much better, a little bit better, no change, a little bit worse, much worse, very much worse. Participants are considered to have positive outcome if they respond that they are “very much better” or “much better” (Yalcin I and Bump R 2003, Srikrishna S et al 2010) POP-SS – The POP-SS consists of seven items, each with a 5-point Likert response set (0 = never, 1 = occasionally, 2 = sometimes, 3 = most of the time and 4 = all of the time) .Total score ranges from 0-28.The question format and response set were modelled to standardise outcome measures in pelvic floor dysfunction research and clinical practice. (Hagen S 2009) McGill’s pain questionnaire short form – The main component of the SF-MPQ consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or 3 = severe. Three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective and total descriptors. Maximum score is 45 ( 33 on somatic subscale), with higher scores indicating worse somatic pain. The SF-MPQ also includes the Present Pain Intensity (PPI) index of the standard MPQ and a visual analogue scale (VAS). ( Melzack R 1987) EGGS – The term EGGS has been coined to improve physician understanding of these outcomes. (E- Expectations, G-goal setting, G-goal achievement, S-satisfaction) (Brubaker L 2005) Women undergoing pelvic organ prolapse surgery were recruited and asked to complete: the Central Sensitisation Inventory (CSI) to identify women with possible evidence of CSS. The CSI was originally designed to capture patient’s multiple somatic and emotional symptoms related to central sensitization (2). Part A of the CSI assesses 25 symptoms common to CSS with a Likert scale from 0 (never) to 4 (always). The total score ranges from 0 to 100, and higher scores indicate a greater degree of symptomology related to CSSs. Part B of the CSI asks if subjects have previously been diagnosed with one or more specific CSS diagnoses. The CSI is presented in Appendices A and B. For screening purposes, a single cut-off score of 40 of the CSI was used to identify the group of women who may have a central sensitivity syndrome.(Neblett R 2013) Women were also asked to complete the validated prolapse symptom severity score (POP-SS) , EGGS and McGill’s pain questionnaire before surgery. The objective assessment of prolapse was done using pelvic organ quantification system (POPQ) (Bump et al 1998) by vaginal examination to assess the stage of prolapse. The prolapse surgery was conducted with the surgeons being blinded to the status of central sensitisation. Data on basic demographics like age, parity and BMI was also collected. Women were then followed up at 3-6 months after their surgery (by telephone and/or clinics) and were asked to complete: 1 the prolapse symptom severity score (POP-SS), 2 EGGS, 3 McGill’s pain questionnaire and 4- patient global impression of improvement questionnaire (PGII). The objective assessment of Prolapse was done by vaginal examination (POP-Q). Successful outcome of surgery was defined if 1) there is minimal improvement of 6 points in POP-SS score for ques A1-A4 2) (the minimally important difference (MID) for the POP-SS. If the symptoms are “very much better” or “much better” on PGII scale 3) if the patients had achieved their goals and satisfied with their surgery 4) If there is improvement in McGill’s pain scores . The objective prolapse is said to be persistent if the prolapse is up to or beyond hymen during maximum Valsalva manoeuvre. The definitions used are similar to definition used in previous large epidemiologic studies looking at prevalence and trends of pelvic organ prolapse ( i.e. greater than point -1)( Wu JM et al 2014) on POPQ. For the ease of discussion women with evidence of CSS were designated as group 1 and women without evidence of CSS were named as group 2 Sample size -Hagen et al 2008 report the POPss scale, which is scaled from 0-28 is likely to be skewed, therefore for a simple sample size we will use non-parametric tests. Again, from Hagen the type of differences in scores may be 6 points on the scale, with two group average points being 9 and 3. We did not have any good estimates for variance so choosing a conservative value equal to the difference (6 points) using a Mann-Whitney rank sum test we would need at least 20 per group for a power of 80% at a 0.05 significance level (two sided). Statistical analysis was performed using SPSS VERSION 2.5 . Chi Square test and non -parametric (Mann Whitney U ) tests were used to compare the data.

Result- Total 78 women were recruited. Complete data was available in 62 patients. Out of 62 patients 23 patients were with evidence of CSS and 39 patients were without evidence of CSS.

There were few repeat POPQ assessments as some of the patients declined vaginal examination (n-4 in group 1 and ) and some had telephone follow up (n-6 in group 1 and ) because patients did not attend outpatient clinics. The mean BMI was 28.9 in group 1 and ,26.7 in group 2 with mean Parity of 2. The cut off CSI score of 40 was used to identify women with evidence of CSS ( chapter 2).The mean CSI score in group 1 was 53.13 ( std deviation-11.90). The mean CSI score in group 2 was 21.23 (std dev-9.76)( table 10).The distribution of CSI scores in both groups is shown in fig 1 . Two sample Kruskal wallis test was used to compare the distribution of CSI scores, demonstrate that both groups followed different distribution(p-.000). (fig1).

Mean stage of prolapse in group 1 before surgery was stage II for anterior (mean POP-Q system point Ba, 0 +/- 1.41, stage II for posterior ( system point Bp, 0.3 +/- 0.7) and stage I for apical, uterine ( mean point C, -2.60 +/- 2.7) and in group 2 mean stage of prolapse for anterior compartment was stage III(mean POP-Q system point Ba, 1.5 +/-2.56), for posterior compartment stage II ( mean system point Bp-.1+/- 1.64) and stage II for apical compartment ( mean system point C, -1.05 +/- 2.85). Regarding the primary outcome to evaluate prolapse symptomology, women with evidence of CSS have higher pre- and post-operative POPSS scores compare to women without evidence of CSS. This was statistically significant (table 11 & 12). The study also demonstrated that women with evidence of CSS ( Group 1) have higher bother with their symptoms with less objective prolapse compare to women with no evidence of CSS. ( table 13) (p-0.00)

Seventeen(73.9%) women in group 1 demonstrated improvement of minimum 6 points on POP-SS scale ( a1-a4 ) where as 38(97.4%) women showed improvement in group 2. Although both groups have improvement in Mc Gills pain score following surgery, pain scores were higher in group1 than group 2 both pre and post- surgery (table 14,15) .

Majority(95%) of women in group 2 achieved their goals and were satisfied with the surgery ( 37/39), while only 69.5% achieved their goals and were satisfied with the outcome of the surgery in group 1. ( p-0.005) (table 16) .

Seventeen (73.9%) reported their symptoms to be very much better or much better on PGII scale in group 1 while 97.4% women in group 2 reported symptoms to be much better or very much better ( table 17)(p-0.00)

In terms of persistence of objective prolapse 2/13(15%) women in group-1 had persistence of prolapse with successful anatomical correction in 11/13 ( 85%) while, 2/25 ( 8%) had persistence of objective prolapse in group 2.(p- 0.00) with successful anatomical correction in 92% women.(table 18,19)

Discussion

Our study has demonstrated that women with evidence of CSS has less successful outcomes of surgery as far as patient satisfaction, achievements of goals and persistence of symptoms and pain are concerned. Although, there was no persistence of objective prolapse 11/13 women (85%) , the global impression of improvement was seen only in 74% in women with evidence of CSS, whereas in women without CSS, the global impression of improvement was seen in 97.4% women with no persistence of objective prolapse in 92% women.These finding demonstrates that in group with CSS, the subjective outcome is less favourable than in group without CSS.Jacob N and his team demonstrated that patients with presurgical evidence of FMS-like symptoms experienced a less significant improvement in pain and no improvement in somatic symptoms as opposed to patents without evidence of FMS, who experienced significant improvement in pain and other symptoms. ( Jacob N 2017). This is similar to the findings of our study where patients with evidence of underlying CSS has less satisfaction with the surgery and less improvement in their symptoms. Central sensitization, is a concept developed over recent years to explain the possible pathogenesis of chronic pain in which there is no clear anatomical basis.The understanding of CS and CSS is more than a semantic consideration and appears to carry important practical relevance. Patients can potentially be stratified according to the degree of the symptomology relating to the underlying CSS. This information may subsequently tailor the treatment modalities used to improve the chance of successful outcome of the treatment. Management of women who are considered candidates for prolapse surgery typically includes anatomical evaluation by vaginal examination/POPQ and effect of prolapse on women’s quality of life. While these factors will undoubtedly continue to be important in the process of surgical decision-making, the results of the current study imply that additional factors may be worthy of evaluation.eg CSS as it might lead to persistent symptoms despite anatomical correction. Issues such as disturbed or unrefreshing sleep, symptoms of irritable bowel, difficulty with memory and concentration, presence of widespread pain, previous diagnosis of fibromyalgia, CFS, TMJ, PTSD and depression, which are components of the CSS, are all useful and easily obtainable parameters to incorporate in our assessment. It also seems appropriate and sensible to include identification of myofascial trigger points during vaginal examination as a part of prolapse assessment as it is evident that Levator myalgia , present in 24% of gynaecological patients represents another form of central sensitisation and contribute significantly in pelvic floor dysfunction ( Adams K 2014). Patients then can be stratified according to the degree of the symptoms and signs relevant to possible presence of underlying CSS, which implies that the treatment modalities may be tailored based on the presence of these parameters . There is evidence in literature that baseline preoperative pain is a predictor of chronic postoperative pain after hysterectomy [Theunissen M 2016)]. Similarly, meta-analysis of patients undergoing total knee arthroplasty found that pain at other sites, catastrophizing, and depression were found to be predictors of chronic postoperative pain (Lewis GN 2015). Our study also demonstrated that there is persistent higher somatic pain score in women with evidence of CSS. Women with FM were also found to report pelvic floor symptoms at a severity greater than women presenting to a urogynaecology practice despite being the same age (Kim Jones 2015) and therefore, it is possible that enhanced sensory processing makes women with FM more aware of organ prolapse symptoms than women without FM. This was similar to the findings of our study . FM is also found to be a risk factor for development of pelvic pain after mesh implantation for treatment of pelvic organ prolapse (Geller EJ 2017) There is a large body of evidence that sensation is enhanced through a variety of dysfunctional pain pathways (Julien, Goffaux, Arsenault, & Marchand, 2005), which may explain why these patients were highly symptomatic . Various treatment modalities have been used in effort to desensitise the CNS in patients with CS. These are pharmacological ( pain modulators), manual therapy such as release of myofascial trigger points and stress management and to be able to provide comprehensive treatment to women with CSS , it is advocated to combine the treatment modalities known to target CS ( Jo Nijs 2011). Our study has also demonstrated that there is need to evaluate these strategies in women with POP and CSS to obtain optimal outcome. The strength of this study is that this is the first study to compare the outcomes of prolapse surgery between women with underlying CSS and women without CSS. The limitations of the study that there is no objective quantification of Pain (NB need to state that POP does not produce pain but heaviness and dragging) and measurement of CS and relatively small number of patients with short period of follow up. However, the CSI used to identify women with CSS is a validated questionnaire and there were no previous studies to evaluate women with POP for underlying CSS to guide us on numbers. The other limitation of the study was few patients who had post-op POPQ. due to either telephone follow up or refusal of patients to be examined vaginally at the time of follow up. It is important to note that the results of the current study should not be interpreted as avoiding prolapse surgery in patients with CSS but careful considerations to be given for proper assessment of these group of women with understanding of their needs and may be adding alternative treatment strategies as discussed with full discussion at counselling and consent for the risk of persistence of symptoms. The study highlights the need to find the strategies to best manage women with POP and CSS. Should we offer physio in all stage 1 and 2 POP in this group or women ?. Should we do trial of pessary in all women in this group first, to assess its effect on symptoms and then undertake surgery only if symptoms are improved. Further research is required to answer these questions. However, with the results of our study we can recommend that we should screen all women for CSS before POP surgery so we can better counsel on the likely outcome. In Conclusion, our study has demonstrated that there is less favourable outcome of surgery in women with CSS especially in terms of persistence of symptoms, pain and overall satisfaction. Main expectation of women in both groups was to become comfortable however, only 70% of women in group 1 felt their goals were met and were satisfied while 95% of women in group 2 felt their goals were met and were satisfied ( see table 7). This enables us to counsel women for realistic expectations from the pelvic organ prolapse surgery and evidence of underlying CSS is found to be useful predictive factor in decision making regarding prolapse surgery. Additional research is indicated in order to evaluate the interaction between CSS and surgical interventions, interaction between CSS and treatment interventions targeting CS and the impact on the symptoms of pelvic organ prolapse. Additional research is also needed to assess the impact of early treatment of prolapse on the symptoms of CSS/CS.

chapter 4- Understanding women’s experience of prolapse surgery in women with evidence of central sensitivity syndrome and their view on reasons for poor outcomes: A qualitative study

Introduction

There is an increasing trend to include outcome measures based on patients expectations. Expectation from the treatment can be affected by several factors such as previous personal experience, those of friends and relatives, mental state of patient and attitude of clinician. This can impact on the understanding of the concept of cure in surgery. Achieving normal restoration of anatomy might be the aim of the surgeon but, for the patient it may not be a cure if there is persistent or development of new symptoms related to bowel, bladder or sexual function following surgery. ( Srikrishna S 2008). Several qualitative studies have been undertaken to understand women’s preference of treatment( M basu 2011), women’s perception of risk reduction ( Kate Brain 2003), exploring patient experiences both pre and operatively to produce positive outcome following treatment( Sacha L 2015). This enables us to make our patients partners in decision making of the proposed treatment to potentially enhance outcome. It has been previously demonstrated in the prospective cohort study ( chapter 3) that there is poor subjective benefit following prolapse surgery in women with central sensitivity syndrome . This qualitative study was undertaken to understand patients experience, expectations of prolapse surgery in women with central sensitivity syndrome and their views on reasons for poor outcome of surgery. This will help us to identify areas of improvement in this cohort of women to improve positive outcome.

Method

The method has utilised a qualitative study, through the utilisation of semi structured interviews amongst the female patients suffering from Central Sensitivity Syndrome, who had experienced poor treatment results after undergoing pelvic organ prolapse surgical intervention procedure and the study was performed in the month of July 2018. The research investigation was endorsed by the Scotland Research Ethics Committee. Female patients were monitored after 4-6 months post-medical surgical procedure the prospective study in a coordinated manner (part 3) to analyze the results of pelvic organ prolapse surgery on female patients who had been suffering from as well as those who did not have central sensitivity syndrome. Female patients with considerably decreased measures of results, which had been dependent on the symptom persistence rate and improvement scale of global impression of patients were recognized by the researcher under consideration. Having affirmed that formal assent had been recorded amid the preliminary pilot study, semi structured interview based investigation has been scheduled to be undertaken. The necessary opportunity had been accommodated additionally for various different questions identified with the research exploration while the phone based acquisition of the introductory consent based conformation could be achieved. Interview based meetings were directed by two independently operating research specialists who had not been engaged with considerations of patient care. All the procedure had been undertaken within a private room situated inside the clinic. Data of demographics as well as the details of surgical interventions were preserved through a proforma which had been standardised in the earlier consultations preceding the interviews. Meetings kept going from 15 - 25 minutes (Mean length: 17.8 minutes) and had been recorded in running audio tapes. All of such recordings were anonymised and interpreted through transcribing them through the utilization of Trint software.

Analysis

The thematic approach based framework had been utilised regarding the data collection and analysis which had been put forward by Marshall & Rossman. This could be understood to be an approach which has been generic in nature concerning the analysis of data and is a commonality concerning the utilisation in Qualitative research. This provides the capability regarding the analysis of the source of data concerning the primary themes and concepts so as to equip the data research and analysis process to reduce the accumulated information into effective ideas.

The structure of the analysis used in this study has been demonstrated below 1. The organisation of the process of familiarisation of the data through the proper listening of the interviews and through the formulation of the transcripts which could be consistently read and reiterated by 2 researchers for the purpose of familiarisation of themselves with the information which is embedded into the transcripts.

2.The recognition of all of the categories regarding the thematic constructs which could indicate the significance of the necessity to address the fundamental research questions.

3. The indexing of the interviews and the coding of the categories in an according manner.

4. The utilisation of the QSR NVivo 8 Computer-Assisted Qualitative Data Analysis Software for the purpose of charting the interview derived data.

5. Once coding system had been completed, the primary themes had been identified and summarised to determine the conclusions which could then be derived from the most important as well as vital thematic constructs. The process of analysis of such data has outlined the discussions regarding the utilisation of categories as well as coding to further the objective of the research study. To this effect, the process of the coding had been also modified accordingly to better accommodate the variable in the most appropriate manner regarding the highlighting of the messages which could underscore the entire analytical effort investment process.

Results

A total of 23 women with evidence of CSS had POP surgery during the prospective cohort study. Out of 23, 7 had poor subjective outcomes in terms of patient global impression of improvement, goals achievement and satisfaction, 1 patient had achieved their goals partially. These eight women with poor outcome were approached . Five women replied and agreed to the interview. The demographics , detail of surgery, CSI scores patient global impression of improvement scores, POPSS scores, McGill’s score, POP-Q, expectation and goals of these women are shown in table 1 and 2. All the questionnaires used have been explained in chapter 3

Five categories were identified.

Understanding

Women’s understanding of their symptoms and their relationship with prolapse was poor. The majority sought help due to their bowel, bladder problems rather than feeling the bulge of prolapse. They were aware of prolapse only when they visited a clinician for their bowel or bladder concerns. Typical examples include: “Initially I went to doctors for haemorrhoids and during smear test,they told me I had a prolapse.”(p2) “I saw the GP due to feeling of urgency to urinate, burning sensation when I would urinate and it was getting worse and not manageable. My first thoughts were that I was suffering from cystitis.”(p4) “Below were very uncomfortable with leakage of stuff coming down with often pains in the lower back.”(p5) “I got a lot of diarrhoea, I had difficulty in emptying the bowel properly, it was very uncomfortable. I had to put my hand up and press my perineum to empty my bowels and, in the end, I had to do irrigation which was not fun.”(p1) Some women expanded on this theme with comments that shows their worries and concerns rather than them being bothered with the symptoms. “I understood if this is prolapse, then that can get worse and can actually become external and that something I did not want.”(p2) “My concern was the worsening of urinary leakage and worsening of back pain “(p5) “I think everybody on their mind thinks cancer.”(p2) “I was concerned of it getting worse and with old age more likely to have lots of problems.”(p3)

Preparedness

It is a common issue that women don’t seek advice or help for pelvic floor dysfunction and suffer in silence as they feel embarrassed about the condition and find it difficult to talk. In this study, most were prepared to seek treatment for their symptoms and concerns , however, social circumstances could affect the timing of seeking help. “I had the advice basically I had the problem for years and years before I did anything about it and the reason for that was because I had one son who was severely disabled with severe learning disabilities so could not have operation till he was living at home.”

Expectations

All Women were hoping to have normal bladder, bowel , sexual function along with complete resolutions of discomfort and back pain except one “I would be able to function normally, not have problems in opening bowels, able to have normal sex.”(p1) “I expected it really improve my bowel control.”(p3) “I hoped it would all go away- the discomfort, back pain, pain on passing urine and urgency.”(p5) “I have little expectation other than to prevent the problem getting worse”

Relevance

None of the women said that they feel that there is any relevance between persistence of their symptoms or poor outcome and the presence of an underlying central sensitivity syndrome. They all felt that persistence of symptoms were either due to poor surgical repair or some unidentified internal pathology in bowel/ bladder. “I would say that the reasons for no improvement in my symptoms is due to bowel and nobody says anything. I believe I have got cyst in the bowel. In terms of repair, smear people did not say anything that anything changed or I have prolapse so I assume everything’s okay.”(p2) “I don’t know whether things have come back down again or something like that I don’t know, I had a full hysterectomy but repair jobs? I don’t know whether one did well.”(p5) “I know repair was not good , I could feel stiches turning around(p1) “I had no issues with healing, the defect is gone however, it has make vagina very tight and has been very- very uncomfortable and painful which I am not happy about.”(p3) “I felt my all symptoms are due to prolapse totally.”(p4)

Dissatisfaction , Frustration and Anger

Women felt that their concerns for the persistence of their symptoms after surgery has been dismissed and not properly listened and addressed. They felt frustrated and started developing disbelief in the advice offered by the medical professionals. “ They said it healed all well and held nicely up and that’s all in my head. Till now I haven’t done anything about it because I thought should I be making fuss about this. “(p3) “I was actually more concerned with my haemorrhoids and bowel and no further treatment for this was offered.“Very sensitive subject. I was told that there is nothing wrong. I am only constipated.”(p2) “I knew the repair had not worked but nobody believed me. To be honest, I just gave up and stopped going to the hospital.”(p1)

Discussion-

The outcome assessment and definition of cure is poorly defined in clinical settings ( Robinson D 2003). Usually, objective cure is favoured in clinical trials whereas subjective cure is preferred in daily clinical practice.(Robinson D 2007). The objective data may lack the sensitivity to compare the outcomes in a meaningful way to women. In this qualitative study we have explored women’s view on prolapse surgery and the reasons for poor subjective outcome following surgery in a cohort of women with a central sensitivity syndrome . The results from this study would suggest that most women presented with bowel , back pain, dragging sensation or sexual dysfunction which are not necessarily cured by surgery. This finding is similar to previous studies ( Srikrishna S 2008). Dissatisfaction is not found to be related to the type of surgical procedure but appears to relate to unrealistic expectations from surgery. For Example,Finley in his study demonstrated that the degree of satisfaction is high if orthognathic surgery patients were well adjusted psychologically and that the majority seek orthognathic surgery for aesthetic reasons. Dissatisfaction was not related to sex, age or procedure. Patients who were dissatisfied tend to have higher neuroticism scores on the Eysenck Personality Inventory and those patients who had had unreal expectations of post-surgical pain, numbness and swelling(Finlay PM 1995). It’s important to consider that there may be other psychological factors responsible for sexual dysfunction . Similarly, there may be a primary bowel problem leading to constipation. Equally, there may be underlying central sensitisation responsible for a heightened perception of this dragging sensation or back pain. Women expressing the wish to cure these symptoms may thus face high level of dissatisfaction in the post-operative period. This finding has been demonstrated in this study . None of the women had heard about central sensitisation or any link between severity of symptoms and conditions included in central sensitivity syndrome during their journey from presentation to treatment. All of them felt that poor outcome is either due to poor repair or some internal unidentifiable pathology of bowel/ bladder. However, they do feel frustrated and angry for not been listened and believed for the persistence of their symptoms. This raises questions on the surgeon’s ability to manage women with chronic problems and complex needs. It may very well be due to their lack of understanding of a potential underlying condition responsible for a heightened Symptom profile. The study is possibly the first qualitative study to explore women’s views of poor surgical outcome from prolapse surgery in women with a Central sensitivity syndrome. However, the limitations are its small numbers therefore, the data should be interpreted with caution. It is also important to consider whether open ended questions were good enough to capture adequately the views of these women. By undertaking this study, we have gained insight about women’s concerns, frustration, and anger after poor outcome from surgical treatment especially when clinicians dismiss their concerns. This appears to highlight the need for the involvement of other health professionals such as physiotherapists, specialist bowel and incontinence nurses and psychologists who can help the surgeons to gain understanding of the patients concerns as a whole rather than focussing primarily on anatomical correction of the problem.

Conclusion-

This qualitative study highlights that there is little understanding that a process involving central sensitisation can affect the outcome of the surgery. It may be due to a lack of awareness and understanding of this condition amongst clinicians themselves. It would be interesting to assess whether women with evidence of a central sensitivity syndrome but positive outcomes post prolapse surgery have greater understanding or whether awareness of central sensitivity syndromes affects their decision making regarding surgery.

Summary of Findings:

Quite often we were seeing patients having multiple re-operations for their symptoms of prolapse but with little anatomical prolapse and therefore, we undertook this project to have more insight into the reasons of the poor outcomes for this group of patients hypothesing that presence of underlying CSS could be one of the factor. One of the primary findings of this project is the identification of a gap in the knowledge, understanding and awareness of central sensitivity syndrome amongst clinicians. There is still disagreement that patients with central sensitivity syndrome might have more bothersome symptoms compared to those without. Similarly , patients rejected the hypothesis that central sensitisation could play a role in negative outcomes following POP surgery. They believe that less improvement in their symptoms is either entirely due to poorly performed surgery or some internal pathology which has not been identified. The second part of the study revealed that around 32% of women with pelvic organ prolapse presented to gynaecological outpatient clinics with evidence of CSS as judged by the validated CSI questionnaire and around 40% with other gynaecological problems had evidence of CSS. The prospective cohort study conducted to compare the outcomes of pelvic organ prolapse surgery in between two groups i.e. ( those with and without CSS),found that women with CSS had less satisfaction, impression of less improvement and persistence of pain over the period of observation. Although the predominant expectation of women from surgery in both groups was to become comfortable with respect to prolapse symptoms, only 70% of women in group with CSS felt their goals were met and that they were satisfied while, 95% of women in group without CSS felt their goals were met and were satisfied. Only 74% women with CSS reported the symptoms to be “very much better” or “much better” compared to 97.4% of women without CSS who reported their symptoms to be “very much better” or “much better”. This was statistically highly significant There was persistence of pain after surgery in women with CSS with higher pain scores compared to women without CSS who have very low pain scores. These findings are likely to be of interest to clinicians as it will enable them to adequately counsel those women with CSS during consenting for the possible outcome of the surgery while also enabling those patients to have realistic expectations from the surgery.

Implications and conclusions

Several factors account for poor outcomes following POP surgery such as patient characteristics , co-morbidities, unrealistic expectations, high BMI , infection, smoking and poor surgical technique/surgeon factors ( NB these are difficult to quantify) One of the factors identified in this study is presence of underlying central sensitivity syndromes which might contribute to an unfavourable outcome from surgery. The measure of evidence concerning the existence of aspects related to the altered central pain modulation e.g.CSS which could lead to the detrimental surgical outcomes could be considered to be extensive. Such problems inhibit the possibility of recovery of the patient and could as well curtail the resolution of the complete pain and the complete functional restoration and these cumulatively impact the patients emotionally (I.A.C Baert 2016, Lewis GN 2015). As far as the existing literature is concerned, there could be found nothing regarding the resultant outcomes of the pelvic organ prolapse surgery of the patients who could be suffering from CSS and the corresponding study could be acknowledged to be a pioneering effort in this direction to demonstrate that the complete resolution of the problems and associated symptoms could be impossible amongst the female patients in comparison to the patients who could not have been suffering from CSS and this generally leads to considerable extent of frustration and gloom amongst the patients under consideration in this context. With regards to treatment of CSS, both pharmacologic and non -pharmacologic approach are described in the literature in order to reduce sensitisation. Regarding pharmacological approach – drugs can work either by: (1) blocking the peripheral drive which is maintaining the sensitisation or (2) inter acting with the central transmitter systems involved in the facilitated gain.( L A Nelson 2017). Examples of drugs showing an inhibitory effect on temporal summation are e.g. dextromethorphan (Price et al., 1994), ketamine (Arendt-Nielsen et al., 1995), imipramine (Enggaard et al., 2001), gabapentin (Arendt-Nielsen et al., 2007), oxycodone (Suzan et al., 2013), and venlafaxine (Yucel et al., 2005) . Serotonin-noradrenaline reuptake inhibitors (SNRIs), such as duloxetine, have a broad efficacy across a number of different chronic pain conditions, such as Osteoarthritis, fibromyalgia and peripheral neuropathic pain (Lunn et al., 2014). The a2-δ ligands centrally inhibit the release of neurotransmitters (e.g. noradrenaline, serotonin, substance P) and potentially reduce CS by decreasing descending pain facilitation (Donovan-Rodriguez et al., 2006) The effect of repeated dosing with tapentadol (μ-opioid receptor agonist plus a norepinephrine reuptake inhibitor) has been seen in various chronic pain conditions (Riemsma et al., 2011) such as OA pain (Steigerwald et al., 2012b), Low back pain (Buynak et al., 2010 ) painful peripheral diabetic neuropathy (Schwartz et al., 2015 ), and cancer pain (Kress et al., 2014). Non -pharmacologic strategies such as exercise and cognitive modulation can influence pain sensitisation in some patients. Some of the symptoms of POP like back pain , vaginal pain, bowel dysfunction, bladder dysfunction can be due to a non-relaxing pelvic floor or Levator myalgia which is also a type of central sensitisation ( Kerrie Adams 2014). Physical therapies to alleviate hypertonicity should be undertaken in these women before surgery. There are other strategies for non-relaxing pelvic floor such as injection of local anaesthetics on trigger points, acupuncture, biofeedback, neuromodulation which can also be used( Stephen S 2012) However, the important question is whether the therapeutic strategies ( pharmacological and non- pharmacological ) aiming to desensitise the central nervous system before any surgery in patients with CSS improves the outcome of the surgery or not ? Further longitudinal studies are required to establish this. Another important feature highlighted in the qualitative part of the project is that women perceive the reason for poor outcome was either due to poorly performed surgery or underlying missed pathology. The role of counselling is again highlighted in this section of the study. Appropriate counselling about surgery can only be undertaken if we have understanding of all the conditions and factors which can affect the treatment outcome otherwise this could result in challenging consultations anddisengagement by the patient with perceptions that the clinician thinks that “the symptoms were all in their head” (Sharpe M 2013). There are clearly gaps in the awareness and understanding of CSS and CS by both clinicians and patients. It might therefore be important to screen women for CSS and educate them about the condition so that they have better understanding of the cause of their bothersome symptoms while helping surgeons to better counsel them on the possible outcomes. This might impact on the decision to proceed with surgery or not. Further work to replicate our findings might be required before this form of screening is undertaken.

Limitations

The current project contain a number of limitations. Firstly, the survey, like many surveyshad a low response rate . Secondly, there was no objective quantification of pain (although POP rarely produces acute pain but rather heaviness and dragging)and there are no other biological markers of CS. The numbers were small and there was a relatively short period of follow up. The CSI questionnaire used to identify women with CSS is a validated questionnaire and there were no previous studies to evaluate women with POP for underlying CSS to help with a power calculation. However, our data might help power a larger study . Another limitation was that few patients had post-operative POPQ evaluation due to either telephone follow up or refusal of patients to be examined vaginally at the time of follow up. The POPQdata was not completed by anindependent researcher which might result in observer bias. In quantitative study, the limitation was the small numbers and so, the data should be interpreted with caution. It is also unknown whether open ended questions were sufficient to capture adequately the views of these women and the interviews were undertaken sometime after surgery and therefore the answers may be affected by recall bias.

Recommendations

POP significantly affects a woman’s quality of life and results of treatment can be unpredictable It’s important to identify risk factors responsible for the poor outcome after surgery and the findings of our study suggest that patients with underlying CSS can be one such group . Therefore, screening women for CSS prior to undertaking surgery for POP might be a useful way to identify and counsel patients. A broader therapeutic approach in terms of physiotherapy and cognitive treatment should be actively consideredin these women especially If there is little prolapse objectively e.g. stage 1 or 2 prolapse. Before proceeding with surgery in such patients, a trial of vaginal pessary for POP could be undertaken in all women with CSS to assess the impact of prolapse reduction on their symptoms before considering surgery. If the pessary alleviates the symptoms then there are chances of improvement after surgery however, if the symptoms are not helped after reduction of prolapse with pessary then surgery is not the preferred treatment for that patient. This will allow us to counsel women with POP and CSS for realistic expectation and allow women to decide whether they would chose the path of surgery or not. Further studies with long term follow up are required to assess the impact of attempting to reduce central sensitisation by pre-surgical pharmacologic or non-pharmacological intervention on the outcome after surgery to provide guidance on how to best manage women with POP and CSS. There is likely to be a role for physiotherapists and psychologists in the management of these patients both before and after surgery.Finally, both care providers and women need to be educated about CSS and CS and clinicians need to know how to assess various manifestation of central sensitisation and in particular how to manage patients with a central sensitivity syndrome such as Fibromyalgia. In the short term our evidence suggests that the validate questionnaire tool CSI should be used before any patient considered for pelvic organ prolapse surgery

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