Introduction

Parts of this chapter have been reproduced from Lewis et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Clinical background

Chronic pelvic pain (CPP) is as common as asthma, migraine and back pain,2 and affects more than 1 million women in the UK.3 It is associated with significantly reduced quality of life4,5 and a 45% reduction in work productivity, and it has been estimated that caring for women with CPP in the UK costs £154M annually.6,7 CPP can be associated with an underlying pathology, such as endometriosis, but in up to 55% of women no obvious cause can be identified at laparoscopy.7 Management of CPP is difficult when no pathology is identified, as no established gynaecological treatments are available, but careful exploration of the patient’s symptoms and history may point to non-gynaecological causes of CPP for which some effective treatments exist.

Increasing evidence demonstrates that people suffering with chronic pain conditions show many physiological similarities to healthy pain-free controls, no matter what/where the underlying cause of the pain.8–11 This has led some to argue that ‘chronic pain’ should be considered as a disease in its own right,12 and at the very least points towards the use of treatments targeting central pain mechanisms in addition to disease-specific therapies.

Drugs targeting central pain mechanisms

There are three main classes of drugs that are used as adjunctive analgesics for both the treatment of neuropathic pain and the treatment of conditions thought to have a central component (e.g. fibromyalgia):13,14 tricyclic antidepressants, gabapentinoids and selective serotonin and noradrenaline reuptake inhibitors. However, much of this use is currently ‘off-licence’, as the specific indications for which each drug is licensed varies. At the time of the design of the pilot study for this trial (GaPP1),1,15 there was an increase in the prescription of these adjunctive analgesics for CPP in both primary and secondary care16 owing to their effectiveness in managing other chronic pain conditions. The rate of patients newly treated with gabapentinoids in primary care tripled from 2007 to 2017 and, by 2017, 50% of gabapentinoid prescriptions were for an off-label indication. We also observed at the time that there was considerable use of gabapentin for CPP (largely because of its perceived effectiveness in other chronic pain conditions). First, with the support of the Scottish Primary Care Research Network, we surveyed a random group of general practitioners (GPs). Of the GPs who responded to our survey, 74% said that they would consider gabapentin as a treatment option for CPP in women. Second, with the support of the Royal College of Obstetricians and Gynaecologists, we surveyed a random group of gynaecologists and 50% said that they currently prescribe gabapentin for CPP, and > 90% said that they would consider gabapentin as a treatment option for this condition. Since then, awareness and use of gabapentinoids has continued to increase in gynaecology, with the publication of reviews in this area17 and reference within the National Institute for Health and Care Excellence (NICE) guideline for endometriosis18 to the NICE guideline on neuropathic pain for treatment of CPP with neuromodulators.19 This was despite the fact that there was no good-quality evidence of efficacy in CPP specifically on which to base this practice, and the fact that these drugs were not licensed for CPP. One randomised controlled trial (RCT)20 compared the efficacy of gabapentin and amitriptyline for CPP in women with a range of pelvic pathologies; however, this study was open label, there was no placebo group, the population had a mixed aetiology of pain symptoms and the numbers analysed were small (n = 56). Another placebo-controlled trial of 60 women from Egypt21 did show a statistically, and potentially clinically, significant difference in patient-reported pain after 12 weeks of treatment, but the variability of the patient responses was considerably lower than all previous studies of CPP and not generalisable outside that population. The trial was not powered to detect meaningful differences and had substantial attrition.21 Our own pilot trial (GaPP1)1 was not powered to detect meaningful differences and experienced significant attrition. There were no studies investigating pregabalin or duloxetine for this indication. Interestingly, there was one RCT of pregabalin for treating CPP in men that showed no benefit of treatment over placebo after a 6-week course of treatment.22 During the course of our trial a subsequent paper was published (albeit a retrospective database analysis rather than a clinical trial) that reported greater benefit of gabapentin than pregabalin for CPP in men.23 To date, to our knowledge, there remain no studies investigating duloxetine for this indication in men or women. Given the benefit of gabapentin over amitriptyline in the one existing study of CPP in women,20 this was the adjunctive analgesic chosen for further investigation in GaPP1 and subsequently the full trial reported here (GaPP2).

Although there is limited evidence of the efficacy of gabapentin in CPP, there is proven benefit of the efficacy of gabapentin in other chronic pain conditions. A systematic review showed that the number needed to treat against placebo to be 5.8 [95% confidence interval (CI) 4.3 to 9.0] to achieve at least 50% pain-intensity reduction in painful diabetic neuropathy (829 patients); 7.5 (95% CI 5.2 to 14) to achieve at least 50% pain-intensity reduction in postherpetic neuralgia (892 patients); and 5.4 (95% CI 2.9 to 31) to achieve at least 30% pain-intensity reduction in fibromyalgia (150 patients).16 Furthermore, gabapentin is a drug that is very well tolerated: all-cause withdrawal rates are similar to placebo (gabapentin, 20%; placebo, 19%; n = 17 studies; n = 3063 participants).16

Recent safety concerns regarding gabapentinoids

Despite clinical trial data suggesting gabapentin to be well tolerated, there have been significant concerns regarding the risk of both abuse and dependence associated with the use of gabapentinoids, both their use clinically and their illicit use recreationally. There is certainly good evidence of misuse of gabapentin in the population as a whole, and this seems to be particularly the case for individuals with a history of substance abuse and if there is concomitant opiate or benzodiazepine use.24,25 Of relevance to GaPP2, it does appear that men may be more vulnerable to these effects than women.26 Nonetheless, given that gabapentinoids are commonly prescribed for symptoms that are significantly more prevalent in women (chronic pain, anxiety and climacteric symptoms), large data sets will be required to discern with certainty whether or not a sexual dimorphism exists. However, in April 2019 (while GaPP2 was recruiting), gabapentin and pregabalin were reclassified as controlled drugs under the Misuse of Drugs Act 197127 as class C substances, and scheduled under the Misuse of Drugs Regulations 2001 as ‘schedule 3’.28

Recently, there has also been increased concern of the side-effect profile of gabapentinoids.29 A large, retrospective, cohort study identified an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries and road–traffic incidents and offences with gabapentinoids. The risks were, however, significantly higher for pregabalin than for gabapentin, and associations with adverse outcomes were mainly seen in the 15–24 years age group. In fact, gabapentin was not associated with an increased risk of suicidal behaviour and was associated with a decreased risk of road–traffic incidents and offences, and violent crime. These data suggest that the risks of pregabalin, particularly in adolescents, may have been underestimated; however, these data are reassuring for gabapentin, except when combined with opiates or for those with a history of substance abuse.

Potential mechanism of action of gabapentin in chronic pelvic pain

The gabapentinoids are thought to exert their analgesic effect by binding to the alpha-2/delta subunit of voltage-gated calcium channels on primary afferent neurons, thereby reducing the release of neurotransmitters from their central terminals.30–32 In line with the observed centrally mediated adverse effects (somnolence, dizziness and nausea) of gabapentin, neuroimaging studies have also demonstrated gabapentin to exert an effect on the activation of specific brain regions in both humans33,34 and rats.35 The preclinical study35 looked at anaesthetised animals at rest and observed reduced activation in areas of the brain known to be involved in pain perception after infusion of gabapentin; these data were also consistent with known pharmacokinetics with respect to transport of gabapentin across the blood–brain barrier. The human studies33,34 were both carried out on healthy volunteers, but used an induced model of central sensitisation (capsaicin induced). They show that gabapentin is able to reduce the abnormal brainstem activity in response to a mechanical stimulus associated with this sensitised state,33 and that this effect could distinguish between gabapentin, ibuprofen and placebo.34 Of relevance to the GaPP2 trial, the first study was undertaken in a cohort of 12 men33 and the second in a mixed cohort of 25 subjects, 13 of whom were women.34 There has been one study36 exploring the central effects of pregabalin on a female cohort of fibromyalgia patients (n = 27). To the best of our knowledge, there are still no other studies focusing on the effects of gabapentin in a solely female cohort of chronic pain patients, except a pilot neuroimaging analysis from the GaPP1 study.37

Clinical research questions

1. What is the efficacy of gabapentin compared with placebo in the alleviation of pain in women with CPP without any obvious pelvic pathology?
2. Does gabapentin, compared with placebo, significantly improve physical and emotional functioning in women with CPP without any obvious pelvic pathology?

Mechanistic substudy research questions

1. Are there central nervous system changes in women with CPP and no underlying obvious pelvic pathology?
2. What is the effect of gabapentin on central pain processing in women with CPP and no underlying obvious pelvic pathology?
3. Are there any baseline functional magnetic resonance imaging (fMRI) measures that correlate to response to treatment?
4. Are there clinical measures that correlate to response to treatment?

To address these research questions, we proposed the following:

1. to conduct a high-quality, multicentre RCT comparing gabapentin with placebo in women with CPP without any obvious pathology
2. to explore possible subgroup effects of gabapentin owing to the presence or absence of dysmenorrhoea, psychological distress and hormone treatment
3. to conduct fMRI studies on a representative subsample of trial participants to identify changes in brain activity that are altered by gabapentin and identify potentially predictive brain activity markers of treatment response.