Item: BMJ-UK; Article ID: hora036025;
Article Type: Standard article; TOC Heading: Practice; DOI: 10.1136/bmj.j3520
BMJ paper Is gabapentin effective for women with unexplained chronic pelvic pain?
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1572
Uncertainties
Is gabapentin effective for women with unexplained chronic pelvic pain?
Andrew W Horne, Professor of Gynaecology and Reproductive Sciences and Honorary Consultant Gynaecologist,1 Katy Vincent, Senior Pain Fellow and Consultant Gynaecologist, 2 Roman Cregg, Consultant in Pain Medicine and Anaesthesia and Honorary Senior Clinical Lecturer,3 Jane Daniels, Professor of Clinical Trials4[Author: Please supply job titles for all authors]
1MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
2Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK
3Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
4Nottingham Clinical Trial Unit, University of Nottingham, Nottingham, UK
Correspondence to AW Horne
Education, doi: 10.1136/bmj.j3624
This is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The series advisers are Sera Tort, clinical editor, and David Tovey, editor in chief, the Cochrane Library. To suggest a topic for this series, please email us at
This article is linked with a commentary on ‘What to do in the light of this uncertainty’ by James Duffy (Education, doi: 10.1136/bmj.j3624)
Box start
What you need to know
• Up to half of all women with chronic pelvic pain in secondary care have no obvious underlying pathology
• For pain relief, a combination of drugs, physiotherapy, and cognitive behavioural therapy can be tried
• There is no strong direct evidence to support the use of gabapentin for women with chronic pelvic pain, and uncertainty remains regarding its safety, and clinical and cost effectiveness
Box end
Chronic pelvic pain in women is a common presentation in primary care. Pain persists or recurs over at least six months3 and can be distressing, affecting physical function, quality of life, and productivity.1 Nearly 38 per 1000 women are affected annually in the UK. Global estimates range from 2.1% to 24% of the female population.2 3
Endometriosis, adenomyosis, adhesions, pelvic inflammatory disease, irritable bowel syndrome, bladder pain syndrome, nerve entrapment, and musculoskeletal pain are among the common causes.3 4 These are often identified by screening for pelvic infection (eg, Chlamydia trachomatis), pelvic imaging (eg, ultrasound, magnetic resonance imaging), and diagnostic laparoscopy.5 Some 40%-55% of women with chronic pelvic pain in secondary care appear to have no obvious underlying pathology based on clinical history, examination, and investigations.3 6 Management of this group of women is challenging and there are few established gynaecological treatments. The Royal College of Obstetricians and Gynaecologists recommends a combination of pharmacological interventions, physiotherapy, and cognitive behavioural therapy.5 Often women try several methods sequentially or in combination.3 7 8 Figure 1 presents a common diagnostic and treatment approach that women with chronic pelvic pain might be offered.
Fig 1Flow diagram showing the possible “treatment journey” (and timelines) for a woman who presents to primary care with chronic pelvic pain(adapted from guidance from the Royal College of Obstetricians and Gynaecologists)
One option is the prescription of neuromodulators, including gabapentin, which can help address some of the potential pain generating/maintaining mechanisms that could be responsible. Neuromodulators primarily affect modulation of pain by the central nervous system, in contrast with non steroidal anti-inflammatory drugs, for example, which act on peripheral mediators of inflammation. Neuroimaging studies have shown gabapentinoids to affect brain function in models of central sensitisation and in patients with chronic pain.9 10 Like most neuromodulators, gabapentin and pregabalin are only licensed for peripheral neuropathic pain11 and their use in chronic pelvic pain is off licence. There is uncertainty around the effectiveness and safety of gabapentin in women with chronic pelvic pain.
What is the evidence of uncertainty?
Box start
Box: Search strategy
We searched PubMed, Embase, the Centre for Reviews and Dissemination database, and the Cochrane Library from their inception to 20 December 2016 for published studies on effectiveness of gabapentin for treatment of women with chronic pelvic pain.
Box end
There is very sparse data from trials of the use of gabapentin in women with chronic pelvic pain. We found one randomised controlled trial comparing gabapentin and amitriptyline for chronic pelvic pain in women with a range of pelvic pathologies,12 and our own recently published pilot trial (GaPP1) comparing gabapentin with placebo in women with chronic pelvic pain and no identifiable pelvic pathology.13 In both studies, gabapentin was shown to improve pain scores compared with the control arm; however neither study has sufficient power to guide practice.
Data on harms from trials in women with chronic pelvic pain is lacking, although side effects such as drowsiness have been reported.
In the first trial, 56 Austrian women with chronic pelvic pain were randomised to receive either gabapentin or amitriptyline. At 24 months, gabapentin was shown to improve pain scores on a visual analogue scale (0-10), with a mean pain score in the gabapentin group 1.5 points lower than in the amitriptyline group (95% confidence interval −2.06 to −0.94), although the difference was not clinically important.12 14 Side effects occurred equally in both groups (no extractable data). This study had no placebo arm, and physiological outcomes and impact on quality of life were not evaluated.
In our pilot trial designed to inform a future multicentre randomised controlled trial, 47 women with chronic pelvic pain with no identified pathology on pelvic imaging and diagnostic laparoscopy, were randomised to gabapentin (22 participants) or placebo (25 participants). Patient compliance to the trial was poor, and 25 patients (53%) completed six month follow-up. Participants on gabapentin had lower pain severity (brief pain inventory difference 1.72 points on a 11 point scale, 95% confidence interval 0.07 to 3.36), and a greater improvement in mood (hospital anxiety and depression score difference 4.35 points, 95% confidence interval 1.97 to 6.73) at six months than in those allocated to placebo. The study was not large enough to produce reliable estimates of treatment effects. 17/22 gabapentin participants had an adverse event compared with 16/25 in the placebo group. Most events were mild, such as drowsiness. There were two reported exacerbations of chronic pelvic pain involving inpatient hospitalisation in the gabapentin group, although it is not possible to confirm these were related to the study drug.
Is ongoing research likely to provide relevant evidence?
We searched the World Health Organisation trials portal, ClinicalTrials.gov, and the ISRCTN registry, for ongoing randomised controlled trials in women with chronic pelvic pain comparing gabapentin with no treatment or a control treatment or placebo to alleviate pain. Our search identified our own trial, GaPP2 (box 1).
Although this study will likely provide evidence on whether gabapentin (monotherapy) is beneficial in the management of women with unexplained chronic pelvic pain, further research is required to determine the effectiveness of gabapentin in women with chronic pelvic pain with endometriosis,15 or other pain conditions, and how it compares with other treatments. Box2 lists recommendations for further research.
Box start
Box 1 Ongoing trial on effectiveness of gabapentin in women with unexplained chronic pelvic pain
The GaPP2 trial (ISRCTN77451762) is a multicentre trial in the UK. Recruitment started in November 2015 and will continue for 24 months.
Population: 300 women of reproductive age with chronic pelvic pain, without demonstrable pelvic pathology on pelvic ultrasound and diagnostic laparoscopy and not desiring pregnancy.
Intervention/comparator: women will be randomised equally between gabapentin and matched placebo.
Primary outcome measures: patient reported worst and average pelvic pain scores, on a numerical rating scale (NRS) of 0-10, collected over four weeks.
Secondary outcomes: physical and emotional function, quality of life, satisfaction with treatment, concomitant use of analgesics; doctor/hospital consultations; time off work and work “presenteeism.”
Box end
Box start
Box 2 Recommendations for further research
Research question
What is the clinical effectiveness, cost effectiveness, and tolerability of pharmacological monotherapy compared with other pharmacological interventions (monotherapy v combination therapy), physiotherapy, and cognitive behavioural therapy for treating women with chronic pelvic pain?
Population
Women with a diagnosis of chronic pelvic pain with and without demonstrable pathology. Demonstrable pathology could include: endometriosis, adenomyosis, adhesions, pelvic inflammatory disease,, irritable bowel syndrome, bladder pain syndrome, nerve entrapment, and musculoskeletal pain
Intervention(s)
Any pharmacological agent as monotherapy or combination therapy, physiotherapy, and cognitive behavioural therapy. The pharmacological agents include
(a) Neuromodulators, eg, amitriptyline, imipramine, nortriptyline, duloxetine, gabapentin, pregabalin
(b) Opiates, eg, co-codamol, co-dydramol, dihydrocodeine, fentanyl, morphine, oxycodone, tapentadol, tramadol
(c) Ovarian suppressive drugs, eg, combined oral contraceptive pill, progestogens, gonadotrophin releasing hormone agonist
(d) Others eg, cannabis sativa extract
Comparator(s)
Any of the above listed pharmacological agents as monotherapy compared with any combinations of the above listed pharmacological agents as combination therapy compared with physiotherapy and cognitive behavioural therapy. Compare the treatment response across different groups of participants with different underlying aetiology
Outcome(s)
Patient reported global improvement (on a 7 point scale)
Patient reported improvement in daily physical and emotional functioning including sleep (on a 9 point scale)
At least 30% and 50% pain reduction (on a 0-10 -numerical rating scale)
Mean change from baseline pain scores (on a 11-numerical rating scale)
Withdrawal due to adverse effects of the pharmacological agents.
Adverse effects of the pharmacological agents
Health related quality of life (for example, EuroQol five dimensions questionnaire).
Study design
Randomised controlled trial or prospective cohort study.
All participants should have a “wash out” period before assessment for inclusion in the study.
Baseline pain scores between treatment groups should be equal and clearly documented.
Concomitant medications should not be allowed, or should be restricted and maintained at stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.
Rescue pain medications either not be allowed or, if used, their use should be accurately documented
Box end
What should we do in light of the uncertainty?
This article has a linked commentary on what we should do in light of this uncertainty[AH1]written by an author with fewer financial interests (Education, doi: 10.1136/bmj.j3624).
Box start
How patients were involved in the creation of this article
A patient representative kindly agreed to review this paper. She asked to clarify the criteria for chronic pelvic pain. We have now used the definition from the International Association for the Study of Pain, though consensus on criteria for defining chronic pelvic pain is lacking. The reviewer patient also stressed that clinicians must be vigilant in the assumption that no treatable pathology exists. We have clarified the importance of history, examination, and investigations to identify any pathology. We also include the estimated proportion of patients based on earlier studies in whom no pathology might be detected.
Box end
We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: AH reports collaborating with Roche on a project to identify a biomarker for endometriosis. KV reports advising Grunenthal on a set of documents regarding conditions associated with chronic pelvic pain and receiving a grant from Bayer Healthcare to investigate pain mechanisms in endometriosis. KV also received payment from Bayer Pharmaceuticals on chronic pelvic pain. RC consulted Allergen on the mechanism of botox to treat chronic pelvic pain.[Author: Please confirm that these are correct][AH2]
Provenance and peer review: commissioned; externally peer reviewed.
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[AH1]I would be grateful if this comment about financial interests is removed – it implies all of the authors have personal financial interests in gabapentin – and this is incorrect. Any perceived conflicts are listed below.
[AH2]This is correct