Pain the 'fundamental' symptom in endometriosis but is still poorly understood

Published 11 October 2018

Still little agreement on whether chronic pain in endometriosis is driven by central or peripheral nervous system: Campus meeting hears the case for both.

The hot topic in chronic endometriosis pain right now is which part of the nervous system - peripheral or central - is the major influencer. This reflects the fact that its underlying mechanisms are still poorly understood, despite pain being the fundamental symptom in endometriosis.

At a September Campus meeting on pain in endometriosis Steve McMahon described the central vs peripheral debate as causing 'quite a ding-dong', while outlining his case for the role of pain generators outside the brain and spinal cord. While 'not denying' central cases, he proposed that peripheral sensitisations are an important therapeutic target for endometriosis and so could benefit patients. The evidence he presented included the 'one-in-a-million' person with a SCN9A mutation, a gene that encodes a sodium channel only expressed in nociceptors and not in the brain. The nerve fibres carrying the mutation are 'not as excitable', so patients feel no pain, he explained. McMahon referenced the case of one patient who experienced a totally pain-free childbirth. He noted that this sodium channel is 'absolutely obligatory in the sensation of pain'.

Data on heart-sink patients whose lives are 'turned upside down by pain', he said, strengthen the argument for peripheral sensitisation. A study found that symptomology disappeared temporarily after a local anaesthetic block was administered. 'Their chronic pain is driven by peripheral processes- it's sustaining a lot of that abnormality,' he added.

A more relevant study involved injecting local anaesthetic into the bladders of women with bladder pain syndrome. Chronic discomfort was abolished in 60% of participants, while 40% experienced no benefit. The inference is that some may have predominantly peripheral-driven pathology and others mostly central. McMahon suggested that stratifying patients into those with or without a clear peripheral drive could assist experiments, and help understand and treat patients 'more rationally'.

As for the molecules driving this activity, the neuroscientist outlined that 'too many' could be driving the pathology. The list of ligands capable of sensitising receptors is long, and the worst case may be that a 'whole cocktail' is responsible. The picture for what underpins the sensitisation at a molecular level though is clearer, with only three mechanisms involved.

The search for specific molecular markers of pain hypersensitivity is already under way. McMahon referenced the work on CHRNA3 and noted optical imaging and sequencing technologies as offering new insights into how nerve fibres become sensitised.

The case for central mechanisms was outlined by Katja Wiech. Her presentation began with the message that the neurological signature of pain is complex, involving a 'wide scattered network' of affected regions. As the psychologist stated: 'I'd be lying if I said I was presenting a nice story.' In chronic pelvic pain, studies show that structural changes such as a decrease in grey matter could be a sensitisation predictor, and the good news is that these changes are partly reversible.

Meanwhile, psychology is becoming acknowledged as an 'influencer' in chronic pain. Wiech said the 'new hype' is around expectations of pain which is also the current focus for her work. A recent study she conducted left her 'stunned' by the effects of expectation on behaviour. The methodology involved giving each patient the same dose of pain-relieving infusion. The analgesic effect was doubled in those told they may experience pain-relief, a finding confirmed by brain scans.

The fear among patients is that chronic pain will affect their identity: 'everything is tinted' by being a pain patient. Wiech described experiments involving laser stimuli to the back of the foot showing that a high threat of pain increases the pain itself. It is not just healthy volunteers who experienced this - those with endometriosis also reported higher anxiety. This suggests a direct link, said Wiech, for the first time between two parts of the brain - the anterior insula and middle cingulate cortex.

As she pointed out: 'Some find it incredibly distressing not knowing when their pain will come on, and not having anything available to deal with it.' Her message was that the more that's known about the mechanisms underlying endometriosis pain, then the greater 'the potential to use psychological therapies' to manage it.

Aside from the role of central and peripheral influences, hormones have a role too in chronic pelvic pain. Katy Vincent referenced the importance of the oestrogen oestradiol as a modulator of pain behaviour. In addition, evidence exists associating high progesterone levels with a reduction in pain unpleasantness. A study by Vincent found the hormone reduces pain-related brain activation, as evidenced through (brain) scans.

However, estradiol and progesterone only influence the emotional regulation network when levels of both are high. Gaps exist in the literature around the effect of low estradiol and high progesterone. What is clear, says Vincent, is that low levels of both hormones make healthy women 'pain-vulnerable', and that chronic pain is more sensitive to hormonal variation.

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