Functional somatic syndromes

1. Functional somatic syndromes Emerging evidence Mary Blatchford September 2018 HEOPSmary@drsblatchford.com

2. Original Source Bourke J H et al. The common link between functional somatic syndromes may be central sensitisation Journal of Psychosomatic Research 78 (2015) 228–236. Lumpers and splitters

3. What are they? • Irritable bowel syndrome • Fibromyalgia • Chronic fatigue syndrome • Temporomandibular joint disorder • Idiopathic lower back pain • Multiple chemical sensitivity • Tension headaches • Interstitial cystitis • Chronic pelvic pain/vulvodynia • Myofascial pain syndrome • Lyme Disease

4. Functional Gastrointestinal Disorders • IBS • Chronic abdominal/pelvic pain • Indigestion • FGID are common and chronic • Prevalence: • 5%--‐20% Primary care • 40+% of GI OPD. • Chronic relapsing/remitting course • Can be severe : suicide risk x 2-3

5. Seek the depression • Antidepressants for abdominal pain and discomfort • NNT = 4 for 50% pain reduction • NSAIDs NNT= 3 • Tramadol NNT = 5 • TCAs, SSRIs, SNRIs – Improvement in overall wellbeing in most patients • Improve IBS independent of depression and anxiety • In the gut, stress potentiates inflammation (measured by inflammatory markers) and increases permeability (diarrhoea)

6. Lumpers DSM V now lumps functional somatic syndromes together. • Patients with one FSS are more likely to also suffer from another. • 51% of patients with CFS and 49% of patients with FM also have IBS. •  Those with FGID are more sensitive to visceral stimuli, which are interpreted as pain (such as balloon distension in the rectum).

7. Multiple symptoms &psychopathology Kroenke et al, Am J Med, 1997

8. Features common to FSS Response of pain to centrally acting agents: • Antidepressants: TCAs SNRIs • Antipsychotics: quetiapine, amisulpride, • Alpha 2 delta ligands: pregabalin, gabapentin Cognitive–emotional processes common to the FSS and associated with amplification and extension of pain: • Somatisation • Catastrophising • Fear avoidance • Kinesiophobia • Autonomic nervous system dysregulation • Sleep disruption • Neuroendocrine dysregulation

9. Chronic Pain Two components • Spinal component • Supra-spinal component • In reality these are confluent – Central Sensitisation (CS). • CS refers to a ‘pain phenotype’ generated by processes that result in the amplification of the pain, which are thought to underlie many chronic pain states. • This sensitised state involves both spinal mechanisms, at the level of the dorsal horn and below and supraspinal mechanisms that involve the disproportionately augmented response of a network of higher brain centres.

10. Central sensitisation • When exposed to a constant stimulus, we may habituate • The pain is still noticeable • But is less ‘painful’ • Or we may become sensitised • Pain persists • Pain becomes worse (hyperalgesia) • Pain moves from one site to another (healthy) site (allodynia) • Memory, interpretation, evaluation, cognition, motivation, reward all influence central pain perception.

11. Role of neurotransmitters • Serotonin (5HT) & Noradrenaline • suppress sensation of normal bodily functions • Dopamine • Dampens pain, application of salience and focuses attention • Opioids • prevents spread of pain, dampens pain, reinforces behaviour • Duloxetine, pregabalin, amitriptyline, amisulpiride, quetiapine, etc.

12. Genetics of FSS • A genetic predisposition may exist for the FSS, which is independent from the mood disorders that frequently co-occur. • Genes may “lump” these disorders together, but environmental influences “split” them apart into individual syndromes (FM, CFS, IBD) • ? Does this explain current prevalence of FSS and “epidemics” of CFS? • Sensitivity to pain of itself may be a heritable trait. • CS, or susceptibility to it, also demonstrates heritability; both secondary hyperalgesia and allodynia are heritable with an estimated 50% genetic contribution to the pain variance

13. Women • Oestrogen receptor density is high in brain areas involved in pain perception and in women, • Pain sensitivity varies during the menstrual cycle with lower pain thresholds being present during the luteal phase

14. Sleep • Non-restorative sleep (NRS), poor quality • Increased light sleep during slow wave (deep) sleep induces NRS • mini arousals • “Alpha-delta sleep” • Experimental disruption of deep sleep • increases pain and fatigue in volunteers • Increases pain, depression & disability in FSS • Threat detection remains active • Transient rises in autonomic activity • Motor restlessness

15. Salience • the state or condition of being salient • a salient or projecting object, part, or feature. • During sleep, CNS is arousable by highly salient stimuli – threat detection • Less discrimination in FSS • More mini-arousals • NRS may be a consequence of CS rather than a cause

16. Neuroendocrine axis dysregulation • Disturbed circadian rhythm • GH is released at onset of deep sleep • Waking halts its secretion • Part of its function is cell growth and repair • Disruption of normal healing • Increase in pain and fatigue • Cortisol is pain inhibitory • CRF is leads to release of ß - endorphins • Childhood adversity: poor growth • Hypocorticolism • Increased vulnerability to FSS • Meta-analysis is inconclusive regarding HPA/cortisol and FSS

17. Theoretical summary • FSS are disorders united by CS with different phenotypes determined by triggering environmental exposures – particularly childhood exposures • Vulnerability to the development of FSS may be marked by CS, • CS is manifested in both those with and without FSS, being more common in unaffected family members • Search for biomarkers specific to the individual syndromes has been unfruitful • Precipitating events such as environmental exposures might thereafter mark the development of specific syndromes or their sub-phenotypes • We should lump first, then split afterwards.

18. Somatic syndrome disorder • DSM-V (APA, 2013, p311) • Disproportionate and persistent thoughts about the seriousness of symptoms • Persistently high level of anxiety re: health or symptoms; or • Excessive time and energy devoted to symptoms or health concerns

19. DSM –V controversy • Allen Frances chaired the DSM-IV taskforce and is founding editor of the Journal of Personality Disordersand the Journal of Psychiatric Practice. • SSD will apply to 15% of patients with cancer or heart disease • 26% of patients with IBS or FM • 7% of healthy people • Frances (2013) “ the mislabelling of potentially millions of people with a fake mental disorder that is unsupported by science and flies in the face of common sense” • http://www.bmj.com/content/346/bmj.f1580 • Helpful or unhelpful? “The fuzzy boundary between psychiatry and general medicine is about to experience a seismic shift”

20. Additional Reading Saving Normal: An Insider's Revolt Against Out-of-Control Psychiatric Diagnosis, DSM-5, Big Pharma, and the Medicalization of Ordinary Life ISBN-10: 0062229257 ISBN-13: 978-0062229250 Twilight of American Sanity: A Psychiatrist Analyzes the Age of Trump ISBN-10: 0062394509 ISBN-13: 978-0062394507

21. Functional therapy for functional illness • Gradually increasing exercise (graded exercise therapy) has been shown to improve fatigue. • A strategy for graded exercise therapy includes establishment of a baseline of achievable patient-specific exercise or physical activity, followed by an incremental increase in the duration of time spent physically active. A target heart rate range should be set to avoid over-exertion, generally less than 100 beats per minute. • Patients should aim for an ultimate goal of 30 minutes of light exercise five days per week. When this goal is achieved, the intensity and aerobic nature of the exercise can be gradually increased. • Any type of activity is appropriate, including walking, swimming an the use of exercise machines and exercise types can be mixed.

22. Can Exercise or CBT harm? CDC guideline update July 2017 https://www.cdc.gov/me-cfs/index.html “Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, long-term illness that affects many body systems. People with ME/CFS are often not able to do their usual activities. At times, ME/CFS may confine them to bed. People with ME/CFS have severe fatigue and sleep problems. ME/CFS may get worse after people with the illness try to do as much as they want or need to do. This symptom is known as post-exertional malaise (PEM). • CBT and GET were removed from the CDC and Dutch guidelines • ME societies are campaigning for their removal from the NICE guidelines • No evidence presented in favour of any other treatments “Some people with ME/CFS might benefit from trying techniques like deep breathing and muscle relaxation, massage, and movement therapies (such as stretching, yoga, and tai chi). These can reduce stress and anxiety, and promote a sense of well-being.”

23. PACE controversy • http://www.meassociation.org.uk/2017/07/the-pace-trial-the-making-of-a-medical-scandal-29-july-2017/ • Allegations that the researchers altered the definitions of “improvement” to suit their desired outcome • All data has been released • Researchers deny the accusation • http://www.bbc.co.uk/news/health-43490335 • Dr Jon Stone, consultant neurologist at the Western General Hospital in Edinburgh, said better treatments for chronic fatigue syndrome were needed, or more effective forms of rehabilitation. "Until we have these, the question is whether it is better to offer a modestly effective treatment supported by data from many other trials, with a realistic discussion of its pros and cons, than none at all.“ • NICE are updating the 2017 guidance – due October 2022!

24. Suicide risk • Roberts, Wesseley et al (2016) Lancet http://dx.doi.org/10.1016/S0140-6736(15)01223-4 • There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65–1·85; p=0·67) or cancer-specific mortality (1·39, 0·60–2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. • This remained the case when deaths from suicide were removed from the analysis. • There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22–15·98; p=0·002).

25. Messages • Central sensitisation may be genetically determined & precede the development of FSS • CS may be the cause of sleep disturbance • May affect many people with serious physical illness • Functional therapy and neuromodulation seem most promising • Seek the depression and ask about suicide

26. Media and ME • Extreme examples Chronic fatigue: I was 'held hostage by ME' • https://www.youtube.com/watch?v=XLPCuEdqIWY • http://www.bbc.co.uk/programmes/articles/3zwwH9C8fRfGBdQl0c8gVGQ/why-do-we-know-so-little-about-me ME and me • https://www.bbc.co.uk/news/av/newsbeat-44037216/me-and-me-how-do-people-cope-with-chronic-fatigue • The ME association was “heavily involved” in the making of this documentary • During the film, Emma meets sufferers and family members of those living with the debilitating condition such as young mum, Sophie, whose severe M.E. means her body is so sensitive she can only tolerate to be around her toddler for five minutes a day. • She also meets Hannah whose condition means that when all of her symptoms flare, she can’t even drink water without vomiting. • And finally, Emma is left in tears after meeting the family of Merryn Crofts who lived with severe M.E. for six years and passed away in May 2017 just 10 days after her 21st birthday.

27. 'Vindication' for woman who wanted ME on death certificate https://www.bbc.co.uk/news/health-44969741 Merryn had started to doubt herself after being misdiagnosed by doctors. Hearing the coroner's verdict "meant everything". "It's vindication for Merryn because it would have meant so much to her. She was scared of doctors and of telling people she had ME." "She was like a wind-up toy - when you see the Duracell bunny and the batteries are going. If you went for a walk or went shopping, you'd see her deteriorate. Then one day she was at school and she couldn't move her legs, she couldn't stand up.“ “She used to say, 'Exhaustion, tiredness, fatigue, I don't care about that, I can cope with that,'" said Clare. "But she was in a dark room because she couldn't stand the light. She couldn't be touched because her skin was so sensitive. She was in constant pain, different types of pain." Merryn's sister Amy described the final three years of her life as "horrendous", adding: "Her hospice doctor likened it to having a heart attack in your stomach."

28. Prognosis for work This Photo by Unknown Author is licensed under CC BY

29. Work outcomes for FSS • Population based or specialist clinic? • Cairns (2005) Occupational medicine • Systematic review • Heterogeneity • for the 14 studies of subjects meeting operational criteria for CFS, the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%).

30. Population (1)Joustra 2015 89 000 participants (Netherlands) • Compared self-reported working status of patients with FSS and organic illness • CFS 666 vs MS 198 • FM 1686 vs RA 1572 • IBS 8509 vs IBD 625 • CFS take half the sick leave as MS patients • FM take the same as RA • IBS take the same as IBD. • FM, RA and IBD work fewer hours than healthy controls. • FSS are as likely to be ill health retired as those with MS (20.5% cf CFS 15.4% ) or with IBD (4.7% cf IBS 3.4% ). • FM are more likely to be ill health retired than RA (10.8% cf 7.8%)

31. Population (2)Rask (2015) Functional Illness in Primary Care Study • 10 year cohort study established 2000 • reviewed at 4 years • Reference group were patients with well-defined illness • At index consultation, disability pension (full or partial) was received by 19.1% (n=35) in the somatoform disorder group, by 8.3% (n=7) in the recent-onset multiple MUS group and by 3.5% (n=29) in the reference group. • At 10-year follow-up, this was the case for 23.5% (n=43) in the somatoform disorder group, 16.7% (n=14) in the recent-onset multiple MUS group and 6.0% (n=50) in the reference group.

32. Tertiary centre (1)Wilson and Hickie 1994 (CFS) • 139 subjects, mean duration of review 3 years • 103 responded • 65 improved , but only 6 recovered completely • 31 unable to work at all (so 70 % were in work) • 21 reported no physical activity, 41 no social activity • mean duration of symptoms 9.2 years • Psychiatric diagnosis at onset or belief in physical disease were poor predictors

33. Tertiary centre (2) Collin et al 2011 2100 patients in tertiary centre (CFS)

34. Tertiary centre (3)Nyland 2014 • 111 young patients (mean age 23) • Mean disease duration at contact 1 was 4.7 years and at contact 2 11.4 years. • At contact 1, 9 (10%) were part-time or full-time employed. At contact 2, 49 (55%) were part-time or full-time employed. • FSS≥5 at contact 2 was associated with depression, arthralgia and long disease duration (all at contact 1).

35. Tertiary (4)Walitt 2011 • 1555 patients, follow-up for up to 11 years (mean duration 4 years) • Reported five-year outcomes • Symptoms waxed and waned • Patients switched between criteria-positive and criteria-negative states, with 716 patients (44.0%) failing to meet criteria at least once during 4228.5 patient-years (7448 observations). • About 10% of patients had substantial improvement and about 15% had moderate improvement of pain. • Overall, FM severity worsened in 35.9% and pain in 38.6%. • no average clinically meaningful improvement in symptom severity overall, • generally continuing high levels of self-reported symptoms and distress for most patients, but a slight trend toward improvement.

36. Poor prognosis • Older age • male sex • higher disability score • more fatigued • more pain • Psychiatric illness • Belief in a physical cause • Non-acceptance of condition (Brooks 2011)

37. And finally…