BMS 24/5/2014

Is fibromyalgia part of the climacteric syndrome?

A Pintiaux

1.usually affecting middle aged women

2. diffuse musculoskeletal aches, pains or stiffness

3.tiredness

4. anxiety

5. poor sleep

Fibromyalgia syndrome (FMS)

FMS was confirmed definitively as a clinical specific entity when the American College of Rheumatology (ACR) defined the criteria

for fibromyalgia diagnose in 1990

The proposed criteria for FMS classification were: history of widespread pain (axial pain, left- and right-sided pain and upper and lower segment pain) lasting for a minimum of three months and tenderness at 11 or more of the 18 specific tender point sites.

In 2010, the ACR updated the FMS definition by considering that

the presence of widespread pain, fatigue, waking unrefreshed, cognitive symptoms and somatic symptoms were required for its diagnose.

FMS definition

Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism 1990;33:160–72. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care and Research (Hoboken) 2010

J.E. Blümel et al. / Maturitas 73 (2012) 87– 93

1.middle aged women

2.musculoskeletal pains

3. mood disorders

4. poor sleep quality

The climacteric syndrome shares some features with FM

J.E. Blümel et al. / Maturitas 73 (2012) 87– 93

J.E. Blümel et al. / Maturitas 73 (2012) 87– 93

defined as ‘an unpleasant sensory and emotional experience associated with tissue damage’

a normal protective homeostatic mechanism to avoid or reduce the environmental injury.

trauma or disease can result in the development of chronic, often

intractable pain such as that associated with inflammatory disorders, cancer and neuropathies.

In the United States, pain affects more people than diabetes, coronary

artery disease and cancer combined and remains an area of major unmet medical need

Pain

Goldberg YP, Clin Genet 2012

• widespread musculoskeletal pain affects 10% of the population, reaching the highest prevalence (21.1%) in women aged 55–64 years

• labour absenteeism in middle aged women due to medical reasons is caused by osteoarticular pain (44.3% of workers), being psychiatric disorders responsible for only 18.1% of it.

• pain, especially musculoskeletal disorders and headaches cause labour losses of 61.2 billion dollars per year in the USA. Most (76.6%) of the productive time lost was explained by underperformance at work and not by work absence

• a Spanish study shows that about 6% of the elderly population in that country are affected by invalidating musculoskeletal disorders which proves detrimental to their labour capacity or their leisure activities, being pain prevalence in women almost twice than among men

Public health issue

Jiménez-Sánchez S. Has the prevalence of invalidating musculoskeletal pain changed over the last 15 years (1993–2006)? A Spanish population-based survey. Journal of Pain 2010 . Stewart WF. Lost productive time and cost due to common pain conditions in the US workforce. Journal of American Medical Associations 2003

Current therapeutics offer only limited efficacy with approved gold standard therapeutics substantially improving pain (≥50%) in no more than 40–50% of subjects in controlled clinical trials

Dworkin RH, Turk DC. Accelerating the development of improved analgesic treatments: the ACTION public-private partnership. Pain Med 2011:

Understanding the mechanisms of pain, nociception

Genetic models can help to understand the mechanisms and to develop pharmacologic approach

Environment : identifying modulating factors

What can we do?

• Loss of function

• Gain of function at some degrees : with either lowered thresholds of activation or defective inactivation

Reduced pain perception syndromes-congenital-indifference to pain (CIP)/gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder

Goldberg YP, Clin Genet 2012

GABRB3 (in the promoter region of the GABA-A β receptor gene),

TAAR1 (trace amine-associated receptor 1),

GBP1 (guanylate binding protein 1),

RGS4(regulator of G-protein signaling 4),

CNR1 (CB-1 cannabinoid receptor gene), and

GRIA4 (AMPA ionotropic glutamate receptor 4 subunit).

Three of these genes, TAAR1, RGS4, and CNRI play roles in the modulation of analgesic pathways

Largest candidate gene association study of the fibromyalgia observed significant differences in allele frequencies between cases and controls for several genes:

Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, et al. Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia.Arthritis Rheum. 2012;

first study to report genome-wide suggestive linkage of fibromyalgia to the chromosome 17p11.2-q11.2 region.

The Fibromyalgia Family Study: A Genome-Scan Linkage Study

Lesley M. Arnold , Arthritis Rheum. 2013

Are estrogens able to modulate nociception ?

More symptoms of pain, fatigue, stiffness and depression in FS patients with surgical menopause, which is a condition with a higher hormone withdrawal and more climacteric symptoms than FMS women with natural menopause

Increase of musculoskeletal pains, without inflammatory signals amongst breast cancer patients using aromatase inhibitors, which breaks the oestrogen synthesis.

Vincent A, Whipple MO, Luedtke CA, et al. Pain and other symptom severity in women with fibromyalgia and a previous hysterectomy. Journal of Pain Research 2011; Shanmugam VK, McCloskey J, Elston B, Allison SJ, Eng-Wong J. The CIRAS study: a case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induced musculoskeletal symptoms. Breast Cancer Research and Treatment 2012;

Anxiety has been linked to four neurotransmitter systems that are distorted in menopause: gamma amino-butyric acid, serotonin, noradrenalin and dopamine

In relation to insomnia, dopamine and serotonin are related to sleep regulation

Oestrogen-related changes in serotonergic neuronal transmission, including changes in the number of serotonin transporter (SERT) binding sites, have been cited as a possible cause for changes in sleep, mood and memory and this occur during menopausal transition

Additionally, serotonin selective depletion in the brain is associated with insomnia in experimental animals

Becker S, Schweinhardt P. Dysfunctional neurotransmitter systems in fibromyalgia, their role in central stress circuitry and pharmacological actions on these systems. Pain Research and Treatment 2012 Monti JM, Jantos H. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Progress in Brain Research 2008;

Durant C, Christmas D, Nutt D. The pharmacology of anxiety. Current Topics in Behavioral Neurosciences 2010;2:303–30. [38] Monti JM, Jantos H. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Progress in Brain Research 2008;172:625–46. [39] Krajnak K, Rosewell KL, Duncan MJ, Wise PM. Aging, estradiol and time of day differentially affect serotonin transporter binding in the central nervous system of female rats. Brain Research 2003;990:87–94.

Neurotransmitter systems : the link between estrogen deprivation and FMS ?

Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing

Ovariectomy Results in Variable Changes in Nociception,

Mood and Depression in Adult Female Rats

Li-Hong Li, PLoS ONE, April 2014

Effects of estrous cycle on basal paw withdrawal threshold (PWT) to mechanical stimulation and tail-flick latency (TFL) to radiant heat stimulation. (A) PWTs of both hindpaws. (B) TFLs of proximal and distal. P, proestrus stage; E, Estrus stage; M, metaestrus stage; D,diestrus stage.

OVX induced mechanical allodynia (PWT decreases during the von Frey test) and thermal hyperalgesia (tail flick reflex test)

Plasma E2 , uterine weight, animals weight in the three conditions

OVX enhanced formalin-induced nociceptive responses during phase 2

Effects of OVX on depressive-like behaviors and spatial ability. The forced swimming test was used to evaluate behavioral despair. Depressive-like behavior (behavioral despair) was defined as an increase in the time (in seconds) spent immobile /The open-field test (OFT) was use to determine locomotion and exploratory behavior.

Effects of OVX on spatial ability.

(E) Showing animal’s escape latencies to find the submerged platform. Cutoff time was 60 s. (F) Showing animal’s swimming speed in the training and testing trials. Morris water maze training consists of two training sessions of six trials each with a 30-min resting period between the two sessions. Memory retention was tested 24 h after training. The retention values are calculated as the mean of three-trial retention test. (G) Animal’s escape latencies to find the visible platform. The platform was raised above the turbid liquid surface to be visible. FST, OFT and Morris water maze tests were performed at the 5th week after OVX or sham-OVX surgery.

OVX facilitated acute pain and formalin tonic pain, attenuated pain-related negative emotion and produced depressive-like behaviors, but did not affect spatial ability and fear-related learning and memory n-related negative emotion and produced depressive-like behaviors, but did not affect spatial ability and fear-related learning and memory

A decreased synaptic strength at the hippocampal CA3-CA1 synapses was

found only in long-term ovarian hormone loss rats (5 months after

OVX) but did not in short-term OVX (7–10 days), suggesting

OVX-induced hippocampus-dependent learning and memory

deficits might be delayed

Wu WW, Bryant DN, Dorsa DM, Adelman JP, Maylie J (2013) Ovarian hormone loss impairs excitatory synaptic transmission at hippocampal CA3- CA1 synapses. J Neurosci

• Fibromyalgia shares some epidemiological, etiopathogenic, symptomatic and therapeutic characteristics with climacteric syndrome.

• As there are FMS patients who are not climacteric women, it is clear that the hormone deficit is not the only physiopathological mechanism compromised in the etiopathogenesys of this disease.

• For FMS middle aged women : are hormone disorders involved in the symptom genesis ?

• Usefulness of HT in fibromyalgia climacteric patients, especially in those who have not responded to currently accepted therapies ?

• Need to carry out studies which evaluate the FMS clinical response to HT in a prospective manner

Conclusions