The Neuropsychiatry of Fibromyalgia – Etiology and Management

DIAGNOSIS OF FIBROMYALGIA

The diagnostic criteria for fibromyalgia were originally published in 1990 by the American College of Rheumatology (ACR). [3]

These criteria emphasised pain based on tender points which resulted in a gender bias and a female to male ratio of 2:1.

The 1990 American College of Rheumatology criteria for fibromyalgia were research classification criteria and were never intended to be used as strict diagnostic criteria for use in clinical practice.
These criteria require that individuals have widespread pain (pain in the axial skeleton, above and below thewaist, and on both sides of the body) as well as tenderness in 11 or more of 18 possible “tender points.”

Many individuals who clearly have fibromyalgia do not have pain throughout their entire body or may not have at least 11 tender points.

Moreover, the symptoms of pain and tenderness are common and it is impossible to know where to draw the line betweenan individual with isolated symptoms and someone with a pain-inducing illness. (Häuser et al., 2015)

The 2010 ACR preliminary criteria [4] had the following diagnostic items:

The Widespread Pain Index (WPI) and the composite Symptom Severity (SS) scale.  The SS scale, composed of physician-rated cognitive problems, unrefreshed sleep, fatigue, and somatic symptom count to measure fibromyalgia symptom severity. The total score ranges from 0-31. (WPI -0-19; SS in 4 domains (0-3)).

The modified 2010 ACR criteria [5] is an entirely self-reported version, and the symptom severity (SS) scores are modified to include headaches, pain or cramps in the lower abdomen and depression. The total score ranges from 0-31.

A patient satisfies modified ACR 2010 fibromyalgia diagnostic criteria if the following 3 conditions are met:

1. Widespread Pain Index ≥ 7 and Symptom Severity Score ≥ 5 or Widespread Pain Index between 3–6 and
2. Symptom Severity Score ≥ 9.Symptoms have been present at a similar level for at least 3 months.
3. The patient does not have a disorder that would otherwise sufficiently explain the pain.

In clinical practice, fibromyalgia should be suspected in patients having multifocal pain not fully explained by injury or inflammation. In most cases, musculoskeletal pain is the most prominent feature.

Because pain pathways throughout the body are amplified, pain can occur anywhere.

Consequently, chronic headaches, sore throats, visceral pain,and sensory hyper-responsiveness are very common in individuals with fibromyalgia. [2]

Studies suggest that establishing a diagnosis of fibromyalgia provides substantial relief for patients. [6]

ETIOPATHOGENESIS OF FIBROMYALGIA

Below is a summary of the key pathophysiological mechanisms in the development of fibromyalgia based on two key reviews by Clauw [1] and Hauser [2].

1. Genetics:

First-degree relatives of patients with fibromyalgia show an increased risk by 8x of developing the syndrome.

There are no genes with a large effect size identified, but some polymorphisms related to neurotransmitters involved in pain modulation have been identified, which may be considered genetic markers for the condition.

Genes involved:

• Catechol-O-methyl-transferase (COMT)
• Dopamine type 4 receptor
• 5HT-2A receptor
• Serotonin transporters (SERT)

2. Environmental Factors

• Infections: Ebstein Barr virus (EBV), parvovirus, brucellosis and Lyme disease are associated with fibromyalgia.
• Physical trauma: e.g. spinal trauma, motor vehicle accidents
• Inflammatory joint conditions: Osteoarthritis, Rheumatoid arthritis etc.
• Childhood abuse and trauma
• Exposure to war
• Psychological stressors in daily life

3. Pain Centralisation

When a peripheral injury occurs, the nociceptive stimulus is transmitted by primary afferent neurons to the dorsal horn neurons. The dorsal horn neurons in the spinothalamic tract project to the thalamus and then to the primary somatosensory cortex resulting in the perception of pain.

In sensitisation, the CNS perception of pain is amplified which results in the continued experience of pain in the absence of a peripheral nociceptive stimulus.

4. Decreased activity of Serotonergic and Noradrenergic pathways

Descending Noradrenergic neurons inhibit neurotransmitter release from the primary afferent neuron via presynaptic (α2) adrenergic receptors and inhibit transmission of impulses from the dorsal horn via postsynaptic (α2) adrenergic receptors, which prevent nociceptive bodily stimuli from reaching the brain and interpreted as pain.

Serotonin inhibits primary afferent terminals via pre-synaptic 5HT-1B/D receptors. However, in certain parts of the dorsal horn, serotonin facilitates the release of neurotransmitters from the primary afferent neurons.

5. Dopamine Transmission: 

• Dopamine dysregulation has been linked to increased pain sensitivity and cognitive symptoms in fibromyalgia. [Ceko et al, 2012]
• A PET study showed that patients with fibromyalgia have abnormalities of regional cerebral blood flow in several brain regions where dopamine plays an important role in modulating the transfer of pain signals. [Yang et al, 2020].

6. Opioid pathways

The thalamus is a key area for pain processing and is rich in endorphins.

The periaqueductal gray (PAG) is another important area for opioid activation of descending inhibitory pathways into the spinal cord.

Decreased opioid binding in pain processing areas is associated with increased endogenous opioids. 

Some patients show a decreased μ-opioid receptor binding which is associated with increased baseline endogenous opioidergic activity and subsequent opioid-induced hyperalgesia. These patients may not benefit from exogenously administered mu opioid agonists but may benefit from opioid antagonists e.g. low dose naltrexone.

On the other hand, some patients may have an opioid deficiency.

7. Increased glutamate levels: Patients may thus benefit from agents that inhibit glutamate e.g. ketamine, amantadine.

8. Increased pro-nociceptive neurotransmitters – Nerve Growth Factor (NGF) and Substance P

9. Glial cell activation resulting in the production of inflammatory cytokines.

NEUROPSYCHIATRIC CO-MORBIDITIES

While chronic pain is a central feature of fibromyalgia, many other brain areas are also involved giving rise to multiple psychiatric co-morbidities. [7]

1. Depression

Clinical Features

Depression is prominent in fibromyalgia patients with a lifetime prevalence of approximately 90% for depressive symptoms and 62-86% for major depressive disorder. [8], [9]

Depression in fibromyalgia may be due to the adjustment issues related to the chronic pain and functional impairment resulting in reactive depression.

On the other hand, there may be shared biological mechanisms common to both fibromyalgia and depression.

Some studies have profiled fibromyalgia patients by their depression and have shown that atypical depressive episodes (ADE) and melancholic episodes (MDE) are considered to represent the majority of cases. [10]

A study published in 2010 showed that ADE was 1.5 times more common than MDE in fibromyalgia patients. [11]

A comparison of clinical characteristics of both diagnostic groups showed that although the number of tender spots was the same between groups, the level of tenderness was statistically worse in MDE. Furthermore, the same was true for severity of depression and quality of life.

Etiopathogenesis

There is considerable evidence that shows that there are genetic and environmental factors that predispose individuals to fibromyalgia or depression.

1. Firstly, genes that are related to serotonin, catecholamines, monoamines, and glutamate functions are suggested to make individuals susceptible to both depression and fibromyalgia.
2. Secondly, environmental stressors such as psychosocial issues, physical injury, infections, and autoimmune disease can also precipitate both depression and fibromyalgia.

Treatment

Due to the similar aetiologies of fibromyalgia and depression, the treatment of both conditions is best approached using dual serotoninergic and noradrenergic drugs.

Tricyclic antidepressants (amitriptyline and cyclobenzaprine) and SNRIs (duloxetine and milnacipran) have significant success in treating fibromyalgia. [12], [13], [14]

Duloxetine has superior effects on pain, depressed mood and sleep disturbances whereas milnacipran is more superior to duloxetine at reducing fatigue.

However, there is limited evidence of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine even at higher doses.

Furthermore, non-pharmacological therapies such as cognitive behavioural therapy (CBT) can also help provide effective pain management of fibromyalgia and depression.

2. Anxiety and Panic Disorder

Clinical Features

Fibromyalgia is associated with incapacitating pain and suffering and as such 78.4% of patients are susceptible to developing mood or anxiety symptoms that are associated with the increased perception of pain and tenderness. [15]

Fibromyalgia is recognised as being associated with panic disorder and among fibromyalgia patients, 27% have a lifetime panic disorder. [16]

The presence of panic disorder in fibromyalgia patients is known to increase functional impairment. [17]

Etiopathogenesis

Similar to the development of depression, the manifestation of anxiety may be due to a neurobiological association such as genetic disposition, the presence of psychosocial stressors or a shared environmental factor.

Evidence suggests that a fear of pain can initiate the development of a chronic pain syndrome, such as fibromyalgia. [18]

Also, chronic pain and suffering can cause patients to feel hopeless about the future, which therefore may develop into anxiousness and fear of the future.

Treatment

Effect sizes are shown to be greater for pharmacological options rather than for psychotherapy in treating anxiety. [19]

The SNRI duloxetine and milnacipran are recommended for the treatment of fibromyalgia and also have anti-anxiety effects.

3. PTSD

Clinical Features

Clinical features include nightmares, intrusive and recurrent thoughts, avoidance behaviours, and increased arousal.

Fibromyalgia patients have reported greater pain severity and life interference as well as increased disability scores when PTSD-like symptoms are present. [20]

Furthermore, fibromyalgia patients who were classified as having adaptive pain-coping strategies were less likely to exhibit PTSD-like symptoms.

Etiopathogenesis

Traumatic life events play a role in the etiopathogenesis of fibromyalgia. [21]

Research shows that PTSD-like symptoms are present in almost 50% of fibromyalgia patients. [20]

Treatment

Although trauma-focussed CBT is an evidence-based therapy for PTSD, patients with fibromyalgia report exacerbations of pain with exposure to stress.

Therefore caution is to be exercised with trauma-focussed CBT as it could be detrimental by influencing and exacerbating their pain.

MANAGEMENT

Fibromyalgia is best approached by integrating pharmacological and non pharmacological treatments while engaging patients as active participants in the process.

Current challenges in the management of fibromyalgia are due to heterogeneity in clinical presentation and multiplicity of core symptoms, which makes fibromyalgia a prototypic example of the dictum ‘one size does not fit all’ – (Häuser et al., 2015)

Management Modalities:

1.Non-Pharmacological Management

• Graded exercise
• Patient education
• Cognitive Behavioural Therapy (CBT)
• Complementary and alternative therapies: Water therapy (Balneotherapy), acupuncture, yoga, Tai-Chi.
• CNS neurostimulation: Transcranial Magnetic stimulation, Transcutaneous electrical nerve stimulation.

2.Pharmacological Management

In considering pharmacological management it is important to recognise that fibromyalgia may be co-morbid with chronic fatigue syndrome which means patients may have  cognitive, affective, circadian rhythm dysfunction, post exertional malaise etc.

Chronic Fatigue Syndrome | Myalgic Encephalomyelitis – Neurobiology | Diagnosis | Management

It is therefore important for the clinician to consider these additional symptoms and target the symptoms with appropriate psychopharmacology.

For example patients with an activated mesolimbic system (hyperarousal, insomnia, agitation ,racing thoughts and mood swings) may experience side effects from activating antidepressants; hence the initial treatment strategy should be treating the activated mesolimbic system through alpha-2 agonists e.g clonidine, mood stabilisers or antipsychotic mood stabilisers depending on the severity.

On the other hand patients with prominent psychomotor retardation, cognitive symptoms, slowing of thoughts, anhedonia, amotivation indicate decrease in NA and DA in the PFC; these patients may benefit from dopaminergic and noradrenergic potentiation.

Based on the above the following principles are useful: [Arbuck, 2012]

Dopaminergic Pathways: 

• It is possible to clinically identify patients with fibromyalgia who may be speculated to have lower levels of dopamine. Such patients suffer with significant anhedonia, lack of interest, decrease in motivation, procrastination, and hypersomnia. These patients may have difficulty getting up in the morning. Patients with fibromyalgia and low levels of dopamine tend to overuse caffeine and tend to use stimulants, including cocaine. Patients with the above-mentioned symptoms may benefit from dopamine augmentation through the use of stimulants (of course while close attention is paid to addiction issues).

• At the same time, clinicians should suspect the possibility of overactive dopaminergic function in patients with fibromyalgia and symptoms such as dissociations, “out of body experience,” thought process problems, bizarreness, and oddness in behavior, out of context emotions, suspiciousness, and possibly hallucinations, paranoia, and delusions. Antipsychotics not stimulants should be utilized in the treatment of such individuals. In addition, in people who are prone to experiencing nausea, excessive salivation, and tongue burning, as well as muscle twitching and odd posturing, may be a sign of excessive dopamine activity. Therefore, patients with such symptoms may benefit from administration of dopaminergic antagonists (novel antipsychotic/mood stabilizers).

• The hallmark symptom of dopamine excess is oddness and peculiarity of the clinical presentation (use dopamine blockers). The hallmark of dopamine deficiency is psychomotor retardation (use stimulants)

Noradrenergic Pathways: 

• Norepinephrine deficiency is linked to diminished energy, interest, and motivation. It is associated with depression. The deficiency of norepinephrine decreases response to stress and is associated with low endocrine function. It also may be associated with decrease in attention/ concentration and suppressed blood pressure. Low norepinephrine also shows as decrease in memory which is sometimes described as “brain fog” or “fibro fog.” Noradrenergic medications help patients with such symptoms and include noradrenergic antidepressants such as dual acting antidepressants venlafaxine (Effexor), duloxetine (Cymbalta), and milnacipran (Savella). The last two are FDA-approved for the treatment of fibromyalgia. Alpha-2 blockers also are used and include tizanidine (Zanaflex), clonidine (Catapres), as well as prazosin (Minipress).

• An increase in norepinephrine level is associated with moodiness, irritability, edginess, increase in blood pressure, and headaches. Palpations, anxiety, nausea, and pallor are other signs of norepinephrine excess. Increase in norepinephrine level is also associated with fears, impaired concentration, restless sleep, muscle tension, and muscle cramps. It is important to avoid caffeine intake in fibromyalgia patients with excessive norepinephrine clinical signs. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to addiction potential. Short-acting benzodiazepines such as alprazolam (Xanax) and lorazepam (Ativan) must be specially avoided. Chlordiazepoxide (Librium) has the least adverse effects and the least abuse potential.

• The hallmark symptom of norepinephrine excess is anxiety and moodiness (avoid caffeine, judiciously use long-acting benzodiazepines). The hallmark symptom of norepinephrine deficiency is low energy and “brain fog” (use noradrenergic antidepressants and alpha blockers).

Endorphins / Opioid pathways: 

• Opiate deficiency may be suggested in a patient with depressive symptoms with heightened perception of pain and moodiness. Patients with dopamine deficiency may have chronic, unexplained pain and general body aches in presence of objectively verifiable chronic pain generators. Such patients may have a problem with orgasms, decreased sexual drive, and emotional sensitivity.

• Endorphin excess in the brain may be associated with dopamine hypersensitivity associated headaches, abdominal pains, thrill seeking, poor judgment, self-image problems, decrease in appetite and sleep, and low pain threshold, impulsivity and unexplained pains in absence of objective tissue damage. Such patients benefit from opioid antagonists such as naltrexone and complete abstinence from opioids of any sorts.

• The hallmark symptom of endorphin excess is unexplained pains in absence of objective tissue damage (use opioid antagonists). The hallmark symptom of endorphin deficiency is general body aches in presence of objectively verifiable chronic pain generators (use opioid agonists).

a.Tricyclic antidepressants:

Amitriptyline (10-70mg nocte).

Clinical pearls: They can improve pain, sleep bowel and bladder symptoms.

b.Serotonin-Noradrenaline Reuptake Inhibitors (SNRI’s)

• Duloxetine (30-120mg /day)
• Milnacipran (100-200mg/day)

Clinical pearls:

Milnacipran is more adrenergic than duloxetine and hence may be better for fatigue but can also be more likely to lead to hypertension.

Adverse effects with SNRI’s are nausea, hypertension and headache.

c. Gabapentinoids

• Gabapentin (800-2400mg/day)
• Pregabalin (up to 600 mg/day)

Clinical pearls: sedation and dizziness can be minimised by night time dosing.

d. Cannabinoids:

Nabilone (0.5mg nocte to 1mg BD)

Clinical pearls: Check legislative requirements when prescribing cannabinoids as not approved for this indication.

e. Opioids

Tramadol (50-100mg qds)

Clinical pearls: risk of sedation, dependence and opioid-induced hyperalgesia. Specialist input required.

f. SSRI’s

Clinical pearls: Older SSRI’s (fluoxetine, sertraline and paroxetine) have some efficacy in improving pain at higher doses due to higher noradrenergic effects

Citalopram, escitalopram are less effective as analgesics.

g. Non-steroidal anti-inflammatory drugs (NSAID’s):

No evidence for efficacy.

h. Low dose Naltrexone: [Bruun-Plesner et al, 2020]

There is emerging evidence for low dose naltrexone (1-6 mg with doses of 4.5 mg commonly used).

If clinicians treat fibromyalgia or other chronic pain conditions with drugs alone, they will fail. This is akin to treating diabetes with insulin or drugs alone, without any corresponding attempt to modify diet or weight. In contrast to diseases like diabetes or hypertension that lack physical symptoms, patients with chronic pain hurt, motivating them to be more adherent to nondrug therapies.

Be on the offensive. Be persistent in encouraging your patients about doing exercise and trying web-based non drug therapies. Do not be defensive and think that every time these patients come in, changing to a different drug is the only available approach.

If practitioners use non drug therapies more aggressively and use fewer opioids, nonsteroidal anti-inflammatory drugs, and procedures and more centrally acting analgesics, fibromyalgia is easier to manage. (Clauw, 2014)

CONCLUSION

What the future has in store for fibromyalgia is uncertain.
However, it is clear that many people will continue to
experience severe and clinically invisible pain and aversive
symptoms and that their plight cannot be ignored by
medicine, science or society. [2]

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