Neurobiological and Neuropsychiatric Mechanisms of Fibromyalgia and Their Implications for Treatment

As we established in Part 1 of this series of articles on fibromyalgia (“Fibromyalgia Classification, Triggers, and Etiology”), the foundation of fibromyalgia is a pathology of central pain perception mechanisms that may be induced and amplified by peripheral triggers.

The musculoskeletal system provides the majority of such triggers. It has a powerful influence on mood and the central pain regulating processes. For instance, Wollmer et al. recently reported in the Journal of Psychiatric Research that injecting botulinum toxin in the glabellar region (the wrinkle in between the eyebrows) improves depressed mood, likely due to interrupted negative feedback of frowning. Rate of breathing is yet another muscular function that influences pain perception and emotions. Satin et al. reported in “Respiration-induced Hypoalgesia: Exploration of Potential Mechanisms,” published in The Journal of Pain, that slow breathing reduces pain relative to normal or fast breathing.

In one way or another, peripheral influences cause central neurotransmission changes. Ample research has shown that dopamine, norepinephrine, endorphins, glutamate, and GABA are the neurotransmitters most responsible in this process. There are medications available that can be used to regulate these neurotransmitters, therefore allowing practitioners to influence central nervous system processes of pain perception.

A number of other neurotransmitters may be connected to pain transduction, transmission, modulation, and/or perception. These include, but are not limited to, prostaglandins, bradykinins, serotonin, substance P, potassium, magnesium, histamine, adenosine triphosphate, calcitonin gene-related peptide, NO, CCK7, NGF, neurotensin, acetylcholine, oxytocin and others. For more on this, see “Central Pain Control,” by Calvino and Grilo; “Anatomy, Physiology and Pharmacology of Pain,” by Farquhar-Smith; and “Central Plasticity and Persistent Pain,” by Ko and Zhou.

Several of these neurotransmitters (such as adenosine triphosphate, calcitonin generelated peptide, nitric oxide, cholecystokinin 7, neurotropic growth factor, neurotensin, acetylcholine, oxytocin, and cannabinoids) and the roles they play in pain transduction, transmission, and modulation have not been as well researched as some of the others. Several of these neurotransmitters are involved on levels below perception (prostaglandins, bradykinin, substance P, and histamine) or are too nonspecific in their pain-related action (serotonin, potassium, magnesium, and calcium) and therefore are not addressed in this article.

The anatomical areas of the brain that play the largest role in fibromyalgia are the caudate nucleus and thalamus; they are responsible for pain perception, among other functions. Another important part of the brain to focus on in fibromyalgia is the locus coeruleus, which is also involved in pain perception, sleep, and stress response and is a major influence of the hypothalamo-pituitary-adrenal axis. Additionally, researchers have studied the effects of abnormal blood flow to various limbic structures, which may provide evidence for the symptoms of low pain threshold, sleeping difficulties, and reduction of tolerance to stress when the areas mentioned above are involved. Singling out these structures is an intentional oversimplification, designed to narrow clinical thinking to the areas of the brain and the neurotransmitters we are able to influence using medications that are currently available on the market. Below I will address the four most relevant neurotransmitters.

Dopamine

Due to frequently opposing functions of any neurotransmitter depending on its location in the brain, dopamine has both a role in suppression of pain and pain induction. It is possible that dopamine’s role changes depending on the baseline dopamine level in the nucleus accumbens. With a lower baseline dopamine level, dopaminergic medications improve pain control. Oppositely, with dopamine being produced sufficiently at baseline, dopaminergic influence increases availability of dopamine which becomes an inducer of pain.

This has direct implications for fibromyalgia pain management due to dopaminergic medications either benefiting a patient or, on the contrary, being counterproductive. Studies using PET scans and D2/D3 receptor antagonist raclopride show that healthy humans release dopamine in striatum in response to painful muscle stimulation. In contrast, other studies show that dopamine response in patients with fibromyalgia did not differ between painful and non-painful muscle stimulation.

What happens clinically in cases of dopamine surplus in the caudate nucleus is that dopamine antagonists such as novel antipsychotics produce improvements in patient function from a pain perception standpoint, as well as improvements in anxiety, mood stability, and general thought process. The use of dopamine stimulants in such patients produces worsening of pain and decrease in overall function.

The other way around, in case of insufficient baseline dopamine level, medications like L-dopa, pramipexole (Mirapex), ropinirole (Requip), amphetamines, and methylphenidate are associated with improvement in pain and function. Such patients do not tolerate antipsychotic medications.

Multiple novel antipsychotic/dopamine blocking mood stabilizers differ greatly in their receptor affinity. The choice of such medications depends less on their effects but more on side effects to be desirable or to be avoided in certain patients.

Clinical pearls

• 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).

Endorphins

Thalamic influences on pain perception are well known. The thalamus is rich with endorphins, and influencing thalamic function in fibromyalgia depends on the endogenous level of these endorphins. The periaqueductal gray matter region is a major anatomical locus for opioid activation of descending inhibitory pathways to the spinal cord.

As in the situation of dopamine excess or deficiency, endorphins may play an opposite role in pain perception. Therefore, some patients with fibromyalgia may benefit from treatment with opiates, while others may benefit from the use of opioid antagonists in the treatment of their pain.

Delta and kappa opioid receptor subtypes are mainly presynaptic close voltage-gated calcium channel receptors. They cause postsynaptic hyperpolarization and inhibition of postsynaptic neurons by opening potassium channels. Opiate receptors are primarily G-protein coupled receptors. Calcium and magnesium supplementation, as well as vitamin D, may be beneficial in patients with fibromyalgia for both reasons of influencing calcium channels and calcium deposit in the bones making the matrix stronger; therefore, decreasing likelihood of peripheral influences on a large number of nerve endings.

The concentration of endogenous opiates is elevated in some fibromyalgia patients. As a result, patients show decreased binding potentials for exogenously administered mu opioid receptor agonist in several brain areas including ventral striatum, anterior cingulate cortex, and amygdala.

Opioids inhibit release of glutamate from peripheral nociceptors and postsynaptic neurons in the dorsal horn as well as periaqueductal gray, anterior cingulate cortex and mid anterior insula. Any medications which increase glutamate inhibition in addition to direct mu receptor agonism provide better control of pain in fibromyalgia. Therefore, in some patients, medications which have NMDA receptor influences such as methadone, ketamine, amantadine, and others may provide additional benefits in fibromyalgia if use of such medication is warranted. Tramadol (Ultram) or tapentadol (Nucynta) may be recommended as first-line opioid treatment (if such is indicated) due to less addiction potential and beneficial influence on serotonin and norepinephrine. The use of buprenorphine may be even more practical due to inhibition of kappa receptor and therefore decrease in likelihood of abuse and improvement in mood and cognition.

Clinical pearls

• 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).

Norepinephrine

The next major neurotransmitter involved in pain perception in fibromyalgia, and in pain in general, is norepinephrine. Locus coeruleus is the pinnacle of this neurotransmitter. Norepinephrine levels may be too low or too high in fibromyalgia patients and those subtypes of patients have to be clinically distinguished for appropriate treatment with either enhancing or decreasing noradrenergic transmission.

Clinical pearls

• 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).

GABA

The next central neurotransmitter involved in fibromyalgia symptoms is GABA. It is the most prevalent inhibitory neurotransmitter with high concentrations in the brain and spinal cord. It is present in 60-70% of all synapses in the central nervous system; it is widely distributed and found in all brain regions. It plays an important role in sensitivity for neuronal firing, mood, cognition, pain, sleep, and movement disorders. As in the instance of other neurotransmitters, both deficiency and excess of GABA may contribute to fibromyalgia symptoms.

Clinical pearls

• GABA deficiency symptoms may be identified clinically in patients who feel stressed and pressured, have abdominal discomfort, lump in the throat, problems relaxing, low stress tolerance, twitching, problems with sleep, and pain perception pathology.
• As it is quite clear from the above description, there is significant overlap of symptoms of GABA deficiency and excess of other neurotransmitters. Deficiency of GABA ultimately causes increase in norepinephrine and dopamine levels; therefore, GABA deficiency symptoms are closely aligned with dopamine and norepinephrine excess. The lack of GABA is a frequent culprit in fibromyalgia patients.
• There are a number of treatment modalities used for this problem including direct stimulation of the GABA receptor with GABA agonists such as baclofen (Liorisal), modulation of GABA receptors with specific increase in sensitivity of GABA receptors through the use of benzodiazepines (remembering addictive properties, sedation and decrease in cognition associated with those medications). Other approaches include inhibition of GABA metabolism, specifically GABA-t inhibition as in case of vigabatrin (Sabril) or inhibition of GABA-reuptake into presynaptic neuron and the glial cells with tiagabine (Gabitril). Multiple other anticonvulsants are used as well. Gabapentin (Neurontin) and pregabalin (Lyrica) are possibly involved in stimulating presynaptic release of GABA, though the main effects are achieved through alpha-2-delta receptors.
• Excessive GABAergic effects may be associated with oversedation, tingling, and itchy sensation in skin. Slow breathing, grogginess, and mental slowness may also be observed. Excessive GABA is less frequently associated with fibromyalgia symptoms.
• The hallmark symptoms of GABAergic deficiency include simultaneous presence of anxiety, insomnia, and pain sensitivity alongside with muscle stiffness and twitching (use GABAergic medications). The hallmark symptoms of GABAergic excess includes mental slowness and tingling (no direct treatments are available. Caffeine and stimulants, including modafinil (Provigil) and armodafinil (Nuvigil) may be of use).

Combination of pathology

It is obvious that a combination of treatments is necessary to address various neurotransmitters depending on clinical presentation. The changes in neurotransmitter activity may be translated into changes in brain volume in fibromyalgia. The total gray matter in fibromyalgia patients is less than in healthy controls. The longer an individual has fibromyalgia syndrome, the greater the loss. Each year of experiencing fibromyalgia symptoms is equivalent to about 9-10 times the loss in normal aging. It especially applies to the cingulated gyrus and insular, medial, frontal cortexes and thalamus. Gray matter at the same time increases in the striatum and cerebellum, possibly showing an increase in neurotransmitters such as dopamine in those areas.

The most underappreciated neurotransmitter which is not attended to by many physicians who treat fibromyalgia is dopamine. Excessive dopamine is in extreme cases associated with somatic psychosis, somatization disorder, factitious disorder, pain disorder, and hypochondria. It may come with odd and bizarre/peculiar symptoms that are out of proportion with objectively identified pathology. Those symptoms are common in fibromyalgia patients and have to be dealt with by appropriate use of dopamine antagonizing medications.

Non-pharmacologic means

With all the attention to pharmacological methods of treatment of fibromyalgia, it is important to remember that such general modalities as exercise, diet, hydrotherapy and appropriate mental health do normalize neurotransmitter balance in the brain and ultimately help patients with fibromyalgia. Careful use of nutritional supplements and vitamins may be justified. Paradoxically, at the present day patients usually overuse vitamins and supplements, applying them indiscriminately. I limit the list of recommended supplements to omega-3 fatty acids, vitamin D, methylated vitamin Bs, and CoQ-10. Rarely anything else is needed. Multivitamins may be especially counterproductive.

Normalizing abnormal

It is important to supplement deficiencies commonly seen in fibromyalgia patients, especially of DHEA, testosterone, thyroid, adrenals, vitamin D, and B vitamins. It is prudent to remember that such supplementation rarely produces meaningful clinical improvement but is crucial in preventing further complications. Excessive testing that ends up in excessive supplementation is expensive and, as a rule, not justified.

Allergies, especially to gluten, have to be controlled. In women, hormonal balance and cycle normalization is paramount. Treatment of comorbid conditions, both physical and mental, is crucial. Patients with fibromyalgia who avoid mental health treatments have much lower chance of improvement.

Future means of treatment

The future treatments of fibromyalgia are on the horizon and may involve increasing levels of inhibitory neurotransmitters by the way of use of cannabinoids and adenosine as well as use of antagonists of neurotransmitters involved in pain process. It includes neurotensin, cholecystokinin, and nerve growth factor. Such medications will be a welcome addition to the existing medication armamentarium.

Conclusion

In conclusion, multiple peripheral and central mechanisms define various neuropathic pain symptoms, including fibromyalgia. Therapeutic options used in the treatment of fibromyalgia syndrome should be both symptom-oriented and suspected mechanisms-oriented.

The variety of mechanisms of pathologic pain perception may happen to a different extent and in countless combinations in individual patients. This explains variable response to different treatment approaches useful in specific patients.

Treating practitioners should always remember that fibromyalgia is not one condition but an assembly of different syndromes; therefore, one treatment does not fit all patients. More than that, treatment of two patients with similar fibromyalgia symptoms may be drastically different due to different underlying mechanisms being in contrast to each other but manifesting in the same pain perception pathology.

Remembering that every neurotransmitter deficiency or excess has identifiable clinical correlation is important. Basing treatment approach on specific clinical presentation in a particular patient and not on general concepts of fibromyalgia would assure more successful and reliable outcomes.

Dmitry Arbuck, MD, is a psychiatrist specializing in pain management. He a member of the Pain Management editorial board and president of Meridian Health Group, a multidisciplinary pain management practice.