The variety of mechanisms that play a part in pathologic pain perception leads to a great deal of complexity and variation in the clinical presentation and severity of fibromyalgia symptoms, as well as a high degree of variability in patient response to 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.
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.
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.
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.
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.
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.
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.
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.
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.