Part 2: Fibromyalgia: Practical Approaches To Diagnosis and Treatment
Editor's Note: In Part 1 of this two-part series on the presentation, diagnosis, and treatment of fibromyalgia, the author reviewed the epidemiology of fibromyalgia and discusses new diagnostic criteria.
It has long been recognized that the optimal management of fibromyalgia (FM) syndrome is multimodal and multispecialty—multimodal in all patients and invoking multispecialty consultation when indicated. The specialties to be consulted would depend on the most troublesome manifestations needing intervention. Typically, at initial diagnosis, patients are worried that they have cancer or some other dreaded malady. What they need from their physician is a confident understanding of FM and a supportive attitude.
Table 1 provides an acronym to help recall the six main types of interventions in the multimodal care of patients with FM.1 The acronym “ADEPT Living” stands for Attitude, Diagnosis, Education, Physical modalities, Treatments, and Living assessments to document clinical improvement. It is recommended that each of the ADEPT Living components be considered and initiated soon after the diagnosis of FM is made and contemporaneously with prescription of medications. Although it is often easier for the healthcare professional to just write a prescription for a medication, it is seldom true that such an approach alone is adequate.
Overview of Pharmacologic Treatments
The medical "treatments" commonly used in managing FM are shown in Table 2.2 Unfortunately, the tabular format fails to communicate when and why a given agent should be used in the treatment of a patient with FM. Just because an agent is listed in the table does not mean that it is considered optimal therapy for FM. Medications are preferred when they offer benefits for more than one of the comorbid manifestations of FM. For example, selective analgesic medications (eg, anticonvulsants and dual-reuptake inhibitors of biogenic amines) block afferent pain pathways by limiting the release of neurochemicals or by augmenting descending inhibition. Amitriptyline and pregabalin (Lyrica) are used for their analgesic properties, but they are also sedating and can improve sleep patterns in FM. The dual-reuptake inhibitors, such as duloxetine (Cymbalta) and milnacipran (Savella), are analgesic but they also can favorably influence mood because they exhibit antidepressant and anxiolytic properties. The patient derives a bonus when a medication can provide more than one of the needed benefits. By contrast, a commonly used sedating medication, zolpidem, increases apparent sleep time without benefit on pain.
The initial pharmacologic management of FM hinges on knowing the patient’s priorities, comorbidities, and current medications. It is important that the prescriber know the mecahnism of action of medications being considered to avoid facilitation of adverse effects, such as the serotonin syndrome,3 which can develop when more than one biogenic amine reuptake inhibitor (eg, serotonin, norepinephrine, dopamine) are used in the same patient. This concern also applies to nonprescription medications that the patient may be taking. For example, German research on the herbal remedy St John’s Wort, has shown it to be a weak inhibitor of monoamine oxidase-A and -B activity but it also inhibits the synaptosomal uptake of serotonin, dopamine, and noradrenaline (norepinephrine) with approximately equal affinity.4 Like many herbal remedies, this agent can produce potent pharmacologic effects, including side effects and drug-drug interactions. It cannot be ignored, especially because variations in its potency from brand to brand or from batch to batch are not legislatively regulated.
Only three pharmaceutical agents have been approved by the FDA for the management of FM. They are, in order of FDA approval: pregabalin,5 duloxetine,6 and milnacipran.7
Pregabalin is believed to decrease central sensitization by inhibiting the excessive release of substance P and glutamate from afferent neurons in the dorsal horn of the spinal cord. Duloxetine and milnacipran both appear to exhibit analgesia by augmenting descending inhibition in the spinal cord. Pregabalin is excreted unchanged through the kidneys, whereas duloxetine and milnacipran are metabolized in the liver. Thus, the approved agents exhibit different mechanisms of action and different paths for elimination. Indeed, these medications may be complementary with each other in the down-regulation of the central sensitization of FM. For these reasons, it is has been proposed that pregabalin and either duloxetine or milnacipran, but not both in the same patient, would represent useful combination therapy.1
The theory of "strategic polypharmacy" would predict that combining such effective drugs with different mechanisms of action might achieve increased benefit and/or allow lower dosages of one or more therapeutic agents in order to spare adverse effects. Currently, little data exists to confirm this prediction, but many clinicians already do apply such strategic combinations to their management of FM.
Note that FDA approval of these three medications was based on data derived from monotherapy trials. Combinations of FDA-approved medications have not been evaluated nor approved by the FDA. Monotherapy with one of these agents for treatment of FM would be considered to be on-label, whereas various combinations of the same approved agents for treatment of FM would be considered off-label. The same could be said, however, for many of the commonly used combination therapy regimens for hypertension, diabetes, malignancies, and rheumatic diseases. Off-label therapy is lawful in the United States if the clinician has a basis for proposing such treatment and the properly informed patient agrees. The following paragraphs and figures illustrate the author’s strategic combination therapy approach to choosing initial therapy for individual patients with FM. In each case, the distinction between on- and off-label approaches are emphasized.
The critical principle of this concept is that complementary medications would address the same symptomatic domain (eg., pain, insomnia, or depression) with different mechanisms of action or address different domains in the same affected individual. Figures 1 to 5 illustrate this concept on a theoretical basis using these same three important symptomatic domains as the therapeutic targets. Some authors have substituted fatigue for the depression domain, but this author believes that change weakens the concept.