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11 Articles in Volume 11, Issue #8
Pain Following Combat Trauma In the 21st Century: A New Look at an Old Problem
Part 2: Fibromyalgia: Practical Approaches To Diagnosis and Treatment
Advances in Regenerative Medicine: High-density Platelet-rich Plasma and Stem Cell Prolotherapy For Musculoskeletal Pain
Implant Technologies for Severe Pain: Why, When, and the Outcomes
Value of EMG in Patients With Non-Migrainous, Persistent Head Pain
Drug Interactions Among HIV Patients Receiving Concurrent Antiretroviral and Pain Therapy
Etiology of Chronic Pain and Mental Illness: The Biopsychosocial Component
Insights Into Patients’ Views About Topical Opioids: Observations From a Small Clinical Study
Teenage Boy With Multiple Pain Disorders
The Bench Delivers and It Matters
Renewing Opioid Prescriptions Over the Phone

Part 2: Fibromyalgia: Practical Approaches To Diagnosis and Treatment

In part 2 of this two-part series on the presentation, diagnosis, and treatment of fibromyalgia, the author reviews treatment strategies for managing patients with this disease.

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.

Strategic Polypharmacy
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.

Prominent Domain of Pain
When addressing the prominent domain of pain alone, tramadol (Ultram) is a logical choice. Figure 2 shows treatment of each of the three domains by a separate agent. In clinical trials, tramadol monotherapy reduced the impact of pain on patients with FM,8 but it had little effect on insomnia or depression.9 If tramadol (mechanistically, weak µ-opioid agonism combined with serotonin norepinephrine reuptake inhibition) is used to treat the pain, then the antidepressant chosen to address depression should not be a selective serotonin reuptake inhibitor (SSRI) because it could predispose the patient to the hyperserotonin syndrome.3 In that situation, a dopaminergic antidepressant such as bupropion could be considered.

Prominent Domains of Pain and Depression
Depression is present in 30% to 40% of patients with FM. An alternative to using two separate medications to treat the pain and depression in FM is shown in Figure 3. In this scenario, the use of duloxetine would be logical because it has both antidepressant and analgesic activity.10,11 It is on-label to administer the full 60 mg per day dosage of duloxetine in the morning, preferably with breakfast to reduce the risk for nausea. Of course, duloxetine could be used to treat the pain even if depression were not present (as is true of more than 70% of FM patients) because it was shown to be as effective for the treatment of pain whether or not depression was present. It is likely that milnacipran could be used interchangeably with duloxetine but they should not be used together.12

Prominent Domains of Pain and Insomnia
The use of pregabalin for the pain would be logical for a FM patient whose most prominent clinical domains are pain and sleep dysfunction (insomnia), and who has no depression or whose depression is adequately managed with an SSRI (Figure 4).13,14 This is because pregabalin acts as both an analgesic and sedating agent. It would be on-label to administer the therapeutic dosage of 300 mg to 450 mg as morning and evening divided monotherapy doses. The author’s preferred approach is an off-label regimen. The starting dosage is one capsule of 150 mg at bedtime for 2 weeks, then the patient increases the dosage to two capsules or 300 mg, all at bedtime. If after 2 weeks on that dosage, the patient is still symptomatic, the dosage is increased to three capsules or 450 mg, all at bedtime.

The main advantages of this approach are that the drug’s sedating effect becomes a desired therapeutic benefit rather than an adverse effect. If the drug were to cause dose-dependent central nervous system (CNS) effects like dizziness or cognitive dysfunction, they would not be noted while the patient is asleep. By morning, the serum drug level would be lower so those symptoms would be lessened during the daytime. The binding of pregabalin to its receptor is so avid that the analgesic effect of a bedtime dosage tends not to begin to wane until mid-afternoon the next day. After the patient has caught up on the sleep deficit, one of the 150-mg capsules can be moved to the morning if late afternoon pain is a prominent complaint.

If a compliant patient has acceptable analgesia with pregabalin but still sleeps very poorly, the author considers the addition of sodium oxybate (Xyrem) to the regimen.15,16 The mechanism of action is believed to involve binding to γ-hydroxy butyrate (GHB) and γ-aminobutyric acid-B (GABA-B, but not to GABA-A) receptors. Note that sodium oxybate is FDA-approved for narcolepsy with cataplexy or excessive daytime sleepiness but not for FM. Use of sodium oxybate for treatment of FM would be an off-label intervention. Half (1.5 g) of the initial 3 g daily sodium oxybate dosage would be taken at bedtime and the second half (1.5 g) would be taken at 2 am. This starting dosage is low because the drug is being added to a regimen that includes other potentially sedating agents. After about 1 month on this regimen, without any improvements in sleeping habits, the daily dosage of the sodium oxybate can be increased to 4.5 g (two doses of 2.25 g). The patient should take precautions against any diversion of this product.

Prominent Domains of Pain, Depression, and Insomnia
Figure 5 illustrates strategic polypharmacy where all three domains are managed with two or three drugs directed at three different dysfunctional mechanisms (exhuberant pronociception, impotent descending inhibition, and GABA-B) in FM.

In FM patients with three prominent domains (pain, insomnia, and depression), the combined use of either duloxetine, pregabalin, and in some cases sodium oxybate, would be logical and safe. Note that combination chemical therapy for FM has not been evaluated or approved by the FDA. While each of the listed therapeutic agents has shown efficacy for FM in monotherapy clinical trials, available data is inadequate to document the efficacy of the proposed strategic polypharmacy regimen. Clearly, medical therapy of FM must be tailored to the patient, carefully monitored, and considered clinically experimental.

Summary
The FM syndrome is a common clinical disorder that exhibits pain and many comorbidities. There is objective physiologic, imaging, and biochemical evidence to support the concept that patients with FM actually experience the pain that they describe.

Multimodal therapy, involving pharmacologic and nonpharmacologic interventions, is the contemporary approach to managing FM. Pharmacologic therapy of FM has become increasingly mechanistically focused on the correction of documented molecular-level abnormalities. Rational strategic polypharmacy with two or more agents directed at different molecular mechanisms will likely represent the important clinical therapeutic innovations of the next decade.

Last updated on: February 20, 2015
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