Fibromyalgia Drugs are 'As Good as it Gets' in Chronic Pain

Daniel J. Clauw

Disclosures

Abstract and Introduction

Abstract

A systematic review of randomized controlled trials reveals some differences in the effects and indications of the three pharmalogical treatments for fibromyalgia. What can prescribing physicians glean from the results?

Introduction

In a recent issue of The Journal of Pain, Hauser et al.[1] performed a meta-analysis of published trials of the three drugs approved in the USA for use in fibromyalgia: duloxetine, milnacipran and pregabalin. 11 randomized controlled trials including a total of 6,388 patients met the inclusion criteria and were included in the review. Outcomes of interest were improvements in pain, fatigue, sleep disturbance, depressed mood and health-related quality of life, as well as adverse events.

The authors concluded that the three drugs were superior to placebo for all outcomes noted above, with the exceptions of duloxetine for fatigue, milnacipran for sleep disturbance, and pregabalin for depressed mood. They did not note any substantial differences between the drugs in the proportion of individuals who achieved a 30% improvement in pain (the value generally considered to be the minimum clinically important difference), but they did note quantitative differences in the symptoms that were most improved by each drug. Duloxetine and pregabalin were superior to milnacipran in reducing pain and sleep disturbances, duloxetine was superior to milnacipran and pregabalin in reducing depressed mood, and milnacipran and pregabalin were superior to duloxetine in reducing fatigue. Thus, there is some rationale for initially choosing the drug most likely to favorably influence an individual patient's symptom profile.

The analysis suggests that the initial choice of pharmacological therapy can also be guided by the adverse event profile of each compound. The most frequent 'class' effects seen with the two serotonin norepinephrine reuptake inhibitors (SNRIs—duloxetine and milnacipran) included nausea, headache, hyperhidrosis and constipation, and the most serious adverse effects were rare cases of uncontrolled hypertension, hepatotoxicity or suicidality. The most frequent class effects seen with the α2δ-subunit calcium-channel ligands (pregabalin as well as similar compounds such as gabapentin) are dizziness, somnolence, weight gain and peripheral edema; the most serious rare adverse event seen in the meta-analysis was heart failure.

An important lesson from these studies is that these first three approved drugs are likely to be working at the root pathogenic cause of symptom expression in fibromyalgia, rather than just 'covering up' a particular symptom such as pain. When individuals have a favorable response to any of these drugs, they typically improve across many symptom domains. This is probably because the neurotransmitters affected by these agents (norepinephrine, serotonin, Substance P, glutamate) have broad influences not only on pain transmission but also on level of alertness, memory and sleep. Thus, an SNRI might have an analgesic effect by increasing norepineprine and serotonin levels in brain regions such as the locus ceruleus or periacqueductal gray areas of the brain (thus increasing descending analgesic activity to the spinal cord), whereas it might lead to increased alertness by raising norepinephrine levels within the reticular activating system in the brain.

In clinical practice, it is common to use one drug from each of these classes in combination. This approach is beginning to be supported by data showing much higher overall response rates in fibromyalgia patients treated with an SNRI and an α2δ-subunit calcium-channel ligand together, rather than with either class separately.[2] This evidence is not surprising because we have learned that there are many neurotransmitter abnormalities that can be identified in so-called central pain states such as fibromyalgia, which might act in concert to increase the 'volume control' of pain processing in the central nervous system. Thus, the state of diffuse central nervous system hyperalgesia seen in fibromyalgia, identifiable using experimental pain testing and functional neuroimaging, appears to be a final common pathway not unlike other physiological processes that, when hyperactive, can lead to a final common pathway such as autoimmunity or essential hypertension.[3] All of these states can be caused by increases in levels of neurotransmitters, cytokines or hormones that increase the activity of these systems, or by decreases in levels of neurohormonal factors that decrease the activity of these systems. Contemporary therapeutic approaches often use combinations of pharmacological therapies with different mechanisms of action, since no single drug works well in all individuals with an underlying problem that has a heterogeneous pathogenesis.

Finally, perhaps the most important lesson from the meta-analysis by Hauser et al.[1] is that, as measured by standardized effect sizes, the overall analgesic efficacy of these drugs is no different for fibromyalgia than of other analgesics for other chronic pain states. Many practitioners feel that they can effectively treat 'real' pain states such as osteoarthritis, whereas they feel they do not have anything to offer individuals with fibromyalgia even though the data suggest otherwise. The standardized analgesic effect sizes of the three fibromyalgia drugs range from −0.19 to −0.33, which are small-to-modest. However, these effect sizes are nearly identical to those of acetaminophen, NSAIDs and opioids noted in meta-analyses of analgesic agents for osteoarthritis of the knee.[4,5] For chronic pain treated with a single class of drugs, these effect sizes are 'as good as it gets'.

Because of the modest overall analgesic efficacy seen with any class of analgesic drug in any chronic pain state, we should be particularly aggressive about using more nonpharmacological therapies in treating patients with chronic pain, no matter what the 'cause' of the pain. Nonpharmacological approaches such as education, cognitive behavioral therapy and exercise have large effect sizes in fibromyalgia as well as in nearly any other chronic pain state studied, but at present these treatments are rarely used in clinical practice.[6,7]

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