CURRENT DRUG THERAPY LAUREN KIM, MD SARAH LIPTON, MD ATUL DEODHAR, MD Assistant Professor of Medicine, Oregon Chief Resident in Medicine, Oregon Associate Professor of Medicine, Division Health & Science University, Portland, OR Health & Science University, Portland, OR of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, OR Pregabalin for fibromyalgia: Some relief but no cure ■■ ABSTRACT regabalin (Lyrica) is a novel analogue of P the neurotransmitter gamma aminobutyr- What is the role of pregabalin (Lyrica) in the treatment ic acid (GABA) with analgesic, anticonvul- of fibromyalgia? In this article the authors explore the sant, and anxiolytic activity. Its approval by putative pathophysiology of fibromyalgia, pregabalin’s the US Food and Drug Administration (FDA) mechanism of action and evidence of efficacy, and its in 2007 for the treatment of fibromyalgia made emerging role in treating this challenging disease. it the first drug approved for this indication. Until then, management of fibromyalgia en- ■■ KEY POINTS tailed drugs to treat pain, sleep, fatigue, and psychological disorders, and a strong emphasis Several lines of evidence point to functional abnormali- on exercise and physical therapy. ties in the central nervous system as being responsible Those who still question the validity of fi- for fibromyalgia. bromyalgia as a diagnosis object to drug com- panies “benefiting” from the sale of such drugs.1 But many hail pregabalin as an important ad- Clinical trials found pregabalin superior to placebo. Nev- vance in our understanding of the pathogenesis ertheless, patients need to have reasonable expectations of fibromyalgia and how to treat it. A key ques- of its possible benefit. tion remains: How will pregabalin fit into the treatment of this often-challenging disease? In most patients with fibromyalgia, a multidisciplinary approach is used to treat pain, sleep disturbance, and ■ FROM FIBROSITIS TO FIBROMYALGIA fatigue, along with comorbidities such as neurally medi- ated hypotension and psychiatric disorders. Fibromyalgia is a syndrome characterized by widespread pain. Chronic muscular pain is a Research with pregabalin enhances our understanding common problem, but fibromyalgia is distin- of fibromyalgia and may point the way to future treat- guished from other pain disorders by additional ments. findings, such as consistent areas of tenderness (tender points), nonrestorative sleep, severe fatigue, and frequent psychological comorbidi- ties such as depression and anxiety. Fibromyalgia was originally termed “fibro- sitis” in 1904 by Sir William Gowers, who de- scribed it as a painful condition of the fibrous tissue, which he believed was due to inflamma- tion in the muscles.2,3 For several decades, re- search was dedicated to looking for pathology in the muscle tissue, which was thought to be the major source of pain for most patients with doi:10.3949/ccjm.76a.08024 fibromyalgia. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • NUMBER 4 APRIL 2009 255 Downloaded from www.ccjm.org on October 5, 2021. For personal use only. All other uses require permission. PREGABALIN FOR FIBROMYALGIA In the mid-1970s, Dr. H. Moldofsky, a While much of the evidence for central noted sleep researcher, reported on abnor- sensitization in fibromyalgia is from animal malities of the alpha-delta component of non- studies, the phenomenon has also been stud- rapid-eye-movement sleep in these patients. ied in humans. Desmeules et al8 found that, He subsequently collaborated with Dr. Hugh compared with people without fibromyalgia, A. Smythe, who helped define the fibromyal- those with fibromyalgia had significantly low- gia tender points. Fibrositis was subsequently er thresholds of pain as assessed subjectively renamed fibromyalgia syndrome, since it was and measured objectively using the nocicep- agreed that there was no true inflammation in tive flexion R-III reflex, which the authors de- muscles or fibrous tissue. scribed as “a specific physiologic correlate for In 1990, the American College of Rheu- the objective evaluation of central nocicep- matology published “classification criteria” for tive pathways.” the disease.4 The criteria include two main Wind-up. Prolonged stimulation of C fibers features: in the dorsal horn can result in the phenom- • A history of widespread pain (“widespread” enon of wind-up, which refers to the temporal being defined as in the axial distribution, summation of second pain. in both the left and right sides of the body, A painful stimulus evokes two pain sig- and above and below the waist), which nals. The first signal is brief and travels must be present for 3 months or more, and rapidly to the spinal cord via myelinated • Tenderness in at least 11 of 18 specified fibers (A fibers). The second signal, which points that is elicited when a pressure of is related to chronic pain and is described as 4 kg (the amount of pressure required to dull, aching, or burning, travels more slowly blanch a thumbnail) is applied in steady to the dorsal horn via unmyelinated fibers increments starting at 1 kg. (C fibers), the synapses of which use the Although pain is subjective and therefore dif- neurotransmitter glutamate. Temporal sum- ficult to assess, the classification criteria did make mation is a phenomenon observed in exper- it easier to study the disease in a uniform way and iments in which a series of painful stimuli Pain is led to an explosion of research in this field. are applied at regular intervals of about 2 subjective seconds; although each stimulus is identi- ■ FUNCtioNAL ABNORMALitiES cal in intensity, subjects perceive them as and therefore IN THE CENTRAL NERVOUS SYSTEM increasing in intensity. The reason: during difficult this repetitive stimulation, N-methyl-d- to assess Research to date points to the pain in fibromy- aspartate (NMDA) receptors become acti- algia as being mediated by changes in the cen- vated, leading to the removal of a magne- tral nervous system rather than in the muscu- sium block within the receptor. This results loskeletal system, as was initially thought. in an influx of calcium into the neuron and In the dorsal horn of the spinal cord, noci- activation of protein kinase C, nitric oxide ceptive (pain-sensing) neurons from the pe- synthase, and cyclooxygenase. Ultimately, riphery synapse with the second-order neu- the firing rates of the nociceptive neurons rons that carry the pain signal to the brain. In are increased and the peripheral pain signal fibromyalgia, several processes seem to amplify is strongly amplified.6 the signal. Wind-up has been shown to lead to char- Central sensitization is defined as en- acteristics of central sensitization related to hanced excitability of neurons in the dorsal C-fiber activity in animals.7 Staud et al9 stud- horn. Its features include augmented sponta- ied wind-up in patients with and without neous neuronal activity, enlarged receptive fibromyalgia using series of repetitive thermal field areas, and enhanced responses generated stimulation to produce temporal summation. by large- and small-caliber primary afferent fi- Though wind-up was evoked in both groups, bers. It can result from prolonged or strong ac- differences were observed both in the magni- tivity in the dorsal horn neurons, and it leads tude of sensory response to the first stimulus to the spread of hyperactivity across multiple within a series and in the amount of temporal spinal segments.5–7 summation within a series. 256 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • NUMBER 4 APRIL 2009 Downloaded from www.ccjm.org on October 5, 2021. For personal use only. All other uses require permission. KIM AND COLLEAGUES Elevated excitatory neurotransmitters. ■ PREGABALIN In 1994, Russell et al10 showed that the con- centration of substance P, an excitatory neu- Pregabalin is an alpha-2-delta ligand similar to rotransmitter, was three times higher in the GABA, but it does not act on GABA recep- cerebrospinal fluid of people with fibromyalgia tors. Rather, it binds with high affinity to the than in normal controls. alpha-2-delta subunit of voltage-gated presyn- Harris and colleagues11 reported that glu- aptic calcium channels, resulting in reduction tamate, another excitatory neurotransmitter, of calcium flow through the channels, which is elevated within the brain in people with fi- subsequently inhibits the release of neurotrans- bromyalgia. They further showed that the lev- mitters including glutamate, norepinephrine, els of glutamate within the insula of the brain and substance P.15–17 Animal studies suggest are directly associated with the levels of both that the decrease in the levels of these excit- experimental pressure-evoked pain thresholds atory neurotransmitters is the mechanism of and clinical pain ratings in fibromyalgia pa- action of pregabalin, resulting in its analgesic, tients. anticonvulsant, and anxiolytic benefit.15 An- Evidence from imaging studies. Other other potential mechanism of pregabalin is en- objective evidence of central sensitization in hancement of slow-wave sleep, demonstrated fibromyalgia patients comes from studies using in one study in healthy human subjects.18 novel imaging. Besides fibromyalgia, pregabalin is also ap- Gracely et al12 performed functional mag- proved for the treatment of diabetic peripheral netic resonance imaging (MRI) in people with neuropathy, postherpetic neuralgia, general- and without fibromyalgia while applying pres- ized anxiety disorder, and social anxiety disor- sure to their thumbs with