Presentations and Publications SELECTED PAPERS AND LETTERS1 Russell IJ, Holman AJ, Swick TJ et al.  Sodium oxybate reduces pain, fatigue and sleep disturbance and improves functionality in fibromyalgia:  results from a 14-week, randomized, double-blind, placebo-controlled study.  Pain 2011;152(5):1007-17.       This phase 3 pivotal trial of sodium oxybate demonstrated remarkable efficacy for FM, but safety concerned the FDA enough to prevent its approval as the fourth medication indicated for treatment of FM.   Holman AJ, Neradilek MB, Dryland DD, et al.  Patient-derived determinants for participation in placebo-controlled clinical trials in fibromyalgia.Curr Pain Headache Rep 2010 Dec; 14(6):470-6.        A paper reporting why patients may be willing to participate in trials for FM.  #1 reason: altruism. Holman AJ. Pharmacotherapy in fibromyalgia.  In Hakim AJ, Kerr R, Grahame R, Eds. Hypermobility, Fibromyalgia and Chronic Pain. Philadelphia, PA: Elsevier; 2010:107-117. Rahman A, Holman AJ.  Fibromyalgia and hypermobility. In Hakim AJ, Kerr R, Grahame R, Eds. Hypermobility, Fibromyalgia and Chronic Pain. Philadelphia, PA: Elsevier; 2010:61-68.       Two chapters in this important book about hypermobility syndromes, FM and pain. Holman AJ.  Pregabalin for treatment of fibromyalgia: the rest of the story? Current Pain and Headache Reports. 2009;13(6):420-22.       A proposal that the FDA approved treatment for fibromyalgia, pregabalin, may actually work to treat comorbid positional cervical spinal cord compression found in 60% of FM patients rather than on the pathophysiology of FM itself. Holman AJ.  Assessing patients with fibromyalgia: a three step methodology for differential diagnosis from a rheumatologist's pespective. Int J Rheum 2009;4(4):409-19.       A provocative and inovative methodology to assess fibromylagia pain amplification while evaluating patient for complex combinations od diagnoses. Holman AJ.  Impulse control disorder behaviors associated with pramipexole used to treat fibromyalgia. J Gambling Studies 2009;25(3):425-31.       Describes the importance of identifying signs ofcompulsivity among 1.5% of patients taking pramipexole for treatment of fibromyalgia. Wood PB, Holman AJ.  The elephant amonst us: dopamine and the pathophysiology of fibromyalgia. Journal of Rheumatology 2009;36(2):221-4       A new editorial highlighting evidence that FM is a dopamine deficiency state. Holman AJ. Positional cervical spinal cord compression and fibromyalgia: a novel comorbidity with important diagnostic and treatment implications.  Journal of Pain 2008;9(7):613-22.       The third paper on this topic and the first to highlight the dynamic flexion-extension cervical spine MRI, which may transform our understanding of not only FM, but also chronic widespread pain (CWP).  The editors of this journal were interested enough to select these MR images for their July 2008 issue cover.  Over 65% of patients with FM and 85% of patients with CWP had evidence of cord compression usually missed by traditional MRI.   Lyrica and Cymbalta, both FDA approved for treatment of FM, may actually address this spinal cord finding rather than treat FM itself.  Neither affect dopamine or the central mechanisms controlling FM, but both infuence the spinal cord.  In fact, Lyrica is approved in the EU (European Union) for central spinal cord pain. Holman AJ, Ng E.  Heart rate variability predicts anti-tumor necrosis factor response for inflammatory arthritis.  Autonomic Neurosci Basic & Clinical 2008;143(1-2):58-67.      The first pivotal study to predict treatment response with Enbrel and Humira for inflammatory arthritis using measures of autonomic nervous system recativity.  Such prediction could help patients avoid costly and ineffective therapies, and also begin to explain why some patients fail to respond to our best treatments.  Given the EULAR 2002 abstract (below), such a tool may allow indentifiacton of non-responders who may wish to incorporate autonomic options to improve their response to autoimmune disease treatment options. Holman AJ.  Pragmatic consideration of randomized, placebo-controlled trials for treatment of fibromyalgia.  Current Pain and Headache Reports. 2008;12:393-398.       A review of all new FM treatment studies comparing and contrasting efficacy and safety from the perspective of predicting treatment response based on a new understanding of FM pathophysiology.     Holman AJ.  An alternative, autonomic rationale for decreased risk of MI in patients with RA responsive to anti-TNF therapy: comment on article by Dixon. Arthritis & Rheumism 2008;58(6):1886.     Further support of the autonomic influence of cardiovascular disease in patients with RA. Wood P, Holman AJ, Jones K. Novel pharmacotherapy for fibromyalgia. Expert Opin Investigational Drugs. 2007 Jun;16(6):829-41.     Update of treatment options for FM, co-authored with Dr. Wood, who identified dopamine deficiency in FM by PET scan technology. Holman AJ. Considering cardiovascular mortality in patients with rheumatoid arthritis from a different perspective: a role for autonomic dysregulation and obstructive sleep apnea.  Journal of Rheumatology 2007;34(4):671-3.      This is the first description of a hypothesis promoting consideration of autonomic nervous system infuence of cardiovascular disease risk in patients with RA. Holman AJ.  Treatment of fibromyalgia: a changing of the guard.  Women's Health 2005;1(3):409-420.      This review in a new British journal compares the placebo-controlled trials of the investigational fibromyalgia treatment options, including pregabalin, milnacipran, sodium oxybate, duloxetine, pramipexole and ropinirole. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.  Arthritis & Rheumatism 2005;52(8):2495-2505.    This paper reported the highest response rate to date for patients treated for fibromyalgia with a single medication in terms of response defined as > 50% decreased pain (42% of subjects taking pramipexole compared to 14% taking placebo).  Pramipexole was dosed only at bedtime and increased over 14 weeks to the target dose of 4.5 mg.  The most common adverse events were nausea (in placebo and active arms) and weight loss with pramipexole and weight gain with placebo.      This study was unique, in that these 60 subjects were allowed to continue other FMS medications if stable throughout the study.  Over 30% were disabled and 50% required chronic narcotic analgesics.  Arguably, this was a cohort with very severe fibromyalgia.      Important study exclusions included untreated obstructive sleep apnea and  cervical myelopathy (neck pain with prolonged extension).  Both disorders limit the effectiveness and tolerability of pramipexole when used to treat fibromyalgia.  Holman AJ, Neiman RA, Ettlinger RE.  Preliminary efficacy of the dopamine agonist, pramipexole, for fibromyalgia: the first, open label experience. Journal of Musculoskeletal Pain 2004;12(1):69-74.     This paper describes use of pramipexole up to 2.0 mg at bedtime to treat FMS.  At three different rheumatology offices, pain scores 46% and sleep quality ratings improved 64% during this brief, two month pilot study.  Adverse events were not similar to treatment of Parkinson's disease with pramipexole.  The most common intolerence was nausea. Holman AJ. Fibromyalgia and pramipexole: promise and precaution. [letter] Journal of Rheumatology 2003;30(12):2733.     This letter described the first use of pramipexole for treatmet of FMS.  It described the high doses of pramipexole up to 10.5 mg at bedtime and the safety profile in 200 patients over 7 months.  It reviewed the rationale of using pramipexole to treat FMS and the importance of using proton pump inhibitors (PPI) to block nausea when starting pramipexole. Holman AJ. Ropinirole, open preliminary observations of a dopamine agonist for refractory fibromylagia. [letter] Journal of Clinical Rheumatology 2003;9(4):277-9.     This letter describes the first use of the dopamine agonist, ropinirole, for treatment of FMS.  Over 10 months, 19 patients taking an average of 6.0 mg (0.25-24 mg) of ropinirole at bedtime experienced a average pain score decrease from  21.8 to 9.2 (p < 0.001).  Although open label data should always be evaluated with caution, 74% of these patients achieved >50% decreased pain. Holman AJ. The value of rheumatologists to patients with fibromyalgia: comment on the presidential address by Weinblatt. [letter] Arthritis & Rheumatism 2002;46(12):3390.    Dr. Holman disagreed with a proposal by the President of the American College of Rheumatology to limit office visits for patients with fibromyalgia. Holman AJ. Is hypermobility a factor in fibromyalgia? [letter] Journal of Rheumatology 2002;29(2):396-8.     Some articles have supported an association, while others have been skeptical. Emphasis on autonomic dysregulation and hypermobilty was offered as a link between hypermobility and fibromyalgia, a link that has recently been validated by other papers. Holman AJ. Treatment of fibromyalgia: another approach.  The Bulletin, King County Medical Society 2002;80(11):10 21-22.    Summmary article/editorial on fibromyalgia and autonomic dysregulation which reviews the basic hypothesis that fibromyalgia may be the predictable consequence of stage III/IV sleep deprivation inhibited by sympathetic nervous system overactivity. RESEARCH ABSTRACTS   Holman AJ.  Pathological compulsive behavior associated with dopamine agonists used to treat fibromyalgia.  Arthritis Rheum 2008 in press.     The first description of compulsivity related to treatment of FM with dopamine agonists.  Previously, this was seen in Parkinson's disease. Holman AJ, Neiman RA, Dryland D, Brown PB.  Fibromyalgia randomized controlled trials: patient perspective on participation and FDA mandates.  Arthritis Rheum 2006;54(9):S606. The FDA has recommended that all FMS trials be conducted comparing a new drug to placebo.  Participating subjects are only allowed Tylenol for pain and must discontinue all other medications affecting FMS (antidepressants, analgesics, etc.) to participate.  We surveyed patients to examine demographics and their motivation to particpate in such studies if conducted over 1 to 12 months. Most patients felt that a placebo with only Tylenol for pain would limit their interest in participating in such a study.  However, 25% felt that they would discontinue all of their medications to participate for a 3-month study.  Participation was most closely linked to prior participation in an FMS trial and with lower income. Holman AJ, Myers RR, Gray A. Treatment of fibromyalgia with the dopamine agonist ropinirole: a 14-week, double-blind, pilot, randomized controlled trial (RCT) with 14-week blinded extension.  Athritis Rheum 2004;50(9) suppl: A1870.     This was the first placebo controlled trial to evaluate ropinirole as a treatment for FMS.  In 30 patients, 45% on ropinirole noted >50% decreased pain vs. 30% taking placebo.  Although the trial was too small to demonstrate statistically significant difference, the safety profile of ropinirole in FMS patients and the encouraging preliminary results were a prelude to a larger study in Europe planned by its manufacturer GlaxoSmithKline.  The dose increased to 8 mg at bedtime (equivalent to 2 mg of pramipexole) was probably insufficient.  The European study plans to study a dose up to 24 mg at bedtime, equivalent to the dose used in the pramipexole RCT. Holman AJ, DePaso WJ.  High prevalence of obstructive sleep apnea (OSA) in men with inflammatory arthritis.  Arthritis Rheum 2004;50(9) suppl: A947.     This chart review of 80 men with RA, SLE, AS and PsA demonstrated a 45% prevalence of OSA.  All men referred for sleep study has OSA and another 17% refused to have a sleep study.  Therefore, we suspect that over 60% of these men had OSA, much more than the expected rate of 4-8% of the male population.  Men were not reffered for traditional risk factors and 33% were slim.  Only 33% had a BMI >30 (obese).  They were referred for an inadequate DMARD response.     OSA is a potent sympathetic arousal (essentially an drowning reflex to hypoxia).  Untreated, it enhances an autoimmune disease and limits the effectiveness of our best RA, SLE and AS treatments.  Identifying and treating OSA decreases autoimmune disease expression and improves the treatment response.  This phenomenon has also been seen with diabete and hyperternsion.  This was simply another way to begin to discuss the important and adverse influence of the sympathetic nervous system (activated by OSA) on an autoimmune disease.   Three abstracts on fibromyalgia(2) and etanercept (1) were accepted at the 2003 British Society for Rheumatology and the pilot, phase II trial of ropinirole was accepted at the 2004 meeting.  These abstracts are available on their web site www.rheumatology.org.uk. Holman AJ. Safety and efficacy of the dopamine agonist, pramipexole, on pain score for refractory fibromyalgia. Arthritis Rheum 2000;43:9 (suppl)A1599.     Presented at the American College of Rheumatology national meeting in Philadelphia, 2000, this is the first report of treatment of fibromyalgia with pramipexole.  Of 166 patients, at 8 weeks in an open label format: 22% were intolerant from mild nausea or anxiety.  Of 127 increasing pramipexole from 0.125 mg up to 6 mg at bedtime (mean 1.55 mg): 29% were pain free, 43% noted minor pain, 76% imporved to some degree, 20% were unchanged and 3.8% were worse. Holman AJ. Safety and efficay of lorazepam for fibromyalgia after one year.  Arthritis Rheum 1999;42:9 (suppl) A385.     Presented at the American College of Rheumatology national meeting in Boston, 1999, this one year data describes the sustained benefit of lorazepam (and clonazepam) at bedtime for fibromyalgia.  Abuse and significant intollerances were not seen. Holman AJ. Addressing sleep disturbance/fibromyalgia greatly enhances etanecept efficacy for rheumatoid and psoriatic arthritis. Ann Rheum Dis EULAR supplement 2002.     Presented at the European League Against Rheumatism in Stockholm 2002, these observations support theories from the NIH and others suggesting an important link between the autonomic nervous system that regulates sleep and the immune system.  Of 66 patients adding etanercept (Enbrel) to traditional medications for rheumatoid and psoriatic arthritis, those with active sleep disturbance and/or overt fibromyalgia responded much poorly.  Those with normal sleep or effectively treated sleep responded dramatically and were routinely able to control their arthritis with etanercept while discontinuing steroids and methotrexate.    Contact Dr. Holman at:  ajhseattle@aol.com