Analysis of Amitriptyline's Effectiveness for Fibromyalgia and Neuropathic Pain

Amitriptyline for neuropathic pain and fibromyalgia in adults.

– Source: “Cochrane Database of Systematic Reviews”, December 12, 2012

By R.A. Moore, et al.

Abstract:

Background: Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and is recommended in many guidelines. These types of pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.

Objectives: To assess the analgesic efficacy of amitriptyline for chronic neuropathic pain and fibromyalgia.To assess the adverse events associated with the clinical use of amitriptyline for chronic neuropathic pain and fibromyalgia.

Search Methods: We searched CENTRAL, MEDLINE, and EMBASE to September 2012, together with reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own handsearched database for older studies.

Selection Criteria: We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.

Data Collection and Analysis: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using two tiers of evidence.

• The first tier used data meeting current best standards, where studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, reported an intention-to-treat (ITT) analysis, lasted 8 to 12 weeks or longer, had a parallel-group design, and where there were at least 200 participants in the comparison.
• The second tier used data that failed to meet this standard and were therefore subject to potential bias.

Main Results: Twenty-one studies (1437 participants) were included; they individually involved between 15 and 235 participants, only four involved over 100 participants, and the median study size was 44 participants. The median duration was six weeks. Ten studies had a cross-over design. Doses of amitriptyline were generally between 25 mg and 125 mg, and dose escalation was common.

• There was no top-tier evidence for amitriptyline in treating neuropathic pain or fibromyalgia.
• Second-tier evidence indicated no evidence of effect in cancer-related neuropathic pain or HIV-related neuropathic pain, but some evidence of effect in painful diabetic neuropathy (PDN), mixed neuropathic pain, and fibromyalgia.
• Combining the classic neuropathic pain conditions of PDN, postherpetic neuralgia (PHN) and post-stroke pain with fibromyalgia for second-tier evidence, in eight studies and 687 participants, there was a statistically significant benefit (risk ratio (RR) 2.3, 95% confidence interval (CI) 1.8 to 3.1) with a number needed to treat (NNT) of 4.6 (3.6 to 6.6). The analysis showed that even using this potentially biased data, only about 38% of participants benefited with amitriptyline and 16% with placebo; most participants did not get adequate pain relief.
• Potential benefits of amitriptyline were supported by a lower rate of lack of efficacy withdrawals; 8/153 (5%) withdrew because of lack of efficacy with amitriptyline and 14/119 (12%) with placebo.
• More participants experienced at least one adverse event; 64% of participants taking amitriptyline and 40% taking placebo.
• The RR was 1.5 (95% CI 1.4 to 1.7) and the number needed to treat to harm was 4.1 (95% CI 3.2 to 5.7).
• Adverse event and all-cause withdrawals were not different.

Authors' Conclusions: Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many patients with neuropathic pain or fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect.

Amitriptyline should continue to be used as part of the treatment of neuropathic pain or fibromyalgia, but only a minority of patients will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.

It is unlikely that any large randomised trials of amitriptyline will be conducted in specific neuropathic pain conditions or in fibromyalgia to prove efficacy.

Source: “Cochrane Database of Systematic Reviews”, December 12, 2012. By R.A. Moore, S. Derry, D. Aldington, P. Cole, and P.J. Wiffen. Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.

chronic diabetic peripheral neuropathic pain (DPNP)

Drugs similar in efficacy for neuropathic pain in diabetes September 26, 2012 in Diabetes (HealthDay)—In the treatment of patients with chronic diabetic peripheral neuropathic pain (DPNP), there are no significant differences in pain-relief efficacy between amitriptyline, duloxetine, and pregabalin; however, pregabalin improves sleep continuity and duloxetine improves daytime functioning, according to research published online Sept. 18 in Diabetes Care.  Julia Boyle, Ph.D., of the University of Surrey in the United Kingdom, and colleagues conducted a randomized, double-blind, parallel-group study involving 83 type 1 and type 2 diabetes patients with chronic DPNP who were treated with a placebo run-in followed by 14 days of lower-dose therapy, then 14 days of higher-dose therapy, with either amitriptyline, duloxetine, or pregabalin. The authors sought to evaluate the impact of these medications on pain, polysomnographic sleep, daytime functioning, and quality of life. The researchers found that all three medications improved pain compared with placebo, but no statistically significant between-group difference was observed. Pregabalin was associated with improved sleep continuity, while duloxetine increased wake and reduced total sleep time. Despite its negative effect on sleep, duloxetine improved central nervous system arousal and performance on sensory motor tasks. Pregabalin was associated with a significantly higher number of adverse events compared with the other drugs. "In conclusion, amitriptyline, duloxetine, and pregabalin were equally effective analgesic medications in patients with DPNP. Daytime function was relatively unaffected by drug treatment, and all three drugs were well tolerated," the authors write. "In this short, 28-day dosing study, there was no evidence of improved quality of life (Short Form 36) even with the sleep enhancement observed with pregabalin

Read more at: http://medicalxpress.com/news/2012-09-drugs-similar-efficacy-neuropathic-pain.html#jCp

The Concept of Incomplete Fibromyalgia Syndrome

The Concept of Incomplete Fibromyalgia Syndrome: Comparison of Incomplete Fibromyalgia Syndrome With Fibromyalgia Syndrome by 1990 ACR Classification Criteria and Its Implications for Newer Criteria and Clinical Practice
Journal of Clinical Rheumatology (JCR), 03/28/2012

Yunus MB et al. – Fulfillment of the American College of Rheumatology (ACR) 1990 criteria is not necessary for a diagnosis of fibromyalgia/fibromyalgia syndrome (FMS) in the clinic. For diagnosis and management of FMS in the clinical setting, incomplete FMS (IFMS) patients, along with consideration of the total clinical picture, may be considered to have FMS, albeit generally mild.

Pharmacotherapy of fibromyalgia

Philip J. Mease, Kelly Dundon, Piercarlo Sarzi-Puttini,

There have been substantial advances in the pharmacotherapy of fibromyalgia (FM), which have occurred in parallel with advances in our understanding of the pathophysiology of FM in the past several years. Consortia of researchers have established a core set of symptom domains, which constitute the condition of FM, including pain, fatigue, sleep and mood disturbance and cognitive dysfunction, which significantly impact a patient’s overall well-being and ability to function. Outcome measures, which assess these domains, both singly and in composite format, are showing increasing reliability to discriminate between the treatment and placebo arms in clinical trials of emerging therapies, which are targeting the pathophysiologic mechanisms of FM. Several different medications, including the serotonin and norepinephrine reuptake inhibitors, duloxetine and milnacipran, and the α₂δ modulator, pregabalin, have been approved by the Food and Drug Administration (FDA) for the management of FM, based on their clinically meaningful and durable effect on pain in monotherapy trials. They also have been shown to beneficially effect patient global impression of change, function and variably other key symptom domains, such as fatigue, sleep disturbance and cognition. Other medicines, although they have not gone through the formal approval process, have also shown efficacy in multiple domains of FM. Although combination trials have generally not yet been performed, the combined use of medicines with complementary mechanisms of action is rational, and, when done with appropriate caution, will likely be shown to be safe and well tolerated. Adjunctive therapy with medicines targeted at specific symptom domains, such as sleep, as well as treatments aimed at common co-morbid conditions, such as irritable bowel syndrome, or disease states, such as rheumatoid arthritis, should be considered for the purpose of reducing the patient’s overall symptom burden. Current therapies neither completely treat FM symptoms nor benefit all patients; thus, further research on new therapies with different mechanisms and side-effect profiles is needed.
http://www.bprclinrheum.com/article/PIIS1521694211000209/abstract?rss=yes

ACR Diagnostic Criteria for Fibromyalgia

 Fibromyalgia diagnostic criteria

A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met:

1) Widespread pain index (WPI)

2) Symptoms have been present at a similar level for at least 3 months.

3) The patient does not have a disorder that would otherwise explain the pain.

Ascertainment

1) WPI: note the number areas in which the patient has had pain over the last week. In how many areas has the patient had

pain? Score will be between 0 and 19.

Shoulder girdle, left Hip (buttock, trochanter), left Jaw, left Upper back

Shoulder girdle, right Hip (buttock, trochanter), right Jaw, right Lower back

Upper arm, left Upper leg, left Chest Neck

Upper arm, right Upper leg, right Abdomen

Lower arm, left Lower leg, left

Lower arm, right Lower leg, right

2) SS scale score:

Fatigue

Waking unrefreshed

Cognitive symptoms

For the each of the 3 symptoms above, indicate the level of severity over the past week using the following scale:

0

1

2

3

Considering somatic symptoms in general, indicate whether the patient has:*

0

1

2

3

The SS scale score is the sum of the severity of the 3 symptoms (fatigue, waking unrefreshed, cognitive symptoms) plus the

extent (severity) of somatic symptoms in general. The final score is between 0 and 12.

7 and symptom severity (SS) scale score 5 or WPI 3–6 and SS scale score 9. no problem slight or mild problems, generally mild or intermittent moderate, considerable problems, often present and/or at a moderate level severe: pervasive, continuous, life-disturbing problems no symptoms few symptoms a moderate number of symptoms a great deal of symptoms

* Somatic symptoms that might be considered: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or remembering problem, muscle

weakness, headache, pain/cramps in the abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in the upper abdomen,

nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud’s phenomenon, hives/welts, ringing in ears,

vomiting, heartburn, oral ulcers, loss of/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing

difficulties, easy bruising, hair loss, frequent urination, painful urination, and bladder spasms.
http://www.rheumatology.org/practice/clinical/classification/fibromyalgia/2010_preliminary_diagnostic_criteria.pdf

Opioids

A recently published study by McGill University researchers (Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y) titled, Opioid Use, Misuse, and Abuse in Patients Labeled as Fibromyalgia, underscores the need for confirmatory tests for fibromyalgia and more effective pain treatments.

Fibromyalgia, a condition associated with nervous system dysregulation, is currently a clinical diagnosis based on signs and symptoms.  Like many other diseases and conditions, there is no confirmatory test.
In this study, 457 patients labeled with fibromyalgia in primary care were re-examined by a rheumatologist, but only 66 percent were diagnosed by the specialist. The authors stated that taking into account the new revised criteria for a diagnosis of fibromyalgia, which incorporate symptoms other than pain as components of fibromyalgia, some patients with predominant mood or psychiatric disorder and less prominent physical symptoms may be misclassified as having fibromyalgia.
Even though mood disorder is the strongest associated comorbidity with fibromyalgia, prominent mental illness can masquerade as a pain syndrome and should be recognized. Depression is most often a consequence of inadequately controlled pain.
According to the study, of the 155 people who had been misdiagnosed as having fibromyalgia, 65 of them had a current serious mental health/psychiatric problem – although the authors did not specify either the DSM diagnosis or the severity.
Of the remaining fibromyalgia patients twelve or 3 percent were considered to have drug seeking behaviors.
At entry, 144 (32%) of all patients were on daily opioid medication, with strong opioids such as oxycodone being used by 105 and weak opioids such as tramadol and codeine used by 39. However, of the 302 fibromyalgia patients remaining upon re-examination, 60 were taking strong opioids and 30 weak opioids.
The actual prevalence of opioid use by fibromyalgia patients is largely unknown according to the authors. Another study reported that use of any analgesic other than NSAIDS (medications such as aspirin, ibuprofen and naproxen used primarily to treat inflammation, mild to moderate pain) in 52% of patients.

Although opioids are not approved for use in fibromyalgia (hence this is considered off-label use of drug), the FDA has approved three prescription drugs for pain management in fibromyalgia:

• Lyrica (preglabin – an anti-seizure drug),
• Cymbalta (duloxetine hydrochloride- an antidepressant) and
• Savella (milnacipran HCl – an anti-depressant). The anti-depressants are not prescribed for depression however and are generally prescribed in much lower doses than for depression. According to the FDA, studies of these drugs show that a substantial number of people with fibromyalgia received good pain relief, but there were others who don’t benefit.

However there are very few studies of opiod use in fibromyalgia other than for tramadol.
In this study, the authors (Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y) stated that opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts, but did not break out the differences between the two final groups of patients.
According to the Agency for Healthcare Research and Quality, an estimated 12.1 million women age 18 and older reported suffering from chronic pain in 2008 as a result of underlying medical conditions such as chronic fatigue syndrome, endometriosis, fibromyalgia and vulvodynia. Of these women, only 8.7 million reported receiving treatment that year at a total cost of $12.9 billion.

Adrienne Dwello, the guide for the about.com site for fibromyalgia and chronic fatigue syndrome, recently asked patients to comment on their experiences with opioids and garnered 92 comments.

http://trialx.com/curetalk/2011/10/off-label-use-of-opioids-to-treat-fibromyalgia-prevalent-report-mcgill-researchers/

Opiod use

Am J Med. 2011 Oct;124(10):955-60.

Opioid use, misuse, and abuse in patients labeled as fibromyalgia.

Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y.

Source

Division of Rheumatology, McGill University Health Center, Montreal, Quebec, Canada. mary-ann.fitzcharles@muhc.mcgill.ca

BACKGROUND: As pain is the cardinal symptom of fibromyalgia, it is logical that treatments directed toward pain relief will be commonly used. Analgesic drug therapy remains the traditional treatment intervention for most chronic pain conditions, with a progressive increased use of opioids in the past 20 years. Concerns about efficacy, risk-benefit ratio, and possible long-term effects of chronic opioid therapy have been raised. There is limited information about opioid treatment in fibromyalgia, with all current guidelines discouraging opioid use.

METHODS: A chart review of all patients referred to a tertiary care pain center clinic with a referring diagnosis of fibromyalgia was conducted to evaluate use of opioid medications.

RESULTS: We have recorded opioid use by 32% of 457 patients referred to a multidisciplinary fibromyalgia clinic, with over two thirds using strong opioids. Opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts.

CONCLUSION: We have observed negative health and psychosocial status in patients using opioids and labeled as fibromyalgia. Prolonged use of opioids in fibromyalgia requires evaluation.
http://preview.ncbi.nlm.nih.gov/pubmed?term=Opioid%20Use%2C%20Misuse%2C%20and%20Abuse%20in%20Patients%20Labeled%20as%20Fibromyalgia

Symptom based approach to treatment

• "Combination Pharmacological Management of Fibromyalgia" by Chad S. Boomershine, MD, PhD, Vanderbilt University. A symptom-based approach has been recommended that uses several pharmacological agents to manage various symptoms.
http://www.prnewswire.com/news-releases/ubm-medicas-musculoskeletal-network-highlights-changing-rheumatologic-landscape-132626623.html

ACR Diagnostic Criteria revised

2011-10-24

---

Thresholds for the diagnosis of fibromyalgia have been lowered, creating more exposure for claims under the accident benefits scheme.
Dr. Arthur Ameis expressed this view during a panel discussion at the Canadian Defence Lawyer's Accident Benefits seminar held in Toronto on Oct. 21.
The American College of Rheumatology suspended the use of the ‘tender point test,' a physical exam to diagnosis fibromyalgia, in 2010 because it felt too many patients were being left out of the diagnosis. Instead, the physical exam was replaced with a 24-question survey about the patients' symptoms.
"So, we are going to see a new wave of fibromyalgia diagnosis because the tender point test is out and you're not even supposed to touch the patient," Ameis said. "The difficulty is that people can go online and read the answers and the diagnosis will happen more and more."
http://www.canadianunderwriter.ca/news/thresholds-for-fibromyalgia-and-concussion-diagnosis-lowered/1000643328/

Global Market and Medication Forecast

The global market for Fibromyalgia (FM) was valued at $1.7 billion in 2010 and is expected to grow at a Compound Annual Growth Rate (CAGR) of 4.3% to reach $2.4 billion by 2018. The restricted growth in the market is due to the unavailability of approved drugs in the EU and Japan market, expected patent expiry of Cymbalta (2013) and Lyrica (2018) and lack of newer therapies in late stage FM therapeutics pipeline. Currently, FDA (Food and Drug Administration) has approved three drugs for the treatment of FM. Lyrica (pregabalin) was the first drug approved in June 2007 followed by Cymbalta (duloxetine) in June 2008 and Savella (milnacipran) in January 2009. Marketing authorization of these drugs has been rejected by EMEA (European Medical Agency) due low effectiveness and high adverse reactions associated with the drugs. Cymbalta was the first drug to be rejected by EMEA in 2008, followed by Lyrica in 2009 and Savella in 2010. However, increasing prevalence and diagnosis is expected to drive the future FM therapeutics market.
http://www.prnewswire.com/news-releases/fibromyalgia-therapeutics---pipeline-assessment-and-market-forecasts-to-2018-132519348.html

Lyrica and Northwestern University

In a much larger royal monetization deal, Northwestern University generated $700 million cash in 2007 when it sold a portion of its worldwide royalty interest in the Pfizer drug Lyrica® to Royalty Pharma; net proceeds were placed in the University’s endowment. As part of the deal an undisclosed portion of the payment to Northwestern went to the researchers responsible for the chemical compound that serves as the basis for Lyrica, a drug indicated for fibromyalgia, among other disorders.
http://www.genengnews.com/keywordsandtools/print/3/24658/

Pirlindole in the Treatment of Depression and Fibromyalgia Syndrome

 Clinical Drug Investigation, 09/01/2011

Branco JC et al. - The effect of pirlindole on sensorimotor performance relevant to driving a motor vehicle is similar to that of placebo, as pirlindole appears to have an activating rather than a sedating antidepressant profile. Because of its specific and reversible inhibition of MAO-A and relatively short elimination half-life, no tyramine or ‘cheese’ effect is likely after short- or long-term administration. The available evidence supports pirlindole as a safe and effective treatment option for the management of depression and fibromyalgia syndrome.

• Depression and fibromyalgia syndrome are debilitating chronic conditions that impose a significant burden on individuals, families and society.
• Both depression and fibromyalgia have many overlapping symptoms, and antidepressants of several classes are among recommended treatment options for patients with fibromyalgia syndrome.
• Pirlindole is a selective and reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in some European and non-European countries for the treatment of depression.
• The antidepressant efficacy and safety of pirlindole have been demonstrated in a number of placebo- and active comparator-controlled studies and are supported by many years of clinical experience in the treatment of depression.
• The drug's efficacy and safety have also been demonstrated, more recently, in the treatment of fibromyalgia syndrome.
• Pirlindole has a favourable tolerability profile, with no deleterious effect on cardiovascular dynamics.

The Longitudinal Outcome of Fibromyalgia: A Study of 1555 Patients

1. Brian Walitt,
2. Mary-Ann Fitzcharles,
3. Afton L. Hassett,
4. Robert S. Katz,
5. Winfried Häuser and
6. Frederick Wolfe

+ Author Affiliations

1. From Georgetown University, Washington Hospital Center, Washington, DC; Montreal General Hospital, Division of Rheumatology, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; Rush University Medical Center, Chicago, Illinois; Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, Munich, Germany; and the National Data Bank for Rheumatic Diseases and University of Kansas School of Medicine, Wichita, Kansas, USA.
   Dr. Walitt has received consulting feels from Jazz Pharmaceuticals. Dr. Häuser has received honoraria from Eli-Lilly, Janssen-Cilag, Mundipharma, and Pfizer, and travel support from Eli Lilly. Dr. Hassett has received research funding from Bristol-Myers Squibb and Jazz Pharmaceuticals and is a consultant to Jazz Pharmaceuticals and Bristol-Myers Squibb. Dr. Fitzcharles has received consultant fees, speaking fees, and/or honoraria from Boehringer Ingelheim, Eli-Lilly, Paladin, Pfizer, and Purdue.
   B. Walitt, MD, MPH, Georgetown University, Washington Hospital Center; M-A. Fitzcharles, MB, ChB, Montreal General Hospital, Division of Rheumatology, McGill University; A.L. Hassett, PsyD, Department of Anesthesiology, University of Michigan Medical School; R.S. Katz, MD, Rush University Medical Center; W. Häuser, MD, Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München; F. Wolfe, MD, National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine.
   Address correspondence to Dr. F. Wolfe, National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Suite 288, Wichita, KS 67214. E-mail: fwolfe@arthritis-research.org
   Accepted for publication May 6, 2011.

Abstract

Objective To describe the diagnosis status and outcome of patients diagnosed with fibromyalgia (FM) by US rheumatologists.

Methods We assessed 1555 patients with FM with detailed outcome questionnaires during 11,006 semiannual observations for up to 11 years. At entry, all patients satisfied American College of Rheumatology preliminary 2010 FM criteria modified for survey research. We determined diagnosis status, rates of improvement, responder subgroups, and standardized mean differences (effect sizes) between start and study completion scores of global well-being, pain, sleep problems, and health related quality of life. (QOL)

Results The 5-year improvement rates were pain 0.4 (95% CI 0.2, 0.5), fatigue 0.4 (95% CI 0.2, 0.05), and global 0.0 (95% CI –0.1, 0.1). The standardized mean differences were patient global 0.03 (95% CI –0.02, 0.08), pain 0.22 (95% CI 0.16, 0.28), sleep problems 0.20 (95% CI 0.14, 0.25), physical component summary of the Short-form 36 (SF-36) 0.11 (95% CI –0.14, –0.07), and SF-36 mental component summary 0.03 (95% CI –0.07, 0.02). Patients switched between criteria-positive and criteria-negative states, with 716 patients (44.0%) failing to meet criteria at least once during 4228.5 patient-years (7448 observations). About 10% of patients had substantial improvement and about 15% had moderate improvement of pain. Overall, FM severity worsened in 35.9% and pain in 38.6%.

Conclusion Although we found no average clinically meaningful improvement in symptom severity overall, 25% had at least moderate improvement of pain over time. The result that emerged from this longitudinal study was one of generally continuing high levels of self-reported symptoms and distress for most patients, but a slight trend toward improvement.

http://jrheum.org/content/early/2011/07/11/jrheum.110026.abstract

Pfizer Says Lyrica Study Met Key Goal In Central Neuropathic Pain Treatment

6/21/2011

(RTTNews) - Biopharmaceutical giant Pfizer Inc. (PFE: News ) Tuesday stated that its drug lyrica (pregabalin) met the primary endpoint of positive efficacy in reducing central neuropathic pain following spinal cord injury in a global phase 3 study. The company was announcing top-line results for the study.

Central neuropathic pain is a heterogeneous group of pain conditions initiated or caused by a primary lesion in the central nervous system. This pain often occurs following spinal cord injury.

Lyrica is currently approved in 110 countries and regions. In the U.S., lyrica capsules CV is approved to treat diabetic nerve pain, pain after shingles, fibromyalgia and partial onset seizures in adults with epilepsy who take one or more drugs for seizures. It is not approved to treat central neuropathic pain in the U.S.

According to Pfizer, the final stage lyrica study, A0081107, was a randomized, double-blind, placebo-controlled, parallel group, multi-center study, comparing pregabalin and placebo in subjects with chronic central neuropathic pain following traumatic spinal cord injury.

In the study, which was conducted in 66 investigative sites in 10 countries, pregabalin was flexibly dosed as 150-600mg/day or dosed twice daily. A total of 220 subjects were enrolled in the study.

The primary endpoint of the trial was the duration adjusted average change or DAAC, a weighted average of change in pain scores based on the duration a patient is participated in the study.

http://www.rttnews.com/Content/BiotechStory.aspx?Id=1650667&Category=ClinicalTrial

Combination Therapy Needed to Fight Chronic Pain

 Denise Mann : Reviewed by Laura J. Martin, MD

June 23, 2011 -- The last decade brought advances in our understanding of chronic pain, but this has not translated into better treatments yet, an analysis shows. The analysis was published in The Lancet.

It found that treatments for chronic, non-cancer pain such as low back pain, arthritis, headache, and fibromyalgia don't do enough to alleviate pain or restore functioning in the majority of people.
And don't expect any one pill to do the trick, says the report's author, Dennis C. Turk, PhD, an anesthesiologist and pain specialist at the University of Washington in Seattle. "There is this expectation that you will wave a wand and there will be a new pill or new surgery to alleviate your pain, and that is not likely to happen."
"Chronic pain is a complex problem, and the only way to treat it is with a combination of treatments because no one treatment is sufficient," he says. Combination therapy may mean multiple medications or medications plus lifestyle changes, psychological treatments, and/or rehabilitation and physical therapy.
Likening chronic pain to diabetes, Turk says "there are a lot of things to do in addition to medication, as in diabetes, where you also watch your weight and test your urine and blood."
It will involve a more holistic approach, he says. "We have a tendency to try to diagnose people in silos and treat everyone with knee osteoarthritis (OA) the same way," he says. But "we need to treat people as a whole and not just knees." Social, emotional, and environmental factors all play a role in how we experience pain and painful conditions.
One Treatment Not Always EnoughRoger Fillingim, PhD, associate professor in the College of Dentistry at the University of Florida in Gainesville, says that there have been advances in understanding the biology of pain and in awareness of pain as a pressing public health issue in recent years.
But "this hasn't translated into terribly effective treatments of chronic pain, and we will need more multidisciplinary treatments in order to provide more optimal clinical outcome for patients in pain," he says.
The truth is "for many forms of chronic pain, a single treatment is not sufficient to improve quality of life to the point where a patient will be satisfied," he says.
"That pill doesn't exist," he says. "There may be medication that helps alleviate some of the pain, but that needs to be accompanied by other treatments including physical rehabilitation and behavioral or psychological intervention to help people cope with their pain in a more effective manner."
Lesley Arnold MD, a psychiatrist at the University of Cincinnati, takes a more "glass is half-full" view of our accomplishments in treating chronic pain.
"We do have more options today," she says, citing several FDA approvals in recent years for new drugs to treat fibromyalgia and OA.  But "we do need more studies of combinations of medications to see what works well together and most importantly, we need studies looking at nondrug therapies."
"We don't have a good way of accessing the central nervous system to tell us why people are in pain," she says.
http://www.webmd.com/pain-management/news/20110623/combination-therapy-needed-to-fight-chronic-pain

Direct Medical Costs Are Double for Patients with Fibromyalgia

June 9, 2011 

Following is an abstract from a published scientific article regarding medical costs associated with fibromyalgia and the impact of a brief multidisciplinary treatment program. The four year medical cost statistics of fibromyalgia compared to control patients in the study group are staggering. The total four-year medical costs for controls in the study were $7774 compared with $15,759 for those with fibromyalgia. Part of the study’s hypothesis included comparing medical costs over a four year period after administration of a cognitive behavior therapy program. The outcome of the study demonstrated that the increased cost in fibromyalgia medical care is related to the severity of symptoms and was not impacted by participation in a brief cognitive behavior therapy program.

STUDY: Direct medical costs in patients with fibromyalgia: Cost of illness and impact of a brief multidisciplinary treatment program.
The patients diagnosed with fibromyalgia incur about twice as much direct medical costs than that of non fibromyalgia patients, according to the results of a 4-year study by the Department of Physical Medicine and Rehabilitation at the Mayo Clinic College of Medicine in Rochester, Minnesota. The study was published in the January 2011 issue of the American Journal of Physical Medicine & Rehabilitation.

The objective of the study was to compare the direct medical costs of clinically diagnosed patients with fibromyalgia with the medical costs of matched controls during a 4-yr period and to assess the impact of a fibromyalgia treatment program on healthcare utilization and associated medical costs. The study compared economic outcomes in 87 patients who participated in a fibromyalgia treatment program between 2001 and 2004 and who were local residents for the entire 4-yr period spanning their participation in the program, with age and sex-matched controls. Costs for the 2 yrs before and 2 yrs after program participation were also compared.
RESULTS: Four-year medical costs for controls were $7774 compared with $15,759 for those with fibromyalgia. There was no significant change in direct costs after participation in a brief fibromyalgia treatment program. Those with increased symptom severity averaged $2034 higher direct medical costs during the 4-yr period.
CONCLUSIONS: Patients with clinically diagnosed fibromyalgia incur direct medical costs about twice that of their matched controls. This increased cost is related to the severity of their symptoms as measured by the Fibromyalgia Impact Questionnaire and was not impacted by participation in a brief cognitive behaviorally based fibromyalgia treatment program.
http://www.biorx.net/carolsblog/?m=201106

HYPNOSIS: Efficacy of hypnosis/guided imagery in fibromyalgia syndrome

Author: Kathrin BernardyNicole FuberPetra KloseWinfried Hauser
Credits/Source: BMC Musculoskeletal Disorders 2011, 12:133

  
Recent systematic reviews on psychological therapies of fibromyalgia syndrome (FMS) did not consider hypnosis/guided imagery (H/GI). Therefore we performed a systematic review with meta-analysis of the efficacy of H/GI in FMS.

Methods:

We screened ClinicalTrials.gov, Cochrane Library, MEDLINE, PsycINFO and SCOPUS (through December 2010).
(Quasi-) randomized controlled trials (CTs) comparing H/GI with controls were analyzed. Outcomes were pain, sleep, fatigue, depressed mood and health-related quality of life (HRQOL).
Effects were summarized using standardized mean differences (SMD).

Results:

Six CTs with 239 subjects with a median of 9 (range 7-12) H/GI-sessions were analysed. The median number of patients in the H/GI groups was 20 (range 8-26).
Three studies performed follow-ups. H/GI reduced pain compared to controls at final treatment (SMD -1.17 [95% CI -2.21, -0.13]; p= 0.03.
H/GI did not reduce limitations of HRQOL at final treatment (SMD -0.90 [95% CI -2.55, 0.76]; p=0.29) compared to controls. Effect sizes on fatigue, sleep and depressed mood at final treatment and follow-up and on pain and HRQOL at follow-up were not calculated because of limited data available.
The significant effect on pain at final treatment was associated with low methodological and low treatment quality.

Conclusion:

Further studies with better treatment quality and adequate methodological quality assessing all key domains of FMS are necessary to clarify the efficacy of H/GI in FMS.

http://7thspace.com/headlines/386210/efficacy_of_hypnosisguided_imagery_in_fibromyalgia_syndrome___a_systematic_review_and_meta_analysis_of_controlled_trials.html

CYCLOBENZAPRINE: Effects of Bedtime Very Low Dose (VLD) Cyclobenzaprine (CBP) on Symptoms and Sleep Physiology in Patients with Fibromyalgia Syndrome

Jun. 16, 2011

TONIX Pharmaceuticals, a specialty pharmaceutical company developing therapies for challenging disorders of the central nervous system, including Fibromyalgia Syndrome (FM) and Post-traumatic Stress Disorder (PTSD), presented sleep EEG (electroencephalogram) findings from a clinical study in which patients with FM were treated with very low dosage (VLD) cyclobenzaprine (CBP) at bedtime. The VLD CBP treated patients showed a decrease in pain, fatigue, tenderness and depressive symptoms and reported fewer of the side effects often associated with daytime CBP at higher doses. In the new findings, VLD CBP treatment improved sleep efficiency and increased the number of nights with reduced rates of EEG Cyclic Alternating Pattern (CAP) sleep types CAP_A2 + CAP_A3, which are associated with sleep instability and previously were shown to be elevated in FM patients. The findings were the subject of a poster presentation at the Associated Professional Sleep Societies 2011 Anniversary Meeting in Minneapolis, MN.
Dr. Harvey Moldofsky, President and Medical Director, Centre for Sleep and Chronobiology, Toronto, Canada, and lead author of the study, commented, “This study showed that a low dose of cyclobenzaprine taken at bedtime improves the widespread pain and tenderness in patients with fibromyalgia. It also provides a novel algorithm that identifies reductions in a specific EEG pattern of sleep instability that correlate with improvements in the nonrestorative sleep symptoms of fatigue and disturbed mood.”
“These new findings suggest that our technology for bedtime treatment of fibromyalgia with very low dose cyclobenzaprine confers benefits that have been associated with restful or restorative sleep,” stated President Seth Lederman, M.D., Chairman and President of TONIX.
About the Study

The study was a randomized, double-blind, placebo-controlled, dose-escalating parallel-design study in 36 patients with FM conducted at two Canadian sites. The study was analyzed with regard to efficacy, safety and tolerability as well as EEG and other parameters assessed during sleep. VLD CBP treated subjects showed significant improvements over eight weeks in pain, fatigue, tenderness, the Hospital Anxiety and Depression Scale (HAD), and sleep efficiency. In addition, VLD CBP was well tolerated, with no adverse events or discontinuations due to adverse events. The sleep EEG data were analyzed for the types of CAP: CAP_A1 (associated with sleep stability) and CAP_A2 + CAP_A3 (usually associated with sleep instability). VLD CBP treatment increased EEG sleep nights with normalized CAP_A2+A3, or CAP_A2+A3(Norm) ≤ 33%. Increased nights of CAP_A2+A3(Norm) ≤ 33% correlated with improvement in fatigue, total HAD score, HAD depression subscore, and self-rated and clinician-rated change in fatigue. In VLD CBP treated subjects, the correlation of increased nights of CAP_A2+A3(Norm) ≤ 33% with improvement with FM symptoms is consistent with the hypothesized effects of restorative sleep. The symptomatic benefit may relate to VLD CBP decreasing arousal or alarm signals during sleep. CAP_A2+A3(Norm) rate may provide a novel biomarker for assessing treatment effects on nonrestorative sleep and associated subjective somatic and mood symptoms in FM. The full abstract can be found at www.sleepmeeting.org (# 0690).

About TONIX Pharmaceuticals

TONIX Pharmaceuticals is developing new treatments for challenging disorders of the central nervous system. The Company’s most advanced program targets fibromyalgia syndrome based on bedtime treatment with very low dosage cyclobenzaprine. Cyclobenzaprine in higher doses is the active ingredient of U.S. FDA approved muscle relaxants. Based on this foundation, the Company is building a deep and diverse pipeline of high-value medications for other syndromes, disorders and diseases, including post-traumatic stress disorder. For more information, please visit www.tonixpharma.com.

http://www.financialpost.com/markets/news/TONIX+Pharmaceuticals+Presents+Findings+Effects+Bedtime+Very+Dose/4957181/story.html

DULOXETINE: Improvement in multiple dimensions of fatigue in patients with fibromyalgia treated with duloxetine: secondary analysis of a randomized, placebo-controlled trial

Author: Lesley ArnoldFujun WangJonna AhlPaula GaynorMadelaine Wohlreich
Credits/Source: Arthritis Research &Therapy 2011, 13:R86

Introduction
Fatigue is one of the most disabling symptoms associated with fibromyalgia that greatly impacts quality of life. Fatigue was assessed as a secondary objective in a 2-phase, 24-week study in outpatients with American College of Rheumatology-defined fibromyalgia.

Methods:
Patients were randomized to duloxetine 60-120 mg/d (N=263) or placebo (N=267) for the 12-week acute phase.
At Week 12, all placebo-treated patients were switched to double-blind treatment with duloxetine for the extension phase. Fatigue was assessed at baseline and every 4 weeks with the Multidimensional Fatigue Inventory (MFI) scales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Activity, and Reduced Motivation.
Other assessments that may be associated with fatigue included: Brief Pain Inventory (BPI) average pain, numerical scales to rate anxiety, depressed mood, bothered by sleep difficulties, and musculoskeletal stiffness. Treatment-emergent fatigue-related events were also assessed.
Changes from baseline to Week 12, and from Week 12 to Week 24, were analyzed by mixed-effects model repeated measures analysis.

Results:
At Week 12, duloxetine versus placebo significantly (all p<.05) reduced ratings on each MFI scale, BPI pain, anxiety, depressed mood, and stiffness. Improvement in ratings of being bothered by sleep difficulties was significant only at Weeks 4 and 8.
At Week 24, mean changes in all measures indicated improvement was maintained for patients who received duloxetine for all 24 weeks (n=176). Placebo-treated patients switched to duloxetine (n=187) had significant within-group improvement in Physical Fatigue (Weeks 16, 20 and 24); General Fatigue (Weeks 20 and 24); Mental Fatigue (Week 20); and Reduced Activity (Weeks 20 and 24).
These patients also experienced significant within-group improvement in BPI pain, anxiety, depressed mood, bothered by sleep difficulties, and stiffness. Overall, the most common (>5% incidence) fatigue-related treatment-emergent adverse events were fatigue, somnolence, and insomnia.

Conclusions:
Treatment with duloxetine significantly improved multiple dimensions of fatigue in patients with fibromyalgia, and improvement was maintained for up to 24 weeks.Trial Registration: Clinical Trial Registry NCT00673452.

http://7thspace.com/headlines/385919/improvement_in_multiple_dimensions_of_fatigue_in_patients_with_fibromyalgia_treated_with_duloxetine__secondary_analysis_of_a_randomized_placebo_controlled_trial.html

ICAF: Combined Index of Severity of Fibromyalgia

Fibromyalgia (FM) is a complex syndrome that affects many aspects of the patients life and it is very difficult to evaluate in clinical practice. A recent study has developed the Combined Index of Severity of Fibromyalgia (ICAF), an instrument that evaluates diverse aspects of FM and offers five indices: emotional, physical, active coping, passive coping and total.
The objective of this study is to confirm the structure of the ICAF, check its test-retest reliability, assess its sensitivity to change, and compare the results obtained in a sample of patients with fibromyalgia with another sample of healthy controls.
Methods: A total of 232 patients took part in the study, 228 women and 4 men, with a mean age of 47.73 years of age (SD=8.61) and a time of disease evolution since diagnosis of 4.28 years (SD=4.03). The patients from the FM group completed the ICAF.
Between one and two weeks later, they again attended the clinic and complete the 59 items on the ICAF (retest) and immediately afterwards they began treatment (according to daily clinical practice criteria). A sample of healthy subjects was also studied as a control group: 110 people were included (106 women and 4 men) with a mean age of 46.01 years of age (SD=9.35).
The study was conducted in Spain.
Results: The results obtained suggest that the four-factor model obtained in the previous study adequately fits the data obtained in this study. The test-retest reliability and internal consistency were all significant and show a high degree of correlation for all the factors as well as in overall score.
With the exception of the passive coping factor, all the other scores, including the overall score, were sensitive to change after the therapeutic intervention. The ICAF scores of the patients with fibromyalgia compared with those of the control group were markedly different.
Conclusions: The findings suggest that the ICAF is a valid, reliable, sensitive to change instrument with the added advantage that it offers some additional domains (factors) that provide very valuable information regarding the most delicate aspects of the patient, which must be addressed at the time of treatment in daily clinical practice.

Author: Miguel VallejoJavier RiveraJoaquim Esteve-VivesJavier RejasGroup Icaf
Credits/Source: Health and Quality of Life Outcomes 2011, 9:39
http://7thspace.com/headlines/385268/a_confirmatory_study_of_the_combined_index_of_severity_of_fibromyalgia_icaf_factorial_structure_reliability_and_sensitivity_to_change.html