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

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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/