- DR PHILLIP MEASE: Hello. My name is Philip Mease. I’m pleased to bring to you a program known as “Fibromyalgia Diagnostic and Treatment Challenges.”
These are the results of a summit meeting of fibromyalgia experts who came together to discuss a number of aspects of the condition fibromyalgia.
- The program was chaired by myself, Phillip Mease, from Seattle Rheumatology Associates, Swedish Medical Center, and the University of Washington, and Steven Berney from Temple University; also participating in the Roundtable were Leslie Arnold from the University of Cincinnati; Michael Clark from Johns Hopkins; Don Goldenberg from the Newton Wellesley Hospital in Boston; George Griffing from Saint Louis University; and Peter Schur from Harvard Medical School.
- The objectives of the program were to describe the multifaceted pathophysiologic processes that lead to fibromyalgia, identify symptoms commonly associated with fibromyalgia beyond chronic widespread pain and tenderness, recognize the 3 main therapeutic areas that need to be considered, compare and contrast the amount of evidence and the efficacy and safety of pharmacologic and nonpharmacologic agents for the treatment of fibromyalgia, and discuss the fact that many fibromyalgia patients require combination therapy and the advantages and risks of such therapy.
History of Fibromyalgia
- The history of fibromyalgia as a medical condition is actually quite a long one. In 1869, George Beard discussed the concept of neurasthenia in the medical literature, which was the term used for such a condition at that time. Then, in the early 1900s, in 1904, Gowers described a chronic musculoskeletal pain condition, which he termed fibrositis. This was at a time when the conception was that there was some type of inflammation going on in fibrous tissue and muscle that was contributing to the pain of the condition.
It was not until the mid-1970s that we began to have a better idea about the central nervous system pathophysiology of the condition when Moldofsky and colleagues in Toronto found consistent abnormalities in non-REM sleep electroencephalograms of patients with fibrositis. It was at that time that we began to experiment more with some of the centrally acting medications such as amitriptyline. Then, in 1977, Moldofsky along with Smythe, a rheumatologist in Toronto, were among the first to propose diagnostic criteria for fibrositis.
- In 1981, Mohammed Yunus further described fibromyalgia, coining that term as a systemic syndrome with many nonmuscular complaints. And, we began to have more of a notion of the protean aspects of the condition clinically.
In 1990, a multicenter criteria committee of the American College of Rheumatology (ACR) adopted officially the term “fibromyalgia” due to a lack of evidence for inflammatory changes in muscles of patients, establishing the ACR criteria for fibromyalgia.
In 1994, John Russell and colleagues found elevated levels of substance P and decreased levels of serotonin and cerebral spinal fluid. These were some of the first biomarker studies in the central nervous system for this condition. In 2002, Rick Gracely and colleagues, using fMRI technology, showed evidence for augmented pain processing in fibromyalgia patients. We’re going to learn more about some of these findings in our discussion today.
Definition of Fibromyalgia
- The next slide shows the definition of fibromyalgia. The ACR has defined fibromyalgia as chronic widespread pain of at least 3 months duration in combination with pain at 11 or more of 18 specific tender point sites on the body.
- This slide shows a body mannequin, which shows where the tender points as established by the ACR are. As you can see, the tender points are above and below the waist and on both sides of the body, and they tend to be in areas where ligaments insert into bone or at certain muscular or bony sites.
The concept of tender points grew over the years. What we are sensing going on here is that the tender points serve as a barometer for allodynia and hyperalgesia and are not, in and of themselves, pathologic, but represent the central pathophysiology. We also know that patients not only have increased tenderness to palpation in these sites, but will have increased sensory sensitivity to a number of different modalities, including heat and noise. And, as we will learn later, this all reflects an increased sensitization of the central nervous system to pain and other sensory phenomena.
- In our discussion at the meeting, one of the points made by Dr Goldenberg was that although some people have used tender points in clinical trials and some use the tender points for diagnosis, in a standard clinical practice, it’s not typical for us to monitor tender points over time. We’ve learned in clinical trials that the tender point binding may not significantly change with treatment, even though the patient is feeling much better in terms of pain response. Nor in clinical practice do we really monitor the tender points as we might monitor the joints of a person with rheumatoid arthritis.
Characteristics of Fibromyalgia
- In addition to chronic widespread pain, there are a number of other characteristic features of fibromyalgia, including fatigue, disordered sleep, food disorders, and cognitive dysfunction. In addition, it is not uncommon for us to see common associated conditions that also fall under the rubric of central sensitization syndromes. Some of these include conditions such as irritable bowel syndrome, irritable bladder or urethral syndrome, chronic fatigue syndrome, headache of various forms, as well as depression and anxiety disorder. These are commonly seen in fibromyalgia patients.
Beyond that, we know that there are certain conditions in which fibromyalgia is a frequent fellow traveler. For example, in studies of rheumatoid arthritis patients, upward of 20% of patients might have fibromyalgia at any given time. In lupus, 30% of patients might, and in Sjögren’s syndrome, up to 50% of patients have been shown to have concomitant fibromyalgia.
Certain chronic infectious diseases such as Lyme disease have seen an increased association with fibromyalgia with the condition, and even an endocrine disease — hypothyroidism. So, there’s something about these types of conditions that help promote the copresence of fibromyalgia.
- The next slide shows results of an exercise that was done with a group of fibromyalgia experts working within the Outcome Measures in Rheumatology Clinical Trials (OMRC) structure. Within OMRC, there is a fibromyalgia working group.
When experts went through what’s known as a Delphi exercise, they ranked as the key elements to measure in clinical trials of fibromyalgia those of pain, fatigue, patient global — that is, how is the disease overall affecting the patient — sleep, quality of life, physical function, adverse effect from medications, depression, multidimensional function, tender point intensity, dyscognition, also known as cognitive dysfunction, anxiety, and then getting a sense of the clinician’s global impression.
So, as you can see, there’s some consistency between what expert clinicians are wanting to measure and the typical kinds of symptoms that a patient is experiencing.
Diagnosis of Fibromyalgia
- Historically, the diagnosis of fibromyalgia has been considered to be somewhat difficult among clinicians in general. And oftentimes, patients may go years before receiving a diagnosis.
There’s a study, for example, that shows that an accurate diagnosis could take as long as an average of 5 years. In a study done by the National Fibromyalgia Association, patients additionally mentioned that rheumatologists diagnosed fibromyalgia 42% of the time and many patients consult multiple physicians before receiving a diagnosis. And fully a quarter of them had seen at least 6. They also acknowledged that the presence of comorbidities may complicate the diagnosis.
So, what are some of the issues here? Well clearly, when a patient is presenting with chronic pain, fatigue, and so forth, they may get worked up for many different types of conditions ranging from a variety of chronic medical illnesses, congestive heart failure, cancer, rheumatoid arthritis, lupus, and so on. It may take a long time sorting through all these things and barking up the wrong tree before coming to a correct diagnosis. Also, I think historically, many clinicians have not really fully understood fibromyalgia and have not had the confidence to make the diagnosis. Many times, it might have been mislabeled inappropriately as depression, anxiety, or some type of sleep disturbance. So, there are many reasons why the condition may have been overlooked.
Also, for example, if a patient presents with a predominant issue of abdominal pain from irritable bowel syndrome, yet also has generalized pain and fatigue, they may have concomitant fibromyalgia and irritable bowel syndrome. But, if they’re just seeing a gastroenterologist, the gastroenterologist may not make the diagnosis of fibromyalgia. The thought that comes to mind is the proverbial number of clinicians that are examining an elephant and whether they’re touching the trunk or the foot or the tail, they may come up with a different diagnosis based on what they’re actually observing.
- The differential diagnosis of fibromyalgia is relatively broad. We’ve already alluded to some of these conditions, and many of them are conditions in which fibromyalgia may coexist with the disease.
I already mentioned lupus and rheumatoid arthritis and Sjögren’s syndrome as examples of that, but clearly you want to be finding out in a person presenting with chronic pain and fatigue whether they may have some of these conditions. And so, for example, if the patient has a symptom suggestive of lupus, then we may want to check blood tests such as antinuclear antibody (ANA) levels.
If the person has symptoms suggestive of rheumatoid arthritis, we may want to check appropriate blood tests for these. These are listed here, and the types of chronic diseases include all of the rheumatic diseases that I have discussed so far.
There are certain chronic infections or inflammation processes that need to be considered, including conditions such as tuberculosis, Lyme disease, Parvovirus, infection, to name a few, inflammatory bowel disease. And then, there are some endocrine disorders, including hypothyroidism and rarer ones such as hypopituitary conditions or vitamin D deficiency.
- The next slide refers to a quote from Dr Goldenberg during the course of the discussion, and really cautioning us to be careful about evaluating patients for a differential diagnosis, because at any 1 time, 30% to 50% of the people with fibromyalgia may have concomitant depression.
- Another phrase that has crept into the medical literature is that of chronic widespread pain (CWP). There have been studies done in Northern England in particular looking at this issue. So, CWP would be patients with chronic pain that doesn’t otherwise have a clear cut explanation such as simply osteoarthritis. But, it’s not with a tender point exam attached to it. And when they’ve done large telephone surveys, for example, or surveys of records of primary care clinicians in England, they have found CWP to be a diagnosis in 11% to 14% of the population at any given time. Fibromyalgia would be considered to be a subset of these individuals, and then having tender points.
But, one of the pitfalls of the tender point exam is that it may underestimate the diagnosis in certain individuals. For example, if you’ve got a relatively stoic male patient who has 6 or 8 tender points and chronic pain in multiple sites and doesn’t otherwise have an explanation for their pain, then this may be fibromyalgia presenting in that male only with less than 11 tender points. And so, really, we have to take the tender point exam with a grain of salt. It’s not until we get into a future era when we have more precise ways of objectively diagnosing the condition, such as with more practical neuroimaging approaches or other types of methodologies, that I think we’ll have more accurate ways of diagnosing this condition.
Pathophysiology of Fibromyalgia
- Let’s now slip into a discussion about pathophysiology. We’re going to be going through a number of areas, including environmental factors, genetic susceptibility, and some of the central neuropathophysiology that leads to pain augmentation.
- What are some of the environmental factors? Well, clearly, problems such as physical trauma or chronic background pain disease states may be responsible for promulgating fibromyalgia in some people. We also know that if an individual has a background of childhood trauma, either physical, emotional, or neglect, that they have a greater likelihood of growing up to have fibromyalgia as a problem.
- Dr Arnold during the course of the meeting noted that in studies examining posttraumatic stress disorder, that the early childhood experience of this may lead to hypothalamic-pituitary-adrenal (HPA) axis development problems, and that subsequent experience of fibromyalgia may be partly mediated through some of these changes in the HPA axis that are determined by early childhood experience.
- One of the more controversial contributors to fibromyalgia is that of whether automobile accidents may do so. One interesting study done in Israel by Dan Buskila’s group looked at patients who were hospitalized with, say, a whiplash injury after a motor vehicle accident and those that had some major trauma such as a leg fracture for other reasons and found that there was a greater likelihood in patients who had had the whiplash problem to then evolve into having fibromyalgia.
In this particular study, the problem was not clouded by the issue of litigation and compensation. Yet, in other studies, long-term tracking of patients who have been in motor vehicle accidents do not necessarily support that there’s a greater proclivity to development of fibromyalgia. And, in a variety of review articles, there is the acknowledgment that motor vehicle accidents may be a contributing factor, as can other physical trauma. And so I think we should just keep that in mind.
It’s not completely a settled question.
- There may be other contributing environmental factors besides physical trauma and childhood issues. For example, we do know that if people are in states or situations of chronic stress, there may be a greater proclivity to development, not only of depression and anxiety, but also the possibility of developing fibromyalgia. This can be due to a number of reasons, including neurohormonal changes.
- Now, in terms of genes and the development of fibromyalgia, this is a fascinating area that’s really evolving in the last few years. There are a number of candidate genes that may be at play here that seem to be present more often in fibromyalgia patients compared with controls.
First of all, we know that some of the genes that have to do with serotonin physiology may be at play. A number of findings about the gene for the promoter region of the serotonin transporter have been shown to be slightly altered or that a gene for the promoter region of serotonin transport may be implicated in fibromyalgia as well as states of depression and that there may be polymorphisms of these genes that predispose individuals to having more pain.
- We also know that some catecholaminergic gene polymorphisms may be at play, and in particular, something called the COMT or catechol-O-methyltransferase gene, which seems to be important in determining whether a patient is going to have more sensitivity to pain.
- There have also been some findings that suggest that the dopamine D4 receptor gene may also be abnormal in patients with fibromyalgia. In many ways, these gene changes make sense because they’re clinical implications that problems with serotoninergic or adrenergic mechanisms, catecholamine mechanisms, or dopamine mechanisms may be at play in fibromyalgia.
- Increasingly, research is showing us that the key pathologic problem in fibromyalgia is a dysregulation of central processing of sensory stimuli, that there is a reduced threshold, if you will, for pain experience. A phrase that’s used to describe this is central sensitization syndrome.
This is one of the key experiments that helps us understand that. This is a study done by Rick Gracely’s group at the University of Michigan, and there was a pain stimulus coupled with a subjective reporting of pain by patients vs controls. There was an fMRI scan done at the same time. So, let me walk you through this. In the graph, we see on the x-axis stimulus intensity. A device in which a rated amount of pressure was placed on the thumb with gradually increasing pressure was used. In the red triangle, you see the response of fibromyalgia patients. When a stimulus intensity of 2 kg/cm2was placed, the patient described a pain intensity level of 12 — quite high. To its right, in the green circle, a control individual needed to have about 4 kg/cm2 of pressure placed before they reported the same amount of pain intensity. Well, you could say, “Well, maybe the fibromyalgia patient is just complaining at a lower level, but they’re not really experiencing pain.”
The fMRI is used as kind of a lie detector here, and it shows that in various key pain processing areas in the brain, that light up did occur when that amount of stimulus intensity was placed at the 2kg/cm2 mark, and it wasn’t until the 4 kg/cm2 that the control individual would have lit up in the same areas. Use of the fMRI helps confirm that a patient with fibromyalgia is truly experiencing pain at a lower threshold, helping us to further understand that there is a disorder of central sensory processing.
- Now that we see from patient report and fMRI scans that there is an abnormality of central pain processing, what are some of the neurochemical problems that are leading to this? Well, we do know that there are problems in both the ascending and descending pain fiber networks in patients with fibromyalgia.
First, on the ascending side, we know that there is increased sensory processing through ascending fibers, mediated through elaboration of nociceptive neurotransmitters such as glutamate or substance P. Studies done by Russell and others have shown us that there are elevated levels of substance P in the cerebral spinal fluid, for example, and more recent neuroimaging studies from the University of Michigan group that suggest that there are abnormalities in glutamate processing.
Similarly, other researchers have shown us that there is an abnormality in descending pain fiber network. For example, we know that the descending pain fiber network works by inhibiting nociceptive input through receptors on the dorsal ganglia for fibers coming down from the brain. And these are mainly mediated through norepinephrine and serotonin. If there is a relative deficiency of norepinephrine and serotonin, as has been demonstrated in fibromyalgia, then there is a less inhibitory role of the descending pain fiber network leading to a net gain in pain sensation, both because of abnormalities in the ascending, as well as abnormalities in the descending, modulatory systems.
- That is demonstrated in the diagram here in which we see the role of norepinephrine and serotonin inhibiting pain signaling in the descending pain fiber network, as well as the role of glutamate and substance P in the ascending pain fiber network.
- There are other problems that have been demonstrated, as well, in work by Roland Staud’s group showing us that the transmission of nociceptive input through myelinated A fibers may get changed in fibromyalgia and be transmitted more by unmyelinated C fibers, which tend to be more chronically turned on as compared with the on and off of A fiber sensory processing.
- We also know that there may be a phenomenon known as kindling, in which hyperexcited neurons may affect nearby neurons, spreading the abnormal pain response throughout the central nervous system. It is this series of investigations that have highlighted these abnormal features in central sensory processing in fibromyalgia patients compared with controls that have taught us more about the central pathophysiology of the condition, pointed toward how some of the therapies that are now showing effectiveness may work in this condition.
Symptom Domains of Fibromyalgia
- Before we get into looking at these therapies, though, let’s ask the questions of what are the key symptom domains to be measured in fibromyalgia and how are they being measured in clinical trials, because you’ll be looking at some of those data in the next few slides.
Shown here are some of the key symptom domains that are being measured, including pain and patient global. Function, for example, is a therapeutic intervention leading to actual improvement in function as well as symptoms, which is a desirable goal. Are we improving fatigue, sleep, some of the psychiatric comorbidities, and this problem with cognitive dysfunction?
There are instruments that measure each of these key domains, many of them borrowed from other disease states. Few of them have been validated in fibromyalgia clinical trials but have shown good performance characteristics. And so, based on this, there are now a number of drugs that are being approved, not only for treatment of the pain of fibromyalgia, but some of the more global aspects of the disease.
- Let’s look at some of the drugs that are currently being used in treating fibromyalgia. This table shows the results of a large Internet survey that was conducted among fibromyalgia patients by the National Fibromyalgia Association, and you can see a quite extensive list of medications ranging from Tylenol to various anti-inflammatory medications to narcotic medications to muscle relaxants to antidepressants, and quite an array of evaluation about whether they are helpful for patients.
So, this is the current landscape of drugs that are being used by clinicians for treating their patients. And shortly, we’re going to look at the evidence for some of the more targeted therapies that are being approved for the treatment of fibromyalgia.
- As we go about thinking how to best manage a fibromyalgia patient, obviously, there are a number of stages that we go through. The first one is to confirm the diagnosis, to make sure that we’re not only dealing with another condition that might be masquerading as fibromyalgia and should be treated differently. We also know that confirmation of the diagnosis helps the patient settle in their clinical quest. As previously mentioned, many patients have seen a number of different physicians in coming to their diagnosis. And oftentimes, they have inappropriate studies or procedures that are done — for example, if a patient presents with noncardiac chest pain, they may have various cardiac evaluations, including even cardiac catheterization. They may undergo needless MRI scanning of various body parts, including the brain. So, we have found, and a number of studies have found, that once the patient has a diagnosis, that overall their anxiety about their condition may diminish. They’re more compliant with fitting into an appropriate treatment regimen and may settle down and have fewer doctor visits and less troublesome or costly procedures done to try to make a diagnosis.
We are keen on figuring out the key symptom domains that the patient has and what the relative severity is. So, for example, if a patient says “My pain is fairly manageable, but it’s really the fatigue or it’s really the sleep disturbance that is most troubling to me,” then that may affect how we go about not only evaluating that particular symptom domain, but staging our treatment accordingly to the appropriate symptom domain.
We obviously want to look for comorbid medical and psychiatric disorders ranging from rheumatoid arthritis to depression and make sure that those are being properly managed. We would like to address the psychosocial stressors and level of fitness or barriers to treatment that the patient is experiencing to try to address those issues in their life. Obviously, we want to not only educate the patient about fibromyalgia — what its pathophysiology is, what the best treatment approaches are — but also their family members.
Then, we settle into reviewing the various treatment options, both nonpharmacologic and pharmacologic. In our practice, what we often do is start with a pharmacologic therapy to try to diminish the severity of some of the symptom domains that the patient is experiencing, which then may get them more able to be involved in modalities such as physical therapy, aerobic exercise, and so forth. Sometimes, it’s helpful to have a patient work with a psychologist or other type of practitioner with modalities such as cognitive behavioral therapy (CBT) to help them with coping with their illness. And of course, throughout all of this, we are encouraging exercise.
Nonpharmacologic Management of Fibromyalgia
- Let’s focus in on some of the nonpharmacologic management approaches to fibromyalgia. Listed here are 3, which have shown the best evidence for efficacy: cardiovascular exercise, patient education, and CBT.
- With exercise, numerous studies have shown that with various forms of aerobic conditioning, there can be improvement in pain and improvement in function. We are constantly encouraging our patients to be involved in some form of exercise. We try to make it as fun as possible for them. For example, doing it in a group format, doing something in, say, Jazzercise, with music, or walking with friends around the lake to try to make it something that they look forward to doing rather than dreading.
- Patient education is key. I’ve already alluded to the point that once the patient has come to a diagnosis and knows more about it, they can be more effective in helping with their self-management as well as working with family members. This kind of approach has been shown to improve pain, sleep, fatigue, and quality of life in patients with fibromyalgia.
Cognitive Behavioral Therapy
- CBT has been shown to help considerably with this condition. The key elements of CBT done in either individual or group format include relaxation techniques, appropriate goal setting, problem solving, self-reinforcement, and a key is substituting maladaptive thoughts with positive cognition.
- There are a number of other nonpharmacologic approaches that have been utilized in fibromyalgia. One of the more successful has been to pull together a multidisciplinary therapy program, which may include a physician, a physical therapist, nursing personnel, psychologist, and others working with patients in a coordinated fashion and possibly in a group format. There are a number of centers around the country where this has proven to be quite successful.
Listed here are a number of other therapy approaches that have been used. Some of these only partially are completely studied in a controlled fashion — multidisciplinary therapy, for example, which is popular in Europe, has to do with mineral baths, biofeedback therapy, electrotherapy, hypnotherapy, strength training, acupuncture, chiropractic treatment, massage, ultrasound, and flexibility exercise.
Tender point injection is something that some clinicians will use, using Lidocaine, for example, to inject into areas of tenderness. We actually don’t do that in our clinic because it tends to be only temporary. But, some of the clinicians who do this do swear by it, saying that it can be very helpful for a significant flare of a painful tender point.
Pharmacologic Management of Fibromyalgia
- There have been, over the last number of years, several agents that have been looked at quite carefully in controlled trials for the pharmacologic management of fibromyalgia. We would like to highlight data from some of these trials because these, I think, are showing the way toward more targeted therapy for the known pathophysiology of the condition in the future.
We’ll be focusing in on the FDA-approved products for fibromyalgia, which now include pregabalin, or Lyrica; duloxetine, or Cymbalta; and milnacipran, also known as Savella. We’ll also show you some data with drugs that have not been FDA approved, partly because they’re older and perhaps generic, The manufacturers are no longer seeking a fibromyalgia approval or may never have been, but they’ve certainly been used off label. We’ll look at a few emerging drugs for fibromyalgia, including amitriptyline and tramadol, which are currently commercially available. And then, I’ll mention sodium oxybate, a drug which is currently used for the treatment of narcolepsy and appears to improve sleep as well as pain and function in fibromyalgia.
- Let’s start with pregabalin, which was the first drug to be approved for fibromyalgia. This drug works by inhibiting nociceptive neuronal signaling by binding to the alpha-2-delta subunit on a neuron, which modulates calcium influx, leading to less activation of the neuron. It is this binding to this subunit that leads to the analgesic, anxiolytic, and anticonvulsion activity of pregabalin. It blunts the expression as well as action of nociceptive neurotransmitters such as substance P and glutamate.
If you remember our discussion about the ascending and descending pain fiber abnormalities in fibromyalgia, then this acts on the ascending pain fiber network, the nociceptive input to the brain that’s telling us that we’re experiencing pain. And by dampening this, it is active as an analgesic.
- The approval of pregabalin for fibromyalgia was based on a number of studies that were done as both 14-week as well as 6-month studies. These are representative data from the 14-week trial. What we’re seeing here are 30% and 50% responder rates in terms of pain using a last observation carried forward (LOCF) analysis. We see that the 300- and 450-mg doses of pregabalin, which are the 2 approved doses, show a 42% and 50% responder rate, respectively, with patients who had at least a 30% pain response. And, if we look at least 50% pain response, that was achieved by nearly a quarter of patients in those 2 dose arms.
The 600-mg dose was tested but not approved, partly because there wasn’t that much more efficacy relative to the increased amount of side effects that that dose yielded. We also were finding that patients are finding benefit from lower doses than the formally approved one. These improvements were clearly statistically significantly superior to the placebo arm in these studies.
The side effect profile of pregabalin includes dizziness, somnolence, and weight gain, among a few other important side effects. Fortunately, many of these side effects tend to dissipate as the patient continues to use the drug. And sometimes we take advantage of the somnolence issue by having the patient take more of the drug at bedtime to help them with sleep.
- Another agent that has been approved for the treatment of fibromyalgia is duloxetine, also known as Cymbalta. This medication is in a class of meds known as serotonin-norepinephrine reuptake inhibitors or SNRIs.
An SNRI, by definition, is a drug that augments serotonin and norepinephrine. And so this drug presumably works in the descending pain fiber system, which is inhibitory or modulatory for nociceptive input. But, it is presumed that by augmentation of norepinephrine and serotonin, we are going to see diminished pain. And indeed, that is what has been shown in studies with duloxetine.
- Here, we see at least 30% improvement being seen in about 50% of patients at 3 months and just slightly less than that at 6 months. This drug was studied in both 60-mg/d as well as 120-mg/d dosage. Because the effectiveness was similar in the 2 doses, the FDA has approved the 60-mg dose for use in fibromyalgia. This dose is usually taken once a day.
- In this next slide, we see the yield for 50% improvement, and that’s seen in 34% of the 60-mg patients at 3 months and about the same number at 6 months so that it shows that there is durability of effect.
The side effect profile with duloxetine: key side effect is nausea. This occurs in roughly a third of patients initially. Fortunately, this tends to dissipate as the patient uses the drug longer. So, we tell patients up front to expect it potentially and to be aware that it will gradually dissipate. So, we usually start at a lower dose, encourage the patient to take it with some food. And ultimately, most patients are able to tolerate the drug just fine. I would like to reiterate that the way in which this drug is working is through its analgesic effect primarily in fibromyalgia patients. Most of the patients in the fibromyalgia trials with duloxetine did not have concomitant major depressive disorder, and although the drug is approved for treatment of depression, we are aware that the majority of the effect of the drug is through its analgesic effect.
- The third drug that has been approved thus far for treatment of fibromyalgia is milnaciprin, also known as Savella. This too is an SNRI medication. It also has mild N-methyl-D-aspartic acid (NMDA) inhibition properties. Both of these SNRI medications appear to have greater antinociceptive properties than the selective serotonin reuptake inhibitor (SSRI) group of medications.
- In the milnacipran trials, novel composite responder endpoints were utilized. There were two of them. The key one was that a patient had to have at least a certain amount of improvement — in this case, 30% improvement — of pain, as well as improvement in their patient global assessment as well as improvement in physical function. And for the patient to be a responder, they had to hit all3, which in this graph is shown as the reddish color in the middle of those 3 circles. There was also what was known as a pain composite in which there was at least a 30% improvement in pain, and the patient had to have a very much improved or much improved evaluation on their patient global to be a responder. So, you can see with this higher hurdle than just a single dimension showing the kinds of responder rates that were seen with milnacipran.
There are 2 forms of analysis. One is the baseline observation carried forward (BOCF), which is the most conservative way of doing analysis. If a patient, for example, drops out of the study because of an adverse effect or let’s say they just simply moved from the city where the study was being done, then whatever their pain at baseline was considered their endpoint pain level. So, this is clearly the most conservative way of analysis.
The observed cases (OC) analysis is one that’s probably more practical to you as a clinician, and that is if the patient made it through the study, what was their pain level at the end of the study, pain as well as function and patient global.
So, what we see from the triple composite responder was that roughly a third of the patients in the OC analysis had achieved this triple response, and about 45% in the OC had achieved the double composite response. Obviously, using the BOCF analysis, the response will be lower because of the more conservative way of doing the analysis.
- In the preceding slide, we saw the composite responder rates in a single phase III study that was with milnacipran. In this slide, we’re looking at 2 large phase III studies that were done and looking just simply at the pain response or the single dimension and looking at what percentage of patients had at least 30% improvement.
There were 2 dose arms of milnacipran, 50 mg twice a day and 100 mg twice a day vs placebo. In the OC analysis, slightly over 50% of the patients in both studies achieved at least a 30% improvement in pain. And then, using the more conservative analysis, the BOCF, roughly a third in the first study and about 30% in the second study with both dosages achieved at least a 30% pain response.
These results are somewhat analogous to the data that we’ve seen previously with the other agents that have been approved for fibromyalgia. This drug, like duloxetine, also has nausea as the most frequent adverse effect, seen in slightly less than a third of patients. Fortunately, this is something that mainly occurs initially as patients are just getting used to the drug. And then, once they get used to it, it tends to not be an issue, for the most part, although there were a few patients who dropped out because of nausea.
One additional point to be made with milnacipran is that its effect can be quite enduring. You saw earlier results of a 6-month trial, and there are data actually going out to 1 year that showed continued effectiveness with this agent.
- One of the older drugs that has been used for treatment of fibromyalgia is amitriptyline, a drug that is the tricyclic antidepressant class. A typical dose ranges from 10 to 25 mg taken at bedtime. Higher dosages often yield problematic side effects, including dryness of the mouth, excessive sedation, constipation.
This drug has been shown in short-term studies to help reduce pain in fibromyalgia. A 24-week study done by Simone Carette showed that there was no statistically significant separation from placebo. This may not have an enduring effect, as well as the issue of its poor tolerability. But this is certainly a drug that has been around for a long time and has been used at bedtime for the treatment of fibromyalgia.
- Another drug that has shown efficacy in clinical trials is tramadol, tramadol alone or tramadol coupled with acetaminophen. This is a novel analgesic agent that has slight effects on the mu-opioid receptor as well as an SSRI effect.
- An example of a study with this agent in which the primary endpoint was the cumulative rate of discontinuation for any reason, there was a significant difference between the patients that were on tramadol vs placebo, showing much less likelihood of discontinuing tramadol, presumably because of its degree of effectiveness in helping control pain. Even though not approved for the treatment of fibromyalgia, this is an agent that is used for treating the pain of this condition.
- Another interesting medication that is currently in development for fibromyalgia and has shown efficacy in studies is sodium oxybate, or Xyrem. This is a drug that improves sleep architecture and is used for the treatment of narcolepsy and cataplexy by sleep physicians.
In studies, it has shown improvements in pain, patient global, as well as function. So, this may be used at some point in the future if approved for fibromyalgia. One of the issues around its use is that it has been used recreationally, unfortunately in date rape, because of its highly sedating effect. It has to be used with some caution in terms of how it is distributed in the public.
- I have alluded to the fact that there are a number of different pathophysiologic pathways that have been demonstrated in fibromyalgia, so it makes sense to potentially couple medicines that target those different pathways with each other. Some examples are shown in this slide in which we discuss that it would make potential sense, for example, to use pregabalin, which addresses pain and sleep, as well as one of the SNRI medications, which may address pain and fatigue. It’s not uncommon for us in practice to use these kinds of medications together.
The formal studies to show whether there is an additive effect of this kind of combination as well as addressing the safety of using the combination have not been done but are anticipated to be done. So, we will have more information in the future about the usefulness of this kind of combination therapy.
It is important to keep in mind that there are some medicines that one should either not use together at all or should use together with significant caution. For example, with the SNRI medications, we do not use them with monoamine oxidase inhibitors (MAOIs). We also use an SNRI with significant caution with a medicine such as an SSRI.
And the problem is that if you use 2 drugs that augment serotonin function, then you may get something known as a serotonin syndrome. And so one must be extremely cautious about this and generally avoid using such medications together. If one has questions about these types of combinations, then discussion with a knowledgeable pharmacist is in order.
- In quoting some of the comments from the meeting, one of the things that we all agreed was that moving beyond the current monotherapy data, which I’ve been showing you, toward using rational polypharmacy is really quite appropriate. And we’ve already known the example of, say, using an SNRI medication in the morning, which helps both with pain and fatigue, and then perhaps pregabalin more at bedtime, and then perhaps taking some tramadol, as well, on a prn basis.
- Not only should we be thinking about how best to use pharmacologic agents with each other, but also how to couple pharmacologic agents with nonpharmacologic therapy approaches, as we have discussed before, including patient education, aerobic exercise, and potentially CBT, keeping in mind that we’re not only trying to treat pain, but we’re also trying to address other key symptom domains such as fatigue and sleep disturbance that are so common in fibromyalgia patients.
- To summarize, we’ve gone over quite a bit of information in this talk, starting with what is fibromyalgia, what is its clinical definition, how does it manifest, what are some current ideas about the pathophysiology of the disease and optimal treatment approaches. We’ve learned that fibromyalgia is a condition characterized by chronic widespread pain, but also a number of key symptom domains, including fatigue, sleep disturbance, cognitive disturbance and other features.
There are often overlapping conditions, including irritable bowel syndrome and irritable bladder syndrome, for example, which are felt to share central sensitization pathophysiology.
Fibromyalgia can also be seen as a fellow traveler with a number of other conditions, including rheumatic diseases such as rheumatoid arthritis or lupus, some chronic infections, even endocrine disorders.
A number of factors predispose patients to fibromyalgia, including environmental factors, developmental issues, including childhood traumas. We know that depression and anxiety can be important comorbid conditions with fibromyalgia. As we’re evaluating fibromyalgia patients, it’s important to distinguish these various elements and to be sure that we’re adequately treating all of the symptom domains.
We’ve learned that the key abnormalities in the pathophysiology include abnormalities in sensory processing in the nervous system, a disturbance both in the input of sensory nociceptive signaling, perhaps mediated by increased amounts of substances such as glutamate and substance P, as well as problems with modulation of pain signaling or in the inhibition of pain signaling through the descending pain fiber network, which is mainly mediated by norepinephrine and serotonin.
There are undoubtedly other abnormalities that are going on, as well, as we’ve learned through some of the genetic studies, perhaps through the dopamine pathways or catecholamine pathways. We also have learned that there are important comorbid psychiatric disorders that may occur in some patients.
All of this leads us to treatment recommendations that are attempting to address not only a number of different symptom domains, but also addressing the fact that these patients have significant problems with functioning and just normal behavior in everyday life. So, to get them back to normal functioning, to have less pain, less fatigue, less sleep disturbance, try to target those with appropriate therapies. Some of the newer therapies that have been approved for treatment of fibromyalgia do address multiple symptom domains. These include drugs such as pregabalin, or Lyrica; duloxetine, or Cymbalta; milnacipran, also known as Savella. And there are a number of other drugs that have not been formally approved but have been shown to be potentially useful.
Sometimes, it’s appropriate to combine these drugs if well tolerated and if it appears that the patient is getting some additive effect. We’re going to have some more research in the future to really teach us better about what the appropriate combination therapies will be.
We also know that it’s important to couple pharmacotherapy with a number of approaches to nonpharmacologic therapy that can be helpful, including patient education, aerobic conditioning or exercise, as well as CBT and other nonpharmacologic approaches. This is often done by a team of individuals, an experienced clinician, along with others who have experience such as physical therapists or psychological counselors and others, interacting not only with the patient, but their family and those with whom they work, for example.
It really is a very complex and multidisciplinary approach that optimally is taken to the management of fibromyalgia.
I appreciate your having listened through this talk today so that you may gain a greater appreciation for how best to manage your patients with this difficult condition.
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