Ottawa Conference Reports III: The Most Expensive Disorder: Clauw on the Fibromyalgia and CFS-ness of Chronic Illness
Clauw is a fascinating figure. Clauw comes from the fibromyalgia side but if you don’t have FM don’t think there’s not something here for you as well. Clauw believes a very large group of people with chronic illnesses suffer from an undiagnosed and untreated FM/CFS-like illness and he’s not alone. The creation of a high-level working group at the NIH composed of FM, IBS, interstitial cytisus, CFS and other researchers indicates considerable cross-fertilization is occurring between these formerly separate disciplines and this is good news. While Clauw is coming from the pain side you may be surprised at the connections you find.
Barking Up the Wrong Tree – He started off stating that, with their unremitting focus on finding and repairing injury, the medical community has missed the boat on pain. In effect he accused them of sticking their collective heads in the sand – for decades.
The fact is there’s not a single pain condition in which pain levels correlate well with x-ray or MRI, etc. scan results; some people with major structural problems feel little pain while others with sometimes undetectable injuries are in severe pain.
Clauw used osteoarthritis of the knee to demonstrate his point. Thirty to forty percent of people with the most severe form of osteoarthritis of the knee – bone on bone – have no pain at all while 10% of people who experience severe knee pain have no discernible injury at all. That pattern, he asserted, persists across every chronic pain illness and the recognition of that is prompting a huge re-evaluation in the pain field. The old paradigm of pain – find the structural problem and correct it – is crumbling….
The medical community is finally learning that a big chunk of that problems lies in the central nervous system; specifically in a disturbance of the pain processing pathways in the brain that causes what Clauw calls ‘Central Pain’.
Where does CFS come in? After noting that five of the eight symptoms from the Fukuda definition of CFS are pain symptoms, Clauw stated he felt that most people with CFS fit into the spectrum of disorders he is describing.
An important part of the shift began occurring when it became clear that central nervous system ‘anti-depressants’ can be pretty effective pain relievers.
How an ‘anti-depressant’ becomes a pain drug: the duloxetine (Cymbalta) Story
The ‘antidepressant’ duloxetine (Cymbalta) has been shown to be as effective in the treatment of osteoarthritis pain of the knee as are NSAIDs and opioids. A FM study indicating Cymbalta effectively treated pain in Fibromyalgia patients who were not depressed paved the way for FDA approval for Cymbalta in FM. Depending on who you are, Cymbalta could enhance your mood or reduce your chronic pain.
Cymbalta’s success in treating pain indicates that some forms of pain in FM are due to central nervous system problems – not a structural injury. Cymbalta’s lack of effectiveness in acute pain , on the other hand, suggests that the two types of pain are very different. Interestingly, some research suggests that the drug may be affecting anterior cingulate functioning – a part of the brain highlighted in the Conference (See Brain Section Overview).
The Fibromyalgia-ness of Disease
Re-interpreted correctly, Clauw believes, ‘fibromyalgia’ isn’t just FM anymore; it’s a condition that may be found in every unrelieved and puzzling chronic pain state doctors face. Every time a physician pulls up an x-ray of a low back patient and frowns because of her/his ability to explain why this person has so much pain – they’re very likely looking at an (undiagnosed) ‘FM’ or ‘central pain’ patient.
Wolfe has shown that a ‘degree of fibromyaglia-ness’ is correlated with levels of pain and disability not just in fibromyalgia but in rheumatoid arthritis, osteoarthritis and regional muscoskeletal pain. If the medical profession wants to get these patients back to work, out of their offices and off disability, it’ll have to deal with their ‘fibromyalgia’, not their swollen or painful joints; i.e. they’ll have to concentrate on what’s going on in their brains.
In fact, Clauw believes that, in the next couple of decades, the medical profession will understand that these ‘fatigue and pain syndromes’ are the most costly and problematic conditions the medical field grapples with.
Central Pain (and Fatigue)
Clauw stated that central pain conditions are very, very easy to spot. He and his colleagues used to joke that it took them about 30 seconds to diagnose fibromyalgia. From Ethiopia to the US he reported that it looks the same everywhere. Currently it’s found under different labels such as FM, IBS, TMJ, etc., but these labels are largely irrelevant; it’s all the same basic condition showing up in somewhat different ways. People with central pain tend to have
- 3 or more regions of pain (a pain diagram is used to diagnose that)
- a higher lifetime history of pain than normal
- a bunch of somatic symptoms (fatigue, sleep problems, concentration problems) are nearly always present.
The pain diagram is particularly useful; if you exclude people with auto-immune disorders (who make up less than 1% of the population) then 3 or more areas of pain is a blinking red light.
Three things stick out in this group; gender imbalance, a high genetic susceptibility to chronic pain and a tendency to have pain exacerbated by stress. Not surprisingly, all are present in ME/CFS as well.
The Central Fatigue CFS Connection – In the early 2000s, two CFS researchers, Chaudhuri and Behan, proposed that the fatigue in CFS is also ‘central’. As evidence for that, they cited numerous study results demonstrating abnormal brain activation and the presence of nervous system symptoms such as problems with concentration and cognition. Chaudhuri and Behan focused on deep brain circuits involved in the planning and execution of physical movement.
- Dig Deeper! – Central Fatigue and CFS
Characteristics of Central Pain
The three central characteristics of ‘Central Pain’ show up in CFS as well.
The Female Connection – FM was originally thought to be 80% female but Clauw now believes women are only 1.5-2x more likely. Whatever the exact gender figures, Clauw believes this type of chronic central pain is pervasive in both genders, striking 8% of males and 12% of females.
Women, however, are far more likely to be diagnosed with FM than men because of cultural mores that tend to place women’s complaints more in the psychological realm while men’s are thought more likely to have a physical basis. This apparent undermining of women’s symptoms has more negative consequences for men, oddly enough, because it leads them to have more unnecessary surgeries as surgeons attempt to repair the problem.
This is not to say that gender does not play a role in who comes down with fibromyalgia. Unusual versions of a gene called GCHI, which is highly sensitive to estrogen, show up more often in fibromyalgia than usual. Clauw noted that high estrogen levels during the premenstrual period could explain the increased pain sensitivity often found in women with these illnesses.
(The estrogen connection in CFS appears to be growing as well…..A CDC study at the conference showed enormously increased rates of heavy bleeding, endometriosis, early menopause and hysterectomies in women with CFS.)
Stressors – the sexual abuse/early life stressor studies were a big bone of contention in ME/CFS research, but early life stressor studies have had similar results in the study of FM and other allied disorders. Clauw reported on a fascinating UK study that is following everyone born during one week in 1958 throughout their lifetime. Every six months, everyone born during that week receives a questionnaire about their medical history. Remarkably, 50 years later, 75% are still participating. People who ended up with chronic widespread pain were 1.5-2x more likely to have been exposed to the death of a parent, severe financial problems, prolonged hospitalization and/or automobile accidents.
Major catastrophic events have long been known to spark a kind of central nervous system reorganization in some people. Surgery, for instance, appears to spark central sensitization in about 5-15% of patients. Cancer treatment results in an FM/CFS-like condition in a subset of patients no matter what type of therapy is used. The Gulf War, of course, produced a significant number of FM/CFS-like conditions. (Reports have surfaced that similar problems occur in a subset of all persons spending time in an intensive care unit (ICU) even after they’ve recovered from whatever problem landed them in the ICU).
In ME/CFS, infections fit the ‘stressful event’ category for Clauw quite well, and he expressed some amazement at the consistency with which the Dubbo study displayed 8-10% of everyone coming down with widely differing infections all coming down with the same CFS-like condition. (At the conference Harvey Moldovsky added SARS to the list when he reported that a similar percentage of SARS patients in Toronto came down with CFS/FM-like conditions.)
A Huge Genetic Contribution – The genetic contribution in both fibromyalgia and CFS appears to be remarkably high. If one person in a family has FM, a near family member has a greatly increased chance of having it as well. To put into perspective how unusual that is, autoimmune disorders are considered to have a high familial component,
but those found in FM are much higher. Except for pure genetic disorders, FM has the highest ‘genetic loadings’ of any disorder.
(A recent CFS study (Albright et. al. 2011) suggested that genes make a major contribution to CFS as well. The study found an increased risk of CFS amongst first, second and even third degree relatives. See ‘All in the Family’ – A Real Disorder After All?)
Interestingly, a gene strongly associated with fibromyalgia has popped up several times in CFS studies as well. About 20% of the population carries polymorphisms or subtle changes in a gene called COMT which has proved to be highly predictive of how much pain a person suffers after a traffic accident. The serotonin transporter gene 5HT2A has also been linked to both disorders.
Neurology Not Psychology
When Clauw says ‘central nervous system’, he’s not talking about psychology. Twenty years ago, researchers thought psychology played far more of a role in fibromyalgia than they do now, but the evidence, now quite substantial, does not indicate that psychological problems prior to illness played a role in the development of these illnesses.
After onset, though, is another matter, Clauw says there is an overlap between FM and IBS and mood disorders and here’s why – the same neurotransmitters that affect pain, sleep, alertness and memory affect mood as well. It’s become clear over time that the two key neurotransmitters at play in FM are GABA, the feel-good neurotransmitter, and glutamate, the excitatory neurotransmitter.
Bad Volume Control
In a statement reminiscent of Dr. Baraniuk’s statement of several years ago regarding CFS, Clauw believes the problem is that the ‘volume control’ that regulates the strength of the signals coming from the body has been turned up too high. Clauw stated that people with these illnesses feel all the sensory experiences that other people don’t feel. The drugs that are effective (at least somewhat effective) in central pain conditions are those that downregulate sensory processing such as SSRIs which increase serotonin and norepinephrine levels in the central nervous system.
Clauw is taking a strong look at a part of the brain called the insula which he called the ‘polysensory integration center’ of the brain.
The Insula – A Key Organ in Central Pain (and CFS?)
The insula is a fascinating organ in the brain that in some ways appears almost made to order for FM and CFS. Got problems with bright lights, sharp noises or painful body sensations? That’s probably due to the insula, because it determines how bright the lights are or how painful a sensation is. Insula problems have been found in a number of ‘central sensitization’ disorders such as FM, IBS, TMJ and CFS.
Remember GABA and glutamate? Allodynia studies have shown that those neurotransmitters are out of sync (low GABA, high glutamate) in the insula in FM but a recent study also found that allodynia is relatively common in CFS as well. (Interestingly, Lyrica – an FDA approved drug for fibromyalgia increases GABA concentrations and decreases glutamate concentrations. A Lyrica study is now underway in ME/CFS with Dr. Bateman and Dr. Light).
Got concentration problems? One recent paper suggests that the high levels of insula activity found in FM may actually impair FM patients’ working memory, since the insula ‘steals’ resources from other parts of the brain. (In this scenario, one part of the brain is so active that it is draining resources from other parts. Several studies have shown an inability of CFS patients’ brains to turn off innocuous stimuli such as background noise – another drain on energy in the brain ).
Interestingly, the insula is activated by two problematic factors for CFS patients – exercise and negative emotional experiences and regulates two key systems in ME/CFS – the autonomic nervous and immune system. (One ME/CFS study (Bogaerts et al. 2007) that showed a propensity for reduced CO2 levels when ME/CFS patients imagined negative experiences suggested poor autonomic nervous system functioning.) The insula helps control blood pressure and blood flows during and after exercise, effects gastric motility (IBS symptoms?) and even speech and coordination – all of which tend to falter after exercise in CFS.
The Central Fatigue Connection – Is the volume in the insula turned up too high in CFS as well? It very well may be. Insula activity just doesn’t affect pain levels; a series of fascinating studies by Dr. Kai Lutz, a Swiss researcher, suggest it plays a major role in muscle fatigue as well, and we’re not talking about the garden variety ‘my muscles feel tired’ kind of fatigue, either; we’re talking about a direct inability to generate force in our muscles.
Like central pain, central fatigue is produced by the brain. (Like central pain, the presence of central fatigue does not mean problems aren’t present in the muscles – they very well may be – but that a central nervous system component is present as well.) Depending on where the problem in the brain is, different kinds of ‘central fatigue’ may exist.
Numerous overlaps can be found in ME/CFS. Clauw’s idea of a broken ‘volume control’ hearkens back to the sensory processing theory of the Lights in ME/CFS, which suggests that key filters in the units (dorsal root ganglia) that relay sensory information to the brain are damaged. It also is reminiscent of Dr. Baraniuk’s idea that the ‘gates’ that control sensory information inputs to the brain are broken in CFS. Interestingly, a CDC paper at the Ottawa conference suggested that the sensory filtering mechanisms in the insula had become damaged in CFS as well. )
Again, Clauw believes that this type of pain sensitization is present in 20-40% of all people with cancer, osteoarthritis and all pain conditions. Instead of looking at x-rays and scans and basing treatment regimes entirely on that, physicians should be assessing the amount of peripheral nerve damage present – treating that and then working on the other end – the central nervous system – when appropriate.
Surprise! The Immune System Shows Up – In Spades – the nervous system may play a major role in the development of ‘central pain’ but that doesn’t mean the immune system is not involved. It is, and to a much greater degree than first suspected. Immune cells that were once thought to be rather ‘inert’, such as the microglia and the astrocytes, are turning out to play a major role. (Researchers looking for the origins of ‘sickness behavior’ are focusing on these cells and speculating that they are over-activated in disorders such as ME/CFS.)
The Decline of Opioids – Clauw believes the dominance opioids have played in pain treatment is ending, and not a moment too soon. It wouldn’t go too extreme to describe Clauw as anti-opioid; he doesn’t think opioids are particularly effective, they have lots of side effects, they commonly result in addiction/tolerance and actually make pain worse for some people. In fact, a Cochrane analysis of opioids in the treatment of osteoarthritis of the knee, says not to use them.
Clauw went so far as to state that with their addictive qualities, the pain sensitization problems and other side effects, opioids wouldn’t have a chance of passing FDA review were they to be introduced today. He expects restrictions on opioid use to increase over the next 10 years.
A Poor Mix: Opioids and FM – Opioids target the ‘descending’ opioid pathways in the brain, but study evidence suggests that the serotonin, norepinephrine and dopamine pathways are where the trouble is in FM. Besides, the opioid receptors in the brains tend to be occupied in FM patients – preventing the patients from deriving benefits from more opioids. This suggests that the endogenous opioid system, i.e. the natural opioid system in the bodies of FM patients, is already hyper-active, not hypoactive, and that some FM patients see big improvements in their conditions when they go off opioids. Clauw is not just down on opioids for FM patients, however; he believes they have been widely over-prescribed for conditions they have little effect on.
Clauw stated that increased pain sensitivity due to opioid drug use is a huge problem in general and is a particular problem in people with central sensitization. He referred to an ‘epidemic’ of opioid-induced pain sensitization (‘hyperalgesia’), but did note the sensitization tends to go away 6-12 months after stopping opioid use.
Drugs and the 30-50 Rule – None of the FDA approved drugs for FM work really well. Studies indicate they are about as effective in FM as NSAIDs and opioids are in osteoarthritis. Most drugs in the field of pain management follow the 30/50 rules; 30% of the drugs make 50% of all patients better and 50% of drugs make 30% of all people with pain better.
Cannabinoids – Clauw is high, so to speak, on the use of cannabinoids in central pain. Another surprise for pain researchers has been the far reach of the endo-cannabinoid system in our bodies. Our bodies produce cannabinoids naturally and we have as many cannabinoid receptors as opioid receptors.
Clauw much preferred the use of cannabinoids to opioids and rued the regulatory system and political factors that put cannabinoids out of the reach of most researchers in the US. He does not see that situation changing in the near future.
Cannabinoids carry their own problems; he emphatically does not endorse ingesting them through smoking, and noted there is strong statistical evidence that adolescents who use cannabis carry an increased risk of developing schizophrenia; but it was clear that if he had his choice, cannabinoids would be the subject of intense study in the pain field and that for adults they are a better choice than opioids.
Acupuncture – Dr. Clauw has done a lot of work with acupuncture. He’s found that it works better for acute pain than chronic pain and has been ineffective in several FM trials, but that 35-40% of people get benefits.
“I Love the Placebo Effect”
Placebo Effect – Dr. Clauw is big on non-pharmacological approaches to these disorders. He believes their value is minimized in clinics but time and time again they have been shown to be helpful. In his experience, people who have successfully dealt with FM or CFS have all used these techniques and they tend to work better than pharmacological treatments. His online guide to Fibromyalgia contains 10 self-management (i.e. behavioral) modules. (Lynne Matallana, the founder of the National Fibromyalgia Association, successfully used them to treat her FM.) He stated the trend in FM toward using these techniques is being mirrored in such disorders as diabetes, asthma, COPD and others.
He has some reasons why. One is the ‘huge’ placebo effect seen in all trials of pain-reducing drugs; apparently there is something about pain that is amenable to these kinds of techniques. The other is that calming and non-stress inducing states of mind and behavior appear to affect the same neurotransmitters that produce pain and fatigue. A third is the fact that studies have shown that calming and ‘happy’ neurotransmitters such as GABA are reduced while excitatory neurotransmitters such as glutamate are increased in fibromyalgia. Clauw is essentially trying to do with the mind what drugs are doing with the brain.
They are not the answer, but can result in 20-30% reductions in pain and he suggests they are a good adjunct to other treatments. (Dr. Fred Friedberg has seen some of his CFS patients reduce their level of pain drugs or get off them entirely using these techniques. His NIH-funded online self-management treatment trial in CFS has just begun.)
The Future in FM (i.e. Central Pain and Fatigue (?)) Treatment
Nerve Growth Factor – Clauw stated that a nerve growth factor antagonist may be the most effective pain drug ever developed but trials were stopped because 1-2% of the recipients developed bone necrosis.
GABA – Remember that GABA is the ‘feel good’ neurotransmitter that appears to be low in the brains of FM patients (while glutamate, the excitatory neurotransmitter, appears to be increased). GABA presents another tantalizing possibility that hasn’t panned out yet. Gamma hydroxybutyrate trials had remarkable results; this was the only drug ever tested, Clauw said, in which people have experienced simultaneous major improvements and GABA was 1½ times more effective at reducing pain than any drug they’ve ever seen.
But GABA was produced in liquid form and required taking two doses; one before bedtime and one in the middle of the night. The drug is such a potent respiratory depressant that taking too much of it could kill you and, in fact, accidental overdoses caused a good number of deaths and the FDA declined to approve it. Clauw hoped that a company would find a way to market it in pill form. The trials did, however, underscore how important a role GABA plays in chronic pain.
The ‘Brain Zapper’ – Clauw is quite hopeful about a technology called transcranial magnetic stimulation (TMS) that appears to be helpful across a wide variety of pain conditions. TMS consists of a very small electrical current ……via electrodes attached to the scalp in two 15-minute treatment sessions a week for 10 weeks. It appears to be modulating the activity of the regions of the brain involved in producing pain and appears to be relatively safe and non-toxic.
TMS is being tested right now and, if the preliminary data holds up, the device could revolutionize how pain is treated. Another plus is its relatively modest cost; the machine costs a mere $25,000 – peanuts compared to many technologies – with a ten week course rolling in about $2,000. From efficacy, cost and safety standpoints, the ‘brain zapper’ appears to be very appealing at this point.
A 2011 FM study concluded that TMS resulted in “long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia. (Baudic. Pain. 2011 Jul;152(7):1478-85. Epub 2011 Mar 11.Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.)
Functionality – A Core Concern: Clauw focuses as least as much on ‘functionality’ as he does on pain management. When he treats patients who are on multiple pain drugs he has them compare their functionality before and after they went on the drugs. If he finds, as he often does, that functionally they’re worse off and they’re still in a lot of pain – he often tries to wean them off the drugs.
In his experience, disability should avoided if at all possible and he noted that often he sees a patient slide downhill after getting disability. He noted that private insurance usually runs out after two years and SSDI usually provides much less than the person is currently earning – leaving the person with more financial problems.
A Legitimate Disorder – Clauw has spent his career in the fight to legitimize FM and throughout his talk he called to task those researchers and doctors who didn’t believe FM is a legitimate disorder, stating that the physiological evidence is overwhelming. The perennial ‘Is Fibromyalgia Real’ panel debate at the American Pain Association meetings every three years has ended. Clauw believes that the credibility of FM has gone up significantly over the past couple of years while the credibility of CFS has declined.
Where to go from here?
Clauw pointed to interstitial cystitis as a kind of exemplar. Interstitial cystitis researchers thought they had it all figured out; all they had to do is look closely enough at the urinary/bladder system to figure out was going. Clauw reported they spent about 100 million dollars doing that before they came to the recognition that IC is primarily a central nervous system disorder. In the next year or so, Clauw expects the disorder to be renamed ‘painful bladder syndrome’ or some such name to reflect that understanding. The formerly separate fields are now beginning to pool their resources and IC researchers are now combining with FM researchers to figure out what’s going in the CNS. (A NIH group that includes FM, CFS, IC and other researchers recently formed to examine central pain and fatigue issues. An interstitial cystitis researcher recently joined the federal advisory committee for CFS (CFSAC).)
The treatment of central pain is evolving, and no method by itself is particularly effective. Clauw supports a multi-dimensional approach to pain using drugs and self-management techniques and looks forward to more effective pain reducing options under investigation.
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Addendum: Central Pain Syndrome
Central Pain Syndrome is a pain syndrome caused by damage to the central nervous system .
Clauw’s and the NIND’s concepts of Central Pain are similar and different; both are characterized by unusually high levels of pain production amplified by stress, made worse by touch, movement, emotions, etc. The difference appears to lie in the cognitive issues, problems with sleep, fatigue and other stimuli that Clauw finds in disorders such as FM, IBS, CFS, etc and the ability of researchers to find specific lesions in some of the disorders described below.
Central pain syndrome is a neurological condition caused by damage to or dysfunction of the central nervous system (CNS), which includes the brain, brainstem, and spinal cord. This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or Parkinson’s disease.
Pain is typically constant, may be moderate to severe in intensity, and is often made worse by touch, movement, emotions, and temperature changes, usually cold temperatures. Individuals experience one or more types of pain sensations, the most prominent being burning. Mingled with the burning may be sensations of “pins and needles;” pressing, lacerating, or aching pain…Central pain syndrome often begins shortly after the causative injury or damage, but may be delayed by months or even years, especially if it is related to post-stroke pain.
Note that increased pain after movement, emotions and temperature changes are all found at least some people with ME/CFS. Burning muscle pain after exercise, in particular, has been a key symptom of my own since I got ME/CFS. Perhaps ‘Central Pain Syndrome’ will someday meet ‘Central Pain’ and ‘Central Fatigue’?