Ottawa III: The Most Expensive Disorder Facing the Medical Profession – Clauw on FM and CFS

December 27, 2011

Posted by Cort Johnson

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.

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.)

Treatment

Opioids not effective in fibromyalgia or chronic fatigue syndrome?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 .

http://www.ninds.nih.gov/disorders/central_pain/central_pain.htm

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’?

 

 

31 comments

{ 30 comments… read them below or add one }

Kathy D. December 28, 2011 at 12:32 am

This is somehow assuming that people with CFS and FM have the energy to do these things, to go regularly for appointments and then to do what’s required. For those of us mainly homebound, for whom a trip to a supermarket is like walking 20 miles round-trip with lead weights on our ankles, and who have to come home and recover and can’t go outside again or do anything, this is not a solution.

Reply

maschelle_mashburn December 31, 2011 at 9:36 pm

This was such a hard article for my CFS brain to read, I had to scroll back to see if the fatigue we experience that you just described so very, very accurately (may I quote you to my doctor, family, and one friend in the “real world”) and I did find it mentioned. It was definitely covered extensively (but I forgot and had to go back to re check, no surprise there). I feel some sense being made in these new ideas..as I have had the best pain reduction with Cymbalta..but had to stop taking it because of severely negative side-effects. I had to go back to opiods, and the horrid pain. I have FM and ME/CFS and attempting to get any sleep is an exercise in nothing but frustration every single night. Never is any position “pain-free” and I am woken up constantly during the night. Only on Cymbalta (an anti-depressent? Or is it a mood stabilizer? not sure) did my severe fibro pain almost literally go away. My caregiver reported to me after a few weeks (per my request at the beginning of the new med..input and observations) that my physical functionality, pain reduction, and ability to actually get up pain free after sleeping had improved to such a degree it might be worth staying on the drug even though the side effects were devestating. I had physical as well as emotional issues from the medication. I ended up having to go off the meds due to the wacky emotions (I was even more dramatic and emo if one can believe it than before the meds..) and the gastrointestinal problems were unbearable. So, I’m hopeful this leads to something..the central pain idea. but, so far I’ve failed EVERY drug they’ve tried that is approved to treat FM. Still, I hope. Hang in there, Kathy. At least they are taking notice a bit more of CFS, even if it’s been a bit negative in the “believeability” factor lately. soon they will notice us.

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Cort January 6, 2012 at 1:47 pm

Sorry to hear that your experience with Cymbalta worked out but then did not work out. (What a shame!) For my girlfriend its a huge help; its one of the only drugs she can take that works but she just happens to fit into that subset. Definitely keep your eyes and ears open – this type of central nervous system pain is getting more attention. (Have you tried Lyrica or Neurontin???)

There’s also Xyrem. Xyrem has been really helpful for some people with ME/CFS or FM. The problem is getting the insurance companies to pay for it since it is very expensive but if you can get you definitely should give it a try. Clauw highly recommends it for sleep.

Marly Silverman December 28, 2011 at 12:57 pm

Cort, Great article on Dr. Daniel Claw. I unfortunately did not have the opportunity to attend his lecture at the IACFS-ME Conference in Ottawa. I have heard several of his presentations in the past and his background in fibromyalgia (FM) and Gulf War illness (GWI) is solid. PANDORA remains grateful to his involvement and commitment to the study of FM. I appreciate his past work and his commitment to FM.

I am though concerned with the new American College of Rheumatology (ACR) fibromyalgia Criteria, in which he is also involved. The new criteria description and definition for FM, has too many strong similarities with the the Complex Somatic Symptom Disorder (CSSD) as it is described in the new Diagnostics and Statistics Manual of Mental Disorders, volume 5 (DSM-5). CSSD has been shunned not only by patients organizations throughout the world but by medical providers as well. This past year thousands and thousands of letters were written about the “CSSD”.

“The outline of CSSD lends to the continuing disbelief by many in the medical community that FM (or CFS, Or GWI, Or MCS and chronic Lyme disease) actually exist and that they are real diseases. Also the elimination of tender points in the ACR research and clinical criteria is an issue that needs to be addressed seriously. Drs. Robert Bennett and Dr. Roland Staud are among the most prominent FM researchers and clinicians in the world and they do not agree with the new ACR criteria. It is also troublesome that this new ACR criteria has not had a vigorous debate in the scientific field either.

For many years now FM scientists have through research studies demonstrated the role of the central nervous system in FM and it is good that this process is now being discussed and better understood. However, instead of working on another research definition that is not strong, and does not address the involvement of the central nervous system on FM, these same scientists should be asking for the reclassification of FM to Chapter 6 in the ICD-10-CM. FM like CFS is in the “vague unspecified area (muskulesketal area/chapter of ICD-10-CM in the U.S. Its location lends to the disbelief that FM is real.

It is my opinion that the reclassification step will move the science and patient care to where it needs to be for FM in a much more efficient and more scientific way than the what the new criteria is doing.

The new criteria ACR criteria for FM is poorly designed. I am yet to meet one FM patient organization or patient advocates who are think this new criteria is the best approach. In fact, the new criteria actually lends to the psychobabble that has plagued FM patient care for decades now. Also, because of the overlapping with CFS, this new ACR criteria further stigmatizes CFS and FM and other related illnesses like MCS, chronic Lyme disease and Gulf War illness.

Celeste Cooper, a retired RN, author, and FM sufferer, recently wrote the following article:”Questioning the Preliminary Proposed Diagnostic Criteria for Fibromyalgia”, which was published in Volume 21, Number 2, Summer 2011 issue of The Pain Practitioner (Journal of the American Academy of Pain Management).

Fibromyalgia patients should take the time to address these issues and pay attention because case definitions directly affect patient care and how insurance companies, physicians, and other medical providers will address the management of patient care. As far as the ICD-10-CM, the deadline to submit a proposal to reclassify fibromyalgia is January 6, 2012. The next opportunity will not be until after October 1, 2013.

Here is where FM is in the ICD-10-CM:
M79 – Other and unspecified soft tissue disorders, not elsewhere classified
M79.7 – Fibromyalgia
Applies to:
Fibromyositis
Fibrositis
Myofibrositis

The location where FM is in the ICD-10-CM is directly related to the lack of priority, belief and funding for this disease.

Thank you Cort for a great article and a great update on Dr. Claw’s work. Thank you for all that you do!

Reply

Cort January 6, 2012 at 1:56 pm

Thanks Marly. For some reason I missed all the early comments and so am getting back to yours late. (:() Unfortunately I missed the presentation on FM diagnoses. It would be a shame indeed if efficacy in the research area (ie using the definition that promotes more research) is sacrificed on the horns of what some researchers believe to be ‘accuracy’; ie if a changed definition is going to imperil legitimization of this disorder – which Clauw admits is a problem – then why do it?

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Marly Silverman January 7, 2012 at 7:50 am

I agree with you Cort… wyh do it? The only answer I have now for this question – the cost – the cost of treating FM and (according to Claw) CFS too. ME/CFS patients need to pay attention to the fact that FM overlaps with ME/CFS. Therefore what happens to FM affects ME/CFS too.

In all of my years of participating in support groups, conferences, meetings and chats on the internet, I noticed that a large majority of ME/CFS patients who are among the most severe bed bound and home bound listed pain in the top 3 concerns as a major disabling and debilitating symptom. Yes, I have also heard from many ME/CFS patients who do not have major pain issue at a certain time of their disease process but eventually at one point develops pain. I have also seen the other way around with FM patients, where the fatigue then becomes worse than the pain and it is even more disabling because they cannot do daily chores anymore because even thought the pain management is in place the fatigue is crushing.

Someone here mentioned Lyme disease. Our organization (PANDORA- http://www.p-a-n-d-o-r-a.org) we embrace chronic Lyme disease because we as patient advocates realized that the symptoms are very similar to ME/CFS and FM, but Lyme disease and or tick borne illnesses have biomarkers that can be addressed with antibiotic treatments. There is why many ME/CFS patients may do well with antibiotics once the Lyme disease is treated. Several researchers are finding that in the subjects of their ME/CFS/ FM research that patients when tested for Lyme are positive leading to the issue of misdiagnosis. Better testing for Lyme and other tick borne illnesses need to be created so more can be diagnosed properly.

We need funding. We need research for NeuroEndocrineImmune Disorders or diseases.

Girl Warrior December 29, 2011 at 11:33 am

Very interesting article…..I wish there was more discussion about the many, MANY other components of FM. Pain may be central, but there is overwhelming fatigue, cognitive dysfunction, dirordered sleep, disordered breathing, endothilial dysfunctions, sympathetic hyperactivity, cardio vascular abnormalities, widespread myofascial trigger points, reduced cellular ATP, post exertion malaise (different than CFS but still present), and so forth. Fibromyalgia has long been referred to as a pian disorder bacause that is the primary SYMPTOM but it is only one symptom.

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Cort January 6, 2012 at 1:53 pm

I agree. I hope that pain is something of an analogue for those other problems; ie if you’re in alot of pain – whatever has caused your pain is also causing disordered sleep, fatigue, cognitive problems, sympathetic hyperactivity, myofascial point problems (what an intriguing problem that is…), etc.

FM and CFS are a disorders in which a group of symptoms show up again and again which is why Clauw says they are so easy for him to diagnose – once you recognize that ‘gestalt’ you can see it easily….and its all over the place…if he’s correct its in many other disorders and eventually the medical system will recognize what a big problem it is and finally devote some real money to it.

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Laura Estrada December 29, 2011 at 4:35 pm

Very interesting!

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Larry Albert Rinne December 31, 2011 at 2:05 am

Cort,

Wasn’t there a study conducted by the University of Cincinnati in 2007 that tested Cymbalta on CFS patients? How did that turn out? I have never heard a report on it.

Thanks and Happy New Year!

LAR

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Cort January 6, 2012 at 1:48 pm

I looked an couldn’t find anything. It might have been reported at a conference and then never published – that sometimes happens with negative studies.

Happy New Year as well :)

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Gigi Yob January 3, 2012 at 3:45 pm

I found this article to be so filled with a certain future of less pain. To finally read these words written from a learned man who does not just diagnose a person with FM and then when asked, “Well, what do I do now?” say, “You just live with it.” No patronizing, disbelief, here is a man with vision with hope, with tenacity to stand up and say, “Damn it, this condition must be recognized and dealt with today.” I’m still running into doctors who either don’t believe FM exists or don’t want to bother with patients with FM because there’s no percieved reward in the end.
In reply to Kathy D: For those of you with CFS and FM who don’t have the energy to make regular appointments or whatever is needed to push forward, have no worry, there are so many of us behind you to carry on, you just be there at the finish line , cuz it will all be good. :)

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Cort January 6, 2012 at 1:43 pm

I think its amazing given all the work on FM (much more than CFS) and the consistent findings (probably more consistent than ME/CFS as well) and the drugs that have been approved for FM that this disorder is still trashed by people in the medical profession. Clauw did state, I think I reported, that the American Pain Association no longer debates whether FM is a real condition at their conferences; its clear to them, at least, that it is real. On the other hand Clauw stated that it takes a long time for information like that to filter down to the clinical level.

We can at least be clear that the evidence is substantial and that the medical profession – all parts of it – will have to accept that at some point.

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telly January 4, 2012 at 6:34 pm

When are they going to stop screaming CFS/Fibro and start acknowledging Lyme?

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Cort January 6, 2012 at 1:36 pm

I don’t know. I don’t know much about Lyme but I can tell you that Dr. Natelson and Dr. Lerner are both testing for Lyme and Dr. Lerner’s last study suggested that CFS patients with Lyme disease and EBV infection need to be treated for Lyme disease if they’re going to get significantly better.

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Svetlana January 5, 2012 at 9:50 am

Lots of rubbish.I had cystitis when i was in my 20th,non stop.No sex no cistitis,its bacterial infection and not in a bran for sure.

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Cort January 6, 2012 at 1:35 pm

We shall see. I don’t know much about IC but I imagine that an undiscovered bacterial infection is a possibility. I also hold open the possibility that a bacterial infection could be prompting changes in the brain as well. This has been shown in some rodent studies. Check out the brain conference overview for a bit more on that.

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allison January 8, 2012 at 2:11 am

Interstitial cystitis is not the same thing as cystitis.
Cystitis is a painful infection of the bladder that can be treated with antibiotics and yes, it is much more likely when you are having a lot of sex.
Not sure of the exact definition but IC is rather rare – many GPs have not even heard of it (like orthostatic intolerance). It is a common symptom though, in those with Me/CFS.
However, basically interstitial cystitis is voiding large amounts and constantly, and so you drink a lot as well but I’m not sure – maybe it is not known – which is the cause and which the effect, ie. do you void a lot because you drink a lot or vice versa; Dr Jacob Teitelbaum defines and explains IC well in his book From Fatigued to Fantastic.

Joan W. January 5, 2012 at 3:42 pm

Good article overall. But the neat theory does not account for the exceptions, or subsets of FMS. I understand the condition more that I did in the day when it was considered a wastebasket, or worse, a psychological condition. Twelve years of various psychotherapies, and medications and alternative therapies have not helped. My experience is that GABA makes me profoundly depressed, not “feel good drug” at all. Cymbalta and Savella were so debilitating in their effects, I stopped in less that a week. Prozac worked for about 2 years. Tried resuming various SE meds, and they increase my pain intolerably. I’ve had this for 50 years and I’m still searching for help.

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Cort January 6, 2012 at 1:31 pm

Ouch! No relief from Clauw’s approach for you…..We are a complex group are we not? I have heard of subsets in FM and that was not taken into account in the talk. There is so much left to be learned….Clauw acknowledged the importance the immune system plays in producing chronic pain but he didn’t include any immune remedies as I remember. Look for an article up this month on Andrew Miller and psychoneurimmunology for something on those.

I do believe that CFS research will inevitably enlighten FM, IBS and other central pain states with regards immune issues and pathogens. They are hardly being looked at all in those other disorders.

Meanwhile, good luck!

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allison January 8, 2012 at 2:13 am

Yes, I have heard there are 10 to 20 subsets of the diseases ME /CFS which would be why there can be such variety in symptoms; more research needs to be done to classify the subsets.
Similar to MS which has lots of variants.

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Cort January 18, 2012 at 8:49 am

Possibly similar to fibromyalgia as well – which appears to have fewer but a good number. Agreed on the need to classify the subsets.

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Kathy D. January 10, 2012 at 12:10 am

Well, I’d not only to be in the finish line, but I’d like to be out there in the race — or should I say — walk to the finish line. But I’d like the muscle pain to end and the bone-deep exhaustion to end, the kind where I can’t life my arms up to type on the keyboard or wash my hair.
And with these medications mentioned, as Neurontin. My doctor, a knowledgeable fellow, told me that high doses are needed to be effective. I can’t do high doses. I have to be careful of a lot of medication and take half or less of certain things. I’ve had way too many bad reactions to medications. When health care professionals tell me to take a certain dose of something twice a day, say nasal steroids, I say I can only do 1/4 of that and not every day or I’m orbiting into the stratosphere. So my doctor opposes any medications that are very strong or high dosages.
It’s chemical sensitivity, I believe, is the correct term.

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Kathy D. January 19, 2012 at 8:35 pm

It’s hard to know what’s CFS or what’s fibromyalgia when there’s much muscle pain. One thing is for sure: When there is a lack of good, long substantial sleep, the muscle pain just increases to an unbearable level. Then total rest and sleep, sometimes for days, is the only way to get relief, along with painkillers.

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Cort January 31, 2012 at 5:00 pm

Studies have shown that poor sleep results in greatly increased sensitivity to pain in many people. I don’t think you can get too far without at least moderately good sleep. Good luck!

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karen h April 21, 2012 at 3:49 pm

Morphine does not work for me ( it didn’t work on my father either). Why is this?

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Cort April 21, 2012 at 4:38 pm

It could be because your opioid receptors are already ‘filled up’ if I remember correctly. In any case, while opioids do work for some people with FM (and presumably CFS) they are not effective for many others. The pain produced in these disorders apparently is initiated through different mechanisms.

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Keir Farnum July 18, 2012 at 6:35 pm

Hello Cort,

I think Dr. Clauw’s opinion about opiate pain meds is extremely unfortunate. In the past 20 years, long acting pain meds have been the only thing that has helped me despite trying just about everything available (meds, exercise, PT, etc.) and without pain medications I would never sleep and I probably would not have made it this long. The interesting thing is that pain meds seem to help with virtually all of the CNS related symptoms (hyperalgesia, cognitive dysfunction, sleep, etc.) without any significant side effects and I am convinced that there is a subset of us who react remarkably well to opiates for a very good reason.

In my research I have discovered that the main antagonists for NMDA/glutamate are endorphins and GABA and considering that research by Frank Duffy has found a micro-seizure with alpha wave intrusion (like the sleep studies) and taking into account that glutamate has a major role to play in seizure disorders, it stands to reason that for the aforementioned subset, the endorphin deficiency found in some studies (which may vary by individual and/or subset; esp. in FM studies) may be allowing excessive glutamatergic neuro-transmission resulting in this micro-seizure.

Not only does a micro-seizure explain the sleep dysfunction, it also explains the cognitive dysfunction. In essence, an absence seizure occurring for a fraction of a second every 2-3 seconds would result in disruptions in long term potentiation in memory, problems with focus and attention, and problems with impulsivity; the exact problems found in neuropsych studies. Before I started on pain meds, not only did I experience an overall difficulty with maintaining attention and focus and memory, I also experienced a really intense sensation of something that I can only describe as being like having my brain controlled by a TV channel changer that someone else was changing the channels on every couple of seconds when I experienced the “raggedy Andy” fatigue in the evenings. I’m pretty sure this was an intensifying of the micro-seizure during the drop out in blood pressure and increase in CNS ischemia (which I’ll return to later) during the “raggedy” fatigue.

Taking into account the seeming palliative success found in various studies and in anecdotal reports with various NMDA antagonists (opiates, cannabinoids, GABA agonists, dextromethorphan, MK-801, etc.) it would also stand to reason that opiates would be one of the main neuro-chemical deficiencies in the brain of at least some ME and FM patients, as found in some studies.

Although it may seem hard to understand how opiates could mediate a seizure dysfunction, not only is this hypothetically predicted by the research on pain/hyperalgesia and the relationship to excitotoxic brain damage and the glutamatergic system, recent preliminary research co-authored by Ian Lipkin is showing that the seizure dysfunction of post -encephalitic rats is mediated by the application of opiate pain meds and the application of opiate blockers had the opposite effect and increased seizure activity.

In addition, it makes a great deal of sense that opiates would be a major part of our sensory gating systems and that sensory gating is one of the main functions of many of these neurochemicals and that deficiencies would result in hyperalgesia. Interestingly, this fits the pattern that I have experienced; the hyperalgesia is the main form of pain affected first and most of the pain that I still experience is the pain caused by the build up of metabolic by-products and the stiffening of the muscles and that is coming directly from the muscles (in other words, the “normal” pain.)

In essence, I would posit the neurochemistry that provides pain control for “regular” pain at elevated levels (with either natural endorphin increases or by replacing deficient endorphins with exogenous pain meds) is the same neurochemistry that provides sensory gating at normal, baseline physiological levels and deficiencies result in a “widening of receptive fields” (as Goldstein puts it) with hyperalgesia. This applies to other NMDA antagonizing neurochemicals as well (for instance the paper entitled, “Hypoactivity of the spinal cannabinoid system results in NMDA dependent hyperalgesia” is a good example.)

In addition, one of the pieces of evidence that brought me to this conclusion was the description of normal healthy people given opiate blockers and how similar the descriptions of pathological hyperalgesia appear to be to this phenomenon. It also occurred to me that the descriptions of people addicted to opiates and going through withdrawl are very similar to the hyperalgesic phenomenon that ME and FM patients experience and what the addicted in withdrawl are in essence experiencing is a temporary form of hyperaglesia (even the temperature regulation issues appear similar and as my pain meds have increased, that too has subsided; although I still have the “cold on skin” tightening and stiffening of the muscles that is related to the systemic micro-circulatory dysfunction and which I believe is occurring outside of the CNS dysfunction.)

The fact that NMDA antagonists are often used in with drawl programs also helps support this idea as well. Of course, the addicted going through with drawl have the advantage that their bodies can restart endorphin production, thus the reason why what they experience is temporary compared to the average ME and/or FM patient.

Considering the pretty well documented evidence for various subsets and the likelihood of individual differences in biochemistry, I do not believe that this applies to all within the ME/CFS and FMS continuum and it is likely that other NMDA antagonists will be more effective for those patients who cannot take pain meds (and this appears to be the case when one takes into account that some people are overly sensitive to opiates; following the well known problems with medication sensitivity for most with ME and FM) and that for those who are NOT overly sensitive to these meds, it’s likely that this can be explained by the possibility that pain meds are in effect functioning as a form of “endorphin replacement therapy.”

I do of course recognize that in some patients the problem may be the opposite and that some patients may actually have too many endorphins (and filled up receptors, as you mentioned) and hence the success with low dose Naltrexone for some patients. This would also make sense since according to some research, the administration of opiates can actually cause hyperaglesia in some patients; again, this points to the complexity of the illness and the need for sub-typing.

Another interesting improvement that I have experienced has been the massive reduction in muscle spasm and twitches with pain medications and as my pain medications have increased (not because of tolerance building but rather because my initial doses weren’t high enough to start with) there has been a linear relationship to the decrease in spasm activity. Considering the research in both ME and FM that is looking at the dorsal horn and root ganglion, it is extremely interesting for me to note that in meningitis, the muscle spasms they experience has been traced back to the dorsal horn. From what I have been able to gather, the dorsal horn contains few receptors for endorphins but I think it’s very possible that the improvement in spasm activity is due to the indirect effect of glutamate antagonism.

In short, opiates have been extremely helpful for me and appear to mediate virtually ALL of the symptoms that can be traced to spinal and CNS dysfunction. I am still left with all of the systemic effects (poor muscle recovery and abnormal post exertional symptoms, muscle stiffness and pain, etc.) and this points out to me that the spinal/CNS symptoms may actually be secondary (at least in part) to the systemic effects caused by diastolic cardiomyopathy/micro-circulatory dysfunction and the underlying immunological dysfunction with the transient ischemia in the brain and spinal cord being a result of these systemic dysfunctions (at the very least it may continue and maintain an initial or previous encephalitic injury; as is likely in Post Polio.)

The combination of cardiomyopathy and nitrosative and/or hyper-coagulable dysfunction is the perfect recipe for decreasing blood flow to the muscles during activity; leaving us to over-rely on the glycolytic energy stored in our muscles. This would explain the research showing that our muscles are metabolising ADP and AMP resulting in a massive, rapid accumulation of non-recyclable metabolic by-products in the muscles and resulting in the intense muscle stiffening with even the lightest activity (such as facial expression, etc.) The lack of blood flow to the muscles that is causing the over-reliance on anaerobic/glycolytic energy sources is also not removing the non-recyclable metabolic by-products, resulting in “lock jaw light” (as I call it.)

Additionally, when the body runs out of glycogen, as any athlete will tell you, the result is what athletes call “hitting the wall.” I noticed long ago that the “raggedy Andy” fatigue was cyclical and reactive to activity and it occurred to me that the “raggedy Andy” fatigue is very similar to what I have experienced when “hitting the wall” in training and competition What I believe is occurring is that the over-reliance on anaerobic energy sources causes us to run out of glycogen in the muscles and body and to experience a pathological form of “hitting the wall” with a massive drop out in blood pressure (although with such global CNS dysfunction, it remains likely that some subsets and/or individuals are also experiencing actual neurologically mediated hypotensive effects as well.) This would explain why former athletes such as myself with a much more developed anaerobic capacity could go most of the day before the “raggedy Andy” fatigue sets in whereas the average person would have a tighter cycles (such as one hour of ability to remain upright followed by several hours of raggedy fatigue.)

Additionally, I have noticed that Goldstein talked about how the SPECT studies could not be completed on patients at an arbitrary time and that often patients would not have a positive SPECT until later in the day. I would posit that what the SPECT is documenting is the drop out in blood pressure concomitant with this phenomenon and the resulting CNS/spinal ischemia.

It also makes sense out of why athletes, while having this slight advantage in anaerobic capacity, do not have an overall ability to mediate the disease since this combination of cardiomyopathic and micro-circulatory dysfunction is affecting the overall ability of the muscles to get energy and recover properly and the aerobic base that athletes possess is NOT providing any real advantage in the overall pathophysiology of the disease. This also explains why aerobic exercise does not help; it’s stressing an already overstressed system and worsening the CNS dysfunction through the transient ischemia. Anyway, I digress.

Most importantly, taking into account the severity of the illness and the lack of any other treatment, I believe we should remain open to anything that can help since someone’s life can literally be on the line and we should at least remain open to the idea of using these medications as a last resort. It’s hard to see how being dependent (which is NOT the same thing as addiction) on opiates would be worse than being dead.

Thanks, Keir

P.S., another interesting thing that has occurred has been the normalization of my bowel movements. Taking into consideration that excessive opiates can cause constipation, one has to wonder if deficiencies can cause the opposite phenomenon; i.e. consistent loose stools. It would also explain why pain meds have also improved these symptoms as well.

P.P.S., I have also noticed that the cognitive effects I experienced before being put on pain meds by my doctors (i.e., the micro-seizure and associated effects) can also be likened to an intense form of ADD and I hypothesized that ADD might actually be a more limited form of micro-seizure (probably only in the areas of the brain related to attention and focus as opposed to the more global version we experience) and that this would also have a glutamatergic mechanism. I recently read an article by a psychiatrist who stated that glutamatergic mechanisms are being investigated in ADD so I think this may be another piece of evidence that I am on the right track.

P.P.P.S., I do not believe that my hypotheses conflict in any way with much of the immunological research since I think it likely that the virally mediated diastolic cardiomyopathy and micro-circulatory dysfunction may be a result of the overall immunological insult. In essence what I am positing is that these ideas relate to the overall pathophysiology and the causes of many symptoms but not the overall cause of the illness, which remains to be discovered. It does fit many of the extant discoveries together and makes sense. Thoughts and/or questions?

Leopardtail March 25, 2014 at 7:39 am

Neurotransmitters are used throughout the whole nervous system. Why is the assumption made that this pain is central? Are these drugs unable to alter Neurotransmitter metabolism in the peripheral nervous system?

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Cort January 18, 2012 at 8:48 am

Thanks Allison for the information. IC is something I want to learn more about.

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