>> Hello. I'm Dr. Russell, I'm speaking to you from a recording studio at the University of Minnesota in Minneapolis. We're going to today finish the series on fibromyalgia. With chapter three. And there's going to be part A and part B. This first slide shows a painting that I did several years ago, after looking at a painting that was a little bit like it by a nother artist. And my intention was to make a painting that was very relaxing. But, the colors are too bright and too sharp and too contrasting, and so I now have it as a wake-up slide. We're talking on the second development or second running of the MOOC Chronic Pain series and so this is going to be the last of the. The last chapter in the big picture of fibromyalgia, so that you can see the first time that we met, we talked about what is it, what is fibromyalgia? And in that section, in that chapter, we talked about presentation of the patients to a physician, or what symptoms they have, what their diagnosis is, and how a physician would make that diagnosis. Next, how the severity of the disorder would be measured, and finally, what misconceptions have developed about fibromyalgia, because there are a lot of them, and they clearly are misconceptions. And so then in chapter two, we talked about, what is wrong with people who have it? Doctors would say that this is the pathogenesis of fibromyalgia, or the pathology, or the chemical pathology of fibromyalgia. And we included in that three sections, one on genetics, one on the physiology of sleep, and pain, and mood, and their relationship to each other, and finally the abnormal chemistry or biochemistry. As it occurs in Fibromyalgia Syndrome. So, now we're ready for chapter three and we'll do that in two segments. The first one will be phar, pharmacologic therapy meaning medications, used to help people with fibromyalgia to control their symptoms. And the second will be non pharmacologic, or lifestyle changes that can be utilized in the treatment of Fibromyalgia. So, we started out by defining the state of the art for Fibromyalgia. And we said that fibromyalgia is a common, chronically-painful, soft tissue pain condition, which is characterized by persistent, widespread pain, tenderness to pressure, and multisystem comorbidities. Those comorbidities we defined, and they are important to the disorder, because it is not just a pain disorder, it is a syndrome involving a variety of constellation of symptoms, and manifestations. Next, we say that relevant abnormalities, which are objective in nature, that is they can be measured, are detected by experiments in genetics, brain imaging, polysonography, meaning the measurement of sleep or the observation of physiology of sleep. Brain wave patterns, physiology, and chemistry. And so, finally, this chapter brings us to a comment or a statement about treatment, and that is, successful therapy is increasingly based on correcting documented abnormalities. Medication therapy should be combined with lifestyle changes, for optimal effects. So, we begin with an acronym which can be used to help, health care providers design a treatment program for Fibromyalgia. It is referred to as ADEPT Living. It begins with A of Attitude, and implies that the physician and the patient, and the patient's family, and others, we even think here of. Politicians and emergency care workers and so forth should know what Fibromyalgia is, at least have some knowledge about it, and should not have an attitude that is discriminating against people who have Fibromyalgia. We then move to D, for Diagnosis. And we think it's very important that the correct diagnosis be made, and that the differential diagnosis, which means other conditions that the person might have or might be somewhat similar be recognized. We go then to E, standing for Education. And we realize that it's quite important to tell people about Fibromyalgia, so if they are experiencing Fibromyalgia as a clinical disorder, and many of the manifestations of that disorder. That can be very threat, threatening to them, and we want them to be more comfortable with themselves and with the things they're dealing with. So, that education is an important contributor to that confidence in themselves and their future. It also can be done, or it can be provided by counselors, or by special evaluations and education programs such as cognitive behavioral therapy. Abbreviated here on the slide SCBT. Cognitive behavioral therapy is a little bit like it sounds, but it's not as easy as one could imagine it might be. And that is, it is a design to help a person who has a clinical disorder understand that disorder, and find ways of coping and dealing with that disorder so it is not such a big distraction or detractor from their lifestyle. The next category is physical modalities and in that we include pacing, exercise and treatments like hot water, physical therapy. So, this can be done at home and there are things that can benefit from the skill and expertise of a physical therapist or an occupational therapist. Not to be ignored, I think, is the concept of pacing. Pacing means that the person who is very limited by their symptoms. Could decide to start everyday with a period of time, lets say a half-hour of working on something. Lets say that this is a homekeeper and that the person is suffering from pain whenever standing for only, for long period of time. And, but is necessary for this person to take care of the dishes after a family has breakfast. And it's dif, necessary to the do the laundry and other chores that are important to the home existence. And so we would suggest that they set a clock, maybe on the, oven, or on an alarm clock in the area where they work, and set that for maybe a half hour, and work during that half hour. And then when it rings, sit down, rest, breathe comfortably. Or read, or do something that completely relaxes the individual for a half hour until the alarm sounds and then go back to the activity again. And doing activity during the day in a pace manner, alternating manner such as that can allow a person to still have energy and ability to function at the end of the day. And then, there is the section referred to as T, or Treatments. Treatments would be recognized as the purview of a therapist of some sort or a physician. And in this case we have listed medications and, or medical treatment and surgical treatment. I think there is very little call for surgery in specific for fibromyalgia, but there are occasions in which a fibromyalgia patient may dele, develop the signs and symptoms of a disorder which should be treated surgically. And, in that case, it seems that people with fibromyalgia heal normally after surgery, and function fairly well, although they experience more pain in association with the surgical procedure, or with the healing afterwards. Medications we're going to focus on quite a bit, and when one uses a therapy or a therapeutic model than it's important we feel to evaluate how effective that model is. So, we would then say, living is describing that evaluation that occurs at periodic intervals, this is kind of interesting because most of the things that we want to know about the fibromyalgia patient in terms of their symptoms and signs can be assessed with a questionnaire. And quest, validated questionnaire instruments have been developed for this purpose. It is very common now for a physician to place the information from a clinical visit into a electronic medical record. And those electronic medical records, almost all have a section that is set aside for vital signs. The vital signs one might be thinking about would be blood pressure, and temperature, and height, and weight, and so forth. But another way of thinking of vital signs is for example, pain and pain measurement has become almost like a vital sign in the hospital evaluated almost everyday on patients who might be experiencing discomfort. And it turns out that vital signs in electronic medical records usually have several spaces in which some new variable could be inserted. And those variables in, in the vital signs are important, because they can be graphed at some time during the life of a patient follow-up, over a series of encounters. And that would allow one to put in the results of some questionnaires that evaluate the status of a patient with fibromyalgia, at any point in time that they have a clinical visit. And then, over a period or a series of clinical visits, it would be possible to document change occurring overtime, presumably as a result of the interventions that the healthcare provider is providing to the patient. That, I think, is going to be increasingly important with time because we are told that in the future, physicians will be compensated for the care of patients on the bases of outcomes. So, did the patient improve? Did the patient improve very much? What proportion of improvement occurred in a patient? And over the period in lets say a year many patents if you look at one practice from one practice to another. And that kind of improvement would be responsible for determining compensation to the practice for that medical care. If one has a ready graphic showing the improvement of patients with fibromyalgia over a period of time that can be very handy in documenting the improvement as a result of the level of care. There have been a number of medical, medicine strategies that have been tried over the years to treat people with fibromyalgia syndrome. For example, there was a time when attempt was made to treat inflammation. The amount of inflammation in fibromyalgia is relatively mild compared to disorders such as rheumatoid arthritis or systemic lupus, but there is some evidence of inflammation in the fibromyalgia patient. So non-steroidal anti-inflammatory drugs and Prednisone were tried, but they failed. In contrast to the benefits that have been obtained by patients with rheumatoid arthritis or systemic lupus using those medications on a case, on a, on a repeated basis. Another approach that was tried, was augmenting descending inhibition. Last time in what causes fiber, fibromyalgia syndrome, we talked about one of the potential causes, that is interference with function of the descending inhibition system by, because the chemicals of the, the biogenic amines of descending inhibition are lower than normal in people with fibromyalgia in their spinal fluid. So, as a result, there were attempts to raise the levels of the biogenic amines, serotonin, norepinephrine, and dopamine in research studies, and those have generally met with some success. In improving the symptoms of pain at least for people with fibromyalgia. Another kind of experiment was attempted because substance P is a amplifier of pain and depression and a number of other symptoms in people with fibromyalgia. So it was thought if we just block its reaction with the NK1 receptor, its receptor, then, perhaps we would prevent the effects of substance P. But that was not successful, that failed. And it's not really very clear why that failed, but there may be other receptors that can accept the signal from substance P. And then there was success with inhibition of nerve signal conduction, nerve signal conduction in this case was inhibited. What was, had gone awry, and was sending constant message of pain, and the cer, certain selective action, anticonvulsants have been found to be successful in treating fibromyalgia. And so, those would be of the alpha two delta receptor ligand class and examples of those would be like pregabalin or gabapentin. And it has been found successful to correct insomnia, but not just any approach to correcting insomnia is successful, and we'll talk more about how to go about that. In the next slide we see medications that have been used for fibromyalgia, and we can see those medications which are directed at increasing serotonin and norepinephrine in the spinal fluid of people with fibromyalgia where it is, where the levels of those two biogenic amines are low. And duloxetine and milnacipran have been found to be effective and are approved by the Food and Drug Administration for that purpose, their trade names are Cymbalta and Savella. One of the anticonvulsant medications that has been used with success in fibromyalgia and was approved for treatment of fibromyalgia pain is pregabalin, or lyrica. There have been medications that have met with success in treating fibromyalgia but have never been taking to the FDA, and have not received FDA approval for their use in fibromyalgia. And they include a, an over the counter preparation called 5-hydroxytryptophan. Somewhat similar to the, structure of, of serotonin and useful in controlling the pain, and perhaps influencing the sleep of people with fibromyalgia syndrome. Then the tricyclics amitriptyline and cyclobenzaprine have been used. We think of them as the older medications and less specific for the, the biologic abnormalities of people with fibromyalgia because they don't aren't as selective for a single receptor, or a dual receptor. But they have been used with some success especially back when we didn't have the newer medications that have subsequently been improved, approved by the FDA. Tramadol was useful in controlling pain of fibromyalgia but does not have activity of anti depressant nature as duloxetine, and milnacipran did or do. So it was never, it was effective in treating fibromyalgia, it was more effective when combined with acetaminophen, but has never been taken to the FDA for evaluation of its ability to be approved for fibromyalgia. And then we have a final category, not effective, and the risks poorly justify use of these medications, and they include opioids which many patients think are helpful to them, but they don't really reduce the symptoms of fibromyalgia. Non-steroidal anti-inflammatory drugs which seem to help some people a little bit, but do carry a substantial risk of gastric irritation, gastric erosions, gastric ulcers. Acetaminophen which, in large quantities, can be hazardous to liver function, and guaifenesin, which has very little to argue in its favor. The early medication category, these medications were found by chance to offer some benefits in the treatment of fibromyalgia, but were not FDA approved for fibromyalgia and really exhibit quite a few side effects. The other problem with these medications that include primarily the tricyclides was that they undergo tachyphylaxis, that means that after two months or perhaps, three, they are no longer any more effective than a placebo. And yet they carry the same potential for causing side effects such as making the heart beat faster and causing severe dryness of the mouth. So, also in this category were opioids which seemed to offer risks rather than benefits in fibromyalgia patients. Fibromyalgia patients' symptoms recede with opioids only to the extent, we believe, that the patient is not so conscious of their symptoms but really not helped. Here we see a slide which shows one of the older medications, that is an over the label, over the counter is available over the counter in many countries, including the United States. And this medication was studied by a group in Italy, and we see a gradual slope down, suggesting improvement with the placebo. But an even more rapid decline in the symptoms of discomfort visual analog scale for pain, and, they were highly, significantly different at the end of the first month of therapy. That medication seems to begin to help very gradually, and so I have been aware of patients who started taking this medication and took it on a regular basis and didn't even realize that they had improved. The tricyclics are among the drugs that we have just discussed and. You can see that in this slide we show a number of studies, trials that were greater than eight weeks. And we see the top study that, if you look at the far right-hand corner did not show significant improvement in the people, in fibromyalgia symptoms, compared to placebo, and that was Amitriptyline compared to placebo. The next study comparing Amitriptyline or Cyclobenzaprine versus placebo, did not show a significant benefit either. However the third study did show significant benefit when evaluating pain and the tender point score. The fourth study, by Honan, Hannonen did show benefit after a 12-week duration of treatment. And the measures were visual analog scales for pain and sleep and fatigue, and disability, so that seemed to be beneficial. However the next study by didn't show benefit, and the last two did seem to show some benefit. So, this is kind of a mixed pattern, and our belief is that back when we didn't have anything else to treat fibromyalgia there was a chance that patients might benefit. And we knew that they would get taciful access. The drug would lose its benefit after a period of a few months and we would stop the drug for a month or two, and then restart it, and it would work again, for a period of time. So, this is not optimal therapy, and we tend to set it aside for the present time. The next group of studies have to do with analgesic drugs. These are drugs which do not have much psychogenic potential, do not alter mood to much of an extent, and the first drug, Tramadol, particularly when compared with when combined with acetaminophen, was beneficial in research studies for up to three months duration. Whereas two studies that we show using an opioid were not. Neither were, was successful and helped significant, providing significant improvement in pain in fibromyalgia. That has been a puzzle to some physicians because opioids are helpful in some other types of certainly acute pain and maybe other types of chronic pain, but they are not successful or useful in the treatment of fibromyalgia and should not be given to such patients. When we look at the results of a tramadol study, in this study what happened was that the patients were treated with tramadol until they felt that they had improved as much as they were going to, and then the medication was switched to blinded either tramadol or placebo, and the investigators observed the rate at which the symptoms came back. When the individuals were given placebo, the symptoms came back fairly quickly, and continued at a fairly level rate, whereas when they were given, allowed to continue blinded tramitol, the symptoms did not return at the same rate. And so the Tramadol was shown and believed to be effective in helping these patients. And then we come to a new group of medications, not necessarily a class, but a group of medications, and they are medications that were developed in response to biologic abnormalities, or maybe one would use the term chemical pathogenesis in people with fibromyalgia. And so the medications were created or found that had the potential to, to help with these biologic abnormalities, and they focused fairly directly on the abnormalities. So they were focusing on specific treatment of an abnormality. They, they were in general non-opioid and non-addicting. They exhibited persistent benefit in therapeutic dosage. That is most of them have been studied now for an extended period of time, six months to a year, and they continued to maintain the benefit that was seen at the point of around three months of therapy. On the other hand, we can't say that they're curative. The symptoms return when the medication is stopped. And in some patients there are side effects associated with these newer medications, that are so troublesome that they're intolerable. The first of those medications to be developed and applied to fibromyalgia, was Pregabalin. Pregabalin is the generic name of this drug, and Lyrica is the trade name of this medication. Dr. Leslie Crawford led the group of investigators who studied this drug in a randomized placebo controlled trial, which was double-blinded and the results of the experiment were successful. It was late, it, it was discovered that this drug binds to a form of calcium calcium channel. And this voltage gated calcium channel, then was prevented from leaking calcium into the cell terminal at the synapse, which has been allowing constant activation of the cell, and leaking of neuro-molecules such as glutamate, the neurotransmitter, and substance P. So that constant flushing or constant bombardment of the wide dynamic range neuron was causing the individual to have constant and chronic pain. And the theory is that with the pregabalin bound to the alpha 2-delta receptor on this calcium channel, there is a decrease in the amount of calcium, or the rate at which calcium influx into the cell terminal occurs. And as a result there is a decrease in the amount of neurotransmitter and substance P being released into the synapse and as a result, decreased pain experienced by the individual. So, if we look at one of the research studies that evaluated the benefit of this medication. You can see first in the gray line the Placebo. There is improvement among patients who are taking Placebo. We see this in almost an, in all of the clinical trials that are placebo-controlled. And you can see why it is important and necessary that a Placebo be in, are be included in the study, because if, if we thought this was active medication you can see we do see improvement a decrease in. The severity of pain over a period of weeks. And so, we would think that the medication was effective, but here we're using placebo, you can see a decrease associated with Placebo. But even greater decrease in association with the drug at a dosage of 300 milligrams, 450 milligrams and 600 milligrams. When the FDA saw this data, they said, the 450 milligram and the 600 milligram doses are not significantly different. But, the 600 milligrams dosage does have associated with it, an increase in the potential for adverse effects. So, we think it would be wise to approve the 300, and 450 milligram dosage for different individuals, for the treatment of Fibromyalgia pain. But, not approve the 600 milligram dosage. Another study was done approximately the same time, with a different outcome measure. In this case, instead of measuring pain, the investigators are measuring improvement in sleep quality. You can see that there is the same Placebo effect. Seen in the red line up at the top, a decrease in the severity of the pain of the sleep dysfunction. But, an even greater change occurring with the 300 milligram, 450 milligram, and 600 milligram dosage. It may be that the sleep benefits of this medication are in fact better and usefully increased in some patients with the 600 milligram dosage. But, this is not included, the, the drug is not approved as a treatment for sleep. Or improvement in sleep quality and so, this information is currently waiting a useful expression. So, then if we think about this drug Pregablin as a medication that is capable of helping restorative sleep. We could ask the question, is this drug a direct sedative? That is, is it just making people sleepy, by a sedative effect? Or, is it helping some of the, relieve some of the pain as an analgesic? So that, then the person no longer hurts, and is able to drop into restorative sleep. And the answer was taken from two studies, two research studies evaluating the effect of the drug on pain and sleep. And the component of pain here was approximately 20%, so there was a little bit of benefit in having the analgesic activity there, but the majority of the sleep benefit was from a direct sedative effect of the drug. Another study showed that the analgesic effect was actually greater than or approximately equal to the sedative effect. And so there may be some variation among individuals, among study groups. But it appears that there is both an indirect Analgesic affect of the drug, and a direct sedative effect responsible for the restorative sleep. We would call this Mediational Analysis or a analysis that is looking at the direction of an effect, and whether it is deviated through an indirect effect or only through the direct effect. Now anytime we talk about a medication, we should talk about adverse effects associated with the medication. And in this table, we show the adverse events that are considered and that were above a certain level, so they were included in the table. But, then we can see the number of people who developed that out of 500 and then see the percentage, and which individuals developed that side effect with increasing dosage of the medication. And you can see that, one of the side effects that we need to think about is Somnolence, day time somnolence. Because this medication is, has sedative effects, and as the medication is given, there is an increase in the number of people who are developing this daytime somnolence with an increase in dosage. So we, you would say that there is a dosage effect in this case. The interesting thing about that is that if this medication, instead of giving twice daily, morning and evening. As indicated on the package insert, approved by the Food and Drug Administration, if one gives this medication only at night, then somnolence is a benefit. Patients go to sleep more readily, and stay asleep more readily. And so this sedative effect is a good thing, if the medication is given at night. Then instead of starting with the very low dosages like 75 milligrams, it's possible to start the dosage at bedtime with 150 milligrams, and most patients appreciate the better improvement in sleep that they experience. We could look at dizziness as another side effect, that occur in as many as 43% of people taking the 450 milligram dose. It's certainly appears as we move from Placebo up through 150, 300 and 450 milligrams to even 600 milligram dosage. There is an increase in the frequency of that adverse event. So we would say, there is a dosage effect of that, and it's more frequent in higher, in inpatient's receiving higher dosage. If that's the case, it may be related to the blood level in the patient. And if we give the medication at bedtime, the patient may be getting dizzy a little bit during the night, but they're asleep because of the somnolent or sedative effect. And so there are not aware of it, and by the time they get up eight to nine hours later. The level of the drug from that single dose has decreased enough, so that it is not longer high enough to cause symptomatic dizziness. And so most of our patients, given bed time dosage of Verica do not experience the problem of dizziness. Occasionally they do and when that occurs we encourage patients to be careful, don't drive and, try to make sure that they have support so that they don't fall and harm themselves and that this side effect will go away in a period of a week or two and that has essentially always happened in our experience. Weight gain can happen in about 10% of patients, but I talked to patients and about this, before I give the medication, I know you're going to be worried about weight gain, and it says that it could happen in about 10% of patients, but realize that this mediation has very few or any calories. So if you gain weight, it's because maybe the medicine caused you to feel hungry, and you ate too much at your meals or you ate between meals. So we advise them to be very careful about the portions of their meals keep the portion size the same, don't eat between meals and we don't have much problem with weight gain, and in the rare case in which the patient does gain some weight at least the doctor is not cause has not caused it. The medicine has not so much caused it and the patient realizes that they were not as careful as they should have been with the amount of food that they ate. So those are most of the side effects, the more frequent side effects that we have to think about and worry about occasionally peripheral edema, swelling of the legs, occurs it's, uncertain whether it's responsive to a little bit of thiazide diuretic. But it has been really not a big problem in our experience and so we mention it to patients and patients read about it but we don't we don't often have to be concerned. The next drug to come on the research arena was Duloxetine which we will recognize manny of you will recognize as Cymbalta. That medication is a medication that increases the levels or the effective, the availability of serotonin and norepinephrine by blocking reuptake. So, typically as we talked about in a previous session regarding descending inhibition,. The descending neuron axons come to the to a synapse and they influence the cell that they're trying to inhibit by releasing norepinephrine and serotonin into the synapse. But one of the ways that the neuron reacts to that biogenic amine that it secreted was to recover some of it. Take it back up into the secreting axon and that is referred to as uptake or reuptake. So one of the ways that it has been possible to influence the availability of those biogenic means at the sites of inhibitory synapses is to block the reuptake receptors with amitriptyline with a tricyclic drug, with a selective serotonin reuptake inhibitor, an SSRI, or in the case of duloxetine with a serotonin norepinephrine reuptake inhibitor. So it inhibits both serotonin and norepinephrine in essentially the same way. The same mechanism is seen with milnacipran and they, its trade name is Isabella. So we'll see now the effect of those medications, Duloxetine Cymbalta had previously been approved as an antidepressant medication so here we see results from a research study. Treating major depression in people with depression, not people with fibromyalgia, just depression. And you can see that there is a placebo effect but the medicine has an effect on depression and decreased the severity of depression or measurement of depression on the Ham D scale by a significant amount, beginning with maybe even the second week of therapy. A significant difference from the placebo induced value and that was with duloxetine at 60 milligrams every day. So, now if we look at a study utilizing fibromyalgia patients, we see decrease in the perception of pain on the y-axis going from top to bottom. And you can see that there is a placebo effect the red line here is placebo. The green line is showing us the effect of 60 milligrams of duloxetine, and the 10 line is showing the effect of 120 milligrams of duloxetine. The decrease in the placebo is not as great as with the active treatment in both of the dosage strengths. And you can see that the green line persistently goes on out toward the end of the study at approximately 28 weeks. When the FDA reviewed this data, they said that the difference between the 60-milligram dosage, and the 120-milligram dosage in terms of benefit was vanishingly small but that there were increased risk of adverse events. And so 60 milligrams was approved for the treatment of fibromyalgia with this medication. Again, here we see, an analysis looking at mechanism of the drug. And here we're asking the question, if we give a person duloxatine, and pain relief is experience, what do the research studies say has been the path of that improvement. We saw somewhat similar type of question being answered with Pregabalin on sleep improvement. So you can see for the fibromyalgia patients. A direct effect would be a direct pain or analgesic effect, whereas an indirect effect would be an antidepressant effect. Since it is widely perceived that depressed patients experience discomfort and that any discomfort they already have is increased because they are depressed. You can see that one might wonder if pain relief might occur, not just because it's a direct analgesic, but because it has the ability to undercut depression and anxiety, and that was responsible for only 17% of the pain relief effect, whereas fibromyalgia direct effect, direct analgesic effect in the same study was 83%. And with the with another research study shown here in yellow highlight you can see that there, this again is a greater effect of anal-, direct analgesic for pain relief, but there is a a little more. Approximately twice as much antidepressant effect influence on pain relief. So, looking at the adverse effects profile for duloxetine, we can see that the number one, top of the list adverse event is nausea. Below that dry mouth and constipation and so forth. But let's just look at the nausea because it occurs in up to 31% of people with 120 milligram dosage, but the 60 milligram dosage that is the most common dosage for treatment of fibromyalgia is also over 20% likely to cause nausea. That's a high enough frequency that it is con, of concern when a physician gives a patient this medication. There are two things the physician can do when prescribing Duloxetine to reduce the likelihood that this adverse effect will occur. One of those is to give 30 milligrams of Duloxetine for three to four days before increasing the dosage up to 60 milligrams. That allows the person to become a little bit acclimated to the medicine in their central nervous system, and decreases the likelihood that they will experience nausea with this subsequent increase to 60 milligrams. Another thing that can be done is for the patient to take the medicine with breakfast. When duloxetine is taken along with a food bolus, the peak level of the peak blood level associated with that dosage is less than it would be if the person took it just with water. And as a result, we believe that the nausea is related to this peaking of the blood level, occurring shortly after taking the dose. So when one takes food, with, takes the dosage with food, there is not the sharp peak at the, very shortly after taking the medication, but the curve spreads out over time, and the area under the curve remains the same. So it is generally recommended that patients start taking this medication with food in the morning, and then as they adapt to the medication, they may be able to take it in the morning without having to eat food. Other side effects associated with this medication can include dizziness in about 10%, and a small number of patients will lose appetite or have sweaty palms. I've seen both of those experienced by patients and weight loss can be persistent, although this medication is not promoted as a weight loss medication. The sweaty palm problem can be solved just by holding a napkin or a Kleenex in ones' hand and then when reaching to shake someone's hand the Kleenex or, or paper towel can be squeezed, and the hand then does not seem to be cold and clammy and wet. The drug milnacipran, has a very similar profile to that of Du, Duloxetine, even though they are different structures, they both work on the same basis. We think that Milnacipran has a slightly higher norepinephrine to serotonin ratio. And you can see in this graph, that Milnacipran at now sold as has a placebo effect. A decrease associated with the placebo group, and an even steeper and clearly different level of effect associated with the active medication. The adverse events profile is somewhat similar at 100, or 200 milligrams. Here we show 200 milligrams a day, and in 100 milligrams, twice daily and in this dosage, about 26% of patients experienced nausea. And so the same kinds of suggestions have been promoted for improving the tolerability of this medication. Next I'd like to show a treatment model, based on the newer medications. Drug selection would be based mostly on the most troublesome symptoms. It's important to achieve a therapeutic dosage as soon as possible, so that the patient can begin to make a valid choice between the benefit associated with taking the medication and any troublesome side effects they're experiencing. And we believe that combination therapy from two medications that work in completely different portions of the pathogenesis of fibromyalgia may be a logical approach. So my wife and I went on a vacation trip to the Arenal volcano in Costa Rica. And while we were there, it struck me that this mountain, with its peak of fire coming out the top, looked very much like a triangle. And thinking much about fibromyalgia at the time. I thought maybe we could represent the fire breathing dragon here of this triangle as the pain of fibromyalgia since it was one of the most troublesome symptoms. And we could represent depression. At one of the lower base of the triangle. And at the other base we could represent insomnia, or sleep dysfunction. Now, I've made the word depression smaller in size on purpose. The reason for this is that pain exists in people with fibromyalgia at a rate of about 100%. Because it is necessary to both of the two criteria, diagnostic criteria that I used the 1990, and the 2010 American College of Rheumatology criteria. Depression occurs in about 35% of patients with fibromyalgia, and sleep dysfunction between 70%, 80%, and 95% of patients. So both pain and insomnia are highly common among this population, and depression is only about a third of those patients. In using this diagram to predict treatment, I have proposed that the physician is seeing the patient from the top. And so the physician sees pain first and knows that it is going to be necessary to treat pain. But then, looking out to the right hand side of this patient represented by a triangle one would see depression and might say depression can be very miserable and we would certainly want to treat that as well. Or could look down and see insomnia and say we must treat that because that is very serious problem and is really troubling this patient. So lets assume that we see depression here, and we say we want to treat depression but we want to treat the pain also. We could use Tremadol, which is has effectiveness in fibromyalgia for treatment of pain, but is not an antidepressant and doesn't have that activity, so an SSRI could be used for treatment of the depression. Then a sedative of some sort wouldn't be needed for the insomnia. Better, I think, to use, perhaps, duloxetine, Cymbalta, or milnacipran, but duloxetine has an indication for depression in the United States, which milnacipran doesn't. Duloxetine can treat the pain and the depression. Both ends of this side bar, and so it seems like reasonable approach to begin treatment of a depressed patient with [INAUDIBLE] depressed fibromyalgia patient with duloxetine. Then once that depression is managed or if the patient is already on an SSRI for treatment of depression we may not wish to disturb that and we might say let's treat the sleep with a medication that is known to help sleep in fibromyalgia, and also help pain. And so, Pregabalin in approved for the indication of treating pain of fibromyalgia, and we might use that to treat insomnia here. Or in a patient who we have started on duloxatine because of depression and maintenance of control of pain, we might then, once the patient is stabilized on their duloxetine therapy in the morning, we might add pregabalin at bedtime. And my typical approach is to start duloxetine as 30 milligrams for three to four days, then increase it to 60 milligrams wait a week, or two weeks, or three weeks and then start Pregabalin for the pain and in, remaining pain and insomnia. And the dosage that I usually start with is 150 milligrams but realize. That I'm giving this dosage at bedtime, rather than the morning. Patients are very tired from having slept very poorly for a long period of time. And so if we give a dose in the morning, they are likely to experience sedation from that medication. That might frighten them and make them not want to take the medication. So giving it to them at night has many benefits. It provides them sedation for sleep during the night. It avoids the problem pretty much avoids the problem of having a side-effect of dizziness. And in addition to those things, patients will be sleeping more deeply, getting more restorative sleep, and awakening feeling more, rested and refreshed, and not so fatigued during the day. So, in summary, fibromyalgia management is focussed on the chemical causes. The drugs were developed to or were proposed as medications that could work on specific components of the fibromyalgia abnormalities. Such as afferent signaling of pain it, using pregabalin, and descend, failure of descending inhibition using the duloxatine. Therapeutic agents now exist for most of the manifestations of fibromyalgia. Evidence for benefit is good for the newer medications. And combinations of certain medications in, under certain circumstances may increase the benefit but also we must be aware that they may increase also the risk. And so, we see our happy dog here happy because we're making progress with the treatment of fibromyalgia. Thank you for your attention. So the second one is going to be shorter.
