**Transcript of Cyberseminar**

**Mild TBI Diagnosis and Management Strategies**

**Management of mTBI Persistent Postconcussive Symptoms: Focus on Sleep Disturbance and Headache**

**Presenter: Murray A. Raskind, MD**

**December 5, 2013**

*This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact Murray.Raskind@va.gov.*

*Moderator:*We are at the top of the hour now, so I’d like to introduce Dr. Ralph DePalma, who will introduce our speaker today.

*Dr. DePalma:*It’s a great pleasure to introduce Murray Raskind, who is the director of Mental Illness Research and Clinical Center in VA Puget Sound Healthcare System.  He is going to speak on the management of mild traumatic brain injury, persistent postconcussive symptoms, one of the most common things afflicting our Veterans, with a focus on sleep disturbance and headache.  He and his group have done ground-breaking work in this area, and we’re pleased to have them onboard.  

*Dr. Raskind:*Thank you for the kind introduction, Ralph.  I want to say, to start, that this is a very challenging topic.  Those of you who have been following the story of blast concussion mild traumatic brain injury in Veterans and active duty service members returning from combat deployments in Afghanistan and Iraq and other areas which we sometimes hear about, sometimes don’t, know that this is an evolving story.  Perhaps four years ago the belief in the field was that it’s really all posttraumatic stress disorder.

One recovers from a blast or blunt head trauma concussion usually within three to six months, so just be patient and don’t worry about it.  Unfortunately, although that optimistic belief would have been nice, many of our Veterans and active duty service members, years after returning from their deployments and years after experiencing usually multiple mild traumatic brain injuries, are still struggling with some symptoms which are very difficult to attribute to posttraumatic stress disorder.

I think the most compelling of those is headache.  Even in the studies which looked at the possibility of parsing PTSD and mild traumatic brain injury epidemiologically, which were published in prominent journals, including the *New England Journal of Medicine*, the one symptom that, regardless of what statistical approach was tried, the one symptom that could not be attributed to comorbid posttraumatic stress disorder was, in fact, headache.  We’ll focus on headaches some today, and also talk about another very distressing symptom, which is still difficult to decide whether it’s due to whatever the neurobiology of posttraumatic stress disorder is, or to the sequelae of multiple mild traumatic brain injuries, and that’s sleep disturbance.  It’s becoming increasing likely that the two, in fact, are connected in many of our Veterans and service members.

Now, what am I *[laughter]*, a psychiatrist, doing in a rehabilitation medicine area?  I’ll take a minute to approach that.  Ira Katz, the former chief consultant for mental health for the VA called the MIRECCs about six years ago and asked them to get involved in the persistent symptoms in Veterans with mild traumatic brain injuries from blast concussions and blunt head trauma, as well.  Our thought there was, well isn’t that a rehab thing?  Then we started doing a trial of prazosin, a placebo trial, a randomized controlled study of prazosin for posttraumatic stress disorder with sleep disturbance and nightmares among active duty soldier at Joint Base Lewis-McChord here in the Puget Sound area.  The soldiers really directed our thoughts appropriately.  Although they were recruited because they were having a nightmare sleep disruption and met criteria for posttraumatic stress disorder, the majority of them had also experienced multiple mTBIs.

During our clinical interview, many of them were writing down thing in a little spiral notebook that they kept in a pocket on their—in a sleeve of their—of the shirt, of the uniform.  When asked about it, they said, “You know, since I’ve been deployed, I just don’t feel that my memory’s quite as good as it used to be.”  That’s been difficult to demonstrate with standard neuropsychologic tests in some studies, but it’s a common complaint.  At that point we said, “Gee, this is real.”  My colleague, Elaine Peskind, who’s also a psychiatrist and the co-director of our Mental Illness Research Education and Clinical Center here at VISN 20, really took this on as an area of interest.  We’ve hopefully learned something by paying attention to this large problem.

Okay, I’m going to go through a couple things that I’m sure everybody is familiar with.  Of the 2.5 million service members deployed to Iraq and Afghanistan, the most frequent weapon that they encounter from the insurgence is the improvised explosive device, which of course, in Vietnam, was called a mine or a booby trap.  These new and improved improvised explosive devices are much more powerful in terms of the blast generated by the large amount of high explosives that are contained in these improvised quote unquote devices.  The incidence of being knocked silly or unconscious by one of these blasts is quite high.  

Now, Junior Seau was not deployed to OIF, OEF, or OND, but I just want people to keep in mind that multiple mild traumatic brain injuries or concussions are not only a product of warfare, but also a product of the intense contact sport environment in which we live.  The problems that our soldiers and Marines, sailors, air personnel have been experiencing also are a big problem in the civilian world among persons engaged in competitive combat sports, as well as persons who’ve experienced motor vehicle accidents and other sources of head trauma.

All right, so a couple of poll slides, just to give me some sense of who’s on the line.  Okay, so excellent.  We have a bunch of folks who are, in fact, immersed in this problem.  What I’ve learned by immersing myself in the treatment of these persistent postconcussive symptoms is to be humble.  The database to direct our care is modest, at best.  We have to take what we have and continue to be innovative in providing care for these service members and Veterans.  

Oh, another poll slide.  I apologize if I left off someone’s discipline here.  For example, if you’re a research scientist, but have a master’s degree, that’s cool, too, or whatever.  Okay, so we have a nice mix of clinicians on the line, and as well as some research scientists.  I want to encourage everybody to use the question box because in this area there are more questions than answers.  I think some discussion among ourselves on this call would be informative for—certainly *[laughter]* for myself and hopefully for the rest of the persons attending.  I think that’s it for poll slides, so you can now go back and relax.  

What’s the epidemiology of chronic postconcussive headache in OEF/OIF/OND Veterans?  It’s Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn.  One out of five, or 19 percent, of these Veterans have sustained deployment-related mild traumatic brain injuries.  The majority of these are the result of blast concussions.  Headache is very frequent for approximately 40 percent.  Again, the studies vary, but 40 percent is a reasonable estimate.  That’s a big number.

Let’s talk a little bit about what we mean by chronic postconcussive headache.  The international classification of headache disorders defines posttraumatic headache as a secondary headache precipitated by head trauma.  Pretty broad etiologic description.  Practically, these have to be new onset headaches within months of trauma.  Notice it doesn’t say how many months and I think that if someone fits the picture, regardless of the duration of time between their mild traumatic brain injury and their onset of headaches, I would consider them as qualifying for this diagnosis.  These are usually chronic situations.  We’re calling them persistent if they last for three months or longer.  

There’s some things which enhance the likelihood that posttraumatic headaches will become chronic.  One of them is sleep deprivation.  As we know, sleep disruption and trouble achieving sleep both are problems that many Veterans and service members have.  When they’re in the active duty combat zone, sleep deprivation is often part of the game.  It’s you’re getting a good seven to eight hours of sleep is not going to get the mission done.  Folks are snatching sleep when they can.  Posttraumatic stress disorder comorbid with mTBI increases the likelihood that posttraumatic headaches will become chronic, as does depression.  This is probably describing a lot of the patients we’re taking care of.  

How frequent is this?  If one looks epidemiologically at soldiers, and this is an active duty population, so Theeler and colleagues looked at 978 soldiers who experienced what they described as concussion, but met criteria for mild traumatic brain injury downrange, and 20 percent met criteria for chronic daily headaches.  That’s defined as 15 days or more per month.  For some it’s every day, for some it’s every other day.  That’s a lot of headaches.  This is four to five times higher than in the general population.  The features of these headaches more resembled migraine than they did tension headaches or any other type of headache.    We should have had a slide, a poll slide, asking people how many of them have experienced migraine.  Maybe the next time we do this, just to get some sense of how many folks know how truly disabling migraine can be.

The problems that, in addition to the pain and result in distress and disability of chronic postconcussive headache is that they often get one into the problem of excessive use of analgesics.  That, in turn, can cause a rebound or medication overuse headaches, particularly within those with frequent headaches at baseline.  This is a bit of a catch 22 because you have to treat with something.  If someone has a very severe migraine, they can’t stand light or sound.  They have to lie in a dark room because they’re nauseated in addition to having severe pain.  They do demand acute treatment with triptans and other approaches.  Be on the alert for those folks who have been given opiates, because it’s not uncommon, who are using them quite a bit and whose headaches are actually exacerbated by the overuse of medications.    

Just to, again, review characteristics, the military mild traumatic brain injury blast concussion headaches tend to be—there’s overlap—they tend to be a little different from the civilian trauma, usually blunt trauma, headaches.  In the civilian population, tension-type headaches are more common, though migraine or mixed types do occur.  In the military combat population, headaches with migraine features definitely predominate.  These migraines result in significantly more functional impairments and more sick call days than other types of headaches.  Seventy percent of migraine attacks in active duty soldiers sampled interfered with duty performed on a mean of two and a half days per month, and I suspect on even more days per month they weren’t working at peak efficiency.  

Our colleague, Lieutenant Colonel Jay Erickson, who is the deputy chief of neurology at Madigan Army Medical Center at Joint Base Lewis-McChord, 40 miles away from the office from which I’m speaking, has had a strong interest in the diagnosis and management of chronic posttraumatic headaches in the soldiers he’s seeing who’ve been deployed to Iraq and Afghanistan, but exposed to head trauma, both blunt and, even more often, blast concussion.  He did a comparison between the characteristics in terms of treatment response to those whose headaches were secondary to blast concussion, as compared to those who had concussions that were caused by blunt impact.  The blast concussion group was larger, 77 versus 23 in this sample of 100 soldiers.  They also had a higher frequency of mTBIs than the solely non-blast impact folks.  Keep that in mind as we looked at the results of this study.  

The blast concussion migraine acutely was usually responsive to abortive therapy with a triptan.  Seventy-seven percent of those with the blast concussion migraines reported headache relief within two hours of being treated with the triptan.  The triptans were also quite effective in those soldiers whose posttraumatic headaches were secondary to blunt impact trauma.  However, when one looks at migraine prophylaxis with amitriptyline or propranolol or Tegretol or what have you, those with blast concussive migraine were poorly responsive to the standard migraine prophylactic approaches, whereas, those with the blunt trauma were quite responsive.  They had a much better response than did the blast concussion migraines.  These blast concussion migraines, whether there’s something different about them pathophysiologically, or whether it’s a function of a much higher number of blast concussions, either way, they represent a real treatment challenge in terms of prophylaxis, regardless of which standard prophylactic for migraine mortality one uses.

To put this into numerical format, if you will, on the left hand side of the slide in the migraine prophylaxis, in the blast headache folks, there was not a significant difference: 17.3 to 15.8 at follow-up during treatment.  Whereas the impact posttraumatic stress disorder had their headaches frequency cut in half, from 16.5 to 9.8.  Not quite, but almost, which was a highly significant change.  

All right, I’m going to shift gears a bit and talk about sleep disruption because, remember that when we looked at what factors made posttraumatic headaches more likely to be chronic, sleep disturbance was high on the list.  The neurotransmitter in the brain whose job it is to keep us awake and alert, and to attend to novel situations in the environment, is norepinephrine.  Norepinephrine or, in other terminology, noradrenaline, is the compound of the brain adrenaline rush that soldiers and civilians encounter when they’re in a situation which is dangerous, or at least demands a substantial amount of attention to preserve body integrity.

It’s interesting that when one, in any experimental model, increases brain norepinephrine release, in addition to inducing wakefulness, there are also untoward effects of small amounts of norepinephrine released during sleep, when it’s supposed to pretty much shut down.  These are disruption of rapid eye movement or normal dreaming sleep, increase in light sleep, and a shortening of total sleep time.  Norepinephrine is a candidate for a potential therapeutic approach to enhancing sleep quality and quantity by reducing its activity.  There are couple ways to reduce its activity.  One is to decrease its output from the locus coeruleus in the pontine brainstem.

Another, which is commonly used to treat hypertension, which, in many ways, is a function of increased norepinephrine response in the periphery at norepinephrine receptors on arterial is with antagonists of these postsynaptic receptors.  Prazosin is an old drug introduced in 1973 by a small Brooklyn pharmaceutical company called Pfizer as Minipress for the treatment of hypertension.  The mechanism was blockade of alpha-1 norepinephrine receptors on the arterials controlling blood pressure, would relax these arterials and would lower blood pressure, especially when one changes from a supine to a sitting or a standing posture.

This drug has a short duration of action, so when used for hypertension, it was prescribed two or three times a day.  It’s a long generic drug, so I think via contract rates, they’re up to about 10 cents, maybe, or 12 cents a pill.  In 2012, because we had demonstrated that prazosin is helpful in reducing trauma content nightmares and sleep disruption in Veterans with posttraumatic stress disorder, approximately 17 percent of all Veterans in the VA healthcare system, all 700,000 of them with a PTSD diagnosis are receiving prazosin for a PTSD indication.   

That raised the question, not to me, but to my good friend, Dr. Robert Ruff, who’s the director of neurology in  a VA, and the question that came to his mind was, does what he considered the PTSD drug, prazosin, reduce blast posttraumatic headaches in the Veterans back from Iraq and Afghanistan he was seeing, as the attending neurologist, at the Cleveland VA who were being evaluated for mild traumatic brain injury, persistent postconcussive symptoms?  I think the reason he became interested in this is because he was visiting the rehab program here in Seattle, and we had a chance to talk.  I just discussed prazosin and PTSD, and he remembered the conversation.  He said, “Gee, when I talk to these Veterans with mild traumatic brain injury and ask them about PTSD symptoms, there is a large comorbidity, especially in terms of nighttime symptoms, including trauma nightmares and sleep disruption.  Perhaps we should try prazosin in these folks.  Might help their sleep, even if it doesn’t do anything for their headaches.”   

What did he find?    Let me describe the study he did, which was a large, but carefully done open label study in which these Veterans received prazosin and sleep hygiene, telling them to avoid caffeinated beverages before they went to bed and try to stay away from bed unless you’re wanting to go to sleep.  There was no sleep restriction or formal cognitive behavioral therapy for insomnia involved in this regimen.  He used a quite conservative dosing regimen.  Started them on one milligram of prazosin at bedtime, and every week increased it, for seven weeks, until he reached seven milligrams at bedtime, then left them on that achieved dose for another two weeks.  Then nine weeks, he used that as his outcome point and compared their mTBI symptoms from baseline before prazosin treatment to week nine, at after nine weeks of prazosin at the usual seven milligrams.  Some received a little bit less of prazosin at bedtime.

He found quite impressive results.  Headaches per month decreased from 12.4 to 4.8.  Headache intensity decreases 7.2 to 4.1.  Daytime sleepiness by the Epworth scale—daytime sleepiness is a fairly good indicator of improved nighttime sleep—was cut in more than half, from 16 to 7.3.  Remarkably, the percentage of Veterans who reported that they had restful and restorative sleep broadly defined at baseline was 7 percent and increased to 87 or 88 percent of what rounds us off, at the end of the study.  He used the Montreal Cognitive Assessment, which is analogous to the Mini-Mental State Exam, but now the Mini-Mental State Exam is under copyright, and the Department of Veterans Affairs actually has to pay to use it.

The decision was made that the VA’s budgetary woes be solved by switching to the Montreal Cognitive Assessment.  It also has a maximum score of 30 for a perfect performance on the test.  It’s probably a little better test than the Mini-Mental State Exam psychometrically, so this is not such a bad thing.  At baseline, these Veterans were scoring 24, which is, if an older civilian came in and scored 24 you’d say, “Gee, maybe we have to evaluate you for mild cognitive impairment,” but this improved to 28 at week 9.  Dr. Ruff, I think appropriately, although he didn’t describe a mechanism and I’m not sure there yet is one that’s been demonstrated in humans, at least, attributed this improvement in cognition and headaches to the improved sleep of these Veterans who were treated open label with prazosin.

Now, this is not a placebo-controlled study, but I think the more we study persons with neuropsychiatric problems, the more we realize that there is value both in open label studies and in long term placebo-controlled studies, especially in terms of the population sample.  When one does a placebo-controlled study, many subjects who would be treated with the intervention in clinical practice decide that they don’t want to go into a placebo-controlled study because they’re having a lot of distress at the present time.

For them to gamble on 50 percent of placebo is sometimes not attractive to them, or often not attractive to them, and also, frankly, not attractive to their providers.  The placebo-controlled studies, at least for neuropsychiatric disorders with substantial amounts of distress and anxiety often select a population of not very distressed and perhaps not very treatment responsive patients.  Whereas, open label studies, everybody gets a shot at it and it’s much more representative of the overall population seeking treatment.    

I’m going to spend the rest of the time, perhaps another ten minutes, talking about a recent randomized controlled trial of prazosin that we completed for posttraumatic stress disorder with an excusing criterion, nighttime symptoms including frequent combat trauma, nightmares, and sleep disruption.  This was done on active duty soldiers who had been deployed to combat operations and had suffered combat trauma in Iraq and/or Afghanistan and were in garrison at Joint Base Lewis-McChord here in Washington state.  It was a parallel group study.  We randomized 67 active duty soldiers.  They met criteria for PTSD, as well, although they were not recruited for having PTSD because of the stigma involved often in that diagnosis among active duty soldiers, especially if they’re pursuing a career.

The mean rank of these soldiers was E5.  These are mostly junior, non-commissioned officers who wanted to stay in the Army and didn’t want a psychiatric diagnosis impeding their progress.  They sure were having problems with nightmares and sleep.  It was a pretty aggressive study.  It was a six week dose titration, aggressive in terms of dosing, to a maximum 20 milligrams of prazosin at night and 5 milligrams midmorning.  The mean achieved doses were 15 milligrams at bedtime and 4 milligrams midmorning.  It was a 15 week study, so everybody was on their achieved dose for at least nine weeks.  We had the usual suspects for outcome measures, measuring nightmares, sleep quality, total PTSD symptoms, and global impression of change that was anchored to function.  How were you doing?  How were you functioning at home and at work?

Just to give you some idea of a successful way to recruit soldiers, if you’re doing a placebo-controlled trial on an active duty post for a behavioral disorder—and so far, this is the only one in the literature that addressed a behavioral disorder in combat experience service members.  We had a big banner at both gates.  This banner was, see, about ten feet long and four feet high that said, “Got nightmares?”  Well, if you do, call the Combat Nightmare Reduction Initiative.  We gave our number and then we talked to them about possible participation in the study.

For those who had the problem, but didn’t want to participate in a study, the VA providers set up a clinic one day a week to take care of them because we didn’t want to put extra burden on the Madigan Army Medical Center Behavioral Health Clinic.  Hopefully this slide will show up a little better.  Oop, so it didn’t.  Okay, so we’re having a slide problem.  Here’s the reference.  It’s in the *American Journal of Psychiatry*, September of this year, in 2013.  I’ll tell you *[laughter]* what the outcome was.  Use your imagination.

*Moderator:*Just give me one second.  I’ll actually be able to pull it up.

*Dr. Raskind:*Oh, Wendy, thanks.  

*Moderator:*Okay, so you can... *[Laughter]*

*Dr. Raskind:*I mean, Molly.   Yeah, yeah, okay.  Okay, so the nightmare outcome was the nightmare item from the CAPS, the Clinician Administered PTSD Scale.  Eight is the maximum.  If you’re having nightmares, combat trauma nightmares, every night and you can’t get to sleep any night, so these soldiers were close to seven.  They dropped to, in the—to about 3.5, so it had a substantial effect compared to placebo, which had only a minimal effect and it was highly significant.  We had the Pittsburgh Sleep Quality Index that measured quality of sleep, and that had the same advantage for prazosin over placebo.

Probably the biggest differential was in the Clinical Global Impression of Change, which is a seven point scale.  Four is unchanged, one is you’re markedly better, seven is you’re markedly worse, and descriptors in between.  We analyzed the difference between soldiers in each group who had achieved either a score of two or one, moderately or markedly improved in terms of their ability to function at home and at work.  The prazosin condition, 65 percent were moderately or markedly improved, whereas in the placebo group it was only 25 percent.  Those numbers will come up soon.

*Moderator:*All right, I’m having a little difficulty with it.  Give me one more second.

*Dr. Raskind:*Yeah, that’s all right.  It’ll just stimulate everybody on the line to run immediately to the *American Journal of Psychiatry*, September, and digest—oh, there it is.  Okay, so in the lower left hand corner is the Clinical Global Impression of Change.  Oh, I misspoke, 64 percent, not 65 percent were moderately or markedly improved in terms of functioning in home at work in the prazosin condition, 27 in placebo.  In the lower right hand corner, we have the total CAPS scores.  This gives you a sense of overall PTSD.  Now, PTSD is really a conglomerate of multiple problems, but all three subgroups numerically, the CAPS: avoidance, hyper-arousal, and re-experiencing, numerically favored prazosin, and the hyper-arousal one was highly statistically significant.  Okay, so how do I move the slide now, Molly?

*Moderator:*Give me one second.  I’ll give it to you.

*Dr. Raskind:*Okay.  We’re almost done, for those who are hanging in.  

*Moderator:*Thanks for everybody’s patience.  I didn’t realize the animation would not show up.  All right.  It should be coming up shortly.

*Dr. Raskind:*Yeah, we ran through this—we ran through this with the Disney people.  I don’t understand.

*Moderator:**[Laughter]*  Exactly.  I had the Obamacare people working on it.

*Dr. Raskind:*Yeah, right.

*Moderator:*This didn’t come up.  All right.  Let’s go *[cross talk]*.

*Dr. Raskind:*Let me talk about adverse effects because, number one, this is well-tolerated.  We did have—

*Moderator:*Now you can advance.

*Dr. Raskind:*Oh, good.  Okay.  Yay!  All right.  We did have two mild sick soldiers who kind of passed out for 15 or 20 seconds.  One of them it wasn’t clear if he was just getting out of bed and then he said, gee, he lost track of the alarm clock and then he woke up again and he wasn’t—but one of them was a soldier in full kit carrying 80 pounds running up a hill on a hot July day and was dehydrated.  You want to make sure you keep your patients reasonably well-hydrated when they’re taking prazosin.  Dizziness was no different between the groups, drowsiness no different between the groups.  It’s important that when using prazosin for sleep, it doesn’t make you sleepy.  It’s not going to make someone get to sleep.  What it does is prevent the norepinephrine-related intrusions into sleep that wake one up.  It’s distressed awakening and trauma nightmares that are the targets.

Interestingly, only one patient in the prazosin group, but seven in the placebo group, developed headaches.  All these folks had had, in addition to PTSD, mild traumatic brain injury.  This is kind of consistent with Bob Ruff’s data.  The other data are consistent with the effects of prazosin.  Again, stuffy—make your nose a little stuffy, increase your heart rate a little bit, but well-tolerated overall.  There was a signal for possibly having an anti-headache effect that was confirmed by looking at those folks who had chronic posttraumatic headaches in the beginning of the study.  In the placebo group, only one out of every five of those had improvement or resolution of headache, whereas half of those in the prazosin group had improvement or resolution of their chronic post mTBI headaches.

I just want to emphasize, give you a little data to—don’t worry about digesting.  I just want you to look at two things on this slide.  The first is that—let’s see if I can do this fancy thing.  Okay, I failed on that one.  Let me try it again.  All right, so anyway, sleep latency, the third set of bars from the Y—from the intersection of the axes.  Oh, thank you.  It actually took a few minutes longer to fall asleep on prazosin than it does on placebo.  This is not statistically significant, it’s probably just random.  Prazosin is not a sedating drug, which actually can be helpful many times, but for those persons prescribe the drug for sleep and expect to knock them out like Ambien, this isn’t it.

Interestingly, if one goes back to the next set of bars on the left, prazosin actually increases rapid eye movement sleep time and increases normal dream.  Nightmares go away.  Normal, bizarre dreams come back.  That may be a good thing because there are important data from Matthew Walker and others at UC Berkeley and Harvard suggesting that normal dreaming in rapid eye movement sleep is important for stripping excessive emotionality from memories.  Finally, to the left, total sleep time.  Despite the fact that prazosin doesn’t get you to sleep any faster, it increases your total sleep time by 94 minutes, which is a lot more than one saw in the Ambien versus placebo studies done when Ambien was seeking FDA approval for a labeling indication.  

Okay, adverse effects, I mentioned those earlier.  It’s important if someone is taking an erectile dysfunction drug or another anti-hypertensive, especially a beta blocker, to be careful while they’re in the titration stage, or even afterwards, not to bolt upright from a lying position rapidly.  If one just takes 30 seconds, 15 seconds in a sitting position, 15 seconds in a standing position before starting to walk, and then only walking when you’re sure you’re solid, all will be well.  Otherwise, orthostatic hypertension occasionally occurs.

There’s concern about using trazodone concurrently, about priaprism risk.  We did not see that in a big analysis of the urology clinic’s data at Madigan Army Medical Center in unpublished data.  Nasal congestion in older Veterans over the age of—those who were getting social security and older, peripheral edema can be exacerbated.  Sometimes people feel palpitations because the reflex response to the slight lowering of blood pressure by prazosin is a compensatory increase in heart rate.  Sometimes that can be disturbing, especially during  physical training and whether it’s daytime or nighttime.

All right, so conclusion.  Then we’ll have some time for questions.  The results of these studies I think provide rationale for a placebo-controlled trial of prazosin for blast concussion posttraumatic headaches.  This study, when planned by whomever, although we’re certainly interested, should and will evaluate relationships between sleep and posttraumatic headache in this population.  I think it’s time for questions, if there are any.

*Moderator:*Yeah, there’s several.  For those of you that joined us after the top of the hour, you can go ahead and just use the Q and A box in the upper right hand corner to submit any questions or comments you have for Dr. Raskind.  I will go ahead and ask them now in the order that they were received.  The first one that came in, I worked—oh, I’m sorry.  Give me one second here.  Okay, the first question that came in: looking over the slides, I did not see botulinum toxin injected mentioned.  I’ve used Botox with good success and have a multi-center protocol with Madigan SAMMC and Fort Bragg pending.  I have used this primarily due to lack of cognitive side effects.  Do you have any comments?

*Dr. Raskind:*Well, yeah.  It’s something I have not used.  I’m sliding into the headache business somewhat as an accessory to the fact.  Sounds promising.  Again, I think I made the point that I’m a big fan of open label case series with just the markers of baseline severity and frequency of the target symptom, and then at the endpoint.  If there are any data out there I’d love to see them.  My email, I’m on Outlook, is murray.raskind@va.gov.  That’ll get to me and also, if you have any other comments that we don’t get to today, I’ll be happy to *[laughter]* share my ignorance as best I can about whatever topic in mild traumatic brain injury.  It’s a big area.  It ranges from Botox to Adderall.  Anyway, fire away.  Yes, next?

*Moderator:*All right.  The next question that came in: I work with a homeless Veteran as a vocational rehab specialist.  Many who have TBIs and the desire to return to work is hampered by the TBI.  Is there any way to work with this?

*Dr. Raskind:*Well, that’s a big question, because we’re talking about multiple types of symptoms.  First of all, you want to make sure that the symptoms are not due to comorbid PTSD, which can be treated, per se, but that’ll still leave you with many symptoms that are due to the mild traumatic brain injury.  They range from a subjective sense.  When you do very careful neuropsychological tests, we’ve been able to demonstrate objective problems in multiple mTBIs in young Veterans on a task which involve a lot of multitasking and are made more complex.  Careful neuropsychological evaluation is helpful, but we still don’t know how to correct that.  The headaches, obviously, there are multiple approaches.  We’ve talked about one here.  There was another one mentioned in the previous question.  Getting those under control is very important.

There are also other symptoms ranging from problems with attention, subjective sense of poor balance, all of which are difficult.  There are many treatments anecdotally reported to have been tried, but we really are left with clinical experience.  I’m not going to give you a satisfactory answer, but more a plea for more carefully designed studies, as well as more descriptions of what people in the field are finding is the impact of the treatments they’re using on signs and symptoms that are likely attributable to previous mTBIs.  

*Moderator:*Thank you.  The next question we have is: here in compensation and pension, with comorbid condition of previous mTBI and PTSD, we are often asked to state whether headache is due to the mTBI or the PTSD.  Have there been any studies that suggest how to differentiate which condition is baseline cause or *[cross talk]*—

*Dr. Raskind:*Yeah.

*Moderator:*- cause the chronic headache?

*Dr. Raskind:*Yeah.  Well, the PTSD does not cause headaches, at least by the definitions that are current in DSM4 and DSM5.  Again, the study that was done by Hoge, Castro, and colleagues in which they looked to see statistically among OEF/OIF/OND active duty soldiers, which symptoms were PTSD and which symptoms were mTBI, the only one that they could categorically say was not PTSD was headache.  To my read, there were others that couldn’t that were not likely PTSD, as well, but I think if it’s headache, it’s mTBI.  This is also why I don’t work in comp and pen, because it’s not an easy business when compensation is involved.  

*Moderator:*Thank you for that reply.  This comes from another writer: we were taught to treat each of the individual symptoms, mTBI or PTSD, with something, but now we know that opioids are likely to make headaches worse in mTBI.  Yet, you also mentioned that the other prophylactic medications were less effective in Veterans with postconcussive headaches.  So if prozasin was not clinically helpful in a particular Veteran with headaches, what would be your recommendation for second or third line prevention medication *[cross talk]*?

*Dr. Raskind:*Yeah.  Well, we’d have to ask Jay Erickson, my good buddy, who is actually a headache neurologist.  I *[inaudible]* or Bob Ruff, so I apologize for not being able to answer about others, but prazosin not being effective is sort of a tricky question because there’s a huge dose response variability.  Some persons respond at two milligrams in terms of getting sleep restored.  Some need 40, four zero, milligrams an hour before bedtime before sleep is normalized.  Of course, not everybody responds.  The best respondents to prazosin are those persons who have the most frequent and severe trauma nightmares, or even if the trauma nightmares were not recalled, sleep disruption that wakes them up in a sweat, their heart’s racing, they’re short of breath, they have to check the perimeter or they can’t get back to sleep at night.  Those folks are good responders.

*[Laughter]*  It’s interesting, but the less distressing the nightmare is, quote unquote nightmares are, and of course we can’t objectively measure nightmares, the less likely prazosin is going to give a major effect.  The more severe they are and disabling they are, the better prazosin works.  It also has to be given multiple times during the day for headaches, so at least three times a day, smaller doses during the day and bigger doses at night.  Again, if you have a management issue with prazosin that I can address, just email me with some specifics and we can have a longitudinal conversation, try to get the Veteran doing better.  

*Moderator:*Thank you for that reply.  The next question is: we know that differential diagnosis of sleep disorders includes depression and substance abuse.  In your study, were Veterans with clinically significant depression or at-risk drinking excluded?

*Dr. Raskind:*Depression was not excluded unless a person was felt to be at risk of self-harm.  Even with those exclusions, we did have two suicide attempts in the active duty soldier study, both, thank God, in the placebo condition, but they were attempts.  They weren’t successful.  That’s a good question.  I, myself, often find it very difficult to separate depression from bad PTSD because there’s so much sign and symptom overlap.  Lots of these soldiers had reasonably high depression scores on the tool that we used.  The depression scores actually numerically, but not significantly statistically, did better the prazosin group than the placebo group.

That’s confounded by—sleep is a depression symptom, and loss, as well as PTSD symptoms, sleep disturbance, loss of interest is both a PTSD and a depression symptom, so it’s often hard to know.  We certainly didn’t exacerbate anybody’s depression.  We did eliminate persons with—this is in the DSM4 days—who had alcohol dependence and—but we did have a few people who met alcohol abuse criteria, but even though we allowed alcohol abuse, we somehow didn’t get that sample who were heavily self-medicating.  

*Moderator:*Thank you for that reply.  The next question we have: can you please elaborate on the time—oops.  We seem to have lost the slide.  I’ll put those back up in just a second.

*Dr. Raskind:*Hey, who needs them, right?  

*Moderator:**[Laughter]*  Please elaborate on the time of onset of PTHA.  How long after TBI can a new onset HA be considered posttraumatic?  What I have read and heard is that TBI-related HA should have an onset within a week or so of the TBI.

*Dr. Raskind:*Yeah, well it’s—that becomes more of a philosophical question because we don’t have a good biologic marker.  Again, not being a headache-ologist, I’ll try to steer clear of that one.  I do think that persons with chronic migraine, at least for the migraine type, usually have onset of their migraines when in their teens, often before they ever deployed, so I think taking good history of what did you have before you went downrange, is that different from what you have now, is one way to get a handle on it.  When we ever get a PET scan, EEG, blood, CSF, biomarker of posttraumatic headache due to mild traumatic brain injury, then we’ll be able to answer it definitively.  Until then, it’s more a philosophic question.

*Moderator:*Thank you.  We have sparked a lot of interest.  We have 14 pending questions.  

*Dr. Raskind:*Yikes.  Okay, so everybody has my email, so you—you can send these if you want.  I can send—I don’t know how to handle this, but please don’t be shy about emailing me with these.

*Moderator:*Great.  Well, I put up your email in the upper left hand corner of the slide.  Also, if you’re able to stay on past the top of the hour, we would like to answer all of the questions for the *[cross talk]*.

*Dr. Raskind:*Okay, sure.  Sure, I could do that.

*Moderator:*Excellent.  Thank you.  Okay, so the next one, let’s see.  Due to potential—okay, this is a comment we received when you were talking about prozasin.  Due to potential palpitations from prozasin, it is contra-indicated in patients with panic attacks.  

*Dr. Raskind:*Yeah, well actually not.  *[Laughter]*  The palpitations can be controlled.  Well, let me say something about panic attacks in persons with combat trauma, posttraumatic stress disorder.  The phenomenon certainly occurs, but it doesn’t occur in a way that’s similar to what you see in civilian panic disorder where the person says she just came out of the blue, or it’s not clear what environmental stimulus set it off.  In the combat folks, it’s usually pretty clear what set it off.  It’s going through—driving through a tunnel or going over a bridge or odors that are reminiscent of a combat trauma.

Secondly, the civilian panic disorder is very responsive to the SSRI antidepressants, so Prozac, I mean, fluoxetine and sertraline, paroxetine, methylthaxine, they’re all—they really are dynamite for civilian.  They don’t work very well in the combat trauma exposed versus with PTSD who report symptomatology similar to panic attacks with tachycardia sense of—you’re breathing fast and afraid you’re going to die.  Now, the palpitations also, if they’re symptomatic, probably can be treated by adding to the prazosin, not prescribing before because that could intensify dreaming.  After prazosin is initiated, adding the beta norepinephrine receptor blocker propranolol.  Anyone who has symptomatic palpitations that’s developed after prazosin will respond to adding low-dose, usually low-dose, propranolol, perhaps ten milligrams twice or three times a day.  Some need a little more, some need less.  It’s an easily fixable situation.

*Moderator:*Thank you for that reply.  The next question: can you elaborate again on the need for formal dreaming?  He stated—you stated prazosin—

*Dr. Raskind:*Oh, normal dreaming, yeah.

*Moderator:*You said it increases REM and maintains normal dreaming and decreases nightmares.

*Dr. Raskind:*Yeah, so well, I haven’t totally—the third Veteran I ever treated with prazosin back in 1995 in the Black Veterans Support Group at Puget Sound that I have been co-leading for 18 years and where the prazosin story arose, was an infantry guy in the 25th infantry division.  He had bad PTSD.  Particularly distressing was this nightmare about his being in an LZ landing zone and with his squad.  They were surrounded by the Viet Cong and they were lobbing mortar rounds in, and he caught a piece of shrapnel in his leg and he couldn’t run anymore.  He was fortunately recovered just by a Huey helicopter pilot, one of those heroic guys who did that thing, but not before one of his best buddies was killed right in front of his eyes by a mortar round.  His nightmare was about that.

I gave him the prazosin and I said six weeks later, “Charles, is it working?”  He said, “Hey doc, I don’t know this stuff.  I mean, I’m still having bad dreams.”  I said, “Well,” and that time I wasn’t convinced that it was helpful, so I said, “why don’t you tell me about it so we can learn some more?”  He said, “Well, that dream I had about the LZ and the mortar rounds and the—I don’t have that anymore, but now I’m in my fifth grade class and I didn’t get the assignment, but there’s a quiz I’m going to have and if I don’t pass this, I’m not going to graduate to the sixth grade.”  I said, *[laughter]* “Charles, that’s my nightmare.  Yours is about the LZ and the mortar rounds.”  Normal, unpleasant dreams with emotional content, they usually don’t wake you up in a cold sweat, having to go check the perimeter.  Those become—they come back.  Good dreams or bad dreams, but normal dreams that are bizarre in quality and not as if you’re in an actual, real time experiencing.

This Matthew Walker is the person who’s been leading this type of research, along with Stickgold and other colleagues at Harvard—Matt Walker’s at UC Berkeley.  He just did some very nice work demonstrating that normal dreaming, whether it’s pleasant or unpleasant, and normal, uninterrupted rapid eye movement sleep is important for reducing excessive emotionality linked to memories.  It doesn’t get rid of the memories, but he describes it as stripping away the excessive emotionality.  In PTSD, I think memories are loaded with what one would consider excessive emotionality.  Then maybe a mechanism by which restoring normal sleep is helpful for posttraumatic stress disorder.  There are other hypotheses about sleep which are interesting.

Recently in *Science* and in *Science Translational Medicine*, there’s a series of excellent articles demonstrating, at least in rodents, that when you’re awake you have very poor clearance of metabolites from between neurons in your brain.  When you’re asleep it dramatically increases the flow of cerebral spinal fluid and interstitial fluid to clear out what are potentially neuronal, detrimental, or even toxic proteins and other molecules from the brain.  That’s another reason potentially why restoring normal sleep in persons who are otherwise sleep-deprived, or sleeping poorly, may be helpful for lots of conditions, including migraine headaches.  If I haven’t confused you with that, I’ll never be able to.  

*Moderator:**[Laughter]*  Thank you for that reply.  The next question: what is the status of the CSP study of prazosin?

*Dr. Raskind:*Yeah, well those results are not available yet, or I’ll be shot on sight.  

*Moderator:**[Laughter]*  No problem.  It looks like you did not confuse the last question asker.  They did respond.  *[Laughter]*

*Dr. Raskind:*Okay, good. 

*Moderator:*A few years ago, we looked at prescribing patterns for prazosin across VAs nationally, and it was very coastal.  Has that changed at all?

*Dr. Raskind:*Yeah.  Bob Rosenheck, who did that, looked at last year.  The strong correlation between prazosin use and proximity to the Puget Sound area and the VA in Seattle, which was present in 2006, is no longer present, so it’s pretty evenly distributed.  That 17 percent comes from Rosenheck’s last survey.  We’ve got everybody fooled, apparently.  

*Moderator:*Thank you.  The next person thinks that you may have cited the wrong doctor Ruff.  Suzanne is key, not Bob Ruff.

*Dr. Raskind:*Oh, okay.  Well, they’re married.  This is the Suzanne and Robert Ruff in Cleveland.  Suzanne is the clinical psychologist, and Bob is the neurologist.  Seeing as they’re married, we don’t want to say who’s key and who’s not, because I don’t know what they decided on.  When they wrote up the data, he was the first author.  Suzanne—

*Moderator:*Well, she said it as a comment, so I think *[cross talk]*.

*Dr. Raskind:*Oh, okay.  Right, because the thing with—

*Moderator:**[Laughter]*

*Male Voice:*I’m going to chime in here.  There’s another Dr. Ruff on the west coast, isn’t there?

*Dr. Raskind:*Right, yeah.  There is another Dr. Ruff, so this is the Cleveland Dr. Ruff.

*Male Voice:*He’s the author of the 15th percent miserable minority.

*Dr. Raskind:*Yeah.  At any rate, yeah, so it’s really not fair to the field to have lots of Robert Ruffs spelling their name R U F F and expecting us in our later years to keep it straight.  

*Moderator:**[Laughter]*

*Dr. Raskind:*Thank you for the comment.  Yeah, it was definitely a joint project. 

*Moderator:**[Laughter]*

*Dr. Raskind:*That’s as far as I’m going to go.  

*Moderator:*Excellent.  All right, this next one is actually a three part question.  We’ll just go ahead and tackle it one at a time.

*Dr. Raskind:*Yes, okay.  Well, we got two more minutes.  Yeah, go ahead.

*Moderator:*All right.  What is the average dose used for (a) sleep nightmares and (b) headache, and how long is the effect sustained after *[cross talk]*?

*Dr. Raskind:*Yeah.  Well, it’s a complicated question because the pharmacokinetics, and I think more dynamics than kinetics of prazosin, for PTSD, sleep disruption, nightmares, and the headaches, if we can continue to confirm that, the dose range is huge.  It’s very hard to say.  Luckily, when one titrates upward, which is what I recommend, gradual dose titration until the symptoms substantially remit, or the prescriber gets nervous—cuz usually once you get past the early stages of using prazosin, adverse effects are minimal.  The orthostatic hypertension is described as quote unquote first dose in the *Physicians’ Desk Reference* for all the alpha-1 adrenoreceptor antagonists, whether it’s prazosin or Flomax, tamsulosin, it’s much more commonly prescribed for benign prostatic *[inaudible]*, whatever, you have to start with a low dose.

It’s when you start with a big dose and the receptors are used to seeing an alpha-1 adrenoreceptor antagonist or the static hypotension, is one of the adverse effects.  After someone has been taking this for a while, you can push the dose pretty liberally, except in some people who are not easy to predict.  I continue to caution people.  Don’t get up from a supine position to a sitting position to a standing position without staying at least 15 seconds in each one of those positions before you start ambulating to make sure that you’re not dizzy.  Because some people don’t read the *Physicians’ Desk Reference* and they can develop orthostatic hypertension after taking prazosin for two years.

It’s not just a first dose effect.  It’s very individual.  It’s not the world’s easiest drug to use.  It takes some monitoring, but not so much the number on a blood pressure machine.  You have to monitor the patient’s reports of postural dizziness or absence thereof.  I can’t give you a definite dose, but you want to not be shy about going in and pushing if someone does not respond, symptoms are severe, and nothing else has worked.  

*Moderator:*Thank you.  Just to clarify, you were referring to real life practice and not clinical trials, correct?

*Dr. Raskind:*Right.  In clinical trials, what we—how we give the dose until trauma in the soldiers study at Fort Lewis and Madigan—I’m sorry, Joint Base Lewis McChord and Madigan are our medical centers.  We pushed the dose until either nightmares were gone for the previous two weeks or we reached the maximum dose.  We were aiming for getting rid of these darn things, so that’s why we got pretty close to the maximum dose.  Our maximum dose was 20 at bedtime and 5 milligrams midmorning.  We got to 15 and 4 midmorning, 15 at bedtime and 4 midmorning.  In my clinical practice, I’m probably more aggressive than the average provider is because I’m more comfortable with the drug.  

*Moderator:*How often was blood pressure monitored during titration?

*Dr. Raskind:*Yeah, so we did that weekly.  They came in for their titration visit weekly and we monitored blood pressure weekly.  That was about it.  The effects on blood pressure were trivial.  At the end of the study there was no difference of a change in blood pressure, which was very minimal between placebo and prazosin.

*Moderator:*Great.  Thank you.  Okay, the next question we have is—lots of good ones coming in.  

*Dr. Raskind:*Oh, damn.  

*Moderator:**[Laughter]*

*Dr. Raskind:*I’m going to have to get off at 12:15 p.m., so you—we’re going to have to—

*Moderator:*Okay.  Could you discuss the dosage again?  I heard seven milligrams at night and later *[cross talk]*.

*Dr. Raskind:*Yeah.  In the Suzanne Ruff study *[laughter]*—I hope everybody got that—at the Cleveland VA, they started at one milligram, and every week they increased by a milligram until at seven weeks they got to seven milligrams.  I’m somewhat more aggressive, and I’m not sure whether it’s better or worse, but I start with a milligram for three days, then go to two milligrams until the end of the first week.  Then if people are still symptomatic, I increase it to four milligrams for the following week, then to six milligrams for the following week, then to ten milligrams for the following week.  Then I increase by five milligram increments.

Usually people are going to get better by ten milligrams, but some people—I have one Veteran who’s on 5 milligrams twice a day and 40 milligrams at night.  It wasn’t because I was brave and said, “I’m just going to push up.”  He did it himself.  He was a warrant officer with medic training.  He said, “Hey, I can do this.  No problem.”  He just went up to 40 milligrams, and at 35 milligrams at night he was still having trauma nightmares and sleep disruption, and 40 milligrams they went away.

I have no idea how to identify persons, whether their body mass index—everything we’ve looked at has not been tremendously helpful in terms of predicting who’s going to be a low dose responder, who’s going to be a high dose responder.  The non-responders generally are the folks who I’ve treated, but are not terribly distressed by the nighttime symptoms, but will say, “Hey, if I can dream and sleep a little better, I’m willing to take this stuff, doc.”

*Moderator:*Great.  We do still have 12 pending questions.  Would it be all right if I emailed those to you and got written responses that we could post in the archive catalog?  

*Dr. Raskind:*Absolutely.  

*Moderator:*Great.  All right, well I want to thank you very much for lending your expertise, and I want to *[cross talk]*.

*Dr. Raskind:*Yeah, no.  I thank everybody for hanging in there who did and—

*Moderator:*The majority did.  *[Laughter]*

*Dr. Raskind:*Yeah, so there are no experts in this area, so we’re all feeling our way forward.

*Moderator:*Great.  Well, for our attendees, thank you so much, and I’m going to close out the meeting in just a second.  Please take just a moment to give us your feedback on the session.  It is your opinions that drive this program forward, so thank you so much, everybody, and have a wonderful day.

*[End of Audio]*

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