**Transcript of Cyberseminar**

**Spotlight on Pain Management**

**Opioids in Chronic Pain and PTSD:   Liability or Potential Therapy**

**Presenter: Karen Seal, MD**

**January 7, 2014**

Dr. Robin Masheb:Good morning everyone, this is Robin Masheb, I am the Director of Education at the PRIME Center and will be hosting our monthly pain call entitled “Spotlight on Pain Management”. Today’s session is “Opioids in Chronic Pain and PTSD:   Liability or Potential Therapy”. I would like to introduce our presenter for today, Dr. Karen Seal. Doctor Seal is a primary care internist and Medical Director of the San Francisco VA Medical Center, Medical Practice Pain Clinic and Director of Integrated Care Clinic for Iraq and Afghanistan Veterans, also at the San Francisco VA She is Associate Professor of Medicine and Psychiatry at UCSF. We will be holding questions for the end of the talk, at the end of the session there will be a feedback form to fill out immediately after. Please stick around for a minute or two to complete this form as it will only be about six to seven questions. 

We have Dr. Bob Kerns, Director of the PRIME Center will be on our call today and he will be around to take any questions related to policy at the end of our session. Now I am going to turn this over to our presenter, Dr. Karen Seal. 

Dr. Karen Seal:Thank you very much, thank you Heidi and thank you Robin and thank  you Dr. Kerns for inviting me to speak today. Can I just do a sound check? Can everyone hear me? 

Unidentified Female:We can hear you just fine, thanks. 

Dr. Karen Seal:Great. I am going to be taking on this topic of Opioids in chronic pain and PTSD and I wish I had done a little poll here  because I care for these patients and I am sure many of you do as well. I think we all know that they are extremely challenging patients to care for. Also, when things improve it can be an extremely rewarding experience as well which keeps me going in this business. 

Without further ado let me just give you an outline of what I am going to talk about today. I will be talking about pain and PTSD and why we think they may be so tightly associated. I will then move into PTSD and prescription Opioid risk and how that comes about. I will then look at therapies for patients with pain and PTSD that are currently being used or being trialed, particularly in the VA healthcare system right now. Then I will move back to why opioids may actually  prevent or ameliorate PTSD or PTSD symptoms. Finally I will conclude with a look at Buprenorphine as a potential therapy for the trifecta of pain, PTSD and opioid use disorder or opioid dependence. 

Pain and PTSD, why this connection? First of all just looking at epidemiology chronic pain is unfortunately the most prevalent problem among U.S. veterans and it is particularly problematic for female veterans. In the Vietnam era sixty-six to eighty percent of veterans with PTSD reported chronic pain and in our current new generation of Iraq and Afghanistan veterans who as many of you know carry extremely heavy combat gear weighing well over a hundred pounds. Chronic pain is really become quite a big problem despite the fact that this is a relatively young population with a median age of about thirty-two. Chronic pain is unfortunately more prevalent in our female veterans who are recently returned combat veterans. And interestingly over fifty- percent of those Iraq and Afghanistan veterans who have PTSD have already received one or more chronic pain diagnoses. 

We actually looked in the VA National Administrative datasets and about a half a million Iraq and Afghanistan veterans and we did our analysis with a reference group of Iraq and Afghanistan veterans who had no mental health diagnoses and compared those to those with mental health diagnoses except for PTSD and those are shown in darker gray. Then those who have PTSD are actually shown in red. We looked at four different pain syndromes here: headaches/migraine, back pain, neck pain and arthritis and joint pain and you can see  a very clear and consistent pattern here. Those with mental health disorders other than PTSD compared to those with no mental health disorders had greater prevalence of all of these pain syndromes. There was an even greater prevalence of chronic pain in those with PTSD again, shown in red. 

I thought it would be important to actually review PTSD diagnostic criteria and I am going to talk about the diagnostic criteria in DSM-V so these are relatively new criteria. All patients who have PTSD must have experienced a traumatic event and that traumatic event must have happened thirty days ago to call it PTSD rather than acute stress disorder. Criteria B is Re-experiencing so re-experienced the traumatic memories, which can be intrusive thoughts or nightmares. And you can imagine how this may related to pain in re-experiencing pain memories. Criteria C is avoidance  which unfortunately in PTSD is a problem but can also be a problem in chronic pain as patients become very avoidant of activities that can trigger pain. Criteria D is Negative alterations in cognitions and mood or persistent negative state. So states like depression have been linked with chronic pain and have been shown to cause more chronic pain. This can also be this emotional numbing that we see in our PTSD patients.  Criteria E  is the hyper-arousal that we see in both PTSD and chronic pain. Of course Criteria F we require negative impact on functioning, which of course is present in PTSD as it is in chronic pain. 

Now that we have reviewed those criteria, let us look at PTSD and the pain link. Why might this occur and these are all hypotheses. There is the hypothesis of shared vulnerability that maybe even from a genetic level those that are pre-disposed to PSTC may be the same patients that are pre-disposed to develop chronic pain syndromes due to the stress and tolerance anxiety sensitivity. PTSD also alters the hypothalamic pituitary adrenal axis and can cause inflammatory conditions. This is because in chronic stress situations you have increased levels of cortisol which over time the adrenals eventually burn out and you have lower circulation levels of cortisol and some of our recent findings are showing that PTSD is actually linked to inflammatory conditions such as inflammatory valve disease; thyroiditis and various forms of arthritis. PTSD is also known to cause dysregulation of the autonomic nervous system, the endogenous opioid and serotonergic systems. New studies are showing that Neuropeptide Y and neuroactive hormones such as allopregnanolone and pregnanolone help with pain control but unfortunately these neuropeptides and neurologic hormones are low in individuals with pain and studies have shown that they are also low in individuals who have PTSD. PTSD has also been shown to decreases frontal lobe inhibition of exaggerated response to pain and fear triggers. We will look at this in a little bit more detail. Finally the theory of  mutual maintenance the  pain and  anxiety actually maintain each other and we will look at that in more detail as well. 

Looking at chronic pain and PTSD in the theory of mutual maintenance. PTSD creates an anxiety state, which can actually exacerbate a patient’s perception of chronic pain, which can also then in turn lead to increased disability because they perceive their pain to be worse, and they become avoidant of activities, which actually feeds back into the syndrome, or the symptoms of PTSD. This crease a vicious downward cycle.

 Looking at shared brain regions for pain and fear response as I mentioned. In PTSD we have 

Poor pre-frontal cortical inhibition, which actually leads to a dysregulated amygdala and limbic systems causing exaggerated responses to both fear, triggers which can exacerbate both PTSD and chronic pain. 

Let us now turn to PTSD and prescription opioid use and let us look at how these things, these two entities are linked. There have not been a lot of studies looking at prescription opioid use in patients with PTSD. Before we did our work I actually was able to find two small studies from the community actually in Phifer et al in 2011 showed that patients with pain and PTSD were significantly more likely to be prescribed opioids for pain than patients without PTSD. Then in an earlier study, there was a dose response that was shown. In other words patients who had greater PTSD symptom severity were the ones, were the PTSD patients who are most likely to receive prescription opioids for pain complaints. 

What we did was we went to the VA administrative databases and this time looked at nearly a hundred and fifty OEF/OIF veterans and we used the same type of analysis where we had our reference group as those with no mental health diagnoses. We compared those to Iraq and Afghanistan veterans with mental health diagnoses but no PTSD and finally looked at those with PTSD and you can see the increasing prevalence in those with opioid prescription and those with mental health diagnoses other than PTSD. And finally an even greater prevalence of prescription opioid use in Iraq and Afghanistan veterans with PTSD. In other words, those with PTSD were over two and a half times more likely to be prescribed opioids than those with no mental health diagnosis. 

This is a little bit of a busy chart but it just makes the point that not only are veterans with PTSD more likely to receive opioids they also tend to have the greatest risk when they are prescribed opioids. Again, those with mental health diagnoses without PTSD are shown in red, those with PTSD are shown in kind of a beige/yellow. You can see again a very consistent pattern of greater risk or greatest risk in our Iraq and Afghanistan veterans who have PTSD. They tend to use the most opioids on a daily basis, they use them for longer, they tend to use two or more simultaneously. They also tend to be the patients who are on benzodiazepine and opioids simultaneously and they have markers of aberrant opioid behavior which international databases are early opioid refills. 

PTSD and opioid use for pain, what are some of the underlying mechanisms here. Well Ben Morasco  in Portland and Steve Dobscha show that their high rates of PTSD and substance use disorder comorbidities so maybe these are patients who are drug seeking and manage to acquire prescription opioids for their pain. Primary care providers and I can say this because I am one, really have not been trained to manage PTSD and chronic pain. It is a very complex and difficult patient and often these patients present to primary care in high levels of distress much of that distress related of course to their PTSD. These patients are the ones that tend to be prescribed opioids both to manage their pain, but also the distress that is related to their PTSD. This of course is done inadvertently. There is the self-medication hypothesis in that opioids have actually ben shown to blunt trauma related negative cognitions. As I will show you in the next two bullets, we will go into this in more detail, opioids have been shown to inhibit adrenocorticotropic hormone and glucocorticoid release. They can dampen down the stress response and opioids can also inhibit the autonomic response to fear by decreasing norepinephrine release from the locus coeruleus. Again I will show you the last two bullets in more detail. 

This is what I would call a system imbalance. This is the endogenous opioid system. As you know we make our own opioids endogenously and this schematic is showing you how the endogenous opioid system helps to mitigate stress. For instance in the top portion of the slide you can see the POMC molecule which is the pro-opioid melanocortin molecule in the hypothalamus which in a stressful situation can be differentially cleaved into endogenous opioids and ACTH, adrenocorticotrophic hormones. The endogenous opioids actually inhibit the adrenocorticotrophic hormone, which in turn inhibit glucocorticoids, which are stress hormones. The endogenous opioids are dampening down that stress response. In the lower portion of the slide, you can see that stress causes corticotrophin releasing factor from the hypothalamus to stimulate the locus coeruleus to release norepinephrine. But in a way that is counterbalanced our endogenous opioids system actually inhibits the locus coeruleus release of norepinephrine. Again, this is a system that is in balance, the two systems counterbalance each other. 

Let us look at what happens when there is an over use of opioids for chronic pain. If you look at the left side of the slide where there is an overuse of opioids for chronic pain there can actually be down regulation of opioid receptors in the locus coeruleus. What this means is that opioids are no longer able to inhibit the locus coeruleus release of norepinephrine and when there is a stressful situation what is happening is that  now the locus coeruleus is releasing norepinephrine in an unopposed way. When you have unopposed norepinephrine or an exaggerated autonomic response you in turn get an exaggerated fear memory response or fear memory consolidation which can exacerbate PTSD or PTSD symptoms. In other words exogenous opioids as opposed to endogenous opioids may drive a feed forward stress enhancing circuit in PTSD. 

I thought it would be good to take a moment and just talk about how we are currently or starting to look at managing patients with what we can call the trifecta of pain, PTSD and opioid use disorder. I think it is important when we start to look at this to actually evaluate whether opioids are actually efficacious in the management of chronic pain. Unfortunately most of the studies looking at this have been surveys or uncontrolled case series or they have been relatively small-randomized control trials of short duration. Unfortunately most of these studies are sponsored by pharmaceutical companies. The outcomes show that there is better analgesia with opioids when you compare opioids to placebo but importantly when you compare opioids to non-opioid pain medications like anti-inflammatory drugs there is no difference in pain control. That is very important for us to know as clinicians and also to educate our patients. There are very mixed reports on whether opioids actually improve function and importantly in many of these studies addiction to opioids was not assessed. 

A lot of prescribe opioids thinking that we will improve our patients quality of life and functioning but unfortunately what the literature shows is that those who received opioids for chronic pain actually ended up having lower quality of life when they were followed up over time. Those who received opioids were actually four times less likely to ever recover from their chronic pain. 

Really what we are doing here when we think about prescribing opiods and it is important for us to know again as clinicians and also educate our patients is we are really weighing the risks versus the benefits. The benefits I think when you really look at the literature are uncertain. We do not really know if opioids are improving pain and in fact the literature is telling us that they may not do much better than other non-opioid medications. There is really very little evidence to show that opiods are improving quality of life or functioning and in many cases they may be doing just the opposite when we review the harms. What are the potential known harms of opioids? Well opioids can lead to physical tolerance, which means that you need ever-increasing doses of opioids to get the same effect, which can lead to physical dependence on opiods. Which in turn in many cases or in some cases can cause addiction or abuse of a medication or diversion of the medication to others, which can cause overdose in others who were never even, prescribed the medication. As we know opioids can lead to overdose, the mechanism is generally respiratory depression. Opioids can cause cognitive impairment and this is a particular problem in our elderly veterans and in somnolence. Opioids have also been shown to disrupt the endocrine system particularly causing hypogonadism in both men and women. In men you can see erectile dysfunction, fatigue, osteoporosis and muscle wasting. Opioids have also been linked to sleep disturbances, and also worsening of both central sleep apnea and obstructive sleep apnea. Opioids have also been shown to cause pain from withdrawal because what is happening particular with the short acting opioids is when they wear off patients actually go through mini-withdrawal where they actually experience pain. Also opioids cause paradoxical situation of hyperalgesia, particularly at the very high doses where patients actually develop a lower pain tolerance. The only way to deal with hyperalgesia from opioids is to taper down to a lower dose or actually lower the dose and switch opioids. It is a very difficult problem. 

Probably the biggest problem that we are all aware of that is often in the media of late is the problem of overdose with opioids. And these are two very important studies, one in VA patients, and one in health maintenance organization patients showing essentially that as you increase the dose of opioids, you greatly and dramatically increase the risk for both fatal and non-fatal overdose. For instance in VA patients the risk for fatal overdose is seven times what is at the lower doses. Once you are hitting over a hundred milligrams, but I want you to look at this chart and notice that even as you are getting to fifty milligrams or morphine equivalents a day of opioids you are starting to dramatically increase the risk for overdose. 

We also looking in our VA National data and noted that receiving prescription opioids versus not receiving these prescription opiods was associated with an increased risk of a variety of adverse clinical outcomes. This was particularly pronounced in our veterans with PTSD and again this is in Iraq and Afghanistan veterans. The adverse outcomes that we looked at were wounds or injuries; opioid related accidents and overdoses; other accidents and overdoses and self-inflicted injuries such as suicide and violence related injuries. 

I thought I would just quickly present a case and then show what we are doing now in the VA healthcare system to try to deal with chronic pain and PTSD. This is a case, and it is a made up case but I think a lot you would recognize some of your patients here of a thirty-eight year old Iraq veteran with chronic lower back pain and PTSD. He is new to you, he comes in and says that he is drinking about twelve beers a night and he is doing this to “relieve pain”. He is also inappropriately receiving benzodiazepines for “anxiety” from outside doctor; he is not receiving evidence-based PTSD treatment right now. He has nightmares of combat nearly every night; he does not sleep well, he gets up, he is checking  doors and windows; he avoids leaving his house; he no longer goes out to gym to exercise. He developed lower back pain in Iraq from an injury. He has been on opioids in past for back pain. In fact he received them from his last doctor. He is requesting that you continue the same prescription he was on before which is MS Contin and oxycodone. This is a new patient. What do you do? 

It is a very common clinical dilemma that many of us find ourselves in. On the one hand you want to establish a therapeutic alliance with your new patient and you want to relief their pain and distress. On the other hand you have learned new things about opioids and you also have the desire to do no harm to your patients. 

How do we get unstuck from this clinical dilemma? And there are general principles that we are now actually teaching our clinicians to follow. Really what we are trying to focus on is Patient-Centered Education/Universal Precautions. I am taking a slight digression here from opioids just to talk about this because I think it is very fundamental in working with challenging complex patients, particularly those with PTSD. It is very important that you approach these patients with a non-judgmental, no-confrontational style and that you contextualize the situation for them so they do not feel singled out. You can say things like—well we learned a lot about opioids over the last decade when we have been prescribing so many opioids and we learn that maybe they are not actually so effective and they have a lot of harms. Then you can go on to educate your  patients about these harms. You can also ask them about their own experience with opioids in the past. You will probably find that many of the patients do not even really like being on opioids. Again you want to educate them about the risks and questionable benefits of opioids. Talk to them about what are some non-opioid and even non-pharmacological alternatives or adjuncts to using opioids for pain. If opioids used which in many cases they are, it is very important especially with a new patient to frame the opioid prescription as a trial******with clear functional goals and to use shared decision-making with your patient, develop a multi-modal**“Pain Care Plan”  that includes not only opioids but also non-opioid and non-pharmacological pain management strategies. It is very important to see patients back and to monitor them and re-assess the risk to benefit ratio-using things like urine drug screening, and monitoring pain using very brief screens. For instance Dr. Krebs developed the pain interference with enjoyment in general activity scale and a COMM, which is a seventeen item validated screen use to assess prescription opioid misuse. It is very important also to have up-front agreements with your patients as to what are going to be the consequences if goals are not met or there is evidence of aberrant opioid behavior. 

We use  a pneumonic VEMA as a communication style in talking to our very challenging patients. VEMA is essentially validate, you validate their pain, their pain is real, you do not get into conflict with patients trying to decide if their pain is real or not real. You validate their experience of their pain. You then educate, you give them realistic expectations. No medication is going to completely eradicate their pain, but what it may do is take the edge off and that medication that you use may not have to be opioids. You really want to move from I will fix it for you to I will assist you in developing some self-management strategies that will help you improve your quality of life and functioning. You then went to motivate, use motivational interviewing to assist your patient moving toward self-management strategies and you want to activate them around collaborative goal setting. 

Specifically if our patients with PTSD you really want to work on developing non-opioid pain management strategies as your first line. There are non-opioid pain medications and procedures that you can recommend. You definitely want to think about targeting sleep in PTSD as it is a real hallmark symptom of PTSD, which can also exacerbate chronic pain symptoms. You will want to treat PTSD comorbidities such as depression, alcohol use disorder that can contribute to worsening of pain. You want to recommend physical therapy ,and certainly get patients moving doing some gentle exercises, yoga stretching. CAM you can use complimentary alternative medicine for pain and  PTSD and we will look at some of the evidence for CAM in just a moment. Also CBT can be very effective for pain and  PTSD. Likewise we will look at a little bit of CBT for pain and PTSD in a few slides. 

I thought this chart was helpful. It looks at various CAM therapies for pain and it really shows that there is promising evidence and potential benefits using acupuncture, massage, spinal manipulation that is chiropractor, progressive relaxation and yoga for chronic pain. Looking at complimentary alternative medicine for PTSD there really are not a lot of studies yet showing conclusive evidence for the use of CAM first line for PTSD. There is really insufficient evidence to recommend CAM as first line, yet CAM approaches such as mindfulness, yoga, acupuncture, massage and others can really help with a variety of PTSD related symptoms particularly hyper-arousal symptoms. CAM approaches can be considered as adjuncts for some of the comorbid conditions that go along with PTSD such as acupuncture for pain. 

In VA we have really quite a wide body of non-pharmacological treatment approaches to PTSD and chronic pain. I thought before I looked at opioids I really wanted to look at what is currently going on in VA, which is quite strong. There is strong evidence for collaborative care models that use the care manager and combine pain and mental health treatment in the treatment of PTSD and pain. This is essentially the interdisciplinary approach that we use in our VA pact. There are promising preliminary results in a limited number of subjects from combined CBT for both pain and PTSD that John Otis published on in 2009. He currently has an ongoing study that is a truncated version of what he did back in 2009 that also looks very promising CBT for PTSD and pain. There is an interesting ongoing exercise trial that is examining changes in pain and PTSD symptoms and measuring stress hormone levels, allopregnanolone and pregnanolone as well as Neuropeptide Y. Finally we were just funded we have not yet started, we were funded to do a trial of shared decision making and formulating pain care plans that include non-opioid non-pharmacological strategies. These are the care manager to conduct phone motivational coaching to promote these alternative pain management strategies and decrease high-risk opioid use in very complex chronic pain patients. 

I wanted to now turn to looking at selective opioid receptor agonists and thinking about whether they could be a possible therapy for PTSD. First some of the evidence for this actually comes from the acute pain contacts. There really have been three separate studies done in their separate populations that show in the setting of acute trauma that administering morphine within forty-eight hours of that trauma created a situation which patients were less likely to develop PTSD or if they did develop PTSD the symptoms were attenuated. 

There was a recent study that was very exciting that was published I should say this last year in 2013 that showed after a model of acute mouse trauma the infusion of a selected nodioceptin opioid receptor agonist blocks fear memory consolidation in the amygdala even though it was injected systemically. The mice that were given the NOP agonist displayed no or few symptoms of PTSD after the trauma and because it is selective NOP agonist spared the Mu opioid receptor it did not produce that same addictive or undesirable reward effects of traditional opioids, which could lead to addiction and dependence.

 In a separate commentary Marie Steen and I thought about what the clinical implications of this could be in humans. For instance could this be post-exposure prophylaxis let us say for first responders had trauma. This is a schematic that we developed actually to try to explain this model. Again this is an acute, I want to explain that this is an acute trauma event. There might be some acute trauma, these are first responders that are shown here. Theoretically if they are traumatized they could receive PEP or post-exposure prophylaxis with an NOP receptor agonist or even a commonly used very inexpensive opioid such as morphine within hours of the trauma. Opioid would then as showed in the mouse model and as we described in looking at all these ways that opioids can actually ameliorate PTSD, opioids blunt that trauma induced adrenergic or autonomic response by the look of coeruleus and therefore can block fear memory consolidation by the amygdala. This would create a decrease likelihood of developing PTSD and the comorbid disorders that go along with PTSD and trauma exposed individuals. Thinking about this globally we are hypothesizing or thinking that this could actually create decreased incidence of PTSD in comorbid conditions when there is a natural disaster.  Again that is in the acute trauma setting. 

Now I want to look at, I want to turn to looking at Buprenorphine and thinking about it as a possible therapy in the chronic setting for chronic pain PTSD and opioid use disorder. I want to emphasize that we are thinking about buprenorphine or patients who really were fractory to all of those other therapies, so non-opioid, non-pharmacological therapies that I reviewed before. These are really our most challenging complex patients. 

Just looking at Buprenorphine and looking at promising features of Buprenorphine, and how it relates to the mouse model that I presented before, Buprenorphine is actually a partial NOP receptor agonist but it is metabolite norbuprenorphine as actually a full NOP receptor agonist. It is FDA-approved for opioid use disorder or opioid dependence and that is in its sublingual form and it is approved for chronic pain as a transdermal patch. Although it is very difficult to get the patch in the VA right now. Partial Mu opioid receptor agonist so it has very high affinity for the opioid receptor which means it can strongly block opioid cravings but it also does not necessarily stimulate the rewards passage in the same way that a full Mu opioid receptor agonist would do. It has lower risk for abuse and addition. It also is a Kappa opioid receptor antagonist, which may explain its  observed anti-depressant and anxiolytic effects, which could have benefits in PTSD. 

Comparing buprenorphine to other opioids for pain control there is this chart and I will walk you through it. Buprenorphine compared to other opioids actually targets moderate to severe pain as do other opioids but it also targets neuropathic pain, which can be very useful in clinical practice. It has less tolerance, less physical dependence and less withdrawal than traditional opioids. Respiratory depression and overdose are rare compared to other opioids yet I think many of you might have seen a *New York Times* article, which did discuss, it was a very balance piece, which did discuss that when buprenorphine is abused or misused or used with other drugs benzodiazepines, and alcohol it too can lead to overdose. Buprenorphine also I did not mention this, also comes generally as buprenorphine the lock zone mixture. The reason for that is it is to prevent injection drug use because if you inject naloxone that automatically blocks the opioid receptor and the buprenorphine would not be bio-available. If buprenorphine is prescribed as straight buprenorphine, which sometimes it is it, can be crushed up and injected and lead to overdose and I think some of the cases that were discussed in the *New York Times*article were actually cases in which buprenorphine was prescribed without naloxone. Cognitive impairment leads to less cognitive impairment than traditional opioids. It does not dysregulated the HPA access, it does not cause immunosuppression, which I did not mention, but methadone can cause immunosuppression. It does not prolong the QTC intervals so it does not lead to sudden cardiac death. It is relatively safe in renal failure or elderly patients who have hepatic dysfunction and there are really few drug/drug interactions with buprenorphine. All in all buprenorphine tends to be a safer alternative than traditional opioids. 

Buprenorphine in PTSD, there is almost no data on this. Remember that I said buprenorphine is FDA approved for the treatment of chronic pain and opioid use disorder. There was one published case report of an incidental improvement in PTSD symptoms when buprenorphine was used as opioid replacement therapy. One published case report. We actually went to the VA databases and just asked the question—if patients who had PTSD, chronic pain and evidence for opioid use disorder were maintained on opioids were converted over to buprenorphine would their PTSD and pain symptoms improve? What we did find was a signal of significant improvement in PTSD and pain in patents that were converted from traditional opioids to buprenorphine in comparison to a control group that remained on moderately high dose opioids at fifty morphine equivalents a day or more. 

We are about to wrap up here. In wrapping up I know I presented a lot of different material but I am going to try to tie this all up right now in the last couple of minutes. We talked about the high co-prevalence of pain in PTSD, which is observed in veterans and other populations. Those who have pain in PTSD tend to be more likely to be prescribed opioids and have higher risk opioid behavior and adverse outcomes. Evidence is accumulating for collaborative care and combined PTSD and chronic pain therapies including CAM as effective non-opioid pain management strategies. Finally we looked at buprenorphine as an NOP receptor agonist that may have some efficacy and greater safety for refractory opioid use disorder chronic pain in PTSD patients, but certainly more research on this is needed. I am going to conclude there and that is my contact information if you have any questions you can email me and I think we have a few minutes for questions now. 

Moderator:Fantastic, thank you Karen. We do have a few questions pending here but I just wanted to let the audience know we are taking questions in writing, please use the Q&A screen at the lower right hand corner of your monitor to submit those questions. 

The first question that we have—was TBI factored for headaches or migraines?

Dr. Karen Seal:No we did not look at TBI in particular in that particular analysis. 

Moderator:Okay. The next question we have here—have you developed a protocol for working with PTSD patients who have been on an opioid for months or years that emphasizes the needed interpersonal intervention?

Dr. Karen Seal:I do not think that we specifically worked on a protocol that we are rolling out in our pain management clinic in primary care. But what we do is we run a series of boot camps where we are educating clinicians to use, even though it was a little off topic I wanted to interject the use of VEMA or Validate, Educate, Motivate, Activate as a communication framework for working with very complex and challenging PTSD and chronic pain patients. We are having clinicians practice the use of a different type of communication style with these patients. I think our recently funded NH study will also use telephone motivational coaching to really give these very challenging patients some extra support around adhering to the pain care plans that they develop with their clinicians. 

Moderator:Great, thank you. The next that we have here—do you have any specific suggestions for suicidal patients with chronic pain?

Dr. Karen Seal:That just triggered something for me and unfortunately one of the things that we sometimes hear is that doctor if you do not give me that medication I am going to kill myself and it is really a very, very tough situation to be in. Because we certainly want to protect our patients from suicide and we want to help with their chronic pain, but at the same time, it is really a tough situation to give suicidal patients opioids particular if you know they are using benzodiazepines or drinking at the same time. There is no short answer to that question but I would say that for me personally I think people have different clinical styles with this. I do not tend to want to prescribe a suicidal patient the means to kill themselves. In other words I probably would not prescribe that patient opioids, I would certainly look to my mental health colleagues for help with a suicidal patient and I would try to get that patient to see a mental health expert. At that point I would also of course give them all of the information about suicide hotlines and implement all of the suicide precautions that we typically do with our suicidal patients. 

Moderator:Great, thank you. The next question—does the VA allow buprenorphine for chronic pain or just for withdrawal from opioids?

Dr. Karen Seal:I think that is probably VA specific, remember that not all VA’s are the same even though we are a national system. The policy around the use of transdermal buprenorphine for chronic pain may vary by VA to VA. I know that we can use transdermal patches for the treatment of chronic pain but this is very limited and on a case-by-case basis. Generally I would say for the most part, there is widespread use in VA of sublingual buprenorphine for the treatment of opioid use disorder but not chronic pain yet. 

Moderator:Great, thank you. The next question here—can you comment on what needs to improve with communication between mental health, those treating PTSD, SUD and primary care providers, those treating patient disorders?

Dr. Karen Seal:What comes to mind most immediately is I think there is a breakdown in communication sometimes between primary care and mental health specifically in terms of the prescription of benzodiazepines. We will be working very hard in primary care to decrease risk of opioid overdose if opioids are being prescribed and we will not have prescribed the benzodiazepines and we will see that those have been or will in the future be prescribed by mental health. Really what I think it takes is emailing or picking up the phone or connecting with mental health providers and explaining that this creates real risk for our patients. and really working with them to either not start benzodiazepines for anxiety disorders in patients that are on opioids or to work with them to start a taper of the benzodiazepines simultaneously to your trying to taper the opioids and work on the drinking as well. Those three are really the fatal cocktail—the opioids, benzodiazepines and the drinking. That really involves a tight collaboration between primary care and mental health often to help with that situation. 

Moderator:Great, thank you. The next question here—with somebody who is interested in work that has been done with VA BPM [sp] to create criteria to support buprenorphine as suggested. 

Dr. Karen Seal:I am sorry can you repeat that?

Moderator:It was sent in by the captioner so I am kind of trying to figure it out here. 

Dr. Karen Seal:VA BPM pharmacy benefits, I think you mean go ahead and repeat the question so I can get that. 

Moderator:Interested in work that has been done with VA BPM to create criteria to support buprenorphine as suggested. 

Dr. Karen Seal:I think what I am suggesting here is really I am way out in front of what is FDA approved right now in terms of suggesting that buprenorphine be used in the treatment of this triad of this clinical tirade of PTSD, opioid use disorder and chronic pain. I mean buprenorphine is FDA approved for the treatment of chronic pain and for the treatment of opioid use disorder but there is really no mention of it being an FDA approved treatment for PTSD. This is just purely in the realm of research right now so I do not think VA is in a position to discuss using buprenorphine standardly throughout the country to treat PTSD.

Moderator:Great, thank you. The next question here—would you comment on how you would handle the following situation. You inherit a Gulf War veteran with chronic pain, PTSD and known history of substance use disorder who has been receiving high dose opioid therapies greater than one hundred and twenty milligrams per day with no other treatments and the patient refuses to see a mental health professional due to prior bad experiences. 

Dr. Karen Seal:That is one of our very challenging patients that really this talk has been about. I think really what we are trying to do is educate primary care clinicians to engage this patient in a relationship that would motivate them to start making some positive changes in terms of their opioid use. This is not something I need to emphasize that can happen overnight. If a patient has been on prescription opioids for many, many years, and has chronic pain, it can take quite a while, up to a year to really get them to a place where they have successfully tapered down to a dose that you consider safe in terms of opioid risk. At the same time that you are asking them to take away a pain medication is incredibly important to be giving them back other tools to help with their chronic pain. At the time that you are tapering, you are giving them other pain management strategies or self-management strategies that can be very helpful such as non-opioid medications. Referring them to acupuncture, referring them for massage or referring them for chiropracotry, referring them to PT. Suggesting that they take a yoga course, engaging their family members to increase their social support around doing this. There are all kinds of things that I think we actually can do out of primary care if the patient is unwilling to be involved with mental health. I mean some of my work involves using motivational interviewing to help patients look at barriers to engagement with mental health. Because I think in this type of situation our mental health colleagues can be incredibly helpful in using techniques such as CBT, as the techniques that I presented to help patients like this really decrease their reliance on opioids and consider other pain management strategies. But in a situation where patients absolutely refuse categorically to go to mental health there is quite a lot we can do out of primary care. 

Moderator:Great, thank you. The next question here—has buprenorphine then used in post-concussive patients without a PTSD diagnosis?

Moderator:That is a great question. I do not know so really what we are talking about is the use of buprenorphine in TBI and I would presume that the person asking the question is thinking about buprenorphine for opioid use disorder or the treatment of chronic pain and I do not know the answer to that. What I can say is that buprenorphine tends to cause a lot less cognitive impairment so anyone out there who wants to look at this would be a great study because I think our TBI patients are particularly at risk for cognitive impairment and formulance [sp?] with the chronic use of opioids for pain. Buprenorphine might be a really excellent choice for these patients just as it is a better choice than traditional opioids for elderly patients with chronic pain. I should say that if buprenorphine is used in chronic pain and you for whatever reason in your VA you cannot get transdermal buprenorphine if you are going to use buprenorphine in a chronic pain patient that is not opioid dependent, be very careful and get support from pharmacy around this. Because you would want to use sublingual buprenorphine and this would be off label, but the doses have to be quite a bit lower. This is really a complex area that you really would need some pharmacy support in doing. 

Moderator:Great, thank you. The next question here—how would I get more information about the VEMA techniques working on goal settings or monitoring?

Dr. Karen Seal:I actually was not, VEMA techniques I came across I think there was a presentation maybe somebody online can type this in and share it with the group. I think VEMA was actually developed by somebody working at one of the Seattle VA’s. I think if you just Google VEMA there would probably be a fair bit of information about it. Really I think for the most part, VEMA really for me boils down to a lot of the principles embodied in emotional interviewing. I think anyone wanting to learn more about VEMA for pain management really also could look into motivational interviewing and I think that can be used. Motivational interviewing actually has been rolled out in VA and courses are available I think on the TMS system even for motivational interviewing. That is also a technique, good communication framework that is very, very similar to VEMA. 

Moderator:Great, thank you. It looks like Twenty Mariano was the one who developed VEMA. 

Dr. Karen Seal:Right.

Moderator:I am sorry I just am completely inundated with questions right now so I am trying to listen to  you and figure this out. The next question I have here—in Dallas we have been using cranial stimulation and micro current and have case examples of success. We did not get a grant to do actual research. Have you run into others who have used this for pain and found diminished PTSD symptoms?

Dr. Karen Seal:That is a great question but no I have not, I really have no experience with that, but that sounds interesting. I am sorry that they have not been able to be funded to do further work in that area but keep trying. It is hard to get funded particularly frankly to do work in off label topics like the use of alternative pain management strategies that might also improve PTSD in conjunction with chronic pain so keep trying. 

Moderator:Great thank you. The next question here—how can community pharmacists communicate with prescribers that they feel overprescribed in a way to not alarm the patient but reject prescriptions that they feel are unsafe.

Dr. Karen Seal:I am just clarifying. How can community pharmacists communicate with providers?

Moderator:Prescribers. 

Dr. Karen Seal:With prescribers. I do not know I often receive calls from pharmacist who say things like did you really mean that or they want to talk through prescriptions that I have written. I think if a community pharmacist feels that there is a pattern that they are observing and a clinician that they do not feel comfortable I do not know the etiquette around this in the community. I feel like a pharmacist could call a clinician and discuss their concerns, I do not see why that would be problematic. 

Moderator:Great, thank you. The next question here—so there is evidence that patients with PTSD tend to have a higher usage of opioids. Is there any evidence that behavioral health treatments for PTSD can decrease opioid use in that same population?

Dr. Karen Seal:We looked at that very, very cursorily and it really needs to go and look at this more. Unfortunately there is a confounder when you look at national data and our veterans that receive more mental health treatment also tend to be our sicker veterans. Paradoxically you often see the situation. You want the answer to be more behavioral health or more mental health treatment will decrease prescription opioid risk, but what you often see because of the confound. There is a term for this but the confound of the fact that our sicker patients are getting more mental health treatment you often see just the opposite. You use that there is an association with more mental health treatment and higher prescription opioid use. I think that that is really an artifact of indications, what is it called? Confounding by indication I believe is the term. It is very hard to this analysis using national VA data and I think you would actually have to have a clinical trial to demonstrate that. 

Moderator:Great, thank you. The next question here—can you comment on the relative risk and efficacy of tramadol as compared to other opioid pain medications. 

Dr. Karen Seal:No we have not specifically looked at tramadol but I think it is a fallacy to think about tramadol as a ‘safe’ opioid. I know that I admit that I used to use tramadol thinking oh I will just give a lighter opioid, but what I actually observed clinically in my own patients, and I am just speaking for myself, is that tramadol really appeared to act no differently than other ‘stronger’ opioids. I noticed my patients getting into trouble with tramadol and developing tolerance, physical dependence and potential misuse. The only indicator I have of that was that I noticed patients requesting early refills of tramadol. I would think of tramadol like I would oxycodone, oxytocin, and morphine. I think it is a fallacy to think of tramadol as really being any different from other opioids or that it is a lighter opioid. I do not think it really works that way. 

Moderator:Okay great, thank you. The next question here—with implementation of new treatments and therapies, has there been any change in rates of ICDs containing suicide and depression?

Dr. Karen Seal:That is another great research question. There have been so many great questions for researchers that have been brought out in this call. I do not know and I think it would be great if somebody could look at that. 

Moderator:Okay great, thank you. The next question here—does the buprenorphine patch also include naloxone?

Dr. Karen Seal:Naloxone. I never used the patch myself because we have not been able to get it easily here at the San Francisco VA. What I have done is used off label, I have treated patients for pain off label with sublingual buprenorphine in lower doses. I do not actually know if there is a pharmacist on the call and they can type that in, if a pharmacist knows that buprenorphine contains naloxone I do not know. 

Dr. Robin Masheb:We did get a comment—no the patch is buprenorphine only. 

Dr. Karen Seal:I want to then comment that I do not know if it is possible, but if the patch can be adulterated and cut up and liquefied and injected then it would be pure buprenorphine, which could potentially put people at risk for overdose if they injected it. 

Moderator:Great, thank you. The next question here—primary care practitioners are the ones caught in the middle between patient demands and clinical treatment guidelines often without sufficient support to enact new recommendations. How are practitioners adapting to these changes?

Dr. Karen Seal:I could not agree with the person who asked the question more in terms of the scenario. I think primary care providers really unfortunately are feeling the brunt of these changes. We are learning new things about opioids and we are learning that we either need to not think about prescribing them as first line for chronic pain in our patients who unfortunately are on relatively high doses, think about tapering monitoring more carefully. It is frankly very, very stressful for primary care clinicians because what happens is they will try to implement these new recommendations or the VA DoD Clinical Practice Guideline is in 2010 and they get pushback from their patients. This can be extreme, I am just echoing I do not know exactly the solution. I will tell you what we have done here at the San Francisco VA in a minute, but they get pushback from their patients. Sometimes it can be extreme and patients will call patient advocate who will then bring this to the attention of hospital administration. Sometimes patients will complain directly to their Congressperson and there is a lot of pressure on primary care providers to actually not implement some of these recommendations that are being rolled out by VA and DoD right now. I could not agree with the person who asked the question more that primary care providers really are caught in the middle very clearly. The only thing that I think a medical center can do to really bolster confidence in primary care providers in going ahead and implementing what we know to be correct medical practice in terms of decreasing risk for overdose in our patients is, maybe there are other ideas out there and I would love to hear that from the community. But what we have done is just we are asking that all of our primary care providers participate in a two hour boot camp in which basically we go through, educate our primary care providers about new findings about opioids specifically focusing on the risks of opioids. We do that in a way that they can then educate their own patients about the risk. We go through how to use shared decision making to develop a pain care plan with our patients that include non-opioid alternatives. We go through the alternatives, we talk about monitoring. We go through VEMA so we emphasize how to communicate with patients in a way that patients can hear and understand why primary care providers are changing the way they have been prescribing opioids in the past. We really try to buffer our primary care providers with this type of interactive education that allows them to practice communicating with patients. That is really all I can say I am sure there are other great ways that medical centers are dealing with this right now and trying to support primary care providers. But it really is a tough situation right now. 

Moderator:Great, thank you. I have just one last question I am going to ask here and then we are going to get things wrapped up for today. We have someone who is wondering if you have declared any conflict of interest with the maker of suboxone or buprenorphine. 

Dr. Karen Seal:I am sorry I have no relationship with the maker, I do not even know who they are actually the maker of suboxone. I do not have any conflict of interest with that company. 

Moderator:Thank you. 

Dr. Karen Seal:I am glad that was the last question thank you very for pointing that out, I did not have that slide and I actually should have that slide since I am talking about buprenorphine. 

Moderator:Thank you so much Dr. Seal, this is Robin Masheb again we appreciate so much your presentation, it was really terrific. I think you can tell by the number of comments and questions we had that everybody really got a lot out of it. I would just like to give one more reminder for everybody to hold on for another minute or two so that we can get the feedback form up. Our next cyber seminar will be February seventh by Dr. Jodie Trafton, we will be sending registration information out to everyone around the fifteenth of the month. I want to thank you for joining us at this HSR&D cypher seminar and we hope to see you at a future session. 

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