Opioids, Pain, Addiction, and the Brain - Saving The Brain 2017

[Music] thank you to the entire team that's put together this symposium and I very much appreciate the chance to come and and talk with you so I'm going to talk for the first half of my time about how did our current opioid crisis which is of an enormous magnitude developed how did we get here and then in the second part of the talk I'm going to talk about opioids in the brain how do they work in acute pain what is chronic pain and what is the role of opioids in treating chronic pain which i think is something we really don't understand very well even though there's enormous prescribing for chronic pain and then how do we understand opioids and addiction so the poppy has been cultivated for many centuries it's the source of opium that thick liquid oozing out was first cultivated in the cradle of civilization the Tigris and Euphrates River by the Sumerians and they cultivated crops but also this plant they called the plant of joy and it was used medicinally was used recreationally and it was recognized to lead to major problems in early times as well it was traded wide and far the Greeks used it in their medicine Hippocrates wrote about it as morphine became a medicine that was available dr. Osler William Osler sometimes called the father of Medicine said it is God's own medicine and I learned actually in doing some reading that that was because he had kidney stones and received morphine when he had kidney stones and that's when he declared it God's own medicine so it has an enormous benefit and it is I think the most widely used medicine in the world still and the opioid epidemic that we've gotten to today is a recapitulation we've been in this place before in the developments in the 19th century when morphine was discovered by a German chemist there was commercial production of morphine in the beginning of use as a medicine in a more specific way the development of the hypodermic syringe and it was God's own medicine when in the Civil War many soldiers had to have amputations and it was like a miracle to be able to have morphine but gradually it also became clear that morphine and related products were becoming a big problem they were marketed as medicines that were available over-the-counter as well as by prescription when heroin was developed it was to be a less addictive opioid compared to morphine so it was developed by Bayer and you could get heroin without a prescription you had to have a prescription to get aspirin but you could get heroin without a prescription and you could get cocaine for your toothaches the big pharma of that time were the chemistry companies they were making enormous amounts of money they wanted to have these products on the market but the the states and the regulatory agencies began to realize what a big problem it was and there was a big fight about regulation of these products eventually there was the Pure Food and Drug Act and then the Harrison narcotics Act which was a real intense reaction to the widespread use of of opium and related products there was a great deal of addiction in late 19th century America and the police and the justice system began to prosecute addicts and also prosecute doctors who went to prison if they prescribed to an addict and the prescribing of opioids changed dramatically became much more restricted they were used in acute pain and end-of-life cancer pain and that's how it was for much of the 20th century and I think the the member the cultural memory of what happened in the late 19th century was lost for a period of time and then an interest in more aggressive and forward use of opioids began with the hospice movement so with the hospice movement there was a great deal of attention to end-of-life care to relieving suffering at the end-of-life palliative care physicians were advocating for the development of extended-release opioids and advocating for continual use of opioids as opposed to as needed use of opioids taking they thought a more preventive approach and they became began to become advocates for treating difficult pain not just in hospice patients but in other patients and simultaneously there was some very bad research that was used to advance this argument that we could use opioids for chronic pain safely so this is a letter that appeared in the New England Journal of Medicine it's about a hundred words it was a letter that came out of one of the first uses of a medical database and it was in the Boston area and about 40,000 patients who were in the hospital were looked at in terms of did they develop an addiction and they found four cases of reasonably well documented addiction in patients who had no prior history of addiction and the conclusion in the letter is that despite widespread use of narcotic drugs and hospitals the development of addiction is rare in medical patients with no history of addiction so this very peculiar small study of patients in the hospital began to be cited and this is through the 1980s with a peak around the year 1999 or 2000 began to be cited over and over as evidence that prescribing opioids to individuals rarely resulted in addiction and there was other research as well that was that was poorly founded so this is a study of the chronic use of opioid analgesics and non-malignant pain a report of 38 cases and dr. Portenoy here was head eventually of the American Pain Society a great advocate for the use of opioids in chronic pain and in going back and reading the paper he published again it's very striking when you look at the details in the paper that this became one of the articles cited as indicating that opioids could be used safely in chronic pain it was 38 cases many of the individuals did not actually improve that much with chronic opioid use and another striking aspect as I read the paper is that there was essentially no improvement in social and work function for these patients so this was cited as a paper that using opioids to treat chronic pain was safe and was effective and should be done more widely but if you look at the details of the paper the case really isn't there at the same time the regulatory agencies the professional agencies agencies like the state medical boards and JCAHO started to get behind this idea that we should be as a medical community more aggressive in treating chronic pain pain became the fifth vital sign even though it's not something you can measure in the same way as other vital sign educational material from JCAHO cited that there's no evidence that addiction is a significant issue when persons are given opioids for pain control so going back again to Jake's letter to port noise research and it turned out that Purdue Pharma who were the makers of oxycontin and who were developing that product in the mid 90s were funding a lot of these entities they were providing funds to state medical boards providing funds to the American Pain Society and became part of the wave of influence that got us thinking that using opioids in chronic pain was safe and effective and it's something we should be doing more it became such a an imperative that state medical boards began requiring that physicians get education in pain management you had to have those CMI's in your recertification by the state board and if you were under treating pain and if that came to the attention of the state board you could be sanctioned so there was just an enormous movement toward more aggressive treatment of chronic pain and along with that the development of a really remarkable advertising campaign so Purdue Pharma was a company that was founded by the Sackler three brothers who were physicians and if you want to read an interesting cultural and societal look at the Sackler family and the founding of Purdue in the development of oxycontin in the most recent New Yorker maybe one or two issues back there's a long article about how the Sackler czar renowned around the world has funders of the Arts of medical research of medical facilities and there they're looked at as great philanthropists but the background of this family if you go and look is one where while they were developing oxycontin they became aware of certain problems for instance that if the pills were crushed and snorted they could be very powerful agents of a high from opioids they were aware that even though they were marketed as a 12-hour interval product people actually started to go into withdrawal after eight hours and this was not information that was made public or acted upon the founder of Purdue Pharma Arthur Sackler had a background where in the 60s he developed a marketing campaign for valium and that was the most enormous blockbuster drug that that was of that era and he was just a marketing genius at figuring out how to market the products he made so physicians were wined and dined brought to conferences and salesmen were sent out with very detailed information and inaccurate information that they eventually got sued about explaining that this oxycontin would relieve pain in people who are suffering greatly and would not lead to addiction they cited that less than 1% of people would become addicted and interestingly if you look at where they went to market these drugs it was it maps over where the opioid epidemic is the worst so they went to the manufacturing parts of the country Appalachia places where people already had high uses of pain medications and marketed very strongly in those areas and this is a graph of what happened with pharmacy opioid prescriptions between 1991 and 2015 or 2013 with the tripling of opioid prescriptions and this the consequence of this was that quarter of individuals began to misuse their opioid medicine 10% became addicted 6 percent of the addicted individuals changed to using heroin and 80 percent of heroin users started with pain pills so people would get their pain pills they would get larger and larger supplies they would no longer be able to obtain them and then heroin became very inexpensive very easily available and people would switch to to heroin here the overdose deaths that paralleled the increase in prescribing and and this next graph really is to me one of the most striking this is drug deaths in America from 1990 to 2015 and there's several things about this that are very striking one is at the right hand side are other public health emergencies in the rates of death per year from those other public health emergencies including deaths by gun violence deaths by car accidents deaths from HIV illness and this epidemic has now exceeded all of those in terms of its public health impact the other striking thing about this curve to me is if you look at the rate of acceleration it is still enormous and has shows no signs of slowing down what what has fueling the the worsening of this crisis at this point is the availability of heroin and now fentanyl and fentanyl is a hundred times or more as potent as heroin to the extent where police handling this on the streets sometimes are overcome and just from from touching it and getting a little bit of it in their in their system here's a little more data you can see that the opioid prescriptions our arm prescribed at the highest rate in the Upper Midwest down through Appalachia into the south a little less oh in the Mountain West in the West Coast California actually is at the lower end of the rate of prescribing if you look at the rates of overdose deaths again they're concentrated in the Appalachia area within California it's more rural regions just as it is across the country that have the higher rates of overdose deaths Santa Barbara's about in the middle of the state in the rate of overdose deaths and if you want to read a one book that will tell you about the development of this opioid crisis and all the different factors that I'm telling you about briefly it would be this book dreamland this is a reporter for the LA Times who went out across the country and he initially began investigating the retail marketing of heroin because they were there were individuals from Jalisco part of Mexico who developed an expertise and an extended network of selling heroin in very small quantities and very conveniently you could call somebody up on your cell phone they would deliver to whatever location you wanted they would give you an extra balloon or two if you referred them a customer and these these individuals would go to methadone clinics and encounter people in the parking lots there to develop their customer base and became very successful in marketing heroin so so if you look at it all together with a hospice movement and the advocacy of more aggressive treatment of pain with the poor research that got behind the idea that we could treat chronic pain with opioids with the adoption of the fifth vital sign and regulatory agencies getting behind this endeavor Purdue Pharma marketing and then the availability of heroin becoming somebody called it the the Walmart evolution of heroin becoming extremely convenient and easy to get this has led to the graphs that you've seen just prior to this so another and another slice of this is that if you look at what's happening to middle-aged white Americans the red line there in contrast to other countries to other ethnic groups the rate of death among these people is increasing and if you look at the bottom part of this graph it's increasing from things like alcohol and drug poisoning chronic liver disease and cirrhosis suicide Bill Clinton's phrase was middle America's dying of broken hearts and I think I think what you're seeing is that while the opioids are good acute pain medicines and then we're thought to be good medicines for chronic pain what what was neglected was that they not only caused analgesia but they caused euphoria so they they are treating the reward system that dr. Halpern was referring to they're treating the emotional circuitry in the brain and that's what's getting captured as people are taking these medicines for chronic pain that leads to misuse and addiction so switching gears to a little bit about opioids and how they work in the brain a very very simple review that the brain has opioid receptors and we had medicines for those opioid receptors before we knew about them and the natural ligands that attach to them the mule receptor is the one that is most involved in analgesia also in euphoria they're also Delta and Kappa receptors and and variants of these of these receptors as well one interesting aspect of the cap receptor which can induce dysphoria feeling very bad is that finding agents that can block this receptor are being investigated for treating depression so if you can sort of reduce the stimulation of Kappa receptors that may be a new avenue for treatment of depression opioid receptor is a very widely distributed brain spinal cord gastrointestinal system periphery and there are endogenous ligands that attach to these we have a natural system that will provide some pain relief and that's what morphine takes advantage of is this system so opiate effects include clinical targets of analgesia cough diarrhea sedation but they also have other effects emotionally they elevate mood they reduce anxiety they reduce emotional pain and how to opioids work acutely so it's primarily in a descending tract in the spinal cord that pain fibers from the periphery when they're injured or when they release substance P prostaglandins other signals that signal pain these fibers enter the dorsal Horn of the spinal cord they synapse with second-order neurons that cross to the other side and go up the spinothalamic tract they eventually are relayed up to the thalamus and the somatosensory cortex and that's how we perceive pain and there are then signals from the thalamus from the cortex and other areas that go back to the periaqueductal gray area there and that's where morphine is released and morphine dis inhibits the descending tract that can influence the pain transmission in the lower spinal cord and the descending tract inhibits pain the net the opioids can also act directly on the inter neurons in the spinal cord may act to some degree on the pain fibers themselves so that the acute pain treatment that opioids provide is really not a central nervous system phenomenon largely there's some component of that but they're most helpful in these pain signaling tracts in the in the spinal cord and this is just another view of that that I think better shows that these signals go up to the midbrain to the thalamus to the cortex there's somatic impact so you you know where the pain is there are emotional and motivational impacts you have an idea of what to do about the pain and there is a typical pain signal for acute pain in the brain that is consistent so there are somatosensory cortex areas that are activated also anterior cingulate cortex and prefrontal cortex and thalamus all of these are involved in acute pain perception and are consistent and typical for individuals when they have acute pain but what about chronic pain chronic pain has been approached as though it's a variant of acute pain so people complain of similar kinds of symptoms the thought has been that it may be somewhat different than acute pain but it's related and probably quite similar to acute pain but in fact as there are better studies and better understandings of chronic pain in the brain is something very different and dr. Jones directed me to have carrion one of the researchers here who's done deal of research on chronic pain in the brain and he's identified a number of different ways in which chronic pain differs from acute pain chemically the dorsal lateral prefrontal cortex has reduced an acetal aspartate and there are other chemical changes as well cognitively chronic back pain and chronic regional pain syndrome patients perform differently cognitively they perform poorly on emotional decision making tasks and they have attentional and memory deficits in terms of the the brain volume and density chronic back pain patients have decreased near cortical gray matter decreased volume and especially in particular areas you can see there another quality that's different in chronic pain patients is that their pain fluctuates in very particular ways and the patterns are consistent and characteristic for different kinds of chronic pain so that you can actually distinguish just from the spontaneous pain fluctuation pattern what kind of chronic pain somebody might have and then finally brain activity is altered in chronic pain it's higher in the medial prefrontal cortex which is an area the nucleus accumbens signals - it's less active in the amygdala and ventral striatum and when you look at chronic pain each of these changes is different in different kinds of chronic pains so if you look at post herpetic neuralgia osteo arthritis chronic back pain the signature in the brain is different for each of these conditions so pain is not pain acute pain is not chronic pain and chronic pain is not one entity it appears to be a number of different entities and his summary statements are that overall the brain activity patterns and changes in morphology and connectivity show a picture that more closely resembles the addicted brain and provides no evidence of increased sensory processing so chronic pain captures the reward circuitry in the emotional circuitry in a way that's similar to addiction and alters the person's experience in a way that's similar to addiction the chronic pain changes we hypothesize reflects suffering and coping strategies that impinge on learning memory and the hedonic sub everyday experience the state of the brains emotional and motivational circuitry determines the suffering and chronic pain and the reorganization and representation primarily involved the emotional areas the limbic and prefrontal brain circuitry and minimally impinge on sensory properties of pain and I was struck as I was learning about chronic pain the similarities between chronic pain and addiction as carrion sites and other articles site with PTSD where in each case there are acquired brain changes with neuroplastic changes there's capture of the emotional limbic reward circuitry there are persistent negative effects and suffering and there's the inability to forget to extinguish experience and here's one I think particularly interesting study carrying performed on looking at 39 patients launched in their totally so they had sub acute back pain and some people with sub acute back pain go on to develop chronic pain and other people get better and they don't have any pain and he was interested in understanding what were the differences between individuals who went on to develop chronic pain as opposed to those who recovered so he followed them for one year to brain imaging each three months and initially all 39 subjects showed the typical pain matrix signature in the brain that acute pain patients have so they showed brain activity that was altered in those these particular areas anterior cingulate thalamus and so on eventually 19 I think for him it was fortunate that about half the patients got better and half didn't eventually nineteen patients recovered and exhibited no pain relevant brain activity of one year but 20 patients went on to experience persisting chronic pain in this group displayed transformation in the brain with pronounced activity in other areas such as the amygdala medial prefrontal cortex basal ganglia and no sign of the previously robust activity in the acute pain related areas and then this was this was particularly striking to me these these patients had after one year measurable reduced gray matter density in these particular areas including the nucleus accumbens and the connectivity between the nucleus accumbens and the medial prefrontal cortex at the start of the study predicted with 80% accuracy who would go on to develop chronic pain so you could measure the connections between the nucleus accumbens the medial prefrontal cortex look and see that those patients who at the beginning of the study had the higher rate of connections were the ones who went on to develop chronic pain pain so the conclusion he cites is that the main determinants of developing chronic pain is not the injury but it's the person's brain and I think this is similar in addiction as well people with a dupe want to develop addiction have a different starting point with their brain just as these chronic pain patients do I think it's similar also with post-traumatic stress disorder most people who are exposed to trauma even severe trauma don't develop post-traumatic stress disorder but a certain percentage of people are vulnerable to developing in and if you look at their brains they have measurable differences they have smaller hippocampus for instance and so so in each of these cases there's a brain difference and vulnerability that predisposes the person in this case to develop chronic pain so do opioids treat chronic pain I think the the answer to this is in part it depends and in part we don't really know very well how opiates work in chronic pain some individuals are treated with opioids and the treatment is not very effective other individuals take opioids and they're impaired they're functioning in their life is not as good when they're taking opioids other people develop tolerance and then they need to raise the dose of opioids they're taking and sometimes keep raising the dose and other patients develop hyperalgesia and Tom and I were talking a little bit about this last night that hyperalgesia is an under-recognized consequence of opioid treatment of chronic pain where individuals become sensitized to feeling pain more intensely after treatment with opioids and then in some cases treatment leads to addiction and those are the individuals who are typically ending up overdosing and dying but many others with terrible addiction problems at a lesser level and then there are some patients where treatment with chronic opioids is effective and this is where I think is very challenging for us as clinicians is is to try to understand what is best for the individual patients so here's an article in the Los Angeles Times last week by somebody who is a teacher in the University of California system who is won an award as for excellence in teaching and who says why do I feel like a criminal when I go into CVS she has chronic pain stage 3 neuroendocrine neuroendocrine cancer she's had she continues to have radiation treatment and she's in constant pain and tried many many different approaches to treating her chronic pain and what works for her is to use some vicodin and it enables her to work and enables her to function better and she's now writing this article because she's afraid she's going to be thrown under the bus as we respond to this opioid epidemic so that's to me one of the complexities of trying to understand this problem in trying to understand what to do is that some people are helped by opioids for chronic pain other people develop develop hyperalgesia so this is a review article about opioid-induced hyperalgesia which is defined as a state of no susceptance 'it is a ssin pain sensitization caused by exposure to opioids it's a paradoxical sensitivity increased sensitivity to not just stimuli the findings of the clinical prevalence of opioid-induced hyperalgesia at least in this article are not available how widespread this is it's hard to know but it's clearly one possible path that happens when people are treated with opioids it's thought to result from neuroplastic changes in both peripheral and central nervous systems that lead to sensitization and there are many proposed mechanisms and and they're actively being investigated but the pollutant emerging system the NMDA receptors seem to play a significant role and there are other kinds of factors as well so how about opioids in addiction how does addiction fit into this addiction is a term that is surprisingly widely misunderstood so when people develop a tolerance and they need to increase their dose of an opioid some people say well now you're addicted if people have developed dependence on an opioid and they're gonna have withdrawal if they stop it suddenly of people will cite that as evidence of addiction and if people develop hyperalgesia sometimes they'll be told that they have an addiction and none of these are addiction they are qualities characteristic of the medicine but they are not addiction I think I'll skip past this so so you know opioids as in many other systems as you influence the cellular mechanics opioids affect and no cyclase reduce cyclic A&P production the cell the cell adapts starts to produce more in the presence of the opioid and then when you take the opioid away the cell is overactive and producing cyclic AM P and in the case of the locus coeruleus with opioids you'll get the withdrawal symptoms but addiction is something different addiction is an acquired disease of the brain that alters fundamental biological processes that alter voluntary behavioral control and the hallmark is the compulsive use of a drug or substance despite clinical and functional impairment with substantial loss of self-control despite the desire to stop taking the drug so addiction may start as a voluntary hedonistic act you like the high from trying opioids but it changes to an altered brain that causes the loss of self regulation and the nature of addiction is that most people who use alcohol or drugs or opiates are not going to develop addiction they may develop tolerance or dependence or withdrawal but they don't go on to have addiction about 8 to 10 percent of those with significant exposure will develop addiction and what makes that 8 to 10 percent different it as in the case of chronic pain it's a different brain individuals who go on to develop addiction have a different genetic makeup they have an addiction history and themselves or their families there are differences in their dopamine le they also are at risk if they have suffered adverse childhood events and I recently read the Kaiser study about adverse childhood events and if you haven't seen that I would encourage you to take a look at it and it's a look at measurements of rates of childhood adverse events and then looking at medical and psychiatric health later in life and the results in this study are absolutely striking both in terms of medical problems and psychiatric problems trauma and PTSD predispose somebody to addiction mood disorders anxiety disorders ADHD other mental health disorders predispose people I work at our cottage residential addictions program and think that a third of the patients there who have significant addiction problems probably have attention deficit disorder high impulsivity predisposes and high exposure at a younger age addiction hijacks the reward system is the the same system that dr. Halpern was talking about ventral tegmental area that projects with dopamine neurons to the nucleus accumbens which has projections to the prefrontal cortex and then there are many other connections to the limbic system as well that's what addiction takes over so where as somebody who doesn't have go on to develop an addiction may be exposed to opioids it may experience some euphoria from them they don't have a reward system that gets taken over in the same way and this is just a illustration that it's a wider system that connects to the amygdala extended amygdala limbic system so how does addiction develop starts with binge and intoxication after the intoxication individuals who are developing addiction experience withdrawal and negative effects and then subsequently they develop craving and anticipation of drug use and the neuroplastic Changez underlying addiction include desensitization of the reward circuits the reward circuits are altered there's increased strengths of association and learning and conditioning to everything associated with the drug so if you're in a particular neighborhood or seeing a particular person or at the time of day when you would usually use all of those things can evoke a craving for the drug there's increased stress reactivity with increased cravings and there's weakening of executive functioning so the prefrontal cortex is involved the desensitization happens after the initial euphoria with the opioid the reward circuit is flooded with dopamine tolerance develops and the reward circuit resets so individuals with addiction after a while will tell you the things they used to enjoy in life don't bring pleasure anymore the reward circuitry has changed there's a dampened ability to feel pleasure and motivation for usual life activities the conditioned responses become very strong all of the memory and learning that takes place around the use of the drug becomes hardwired so that the queues lead to beginning to experience the effects of the drugs people can be exposed to cues for the drugs and start to experience the effects of the drugs because the conditioned responses are influencing the reward system so this leads to drug craving and anticipation there's increased stress reactivity so the limbic system also is remodeled and individuals develop a dysphoric negative effects state and have heightened stress reactivity and lessen stress resilience and they have increased cravings to try to obtain relief from this state and then finally the prefrontal cortex declines in executive functioning so people make poor decisions lose inhibitory control lose self-regulation and you commonly see individuals of the diction say sincerely that they want to stop and they're going to stop and then they get into a situation that provides some cues revocable craving and their ability to use their executive functioning to manage themselves through that situation is impaired so briefly the treatment of addiction involves all these different aspects stabilizing the neurophysiology buprenorphine and methadone are not simply substitutes for opioids they're stabilizing the circuitry involved in opioids it involves treating anxiety depression and negative affect rehabilitating self-care and social functioning strengthening executive functioning and allowing time for a kind of reestablishment of homeostasis in the neural circuitry and this is this is one of the very difficult things in addiction treatment is as a practical estimate people need a year clean and sober to really develop the capacities again to manage themselves without returning to use [Applause]

Channel: Cottage Health

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Rating: 4.6485357 out of 5

Keywords: Cottage Health, Santa Barbara Neurological Institution, SBNI, Saving The Brain, Symposium, Neurology, Brain, Psychiatry, Addiction, Opioids, Chronic Pain, Pain, crisis, poppy, opium, morphine, codeine, hydrocodone, heroin, cocaine, pharma, chemistry, methamphetamine, drugs, prescriptions, oxycontin, pharmaceuticals, valium, neuroscience, seminar, talk, lecture, discussion, conference, speech, address, discourse, presentation, overdose, euphoria, epidemic, endorphins, numbing, acute pain, limbic, consciousness, biochemistry

Id: 5gOEKlLjKhw

Length: 43min 26sec (2606 seconds)

Published: Fri Apr 27 2018