Transcript of Cyberseminar

Spotlight on Pain Management

**Turning the Tide of Chronic Opioid Therapy**

**Presenter: William C. Becker, MD**

June 3, 2014

*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**robin.masheb@yale.edu**.*

*Moderator:*		Good morning everyone. This is Robin Masheb. I am the Director of Education at the PRIME Center and we will be hosting our monthly meeting entitled *Spotlight for Pain Management*. I hear some background noise is somebody still.

*Moderator 2:*	We are getting some feedback. Dr. Kerns, is that you? It seems to have gone away. We’re all set.

*Moderator:*		Great. Today’s session is *Turning the Tide of Chronic Opioid Therapy.*I would like to introduce our presenter for today, Dr. William Becker. *Dr. Becker:* completed his medical degree at Temple University, his internal medicine residency including Chief Residency at Yale followed by a NIDA Fellowship in substance abuse research. *Dr. Becker:* is currently a staff physician at VA Connecticut Healthcare System where he co-directs the Integrated Pain and Opioid Reassessment Clinics. *Dr. Becker:* is currently funded by a VA HS R&D career development award to test primary care interventions for the treatment of comorbid pain in substance abuse disorders. He is also an Assistant Professor at Yale School of Medicine. We will be holding questions for the talk. At the end of the hour there will be a feedback form to fill out immediately following today’s session. Please stick around for a minute or two to complete that form. Dr. Bob Kerns, Director of the PRIME Center will be with us on the call today and he will be around to take some questions related to policy at the end of our session. Now I am going to turn this over to our presenter, Dr. William Becker.

*Dr. Becker:*	Thanks Robin, for that introduction. It is an honor and a pleasure to speak with you all today. I appreciate the opportunity to discuss a prevalent condition, chronic pain, and an increasingly used treatment modality- chronic opioid therapy. Both of these entities require thoughtful approaches at the bedside and increased attention to evidence with full consideration of the risks and benefits. I approach this as a general internist and primary care physician trained in the biopsychosocial model who has also had the opportunity to pursue advanced training and research in this field with the goal of providing useful tools for practicing clinicians. With that, let me add I have no conflicts of interest related to the content of this presentation. I will be covering a lot of material but I do want to reassure that I am going to stick around afterwards for questions. 

The outline of my talk today is as follows. We are going to discuss chronic pain, both the pathophysiology and epidemiology, then opioids...their pharmacology and their role in chronic non-cancer pain as well as the evidence base for their use and then recent prescribing trends. Then we will transition into guidelines that have been established in chronic opioid therapy focusing on some of the limitations and finally spend the remainder of the time discussing next steps in clinical research aimed at improving quality of care. 

First I would like to preview a couple of cases from our Referral Clinic over at VA Connecticut to get us thinking about the clinical challenges at hand. Some of the details of the case have been changed to preserve anonymity. 

Case one is a 29-year-old man with recent back surgery for a large intervertebral disc herniation referred for evaluation of possible opioid use disorder, AKA addiction. His chief concerns are ongoing sciatica and low back pain. Past medical history is notable for PTSD stemming from trauma experienced during active duty in Afghanistan. Now, five months post-surgery, he is on morphine sustained action 30 mg t.i.d. with oxycodone immediate relief 5-10 mg every 4 hours and has recent run out of medication early twice and been to the Emergency Department. He is non-adherent to sertraline and not following up with mental health appointments. He is mostly sedentary but intermittently engages in high intensity activities such as vigorous snow shoveling. His review of systems is notable for insomnia, nightmares, agitation and inability to sit through classes and as such is considering withdrawal from school. 

Case two is a 70-year-old man with severe spinal stenosis as well as bilateral hip and knee osteoarthritis referred for a second opinion about his opioid regimen. His chief concern is increasing frequency of low back pain paroxysm. His past medical history is notable for COPD, obstructive sleep apnea on CPAP and obesity. He has been on oxycodone immediate release 10 mg four times a day for three years and believes that its efficacy had waned and requests a dose increase. He lives independently and is active socially in the Elks and the Moose Clubs. He collects hats and enjoys traditional Hungarian dance but lately his activity is being slowed across the board by pain. His primary care provider is worried about potential consequences of dose escalation and wonders if long-acting agents would be more appropriate. 

So, we have two cases of patients with chronic pain on opioids that bring out many of the salient issues related to efficacy and safety that we’ll refer back to at the end of the talk. To help guide us in thinking about these cases let’s start by discussing chronic pain pathophysiology and epidemiology. Let’s start briefly with acute pain to serve as a contrast. Acute pain has been described as an adaptive warning signal telling us about potential tissue damage. We see light touch depicted by the feather being transmitted innocuously in green to the dorsal horn of the spinal cord via C-fibers in red to the dorsal horn... excuse me, via A-beta fibers but then...

*Moderator 2:*	I’m sorry to interrupt, Dr. Becker. Can I make sure that our presenters have their computer speakers muted and also please mute your telephone? We are getting some background noise. Thank you.

*Dr. Becker:*	Then we have heat, sharp touch and pressure being transmitted via C-fibers in red to the dorsal horn where the peripheral nervous system synapses with the central nervous system and sends pain signals to the somatosensory cortex. Notably, there are descending inhibitory pain tracks shown in yellow coming from the medulla, periaqueductal gray and locus coeruleus. The intensity of the pain can be thought of as the net effect of the ascending stimulus minus the descending inhibition. In contrast to the adaptive and protective nature of acute pain, chronic pain is generally the result of damage that has already occurred. I will discuss two explanatory models. The first is chronic inflammatory pain pictured here. In conditions like rheumatoid arthritis, pro-inflammatory chemokines cause tonic noxious stimulation of the peripheral C-fibers, leading to chronic pain. 

The second explanatory model for chronic pain is one that I think we will be talking more and more about in the years ahead and that is neuronal plasticity leading to central sensitization. Neuronal plasticity occurs when peripheral nerves are injured spurring recruitment of activated macrophages and glial cells that create an environment of disregulated nerve regeneration of both A-beta and C-fibers. This promotes what’s called central sensitization. The excess of A-beta and C-fibers in the dorsal horn of the spinal cord leads to compensatory changes in the NMDA receptors at the synapse leading to lowered pain thresholds. Central sensitization is now implicated in disease processes where pain seems out of proportion to pathology such as fibromyalgia. Some leaders in the field believe it is present at least in some degree in nearly all chronic pain conditions. 

The clinical consequences of these phenomenon are hyperalgesia and allodynia. Hyperalgesia occurs when C-fibers carry pain signals with greater frequency and amplitude leading to a heightened pain response to noxious stimuli. Allodynia, on the other hand, occurs when pain transmission is amplified in the A-beta fibers such that previously non-noxious stimuli, depicted by the feather, now become painful. Beyond what we are learning about how to explain chronic pain at the tissue level, the complexity of chronic pain is magnified by psychological factors. 

At the core is the tissue damage that we just spoke about which leads to an unpleasant painful sensation promoting thoughts like... This pain is never going away... I’m damaged or disabled... which in turn trigger emotions of fear, anger and grief, all of which contribute to overall suffering and pain behaviors which are the outward expressions that an individual displays to others that pain is present. A theme we’ll get back to later is that we can’t expect success in treating this complex, chronic condition unless we address all these aspects simultaneously. 

From an epidemiologic standpoint, chronic pain is remarkably ubiquitous and costly with a point prevalence of 25% in US adults, 10% of whom have disabling chronic pain that limits work and family activity. Chronic pain is the second most common reason for outpatient visits in the US and carries with it an annual national economic cost estimated by the Institute of Medicine of up to $635 billion dollars. The IOM also observed in 2011 that only 5 of the US’ 133 medical schools had a mandatory course on pain. 

Now let’s discuss where opioids fit in. First, a few words about terminology. Opioid analgesics is the proper term for the whole medication class together which includes opiates and opioids. Opiates are naturally occurring compounds present in opium from the seed pod of the Papaver somniferum plant, examples of which are morphine and codeine. Opioids are manufactured and can be divided into semi-synthetics such as hydrocodone and hydromorphone and full synthetics such as fentanyl and methadone.

On a side note, I avoid the term narcotic, mostly for its lack of specificity but also for its whiff of criminality. Speaking to any students in the audience, these two guys were in something called a television show. This one was called *Miami Vice*. Televisions were these enormous, heavy boxes we used to keep in our living rooms that aired shows, which only came on at specific times. In any case, these unfathomably cool characters Crocket and Tubbs used the term narcotic primarily when referring to cocaine which, of course, makes no sense at all and further underscores the need to avoid the term no matter how cool it makes us feel. 

I want to mention the concept of morphine equivalent dose that I will refer to again later. It is a method of standardizing potency across various opioid compounds based on equal analgesic tables from dose ranging studies. As you can see from this standard example, each cell on the table is equal analgesic meaning, for example, 20 mg of oxycodone is equivalent to 30 mg of morphine. Therefore, a patient on 20 mg of oxycodone three times a day would have a 90 mg morphine equivalent daily dose. 

Opioids primarily act on mu opioid receptors which are ubiquitous throughout the peripheral and central nervous system. Going back to our acute pain diagram, activation of mu receptors inhibits release of inflammatory mediators, inhibits transmission of pain signals along peripheral C-fibers, inhibits ascending post-synaptic transmission of pain signals and also activates descending pain inhibitory tracks. 

With those remarkable analgesic properties, opioids have two longstanding undisputed indications. First, in acute pain, as advocated in this letter to *The Lancet*in 1899, supporting the use of subcutaneous injections of morphine for wounded men and also a wide variety of other acute pain diagnoses such as fracture, sickle cell crisis and myocardial infarction. The second undisputed indication is end of life related pain. Shown here is the World Health Organization’s analgesic ladder for cancer related pain management, which is still used nearly 30-years later. 

Where most of the controversy and complexity lies, and what I am focusing on today, is opioids and chronic non-cancer pain. To understand this complexity, let’s first discuss three important sequelae of long-term opioid administration, the first of which is tolerance. Tolerance means that higher opioid doses are required to achieve the same analgesic effect over time due to down regulation of mu receptors with repeated exposure. It has a high prevalence. Clinically, it should be expected in chronic opioid use. Tolerance also develops to some of the toxic effects of opioids we will discuss later. Withdrawal is a set of characteristic unpleasant symptoms experienced upon abrupt cessation or lowering of the opioid dose. This is also a common occurrence in long-term use. In fact, patients on high doses can begin to experience withdrawal symptoms with one missed dose of their medication. Finally, opioid induced hyperalgesia is a specific subtype of the hyperalgesia we spoke about earlier and is a paradoxical worsening of pain with higher doses. Its prevalence is unknown but certainly lower than that of tolerance and while risk factors for it have not been clearly elucidated, there is an established correlation with total opioid exposure which can be thought of as daily dose multiplied by time and opioid induced hyperalgesia. 

Another complexity involved with long-term opioid use is the relationship between mu receptors and reward pathways. Our bodies actually produce endogenous opioids that are released when we engage in pleasurable activities. These endogenous opioids stimulate the production of dopamine in the so-called reward center of the midbrain in this region. Dopaminergic neurons project to the cortex to stimulate repeated behavior and then recurrent pleasurable feelings that the brain perceives as linked to and caused by the original activity. In the case of opioid analgesics, these medications directly activate the mu receptors that cause dopamine release in the cortex. In susceptible individuals, the pleasurable activity promoted by this reward pathway is taking the opioid analgesic. At the severe end of the spectrum, the compulsive seeking and taking of opioids supersedes in importance virtually every other activity for the patient and impairs the ability to maintain social roles, one of the hallmarks of opioid use disorder or addiction that we will discuss further in the next slide.

Opioid use disorder, also commonly referred to as addiction, is the new term introduced last year in the Fifth Edition of the Diagnostic and Statistical Manual combining the former criteria for opioid abuse and dependence, which should help eliminate some of the confusion caused by those terms. However, there are now 11 criteria that contribute to the diagnosis. For simplicity sake, I am going to just mention that they fall into three categories: physiologic sequelae, evidence of loss of control of use and adverse consequences of compulsive use. A point I want to underscore is that a patient taking opioids long-term for pain is likely to develop tolerance and would experience withdrawal symptoms if they were abruptly stopped. Those two criteria alone do not constitute opioid use disorder. There needs to be at least a third criterion to qualify for the diagnosis. Is the patient exhibiting loss of control or adverse consequences related to social role functioning? True opioid use disorder in the setting of pain treatment is fairly rare... approximately 5% of patients per year, and is likely driven by a genetic susceptibility related to mu receptor polymorphisms that we are now only beginning to learn more about. 

Besides opioid use disorder there are numerous other important toxicities and adverse effects that often complicate long-term opioid therapy, namely constipation, itching, nausea and vomiting, hypogonadism, opioid induced hyperalgesia, sedation, impaired cognition, falls and motor vehicle accidents, blunted respiratory drive and, of critical importance, non-fatal and fatal overdose. 

Recent observational overdose studies show a direct link between increasing dose and odds of serious overdose events including death. This table summarizes three such studies from Dunn, Gomes and Bohnert and as you can see, as the morphine equivalent daily dose increased in the column on the far left the odds of overdose increased steadily. The field seems to be honing in on the 120-150 mg morphine equivalent daily dose as the break point at which we see evidence of accelerated risk. 

To summarize what I have covered so far, when it comes to opioids for chronic pain there are some important limitations. Central sensitization likely plays a large role in much of chronic pain and it may not be responsive to opioids. Chronic pain has a prominent psychological component for which opioids may be particularly poorly suited. Long-term therapy induces tolerance necessitating higher doses, however, higher doses chronically lead to increased risk of opioid induced hyperalgesia and are directly correlated to increase risks of other toxicities both acute and chronic, including overdose deaths. 

With all of these potential limitations it is important for us to consider carefully the evidence base regarding efficacy of opioids for chronic non-cancer pain.

In a systematic review and meta-analysis from our section, we examined randomized control trials of opioids for chronic low back pain, the highest prevalent condition for which they are routinely prescribed. We found a surprisingly small number of RCT’s that even address this question, none that went out past 16 weeks of treatment and even in these short duration studies a decidedly underwhelming effect size for opioids compared to placebo or non-opioids. Here you can see non-significant pooled effect size and in trials where opioids were compared to other opioids, closer to a significant finding but still a pooled effect size that included zero.

Three years later, the Cochrane Collaboration examined the evidence base for long-term opioid use including not only RCT’s but also non-randomized trials and pre-post case series in a variety of pain conditions examining outcomes at 6 months or longer and concluded despite the identification of 26 treatment groups with nearly 4800 participants, the evidence regarding the effectiveness of long-term opioid therapy in chronic non-cancer pain is too sparse to draw firm conclusions. They did, however, find a medium effect size favoring opioids in study completers but completers were a small proportion of the overall sample. Importantly, no long-term studies included functional outcomes which expert consensus groups have determined should be one of the primary outcomes if not the primary outcome of pain clinical trials. 

And yet, despite these physiologic limitations and equivocal efficacy data, opioid prescribing predominantly for non-cancer pain has skyrocketed from the early ‘90’s to today as depicted in this figure. In 2012, opioid analgesics were the single most prescribed class of medication in the US... well ahead of stats. 

In a recent study of nearly 130,000 Veterans, we observed similar overall trends in the VA. You will note a decrease in proportion of patients prescribed oxycodone immediate release and codeine. In most recent data, 2012 and 2013, we have seen a leveling off and even a slight decrease in opioid prescribing within VA. Furthermore, we saw steady increases in high dose and especially long-term opioid therapy shown in red, from 1999-2010. Following nearly in lock step, and this is US as a whole- not just the VA, are trends in opioid overdose death...shown herein the yellow bars.

To offer some perspective, drug overdose of which approximately half are due to opioids, is now the leading cause of injury death in 17 states, ahead of motor vehicle accidents.

So how did we get here, one might ask? The 1990’s and 2000’s saw the rise of many contributing factors- major public health campaigns against pain such as *Pain is the Fifth Vital Sign* as well as the work of patient advocacy groups, one notable example being the American Pain Foundation, which recently dissolved in the face of a US Senate investigation in its link to pharma support. Additionally, aggressive and sometimes deceptive opioid marketing has undoubtedly been a factor. This has ranged from ill-advised extrapolation from cancer and acute pain data to more egregious acts. In 2007, Purdue pharma officials were found guilty in federal court of misbranding OxyContin. They were levied criminal charges and fined $600,000,000. But, perhaps the biggest factor is clinical inertia, which is captured by sentiments many of us I am sure have felt like... I’m not sure this is helping my patient but I don’t know what else to do... or... My patient has been on these so long let’s keep going unless a major problem occurs, both of which we’ll talk more about later. 

The bottom line is, paying attention to pain, which is a laudable and patient-centered thing to do was conflated with prescribing more and more opioids despite a weak evidence base and increasing reports of harm. 

Now that I have outlined the problems with chronic opioid therapy, let’s move into the potential solutions. This starts with understanding the treatment guidelines and building off of them. Certainly, the most widely cited and probably the most widely used guidelines came from the American Pain Society and American Academy of Pain Medicine in 2009. The VA’s 2010 guidelines were based largely on this document, the key summary points of which were as follows: Clinicians may consider a trial of chronic opioid therapy if chronic non-cancer pain is moderate or severe, pain is having an adverse impact on function or quality of life and potential therapeutic benefits outweigh or are likely to outweigh potential harms, which they considered a strong recommendation based on low quality evidence. The guidelines also promoted multimodal care, which we will discuss later on, and structured monitoring of opioid use to assess for harm and benefit with the overall message to continue opioids if and when they are safe and effective and discontinue if unsafe or ineffective. 

While these guidelines took a major step in the right direction by introducing the concept of a therapeutic trial, when it comes down to day-to-day practical issues there are significant gaps, namely, how do we systematically assess harm and benefit in an efficient and effective way? What are the monitoring tools and protocols? Specifically, what do we do once harm or absence of benefit is identified in terms of discontinuation protocols or alternative treatment options? Especially in light of the recent data that we reviewed earlier, what about dose? Should we be considering dose limits especially in primary care where close monitoring is challenging? Without the tools to perform appropriate monitoring it has been lax in primary care. We analyzed a cohort of just over 1600 patients on long-term opiates in primary care followed for up to 4 years and found that only 7% had at least one urine drug test, just under 1⁄2 had regular office visits where face-to-face assessment could take place and only 3⁄4 had limited early refills.

Similarly, without discontinuation protocols and alternative treatment options it should be no surprise that discontinuation is rare, especially with high dose therapy. Here are data from a study examining opioid discontinuation among a cohort of patients with chronic pain. In the high dose group in green, over 75% of patients were still on opioid therapy over 4 years after the start of the study. Were those 75% having robust benefit after 4 years? The clinical trial data suggests that is highly unlikely. 

And so, with these specific challenges outlined let’s spend the rest of the time discussing next steps to improving quality of care. I, for one, feel very fortunate to work in an integrated health system where leadership such as Matt Gallagher, Bob Kerns, Steve Hunt, Lucille Bergo and many others understand that improving pain care quality means a patient centered proactive approach that harnesses all the best practices that we have learned from other evidence based chronic disease management. I hope you have all seen the six essential elements of good pain care. If not, here they are for your review. I won’t read through them one by one but I will say we as the patient care and research community should look to these as a blueprint for clinical innovation and research.

To that end, I will summarize our clinical research agenda that seeks to flesh out some of these elements of good pain care. With regard to systematically assessing harm and benefit of opioid therapy, we plan to develop an easy to use monitoring algorithm.  Regarding next steps for when harm or absence of benefit is identified, we are designing and testing alternative treatment strategies and with respect to dose, we are using large national VA data sets to identify links between opioid dose and adverse outcomes to inform guidelines on dose and duration limits. Regarding development of an easy to use monitoring algorithm, each of these features I will discuss in detail in subsequent slides. The starting point will be development of a brief patient reported checklist assessing opioid safety, efficacy and misuse. We are currently testing a preliminary version of one in primary care. 

Next are three strategies promoted by the National Pain Management Program Office in the Opioid Safety Initiative Universal use of treatment agreements, routine access by providers to prescription monitoring programs and routine judicious use of urine drug testing which we have preliminary data to support as the single best method of improving quality of opioid prescribing. The development of this work is the focus of my VA/CDA which will support this work for the next two years. 

A bit more on the brief checklist for use in primary care that we are developing. We performed a systematic review of other similar instruments and found them to be too long for use in primary care and that they generally lack safety and efficacy items as they were mostly focused on misuse. Furthermore, none have been validated in actual clinical care and so our checklist will include items covering all three domains of safety, efficacy and misuse of opioids and contain 10 items total or fewer to keep it practical for primary care. It will use patient self-report and be patient self-administered. Just like with other high risk medications, it will be used on every patient, every visit and perhaps between visits using interactive voice response or other technology. It will be designed so that any item endorsed by the patient should prompt clinician follow up. 

I mentioned the *Opioid Treatment Agreement* which primary care folks well know is a written document outlining goals of therapy, the plan of care and expectations for safe opioid use that should be thought of as a bilateral agreement between the patient and the provider. Goal setting is an important step for assessing benefit and benchmarking progress. They should ideally focus on function. A nice pneumonic I like to use is SMART. Goals should be Specific, Measurable, Action-oriented, Realistic and Time bound. All three components of the treatment agreement, goals, plans and expectations should be frequently revisited and when necessary, if problems arise, prescribers should cite the agreement as evidence that harm is outweighing benefit of therapy. 

In a systematic review published in the Annals, we found that treatment agreement reduce opioid misuse but beyond that, I think when designed and used appropriately they can be a valuable tool to help open lines of communication and align goals between the patient and the provider regarding opioid therapy. 

By now, I am sure many of you are routinely using your states prescription drug monitoring program which is good, because the new Federation of State Medical Board’s guidance says that not using your PDMP when prescribing controlled substances is, and I quote, “A departure from accepted best clinical practice.” It is a listing by patient of all controlled substances filled in the state. Pharmacy reporting to the database is state law, however, VA pharmacies at least for now do not report to the database. The database allows prescribers to track multiple prescription fills or so called doctor shopping. You need a DEA number to register. As an added bonus, you can also query yourself as a prescriber. I did this a couple years ago and found 9 bogus scripts written under my name that lead to a DEA investigation and an arrest of the prescription forger- not me. Preliminary population level data are equivocal on benefit of these programs, however, prescriber level qualitative data have demonstrated increased provider comfort and confidence when using this tool. 

The last monitoring step I will mention brings together much of what I have already said and that is prescribers should have what is called an exit strategy with every patient on opioids. This includes planning up front, as part of the treatment agreement, the expected duration of therapy and discontinuation plan, the plan regarding dose, what will happen if opioids are not effective and what will happen if the treatment agreement is not followed. For example, based on the scenario a taper, immediate discontinuation and/or transition to alternative treatments. 

Speaking of alternative treatment strategies, one of the messages embedded in this section is that we as treaters may be just as focused on opioids as the only treatment option as we sometimes complain that our patients are. There is a whole range of treatment options there that we need to routinely bring in to pain care plans. This was much of the message that came across in the Institute of Medicine’s report: Relieving Pain in America from 2011 in which they laid out their vision for effective multimodal chronic pain care. We already spoke about how chronic pain is a multifaceted disorder marked by pain related functional disability and affective distress. It is frankly intuitive that mono modal therapy, especially pharmacotherapy, is not going to work. The three modality categories that should be present in some appreciable dose are behavioral therapies, pharmacologic treatments and physical activation with promotion of self-care and self-efficacy as constant factors in the background. Another constant in the background needs to be promotion of healthy behaviors and addressing comorbidities. If we don’t make a dent in either one of those domains it is highly likely that chronic pain will continue to be as disabling for the patient as it currently is. 

What are the evidence based non-pharmacologic treatments for chronic pain? Too numerous to read off to you. I know skeptics in the audience may look at this list and worry about patient acceptance, access and cost issues with some of these therapies- certainly valid concerns. My response to those concerns is that it is then our charge as a medical community to design strategies to educate ourselves, our patients and payers about why this is the sensible approach for while opioid therapy may be less expensive on a day to day basis, the costs accrued from the increasing harms far outweigh anything on this list. 

At VA Connecticut, we have developed a number of programs aimed at making multi modal pain care a reality using some innovative service delivery models and studying outcome. We have the Integrated Pain Clinic which is a two hour multidisciplinary pain assessment involving health psychology, pain medicine, physiatry and physical therapy that leads to a team discussion, a feedback session with the patient and a set of feasible recommendations for the patient aligned care team. Then for those patients with pain whose over-riding issue is unsafe opioid use, we have the Opioid Reassessment Clinic which is a longitudinal, multidisciplinary assessment and treatment clinic including addiction psychiatry, health psychology, nursing and internal medicine where we focus on treating mood and substance use disorders bundled with safer pain treatment. Recognizing that most patients don’t need the intense level of services described above, we deliver educational programming for primary care providers on how to communicate and enhance motivation for multi modal care. 

Other alternative treatments fall under the category of novel pharmacotherapies. One that is of particular interest to me is buprenorphine, a partial mu opioid receptor agonist which has been used for 10-years now as an effective treatment in opioid use disorder. As you can see from the figure, buprenorphine’s partial agonist activity means as the dose increases there is a ceiling to usual opioid effects including sedation and respiratory depression suggesting it would be safer for use in chronic pain. Is it as good an analgesic? Uncontrolled studies suggest promise but we don’t know the full answer to that yet. We have a pilot randomized trial underway funded by VA HSR&D to look at this. My hypothesis is if functional status is the primary outcome rather than pain severity, buprenorphine may in fact be superior. Other potential roles for buprenorphine all in need of testing include, as first line therapy for chronic non-cancer pain and also to assist with the transition off of full agonist opioids when either the maximum duration of therapy has been reached or full agonist therapy is ineffective or when there are intolerable side effects to full agonist opioids such as over-sedation. 

With respect to other novel pharmacotherapies, as we discussed in the beginning, much of the action if you will in chronic pain is at the interface between the peripheral nervous system (shown in red) and the central nervous system (shown here in blue and purple). Are there other receptive targets that could counteract the sequelae of central sensitization perhaps more effectively than opioids? Several agents already on the market in the class of serotonin norepinephrine reuptake inhibitors and gabapentinoids have demonstrated efficacy especially in neuropathic pain syndromes where it perhaps should be studied more broadly in other chronic pain. 

Regarding improving our understanding of the relationship between dose and adverse events, I have had the good fortune of being introduced to the Veterans Aging Cohort Study and working with Amy Justice and her team. The VACS, as it is known, is a large national prospective observational cohort study of HIV positive and demographically matched HIV negative Veterans that examines the role of comorbid medical and psychiatric disease in determining clinical outcomes in HIV infection. It harnesses the robust VA electronic health record which includes, among other things, lab, pharmacy and diagnostic data over 14-years and counting on hundreds of thousands of patients. As you can imagine, this is a golden opportunity for understanding the relationship between opioid exposure and outcomes and thus the opioid work group was started.

Just to give you a flavor of some of the work groups’ analyses, the foundational paper describing the creation of the data set as well as the demographic and clinical correlates of any high dose and long-term opioid receipt was published two years ago. We have a follow up 12-year trends analysis that I showed you data from in the introduction. A number of next steps are in the works. We will be looking at the crucial issue surrounding opioids and polypharmacy. We are planning several analyses examining the associations between opioid dose and important adverse effects such as falls and fractures, sleep disordered breathing as well as non-fatal and fatal overdose. Given this topic’s importance to Veterans’ health, we are also collaborating with the VA National Medication Quality and Safety Office to share our message and data.

And so, to wrap up, let’s go back to our cases. Case one...the 29-year-old man now 5-months after back surgery with chronic low back pain on morphine long acting with oxycodone for breakthrough who has run out of his medications early twice. Our assessment was that he had opioid use disorder evidenced by tolerance, withdrawal and craving as well as adverse consequences evidenced by his withdrawal from school. But, importantly, also poorly controlled pain and non-engagement with a multi modal pain treatment plan. 

Our treatment recommendations and plan were first to improve care coordination and assist his patient align care team, enrolled him in our Opioid Reassessment Clinic where he transitioned to buprenorphine and underwent substance abuse counseling. We provided motivational enhancement to re-engage with PTSD treatment and physical therapy. We added gabapentin to be titrated up as tolerated and we plugged them in with vocational counseling and a caseworker. 

And then case two is our 70-year-old man with severe spinal stenosis, generalized osteoarthritis and oxycodone 10 mg 4 times a day for 3-years with wanting efficacy. Our assessment was that the patient was demonstrating safe opioid use but was experiencing tolerance, a normal finding after 3-years of therapy but also that he was unable to achieve functional goals despite engagement in multi modal therapy. Our treatment recommendations were for primary care to consider a 10%-20% dose increase which would still result in moderate dose therapy at 75 mg morphine equivalent daily dose and to continue to encourage appropriate coping strategies and social engagement. Finally, to avoid a greater than 20% dose increase or a switch to long-acting formulation, out of concern for risk given his comorbidities including obstructive sleep apnea. 

In summary, despite physiologic limitations and modest evidence of efficacy, opioid prescribing for chronic pain skyrocketed. Guidelines regarding chronic opioid therapy may not curtail current trends although there is evidence within VA as safety strategies are increasingly adopted for improvement in the prevalence of long-term opioid therapy. Improved monitoring tools, discontinuation protocols and alternative treatment strategies are needed to improve safety and efficacy of chronic pain treatment. Research is ongoing to inform guidelines regarding dose and duration limits needed to decrease opioid exposure over time. 

With that, I want to thank you for your attention. I would also like to thank way too many people to name individually but a special thank you to my career development mentors Drs. Kern, Frankel and Feline for their guidance, to VA HS R&D for their support, our fabulous ORC and IPC teams at VA Connecticut including Ellen Eden , Dana Cervone, John Selinger and company and then to all the VA Painiacs I’ve worked with...Ellen Krebs, Matt Bara, Joe Frank, Nancy Wetamer, Jody Trass and Amy Bonert along with the folks. I really think VA is leading the way in this country with pain care and I am proud to be part of that effort. So, with that...I would be happy to take questions.

*Moderator 2:*	Thank you. Before we start with the questions I just want to make a quick announcement. I know a large portion of our audience joined us after the top of the hour so I want to let you know to submit your questions or comments please use that Q&A box that is located in the bottom right hand center of your screen. Simply type your question into the lower box and press the speech bubble and we’ll get to it in the order that it is received. With that, I’ll turn it over to Robin for moderation. 

*Moderator:*		Thanks Molly and thanks, Dr. Becker, for a wonderful presentation. We have a couple of questions that have started to come in. The first one refers to the patient checklist for efficacy especially with regard to the functional improvement. Could you give us an idea of what your recommendations are or what the items are about...how you would go about assessing that?

*Dr. Becker:*	Absolutely. Great question. We haven’t quite finalized the questions just yet so I’ll give you what I am currently doing in clinical practice which is identify with the Veteran what their specific, measurable action oriented, realistic and time bound goals are and try to keep it one or two goals that are all those things I just described and document that in the chart. Then, with each follow up visit, specifically ask...How are we doing with those goals? What are the barriers you are facing and so on...and really use those goals for the benchmark for whether the treatment plan is working?

*Moderator:*		Here is another great question which is...How would somebody start to make a recommendation in terms of do you go to that step three multi modal therapy as opposed to just referring to CPT for pain only or referring somebody for pain school. 

*Dr. Becker:*	I guess what we are facing here at VA Connecticut is that we developed this Multidisciplinary Assessment Clinic and now frankly we receive a lot of referrals and we now have quite a bit of a wait time which we are trying to negotiate right now. I think the models we are looking at is...once the patient shows up for their first visit and they talk about pain that is really where the six best care practices for pain care start. I know many primary care providers on call, I am sure, are well versed in this but we really need to start the push for multi modal care right away. We need to engage the patient in all the multi modal options we have at VA and compared to non-VA settings we are really fortunate for the diversity of treatments we can offer. I really think those need to be offered kind of up front and center almost in a menu-type option for the Veteran. Once that plan is launched, if there are problems with engagement or not working or other barriers that is when an integrated type clinic gets involved to help reinforce the message, potentially do further assessment but I really believe that PACT is the bulk of where this triage should be happening.

*Moderator:*  	Could you give us an example of how you would discuss opioid induce hyperalgesia with your patients? 

*Dr. Becker:*	This is a tricky one. As I alluded to in the presentation, our clinical understanding of when this occurs is still in its infancy. I do say to patients...let’s say we are at a medium to high dose and there is a discussion about whether dose escalation is appropriate...I do say we are not sure that is going to be effective and in fact, we have reason to believe it might not be effective but we know for certain that it will increase your risk of a variety of harms one of which is potentially making the pain worse which is opioid induced hyperalgesia. I don’t overplay that. I think there is enough potential harms of high dose opioid therapy that you can discuss all of those but I certainly do mention that making the pain worse is a possibility. 

*Moderator:*		In terms of using measures, have you thought about using the functional capacity evaluations that are used in worker’s comp with things that OT and PT uses?

*Dr. Becker:*	Yes, I think the instrument I described that we are developing is really meant for quick use that will be effective in primary care settings. Right now, at least in my practice we hadn’t been doing that routine so we want something that is feasible for primary care. I think those more detailed functional measures are great for further reassessment. If something is identified on screening then using a more detailed assessment is great and certainly in specialty clinics that is a great idea as well.

*Moderator:*		Interesting. Can you make a prediction... 2 to 5 years from now where would you recommend the safe ceiling dosage to be for primary care management of long-term opioids? 

*Dr. Becker:*	That comes from Dr. Sanger. Great question. Tricky one. I don’t want to stick my neck out too far but I think in 2 to 5 years 100 mg morphine equivalent in someone without potential safety comorbidities, 100 mg morphine equivalent would be the point at which I would say if not gotten benefit we should start decreasing and potentially tapering you off. I think in patients who have comorbidities where safety is a significant concern, COPD, whole list of them...then our ceiling dose should really be ratcheted down to perhaps 60 mg morphine equivalent. 

*Moderator:*		Spinal cord stimulation wasn’t listed as a non-pharmacologic option. Do you know if patients at the VA have access to this therapy?

*Dr. Becker:*	That is a good point. It was not an exhaustive list of non-pharmacologic options and as a non-interventionalist I tend to forget some of those other things. At certain tertiary facilities spinal cord stimulator is available and you just have to be aware of your local resources. 

*Moderator:*		This is a very specific question. Do you use patients on chronic opioid therapy for hypogonadism and if you find low T do you treat it? Have you noticed if testosterone replacement is successful?

*Dr. Becker:*	Unfortunately, I don’t have much experience replacing testosterone on folks who have hypogonadism due to chronic opioid therapy. I will have to defer that to my endocrinology colleagues but I can say that it certainly is something that I say to Veterans about a potential risk and I will often use it as a reason why I believe the harm is outweighing the benefit of the therapy.

*Moderator 2:*		I would like to interject real quick. I just want to mention that we are going to continue on with the Q&A but I am also going to put up the feedback questions now so please take the time to answer those and you still can submit questions. Thank you.

*Moderator:*		Molly...just so you know I seem to have lost all the questions.

*Moderator 2:*		I am going to pull that over in just a minute. Sorry.

*Moderator:*		I am going to try to recreate one that I saw which was kind of a high level question which is that in focus groups it does seem that patients are frustrated and would like some other alternatives to opioid use but that often clinicians find it is easier to just write a script and in some cases it is cheaper and takes less effort than doing this very large coordinated care and other specialized treatments. The question was...are there efforts out there to incentivize clinicians to use these other options?

*Dr. Becker:*	This is a great question. It is a matter of matching... we’ve got resources in VA for multi modal care. It is a matter of if patients are interested, getting them to those resources. I eluded to having primary care be the weight station for that and I might have been feeding into one of the problems that I currently see which is that then we are creating a bit of a bottle neck in primary care and perhaps asking primary care to do something that they may not have time to do. I think there is some balance in getting some sort of menu based option that the primary care provider introduces and then have follow up done in some other venue or having Veterans potentially access some modalities without needing to go through a referral. I am sort of tossing out ideas here but I think these are just the sorts of questions that I think are... the implementation studies that we are working on have to consider these options. It is certainly a good question.

*Moderator:*		Is Bob Kerns on the call?

*Moderator 2:*		I am going to interject real quick. To our attendees... if you do have any more questions you can simply type them into the pod that says.... it is in the bottom center of your screen... do you have suggestions for improvement? I’ll turn it over to Bob.

Dr. Kerns:	Was there a specific question?

*Moderator:*		Bob, I just wanted to say I saw your question pop up and now I have lost it so maybe you can go ahead and...

Dr. Kerns:	Great presentation. Thank you very much. My question was really about your thoughts about outcome measures for the Integrated Pain Clinic and the Opioid Reassessment Clinic and, frankly, similar kinds of efforts. I think evaluating these novel initiatives are really important but they are challenging so I guess I am putting you on the spot in wanting to know what your thoughts are about what we can do in terms of measurement particularly in the context of the folks on the call who are involved in similar programmatic efforts and those related to really addressing the opioid issue.

*Dr. Becker:*	Thanks Bob. I would say thinking about Integrated Pain Clinic, taking a step back and... what is the purpose of this clinic? It is to get Veterans engaged in multi modal care so I think the metrics should be are we succeeding in getting Veterans engaged in multi modal care and you are well aware of the challenges in terms of figuring that out from a secondary data analysis level but that is the metric I see. Are we able to match the resources to them? Are they coming to non-pharmacologic treatments? If not, why not? How can we remove barriers to their access to these treatments? Do they maintain engagement with these treatments? In terms of the Opioid Reassessment Clinic, it is a tricky one to figure metrics because I think what we are primarily trying to do there is increase safety so I think metrics around are we identifying patients who have opioid use disorder and getting them into evidence based treatment for that more quickly and are we decreasing rates of Emergency Department visits and inpatient hospitalizations are sort of the safety related questions that we are trying to measure in the ORC.

*Moderator 2:*		We do have another question that we...

Dr. Kerns:	I wanted you all to know, and to the audience, let me just say think you again Will for a great presentation and to Robin and Molly today for putting this together. I am actually going to drop off the call now because I have to go off to another presentation but I want to thank everybody for your interest and hope you will again join us for upcoming spotlight on pain management calls. Thanks. 

*Dr. Becker:*	Thanks Bob.

*Moderator 2:*		Yes, thank you for joining, Dr. Kerns. We do have another question that came in. It would be great to hear about actual outcomes of interventions to improve pain management. It seems like at this point we know a lot about what people should be doing but when they do what they are supposed to do what happens then?

*Dr. Becker:*	Right. In terms of... I guess they in this question is the providers of the patients, I am not sure. But, I totally agree. Outcomes for the multi modal efforts that we are all trying to do...we need that to drive us forward and that is certainly something I am spending most of my time on. I think it certainly is a valuable comment.

*Moderator 2:*		Thank you. We do have another request for a comment. Dunn, like other studies are retrospective med rec reviews. The editors of Dunn’s study include “a caution that it could not be determined if the rates were due to patient variables or directly due to dose.” Do you have a comment on that?

*Dr. Becker:*	Yes. This is a complex literature and I think another thing you could point to in some of the observation studies, a sizable proportion of patients who had overdose events did not have an active opioid prescription at the time of overdose, which raises questions about were these patients accessing other sources of opioids that had perhaps little to do with whatever dose they were prescribed? I think that literature is not perfect but I think we can’t, on the other hand, ignore what we probably could have guessed all along... that there is a relationship between dose and adverse effects. I think that is almost intuitive. Whether we use these data to motivate us specifically or whether we look at harm as a whole, from 35,000 feet saying we are not getting a whole lot of benefit from these high doses and we are seeing increasing harm, then we have to act. Basically that is the broad way that I think about it.

*Moderator 2:*		Thank you for that reply. I know we are at the top of the hour and we do have some remaining questions. I am happy to send them to you offline or if you are available we can go through them now to capture them in the recording.

*Dr. Becker:*	I’m happy to stay on the line.

*Moderator 2:*		Excellent. Thank you. What research has been done regarding the impact of order of intervention... that is the first part. Second part... opioids tend to be the first intervention with non-pharm treatment coming last. Offering non-pharm treatments last, in my experience, reduces efficacy due to the patient feeling dumped. 

*Dr. Becker:*	That is a really great comment and it actually points out something in my presentation that I didn’t mean to convey. I at one point described non-pharmacologic treatments as “alternative strategies” which philosophically I think of non-pharmacologic treatments as things that should come right up front alongside pharmacologic treatments. I hope I made that point in other parts of the presentation but I totally agree; it should be a bundled treatment plan- non-pharmacologic, pharmacologic and I think we should be messaging to your patients that this is really the only way it is going to work and we shouldn’t even try a pharmacologic only approach. In fact, if you are only trying a pharmacologic only approach we might have to stop it because we know it is not going to work. To answer the first part of the question about research, I don’t know specifically about the order per se but more and more multi-component interventions that are studied are doing everything at once so that is really what I am speaking to. 

*Moderator 2:*		Thank you for that reply. This is a multipart question. Regarding measuring effectiveness of integrated pain self-care training, please address: 1) Self-efficacy, 2) DVPRS for assessment for instance DOD and VA pain related rating scales mainly with four additional questions of sleep, mood, stress and activity.

*Dr. Becker:*	Yes, so...can you repeat the first part of the question? My screen just went blank; sorry.

*Moderator 2:*		Absolutely. Regarding measuring effectiveness of integrated pain self-care training, can you please address self-efficacy, DVPRS and those four additional questions?

*Dr. Becker:*	Yes. I think self-efficacy is hugely important to understand whether or not patients will engage with multi modal care plans. I know in our Integrated Pain Clinic, my health psychology colleagues do measure self-efficacy and I think it is an important moderator basically for treatment effect. I think it is a great thing to be measuring. How do we improve self-efficacy in patients who may be exhibiting low self-efficacy? I am not an expert so can’t comment on that but I think that is obviously another challenge. In terms of the DVPRS it is not a metric that I have used but I like the idea of assessing different functional spheres, sleep, relationships... those are all critically important factors to understand about success of pain treatment. It sounds like something I should look into. 

*Moderator 2:*		Thank you. The final question we have is how can we best use PACT support staff in pain management? 

*Dr. Becker:*	Yeah, that is a good question, a tricky one. I currently... in this model I described where the primary care provider sort of proposes a menu of options to begin with... I really see other pieces of PACT being the follow up to that because we lay out a menu and say that sounds good but really where a lot of the work comes in is what is going on with the follow up and is the patient engaging? I could see certainly a role for a nurse care manager to be engaged in that role. Now, assigning those resources locally is of course another challenge altogether but I do see in terms of follow up on these initiatives taking it out of the providers hands who is generally overstretched as it is and perhaps identifying other key players who could carry the ball forward.

*Moderator 2:*		Thank you very much for that reply. That is the final question. I do want to apologize to Robin for cutting you of and beginning the moderation. It was a little technical hiccough that caused it. 

*Moderator:*		That’s okay. Thank you for taking over, Molly.

*Moderator 2:*		Absolutely. I personally want to thank you for presenting for us, Dr. Becker, and also for Robin and Dr. Kerns for facilitating this and of course to our attendees for joining. Robin, I will turn it over to you and Will for any concluding comments.

*Moderator:*		I just want to thank you again, Dr. Becker, we very much appreciate it. The audience had some really great questions for you. If everybody could please complete the feedback form that has been up. I want to remind you that our next cyber seminar will take place on Tuesday, July 1st by Dr. James Toombs and Dr. Amelia Mitchell. We will be sending registration information out to everyone around the 15th of the month. Thank you so much for joining us at HS R&D cyber seminar and we hope to see you at a future session.

*Moderator 2:*		Wonderful. Thanks everybody. I will leave this survey up for a short while so feel free to take your time with any responses and have a wonderful day.

*[End of Audio]*

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