Dosing and Titrating Opioids

Moderator: Dr. Loretta Jackson-Brown

Presenters: Deborah Dowell, MD, PhD; Jane Ballantyne, MD, FRCA, and MPH; Mark Sullivan, MD

Date/Time: August 17, 2016, 2:00 - 3:00 pm ET

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Coordinator: Welcome and thank you for standing by. At this time all participants are in listen-only mode until the question and answer session of today's conference. At that time you may press Star 1 on your phone to ask a question. I'd like to inform all parties that today's conference is being recorded. If you have any objections you may disconnect at this time. I'd like now to turn the conference over to Dr. Loretta Jackson-Brown. Thank you, you may begin.

Dr. Loretta Jackson-Brown: Thank you (Justin). Good afternoon. I am Loretta Jackson-Brown and I am representing the Clinician Outreach and Communication Activity, COCA with the Emergency Risk Communication Branch at the Centers for Disease Control and Prevention. I'm delighted to welcome you to today's COCA call, Dosing and Titrating Opioids. You may participate in today's presentation by audio only via Webinar or you may download the slides if you are unable to access the Webinar. The PowerPoint slide set and the Webinar link can be found on our COCA Web page at emergency.cdc.gov/coca.

Free continuing education is offered for this COCA call. Instructions on how to earn continuing education will be provided at the end of the call. CDC, our planners, presenters and their spouses/partners wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products suppliers of commercial services or commercial supporters with the exception of Dr. Mark Sullivan and Dr. Jane Ballantyne. They would like to disclose that their employer the University of Washington received a contract payment from the Centers for Disease Control and Prevention. In addition, Dr. Sullivan would like to disclose that he is consulting with Chrono Therapeutics concerning development and testing of an opioid taper device. Planners have reviewed content to ensure there is no bias. This presentation will not include any discussion of the unlabeled use of a product or products under investigational use.

At the end of the presentation you will have the opportunity to ask the presenters questions. On the phone dialing star 1will put you in the queue for questions. You may submit questions through the Webinar system at any time during the presentation by selecting the Q&A tabs at the top of the Webinar screen and typing in your questions. Questions are limited to clinicians who would like information on prescribing opioids. For those with media questions please contact CDC Media Relations at 404-639-3286 or send an email to media@cdc.gov. If you are a patient please refer your questions to your healthcare provider.

At the conclusion of today's session the participant will be able to describe the evidence for the association between opioid dose and opioid therapy benefits and harms, compare and contrast immediate release and extended release long acting opioid formulations, identify methods for calculating morphine milligram equivalent doses, list the steps for titrating opioid and specific dose thresholds, and identify best practices for opioid tapering and discontinuation.

COCA is excited to partner with CDC's National Center for Injury Prevention and Control to offer this call series on CDC Guideline for Prescribing Opioids for Chronic Pain. Missed a call, no worries. View call recordings and earn free continuing education for the June 22, July 27 and August 3 call. All the calls are on the COCA webpage.

Today's first presenter is Dr. Deborah Dowell. Dr. Dowell is the Senior Medical Advisor for the National Centers for Injury Prevention and Control at the Centers for Disease Control and Prevention. She previously led CDC's prescription drug overdose team and served as advisor to New York City's Health Commissioner. Dr. Dowell's the lead author of the 2016 CDC Guidelines for Prescribed Opioids for Chronic Pain.

Our second presenter is Dr. Jane Ballantyne. Dr. Ballantyne received her medical degree from the Royal Free Hospital School of Medicine in London England. She trained in anesthesiology at the John Radcliffe Hospital Oxford, England before moving to the Massachusetts General Hospital Harvard University Boston in 1990. Dr. Ballantyne joined the University of Washington in 2011 as a Medical Professor of Education and Research and served as Director of the Pain Fellowship. Dr. Ballantyne has editorial roles in several leading journals and textbooks and is a widely published author.

Today's third presenter Dr. Mark Sullivan is a Professor of Psychiatry and Behavioral Sciences at the University of Washington. He is an attending physician at University of Washington Medical Center Centers for Pain Relief. And he provides the chronic pain management through the University's Telemedicine program. He has received outreach - excuse me, he has received research funding related to opioid therapy for chronic pain for several federal agencies. Dr. Sullivan helped to develop opioid guidelines for Washington State. As a reminder the PowerPoint slides set and the Webinar link can be found on our COCA Web page at emergency.cdc.gov/coca. At this time please welcome Dr. Dowell.

Dr. Deborah Dowell: Thank you Dr. Jackson-Brown. Today's Webinar content on dosing and titration of opioids is based on the CDC guideline for prescribing opioids for chronic pain. Released in March in the Morbidity and Mortality Weekly Report and in JAMA. Here are some key relevant findings from the evidence reviews for the guidelines: We did not find evidence that extended-release/long-acting opioids are more effective or safer than immediate release opioids. One study found a higher overdose risk when patients initiated treatment with extended-release/long-acting opioids than with immediate-release opioids.

In addition, disproportionate numbers of overdose deaths are associated with methadone. Given these findings, CDC recommends that when starting opioid therapy for chronic pain clinicians should prescribe immediate-release opioids instead of extended-release/long-acting opioids. The supporting text for this recommendation includes additional cautions. Methadone has a particularly long and variable half-life. Its peak respiratory depressant effect occurs later and last longer than its peak analgesic effect. Methadone should not be the first choice for an extended-release/long-acting opioid.

Only providers familiar with methadone's unique risks and who are prepared to educate and closely monitor their patients should consider prescribing it for pain. Transdermal fentanyl absorption is variable because it is affected by heat and other factors. Clinicians should only consider prescribing transdermal fentanyl for chronic pain if familiar with its dosing and absorption properties and prepared to educate patients about its use. In addition, clinicians should avoid the use of immediate-release opioids combined with extended-release/long-acting opioids.

Another finding from the evidence reviews: Benefits of high-dose opioids for chronic pain are not established. A randomized controlled trial found no difference in pain or function between liberal dose escalation and maintenance of current opioid dosage. At the same time risk for serious harm, including fatal and nonfatal overdose, increases with increasing prescribed opioid dosage. Across several observational studies, risk of overdose at or above 50 milligrams of opioids per day in morphine equivalents (or MMEs) was at least double the risk at less than 20 MMEs.

Nine well designed observational studies published since 2010 demonstrated an association between opioid dosage and opioid-related overdose. Four of these studies which used similar cut points and could be combined into one chart are shown here. Compared with dosages less than 20 MME per day, dosages of 50 to less than 100 MME per day increased overdose risk by factors of two to five. Dosages greater than 100 MME per day increased overdose risk up to nine times.

Higher prescribed opioid dosages are also associated with development of opioid use disorder. Edlund and colleagues found that compared with no opioid prescription, patients prescribed more than 120 MME of opioids for 90 days or more had a 122-fold increase in the likelihood of being diagnosed with an opioid use disorder. Because of increased risk of opioids at higher dosages without clear evidence of benefit for chronic pain, CDC recommends that when opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to 50 MME per day or more, and should avoid increasing dosage to 90 MME per day or more or carefully justify a decision to titrate dosage to 90 MME per day or more.

Note that the language in this recommendation statement refers to caution in increasing dosages. These thresholds apply to patients who are not already receiving higher dosages of opioids. So what about patients already taking higher dosages? The guideline recommends offering these patients the opportunity to reevaluate their continued use of high opioid dosages. Patients should be made aware of recent evidence showing that higher dosages are associated with increased overdose risk. For patients who agree to taper opioids to lower dosages, collaborate with the patient on a tapering plan. We'll discuss tapering in a few minutes.

Here is a brief summary of how to calculate opioid dosage in morphine milligram equivalents. First, determine the total daily amount of each opioid the patient takes. Next, convert the daily dose of each opioid to its equivalent in milligrams of morphine. To do this, multiply the dosage by the conversion factor for that opioid. You can find the conversion factor for commonly prescribed opioids in the MME table in the Guideline or on our calculating dosage fact sheet available at cdc.gov/drugoverdose.

Finally, add daily MMEs for each opioid together to determine the patient's total daily dosage. Here is the MME table from our Calculating Dosage Fact sheet. Note that these conversion factors should not be used to convert one opioid to another. There is incomplete cross tolerance when changing to a different opioid. In order to avoid overdose, the new opioid should be dosed substantially lower than the old opioid.

This table includes many of the most commonly prescribed opioids but not all opioids. Buprenorphine is not included because it is not likely to be associated with overdose in the same dose-dependent manner as are pure opioid agonists. Tramadol and tapentadol have mixed mechanisms of action with effects at opioid receptors in addition to other effects. We include a conversion factor for tapentadol of 0.4 in the MME table in the Guideline. Others have used a conversion factor 0.2 for tramadol. But we don't know whether or not these drugs are associated with overdose in the same dose-dependent manner as pure mu-receptor agonists.

In our last Webinar, we discussed how to assess benefits and harms of opioids for chronic pain. CDC recommends that if benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids. Work with patients to taper opioids down or off when there is no sustained clinically meaningful improvement in pain and function, when patients are on high-risk regimens such as opioids with benzodiazepine or dosages of 50 MME per day or more without benefit, when patients request dose reduction or discontinuation, or when patients experience overdose, other serious adverse events, or warning signs of adverse events.

Here are some key points to keep in mind when tapering. Taper slowly enough to minimize opioid withdrawal. A decrease of 10% per week is a reasonable starting point. Some patients, especially patients who have been taking opioids for years, will do better with slower tapers for example a reduction of 10% of the original dose per month.

As long as the dosage is going down it isn't usually urgent to taper quickly. Tapering plans can be individualized based on patient goals and concerns. There are some circumstances such as an overdose on the current dosage when more rapid tapers should be considered. Make sure to access appropriate expertise for tapering during pregnancy because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal. Remember to optimize non-opioid pain management and psychosocial support. Anticipate hyper-analgesia or increased pain immediately after tapering; but you can reassure patients that over the long term, most patients who have tapered opioids report improved function without worse pain.

CDC's Pocket Guide on taping opioids was released yesterday and can be found in the Clinical Tools section of our Guideline Resources at cdc.gov/drugoverdose. I'll now turn the floor over to Drs. Jane Ballantyne and Mark Sullivan who will discuss how to apply these principles in the management of chronic pain.

Dr. Jane Ballantyne: Thank you Dr. Dowell. This is Jane Ballantyne. What Dr. Sullivan and I are going to do is discuss two cases that are illustrative of the guidelines that Dr. Dowell has just outlined for you. The first case is a female patient Ms. Brown. She's 67 years old and she has spinal stenosis. She's had steadily worsening symptoms of leg pain, back pain, leg numbness and tingling and difficulty walking. And she now finds it difficult to start moving and ambulating in the mornings.

She's a very motivated patient. She tried a lot of interventions. She's been doing aqua aerobics, graded exercise. She's been helped by physical therapists. She tried several medications including amytriptyline, gabapentin, and tramadol. Because of her age she hasn't been using nonsteroidals.

Just as an aside, I will ask the question about the decision being made whether she is a suitable candidate for opiates. As was been discussed in previous CDC Webinars, a very important part of the treatment is deciding whether a patient is a suitable candidate and that decision is based on the benefit versus the possible harm. In this case, she's an older patient and older patients tend to have less risk at least of abuse. They obviously have risk of other things such as respiratory depression and falls and fractures but are less likely to abuse opiates.

This patient alert isn't stated in the case description. She doesn't have a history of abuse or any psychiatric history or posttraumatic stress disorder which again makes her low risk. On the benefit side, she's tried everything else. And because of her age, some of the treatments that might be appropriate in a younger patient such as aggressive exercise regime or nonsteroidals are not really available to her. So on balance, the decision was made to offer her a trial of strong opioid. The possible benefits include improving her function. And in fact another aspect of this case is that or any case is that we wanted to be goal directed. In this case, the goal of this treatment is to improve her function.

So having made the decision and patient agreeing to try a trial of a strong opioid, which opioid are we going to choose? Dr. Dowell has already outlined some of the thinking behind what opioid choice we would select now that we have new evidence particularly about the longer acting opioids and the dangers of using long-acting opiates. We would suggest choosing something simple with simple pharmacokinetics and pharmacodynamics. That's because patients find it much easier to manage and it's safer. We have an active recommendation not to use long-acting opioids at the beginning of the treatment with an opioid naïve patient.

And just as a note the long-acting opioids include not only the preparations that make standard opiates such as morphine, oxycodone, hydromorphone and hydrocodone longer acting but also methadone which has inherently long half-life, and transdermal fentanyl which is made to have a long half life because of its transdermal absorption. So the CDC guideline words are written on this slide just to reiterate: choose a drug with a predictable pharmacology, avoid ER/LA opioids at the start of treatment.

So why not start with the long-acting opioid? Quite apart from the evidence that the long-acting opioids are probably no better in terms of either efficacy or safety there also the issue that these preparations tend to be much higher doses than would be suitable for the initiation of treatment particularly in an opioid naïve patient. As it happens most patients actually prefer taking their opioid as needed rather than round the clock and paradoxically most patients find it easier to control the usage if they're not taking it round the clock.

You would tend to think that if you're told to take your medication at 8 o'clock in the morning and 8 o'clock in the evening that would be easier. But because pain patients are different they actually prefer being able to choose- they find it easier to not overuse opiates if they take the opiate as needed. And also the doses overall tend to be much lower if immediate-release opioids are taken intermittently. And no opioid is taken around the clock and that's probably because taking opioids around the clock is going to lead to much more tolerance.

So is there a role for long-acting opioids? Yes there is, but not at the start of treatment. They have a role when treating end-of-life pain and when treating some serious long-term pain conditions, not necessarily cancer. And yes they may have a role when a patient does have difficulty controlling usage. For example someone who develops a serious pain condition that warrants opiate treatment but has a history of substance use disorder, those patients may find it very difficult to take as needed or to control their usage if they're taking it as needed.

And we now recommend not using the long-acting opiates in conjunction with immediate-release opioids except during palliative or end-of-life pain care. And that's also because doses tend to escalate much more if you're using a combination and particularly because the around the clock usage leads to tolerance.

So why not methadone? Methadone is a very complicated drug. Dr. Dowell has already described some of the pharmacokinetics of the drug, that are possible cardiac effects. There are many, many drug interactions.

So it's possible that during methadone treatment if something changes with a patient, particularly if they're put on a new medication, that may alter the clearance of methadone. And apart from being very long-acting the clearance is also idiosyncratic. That means you can't necessarily predict it and that can be a problem particularly at the start of treatment. The other reason we tend not to use methadone for the treatment of chronic pain is that it's very hard to get off methadone and so it's not very easy to titrate to effect. It's a dangerous tricky drug to use and should be reserved for specialist, cancer pain, or addiction treatment.

Why not fentanyl? Well even the lowest dose is too high for the start of the treatment. And as Dr. Dowell said, the absorption can be unreliable. Heat alters the absorption, and it's not again, just like methadone, not possible to titrate to effect or provide intermittent or as needed doses. The patch is recommended for 72 hours. It's often used for 48 hours, but still that's a long time where you have no control. You can't up or down the dose.

So what was the choice of Ms. Brown? Her physician decided to try a very low dose. That is 2.5 mg of oxycodone and half a tablet every four hours as needed. This also speaks to CDC Recommendation Number 5 to use the lowest dose effective dose and carefully assess the effects. And as they say, and we'll get to later, not increasing the dose to more than 50 morphine equivalents and to have special cautions at more than 90.

As it happens when Ms. Brown came to the clinic for follow-up a week later, she reported no improvement but she was tolerating the opioid well and taking it as prescribed. Her physician thought it was worth trying an increase in dose. It is true that, at the beginning of treatment, sometimes it is necessary to titrate up to be able to achieve the minimum effective dose. So in this case she had a dose increase -- and in fact had two further dose increases -- and stabilized finally at 5 milligrams four-hourly, take up to four times daily.

The seventh recommendation in the CDC Guideline emphasizes the importance of reevaluating benefits and harms regularly. It's suggested that within one to four weeks of starting a reevaluation is made, and from then onwards, every three months or even more frequently. And that's an important milestone or goal point because after three months if you've been taking opioids continuously it - you're very unlikely to come off opioids. So the initial evaluation is very important. At her three months follow-up she came to her appointment with her daughter who said that her mother was drowsy all the time and getting out and about even less than before. So the decision at that point was made to taper off the opioid. And that was agreed by the daughter, the mother, and the physician.

So how do we do a straightforward taper? What we recommend is not to try to taper too quickly even for someone who hasn't been on opioids for very long because it's a real disincentive to tapering if you get unpleasant withdrawal symptoms. And an important symptom of withdrawal is increased pain. A reasonable regime for her, since she hasn't been on opiates very long is what Dr. Dowell suggested and what is in the Guideline that 10% reduction per week until she's off completely. You need to warn about possible symptoms and be prepared to treat them if necessary. I was going to ask Dr. Sullivan if he had any comments on this case or would like to add anything before we move to the next case?

Dr. Mark Sullivan: Jane thanks. Yes, I think this is a very reasonable approach for Ms. Brown. But it's important to remember that we don't have good efficacy data. And I like the way that you followed comprehensive sense of patient benefit. We're not just looking at pain intensity, because we're trying to make Ms. Brown's life overall better. And it sounds particularly with the help of her daughter we're able to see that opioid did not do that. So I thought it was a nice comprehensive look at benefits.

Dr. Jane Ballantyne: Thank you. So the next case is a male patient 55-year-old Mr. Casey. This is a very different case. This is a patient who's been on opioids for some time and was treated a long time before the new CDC Guideline came out. So he's one of the patients that we've also talked about when we've been running through the CDC Guideline and what it means to primary care physicians when they're treating chronic pain with opioids. And that is that the patients who were treated by the older regimes really need to be treated differently. The CDC guideline is mostly aimed at making sure we don't get future patients into the condition that he finds himself in.

He is a 55-year-old self-employed truck driver who's had back pain for seven years and that started with a back sprain injury. When he was initially evaluated he was found to have a disk protrusion but it is now resolved and he has an MRI currently that's consistent with his age. And he also has a normal exam.

He's been treated with opioids since the initial injury. His current regime is 30 milligrams of OxyContin three times daily with 30 milligrams of oxycodone six times daily and intermittently as needed. When you calculate his morphine equivalent dose at that daily dose, that's 405 milligrams. So as you can see, he illustrates some of the things that the CDC Guideline is now teaching us not to do.

One of the things that wasn't actually discussed in this Webinar but has been discussed and is the Guideline is the importance of limiting initial treatment to-- especially for acute pain -- to three to seven days. Another that we have discussed is that is not continuing opioids if the functional goals haven't been reached. Another is not to exceed the dose of 90 or to have special precautions in place if the dose does exceed 90 but in general not to exceed even 50 but 90 being the new thought for a so-called ceiling dose and finally not to use a combination of extended-release and immediate-release opioids.

So he'd actually tried other medical and nonmedical treatments but he says, and this is common with our patients, that none of them work other than the opioids. He works at night to try and make up for time lost during painful episodes. He doesn't remember what it's like to sleep well. His wife of 18 years recently asked him to leave because he's dragging down the family. And he's convinced that opioids are the only thing that enable him to work.

So what are you going to do? Now you know that his opioid dose is higher than currently recommended. His function is poor and his life is in tatters. He's almost certainly dependent on opioids having been on high doses for seven years. It will be very hard to persuade him to taper and very hard to achieve a taper. And he will need a lot of ancillary help if he's going to improve.

So again just to reemphasize CDC Guideline Number 7 that reevaluation should take place frequently during early treatments and at least every three months during established treatment. And that allows the treatment to be discontinued if it really isn't helping. And in many cases since for his type of pain opioids may not be recommended these days anyway he might have been tapered off much, much earlier than the seven-years point that we've reached now.

So how do we taper in a patient who's been on opioids for a long time? It's not as easy as for the female patient who hasn't been on opioids for very long. It's important to spend as much time as necessary convincing the patient that tapering is the right thing to do because a cooperative patient who is agreeable to a taper is going to be much more successful taper. And it may take more than one visit. It may mean you have the discussion, let him go away and think about it, maybe even have a second third time but try and get him on board. So taper slowly. In this case, I would recommend tapering more slowly than 10% a week because of the duration of the treatment of seven years.

So you could try a 10% reduction per month. Always be prepared to stop and give it a rest or let it plateau for a while because tapering is terribly difficult. And what a lot of patients who are tapering will experience is initially they feel okay but there comes a point where they begin to think they're not functioning as well as they were when they were on the higher dose and they start pleading for you to give the higher dose back. And that usually all goes away if you just give it time.

As long as the trend's downward the amount of time doesn't matter. And it's also important to never go up again - as long as the taper is progressing even if it's taking years that's not important. What's important is not to increase the dose again. Sometimes it's difficult when somebody has an added injury, surgery, or trauma. But the general principle for that event is to always go back to the pre-event dose as soon as possible after the event to use whatever opioid is needed during the acute period but to restore the pre-event doses as quickly as possible.

Sometimes it's necessary or desirable to do a rapid taper. And in that case buprenorphine is a useful tool. In fact, buprenorphine we find since we do quite a lot of tapering is very, very useful in a lot of patients. But as you probably know buprenorphine, especially for the treatment of opioid disuse - problematic opioid use, needs to be done after training and obtaining of a waiver from the DEA. But I would strongly urge anyone who has a lot of these patients and who's struggling with these patients that they get the training because the training helps to treat them anyway even if you don't use the buprenorphine. And if you do use the buprenorphine in select patients it actually can be life-changing for them.

So work with patients. This is actually the CDC wording. Work with patients to taper down or off when there is no meaningful improvement in pain and function as was the case with Mr. Casey. Try and get down to a target of 50 or ideally off all together. It's problematic when patients that - are also on benzodiazepines. And they often are also on benzodiazepines because of the old principles of treatment often included adding an anxiolytic. You then have to choose what we would recommend is that you taper either the opioid or the benzodiazepine. And sometimes it's easier to taper the diazepam - the opioid first and the benzodiazepine second. The general principle is no patient should be on both opioids and benzodiazepines. This is the CDC wording. So I would now like to ask Dr. Sullivan if he has anything to add to this case.

Dr. Mark Sullivan: I would simply add that patients like this often do have psychiatric comorbidity, anxiety, depression disorders most importantly PTSD. But diagnosing and addressing this disorder can be a crucial component of a taper strategy because oftentimes taper will unmask the disorders and that can cause a taper to be aborted, lose contact with the patient, they can go to the street for drugs.

Staying engaged with them, stressing that you're not going to abandon them, doing your best to provide alternative treatment for any underlying mental health disorders is something that we've found to be pretty important in our tapering clinical experience and in a trial that we just finished.

Dr. Jane Ballantyne: Thank you.

Dr. Loretta Jackson-Brown: So thank you presenters. Dr. Ballantyne do you have additional comments?

Dr. Jane Ballantyne: No. I was just going to say maybe we want to hand it over to questions.

Dr. Loretta Jackson-Brown: Wonderful. So thank you presenters for providing our COCA audience with such a wealth of information. We will now open up the line for the question and answer session. Questions are limited to clinicians who would like information on prescribing opioids. For those who have media questions please contact CDC Media Relations at 404-639-3286 or send an email to media@cdc.gov. And remember, if you are a patient please refer your questions to your healthcare provider. When asking a question please state your organization and also remember you can submit questions through the Webinar system. Coordinator?

Coordinator: Yes, thank you. We will now begin the question and answer session. If you'd like to answer - to ask a question please press Star 1, unmute your phone and record your name clearly. Your name is required to introduce your question. If you need to withdraw your question press Star 2. Again to ask a question please press Star 1. It will take a few moments for the questions to come through. Please stand by.

Dr. Loretta Jackson-Brown: So while we're waiting for the first question for the phone I do have a question from the Webinar system. And it is has anyone actually seen a patient stop taking buprenorphine? Is it realistic to suggest that it's rapid way to taper off opioids?

Dr. Jane Ballantyne: Yes, are you hearing me?

Dr. Loretta Jackson-Brown: We are hearing you. Continue.

Dr. Jane Ballantyne: Okay, so this is Dr. Ballantyne again. Buprenorphine is a very different opioid. It's not a pure μ-opioid agonist. It's a powerful agonist and antagonist. So it has some particular characteristics not all of which I have time to go into. But one is that it will occupy the receptor and make the use of a second opiate unpleasant or at least ineffective. And it will also occupy the receptors very rapidly so that if someone's on an opiate already or taking heroin you can do what's called an induction. And that is to deliberately put them into withdrawal or in the case of a heroin user they let themselves go into withdrawal.

And the buprenorphine is a very effective treatment for the withdrawal. So you can actually get people off very high doses quite quickly and buprenorphine will successfully treat the withdrawal. And there isn't really another drug that will do the same thing without replacing the opiate. In other words it can do it is a much lower dose. Other opiates can treat withdrawal but only at higher doses. So that can be a first step to stabilizing a patient either maintaining them on buprenorphine or just using buprenorphine for a week or two to get them off opiate all together.

Dr. Loretta Jackson-Brown: Thank you. Coordinator do we have a question on the phone?

Coordinator: Yes our first question is from Mordecai. Go ahead. Your line is open.

Mordecai Potash: Okay. Hi. This is Mordy Potash at Tulane University. I know buprenorphine has been mentioned on several of the calls. And one thing that's kind of a curious dichotomy is although buprenorphine is being recommended and advised for good reasons in several areas of the country it is a highly, highly diverted medication and that local and state regulatory and law enforcement agencies are trying to discourage more Suboxone clinics from opening.

And also a high prevalence of Suboxone practices, you know, seem to have some of the unsavory characteristics of pill mills such as absolutely not accepting insurance, accepting cash payment only and spending very little time with the provider with odd hours. And so there's this I'm wondering if the presenters can address that dichotomy where some providers legitimately feel that there are some government agencies that are recommending more training, education and involvement in buprenorphine treatment and other state local agencies recommending that doctors abstain from getting involved in that?

Dr. Jane Ballantyne: Well I'll comment on that first and then see if Dr. Sullivan wants to add anything. I mean first of all buprenorphine when used legitimately is a very useful tool particularly for the treatment of opioid independent individuals. When it's diverted and used illegitimately it's usually sought because it's effective at treating withdrawal. It's not a drug that gives you a particular high. So just as methadone became very popular as a street drug, similarly buprenorphine it is true has become popular as a street drug mainly though for the treatment of withdraw because there are so many people who've become addicted now and are seeking drugs like buprenorphine and methadone just because they feel better.

There's no doubt there is crime associated with this. There's no doubt there's some illegitimate behavior and pill mill sort of activity. But even if all that's happening buprenorphine is still a lot safer than heroin and in fact a lot safer than all the other opioids. So nobody would advance or promote diversion or misuse of buprenorphine. But just, you know, the fact that it's - it is diverted and misused should not be a reason to not recognize it as a useful tool when used legitimately. I wonder if Dr. Sullivan wants to comment, or Dr. Dowell, in fact?

Dr. Mark Sullivan: Yes, I completely agree that despite its problems, buprenorphine is just so much safer an opioid and such a better alternative than either street opioids or frankly the other Schedule 2 opioids that while I think we can improve standards for buprenorphine clinics, I know that here in the state of Washington, we've just had a lot of trouble getting adequate buprenorphine availability, particularly away from urban areas. There's just rural areas that are desperate for treatment of opioid use disorder and the folks who live there can't drive the many hours that it takes every day to get to a methadone clinic. So it's not a perfect tool, but I agree with Dr. Ballantyne, it's valuable and safer than the alternatives.

Dr. Deborah Dowell: And this is Dr. Dowell. I would agree with what Dr. Ballantyne and Sullivan have said. We know from national studies that in most of the country there is inadequate access to medication-assisted treatment. And medication-assisted treatment has very good evidence as an effective treatment for opioid use disorder. We think that at least some of the diversion that we see is for the reasons that Dr. Ballantyne alluded to--that buprenorphine is treating withdrawal, it's not... When studies have been done about, you know, drugs of choice and likability of drugs to get high, buprenorphine is not high or anywhere on that list. It is not going to be the drug of choice among other alternatives such as heroin or prescription opioids that are pure mu antagonists. And it may be that increasing access to treatment with buprenorphine, done well, you know, with counseling may decrease a lot of the diversion we're seeing that's due to diversion for use to self-treat withdrawal.

Mordecai Potash: If I can make one other point about buprenorphine. I spoke with several clinicians who've gone through the training for buprenorphine for their existing practice. They feel that it would be useful as part of their existing practice. And then they get placed on a list at some point and their practices at times get flooded with calls, you know, asking for treatment which is really outside of, well outside of what they intended to use buprenorphine for. And in a way, it becomes more trouble than it's worth.

Dr. Jane Ballantyne: Well I appreciate that - understand that and I know that's happening. And I know a lot of people are reluctant to get the training for that reason. And, you know, it's something we have to tackle because if more people have the training then there wouldn't be only few people burdened with all of these difficult patients. They are a challenge. But, you know, the fact is that the prescribing recommendations over the last 20 years have produced thousands if not millions of people on doses of opiates that we no longer consider safe and we need to respond to that.

Dr. Loretta Jackson-Brown: Wonderful. Let's go on to the next question so we can hear some more from our participants. Coordinator do we have another question on the phone?

Coordinator: Yes. Our next question is from Elizabeth. Go ahead your line is open.

Beth Bilden: Yes. This is (Beth Bilden) in Duluth, Minnesota. And my question you've - I think you answered part of it but with regard to using buprenorphine during a rapid taper. You know, with the high affinity for the μ-receptor for the partial agonist component my first question was going to be how are you avoiding withdrawal, but it sounds like you anticipate the patient will develop withdrawal during that rapid taper if you offer this. Then how are you counseling them and really convincing them to do this?

Dr. Jane Ballantyne: Well, you know, someone who's using opiates illegitimately goes into withdrawal all the time. And when they are seeking help they understand that they need to go through the withdrawal and then they can use the Suboxone to treat their withdrawal and they're usually completely on board. It's true that the pain patient is very different. The pain patients are in a different situation. But I think if you talk to them and they understand it's not that the withdrawal lasts very long. As soon as they're in withdrawal you can start the buprenorphine.

You can also give them medication to treat the unpleasant symptoms. And we do it in our clinic actually in the clinic. You know, we don't expect them to be at home for days suffering withdrawal. They come into the clinic and we assess their symptoms and if they're in full withdrawal then we start the buprenorphine. I mean it's not completely pleasant. There are symptoms but it is a way of rapidly reducing the opiate. Also, sometimes you have to rapidly reduce it because it's just not safe, or because one physician is just not willing to prescribe a very high dose if another physician who's retired or the patient's moved a state was willing to prescribe. So the withdrawal they would suffer if they didn't have a buprenorphine induction as it's called would actually be far worse. I don't know if Dr. Sullivan wants to comment?

Dr. Mark Sullivan: I don't have much to add because I really completely agree with it that the - just as long as your patient is in withdrawal they shouldn't experience further withdrawal when you do the induction. And the safety of the treatment is really so positive, such a real advance that I think the Buprenorphine is worth doing.

Dr. Loretta Jackson-Brown: Okay wonderful. We're going to pull a couple of questions from the Webinar system. And one has to do with whether or not blood levels need to be assessed to verify whether or not a patient may be on street drugs. Is that a part of the practice that you all utilize?

Dr. Jane Ballantyne: We don't generally use blood levels. We use urine, you know, advanced analysis in the lab. We just don't use the simple clinic dipstick. In fact we do use that but we don't rely on that. If there's any suggestion of aberrancy then it's followed-up with a more extensive evaluation in the lab. Its urine testing is complex and so we always ask the people doing the testing to advise us is what a result means especially an aberrant result but we don't usually use blood.

Dr. Loretta Jackson-Brown: Okay.

Dr. Jane Ballantyne: Dr. Sullivan you want to comment?

Dr. Mark Sullivan: Yes. I think that the urine drug screens are very reliable for detecting illicit drugs. Of course you need some sophistication. There's some drugs like cocaine that are very rarely a false positive, others like amphetamine where there is more of that problem. But it is a valuable tool and I agree with Jane that having a toxicologist you can talk to about findings is helpful and confirming any negative findings that might affect care with something of the highest quality like the gas or liquid chromatography is important as well.

Dr. Loretta Jackson-Brown: Okay so thank you. So Dr. Ballantyne related to the case study for Mrs. Brown we have a participant who wants to know that after opiates are stopped what's the next strategy for pain control?

Dr. Jane Ballantyne: Well, you know, she has been a very good patient and tried a lot of things. I think that medication probably isn't the answer. She's had a trial of many medications including now opioids. I think she should continue to do things like aqua aerobics. But people of her age stretching can be helpful. And, you know, I'm not a great fan of surgery or injections but sometimes epidural steroid injections especially if there is a radiculopathy can help, you know, keep people with spinal stenosis going for a while.

Unfortunately spinal stenosis tends to get worse with increasing age but you can hold off the pain sometimes with steroid injections. And there are some very simple procedures sometimes although I think the days of doing elaborate spinal fusion surgery have passed thank goodness. So I think I would just encourage her to continue the exercise and to gather advice about whether injections would help.

Dr. Loretta Jackson-Brown: All right thank you. Coordinator do we have another call on the phone?

Coordinator: Yes. Our next question is from Robert. Go ahead your line is open.

Robert: I had two questions. The first you answered. The second is we had heard that SAMHSA would be offering the buprenorphine training for free for physicians. That's not apparent on the website how you do that. I was wondering if you had information about that?

Dr. Jane Ballantyne: Dr. Dowell may have information about that.

Dr. Deborah Dowell: I don't know specific information about that but we can talk - we can find out from SAMHSA and get back to you.

Robert: Thank you.

Coordinator: We show no further questions at this time.

Dr. Deborah Dowell: Dr. Jackson-Brown, I saw question come in through the Web chat about the threshold cut points. Should I address that? Do we have time?

Dr. Loretta Jackson-Brown: Yes, please.

Dr. Deborah Dowell: So the question was, "Please discuss the rationale for threshold cut points for 50 MMEs per day and 90 MMEs per day as most studies use 100 or 120." And thank you very much for that question. The 120 MME's per day was something actually used in Washington's state guidelines several years ago and that was actually before many of these studies on the relationship between dose and overdose came out.

My understanding is that that was a pragmatic cut point based on the numbers of patients who were receiving more than 120 MMEs per day at that time. Since that time a number of well-controlled, well-designed controlled observational studies have come out showing a relationship between their prescribed opioid dosage and overdose.

And they've used somewhat arbitrary cut points: zero to 20 MMEs 20 to 50, 50 to 100 and above 100. We looked at a more granular level in a national database of Veterans Affairs patients and we did a case-control study. And we found that among patients prescribed opioids and dying of fatal opioid-related overdose the mean prescribed dosage was 98 MMEs, suggesting that cutoffs of 120 or 100 are too high.

In addition, we found that the decedents from opioid overdose among patients prescribed opioids at more than 120 MMEs would only - only 21% of patients dying of opioid-related overdose were prescribed that level, whereas at 50 MMEs a majority of cases dying of opioid related overdose were prescribed 50. And overwhelming majority of patients not experiencing fatal opioid overdose--76%-- were prescribed less than 50 MMEs. So that - those were important parts of the rationale in determining those dosage thresholds. Thank you for that question.

Dr. Loretta Jackson-Brown: Thank you Dr. Dowell for that wonderful explanation. And so another question from the Webinar system Dr. Ballantyne it is related to your second case study. And the question is, "Can you give a couple of suggestions on how to convince the patient to taper particularly some talking points about dealing with a patient when they feel that they don't need - when they feel they need the opioids but they are not experiencing any adverse effects?

Dr. Jane Ballantyne: Well thank you for that question. The first thing is I didn't actually say this but one thing that's terribly important and helpful and that's convincing someone to change and to try coming off opiates is to include the family because often the family, the family's perspective is very different from the patient's perspective. Patients who are on opioids have a very strong belief system that they need the opiate and the opiate is the only thing that's helping them cope with their pain. And sometimes it's only the family that sees the function of their loved one is actually deteriorating, that they're not getting good pain relief, that they're not participating in life, they're having problems with their social life and their family life. And they see that much more clearly than the individual.

And then the other part of it is really convincing people that the evidence has changed and that we now understand safety and efficacy of opiates in a very different way than we did 20 years ago. And that in a way is the most difficult to convince people about because they feel sort of injured by doctors they've lost - they tend to lose trust. They say, "You told me to take this and now you're telling me it's not safe and it might kill me." And those I wouldn't say I wouldn't belittle the difficulty of those conversations. They are very difficult conversations to have.

But it's part of the skill of, you know, of successful treatment. It lies in the skill of being able to have those difficult conversations and persuade people that their treatment is unsafe and also persuade them that at the end of the taper they will feel much better. And they really will. That's an overwhelming experience with people that we've worked with to lower their dose and ideally get them off altogether. I don't know if Dr. Sullivan wants to comment?

Dr. Mark Sullivan: I would stress a couple of things. One is that even the patients that seemed very dedicated to their opioids will say things like, "you know, if my pain could be controlled I would love to come off" or "I really wish I didn't have to take the opioids." So there's a lot of ambivalence that you can explore using motivational interviewing techniques that you can pull out and reinforce.

And the biggest fear of patient considering taper is that their pain levels are going to go through the roof as they taper off. And with a supported gradual taper that's just not true. In fact the bulk of evidence is that pain levels go down rather than up. And that's quite a revelation to patients. They may not believe you to begin with. For example, we used a video of previously and successfully tapered patients to help convince our subjects in our recent trial. But just telling patients that you're going to stick with them and their pain levels are not going to be ignored nor are they going to be worse as you go through the opioid taper is quite powerful.

Dr. Loretta Jackson-Brown: And the second part to that from another participant relates to her and looking at her age and other risk factors for falling. And the comment is related to, are there other nonpharmacological approaches that could have been done instead of opioids to help her? So essentially why put her on there because of the risk factors?

Dr. Jane Ballantyne: Well I think that's, you know, it's tough. I mean you could say I actually chose that case because I think spinal stenosis is a condition that is very painful and it doesn't respond as well to things like exercise as other muscular skeletal pain where stretching is very effective things like yoga or tai chi particularly for older people is very effective.

And so it was chosen advisedly as a case where it might be worth a trial of opiates to see if it helps and in fact although it didn't help her and that was partly we wanted to illustrate how important it was to make sure that function that it was achieving the functional goals and what to do if it didn't. But for some patients it does actually help. It does achieve the functional goals especially low dose taken intermittently. Some people do quite well. In fact the evidence now is that the most successful if you look at, you know, broadly globally at opiate treatment and what we've seen with this vast experience we now have that people who are taking low intermittent doses occasionally are actually the people who are doing the best. So...

Dr. Loretta Jackson-Brown: Okay. And we have one final question. And that is please clarify when the usage of immediate-release formulation in combination with extended-release formulations for opiates is appropriate?

Dr. Jane Ballantyne: I don't think it's appropriate for chronic pain management at all unless it sort of crossed the border into being palliation so that type of treatment was developed specifically for the treatment of cancer pain at the end of life where the goal of treatment is really just comfort and maintenance of medical alert - mental alertness and being able to be interactive. But, you know, basically your goals of function and having normal functional life have sort of passed because you're at the terminal stage of life.

And then it is appropriate. And then it's useful. But chronic pain we should always come back to this: chronic pain is completely different from acute pain or pain at the end of life. And that sort of approach for chronic pain just hasn't been successful. And apart from anything else, it tends to lead to dose escalation because you have a long-acting opiate that's in the system 24 hours a day causing all sorts of adaptations that result in tolerance hyperalgesia and dependence. And to make matters worse, you then add intermittent doses. Now I understand that's become common practice but it's a practice that nowadays we would discourage when you're treating chronic pain.

Dr. Loretta Jackson-Brown: Any additional comments from any other presenters?

Dr. Mark Sullivan: Nothing to add.

Dr. Deborah Dowell: Nothing to add.

Dr. Loretta Jackson-Brown: So on behalf of COCA I would like to thank everyone for joining us today with a special thank you to our presenters Dr. Dowell, Dr. Ballantyne, and Dr. Sullivan. The recording of this call and the transcripts will be posted to the COCA webpage at emergency.cdc.gov/coca within the next few days.

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Coordinator: This now concludes today's conference. All lines may disconnect at this time. Thank you.

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