79. ADHD Meds: When stimulants don't work, what do you do? Alpha agonists as an option

While stimulant meds are first-line treatment for ADHD, they do NOT work for everyone... or sometimes they only PARTIALLY help.  So, what can you do in these situations?

• When is the right time to try a non-stimulant medication like Guanfacine and Clonidine (a.k.a - alpha-agonists?)? 
• In which clinical situations can these alpha-agonists be helpful?  
• How do you know when to switch from one stimulant to another stimulant
• When should you try adding on or switching to an alpha-agonist?

In this episode, Dr. Elise Fallucco talks about guanfacine XR (Intuniv) and clonidine (Kapvay/Onyda XR)—and how to decide whether to switch stimulants or augment them. Using an 11-year-old with improved attention on a stimulant but persistent impulsivity/oppositionality and dose-limiting side effects, she explains that switching is best when there’s little benefit or unacceptable side effects, while augmentation makes sense with partial response. She reviews key scenarios for alpha agonists: residual impulsivity/hyperactivity/behavior dysregulation, ADHD with tics, possible adjunct use in ADHD with anxiety (not primary anxiety treatment), and late-day rebound near bedtime. She describes “peanut butter and jelly” synergy with stimulants, monitoring vitals, dosing/titration, sedation differences (more with clonidine), and the need to taper to avoid rebound hypertension.

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Pediatric Mental Health CME Toolkit - Cracking the ADHD Code: Essentials for Pediatric Clinicians. 

https://ce.nemours.org/content/podcast-series-cracking-adhd-code-essential-skills-pediatric-clinicians#group-tabs-node-course-default1

Transcript

SPEAKER_00 0:21

Welcome back to ADHD Anxiety and More, Mental Health for Pediatrics. I'm your host, Dr. Elise Falucco, child psychiatrist and mom. Today we're continuing our discussion about treatment for ADHD, which we know is one of the most common neurodevelopmental disorders affecting one out of 10 U.S. kids. In our previous episode, we talked about how stimulant meds are first-line treatment for ADHD. They lead to improvements in your ability to remain alert, pay attention, and have motivation for tasks, and even improve a child's quality of life. But what do you do when stimulant meds don't work? Or when they're only partially helpful? What are other non-stimulant options that you can reach for to help your patients with ADHD? This brings us to the topic of today's episode, which is non-stimulant meds, specifically guanphysine XR, which is in tunive, and clonidine. Both of these meds are considered alpha agonists. And one of these meds I think can be extremely helpful and is highly underutilized in ADHD treatment, particularly in pediatrics. So we're going to talk about in what clinical situations you should think about using these meds, which one should you choose? And finally, we're going to talk about how combining an alpha agonist with a stimulant is like peanut butter and jelly or peanut butter and chocolate. But let's go ahead and start with a case so we can demonstrate the most common way that alpha agonists like these meds can be helpful. We've got an 11-year-old boy who presented with ADHD symptoms around the start of sixth grade, which we've talked about before. The transition to middle school is often a time when we see emergent problems related to ADHD due to the increased demand in executive functioning and the locker situation of it all, and the changing classes and trying to keep track of your schedule in your homework and whatnot. So this little guy was started on a stimulant. He came back, and his teachers and his parents say he's much more focused at school. Seems like his grades are getting better. He's getting his work done. Homework is not as much of an issue, but he's still impulsive and emotionally reactive and oppositional. So you try to increase his stimulant dose further, but when you got to a higher dose, it caused stomach problems and some more appetite suppression that the family really didn't like. So you went back to the previous dose, the side effects got much better. His attention and schoolwork are great, but we've still got some impulsivity and he remains oppositional. So what do you do? Do you switch stimulants like we've talked about in the previous episodes? Or do you consider augmenting the stimulant with an alpha agonist? And we're going to answer a larger question, which is when does it make sense to augment with an alpha agonist as opposed to switching from one stimulant to another? Well, let's start with the easy part, when it's a clear-cut case that you really should just switch, you know, get rid of that first stimulant and try a different option. So switching makes sense if the stimulant basically isn't helping at all or just isn't really helping enough. You have sort of a little or no meaningful response. Or if you're getting unacceptable side effects, then you just abandon ship and say, let's try something else. But in this case, with this 11-year-old, we see that there's a partial, pretty good response, but not a full response. And we only saw intolerable side effects when we escalated the dose. So in this case, you're really asking, do I throw out a medication that seems to be helping the child and start over with a totally different stimulant, or can you build on the benefit that you're already getting? The general rule of thumb is if a stimulant is helpful, if it seems to be getting you a pretty good response, but not 100%, then you think augmentation. And of course, I'm assuming that you're giving the stimulant an adequate trial and you have the child at a reasonable dose. So in this case, augmenting would make the most sense. Now I want to go over a couple of clinical examples or clinical situations where augmenting makes sense as opposed to switching. The really classic case is for kids whose attention is fairly well controlled but have residual impulsive behavior. So sometimes these are the kids with ADHD and ODD or just ADHD and behavior problems, but maybe a little bit of oppositionality. So the stimulant's going to be very effective at the core symptoms of ADHD, but often you need an alpha agonist to help address the residual impulsivity. Alpha agonists are very good at addressing hyperactivity and impulsivity. So that's kind of the classic case. Another clinical case where you might consider augmenting would be ADHD and ticks. We know that the alpha agonists can be very effective as tick treatment in the cases where medication is warranted or is appropriate. So here's this gray area that I get really excited about, but I'm going to try to temper my enthusiasm. So the gray area is the case of ADHD and anxiety. Now, you may have heard me talk about this on the pod before, but there is a small pilot study suggesting that Guanfacine XR, which is in tunive as the brand name, is safe and potentially helpful for anxiety in kids with ADHD. So what this means clinically, if you have a child with ADHD and anxiety that has a partial response to a stimulant, but let's say you're running into problems with tolerability, like you try to increase the dose and you get activation, in those cases, you might consider adding an alpha agonist to the stimulant as adjunct. But again, I want to be really crystal clear, guanfacine is not a primary treatment of anxiety. Of course, if you have true clinically significant anxiety, then you want to think about evidence-based treatments like cognitive behavioral therapy and then potentially SSRIs. Okay, so to recap, we've talked about alpha agonists as adjunctive treatment for kids with residual ADHD symptoms, particularly residual oppositionality or impulsivity, potentially ADHD plus ticks, potentially ADHD plus anxiety. One more indication that you want to be thinking about alpha agonists is with evening rebound. We've talked before about how sometimes as kids are coming off of stimulants in the mid to late afternoon or even in the evening, they can get this rebound, super hyperactivity, irritability, maybe they're extra emotional and very impulsive. And let's say this rebound, you know, if this rebound is occurring around three o'clock, you could always add a short acting stimulant to help with that. But if you're noticing this rebound much closer to bedtime, of course you don't want to add another stimulant because that's going to interfere with their ability to fall asleep. And so in this case, adding an alpha agonist around the time that the rebound occurs to try to help with the rebound and also help with sleep initiation would make sense. So to sum up, really think about these four clinical situations where you might think about an alpha agonist for adjunctive treatment. The first one is the obvious. You've started a stimulant, you're getting pretty good coverage for attention, but have residual impulsivity or oppositional behavior. The second one would be ADHD in ticks. The third one is ADHD in anxiety. And the fourth one would be in the case of really late afternoon, early evening rebound. So now let's do a quick pop quiz. This quiz is called switch or augment, and you have to decide whether you want to switch the medication or you want to augment the medication with an alpha agonist. Okay, so first question clinical case. Somebody's on a stimulant, you've got them up to what you think should be a therapeutic dose, but you're really not seeing much of an effect, but no side effects. Do you switch or augment? Doo doo doo. Okay, in that case, you definitely switch because you're not seeing much of an effect. We want everybody on a dose of medication that's clinically helpful but with minimal side effects. So let's move on, try a different medication. Okay, second case, you have a child who's on a long-acting stimulant medication, which they're tolerating really well. It seems to be working throughout the day, but you've noticed that you have problems when it comes to after school activities that run from like 4 to 6 p.m. And sometimes with early evening activities like dance class doesn't start till 6.30 p.m. And so the long-acting stimulant has worn off by then. Okay, wait, this is a trick question because it's actually two questions in one. If you've got a child whose stimulant wears off around 3 p.m. and it's needs help for after school activities from 4 to 6 p.m., you probably would just do a short acting stimulant in that case. But in the second case, let's say they're able to get coverage all the way through 6 p.m. but are having trouble in the early evening. In that case, you'd want to be cautious about adding a short acting stimulant because it is so close to bedtime. And it's very likely that some of that may remain in their system, which could make it harder to fall asleep. So in that case, you might consider an alpha agonist. So we've talked about the main role of alpha agonists being augmentation of stimulants. But before we talk about the other role for alpha agonists, I want to answer this question that I know you're wondering. I bet you're thinking, if we're combining two meds, a stimulant and an alpha agonist, aren't we just creating more of a side effect burden? So when you combine an alpha agonist with a stimulant, it does not necessarily mean that you're getting twice the amount of side effects. So here are the two surprising findings that happen when you combine a stimulant med with an alpha agonist. The first, in one randomized trial, they found that appetite suppression occurred less frequently in kids on a stimulant and an alpha agonist than in those treated with stimulant monotherapy. The second surprising thing that happens when you combine these two meds is that they have somewhat opposing effects on the cardiovascular system. Stimulants tend to push blood pressure and heart rate up, while alpha agonists tend to push them down. So when you combine them, the cardiovascular effects can partially offset one another. Now, here's where we need that mind-blown emoji. So what we find with combination treatment is that there's some synergy, there's additional symptom improvement with the two combined meds, with potentially less appetite suppression and a more moderated effect on blood pressure and heart rate. And it's this kind of paradox, which is why Dr. Jeff Strawn has described this combination treatment as peanut butter and jelly or peanut butter and chocolate, because the stimulant and the alpha agonist tend to pair well together. But before you get too excited, it's important to remember that when you add the alpha agonist, you're going to expect to see the common alpha agonist side effects, which are sedation and perhaps fatigue. And these tend to be more prominent with clonidine than guanfacine, as we'll talk about later. And one more thing, anytime you're treating a child with either stimulants or alpha agonists or both of them, of course, you're going to want to monitor blood pressure and heart rate, even if, in theory, the stimulant and the alpha agonist have somewhat opposing effects on the cardiovascular system. As a little recap, we've talked about when does adjunctive treatment with alpha agonists make sense in which clinical cases. And we've discussed this odd paradox of peanut butter and jelly, how sometimes the combination of a stimulant with an alpha agonist can lead to increased efficacy in terms of reduction of core ADHD symptoms, and that paradoxically we may actually see a little bit less of an effect in terms of appetite suppression and potentially in terms of changes in heart rate and blood pressure with the combination. So now we get on to the second major time where we consider using alpha agonists. And this one is just as an alternative to stimulants. So remember, alpha agonists are effective, but their average effect on core ADHD symptoms is smaller than what we typically see with stimulant meds. So for kids who don't tolerate stimulants, or for those kids who've tried stimulants but they were just not effective, these are cases where you want to think about alpha agonists. Alpha agonists tend to be particularly useful and good at helping with hyperactivity and impulsivity, which we see a lot of in the child and adolescent population. And in addition, they do improve attention, but I think their strongest effects are typically in the areas of hyperactivity and impulsivity. So we're going to talk about guanphysine and clonidine, the two alpha agonists most commonly used in our child mental health population. Which alpha agonists do you choose? And how do you dose and titrate them? So when you're choosing which of these to start, you have to ask yourself, what am I hoping that this medication will improve and what symptom am I targeting? So if you're thinking daytime impulsivity and hyperactivity, I would choose guanfacine. Guanfacine is fantastic at addressing impulsivity and the extended release version can be dosed once daily and can last throughout the day with pretty great coverage. Okay, what if the symptom you're thinking about is behavior problems, maybe some behavioral dysregulation, a little bit of oppositionality? Before we answer this, it's a little bit of a trick question. Make sure that this child and family are in therapy and getting some evidence-based therapy to help deal with behavioral management and to try to understand the root cause of the behaviors, because a medicine is not going to treat behavior problems or oppositionality. But if you're in therapy and have ADHD with residual behavior problems that aren't responding to stimulants, in that case, you would think about guanfacine for some of the reasons that I listed previously. Okay. Here's another situation. Which one would you choose? Clonidine or guanphysine? And the answer is Guanfysine. Okay, by now you're beginning to suspect a little bit of a pattern. I think guanfacine is an incredibly helpful tool that should be in every pediatric clinician's toolkit. And I hope by the end of this podcast episode you'll be able to feel more comfortable in using this. Okay. If we're talking about a child who has good ADHD symptom control but needs some help winding down before bed, after dinner, in that case you might consider clonidine, which tends to be much more sedating. Okay, so now let's dig a little bit deeper into these without getting too psychopharmacologically intense. I'm just going to try to give you the information that you need to know, plus a little bit of background for thoughtful prescribing. Okay. So let's start with guanfacine ER or in tunive. And sometimes I'll call it Guanfysine XR. I sort of use those terms interchangeably. Guanphosine XR is the extended release. It's longer acting, once daily dosing, much less sedating than clonidine, and great for controlling daytime ADHD. Your starting dose of Guanfisine XR would be one milligram once daily, either in the morning or the evening. And if you need, you can increase the dose by no more than one milligram each week until you get to an effective response. If you look up the target dose range, it falls around 0.1 milligrams per kilogram per day. 0.1. Most kids don't need ultimately high doses of guanfysine XR. If you're using it as adjunctive treatment, so in addition to a stimulant, you really want to stay at about 4 milligrams or lower. If it is monotherapy and you don't have a stimulant on board, in that case, some studies have dosed it up to as high as 6 milligrams in adolescents 13 to 17 years old. Common side effects of guanfysine, we know them, sedation, orthostatic hypotension, bradycardia, potentially dizziness. And I will say while these side effects exist, guanfysine XR tends to be much better tolerated than clonidine. So to recap, on guanfysine XR, you're going to start dosing at 1 milligrams per day and increase to an effective or target dose around 0.1 milligrams per kilogram per day. Next, we'll switch and talk about the extended release form of clonidine, which has FDA approval for treatment of ADHD. It comes in tablets as CAFE or as a liquid form in something called ONEDAXR. Importantly, you start dosing at 0.1 milligrams per day, an increase by no more than 0.1 milligrams a week, watching out for sedation and blood pressure changes. The tablet is dosed twice daily, whereas the liquid can be given once a day. And a big word on safety, both of the alpha agonists lower blood pressure and lower heart rate, and neither of them should be stopped abruptly because the risk of rebound hypertension. So always make sure to check blood pressure and heart rate at baseline and as you're titrating and continuing kids on these meds, and make sure to taper down rather than abruptly discontinue them. All right, so wrapping up, here are five clinical pearls to try to take with you on your walk or as you are sitting in the carpal line or doing whatever you're doing. Number one, if the stimulant is not working in your treatment for ADHD, then switch. Pearl number two, if the stimulant is working for ADHD but isn't quite working enough, consider augmenting with an alpha agonist. Pearl number three, think alpha agonist, particularly when you've got a child with ADHD who has residual impulsivity, hyperactivity, behavior dysregulation, or ticks. Pearl number four, this is the super fun one that I think you're gonna remember. This peanut butter and jelly or peanut butter and chocolate. Combination therapy does not necessarily mean adding side effects, but you will see additional sedation and fatigue when you add an alpha agonist on board, particularly clonidine. And then our fifth clinical pearl, Guanfacine is generally the more daytime-friendly alpha agonist. Clonidine tends to be more sedating and is more useful when you're trying to target evening or bedtime sedation. So that's really the key. Think of alpha agonists as another tool in your toolbox. Sometimes they're an alternative for stimulants and sometimes they can help augment. And tune in next time when we talk about the other non-stimulants that are elephants in the room, the norepinephen reuptake inhibitors like Veloxazine, which is Calbury, or atomoxetine, which is Stracera. Also, as part of this series, as we continue, we're going to talk about some non-pharmacologic approaches to ADHD. To learn more about ADHD, take a peek at our CME toolkit on ADHD called Cracking the Code: Essentials for Pediatric Clinicians, which will be linked in the show notes. Thanks for listening. See you next time.