Two people watching a videoPain 4: Choosing Analgesics, Dosing Principles

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Apply an evidence-based and safe approach to choosing analgesics based on the patient’s report of pain severity, and dosing based on pharmacokinetics. You can watch and / or download the video or select individual chapters 

Please always use your careful clinical judgement when caring for each patient and family.

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Hi, I’m Frank D. Ferris, and I’ll be joined a little bit later in this video by Jessica Geiger-Hayes, one of our pharmacists. Today we’re going to be talking with you about pain management, specifically focusing on how do we choose analgesics and how do we dose effectively, what are the principles guiding our prescriptions? Why do we do this?

Well, it turns out, pain management is a fabulous model for prescribing most of the medications that you and I use in palliative care. As we start out, I’d like you to think about this for yourself.

Imagine that you’ve been living with some sort of advancing illness where you’ve been having a lot of pain. My question is: How long would you like to enjoy 8 to 9 out of 10 pain for? Are you one of these folks who would say, “Oh, no problem, I can stand it for a week or more.” Or are you one of these folks who says, “No, you better get rid of it today.” Or many of my colleagues even say, ”You better get rid of it in the next couple of hours. Please, I don’t want this kind of pain.”

What we know is: Pain impacts everything that you and I do. It changes people’s ability to function, they can’t move around, they don’t have appetite, they reduce their nutritional intake, they don’t sleep well, they have insomnia, they don’t think, they become totally focused on the pain, they can’t think about anything else, and they often get either grumpy or even depressed. It totally impacts their mood.

So, our goal as health care workers is to give people the capacity to continue to do the things they want to be able to do. We need to manage the pain quickly and monitor – are we improving their experience of their lives?

So, you and I need to always treat the cause, and we’re going to be talking about pathophysiology and specific medications for specific situations in another video. But at the same time, we always need to manage the experience for the patient.

And what I’ll say is when we know what to do, and here we do know what to do in terms of managing the experience of pain, if we don’t do it, or we under-treat it, it is effectively medical torture. I don’t think you want to be involved in that. Didn’t you get into medicine or nursing, or pharmacy to really do a good job and care for patients? That’s our role.

So, concurrently, we need to treat the cause based on the pathophysiology as well as we need to treat the experience. For everybody think about the non-pharmacological interventions. For everybody think about the pharmacology that would be appropriate to manage their situation and the cause, and their experience. And for some patients interventional procedures will be really helpful. You and I need a comprehensive approach, and that’s what we’re going to focus on in the next video series.

Overview of Pharmacological Management

So, let’s begin our conversation about pharmacological management. We’re going to be talking about how to choose analgesics, analgesic dosing principles, and in this we’re going to be focusing on pharmacokinetics. And then, using a case, we’re going to actually titrate using a “catch-up” technique in order to optimize efficacy to control the pain as quickly as the medication and the patient will allow, at the same time ensuring that we’re always safe.

To do this I would like to introduce you to Bill, a 72-year-old gentleman whom I met in Cyprus several years ago. He was a war veteran living with cancer who was delighted that we will tell his story as part of our teaching.

By August of 2009 he had extensive bone metastases. You can see them here on the nuclear medicine scans. He’d actually had some radiation therapy, 20 grays and 5 fractions. And the day I was seeing him he said his pain was like a severe toothache, shooting pain from his perineum down his legs. His legs were cold and numb. He was really feeling uncomfortable.

In fact, he said it was 8 to 9 out of 10 in severity. He described it as excruciating, like a g-clamp, it was terrible. He said, “You’d be yelling your bloody head off.“ I dared to ask him, “How would you feel if we didn’t control your pain?” There was a long pause. And he said, “Oh my god. . . life would not be worth living.” He said, “the problem with pain is you can’t see it, and people don’t believe you.”

So, I’m hoping as you will meet Bill or a patient like Bill that you’ll start out with believing them. That’s the best place. Everybody, until proven otherwise, we should assume is trustworthy. So, let’s begin our discussion.

Choosing Analgesics

So, let’s start by talking about how do you effectively choose analgesics? There are no randomized control trials related to these particular medications. They’ve been around for years, some of them several hundred years. They are inexpensive, and nobody is going to pay for these clinical trials.

So back in the 1990s, the World Health Organization convened a group of experts to get together and build what has become known as the World Health Organization Ladder.

They grouped medications by relative strength. Acetaminophen or paracetamol, aspirin and the nonsteroidals fall into the weak medications or analgesics group.

Codeine, tramadol, and the combination products, such as codeine with acetaminophen or paracetamol, hydrocodone or oxycodone in combination, all fall into the moderate analgesic group. And the combination products are here because there is a limit to how much aspirin or acetaminophen a patient can take in a day.

The other analgesics, such as morphine, oxycodone, hydromorphone, fentanyl, and even methadone, all fall into the strong analgesics group. So, we have basically groupings based on the relative strength of the medications.

Then what was realized is based on the patient’s self-report of the severity of their pain, we should start with either Group 1, Group 2 or Group 3 analgesics.

If the patient reports 1 to 3 severity out of 10, let’s start with the relatively weak analgesics in Group 1. If the patient reports pain severity 4 to 6 out of 10, let’s start with the moderate strength analgesics in Group 2. And for anybody reporting pain severity 7 or greater let’s start with Group 3 analgesics, even though they might be naive.

Now, for many people that feels alarming. But I really want to say, based on expert opinion, and I personally have been doing this for more than 30 years, it’s very real. For Bill who says, “My pain is 8 to 9 out of 10,” we should start with a Group 3 analgesics.

Now, some people say, “Well, the Group 3 analgesics, they’re dangerous. I’m really worried about respiratory depression and lots of side effects.“

Well, we’re going to teach you a technique to make sure the patient is safe when you start with these medications. But I want to focus on the fact that, in fact, one of these groups, Group 1, Group 2, Group 3, actually has significantly dangerous medications that can cause side effects spontaneously, and we wouldn’t have necessarily predicted it in the particular patient. You might be surprised. It’s actually the Group 1 analgesics.

It used to be stated that there were more aspirin overdoses in America than there were heroin overdoses. That’s shifted, but there are still significant mortality associated with aspirin, the nonsteroidals and acetaminophen or paracetamol.

In fact, what we know today our Center for Disease Control recently reduced the recommended maximum per day for acetaminophen from 4 to now 3.25 grams per day, or, simply, 3 grams. And if you think about acetaminophen extra strength tablet that has 500 milligrams in one tablet, that’s only six tablets in a day. It’s not a lot, but these are the medications that cause the problems.

Now, people also say, “Well. . . you know, morphine, it’s really strong.” I want to point out that that’s not necessarily the case. In fact, what we now know is, every single analgesic as an equivalent analgesic potential to morphine, what we call oral morphine equivalents. Those medications that are in Group 1—you don’t need to remember. You can just look at the table.

It’s, in fact, between one and three oral morphine equivalents for a standard or typical dose. So, if I look at acetaminophen or paracetamol 500 milligrams, it’s actually 1 to 2 milligrams of oral morphine equivalents. Ibuprofen, 400 milligrams, the same. And we can continue with any of the medications in this group.

If we go to the Step 2 analgesics, actually it follows a very similar pattern. Their approximate equivalents is 4 to 6 oral morphine equivalents. In fact, 60 milligrams of codeine is actually 6 milligrams of oral morphine and 50 milligrams of tramadol is 5 milligrams of oral morphine. And if we look at combination products, they are similar.

So we can see oral morphine equivalents: Step 1 is 1 to 3, Step 2 is 4 to 6, and for severe pain, Step 3, is at least 7 oral morphine equivalents, and, of course, we get more sophisticated as we talk about changing opioids and changing routes of administration in another video.

So, as an example of the Step 2 analgesics, something that typically surprises folks, Vicodin, America’s favorite prescription for early pain, contains acetaminophen 325 milligrams and hydrocodone 5 milligrams. It’s actually equivalent to 1 to 2 milligrams for the acetaminophen and 5 milligrams for the hydrocodone. So, each tablet contains 6 to 7 milligrams of oral morphine equivalents. Does that surprise you?

And, in fact, in America, it’s frequently prescribed as 1 to 2 tablets every four to six hours, if needed. So, we’re giving patients between 6 and 14 milligrams of oral morphine equivalents, if needed, any time they take it. Many of the students I train are really surprised by this. You can see, it’s more than most people expect.

And what about the Percocet? Again, certainly in Ohio it’s the favorite prescription, and it’s the second most common in America for what people would think of as early or moderate pain. It’s got acetaminophen 325 milligrams and oxycodone 5 milligrams.

Now, the oxycodone is a little bit more potent than morphine. It’s got a ratio of 10 milligrams of oxycodone is approximately 15 milligrams of morphine. So, in a single tablet we see that there’s 1 to 2 for the acetaminophen and 7.5 milligrams for the oxycodone, giving us 8.5 to 9.5 milligrams per tablet.

So, a typical prescription, which is 1 to 2 tablets every four hours, as needed, actually contains anywhere from 8.5 to 19 oral morphine equivalents every four hours.

Again, when I show this to many learners here, they’re absolutely shocked. They thought 5 milligrams of morphine was a lot. In fact, it’s equivalent to less than a single Vicodin tablet.

So, we’re providing you with reference cards. I’d just like to highlight: On the “Choosing Analgesics” reference card each of these steps is clearly laid out and the recommendation that based on the severity we should start with Step 2, if the patient reports 4 to 6, and for somebody like Bill reporting 7 to 10 pain, we should start with Step 3.

Dosing Principles

Hello. My name is Jessica Geiger-Hayes, and I would like to continue this by talking about dosing principles.

The first topic I would like to touch on is First Order Kinetics. And this is important because our medications that we use in palliative care, most of them follow first order kinetics. This is convenient because we know how the medication is going to act in someone’s body. As the medication is administered and reaching appropriate levels we can expect a decrease in the symptom. And then, as that same medication is being eliminated, the symptom may start to worsen again. So, we have a predictable response.

Most of the analgesics that we use in palliative care follow first order kinetics. Methadone is the exception. Other medications that we use to treat different symptoms also follow first order kinetics. So, these dosing principles can be applied there as well.

The side effects for these medications follow the same type of profile. The risk of side effects starts to increase as we start to reach maximum serum concentration and then, as the medication is eliminated the risk of side effects then starts to decrease.

Let’s start with talking about how we’re going to dose our extra or breakthrough doses for pain, the PRN orders. We know that the greatest analgesia is going to happen when that medication reaches the maximum serum concentration. We also need to know how long it’s going to take to reach maximum serum concentration. We refer to this as T_max.

For an oral dose, let’s use morphine as an example. It takes 60 minutes after administering the dose for the maximum concentration to be reached. This is also when the patient should experience the maximum amount of pain relief.

Let’s talk about quickly why it takes an hour for an oral dose to reach maximum serum concentration.

Rectal administration follows the same pathway. The medication has to either be swallowed or inserted. It then has to dissolve. From there it has to be absorbed into the bloodstream and pass through the liver. We do lose part of our dose when it passes through the liver. The medication then mixes in the circulation, crosses the blood brain barrier, mixes again in the cerebrospinal fluid and finally reaches the site of action, which is the opioid receptor located in the neurosynaptic junction inside the brain.

So, this is a long road that this dose has to go down to get to the site of action, and you can see why it would take about an hour for this to happen.

For other routes of administration, it does not take nearly as long to reach maximum serum concentration. For subcutaneous or intramuscular, it only takes about 30 minutes. For IV, it only takes about 15 minutes. And this is because we get to bypass the GI tract all together.

Now, if you looked up these values in the pharmacokinetic literature, you would find ranges for every single one of them. I’m going to use IV as an example. You would find a range of 10 to 15 minutes for that dose to reach maximum serum concentration. And that’s just because of the differences in people.

We have chosen the higher end of all of these ranges because we want to ensure maximum safety. We know, if we wait this long, we are going to see the maximum effect of the medication. We’re also going to know whether or not that patient is going to experience side effects.

So, to summarize: Our first principle is for extra or breakthrough doses, the PRN orders, and they should be offered every T_max. For IV that’s every 15 minutes, as needed, sub cute, that’s every 30 minutes, as needed, and for oral it’s hourly, as needed. This principle should not be used on extended-release opioids. Let’s see what this looks like graphically.

If we give a dose of oral morphine to a patient, we wait one hour and then we reassess. We may come to find that their pain is not well controlled. At this point we can safely administer a second dose and expect a little bit higher serum concentration, which might be exactly what our patient needed to be able to experience the type of pain control that they were hoping for.

Let’s talk about how to schedule doses for someone who is experiencing constant pain.

We have to introduce one more pharmacologic principle, and that’s the principle of half-life. For medications that follow first order kinetics, this means that when you give a dose, half-life is the amount of time it takes for half of that dose to be eliminated from the body.

Let’s use morphine as an example. If you give a patient 10 milligrams of morphine, after the half-life, which is four hours for morphine, the equivalent of 5 milligrams of that dose would remain in the body.

For constant pain, we want to achieve steady state. And to do this we need to dose the medications routinely every half-life. It takes five half-lives to reach steady state. As you can see here, after about three half-lives we are pretty close, we’re almost 88% of steady state. And then, after five half-lives, or about 20 hours for morphine, we are at steady state.

You may be wondering what is steady state? That’s the level of medication that we reach where the amount coming into the body is equal to the amount going out of the body. We want to target steady state to be at a place where we are adequately treating someone’s pain without causing too many unwanted side effects.

Let’s talk about another Group 1 analgesic that follows a similar pharmacokinetic profile, acetaminophen, or paracetamol. The T_max for this medication is one hour, the half-life is four hours. It takes about 20 hours to reach steady state. We start our dosing of this medication at 325 milligrams every four hours routinely. But we have to keep in mind that we have a maximum dose. We have to stay below 3 grams per day to avoid hepatotoxicities.

Ibuprofen is another Group 1 analgesic that has the exact same pharmacokinetic profile. One hour to T_max, four hours is the half-life, it takes 20 hours to reach steady state. Again, we start this medication at a dose of 200 milligrams every four hours. but we have a maximum dose we have to think about. And that’s 600 milligrams every four hours–we can’t go higher than that.

Morphine, as we’ve mentioned, follows the same profile. But the unique part about this is we don’t have a maximum dose. We can titrate this medication to the effect that our patient needs or until they’re experiencing side effects that they don’t like. Again, it takes about 20 hours to reach steady state. We sometimes round this up to 24 hours to make it easy to follow up. If we routinely dose morphine every four hours, we can follow up a day later to find out how their pain is doing to determine whether or not we need to make dose adjustment knowing that we’ve reached steady state.

Tramadol is an outlier. It takes a little bit longer for tramadol to start working. The T_max for tramadol is two hours, and the half-life is seven hours. This makes steady state 30 hours, five half-lives.

It’s important to talk about these things regarding tramadol with any patient that you put on this medication, because they need to know it’s going to take about two hours for them to really feel the effects of this medication on their pain.

You can start tramadol at 50 milligrams every six hours routinely with the maximum dose of 100 milligrams every six hours.

We’ve summarized all of these points for you in a reference card. You can see here that we can remind you that the T_max for IV medications is 15 minutes, for subcutaneously administered medications, it’s 30 minutes, and for orally administered medications, it’s 60 minutes. The half-life stays consistent regardless of the route of administration. So, for morphine it’s always four hours.

This information is also summarized for you on the provided medication tables.

Starting Doses

Now let’s talk about dosing. If you remember, back to Bill–he was experiencing 8 out of 10 pain. We need to determine what starting dose should we use for an opioid.

We have to take a couple of things into consideration. If Bill had not had any previous analgesics–we would call that opioid naive–we would start at a low dose. We would offer morphine immediate release 10 milligrams hourly, as needed, and we would leave it at that. If he was much older or very frail, we would start with even less of a dose, 2. 5 to 5 milligrams of oral morphine given hourly as needed.

But if you remember, Bill had been taking a previous analgesic and we refer to this as opioid tolerant. He was taking tramadol, and he was taking 400 milligrams of oral tramadol a day. This is equivalent to 40 milligrams of oral morphine in a day.

We would then double this dose to get 80 milligrams of oral morphine in 24 hours. Now, when we consider the availability of oral morphine tablets, we would find that we can schedule this dose as immediate release morphine 15 milligrams or ally every four hours around the clock. Notice we’re starting Bill with routine dosing because he has already been on an opioid and he’s experiencing severe pain. We know he’s going to be able to tolerate this.

We also need to make sure we have PRN doses available for Bill. We can’t just rely on the scheduled dose because he’s going to have breakthrough pain. To calculate the amount of this dose we use 10 to 20% of the routine dose that we would give in 24 hours. We would then offer this every T_max as needed and since we’re using oral medications for Bill, this would be every 60 minutes as needed.

So, what would the dose be for this PRN? We know that he is taking 90 milligrams of immediate release morphine in 24 hours, based on that order10 to 20% of it would be 9 to 18 milligrams. To keep things simple, we can choose 15 milligrams of immediate release morphine offered hourly as needed for his breakthrough dose.

We would want to educate Bill to answer the following questions every time he uses a dose of his morphine. The first would be is if he recorded the last dose and what it was, his current pain severity, and also if he’s experiencing any effects that he is not liking. And if he is experiencing side effects, we would want him to call his nurse or doctorand let us know.

So, what does this look like? Let’s say Bill takes a scheduled dose of oral morphine, 15 milligrams at 10 o’clock in the morning. If he needs it, he can take additional breakthrough doses at 11 o’clock, at noon, again, at 13:00. And then at 14:00 he takes the scheduled dose, and he can also take a breakthrough dose, if he needs it. So, at 14:00 he could take a total of 30 milligrams of oral morphine, and that’s okay.

I’d like to show you what an example of a simple pain diary would look like based on that previous illustration. Bill would record that he took 15 milligrams of oral morphine at 10 a.m. His pain severity was an 8. And then you can see, as he progresses through this pain diary by the time we get to 14:00 his pain score has decreased, but he’s showing you that he took 15 milligrams of his scheduled dose and an additional 15 milligrams of his routine dose.

We also have to consider opioid side effects. Constipation is a primary effect of any opioid. Opioids interact with the mu receptors in the brain as well as the mu receptors along the GI tract and the bladder. We will always expect slowing of the GI tract with anyone that’s on an opioid. Nausea and vomiting is also another common side effect that could be experienced. The rest of these may happen for some patients and may not for others.

Two types of orders that should accompany any prescription for an opioid are an order to address nausea and an order to address constipation. For nausea we can use haloperidol, and for constipation we can use a combination of a stimulant laxative and an osmotic laxative.

Now you’ll notice the haloperidol is written as needed, and that’s just so that Bill can take it if he happens to experience nausea.

The orders for constipation are scheduled, you’ll see there that senna is written one tablet by mouth twice a day. The osmotic laxative will be ordered to be given daily. We can always expect interaction from the opioids with the mu receptors along the GI tract. This may be bothersome to some patients and it may not to others, but we should always routinely schedule these laxatives unless they tell us something different.

So, for initial dosing we want to use the pharmacokinetic profile of our medications. This allows us to very safely dose these medications and provide the most efficacy that we can to our patients. It’s also very important to anticipate the common side effects and provide medications to treat them.

Dose Titration

Now let’s talk about how we would titrate Bill’s opioid to achieve maximum pain control.

On Day 1, we follow up with Bill, and he has been doing everything that we had asked him to do. He’s filling out his pain diary. We can see that he is experiencing 6 out of 10 pain. He’s not experiencing any side effects, and he’s also taken all of his scheduled doses just like he’s been asked, and he’s required 6 extra doses of the breakthrough medication. That adds up to be a total of 180 milligrams of oral morphine in the last 24 hours.

From here we’re going to use that number to catch up. We’re going to schedule that amount of morphine for the next 24 hours because that’s the amount Bill was able to very safely use on the previous day.

So, our new prescription for our routine dose using that 180 milligrams is going to be 30 milligrams of immediate release morphine given orally every four hours around the clock. And then using our principle of 10 to 20% of the routine dose to calculate our breakthrough dose, we get 30 milligrams of immediate release morphine hourly as needed for breakthrough pain. And remember, we’re using it hourly as needed because that’s the T_max for oral morphine.

On Day 2, we follow up with Bill again. He has been filling out his pain diary as we’ve asked, and we can see that his pain is decreasing, and he’s still not experiencing any side effects. He’s used all of his scheduled doses and he has only required four of the extra doses that he had available to him. This ends up being a total daily dose of 300 milligrams of oral morphine. Using the same exact principles we used on Day 1, we’re going to calculate a new routine dose and breakthrough dose based on the 300 milligrams that we know Bill can safely tolerate.

So, his new routine dose is going to be immediate release morphine50 milligrams orally scheduled every four hours with his breakthrough dose being another 50 milligrams of immediate release morphine hourly as needed for breakthrough pain.

On Day 3, we follow up again. And his pain is much better controlled. And you can see that he has only required two extra doses of his morphine. This takes his 24 hour use to 400 milligrams. We know that he can safely tolerate that. So we’re going to schedule that moving forward as morphine immediate release 65 milligrams orally every four hours around the clock with another 65 milligrams of immediate release morphine available to Bill hourly as needed for breakthrough pain.

Now on Day 3, Bill’s wife talks to you and says, “You know, I’ve really been noticing that Bill has been sleeping a lot, and that really makes me uncomfortable.” How would you address that?

Well, we would need to talk to Bill’s wife about how do we differentiate here between overmedication and simply that Bill finally feels good enough to be able to sleep. So, we would want to talk Bill’s wife through what it looks like for someone to be overmedicated. This person would be very difficult to wake up, they would have very heavy eyes, they would be confused, and they would have slurred speech. They would appear intoxicated. Bill, on the other hand, might just be tired, and he might just be sleeping. So, we would ask his wife to wake him up and see what happens. And what we might find out is he wakes up very easily and he is able to talk to her, and his eyes open wide, and he’s not confused. He may not be happy that she woke him up, but we know that he’s okay.

So, we want to use this “catch-up” method to increase opioids because it’s very safe. We only increase by the amount that we already know the patient can tolerate. They’re demonstrating their need to us. We’re not just guessing; we’re using what we know to increase a patient’s dose.

Maintenance Dosing

So now that we know what Bill is requiring on a routine basis to control his pain, how are we going to continue that in the most convenient way possible?

With his current regimen, he is having to wake up at 2 in the morning to take his dose of morphine immediate release. I’d like to be able to avoid this for him so that he can get a good night’s sleep.

What we can do is offer an additional dose at bedtime so that he does not have to wake up in the middle of the night.

And what this looks like is, we give an additional 65 milligrams of oral morphine when Bill’s ready to go to bed, and that gives us just enough bump in serum concentration that he’s able to sleep through the 2 a.m. dose without pain.

Now, if Bill becomes a little bit more drowsy because of that extra dose, that’s not a problem, because his goal is to be able to sleep through the night without waking up because of pain.

If extended-release medications are available and are not cost-prohibitive to our patients, we could consider using those. And they provide a very smooth pain control curve with many less peaks and troughs that you might experience with scheduled immediate release morphine.

These extended-release medications can also be very convenient for other reasons as well. It doesn’t require as frequent of dosing, the patient’s compliance can improve, as well as their adherence. Caregivers also appreciate extended-release opioids because they don’t have to constantly watch the clock to make sure they’re giving the doses when they should be.

The dosing interval or these medications is every 12 hours, and that matters because we have to wait 5 dosing intervals before we can adjust the dose. So, 5 dosing intervals ends up being about every two to three days that we’re able to adjust our dosing.

These extended-release medications should not be ever be crushed or chewed. It causes them to lose the extended-release properties, and the medications just turn into immediate release, if that’s done.

It takes about two to three hours to reach C_max for an extended-release opioid. And you can see here that after 5 dosing intervals, or 60 hours, we’ve reached steady state.

Let’s go back to Day 3. What if we had extended-release medications to be able to offer Bill? We would base our dosing off of his total use, which is 400 milligrams in the last 24 hours, except we’re able to offer an extended-release medication now instead. We can give him 200 milligrams of extended-release morphine every 12 hours, plus 65 milligrams of immediate release morphine hourly as needed. You can see how this could be much more convenient.

Let’s fast forward to Day 8. Bill is experiencing an acute increase in his pain. He is still not experiencing any side effects from the medication, but he has required 5 doses of his breakthrough medication, in the last 24 hours bringing his total use to 725 milligrams of oral morphine.

If we were going to write a new prescription for him, we would give him 360 milligrams of extended-release morphine every 12 hours plus 100 milligrams of immediate release morphine hourly as needed.

Now, this may seem like a lot of morphine. But what we know from our setting is that patients that have metastatic cancer on average use 200 to 600 oral morphine equivalents in a day, especially patients like Bill that have bone mets.

There’s always going to be outliers. There are going to be many patients that don’t require even 200 milligrams a day. But there may be patients that require more than 600, more than what Bill’s requiring. And the big thing to remember is it is so important to continue to titrate these medications until we reach adequate pain control or our patients, or they experience intolerable side effects.

Clearance Concerns

So, for our last topic in this series, let’s talk about what we would call clearance concerns. How do you and I adjust dosing if the patient isn’t eliminating these medications effectively?

What we know is the water-soluble opioids, such as morphine, hydromorphone or oxycodone are all eliminated from our body in our urine.

In contrast, the fat-soluble opioids, such as fentanyl and methadone, are inactivated in our livers. We don’t need to worry about renal function with both of these products.

So, let’s use morphine as an example of what happens with the water-soluble opioids. We know that morphine is metabolized by glucuronidation in our livers and becomes both morphine-3-glucuronide or morphine-6-glucuronide. As you can see from the table, the morphine-3-glucuronide doesn’t have much analgesia where the morphine-6-glucuronide is really quite potent.

The problem is morphine-3-glucuronide actually produces excitation in our brains, we can end up with hallucinations, bad dreams, confusion, even myoclonic jerks. So, we don’t want too much of that for sure.

What we know is all three products are eliminated in our urine. So, if we have dehydration, or patient with renal failure, or the patient is actually dying, and they have reduced urine output, you and I need to adjust how we dose.

Why? Well, morphine thinks of us really just as a basic bucket of water, and we put it in every four hours because we eliminate it every four hours. When we stop urinating, we need to stop putting it in.

So. what we would recommend is for a patient with oliguria, less than 500 milliliters in 24 hours, at least reduce the routine dose by 50%. For patients with less than 250 milliliters of urine in 24 hours or maybe even anuria, stop the routine dosing. You can always give a breakthrough, a PRN dose if the patient has pain.

And you can see all of this summarized on this particular table. Again, below 500 milliliters, at least reduced by 50%. And less than 250 milliliters, stop routine dosing. I can’t emphasize that enough. In both cases we can always give a breakthrough dose. Now, each opioid will be handled slightly differently. We wanted this to be a simple example. We’ll be talking about that and how to manage changes in urine output, changes in liver function, in another video later.

So, let’s finish off by reviewing what happened with Bill. I got to see him in follow-up, and he had an incomplete spinal cord compression, leg weakness, although he was able to get around with aides, incontinence of urine and stool,.

And he was taking morphine extended-release 180 milligrams twice a day as well as the occasional breakthrough of morphine immediate release 30 milligrams some four or five times a day. He had some amitriptyline as a co-analgesic, zoledronic acid monthly. We’ll be talking in another video about how to use these types of co-analgesics based on the pathophysiology.

While I was there, his friends arrived. They came in with a bottle of wine, and in the process Bill said, “Let’s raise our glass. What we would like to do is toast all of you.” And he asked me to share this and toast all of you who do effective pain management. “First of all, thank you for listening to me. Thank you for dosing my pain appropriately, and thank you for making it safe for me.” He asked that we pass that along.

And what I’ll say to you is — we can do the best of care for patients like Bill if we follow the pharmacokinetics and we use that to guide our analgesic dosing. We’ll get control as quickly as possible and as safely as possible.

So, for optimal efficacy and safety, I want you to titrate to effect or toxicity. Start low, dose every T_max, PRN, titrate using the “catch-up” technique that we’ve been talking about, and for maintenance dosing, dose once every half-life. Steady state occurs in five half-lives, elimination also occurs in five half-lives. Wait until the patient reaches steady state.

If you do this, your patients are going to be comfortable, able to live lives the way they want to unless their disease is getting in their way, and it’s going to be safe; you’re going to minimize the risk of side effects. And, of course, if you do get side effects, then you’ll think about how to appropriately manage them.