Hello, my name is Susan Urba. I'm a medical oncologist and I specialized in the treatment of esophageal cancer. I am also a palliative of care physician and I specialized in pain, and symptoms management for these patients. Today, I am going to talk about pain management for patients with thoracic malignancies part two. Part one has covered an overview of a light of the pain syndromes we see. This section will talk a lot about some of the medications that we use for pain management. The objectives are to understand the principles of pain management. Adjuvant medications for neuropathic pain and opioids, which is often the mainstay for treatment of cancer pain. So, let's start with a pre-lecture question. For a patient on an extended release opioid with chronic cancer pain, what is the best dosing for an immediate-release opioid for breakthrough pain? 10%, 20%, 30%, or 40% and those percentages mean of the total long acting 24 hour dose the patient is receiving. If you're going to give a dose of breakthrough medication, what percentage of that 24-hour dose you want to use? So think about that for a minute, pick your answer and then let's move on to the discussion. Let's talk first about neuropathic pain. The main stay of this and remember, neuropathic pain is stinging, burning, shooting electrical lighting like, those kind of unusual descriptive. We also use anticonvulsants, antidepressants and a group called NMDA receptor antagonists. So, let's start with the anticonvulsants. The two most common ones used are Gabapentin or Neurontin is the brand name for it. Typically, we can start very low, 100 milligrams 3 times a day and titrate up slowly. It's very typically well-tolerated, although it may cause some fatigue and some patients. There's a big dosing range anywhere from 100 milligrams 3 times a day up to 1,200 milligrams 3 time a day. So starting a mid does helps a little, but not a lot, then we slowly titrate our way up and see if we can help relieve that neuropathic aspect of the pain. Another drug in that same general category is Pregabalin or Lyrica. This decreases release of calcium-dependent neurotransmitters. And so, it's been tested in several types of neuropathic pain. A lot of these studies for these drugs have been done with diabetics, because diabetics peripheral neuropathy is very common. Some of the studies have been done with the Pregabalin, shingles. And after shingles, the persistent pain that may go along with it. And also, it's been studied in fibromyalgia and partial seizures. So, that's what it has the FDA indications for. But a lot of times even though there's not a specific FDA indication for neuropathic pain related to chemotherapy drugs, if it's done pretty well with diabetic patients, we often just extrapolate it and use it for any patient with neuropathic pain. So, that was once category of drugs. The next category of drugs we often use are antidepressants and the pain effect is separate from the antidepressant effect, because some people will say, well, surely if you have neuropathic pain, you're going to be depressed. And maybe the antidepressant is just making the patient feel better, so the pain seems better. But actually, that isn't the case. It does seem like it is truly a pain medication. The doses that can be effective for neuropathic pain are often lower than those doses that are needed for depression. And when patients have been given surveys after taking an antidepressant, that surveys how they're doing with depression and pain. Sometimes the dose will be too low, it won't effect their depression, but their pain will improve. So, it really does show that this is a useful drug to think about. Unfortunately, there can be some side effects. Dry mouth, sedation, constipation, urinary retention. These are all anticholinergic effects. We used to use a drug called amitriptyline or Elavil a lot and sometimes it's still used, but it has a fair amount of these effects. Nortriptyline is a sister drug that has less of the side effects, so we do tend to use that first. We start low, 10 milligrams a day and we titate up often to maybe 75 milligrams a day. There's another category of drugs called NMDA antagonists. These NMDA receptors are involved in some of the circuitry in the spinal chord and this is involved in the neuropathic pain. And sometimes even with bad neuropathic pain, you can give opiates, you can titrate up. And even though you may get some benefit, you may not get complete benefit. But if you're going to be using an opiate for severe neuropathic pain, a lot of time we do move to methadone. Because not only does it affect the opioid receptor, which is called the mu receptor, it also gets a second receptor called the NMDA receptor and this one is more involved with neuropathic pain. Therefore, we sort of get two approaches for the price of one, so to speak when we give methadone. Another aspect for neuropathic pain, if you remember from our last module when we talked about esophageal cancer. Possibly causing celiac plexus pain by involving the celiac nerve plexus and that can be back, and abdominal pain that's just burning, and shooting. So, the anesthesia pain physicians can do a neurolytic nerve block. They put them under CT imaging. They put in either one or two needles. You can see them angling in towards the celiac plexus, which is back by the aorta. That's why, of course, you have to do this under imaging and be very careful and well-trained and then they usually do a test dose of something like Lidocaine to make sure they're in the right area and that they are hitting the right nerve to relieve the pain. If the patient gets pain relief, that's good. But as you know, once Lidocaine wears off in a few hours, they're right back where they started. So then after a successful test dose, they will often give a second injection of a more long lasting medication, such as Fenol and this may last for several months. So it really doesn't last forever, but particularly for patients who might be have short prognosis and pain, it might be helpful for them and sometimes they even have it repeated later if the pain comes back. So, let's talk now about opioids and the principles of using opioids. Because most surely in many diseases and particular cancer, you will be called upon to prescribe opioids. Keeping in mind that the liver conjugates morphine to its active metabolite and that is cleared renally. So if patients have renal malfunction and they're not getting rid of those active metabolites, they might get more effect from the drug. So we might have to cut back on dosing, if someone's creatinine is rising. Also, if they have trouble swallowing and become hydrated and have renal insufficiency, then this in itself can also lead to excessive effects from the opioids. So a lot of times, if they're very dehydrated or developing renal insufficiency, we're just careful about the dosing. The immediate release preparations, there are several of them. On the milder side is codeine and hydrocodone, we often start with those. Some of the stronger ones are morphine, hydromorphone and oxycodone and these again are immediate release preparations. Typically, you dose them every three to four hours. If someone is having severe or moderate pain and they say, boy, it's helping a little, but not a lot, we often then increase the dose. If we need a little extra, we increase it by 25 to 50%. Sometimes we even double the dose, depending on what level we're at if the pain is really very excessive. There are also extended release preparations. And for patients with chronic pain, the best way to treat it is to get a long-lasting one. Because you know when it wears off, the pain is going to still be there, so you might as well treat for it prophylactically. Morphine and oxycodone come in long-acting pills, usually they're dosed every 8, 12 or 24 hours depending on what product you're using. We always tell the patients, don't chew them, don't crush them, don't break them in half, because then they're really not long-acting anymore. And then usually after you've started dose, about every two to three days, you kind of make sure how you're doing and may adjust the dose. Particularly by asking the patient, how much breakthrough doses are you taking? If they're taking maybe one or two extra short-acting doses, you may not be able to do that better than that. If they're taking five or six extra doses per day, because the long acting isn't holding them, then you need to increase the long-acting medication and you make that decision based on the amount of extra they've been taking. Methadone is also a long-acting opiate, about every six or eight hours. Now, that you adjust every four to seven days. It's a little tougher to get used to using. And therefore, unless you have a particular interest in pain management, that sort of thing, we typically don't recommend using it just occasionally. It's better to get used to using morphine or oxycodone. And then if someone really is not well-controlled, perhaps referring them on to a pain specialist, a palliative care specialist to work with the nuances of methadone. So, breakthrough dosing. So let's say, you've got somebody on this long-acting medication and you're trying to figure out, how much should I give them for the short-acting dosing? The rule of thumb is about 5 to 15% of the 24-hour dose. So I round it off, 5 to 15, I pick the middle. 10%, I can do that math in my head. So if a patient is on 60 milligrams of morphine, long-acting, twice a day, that's a total of 120 milligrams. 10% of that is 12 milligrams, that would be their typical dose. So, the pills come in 15 milligrams. So I'd advise them to take one 15 milligram tablet as needed and that would be a pretty appropriate breakthrough dose. Keeping in mind how you're delivering it, if you give it orally, it may take an hour to be effective. If it's given sub-q or IM, it should be quicker and IV can be really quick. There's also sublingual. Sometimes, particularly towards the end of life, very sick patients. If they're very nauseated, if they can't swallow pills or even liquids, sometimes we use sublingual morphine. They put it under their tongue and because there's a lot of blood supply and lymphatics there, it just crosses right over into the bloodstream without swallowing it. So that can be a good way, lot's of hospice nurse's use this for hospice patients if they're struggling to swallow. There's also a transdermal patch. Now with esophageal cancer, we have a lot of patients who struggle to swallow. So this is really a good method, if they're struggling to get pills down. They put the patch on, we always warn them 12 to 24 hours before you see its total effect and then it can last anywhere from 48 to 72 hours. So it's kind of nice after they're started on it, just every three days change the patch and that's their round the clock dosing. We of course, always give them short acting medication for breakthrough pain if needed. There's also and you don't have to memorize this. This is just showing you that there is a table called an Equianalgesic Dosing of Opiods. So let's say, you have a patient on morphine and the patient is having a lot of nausea or a lot of nightmares from it and you just want to try them on another opiate. Their pain is well-controlled, but you want to get rid of that side effect. So let's say, you want to switch them to oxycodone. So if they're on 15 of morphine, you switch them to 10 oxycodone, because that's sort of equal conversion. So carry one of these in your pocket, because it's hard to memorize all the nuances, but you don't want to just guess and always put the patient at a starting dose, because you're putting them on a new medication. You already know how much they're on of one type of opiate and you really want to be consistent in the dosing, as you switch them to another opiate. Fentanyl is a little tougher, that patch that I talked about. So all you have to remember, if you use it is the ratio of oral morphine to fentanyl and it's two to one. So if they're on 50 of oral morphine for 24 hours and they have a lot of nausea and vomiting from chemotherapy, so they're not keeping down their morphine and you want to give them the patch, how much do you start at? Well, two to one. So, 50 to 25 and you start them on a 25-microgram patch every 3 days. Again, you'll get used to using these things, but these are some very basic principles that will help guide you. Always got to keep in mind the side effects of opioids. The most common one is constipation, 90% of patients. So if you give them an opioid without talking to them about using a laxative, you're really doing them a disservice. Other things that can occur dry mouth, nausea, vomiting, sometimes sedation. Uncommon, but we've all had to switch patients off drugs for these reasons are bad dreams, dysphoria, delirium. Sometimes on really high doses, they can get myoclonus, which is sort of a random shaking of the arm or leg. Sometimes they can get itching, but it doesn't mean all opioids will cause that for them. Maybe morphine does, but fentanyl doesn't or vice versa, o you have to keep trying different things. Again, constipation common to all opioids. Easier to prevent then to treat. So, please remember those laxatives not just a stool softener and really tell the patients they've got to stay hydrated. There are also a couple of relatively new medications that are very specific to opioid induced constipation. We all know of over the counter things like MiraLax, but these two, methylnaltrexon or RELISTOR, which is the first one that came out and it's a sub-q medication. And there's a more recent one, Movantik, which is a pill and a mechanism of action is that it affects the mu receptors. Now if you remember, the mu receptors are what are associated with pain. Now when you give an opiate, you want the opiate to affect the mu receptor in the CNS, because that will give you your pain relief. Unfortunately, there are also mu receptors in the gut. So when it hooks on to those mu receptors, it's going to cut down on peristalsis and cause constipation. So you want the CNS effect, but you don't want the GI effect. So these medications, interestingly are formulated in such a way they don't cross the blood-brain barrier. So, they stay local in the GI tract. They do interact with those mu receptors in the GI tract, but not in the CNS. So it shouldn't affect pain control, but it should allow for peristalsis. In tests that we're done that eventually got this approved, 62% of patients had a bowel movement within four hours of getting this particular drug, so can be very helpful. So, we've talked about neuropathic agents. We've talked about opioids. We've talked about side effects. So, let's now move on to our post-lecture question. So when you've got a patient on an extended release opioid for chronic cancer pain, what is the best dosing for an immediate-release opioid for breakthrough pain? When you look at your 24-hour dosing, you take 10% of that, 20%, 30% or 40% and designate that as your breakthrough pain dose. So hopefully, you've picked your answer and the correct answer is 10%. As we said, typically from 5 to 15%, 10% is easy to work with. The math is typically easy to do. So, that's your typical guideline. And don't forget, if over time you're increasing the long-acting medication and increasing it over time, you gotta keep looking at your breakthrough dosing and make sure that it's keeping pace with it. Otherwise, it's just like a drop in the bucket, if you've got lots of long-acting medicine and just a tiny dose for breakthrough. So in summary, our take home points are if you have a patient with neuropathic pain besides opioids, you probably should consider adding in an anticonvulsant and, or an antidepressant. Chronic severe pain is typically treated with an extended release opioid plus an immediate release opioid for breakthrough pain as needed and you need to give laxatives prophylactically when prescribing opioid to prevent constipation. Because almost all of the time, it will occur if untreated and I thank you very much for your attention and I hope you enjoyed these modules on the treatment of the esophageal cancer patient.
