Use of Opioids for Adults with Pain from Cancer or Cancer Treatment Guideline

Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management.

Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.”

Thank you for being here, Dr. Paice and Dr. Bruera.

Dr. Judith Paice: Thank you.

Dr. Eduardo Bruera: Thank you for having us.

Brittany Harvey:  First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Judith Paice: I have no relevant disclosures.

Brittany Harvey:  Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Eduardo Bruera: Regrettably, I don't.

Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline?

Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids.

We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs.

We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer.

Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic.

So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered?

Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain.

So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease.

And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain.

Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer?

Dr. Judith Paice:  Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another.

So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings.

So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions.

So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent.

The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic.

The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine.

Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use.

And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use.

Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area.

So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated?

Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration.

And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day.

Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain.

And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable.

But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain.

An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through.

Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed?

Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective.

But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention.

And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer.

Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment?

Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction.

One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used.

And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we’re using to reduce the risk of accumulation in a given patient.

There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure.

With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important.

But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver.

So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids.

Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain?

Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough.

And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose.

But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain.

Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose.

And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency.

And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about?

So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose.

Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated?

Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing.

The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects.

Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion.

And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects.

But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another.

So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline.

But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist.

There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa.

We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there.

And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough.

And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this.

Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients.

So, I want to thank you both for reviewing all of those recommendations that the panel came up with.

So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment?

Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively.

There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients.

We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective.

Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients.

So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies?

Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences.

But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas.

Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder.

That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful.

Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera.

Dr.  Judith Paice: Thank you.

Dr. Eduardo Bruera:Thank you so much.

Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines.

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