Fentanyl Revisited

One of my most faithful readers, Elizabeth Munroz, suggested that I expand on my discussion from my last blog entry about pain management and the role of fentanyl. I think that’s an excellent idea, because this is a topic I feel very strongly about.

A computerized search of the medical literature (http://www.ncbi.nlm.nih.gov/sites/entrez/) for articles about chronic pain turned up 45,290 articles. Clearly this is a topic of intense research, and my goal here is not to write a textbook, but rather to touch on the highlights of pain management in the cancer patient, so that articles in the popular press about pain medications can be read in this context.

Acute vs. Chronic Pain

One of the points I made, and one of the concerns raised by the FDA in their recent warnings regarding fentanyl patches, is the difference between acute and chronic pain. At its simplest, the difference is obvious: acute pain happens suddenly (think of your last headache) and eventually goes away, while chronic pain lasts a long time (like someone with a bad back, whose back hurts every single day). But upon a closer look, these differences become less distinct. Someone with a bad back might have pain every day, but if they try to lift something heavy, that can send a sharp spasm of significantly increased pain shooting through them. Is that acute pain? Actually, for people who have pain every day, we usually think in terms of chronic pain with acute exacerbations. This acute jolt of pain takes place on the background of the daily pain… an important distinction for treatment.

Different Types of Pain

Pain can not only be acute or chronic, but there are different types, one of the most important being neuropathic. Imagine the pain that comes from bumping into a bruise on your thigh. Now imagine the pain that you feel when your leg has “fallen asleep.” The first of these is what pain management doctors call “nociceptive pain” and arises from tissue damage or inflammation, and the second is “neuropathic pain” and arises from damage to a nerve. Biologists have learned that these different types of pain are transmitted through different types of nerves and using different molecular mechanisms. Doctors have learned that these biological differences mean that the management of these different types of pains requires different strategies.

How do we feel pain?

There actually is no easy answer to this seemingly simple question. However, scientists do understand to some extent. When there is damage to tissue (such as from trauma or inflammation), nerves sense this damage, fire a signal to the brain, and the brain interprets this signal as pain. There are proteins in the brain called opiate receptors. These proteins help determine how active certain nerves are – the nerves that mediate the sensation of pain. Your body makes substances that attach to opiate receptors and turn down the activity of the pain-sensing nerves, decreasing the sensation of pain.

How do pain medicines work?

Opiate receptors are the targets of narcotic pain medicines, like morphine and fentanyl. The medicine attaches to the opiate receptor and turns down the activity of the nerve. Inflammation is the target of most over the counter pain medications, like ibuprofen. Less inflammation means less tissue damage, which means less activity of the nerve, and less pain. Neuropathic pain arises from damage to nerves, and medicines like neurontin help treat neuropathic pain by directly turning down the activity of the damaged nerve. These differences are very important, because the different types of pain have different causes and need different medicines to treat them.


Courtesy of NIAAA
The figure shows how some nerves make opioids (endorphins) that send a signal to other nerves. Narcotics (exogenous opiates) mimic this signal, turning down the activity of a nerve involved in sensing pain. Naltrexone is a drug that blocks the action of opiates by blocking their ability to attach to the opiate receptor.

How are narcotics different from each other?

All narcotics work basically the same way – they attach to the opiate receptor. So what’s the difference between morphine and fentanyl? The major differences relate to how the drug is handled by the body. Fentanyl attaches much more tightly to the opiate receptors than morphine, so you need much less drug to ease the same amount of pain (in fact, fentanyl is about 100 times more potent than morphine). But fentanyl doesn’t last as long in the body. A dose of morphine can kill pain for 4-6 hours, compared to only an hour or so for a single dose of IV fentanyl. This short duration is the reason for the development of fentanyl patches… by slowly releasing the drug into the body, it can be made to last much longer. A fentanyl patch can provide pain relief for days at a time.

What about tolerance?

In an earlier article, I talked about the difference between tolerance and addiction. How does tolerance happen? Well, if the opiate receptors all have narcotic attached to them, the nerve senses this and makes more receptor. Now there are new opiate receptors that are not bound up with narcotic, and the pain comes back. With more opiate receptors on the nerve, a higher narcotic dose is needed to turn off the nerve’s activity. We call this tolerance. This happens to every chronic pain patient. They need to take more medicine to experience the same degree of pain relief. This isn’t a character flaw, and it isn’t addiction. It’s the body’s response to being treated with the drug every day.

Tolerance is exactly why fentanyl patches are meant for chronic pain and not acute pain, and why putting on a fentanyl patch for a headache can lead to an overdose. Fentanyl, being so potent, rapidly saturates the opioid receptors on the nerves of patients who don’t take these medications every day.

Pain management strategies for the chronic pain patient

So how do I treat pain in my patients? The first step is to try to determine the type of pain, so that I’m using the right drugs. If the patient has neuropathic pain, morphine won’t work as well as neurontin. If the patient has chronic pain, they need something long lasting, like a fentanyl patch or methadone. But even chronic pain patients have acute pain episodes on top of their chronic pain. For these acute pain episodes, the patient needs something that will work quickly to relieve the pain fast, but won’t last too long, so that when the pain is gone, so is the medication. Oxycodone is perfect for that type of pain: it starts to work in minutes and only lasts a few hours (unlike the sustained release version, oxycontin, which takes an hour to kick in and lasts for 8-12 hours).

Some final thoughts

Pain is manageable. The key to helping a cancer patient with their pain is to understand the different types of pain, why some medications work for some kinds of pain but not others, and to work hard to balance the benefits of pain medications with the side effects in order to maximize the quality of the patient’s life. Thankfully, here in the US, we have an abundance of pain medications available, and no one needs to live in pain for lack of taking pain medications (which is not the same thing as saying no one needs to live in pain, because unfortunately, we can’t relieve all pain). Fentanyl is a potent drug, but it’s the misuse of fentanyl that the FDA is warning about, not the correct use. Used properly, fentanyl is (in Elizabeth’s words) “a godsend” for patients with chronic pain. It shouldn’t be taken off the market, it should be used correctly.

Breaking News: the FDA (re)issues warning about fentanyl

In September, I wrote about the double-edged sword of narcotics and pain control for cancer patients. Around that same time, there were news reports of patients dying from improperly prescribed Fentora, which is a preparation of the powerful narcotic, fentanyl, that is absorbed through the lining of the mouth.

Fentanyl is in the news again this week. This time, the issue is with fentanyl patches. These are a favorite tool for oncologists, because the drug is absorbed through the skin. This means the patient need not swallow a pill, a big deal for patients receiving chemotherapy (notorious for causing nausea and vomiting). Fentanyl patches are also great for managing chronic pain in patients who have significant prior narcotic exposure, and it’s hard to imagine practicing oncology in the US without this tool.

However, like all tools, improper use can result in great harm.

At a news conference last week, the FDA reissued a 2-year-old warning about fentanyl patches, which have been linked to at least 120 deaths. They repeated their advice that these patches be reserved for patients with chronic pain and a tolerance to opioids. The patients who have died have all been prescribed for acute pain (in one case, a headache) and had never taken narcotics before.

Fortunately, the FDA does not seem likely to heed the call from some people to limit the ability to prescribe fentanyl patches to pain specialists. This would be a big mistake, because there are only 4,000 pain medicine specialists in the US, and many, many patients with chronic pain are treated safely and effectively by experienced physicians without specific pain training.

Bottom line? Pain medicines are powerful medicines. Used incorrectly, these medications can be deadly. But, used correctly, they can make life tolerable for people who would otherwise suffer terribly. That fact alone is sufficient to keep them on the market, and in the hands of doctors who know how to use them and patients who need them.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 1)

Is cancer a contagious disease? The simple answer to that question is “No.” At least, that’s what we tell people. You can’t catch cancer from someone who has it. If a cancer patient is isolated, it’s to protect the patient from us, not the other way around. But, as is often the case, the truth is not quite so simple.

Let’s take a trip back in time. It’s 1984. Arguments rage about what to call the newly discovered virus that seems to cause this new disease called Acquired Immune Deficiency Syndrome (the American group proposed calling the virus HTLV-III while their French competitors wanted to call it LAV). When the dust settles, the virus is called HIV, and it quickly becomes clear that infection with HIV is not the same thing as having AIDS. So how do we define AIDS? Well, a person has AIDS if s/he is infected with HIV and has one of the so-called “AIDS Defining Illnesses.” Interestingly, one of these is a kind of cancer called Kaposi’s Sarcoma. Kaposi's Sarcoma causes nodules or blotches that may be red, purple, brown, or black. They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and may be fatal.



All of the other AIDS defining illnesses, however, are infections that usually strike people with weakened immune systems (like cancer patients). So what is Kaposi’s Sarcoma doing on the list?

That question remained a mystery for quite a while. After all, although Kaposi’s Sarcoma was first described in 1872, it was originally known as a disease that affected older men from the Mediterranean region or who were of Ashkenazi Jewish descent. Yet, these men didn’t have AIDS, and no one knew why Kaposi’s sarcoma seemed to disproportionately affect this population. There is also a form of Kaposi’s Sarcoma endemic to sub-Saharan Africa, and although HIV infection is prevalent there now, that was not the case when endemic Kaposi’s Sarcoma was first described.

An answer to this mystery became apparent in 1994 when a group at Columbia University showed that Kaposi’s Sarcoma is actually caused by a virus. Originally they called it Kaposi’s Sarcoma Herpes Virus (because it is closely related to the viruses that cause herpes), but is has since been renamed HHV-8 (human herpesvirus 8). Subsequent work has shown that all forms of Kaposi’s Sarcoma are associated with an HHV-8 infection.

Over the years since the beginning of the AIDS epidemic, we have gotten pretty good at treating HIV infection, and with HAART (highly active anti-retroviral therapy), HIV infection has morphed from a rapidly fatal infection to a chronic disease. A by-product of the advent of HAART was the apparent disappearance of Kaposi’s Sarcoma. What was once an AIDS-defining illness, affecting as many as 80% of AIDS patients, there have been very few cases in the past 10 years.

Until now.

15 Kaposi’s Sarcoma cases were recently identified by doctors at San Francisco General Hospital. Surprisingly, these cases occurred in patients whose HIV infections were well controlled on HAART. This has prompted speculation about what happens as the immune system ages. These men all have undetectable HIV levels and normal numbers of white blood cells. Of course, so do the Ashkenazi Jewish men who used to be the primary group of KS patients. So what does this mean? Right now, no one is certain. But like all medical mysteries, we will all be a lot smarter once we figure it out.

Blog Carnival, Part Deux

Some months ago, I was invited to participate in the second Cancer Research Blog Carnival. I recall what an honor it was to be asked to participate, and how pleased I was to see the excellent entries that my colleagues had contributed. Well, I’m happy to say that there is another Cancer Research Blog Carnival. If you have a moment, please stop by and read some of the entries. They are all excellent… it is once again an honor to be in such company.

A Day in the Life of a Pediatric Oncologist

No, not a Beatles song… but rather a look at a typical day for an academic pediatric oncologist. Actually, one of the things I love about my job is that no two days are alike. So there really isn’t any such thing as a “typical day.” Some days, though, see a good combination of clinical work and lab research, so I’ll try to describe what this past Tuesday was like for me.

It’s Tuesday. I get to my office around 9am. The first order of business is checking email (I live on the internet, despite being in my 40’s). Most mornings there are quite a few waiting for me, and this morning is no exception. One email has to do with making some changes to a clinical trial protocol that were suggested by the FDA, so I open that file, make the changes, and send it off to Tammy, my research nurse, so that we can submit the protocol to our Institutional Review Board (IRB). All clinical trials have to be approved by an IRB to ensure that they are ethical, and under certain circumstances (like testing very high doses of a new chemotherapy drug) this can’t happen until the protocol is approved by the FDA.

I answer a few emails, and then I go downstairs to my lab to check on my staff. I spend an hour and a half talking with the folks in the lab about our various research projects. As usual, some are going well, and some are progressing more slowly. I visit each person in turn and we talk about their data from the last week, what it means, how to interpret it, and what we need to do next.

On Tuesdays we have Tumor Board, which is a meeting I run. Tumor Board is the largest regular meeting we have, and is attended by my colleagues in pediatric oncology (including faculty, fellows, nurses, social workers, and pharmacists), as well as by colleagues from surgery and radiation oncology. For the next two hours we will discuss each new patient, review scans that patients have had that require a change in therapy, and talk about the progress of every inpatient. Time permitting, we also have a 20 minute lecture by one of the fellows on a topic relevant to one of the current patients. On Tuesday there were so many scans to review, and the decisions to be made required so much discussion, that we did not have time for the fellow’s lecture. The conversations we had were important, though, because we were able to make treatment plans as a multi-disciplinary group, thus assuring the patients that all of the doctors were in agreement and were communicating well with each other.

After Tumor Board comes the weekly meeting of our bone marrow transplantation (BMT) group. This group typically meets twice a week. On Mondays we talk about upcoming patients, and on Tuesdays we discuss patients currently being treated. As one of my patients is in the ICU, we talk about him for a while. Fortunately, though, he is getting better, and we decide to just hold the course and keep doing what we’re doing.

After the BMT meeting, I stop in to see some of my hospitalized patients. The visit to the ICU is the hardest, because even though the patient is slowly getting better, he is still very sick, and I really want him to get well. I touch base with the ICU staff and discuss his status with them and with the patient’s mother, offering her words of encouragement along the way.

Finally, it’s time to go back to the office. In the last few hours before I head home, I can work on one of the many writing projects I am balancing, including a manuscript describing some new findings from the lab and a draft of a grant application soliciting money to support our lab work. It’s quiet in my office most afternoons, so I get a fair amount done before I go home.

It’s been a long day, so I’m looking forward to being home. Of course, there’s always more work to be done, so after the kids are in bed, I’m sure I’ll get back to work on the grant application. It will be close to midnight before I put that aside and relax for a bit before I go to sleep.