International Research Foundation for RSD / CRPS

Last Update Saturday 29 January, 2005


Video Transcription By:

Lori A. Eley, RN

Wife of Physician husband afflicted with RSD / CRPS and

advocate for more research on this disease.




Live Internet Broadcast
University of South Florida
August 6, 2003

Use of Opioids (Narcotics) to treat RSD / CRPS in
Adults and Children

 

CLICK HERE FOR VIDEO PRESENTATION

 

CONTENTS:

Introduction
Adverse Effects
Addiction
Use in Children
Take Home Messages
Questions & Answers
References

Addendum: Warning about methadone Use

 

Moderated by: Dr. Anthony Kirkpatrick

International panel of experts representing neurology, anesthesiology and psychiatry:

Dr. Ralph-Thomas Kiefer
Anesthesiologist
Eberhard-Karls University Medical School (Tuebingen, Germany)

Dr. Stephen M. Butler
Anesthesiologist
Uppsala University (Uppsala, Sweden)

Dr. Robert Schwartzman
Neurologist
MCP Hahnemann University School of Medicine (Philadelphia, Pennsylvania, USA)

Dr. Maria Wilson
Neurologist
University of South Florida (Tampa, Florida, USA)

Dr. Anthony Kirkpatrick
Anesthesiologist
University of South Florida (Tampa, Florida, USA)

Dr. Alyssa LeBel
Neurologist
Harvard Medical School (Boston, Massachusetts, USA)

Dr. Sabine Kost-Byerly
Anesthesiologist
Johns Hopkins University (Baltimore, Maryland, USA)

Dr. Seddon Savage
Anesthesiologist
Dartmouth Medical School (Manchester, New Hampshire, USA)

Dr. Martha Brown
Psychiatrist
University of South Florida (Tampa, Florida, USA)

UPDATE: December 1, 2006

FDA ISSUES ALERT ABOUT METHADONE


INTRODUCTION


Dr. Kirkpatrick:
Welcome! We have been very fortunate to gather as our faculty, a group of renowned physician's recognized for their expertise in the use of opioids to treat chronic pain syndromes. I am Anthony Kirkpatrick, Vice president of the International Research Foundation for RSD / CRPS, and a member of the faculty at the University of South Florida.The International Research Foundation for RSD / CRPS has been a leader in educating healthcare professionals worldwide on a chronic pain syndrome called Reflex Sympathetic Dystrophy or RSD.

This syndrome belongs to a class of chronic pain syndromes called Neuropathic Pain, meaning pain attributable to pathology of nerves. More recently this syndrome has been referred to as a Complex Regional Pain Syndrome. This syndrome is a chronic, painful, debilitating neurological condition that affects millions of people here in this country and around the world. Many persons in this room might recall the first International Symposia on RSD held at this university a little over a year ago.

This year we are taking a different approach. This year we will be using advanced technology. For the first time this University's College Of Medicine will conduct a live and interactive health symposia to a worldwide audience of health professionals using the Internet. In a few moments we will engage experts from Germany, from Sweden, as well as from universities throughout the United States in a live, interactive discussion over the Internet. This symposium will focus on the use of opioids to treat RSD in both adults and in children.

The International panel is multi-disciplinary representing the fields of Neurology, Psychiatry and Anesthesiology. We are broadcasting today live in a low-band width in order to make this program accessible to the largest global audience; however, the post-production version of the program will be broadcast in high-resolution broadband over the Internet. The program is divided into three separate topic areas. Each of these three topics will be presented by faculty known for their expertise in that area followed by a live discussion among experts in our studio audience as well as by experts at various universities around the world.

For speakers at remote sites, you will not be able to see them because they will be on the phone. We've had to do this in order to avoid the 15 to 20 second lag-time caused by transmission of video over the internet. However, their slide presentations will be broadcast live over the Internet from here on the campus of the University of South Florida. The speakers will be making reference to specific publications during the course of their presentations to support their conclusions. These references will be published separately on this website. At the conclusion of the presentations and discussions, the symposium concludes with an opportunity for all speakers to provide their take-home message. We estimate that this live symposium will last for one hour and a half.

Here are the three topics to be discussed:

During the first presentation you will learn about the adverse effects of opioids.

This presentation will come to us live from Eberhard-Karls University Medical School in Germany.

During the second topic we will discuss concerns about addiction, diversion as well as aberrant behavior while taking opioids. This presentation will come to us live from Dartmouth Medical School in the United States.

The final topic will be a discussion concerning the use of Opioids in Children. This presentation will come to us live from Harvard Medical School in the United States.

The viewing audience is invited to fax questions for our experts. The fax number to call in the United States is area code 813-974-9099. These questions will be addressed at the end of the program.

Before I introduce our distinguished panel of experts in the room, I would to thank two groups of people at our University that have made this live, global event possible. These persons represent the Department of Academic Computing Technologies and the Video Production Group, which is part of the Media Innovation Team at the Center for 21st Century Teaching and Excellence.

Now, allow me to introduce our outstanding panel in the room. To my immediate left we have Dr. Maria Carmen Wilson of the Department of Neurology at the University of South Florida. Dr. Wilson is Director of the Pain Management Program at Tampa General Hospital. She is widely published in the field of chronic pain headaches.

Next to Dr. Wilson, we have Dr. Martha Brown. She is with the Department of Psychiatry for the University of South Florida. Dr. Brown is an Addictionologist. For nearly over 2 decades she has served as a consultant to numerous State and Federal agencies in the field of Addictionology and has published numerous papers on the subject.

Finally, I would like to make one amendment to our panel today. Dr. Robert Schwartzman really needs no introduction. He was here at our University this week as a visiting Professor. Just before this broadcast went on the air, he received an urgent call from Philadelphia and has had to catch a plane back to Philadelphia; in fact he is on a plane right now. So, what we're going to do here is focus a little bit on the research that Dr. Schwartzman has been doing in collaboration with investigators in Germany, looking specifically at use of Ketamine in low doses and high doses.

ADVERSE EFFECTS OF OPIOIDS (NARCOTICS)

And fortunately, we have here with us today, our first speaker.

Our first topic is Adverse Effects of Opioids.

I cannot think of someone more qualified to discuss this topic than Dr.Thomas Kiefer in Germany and as I've noted, Dr. Kiefer has been collaborating with Dr. Schwartzman, so we're going to see some very cutting-edge research that's going on in trying to find, hopefully, a potential cure, or at least a way to put these patients in some type of partial remission. The reason I can say that Dr. Kiefer is an expert on Adverse Effect is because his colleague, Dr. Rohr and he have been doing this research at their University the Eberhard-Karls University Medical School in Germany. Their research with the NMDA-antagonist Ketamine shows great promise in the treatment of advanced RSD.

Welcome Dr. Kiefer!

Thank you for offering to discuss with us the adverse effects of opioids at this late date. Would you just please give us a nice succinct presentation on some of the important things physician's need to know about the adverse effects of opioids and after you do your presentation we're going to have a discussion among experts here in the United States and elsewhere in the world, and I would like you to stay available to us because then I want to come back to you after those discussions; and I'm sure there's going to be some questions for you. Dr. Kiefer, welcome. Please tell us what you know about the adverse effects of opioids.

Dr. Kiefer:
Dr. Kirkpatrick! Thank you very much for your kind introduction and above all the great opportunity to participate in today's event. Now, let's get to our presentation, which is concerned with the adverse effects of opioid treatment.

A few days ago we performed a Medline search from 1966 up to today to review the existing evidence in treating RSD / CRPS with narcotics. We found a total of 2,788 Medline-referenced articles concerned with RSD / CRPS. Combining this research with the term "Opioids" resulted in only 32 articles. Out of those, only 2 articles were randomized controlled trials, thus high quality of evidence.

One of those articles by Dr. Harke and colleagues, published in Anesthesia and Analgesia in 2001, investigated the effect of either carbamazepine or morphine after a primary successful treatment of spinal cord stimulation, in a mixed population of 43 patients with neuropathic pain. While carbamazepine showed significant delay in pain increase after successful spinal cord stimulation, morphine did not. Only 2 (two) patients of the carbamazepine and 1 (one) patient of the morphine were reported to be pain free. Concerning morphine, they concluded that probably the dosage of 90 mg (ninety-milligrams) a day was insufficient for neuropathic pain states.

The second article by Glynn and colleagues, published in Pain in 1993, investigated the effect of morphine injection around the stellate ganglion. They reported neither a modulatory effect on the sympathetic nervous system, nor an effect on pain relief in patients with RSD of the upper extremities; but the most important conclusion of this modeling research seems that valid and high quality evidence to treat RSD / CRPS with narcotics is still missing.

As Dr. Kirkpatrick stated before, RSD / CRPS is classified as a neuropathic pain state.

Let us first take a look at the data existing for opioids in the treatment of neuropathic pain.

Up until the late 1980's, pain treatment with opioids have been reserved for acute pains; and in chronic pain medicine for the treatment of cancer pain. Then this particular stigma changed and today it is generally accepted that opioids may be of promise for non-malignant pain; for example, often neuropathic pain states.

We selected a few exemplary studies reflecting the current knowledge of opioids for neuropathic pain. Cherny and colleagues published in 1994 in Neurology described that neuropathic pain apparently is less sensible to opioids, meaning higher doses are required compared to known deceptive pains. Thus, observation that higher doses of opioids are needed in neuropathic pain has been confirmed by many other studies. For example the work of Portenoy and colleagues published in 1990 in Pain, and colleagues in 1998, also published in Pain, only to name a few studies support the use of opioids for neuropathic pain. In a very well designed and conducted study by Rowbotham published this year in the New England Journal of Medicine, demonstrated that higher doses of narcotics produce a better effect on pain relief in neuropathic pain, but also high dosages are associated with a higher incidence of adverse and side effect.

Let's now take a closer look at the most common side effects, which are typically seen when taking narcotics.

Most of the side effects are clinically seen when the treatment with opioids is started, and many of them improve or even disappear in the course of treatment.

The clinically most common side effects are:

Nausea and vomiting, constipation, sedation and other unspecific central nervous system symptoms. Nausea and vomiting is a direct effect of opioids on the chemo receptive trigger zone, or the so-called emetic trigger zone in the brain. Nausea and vomiting are specific side effects of all opioids.

One of the most important side effects of narcotics is constipation, which can lead to severe clinical problems. Opioids directly impair the motility, thus the normal function of the stomach and the entire intestines and leads to an increase in tone in the gastrointestinal sphincter, altogether, leading to constipation. In this matter it is most important to realize that the effect of narcotics on the gastrointestinal system apparently does not show any tolerance, therefore, bowel function cannot be expected to improve during the course of therapy.

Opioids may also cause urinary retention mostly by increasing the tone smooth muscles in the urinary pathways and the sphincters of the urinary bladder. This problem seems to be more significant when opioids are used by intraspinal injection. Commonly, patients also report unspecific central nervous system effects. These include tiredness and fatigue, impairment of cognitive function, such as the ability to think, sometimes dysphoria, or impairment of the mood, significant confusion and dizziness.

Clinically and legally important is an impaired reaction capacity above all when starting for therapy with opioids; therefore, patients in our country (Germany) are not allowed to drive a car when the therapy with narcotics is started. In patients with a good response to opioids, these adverse effects are intermediate and may improve or even disappear after about one week of treatment. Apart from these common side effects other rare side effects occur.

The side effects listed in this slide are either uncommon or the exact prevalence is not known. Pruritis or a severe itching feeling is currently thought to be an effect on the central nervous system. It is rarely seen when opioids are given orally, but is very common after epidural and intrathecal use. Dahl and colleagues reported in 1999 in Anesthesiology, an incidence of pruritis of 51% after the use of spinal morphine. Unclear are data concerning the effects of opioids on diuresis. The existing data were reported in the 1950's to 1970's, mostly collected peri-operatively and most of the reported effects are currently thought to relate to inadequate peri-operative fluid management, rather than to a specific opioid effect.

Diaphoresis, or increased sweating, is reported by some patients, but the underlying mechanisms remain unclear. Myoclonic involuntary contractions of muscles are also seen in some patients. Mechanisms underlying these myoclonic movement and opioid-induced muscle rigidity, however, remain unclear. Seizures have also been reported with the use of opioids, specifically after the use of meperidine.

In recent years it has also become clear that opioids have neuroendocrine effects. Clinically very important and relevant are the patient's effects on sexual functions. Opioids apparently negatively effect libido, but also may lead to erectile dysfunction. This depression of sexual function seems to be more common in men than in women. Interference with the female menstrual cycle also has been reported. For spinal opioids in young women, amenorrhea, or the stopping of the period, and galactorrhea, or the production and flow of milk, have been reported.

Last, but not least, there remains some very rare side effects of opioids resulting from single or very small case reports. These include: edema, or the accumulation of fluid, above all in the lower extremities, probably caused by a peripheral venous pooling that occurs under opioid therapy. Other psychiatric symptoms, mainly hallucinations and psychotic symptoms have been reported. Respiratory depression is known to be a specific effect of opioids. However, in the presence of severe pain, which is a strong respiratory stimulus, respiratory depression is clinically almost irrelevant when opioid therapy is used at the right indications and carried out correctly.

Polyarthralgia's are severe pains in numerous joints appearing after opioids has been reported, after the use of spinal opioids, mostly in young women. So far, the mechanism is unclear, but the suppression of the cortisol-release is suspected. Asthma or so-called analgesic asthma is a very rare condition following opioid administration. Again, the mechanisms are not fully understood.

Recently, a growing number of reports suggest that treatment with narcotics under certain conditions, for example, long-term administrations with larger doses may lead to pathological pain stage, such as hyperalgesia or allodynia. Basic research suggests that opioids may lead to formation of a spinal pathway, resulting in these symptoms.

In conclusion, we would like to state the following:

The adverse effects of narcotics or opioids seem to occur in dose-dependent manner. Clinical experience and published evidence suggests that the rate of adverse effects with opioids is high with non-responders and partial responders compared to patients showing a clear benefit under the treatment with narcotics. Apart from dosage, the rate of rise of blood concentrations of opioids is very important. Thus, immediate release formulations will be more likely to produce adverse effects than sustained or slow-release formulas.

Clinically, it is most important for physician's to realize that when patients experience severe side effects, patients are often not willing to continue opioid therapy. Thus, detailed information on the patient is very important to gather during the course of treatment with an understanding that many initially observed side effects will disappear in the course of treatment.

Also, it seems very important for us to state that in the case of persistent and intolerable side effects, this may be indicative of a lack of opioid sensitivity. If this is suspected, it seems mandatory to check the opioid sensitivity and to prove that the patients clearly benefit from opioid therapy. Should severe side effects nonetheless persist, however, together with a significant pain relief, then a so-called opioids rotation, that is, changing the type of opioid, might be of promise.

Please allow us to emphasize a last issue. Be careful to closely monitor patients treated with opioids. Before starting long-term therapy with narcotics, a significant pain reduction following opioid treatment needs to be clearly demonstrated. Side effects have to be recognized early and treated consequently. Constipation prophylaxis should be given in all patients routinely. After all, it should not be forgotten that the therapy with narcotics only represents one piece in the puzzle of a multi-disciplinary approach in the sufficient treatment of chronic pain.

We hope that we were able to give you a short impression about the adverse effects in the use of narcotics in chronic pain disorders. And thank you very much for your interest and attention.

Click Here For Dr. Kiefer's References

See ADDENDUM on Methadone



Dr. Kirkpatrick:
Dr. Kiefer, thank you very much for that very scholarly, very comprehensive review of the potential adverse effects of opioids. Now we're going to open this up to a further discussion. We have a total of eight (8) physician experts distributed in the United States and around the world to comment on this topic. For the sake of efficiency, however, I'm going to ask the speakers at these different sites, and including in the studio here, to try to limit their presentations to one or two minutes. We have an individual sitting here who is going to keep score and let us know if we're exceeding these time limits. We want to give as many people as possible an opportunity to offer different views on this topic. Now, fortunately we have with us at a remote site a Dr. Stephen Butler.

Dr. Butler began his career as a pain management specialist at the University of Washington. There, he ran the Pain Management Program. For those of you that are experts in the field of pain, you know that is where John Bonica started a pain management program. That program is highly regarded all over the world as being a leader in pain management. From there, he went to Sweden, and there at Uppsala University, he's now the director of their Pain Management Program. One of the areas of his current research is focusing on the impact of immobilization on exacerbating the syndrome reflex sympathetic dystrophy. Dr. Butler, are you with us here?

Dr. Steve Butler:
Yes, I am.

Dr. Kirkpatrick:

Let me also clarify. Dr. Butler, it was very thoughtful for you to join us today, because, you know, Dr. Butler is on vacation right now. He's not in Sweden, he happens to be in Canada. And from what I understand, Dr. Butler, you're in some cabin someplace over looking a lake, and the only thing you've got is a telephone. Is that pretty much the picture here?

Dr. Butler:
That's right. But today we also have the rain, so this is a nice way to pass the time when I can't be outside.

Dr. Kirkpatrick: Well, listen. I just personally want to thank you for taking time out of your vacation to share with us your skill, your experience with this audience. On the topic of adverse effects, is there something that you would like to emphasize or to comment on or to question us on in that particular area?

Dr. Butler:
Well I think Dr. Kiefer did a wonderful job about going through the side effects of opioids and I don't have too much too add. One thing that surprises me is the limitation of driving with opioids in Germany, and there's some new research underway in Finland that shows that in pain patients, untreated pain, has a greater effect on driving ability than does opioids, and patients performance improves when their on opioids. That's just a small side-light. The other thing I would like to talk about is long-term opioids.

One of my colleagues has been doing some research that shows that it's not only libido that's decreased with long-term opioids, but they seem to depress the hypothalamic pituitary axis, and there's a depression of a lot of endocrine function including thyroid and adrenal on chronic high-dose opioids. And this is something that might account for a lot of the side effects in a broader sense, why patients feel generally unwell on high-dose opioids for a long time.

Dr. Kirkpatrick:
Dr. Butler, I would like to raise another area that's of interest. As you know, Dr. Kiefer mentioned the idea of switching from one opioid to another by sequencing the medications. We do know there's one clear-cut example of an opioid, a very commonly used opioid that has some unique properties that the others don't have, and that happens to be methadone.

As you know, methadone has this NMDA-antagonist activity. For those of you that may not be familiar, we believe the NMDA receptor is very important in neuropathic pain. And what's been reported in literature. When you look at the conversion tables for methadone, going from morphine for example, you find that you get a higher analgesic effect, in other words, more than what you would expect. This has been attributed to the NMDA-antagonistic effects of methadone. Methadone really is a racemic mixture, it has a D-isomer. It's the D-isomer in there that seems to be the active antagonist of the NMDA receptor. And so what I would like to ask you is what role in Sweden do you have for methadone besides, well just tell us in terms of in addiction programs, recovery programs as opposed to treating pain?

Dr. Butler:
The Swedish government is very restrictive in the use of methadone, and most physicians think that it can only be used for treatment of addiction, of opioid addiction. This isn't exactly true and we've been using more and more methadone over the last 5 years because we found in some patients that this has a much better effect than any other opioid. Many of the patients like it also because they feel more stable than when they've been using shorter-acting agents. We now have more longer-acting agents on the market in Sweden and so there are other options. Personally, I think methadone is probably underused in chronic, non-malignant pain and that we need more studies to look at its specific uses in neuropathic pain and probably in complex regional pain syndrome.

Dr. Kirkpatrick:
OK. Now, there's another area that I feel compelled to bring up and that has to do with this constipation problem that we see in these patients when they're on chronic opioids. I don't know how many other physicians that are speaking today have had this experience, but I have had some unbelievable, great experiences with using opioids in patients, literally transforming their lives, and we're primarily talking about treating reflex sympathetic dystrophy. On the other hand, I have to tell you about one patient because I think it's relevant to this story.

A relatively young lady, 28 years old, has RSD of the upper extremity and right lower extremity, sympathetically independent pain, so the nerve blocks, the sympathetic blocks, really weren't that effective. So, we're really running out of treatment options here, and so we put her on a trial of opioids; and it literally changed her life. She went back to work; she was more active, engaged with her family and so forth and so on.

Five years later she comes back to me and she has this scar from here, well basically from here, down to here (Dr. Kirkpatrick demonstrates from the upper to the lower abdomen); and I asked her what that scar was about, from here down to here, in case you missed that. And she said that she had a swollen abdomen and that they brought her in to the hospital and they did an ultrasound, ruled out that she was pregnant, and determined that she had a fecal impaction. She didn't think that was very alarming because she actually had diarrhea on occasion. So they went in there and removed it because they were afraid of getting an ischemic bowel. And when they took it out and weighed it, it weighed 22 lbs. (pounds). 22 lbs! And she enjoyed 5 years, but then she ended up with this as a problem.

I would like to ask our panel here in the studio if they've had this type of experience. What do you think Dr. Wilson? Have you run into the narcotic bowel syndrome?

Dr. Maria Carmen Wilson:
I have, but fortunately not to that extreme.

Dr. Kirkpatrick:
It was less than 22 lbs.?

Dr. Wilson:
Definitely. And I really haven't had anybody that actually needed surgery. I am very aggressive with prophylaxis of that. I put everybody on a very aggressive bowel regimen, but once in a while people still have problems.

Dr. Marsha Brown:
I actually haven't had that problem in any of the patients, but I don't treat...I'm on the opposite end in terms of addiction, and looking at trying to get people off at times, or whether they need to be on or not. But certainly I have heard of a lot of folks having that difficulty, and particularly in the methadone clinics where they're being treated with methadone, that's one of their common complaints is that they have constipation.

Dr. Kirkpatrick:
Good! Now - let's talk a little more about these NMDA receptors because this has a lot to do with neuropathic pain syndromes. Dr. Kiefer?

Dr. Kiefer:
Yes, I'm still on the line.

Dr. Kirkpatrick:
Good! Dr. Kiefer, you and Dr. Rohr have been doing some very cutting-edge research on high-dose ketamine. That is where you put patients under general anesthesia, you intubate them, and have them in Intensive Care Unit for 5 or 7 days; but you've also done some work on low-dose ketamine. Could you bring us up to date Dr. Kiefer. I know you've been doing this in collaboration with Dr. Schwartzman, (as I indicated earlier he had to leave for Philadelphia on short notice), but bring us up to date of where you are at in your studies in both the high dose ketamine patients and in the low dose ketamine patients, and compare those two different treatment protocols, if you would please.

Dr. Kiefer:
OK. I would like to start with the low-dose ketamine. Actually, we started working with ketamine, as you mentioned correctly, is one of the strongest or the strongest currently available NMDA-antagonist. We actually started this work in 1998, and you mentioned also the treatment of high-dose Ketamine, which actually is the result of our experiences with the low-dose ketamine. So, let's start with the low-dose ketamine.

Low dose ketamine is basically infusion therapy with increasing doses of ketamine over a prolonged period of time, normally between 6 (six) and 10 (ten) days. The ketamine is administered IV. And what we can say in summary is that if you have patients with RSD / CRPS that come to the clinic in very early stages, the onset of disease should not be longer than 6 months, and the disease is still localized, it means that the disease is not spreading to other than the primary effected extremity, then you see some success with low-dose ketamine. The problem with low-dose ketamine is to maintain pain relief.

We recently performed a series in very severe affected patients, who all had long standing disease between 4 and 6 years of CRPS, most of them with entire body RSD. We performed a trial of low-dose Ketamine on these patients. And we are seeing that these patients basically did not profit much from the ketamine. However in measurements you could detect that their touch sensitivity, or allodynia, got better, but the clinical outcome was that the pain in those patients was mainly not changed.

Now if you go to the high-dose ketamine. The high-dose ketamine treatments were invasive treatments, as you said; it's basically Intensive Care treatment with the patients being intubated, and mechanically ventilated for a period of 5 days with high-doses of ketamine, together with midazolam to prevent the patients from showing the typical ketamine side effects, such as agitation and involuntary movements. Up to today we performed this treatment in 13 (thirteen) patients, together with Dr. Schwartzman. Those patients all had intractable patients with worsening RSD / CRPS, who had many treatments attempts with no prior success. And in those patients we saw always, meaning all of the patients, a primary response, which was very, very promising. All those patients were being pain-free for some period of time. The problem in the high-dose Ketamine treatment also is maintaining of this primarily very effective pain reduction over longer time periods. Up to today we would say that about 50% to 60% of the patients of the high-dose ketamine, can you still read me?

Dr. Kirkpatrick:
Yes, oh yes! We're sitting on the edge of our seats!

Dr. Kiefer:
OK. So I'll proceed! There was just a click in the line. OK. Today we can say that about 50% to 60% of the patients have longer time periods, months, up to the longest pain-free patient is now 4 1/2 years (four and a half years) without any problems, and we see that in about 50% to 60% of the patients. Some patients, about 40%, they have a relapse of pain symptoms, and we are not sure what causes those problems. In some patients we could locate a triggering pathology, such as a chronic arthritis in the foot, which seems to re-trigger the neuropathic pain. In 2 out of those 13 patients, we had a real CRPS relapse to the intensity of pain that existed before treatment.

Dr. Kirkpatrick:
Dr. Kiefer. Thank you so much. That's really putting us right up to date with what's going on with NMDA-antagonists in managing neuropathic pain, and I thank you very, very much for that information.

Dr. Kiefer, please stand by. Towards the end of this program we're going to invite you back because we're asking all the speakers to come up with some take-home messages, and we'll be asking you to help us out with that.

Dr. Kiefer:
OK. I'm on standby.

Dr. Kirkpatrick:
Very Good!

ADDICTION

Dr. Kirkpatrick:
Now, we're going to move on to the second topic here which is addiction, aberrant drug behavior, that sort of thing while on opioids.

Fortunately, we have with us today, a world-renowned expert on that at a remote site. It's Dr. Seddon Savage at Dartmouth Medical School.

Dr. Savage has been investigating primarily in the context of a patient who is a known addict, and how do you manage their pain. And some of her work is being done in collaboration by someone else that we all know, and that's Russell Portenoy, in New York. So I can't think of someone that is better at giving us an up-to-date current picture of what to do with a patient who is an addict, or has a propensity to be in that situation. Dr. Savage?

Dr. Seddon Savage:
Yes! Thank you very much Dr. Kirkpatrick and I want to thank you and your colleagues for putting together this conference, which I think, is extremely valuable and very innovative and exciting. Thank you very much for inviting me.

When we consider addiction issues in the use of opioids for the treatment of chronically painful conditions, including such conditions as CPRS/RSD, it's important for us to be very clear in our use of terminology.

Confusion regarding terms such as addiction, physical dependence and tolerance contribute significantly to the under treatment of pain and to the trivialization of addiction when it does occur.

Physical dependence and tolerance are both expected physiological consequences that may occur when opioids are used over time. This is in contrast to addiction that is a disease state, not an expected consequence of appropriate therapeutic opioid use. Physical dependence and tolerance are not usually clinical problems. They can usually be easily managed when they occur, and their presence does not mean an individual is addicted to his or her medication.

As defined by the American Society of Addiction Medicine and also accepted by the American Pain Society and the American Academy of Pain Medicine addiction is a primary, chronic, neuro-biologic disease that has genetic, psychosocial and environmental factors influencing its development and its manifestation. Addiction is characterized by behaviors that include one or more of the following:

Impaired control over drug use, compulsive use of medications or drugs, continued use of the drug despite harm and craving for purposes other than pain relief when we're referring to opioids.

It is important that we distinguish addiction from a number of other states that may generate some of those behaviors, however. For example, when pain is inadequately treated, a patient may appear to seek opioids when their really seeking relief of pain, some instances referred to as pseudo-addiction. Or a person may have anxiety, depression, other mood issues or sleep problems and they may misuse their opioids prescribed for pain in an attempt to treat these other problems. But in order to address those problems it's usually more effective if we identify their misuse, why they're using them, and institute more effective and appropriate treatments, and reserve the use of the opioids for the treatment of pain.

Now, thinking about the causes in the etiology of addiction, both biogenetic vulnerability and a pattern of drug use that produces a rush or a high by stimulating limbic reward systems are believed to be important factors in triggering addiction. Psychological and social factors are also important, but primarily as they shape, encouraging or discouraging risky patterns of drug use. In addition, they are important in recovery from addiction, shaping the psychological and social factors. Stress, the physiologic effects of stress, may also play a role in the development of addiction in vulnerable persons.

The risk of developing addiction when using opioids on a long-term basis for the treatment of pain is not really known.

Available data suggests that the risk of the development of addiction or serious drug abuse problems in medical patients, who use opioids on a short-term basis for pain control, is very low, probably in the range of 1(one) in 10,000 (ten thousand) persons. However, when we treat pain in individuals who have complex regional pain syndrome, we often require long-term opioid use and we need to be aware that many of our patients may have histories of addictive disorders, so we can't rely on these very low estimates of risk.

Now, the most common estimate of the prevalence of addictive disorders in the general population, including alcoholism is about 10% (ten-percent), though studies range from about 3 to 18% (three to eighteen-percent) depending on the methodologies and definitions that are used. However, studies consistently show much higher rates of additive disorders in hospital patients, ranging between 20 and 25% (twenty and twenty five-percent). And for patients who present to hospitals or emergency rooms with significant trauma, the rates are between 40 and 60% (forty and sixty-percent), this is consistent over many, many studies.

We have to be aware then, particularly when we're treating patients who have complex regional pain syndrome that began with significant traumatic injury, that the group we're treating may have a higher prevalence rate than the general population of addictive disease.

Now, while patients with addictive disorders may be more at risk for developing abuse or addiction problems when opioids are used for pain, clearly such problems are not inevitable.

There is likely a spectrum of risk in terms of the vulnerability to developing addiction when opioids are used therapeutically, that includes both host, or patient factors, and drug use factors. Based on our understanding of addiction in general, individuals with no personal or family history of any form of addictive disorder are likely at lowest risk. While those who have a family history, but no personal history, may have a slightly increased risk, though there are no good studies that evaluate this. The little data that we do have suggests that persons with a history of opioid addiction themselves, a personal history of opioid addiction, have a greater risk of developing addictive patterns of behavior when using opioids on a long-term basis for chronic pain than persons who are in recovery from alcoholism or other non-opioid addictions, though those persons may have a somewhat increased risk over individuals with no history of addiction.

Now, medication use patterns may also impact addiction risk when opioids are used for pain and some factors include the routes of administration, schedules of administration and certain receptor effects. It is well understood by Addictionists that the more rapid the increase in blood/brain levels of a drug, the more likely it is to cause a rush or a high, which is often termed a reward which may, with repetition, trigger addiction in vulnerable individuals that theoretically, we'd expect opioids use by rapid IV (intravenous) bolus to propose more risk for vulnerable individuals than the use of oral opioids.

And we'd expect the use of a slower onset long-acting opioid, such as methadone or a sustained release preparation, morphine or oxycodone or fentanyl, when used as directed to pose less risk than frequently repeated doses of quick onset short-acting opioids. However, I think we're all aware that persons who want to abuse sustained release preparations can adulterate them to get a quick onset high bolus dose that may be very rewarding and potentially addictive.

Finally, mu opioid receptors appear to be more involved in stimulation of psychic reward, that rush and high, than kappa or other opioid receptors. Therefore, kappa analgesic agonists such as pentazocine and butorphanol may pose less risk than mu opioid receptors, but of course the use of these for pain is limited by their ceiling effects, and because they may reverse mu analgesia in persons who are dependent on mu opioid analgesics. Partial mu agonists such as tramadol or buphinorphene may also have less abuse potential, though their use as analgesics is also fairly limited. Importantly, some studies suggest that pain may actually interfere with the reward effects of opioids so that the risk of addiction to administered opioids may be lower when pain is present then in the absence of pain.

In summary, looking at things from a clinical perspective, it's helpful to view the risk of addiction when opioids are used for pain as an interaction of host vulnerability and pattern of medication use. From the patient perspective, if one has no personal, no family history of addiction, one can generally feel confident that opioids are safe and effective when used as directed, and that the risk of becoming addicted to the medications is low. For patients who do have an addictive disorder, or known risk of an addictive disorder, these patients can also achieve relief with opioids, but it is important that they and their doctors' use special care. It is important that individual lets their physician know of their addiction history, pays close attention to cultivating addiction recovery, takes special care to use medications only as directed, and consider in some circumstance having a partner monitor their use of the medication.

From a physician perspective, since risk of abuse and addiction can never be 100% (one hundred percent) certain prospectively, it is best practice to use care and vigilance in prescribing opioids to all patients. We need to screen our patients for personal and family history of substance use problems and inquire about current patterns of drug and alcohol use. Encourage recovering patients to be involved in active recovery programs and support their recovery. We need to treat pain aggressively, but when faced with a patient who may be at high risk for relapse, try and use less rewarding forms and schedules of opioid medications, when these meet their needs for analgesia.

We need to apply a clear agreed upon structure that often may include a written opioid contract when it's appropriate. We need to monitor not only pain, but also function, mood, sleep, and the patient's ability to comply with our structure of use, to assure that opioids are helping rather than leading to a spiral of abuse or addiction that may be harmful to the patient. It's often helpful to monitor patients with urine drug screen using care to interpret them appropriately, as such monitoring can be an important support to recovery and can detect early relapse.

Finally, for patients with a history of opioid addiction, who appear to have difficulty controlling use of opioids, participation in a methadone maintenance program to achieve blocking doses of opioids, then providing additional opioids or other pain treatment for pain control, as needed, may be the best option. In those circumstances, however, close communication between addiction treatment providers and pain treatment providers is really critical.

Thank you.

Click for Dr. Savage's References

see ADDENDUM on Methadone

Dr. Kirkpatrick:
Dr. Savage, thank you very much. That was just a fantastic review of the issue of addiction with medications. I'm going to ask you if you would please stand by, because I want to come back to you here, because I know there are going to be some questions for you. But before we do that...Dr. Brown. I know you've been treating patients with addictive problems and pain problems going on at the same, time for a couple of decades, and, you know, tell us what you're perspective is on the addiction problem as it relates to this topic. We have outpatient, we have a contract you can give the patient, we have outpatient ways to get control with these patients and then we have inpatient programs. Can you give us some perspective on when you have a patient in pain, where they go to get the proper treatment in this situation?

Dr. Martha Brown:
I think it's a very difficult issue. And I think that over the years we have certainly had a lot of conversations with pain management specialists and with addictionologists. I think that Dr. Savage did a wonderful job in terms of distinctly putting down some of the issues I think we need to look at. Sometimes what I find is that some patients don't do well as outpatients, and there's a lot of miscommunication, sometimes not on the Dr.'s part but purposely on the patient's part, because they may have that addiction potential or may have the disease of opiate dependency. Yet, on the other hand they have pain, and they have legitimate pain, and how do you put those two together in terms of that?

One of the things certainly, I have done is work very closely with the pain management specialists in developing a program. First, if we can do it on an outpatient basis, looking at all the different methods that we can do and going through different processes working up to the opiates, particularly if they have a problem. Contracts, setting up a contract in terms of only one doctor prescribing a medication, you know. Monitoring urine drug screens --- I think all of those things work together and only as a last resort, sometimes then we put somebody in an inpatient unit to work out what's the plan going to be.

Click Here For Dr. Brown's References



Dr. Kirkpatrick:
Thank you Dr. Brown. Dr. Wilson, I know you have also been at this also for a couple of decades and I know you have an inpatient program at Tampa General Hospital, which is outstanding. What would you add to this, I mean, because your focus is on the pain, but also sensitive to the addiction issues and how do you handle that in a hospital setting?

Dr. Wilson:
Well, I am very fortunate that I have a wonderful team that helps me out. I have nurses that are excellent in keeping track of medications. And actually developing a relationship with the pharmacists and the family members is like a combined effort. And we find that the urine drug screens, the contracts and close monitoring, close monitoring are truly, truly invaluable. So, I think that, ditto to what they both said, and then I do have a question, however, for Dr. Savage and Dr. Brown.

We know that rotating opioids helps tolerance issues, but are there any data as to rotating opioids having a positive effect, minimizing addiction issues on those that are at high risk?

Dr. Kirkpatrick:
Dr. Savage?

Dr. Savage: We're not aware of any data regarding opiates, rotating opioids to avoid addiction. I think selecting opioids may make a difference. As I suggested before, theoretically, there's reason to believe that slow onset, more continuous stable blood levels, are really less likely to stimulate that reward, that rush and that high, that in a recovering patient may trigger relapse or lead to it. I had a patient who once referred to using one of his short-acting medications, his opioids, as dancing with an old lover. I thought that was in solid recovery, but he didn't like using those short-acting opioids because it just was like dancing with an old lover, and I really appreciated that characterization.

Certainly, you know, methadone is used for the treatment of opioid addiction, and I haven't seen studies comparing it to slow onset morphine, or, I mean sustained release morphine or sustained release oxycodone, in terms of risk, but it's not adulterable in the same way. It's easy for patients if they have a slip and want to chew up a tablet of the sustained release formulation and get a buzz to do so, where as with methadone, there's not much you can do to increase the rapidity of onset. So, those are my thoughts.

Dr. Kirkpatrick:
Dr. Savage. Since you opened up the "dancing with lover" theme...

Dr. Savage:
Yeah!

Dr. Kirkpatrick:
...let me follow up with that with you, just to make sure I understood you. Are you suggesting that it is an absolute that you can't have a patient on short-acting opioids chronically for pain?

Dr. Savage:
Not at all, not at all!

Dr. Kirkpatrick:
OK. So, some patients like that exquisite control, that sense if they have an exacerbation they can hit it.

Dr. Savage:
Right! And thank you, thank you for pointing that out. I did not mean to say that any person whose at risk for an additive disorder or has a history, can't use opioids when they're needed, short-acting opioids for chronic pain. I think it has to be an individualized decision and talk about what the effects of the opioids are. In some patients they're very clear; it just relieves the pain and they don't feel the psychic effects from it. And some patients don't need around the clock medications. They have pain and they need a short-acting medication when they're doing an activity that they value that causes significant pain. So there are a lot of variables that have to be weighed against each other, I think in decision making.

Dr. Kirkpatrick:
OK. I would like to turn back to another subject that you touched on, obviously you can only touch on it in a short presentation that you gave, but I feel it's worth going back over, and that's this whole concept of pseudo-addiction. In other words, under-prescribing the opioids in someone who has pain. As you know, one of your colleagues, Dr. Russell Portenoy has done some studies on patients under-prescribed their medication, in two patient populations; cancer patients and HIV patients. And I believe on average in the cancer population, even today, the data suggests that maybe 50% (fifty-percent) of them are not being adequately medicated with opioids. In the HIV patient population it's like 85% (eighty five-percent). And what they have found, and what they have reported is, that, pseudo-addiction sort of sets in motion behaviors that actually trigger or produce real addiction. And the examples they use are in the female population where some women had HIV, who were not getting adequately medicated, would actually exchange sex for drugs, obviously a major health problem. So, I think our audience really wants to know what you think about that and I'm going to ask Dr. Brown to comment on that as well. Pseudo-addiction...a little bit more on that, please.

Dr. Savage:
OK. While I certainly think pseudo-addiction does occur, I think the best way we manage that is after we've done a thorough evaluation to try and sort out as best we can whether there's under-treated pain or that there may be abuse or addiction of medication. If we consider under-treated pain part of one of the strong possibilities, a trial of carefully structured, effective, aggressive pain treatment is appropriate with careful monitoring to assure safety in case there is abuse or an addiction problem that puts the patient at risk for having medications. So, giving doses of medications that the patient states relieve their pain and watching what happens to their function; their ability to work or do activities of daily living; what happens to their relationships; to their mood; to their sleep; if all of it improves, and their pain is reported to be improved, and, then we've treated pseudo-addiction in most circumstances.

One of my colleagues raised, or...made the observation that in some cases when we...if someone truly has and opioid addiction and we do supply them with, or prescribe to them larger doses of opioid medications, we may in fact be blocking their craving and blocking their addictive disorder, just as methadone maintenance therapy would, and therefore allowing them to return to a better level of function and normalize their lives and improve their quality of life. From a clinical point of view that's really a moot point. We've provided a medication that has treated an underlying disorder, be it pain or opioid craving, provided it safely and allowed them to return to a higher quality of life. That's our goal as clinicians. From a legal point of view, of course we need to be licensed appropriately if we are treating opioid addictions with opioids.

Dr. Kirkpatrick:
Dr. Brown, would you like to add something to the issue of pseudo-addiction?

Dr. Brown:
I would certainly agree with Dr. Savage in terms of her comments. I think that it's a very difficult issue, particularly at lower levels of opiates, when you have a patient who has that craving and has the pain, and you don't want that patient to be in pain. And so you really do need to adequately treat it and see what happens having taken a good history, and looked at their family history; and also the issue of loss of control, because if somebody hasn't, that's one of the cardinal symptoms of addiction, that's in terms of a loss of control so if they're maintaining and taking as prescribed you're less likely to get into problems.

Dr. Kirkpatrick:
Dr. Savage?

Dr. Savage:
Yes!

Dr. Kirkpatrick:
I would like you to stand by. We're going to have an opportunity for you to share with us, what you might say a take-home message.

Dr. Savage:
OK

Dr. Kirkpatrick:
Thank you.

USE OF OPIOIDS (NARCOTICS) IN CHILDREN


Dr. Kirkpatrick:
We're going to turn to our final and very important topic here, which relates to the use of opioids in children.

Now, for that, we have really...we've really got great, great people here. We have Dr. Alyssa LeBel from Harvard Medical School. What makes her rather unique is she's collaborated with some of the great people in pain. For example she was with Dr. Schwartzman for a while and they did that landmark paper on spreading RSD patterns. Now she is at Harvard working with another outstanding scholar in the field of pain as particularly as it relates to children, Dr. Charles Berde. She is doing some very important research on RSD in children. Dr. LeBel is primarily a Neurologist, but she is in the Department of Anesthesia because of her special expertise as it relates to the pharmacology and so forth in the area of Pain Management. Um, Dr. LeBel?

Dr. Alyssa LeBel:
Hello!

Dr. Kirkpatrick:
Hello! Share with us some of your vast experience, I know it is quite vast, share with us your experience in dealing with the issue of the use of opioids in children that have chronic pain, please.

Dr. LeBel:
Thank you very much for that very kind introduction, and I just want to thank all our colleagues and the staff of this conference for providing such excellent presentations. Many of these topics are, of course, applicable to their pediatric correlates, but I wanted to talk about pediatric pain in terms of what special aspects are presented with this group.

So, first I just wanted to just show a photo of one of our patients who also, although not seen in this photo, had lower extremity involvement at the time of her initial presentation; and of course the effected limb in this photo at this time is on the right side.

To briefly review, turning toward the definition of CRPS, again, just since we've discussed so many issues so far. CRPS, or complex regional pain syndrome, is defined by clinical phenomena. The specific pathophysiology of this disorder is really still yet to be elucidated, but Neuro Science holds many promises for that. It's likely to involve multiple mechanisms and to multiple levels of the pain transmission and the pain modulation systems, which will welcome a number of treatment strategies to our armamentarium.

The clinical features, associated with CRPS are just to briefly review: neuropathic pain; abnormal regulation of blood flow and sweating; edema, trophic changes of the skin and appendages; and active and passive movement disorders that have been well described by Dr. Schwartzman.

In the pediatric population, there are also unique epidemiologic features. The epidemiology of CRPS, as well as other chronic pain syndromes in children is, unfortunately still not well documented. I will direct your attention to a report by Dr. Robert Wilder, who is now at the Mayo Clinic, who reported more than 395 cases in the literature as of 1996:

At Childrens' Hospital in Boston, we receive about two new referrals for patients who are less than 18 years with features of CRPS every week, and generally the patients that come to us have failed conventional therapy. What's unique about the pediatric presentation is that it's very rare first to see this presentation at all before 6 (six) years of age. The most common age of onset is 10 to 12 (ten to twelve) years, and continues into young adolescents.

In the pediatric population as opposed to the adults, the lower extremity is more generally involved than the upper extremity. In fact, in our collection of data here at this institution, we see a 6 to 8 over 1 ratio (six to eight over 1 ratio) of lower extremity to upper extremity involvement. Girls are effected 6 (six) times more often than boys. The signs and symptoms often spread from one extremity to another, and frequently in the pediatric population, these episodes of pain associated with the other physiologic changes in the clinical features that define the entity are recurrent. With each occurrence after the original presentation, the presentation is usually much less severe and more brief and more readily treated by our current treatment strategies.

Resolution in the pediatric population is much faster and more robust with physical therapy, behavioral medicine intervention, cognitive and behavioral medicine treatment, and sometimes the addition of the transcutaneous nerve stimulator. And in the pediatric population, thankfully, the prognosis is much more favorable despite duration of signs and symptoms. So, although the pediatric patient may have a longer period overall carrying this diagnosis, the extent of their disorder is often less than an adult may present with. They have less severe disease and more readily treated disease.

Now, turning toward opioids. We readily use opioids in the pediatric population, certainly for somatic and cancer pain, and we have to individualize as happens in the adult population, their use for non-malignant pain problems. As Dr. Kiefer had mentioned, you know the research data is very limited for the use of opioids in non-malignant pain in general and is especially true for the pediatric population. We have many anecdotal reports and a lot of experience with the use opioids with intraspinal administration. Some effective uses of opioids, some examples in patients with CRPS include: when we use our opioid doses at times of physical therapy, knowing that physical therapy is still the gold standard of treatment in these patients; and when we use brief courses of sustained opioids followed by a taper when there's onset of severe pain in this pediatric population.

The role of opioids in CRPS is somewhat restricted and in the pediatric population, especially where comprehensive approach is needed and a family oriented as well as patient oriented direction is taken, we need to use opioids as part of a multidisciplinary approach to pain management.

In terms of pharmacology of opioids, the pharmacology is very similar to that of adults, as are the side effects described by Dr. Kiefer. And the pharmacology is similar for pediatric patients that are previously full-term infants from about 3 (three) to 6 (six) months on. So, our only concern in adjusting the pharmacology of opioids is in regard to the premature infant in the first year of life and in the neonate.

I'd like now to say that opioids are not the primary therapy for chronic pediatric neuropathic pain. Dr. Kiefer and Dr. Kirkpatrick have appropriately emphasized that the NMDA receptor antagonists as being a very important area of research and increased clinical trial. In the pediatric population we use these non-opioid therapies as well, which include such things as the ion channel blockers; another very important area of research includes the sodium channel blockers such as the anti-epileptiform agents Trileptal, Neurontin; and the N-type calcium channel agents, which also includes Neurontin as well as the NMDA receptor blockers that are primarily glutamate antagonists, such as ketamine and dextromethorphan.

There is some work that is directed toward specific opioid receptor agonists, but this is still quite early. Looking at these receptors...as Dr. Savage did, she presented the receptors in terms of kappa versus mu receptor agents. Clonidine, as an Alpha-2 adrenergic adjuvant for treatment of pain is often used in combination with our opioids intra-spinally as well as orally, allows us to use much less opioid with less side effects. And inflammatory mediator antagonists, things that antagonize cytokines like anti-tumor necrosis factor alpha, which is being used in inflammatory states in adults, may hold great promise for the neurogenic inflammation of CRPS.

I wanted to bring up next some research that has occurred with Dr. Berde and again Dr. Wilder, back in 1992 regarding the spinal infusion of opioids and local anesthetics. And this particular study that I'd like to talk about that happened in 1992 looked at combined infusions, via a lumbar epidural, because again remember our population is mostly lower extremity, or paravertebral sympathetic indwelling catheters, in a group of patients who had persistent pain despite very extensive outpatient physical therapy and cognitive and behavioral therapy. And, a subgroup during this study showed a very interesting phenomenon that again shows somewhat of a unique neural substrate in pediatric patients as opposed to adults, at least as has been reported. But there was a marked right-shift in the epidural and spinal local anesthetic dose response curves. There are some patients that required very high doses of local anesthetics to even achieve any pain relief, or, at a level that one would expect you'd have a complete spinal block, they just barely had a little bit of pain relief. And that was a very interesting observation and something that we've continued to explore with the pediatric patients.

A subgroup reported pain despite achieving complete sensory, motor and sympathetic blockade, prompting our colleagues to suggest a supratentorial diagnosis, which in part may be true, but pain is a very distributed system, and there are supratentorial aspects of pain that create a real perception of pain and certainly functional MRI studies have born that out recently. So, sympathetic blockade overall as opposed to the adult literature appears to be less helpful in pediatric CRPS in part because of some of these phenomena, but there is a subgroup of patients that we still put through this treatment regimen that benefit from spinal analgesia more as a springboard to increasing their participation in functional rehabilitation, physical therapy and cognitive/behavioral therapies.

Rehabilitative treatment remains the cornerstone of therapy, as it is I think as well in the adult literature. There was a Children's Hospital study published in Journal of Pediatrics in 2002, looking at the use of rehabilitative treatment in this population. Physical therapy once, versus three times per week, with cognitive behavioral therapy, once per week for six weeks was provided. And that was the comparison. 28 (twenty-eight) patients completed the protocol and the measures that were looked at to assess efficacy were pain scores; gait; stair climbing; psych inventories; regional and systemic autonomic examinations; and quantitative sensory testing looking at small fiber function.

And in the outcome of both groups, both physical therapy once a week and physical therapy three times a week showed a greater than 50% (fifty-percent) improvement in their visual analog pain scores. There was improved gait and stair climbing, and most patients relinquished their assistive devices by 6 (six) weeks, which is an excellent response to rehabilitative therapy.

Therefore, in the pediatric population, we still hold the dogma that the primary treatment objectives are to prevent atrophy and to restore function; that patients really need to embrace the course of functional rehabilitation above all, and that analgesic interventions, intraspinal injections of medications and even less use in our population, nerve blockade, are really just adjutant's to allow the patient to experience a functional rehabilitation program actively to the best ability that they can have.

And so, in having that discussion when we meet with our patients in clinic, we usually sit down and provide feedback to the family and try to explain the issue of neuropathic pain as not being a protective pain, but being a pain that is something that does not mean that they should stop their functional activity. And so, we provide information to the patients and the parents about neuropathic pain, saying that ordinary pain is what you feel when the normal nerves send messages from the inflamed or injured body tissues; and that nerve pain is really caused by abnormal messages sent by the nerve, even after tissue healing.

We explain the issues of nervous system elasticity. We validate the patients pain as being real, but that the information ultimately received at the most rostral center, the cortex, is wrong; that people with nerve pain are not crazy, but the cognitive behavioral therapy is an inmate part of functional rehabilitation; and that treatment of nerve pain involves working through the pain and re-programming the nerves to send the messages properly.

This is sometimes a very difficult message, but we emphasize always to the pediatric population that the prognosis for pediatric chronic regional pain syndrome is generally good. And that we hope that opioid treatment when used appropriately in the population is a brief adjuvant, as are other adjuvant therapies for most children who have this neuropathic pain syndrome. Thanks.

Click Here For Dr. LeBel's References



Dr. Kirkpatrick:
Dr. LeBel, thank you very much. I think what you've really helped us do is put the whole problem of chronic pain into a much, much broader perspective, looking at multiple modalities in managing these patients.

We're very fortunate to have with us today at a remote site, at Johns Hopkins University, Dr. Sabine Kost-Byerly. Dr. Kost-Byerly has probably seen some of the worst-of-the-worst in children that have chronic pain syndromes, in particular patients with reflex sympathetic dystrophy. And I've asked her to join us today because, I think we really want to make sure we explore all of the potential treatment options, and that we look at where the opioids fit in...into the bigger picture. And I think if we can understand children, which are the most challenging, with all the problems they have from an emotional standpoint and so forth, I think the adults become a piece of cake. Dr. Kost-Byerly?

Dr. Kost-Byerly:
Yes! I wanted to first thank you for this wonderful opportunity to participate in this symposium. I think it's an exciting new tool and I think it's something that should be explored further in the future as well.

I listened carefully to Dr. LeBel's presentation and I would agree with her and most of it. I think the patients I've seen in Boston are similar to what we see here. This is a Tertiary Care Medical Center, so most of the patients that I would see in the clinic or for in-patient therapy are rather complex and might have failed therapy in other locations.

We use a multi-disciplinary approach to the treatment of RSD. The primary tools are as Dr. Lebel said, physical therapy, behavioral intervention; and they will lead to an improvement in the majority of patients. We do use opioids as adjuncts to the therapy, though not as the first pharmacological intervention, but usually as the third, fourth or fifth.

I see that there are essentially three forms for the treatment of opioids. The one that we use probably most frequently and intermittently is to facilitate physical therapy, or to treat acute increases in pain due to other activities throughout the day. We will use, in a certain patient population, long-acting opioids at night if the patients report to me that they have poor sleep due to pain. This is not as a sleep agent, but really it's a poor initiation of sleep, or poor...they do wake up in the middle of the night because of pain; and then we will attempt to treat them with a long-acting opioid to see whether this will improve.

Finally, there is the around-the-clock treatment. This is really a very small sub-group of patients. In this population, the goal is an increase in function activity and the quality of life. For a child that usually means the child will be able to return to school; participate in activities with a peer group; that should be the goal. When around-the-clock opioids are used, then the treatment should be re-assess at regular intervals, then every few months to check for the continued need and the effect. As I said, that is a small sub-group.

For my in-patients, it's not unusual, because a lot of them have severe pain, are very hesitant to participate in physical therapy programs. It's not unusual then that we will use a peri-spinal infusion, like a lumbar epidural catheter with local anesthetic and opioids and try to alleviate some of the fears of this patient so that they will participate in physical therapy more easily and a little bit more ready to do this.

There is one point that has not been mentioned by previous speakers, but I think it is important in the pediatric population. I'm a little bit hesitant to provide long-term opioid therapy in children adolescents, not necessarily because of development of tolerance or the development of addiction, which I think is pretty rare; but I'm worried in this population particularly about the long-term effects of opioids in the developing body. Opioid therapy, as Dr. Kiefer in Germany said, can result in abnormal endocrine effects and can result in hypogonadism, and lead to low levels of testosterone and estrogen. And, we don't really know what this means for an adolescent, a child going through puberty. So, the risk of osteoporosis or mood changes, or how this will influence the immune system...there are really still many questions, so I think I would be very hesitant to provide long-term opioid therapy in an adolescent patient.

This is what I have to add to this discussion at this point.

Dr. Kirkpatrick:
Dr. Kost-Byerly, thank you very much. I know that there's nothing like experience in trying to navigate through this, through all of the treatment modalities that are available, especially in children. At this point, what I would like to ask Dr. LeBel to please standby. ...Dr. Lebel, could you please stand by here?

Dr. LeBel:
Yes!

Dr. Kirkpatrick:
Because I'm going to come back to you in just a second here.

 

TAKE HOME MESSAGE

What I'd like to do at this point is to go ahead and try to put together, start to put together, construct a "Take-Home Message" thing.

And, what I want to do I guess, first of all, is to kind of weigh in with my two-cents. So, I was taking notes as we went through these presentations and here's what I got out of it, and then I'm going to invite each of our speakers to contribute something more to that.

First, opioid therapy should be considered in anyone with moderate to severe pain. There is no evidence that there is any characteristic in a given patient that imparts a total resistance to the analgesic effects of opioids. But, every case requires the physician to weigh the factors that would influence opioid therapy sooner, rather than later, after other treatment modalities have been tried. We've heard a beautiful discussion of that with Dr. LeBel and Dr. Kost-Byerly about how they've tried to navigate in placing, positioning the opioid in the proper clinical context.

Point number 2 (two). Opioid therapy is not easy; and you said that (Dr. Kirkpatrick speaking to Dr. Marsha Brown), it's not easy, it's very difficult. What does it really require? It requires us starting with a comprehensive assessment of the patient, which includes looking at the issue of potential addiction, aberrant behavior and so forth as part of our assessment. It requires a certain knowledge base about the adverse effects of opioids, and we have to have knowledge about addiction medicine, that's important. We have to have certain skills, certain experience in order to navigate our way most effectively with these patients.

Documentation was noted, the importance of documentation...Dr. Savage brought that up; Dr. Brown, you brought that out as being very, very important...contracts with the patients.

Communication, very important. Communicating with the patient, communicating with the primary care physician. As pain experts, we depend on them to care for these patients. We have to consider their preferences, their resources and so how do we do that? We educate them. that's our job. We have to do that. And of course, the patient can't make an informed decision without being informed about some of these potential problems we've talked about... as Dr. Kost-Byerly pointed out, what about the long-term effects in children on the pituitary axis? So, all of these things are important.

A third point that I think needs to be pointed out here is that, although there's nobody that's resistant, chronic therapy with opioids but opioid therapy might unmask problems. And we've talked in great detail about those things: intolerable side effects; unmanageable side effects; addictive disease. We've discussed the importance to always be aware of the problem, the potential problem of pseudo- addiction.

And we also talked about that not all opioids are the same: methadone is really, really quite different than the other opioids; transdermal fentanyl: there's some patient's where this drug has been a Godsend at 400 mcg patches changed every 2 (two) to 3 (three) days, being required to make them functional. So, they're not all the same and this was something, of course, that Dr. Kiefer brought to our attention.

Dr. Savage at Dartmouth pointed out the potential advantages of long-acting opioids and the fact that you have the slow onset and that you have less risk of this rush, this dancing with the medicine, and of course, it's a little easier to comply in that situation. But I think the point that was made that's very important, there are very few absolutes; each patient is an individual. Maybe a short-acting opioid on a chronic basis for chronic pain would be more appropriate in some patients.

Now, I think what the audience really wants to hear from us today, I really believe this, if I'm sitting out there this is what I want to know: How do I use these opioids, particularly long-acting opioids? So, I'm going to highlight very quickly here, what I think some basic...what a basic roadmap might look like, and I'll invite all of you to comment on this.

I would suggest that maybe when you're starting a long-acting opioid that you may increase the dose until you get adequate pain relief, or, you get intolerable or unmanageable side effects. I would suggest that you increase the dose by 25% to 100% every two to four days. There is no maximum dose! There is no maximum dose for these medications. I think that's a very important concept. You increase the dose until you're limited by toxicity, or one of these other problems related to addiction medicine that would limit you in your prescribing.

Now I would like our speakers to offer their take-home messages and I'd like to start with Dr. Kiefer. Are you still with us in Germany?

Dr. Kiefer:
Yes. I am still with you.

Dr. Kirkpatrick:
So, you tell me what you think the take-home message should be from this conference.

Dr. Kiefer:
OK. We think that the take-home message should be that nobody should be withheld opioids if the patient needs opioid treatment. However, we would like to emphasize that it's very important to show that opioid treatment for the individual patient results in a clear benefit, that is a significant pain relief for the patient. We would also like to emphasize that neither the physician's nor the patient should fear adverse side effects. We would point out that opioid therapy has to be monitored very closely and physician's need to watch for those side effects and treat and sufficiently, and above all, very early.

And our last remark is that everybody involved should be stimulated to work on providing sufficient evidence to perform scientific studies to finally provide some high quality evidence in the treatment of opioids for neuropathic pain and especially CRPS. Thank you.

Dr. Kirkpatrick:
Dr. Kiefer, thank you very much. Dr. Butler?

Dr. Butler:
Yes.

Dr. Kirkpatrick:
Welcome back!

Dr. Butler:
Thank you.

Dr. Kirkpatrick:
Did you go out sailing while we were talking, or did you hear the discussion we were having?

Dr. Butler:
Oh, no, no! I've been listening to the discussion, very interesting.

Dr. Kirkpatrick:
OK, good. Well listen, give us your perspective, give us your take on the take-home message, please.

Dr. Butler:
Well, I think if we think of about complex regional pain syndrome use of opioids, you have to think of two uses. One is an acute use to facilitate therapy, and that's probably the best use. The second is chronic long-term use when therapies haven't been very helpful. I'm a little more conservative than you are in use of opioids. You're recommendations sound to me like those for pain in cancer patients, and my experience over time is that we always have been sent the patients on high-dose opioids with the problems, and had to deal with that. And many of those patients on detoxification were significantly better than they were on the high-dose opioids, so you have to be a little careful in how far you go with high-dose opioids.

Another thought is that if you do embark on opioids, especially high-dose opioids for long term treatment, then you marry that patient, because no other practitioner will take over that care. And so, you have to think about not only what's going to happen next week or next month, but in five years. And so, you need to have a short-term plan as well as a long-term plan. But, it has been a wonderful conference, and I've gotten a lot of very good information from the presentations and thank you for having me there with you.

Dr. Kirkpatrick:
And Dr. Butler, thank you for letting us disrupt your vacation. While you were talking, some of your comments resonated pretty heavily here among our panelists in the audience here, so I'm going to ask them to comment a little about...especially about marrying patients. They were both kind of nodding their head a little bit here. Dr. Brown, what is your take-home message from this?

Dr. Brown:
Well, I think there's several. One is obvious, communication. I do think that we have to take a good history and look at the addiction potential, because some of our patients will do quite well on high-dose opioids and they don't have that addiction potential. The one's that do will be the ones that you truly marry and will increase their dose and ultimately, unfortunately, some of those people die in terms of it and so there's always, again, weighing the issues there, I think from the addiction standpoint. It's certainly...I urge all my patients who are in recovery, if they have chronic pain, to let me talk with their physician whose managing their pain, so that we communicate and we talk about what's going on and we form a plan, because we don't want them to be in pain.

Dr. Kirkpatrick:
Hold on for a moment, Dr. Wilson, I'm going to go over to Dr. Savage to follow up on this theme, and then I'm going to come back to you and ask you a question or two. Dr. Savage?

Dr. Savage:
Yes.

Dr. Kirkpatrick:
You've been hearing some of these comments; tell us, what do you think? What would you like the audience to take home?

Dr. Savage:
Well, I'll give you my take-home messages from the point of view of the issues that I've been asked to cover, which are more the addiction and abuse issues. So my take-home messages would be first, that we look at the pain associated with CPRS/RSD and at addiction both as medical conditions, which have potential to cause considerable suffering, and we need to attend very closely to each of them. We need to treat pain aggressively and most often that means an interdisciplinary approach, using cognitive/behavioral approaches, physical therapy, perhaps interventionalist procedures and a variety of medications. But when opioids are used, we need to pay close attention to the potential or risk for developing addiction; monitor patients, not only their pain, but their level of function, their mood, their sleep; to be sure that the medications are helping them and improving their quality of life; and to detect abuse or addiction early because these are life threatening problems, detect them early if they occur. If we need to continue opioid therapy in somebody who does develop addiction, we need to partner with somebody who understands the disease of addiction and work together to help that patient receive the pain relief that they need and to monitor their recovery or help get them into recovery.

One final brief comment. I agree with your recommendation to increase 25 to 100% dose of opioids if you're titrating aggressively, if it's appropriate to titrate aggressively, for most opioids, but I would be very cautious titrating methadone that way. We need to start low and go very, very slowly. It takes 7(seven) to 10 (ten) sometimes even 14 (fourteen) days to get stable state of methadone, so we need to titrate a little more slowly. Thank you.

Dr. Kirkpatrick:
Thank you Dr. Savage. Dr. Wilson, what is the take-home message here today?

Dr. Wilson:
Well, the take-home message, I think that it should be like we're doing. More education at all levels. I think that education is of paramount importance because part of the reason why we have to marry so many patients is because doctors in Primary Care are not comfortable. I mean, in part it's because they don't have appropriate knowledge of opioids, and rightfully so, they should not be doing things that they are not really well informed and prepared and ready to do. But I think it's very important that they get the message that we educate primary care physicians so we can work together, that way our clinics would not be filled with so many patients that we have gotten to be stable, and all we do for a lot of those people is just continue to prescribe and perpetuate prescriptions every 30 days. And then, if we're lucky enough that they take them back, then if the primary care physician is not educated about opioids, in no time the patient is back to us full of problems.

Dr. Kirkpatrick:
Right, right. Well, it looks like everybody is resonating to that as well. Dr. LeBel?

Dr. LeBel:
Yes.

Dr. Kirkpatrick:
Tell us what you think from your perspective, particularly as it relates to the pediatric population.


Dr. LeBel:
Well I think for pediatrics, as emphasized, this is a population that has a generally favorable prognosis, and therefore, opioids as an intervention in this group do adhere more to Dr. Butler's acute use to facilitate functional rehabilitation in all ways, both as in-patients and out-patients and are usually brief courses of intervention and not sustained long term except in very, very, very rare cases. I want to emphasize that we have a chance in pediatrics because of the favorable prognosis, to intervene early and effectively, pushing forward the rehabilitative strategies, adequately treating the pain to allow the child to pursue that type of rehabilitation, and we have the opportunity as practitioners to prevent these patients from going on to having chronic pain disorders, which is a very important mandate. And I would just echo the need for additional research in all type populations, elderly, pediatric and most adults in the use of chronic opioids and acute opioids in neuropathic pain.

Thank you for letting me participate. It has been very educational for me.

Dr. Kirkpatrick:
Again, thank you Dr. LeBel. Dr. Kost-Byerly?

Dr. Kost-Byerly:
Yes, I would agree with Dr. LeBel. I think although opioids are not the first choice of treatment for RSD / CRPS in children, they should be considered as a part of a pharmacological approach within a multidisciplinary management. I also couldn't agree more with Dr. Kiefer in Germany, Dr. LeBel, that more research is needed. I particularly feel that more research is needed for the subgroup of patients that, pediatric patients, that do not respond favorably to the most common physical therapy or behavioral intervention. I feel it is very much in need so we can prevent potentially years of suffering in these patients.

I wanted to say thank you that I was able to participate and I think it was a very exciting symposium.

Dr. Kirkpatrick:
Well, thank you very much Dr. Kost-Byerly, we're privileged to have you join us today.

QUESTIONS & ANSWERS

Dr. Kirkpatrick:
Now, please everybody stand by because, I went back and picked up some of these faxes, some of these questions and, boy, there's some tough questions here. So, I'm going to have to just say just jump right in. Those that are at remote sites and we want to see whose the bravest. This question is asked over and over again, so are you ready for the big question? Here it is.

You have a patient that is on a contract, they break the contract. They have chronic pain, they're suffering. On occasion they may be writhing in pain. They've been into a rehab program, a recovery program and they relapse... you see the question, what do you do? What do you do? Now, don't raise your hands all at once.

Let's take the people at the remote sites first. Is anybody at one of our remote sites either here in the United States or abroad, does anyone want to weigh in on that question?

Dr. Butler:
I can stick my neck out on that one.

Dr. Kirkpatrick:
Thank you.

Dr. Butler:
This is Dr. Butler talking. I've had several patients like that and I just sit down and talk to them quite frankly and tell them what the problem is: I think you're abusing these medications and I'm not sure you're getting any help from them. And I'll tell them if they fail the contract once, I have the talk; if it happens a second time I warn them, then you've got two options. One is that you can go back to drug treatment program. The second is I will do detox myself and then you have to find another physician if you're going to, if you want to continue taking these medications, because I can't do it under this situation. I don't think they're helpful and I think that the problem is not the pain; it's the drug abuse that's the major problem. And that's what I've done. But, sometimes tough love is what these patients need.

Dr. Kirkpatrick:
Dr. Butler, once again, what can I tell you. If you had eyes here you'd see that you're getting a lot of people shaking their head in agreement with you. Does anybody else want to weigh in on that question?

Dr. Savage:
Yes, I would. This is Dr. Savage.

Dr. Kirkpatrick:
Yes, Dr. Savage.

Dr. Savage:
I agree with essentially all of what he has said. I would add though, that it's highly variable the reasons that people break contracts. We have to make an individual assessment of what the reasons for breaking the contract is, and what the facts were, I mean what actually happened. If the person is relapsed into addiction and they have an active addiction disorder, it's probably not safe for them to be using opioid medications, and we need to help them get back into recovery, and be aggressive about doing that and then once in recovery be highly structured in re-providing opioids if we elect to do that, sometimes dispensing even on a daily basis we have done.

The bottom line is to protect the patient, but in the end I think we have to recognize that we can't help all people, and there may be safety issues that are beyond our control. That means that we need to taper people off of opioids, and I would not refer them to somebody else necessarily unless they chose to go to somebody else, but to continue to follow them aggressively with non-opioid approaches to treatment and provide them with support they need for recovery and for pain.

Dr. Kirkpatrick:
If I'm hearing you right Dr. Savage, you're saying that...you almost have to...if you want to play this game; you have to anticipate that some of these patients are going to relapse, and you better have a program, you better have a plan in place. Is that what I'm hearing?

Dr. Savage:
Yes, and that pain treatment, the promise and offer of pain treatment, effective pain treatment, may actually be a support for helping them get into recovery.

Dr. Kirkpatrick:
Good. We have time for one more question. Well, we have a lot of questions, but I think this is a very important question, so I'm going to just lay it out here.

The question is: Patients who develop tolerance to the analgesic effects of opioid, is that a lifetime thing? If they later decide to wean themselves from opiates, do they remain tolerant? Do we have any empirical scientific information, anything that would help us understand that?

And also another question which is related is: What about...what about...do we know...are there some individuals, or some characteristics of individuals that develop tolerance more quickly than others to the opioids? So there's really a 2-part question. Let's take one at a time.

The question is: Is it a permanent change in your body when you develop tolerance to opioids, or do you have a return of your sensitivity to the analgesic effects later on? Who would like to weigh in on that one, anyone either at a remote site or here at the University of South Florida?

Dr. Kost-Byerly:
I could answer this; this is Dr. Byerly from Johns Hopkins.

Dr. Kirkpatrick:
Thank you Dr. Kost-Byerly.


Dr. Kost-Byerly:
As a Pain Specialist and an Anesthesiologist, I can tell you this from my experience, that when we have trauma patients, other patients on high-dose opioids for a long period of time, who eventually come back to the operating room later, their requirement, if they have been off the medication for a period of time, pretty much is back to normal, so they will have a normal analgesic requirement. Of course, if they are still taking high-dose opioids, that has to be considered and they will have a higher requirement for surgery, potentially.

Dr. Savage:
I think from an addiction medicine perspective, I would give the same response. We know that many people who have been detoxified from illicit opioids say during a jail term, who then go back out on the street, are at a very high risk for overdosing because their tolerance has diminished significantly.

Dr. Kirkpatrick:
Thank you Dr. Savage. This is very, very important. It is not only important for Pain Specialists, but for the Anesthesiologist that has to provide anesthesia for these patients. Does anybody know if there's a certain characteristic of person who is more likely to develop tolerance than others either in terms of, well for example, age or in terms of other co-existing medical problems, they develop tolerance more quickly? I don't know of anything. Does anybody at any of our remote sites have any data to share on that question?

Dr. Butler:
I don't have any data, but........

Dr. Kirkpatrick:
We're with you Dr. Butler. We hear you.

Dr. Butler:
I don't have any data, but my experience is that the patients who are treating things like anxiety are ones that are more likely to develop rapid tolerance. If they have a pain problem, but they have an underlying anxiety problem that hasn't been well addressed, they're the ones that tend to escalate doses much, much quicker.

Dr. Kirkpatrick:
Well that certainly makes a lot of sense and I think that some of our panelists here are agreeing with you that in their clinical experience as well, they see the same thing, for sure. So, pain in a way, treating pain itself, is somewhat protective to the developing tolerance to medications, I think that's what I'm hearing from you?

Dr. Kost-Byerly:
Well, in patients, I know that in patients who are treated say, with fentanyl infusions in the ICU, the development of tolerance can be rather rapid. More recently though, that would agree with...I think with Dr. Savage...I think it was Dr. Savage said, the quicker rise in the analgesic blood level, the CSF level, might lead to a higher development, maybe to a quicker development of tolerance. Though more recent studies did not support that for remifentanil, which is even shorter-acting and even more rapid in onset. So, I think it might, if at all, it might depend on the analgesic itself, less so is it on the patient.

Dr. Kirkpatrick:
Thank you very much Dr. Kost-Byerly. I think we're ready to close this symposium, but before I do, I really, really want to thank the faculty from around the world. I want to thank the staff here at the University of South Florida, this has been a Herculean team effort to make this happen in real time and be interactive the way it has been. And, last but not least, I want to thank the audience for participating in this. We hope that you have gained as much as we have from this experience.

Thank you very much.

ADDENDUM:

WARNING ABOUT METHADONE USE

Physicians must be aware of the particulars of methadone.  When switching from opioids with a relatively short half-life (such as hydrocodone and MS-Contin) to methadone, the physician must be aware that methadone has an unusually long half-life and that it might take several days before the patient's blood levels become stabilized.  The maximum analgesic AND respiratory depressant effects of a dosing regimen of methadone cannot be determined until a steady state is achieved.  Therefore, days of drug accumulation may occur after a period of rapid dose titration.  In some cases, this may lead to profound respiratory depression and death.  For this reason, methadone is considered a poor choice for patients who are difficult to monitor.

When administering methadone, start low and go slow! For example, the initial rate of titration of methadone could be no more than by 2.5 mg TID for 7 days since there is such a long half-life, blood levels continue to rise during this period.  After seven days, the dose could be increased to 5 mg per day for another seven days. IF SEDATION OCCURS OR IF THERE IS A PROBLEM WITH AROUSABILITY, METHADONE SHOULD BE HELD UNTIL THIS CLEARS AND RESTARTED AT A LOWER DOSE.  Other shorter acting opioids may be used in the interim to compensate for the slow titration of methadone.

Converting to methadone from other opioids needs to be done with caution.  Some researchers propose that methadone is almost 10 times more potent than opioids such as MS-Contin and hydrocodone when treating chronic pain.  Calculating a morphine equivalent of methadone is essential for patient safety.  Let's assume that prior to switching to methadone, the patient was taking 60 mg of MS-Contin per day plus up to 20 mg of hydrocodone per day for a total of 80 mg of morphine equivalents per day.  If the patient was switched to 80 mg of methadone per day, the patient's dose, in effect, would have been abruptly increased from 80 mg per day to 800 mg of morphine equivalents per day.

In addition, when switching an opioid-tolerant patient to an alternative opioid drug, it is wise to assume that cross-tolerance will be incomplete.  This means that a patient who has developed tolerance to one opioid analgesic may not be equally tolerant to another.  Therefore, when switching to a new opioid, opioid-tolerant patients should be started on a lower dose of the new opioid. 

 

 

December 1, 2006:

ALERT FROM THE FDA ON METHADONE

FDA ALERT [11/2006]:  Death, Narcotic Overdose, and Serious Cardiac Arrhythmias

FDA has reviewed reports of death and life-threatening side effects such as slowed or stopped breathing, and dangerous changes in heart beat in patients receiving methadone. These serious side effects may occur because methadone may build up in the body to a toxic level if it is taken too often, if the amount taken is too high, or if it is taken with certain other medicines or supplements. Methadone has specific toxic effects on the heart (QT prolongation and Torsades de Pointes). Physicians prescribing methadone should be familiar with methadone’s toxicities and unique pharmacologic properties. Methadone’s elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone doses for pain should be carefully selected and slowly titrated to analgesic effect even in patients who are opioid-tolerant. Physicians should closely monitor patients when converting them from other opioids and changing the methadone dose, and thoroughly instruct patients how to take methadone. Healthcare professionals should tell patients to take no more methadone than has been prescribed without first talking to their physician.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available

 

 

 

REFERENCES


Dr. Kiefer's References:

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    Dr. Savage's References

    Selected References Related to Abuse and Addiction Issues in Pain Management

    American Academy of Pain Medicine, the American Pain Society and the American Society of Addiction Medicine (2001)     Joint Public Policy Statement on “Definitions Related to the Use of Opioids in the Treatment of Pain

    American Pain Foundation (2001). Promoting Pain Relief and Preventing Abuse of Pain Medications:  A Critical Balancing     Act. A Joint Statement from 21 Health Organizations and The Drug Enforcement Administration. www.painfoundation.org/page_news.asp.

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    Compton P., McCaffery M. (2001 Jan). “Treating Acute Pain in Addicted Patients.” Nursing 31(1): 17.

    Doverty M., White JM, Somogyi AA, Bochner F, Ali R, Ling W (2000). “Hyperalgesic Responses in Methadone Maintenance Patients.” Pain 90: 90-96.

    Dunbar S, Katz N (1996). “Chronic Opioid Therapy for Nonmalignant Pain in Patients with a History of Substance Abuse: Report of 20 Cases.” Journal of Pain and Symptom Management 11(3): 163-171.

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    Gardner, E (1997). Brain Reward Mechanisms. Substance Abuse: A Comprehensive Text. Lowinson J, Ruiz P and Millman R. Baltimore, Williams & Wilkins: 51-85.

    Heit, HA (2002). “Addiction, Physical Dependence, and Tolerance: Precise Definitions to Help Clinicians Evaluate and Treat Chronic Pain Patients.”: 1-12.

    Jamison RN, Kauffman J, Katz NP (2000 Jan). “Characteristics of Methadone Maintenance Patients with Chronic Pain.” Journal of Pain and Symptom Management 19(1): 53-62.

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    McPherson TL, Hersch RK (2000). “Brief Substance Use Screening Instruments for Primary Care Settings: A Review.” Journal of Substance Abuse Treatment 18(2): 193-202.

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    Savage, SR (2002). “Assessment for Addiction in Pain-Treatment Settings.” The Clinical Journal of Pain 18: S28-S38.

    Scimeca MM, Savage SR, Portenoy R, Lowinson J (2000). “Treatment of Pain in Methadone-Maintained Patients.” The Mount Sinai Journal of Medicine 67(5&6): 412-422.

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