Controversies in the Treatment of Pain with Endometriosis

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Dr. David Olive: "My name is Dr. David Olive, and I'm at Yale University School of Medicine."

Dr. William Schlaff: "I'm Dr. Bill Schlaff, and I'm at the University of Colorado."

Dr. David Olive: "We're involved in a conference regarding endometriosis and a number of controversies regarding the treatment of endometriosis. What we thought we would do is discuss three of those in particular. The first being the patient who fails some type of treatment plan for endometriosis associated pain or at least pain that's presumed to be from endometriosis. They've been treated with oral contraceptives or with non-steroidal anti-inflammatory drugs, and then the question is - how would you proceed from that point? Do you proceed with surgical intervention with a laparoscopy to make the diagnosis and then treat or should you presume to just know that the patient has endometriosis and treat with GnRH agonists in a presumptive way? Bill, I'd like to ask you how you would proceed at that point?"

Dr. William Schlaff: "What I would do is really very consistent with what our consensus showed in our conference today. We had upwards of three hundred physicians from all over the world, predominantly northern and southern Europe, but some from the states and a variety of other areas throughout the world. The conclusion really in all of them - the majority I should say - was that the next step would be laparoscopy rather than a pair of treatment. The vast majority would treat or perform surgical extirpation of the endometriosis, generally speaking, with electrocautery at the same time. That's actually what I would do as well. In the U.K., it's quite interesting because of the management of operative lists and the like. They would often simply do a laparoscopy, make a diagnosis, and then subsequently treat with some type of medical therapy or bring the patient back for a treatment laparoscopy."

Dr. David Olive: "I would agree that the predominant approach, in the world today, is to do laparoscopy at that point. But I think there's a growing movement that says you don't really need to make the diagnosis of endometriosis if you have good evidence that endometriosis probably exists, the patient has pain consistent with it, and you've ruled out other diseases. I think there's a growing number of physicians who are comfortable in that situation using a GnRH agonists as presumptive therapy and seeing if the patient responds. If the patient does indeed respond, you can simply continue the medical therapy. If they don't, then you can proceed to surgery or some other type of evaluation to try and pin down exactly what might be causing the pain."

Dr. William Schlaff: "I actually extend that even further in many ways because I'd submit that it is often the case that we really don't know whether pain experienced by a woman is endometriosis or whether or not it may or may not be classical. I would suggest, perhaps somewhat cynically, that many practitioners don't even bother taking a very extensive history but simply in the face of reported pain that is unresponsive to these other methods - that David was describing - would move directly to the use of GnRH analogue independent of whether the consolation of symptoms was even suggestive of endometriosis. Thereby effectively saying that we are not going to be concerned about diagnosis in the least but rather we're going to use an empiric treatment approach to the treatment of pelvic pain of whatever variety. And only in those women who failed to respond or who have a rapid recurrence we'll be concerned about making a more definitive diagnosis by laparoscopy, and I really think that that speaks to the more difficult problem. I guess what I'd ask you is - in the face of a somewhat cynical approach or even nihilistic approach to diagnosing it or treating pelvic pain, while this is interesting in the women who's twenty-six years old who's life could have a chronic process - how do you fashion a medical approach or any combined approach to treating her pain, not just for the next six months but for the next six or sixteen years?"

Dr. David Olive: "I think the real key in trying to figure out how to deal with endometriosis is coming up with not just a short-term but rather a long-term approach. What you have to end up doing is using all the tools in your armamentarium that are available to you. That includes surgery, medical therapy, and re-treatment with medical therapy - things that have not been well demonstrated to be effective in good studies in the literature but which we believe to be effective, and are frequently utilized today. So I think the idea that you can simply treat, send the patient home, and be done with it - is one that we now know is not a true picture of the situation. What we will end up doing is designing plans to last for one, two, five, ten, or fifteen years as best we can."

Dr. William Schlaff: "That really brings up the whole concept of add-back therapy. A concept that was first published in the late eighties used progestins primarily as adding back to an analogue. The theory here was that by using some sort of an add-back therapy, one could forestall the metabolic and symptomatic side effects of hypoestrogenism at the same time as one allowed continuation of the therapeutic benefit of the treatments in a different way, while the metabolic consequences and side effects were reduced. There was no attenuation of therapy of benefit. So progestins were initially used, followed by hormone replacement therapy, more traditional estrogen plus progestin, and now in a variety of other compounds, and other approaches including disphosphonates, and tibolone outside of the United States. PTH has been used, and there may well be others as well. One thing I'd point out is that throughout all the published studies, one of the really unmeasured components relates to the impact of the ongoing interaction between the subject or the patient and the study site, which is to say - the physicians, nurses, and coordinators who participate with them. One can't really underestimate the importance of an interested ear, the either frankly psychotherapeutic or informally psychotherapeutic approach. One of the things we really have to do is to better develop our understanding of the specific nature of pain related to endometriosis versus the non-specific. And begin to look at other potential ways that we can improve outcomes - things like looking at evidence of depression and treating that or some would suggest, looking at nutritional aspects and the like. I think these are all important and, perhaps, areas we haven't looked at enough."

Dr. David Olive: "Yes, I think there's no question that the therapeutic approach that we use with frequent visits for the pelvic pain patient or any type of pain patient ultimately becomes beneficial. We also have other tools that are further beneficial, and we've proven these in the placebo controlled camp surgery and controlled trials. We know that add-back therapy is effective, and in fact, in all the studies that we've looked at - it's been not only effective but also probably enhances compliance by the ability to remove the side effects. So for that reason, I think both Bill and I are strong advocates of the use of add-back therapy with GnRH agonists and the ability to utilize then the therapy for a long period of time. We noted today in our session that most of the surgeons are interested in operative laparoscopy at the time of initial intervention and diagnosis of the endometriosis, and then the question arose - what should happen at that point? Do we just let the operative laparoscopy stand and see how the patient does or do we continue with medical therapy afterwards? Interestingly enough, an overwhelming number of the physicians from around the world elected to follow their initial operative laparoscopy with additional medical therapy. Bill, I wonder if you could comment on that briefly?"

Dr. William Schlaff: "I think that there is first and foremost, a huge gap in our information. The information gap that I'm alluding to is better knowledge of the percentage of patients who respond to initial surgical therapy and the characteristics of return of symptoms. In most studies, with the rare exceptions absent the control group, and with rare exceptions simply reporting results as opposed to performing any statistical analysis, taking into account drop-out such as a live table analysis, most of these studies will show us a benefit rate of 50%-80% over an indeterminate amount of time ranging from two or three months up to a year or so. So we don't really have a good grasp of, first of all, the percentage of patients who respond by improving their pain, assuming again that this is endometriosis related pain. Nor do we know the characteristic recurrence rate of pain over time. Absent that, I think, it's quite difficult to decide whether or not immediate adjunctive care is important. For example, if we found that 80% of patients had a two or three year cessation of pain following surgical treatment, I would be inclined not to want to treat with adjunctive therapy because presumably 80% of the patients wouldn't even need it. The other question I think is important, David, maybe you could comment about, is what the real benefit of adjunctive therapy is. Said a different way, is it simply a way of providing pain relief for the six months immediately following surgery or does that six month treatment produce more prolonged benefit than simply the surgical approach?"

Dr. David Olive: "That's an interesting question. We have very limited data to address that but it looks as if you don't get much more than the limited amount of time that the patients are on the medical therapy, by which to say you're extending the relief from the pain. So if you have them on for six months postoperatively - you get maybe six more months of pain free interval. If you have them on for a year or two years - you get that much more pain free interval. So I think that's probably what we're looking at although again, the studies have been fairly rare and fairly small to this point."

Dr. William Schlaff: "I would submit that to me that would imply in the presence of imperfect data, if at all, and the virtual absence of good data said a different way, that perhaps the best way of approaching this is to allow the surgery to work or not. If indeed it does, one can hold back the use of a GnRH analogue for a subsequent time when there's a recurrence. In fact, when you think about it, we have virtually no data about the metabolic or symptomatic benefit of re-treatment. To my knowledge, there is one study not very well characterizing these things. So if that's the case, if you treat immediately and there is a recurrence which is forced out by six months or however long, the treatment is what then is the next step. Do you re-treat, and if so, what evidence do we have that that's neither effective nor metabolically appropriate? So my view, frankly, would be in contradiction to the majority of people at our symposium. I would prefer to treat - simply with surgical extirpation followed, if you will, by treatment with medical approaches in the circumstance where there's reoccurrence of discomfort."

Dr. David Olive: "If I could sum up real briefly, we entered our session today because we did determine there was a controversy regarding the treatment of endometriosis associated pain. We were looking to see if we might find a consensus, and we found none. I think that's pretty much been the experience in every place that's looked for a consensus, whether it was the Canadian consensus report or the United States consensus meeting or in this meeting today. What we found was a wide disparity in the approach to endometriosis, and that's not entirely the physician's fault. We have a few randomized trials, a few studies that address specific questions regarding the treatment of endometriosis associated pain but there are a lot of other holes in the literature that have yet to be addressed properly by appropriate studies. So what we clearly need to do is identify those questions, design, and carry out large multi-center trials that address these very specific points so that we might practice in a more scientific manner."