THE RISK /BENEFIT RATIO
It is prudent to have a good idea of the risk/benefit ratio of virtually everything we put into our bodies. Think of foods, supplements, skin treatments, tattoos, and the like (for example, I do not use artificial sweeteners because I believe that the long-term risks are too high).
Drug therapies are no different and should be evaluated on the basis of a thorough evaluation of this ratio. Don’t forget that this ‘ratio’ should be personalized for each patient based on other coincident illnesses, medications in use, activity levels, compliance capabilities, tolerance for side effects, etc.
As a patient looks to establish a risk/benefit ratio, it is also important to consider the source and quality of the information being used. In general, the greater the number of confirming sources the better. The more independent the source of information is from those who stand to profit from widespread use of the drug, the better also.
First I would like to remind the reader of the general classifications of potential benefits from drug therapy for patients with endometriosis:
- Symptom Control: As we know, the symptoms of patients with endo are many and varied. Symptoms are those things that make us aware of the underlying disease. Things like anti-inflammatory drugs, muscle relaxants, pain relievers, etc. are all used to reduce symptoms. It is not expected that they will make endo regress or go away.
- ‘Disease’ Control: The ‘disease’ is the presence of endometrial glands and stroma in locations outside of the uterine lining. Certain drugs may have value in some patients because there is no evidence that the endo is advancing while the patient is on the drug and symptoms are not worsening. In my previous blogs on treatments, you will find some of these drugs listed in the category referred to as ‘suppressive medication.’
- ‘Disease’ Regression: If a drug causes the ‘disease’ to be reduced in volume, I label the benefit as ‘disease regression’. Certain drugs have been able to show reduction in endometrioma size during treatment (again, I refer you to my ‘treatment blogs’)
- ‘Disease’ Eradication: If a drug makes endometriosis actually go away, it would be in this class. I am not aware of any convincing data that documents endometriosis disappearing due to the effects of a drug. To my knowledge, this claim can only be made by surgical techniques.
The first step in evaluation a new drug is to be sure you know which of the above benefits you should expect.
- Potentially Serious:
- Drug Reactions: Any individual may have a unique reaction to a drug. These reactions may be mild or serious (i.e. life-threatening). The FDA makes an effort to note (in the package insert) any potentially serious drug reactions that have been experienced. The problem is that package inserts are not updated as often as I think they should be when events occur that have not previously been observed.
- Drug Interactions: Each time a new drug is marketed for general use, there begins a growing list of drug interactions. Drug interactions are untoward and often unexpected effects of the drugs when taken together. These drug interactions may negate the effectiveness of one or both drugs, and they may cause a variety of new health issues for the patient. In some cases it may take months or even years for these interactions to be recognized.
- Side Effects:
- When a drug is ingested for a specific benefit, it is common to experience other things that are not beneficial. For example, taking a strong iron supplement often leads to an upset stomach. Side effects can be minor irritations or significant impacts on quality of life.
- Drug treatments are considered successful even when there is a significant failure rate. It is wise to know the failure rate when considering the risk/benefit ratio.
As an exercise, let’s pick a new drug chosen by the FDA to ‘fast track’ called ‘Elagolix’ (currently in ‘phase 3’ clinical trials) and come up with a risk/benefit ratio.
Elagolix is a GnRH antagonist. Drugs in this group work at the level of the pituitary gland in the brain to reduce or stop the natural process of ovarian stimulation (gonadotropins are normally involved in signaling the ovary to begin to mature an ova [egg] for ovulation and to signal the time of ovulation). This down-regulation of ovarian activity normally reduces estrogen production. In theory, the reduced estrogen secretion reduces stimulation to all estrogen sensitive cells including but not limited to endo.
- Daily non-menstrual pelvic pain and daily dysmenorrhea (menstrual cramps) are the two most commonly evaluated symptoms. In a New England Journal of Medicine study (conducted by authors I know and respect), a dose related improvement in these two types of pain was documented at intervals up to 6 months. At the higher dose of Elagolix roughly 75% of patients reported a clinically significant reduction in menstrual cramps and roughly 50% reported a significant reduction in non-menstrual pelvic pain. If the lower dose was used, improvement in both categories was less.
- A possibly unique benefit (that is unproven) is the ability to use Elagolix to gain symptom relief at doses that do not result in bone loss. Bone loss is an expected consequence of both GnRH agonists and antagonists.
- Serious drug reactions were not reported in 872 women.
- We do not know if the disease progresses in some despite the improvement in symptoms.
- Studies of other GnRH antagonists give no evidence that the disease is eradicated.
- Side effects were reported in roughly 70% of patients. Most of these are those expected from estrogen deficiency and include: hot flashes, headache, sleep problems, mood swings, and joint pain.
- 5-10% of study participants discontinued the drug before the end of 6 months due to an ‘adverse event’.
- No data on long-term use is available. My personal experience is that soon after drugs in this class are discontinued, symptoms return.
- If the diagnosis of endometriosis has not already been established by a surgical observation, it is possible that the wrong disease is being treated. The incorrect presumption that endo is present then leads to mistreatment and the consequences.
To sum up the risk benefit ratio of Elagolix based on available data, I would say that Elagolix is an as yet mostly unknown drug that has a moderately good chance of reducing an endo patient’s non-menstrual pelvic pain and dysmenorrhea. Its benefits are in the ‘symptom control’ group. Side effects should be expected and can be significant. The treatment is temporary, and is not expected to eradicate the underlying disease. Long-term follow-up of patients who have used Elagolix is not available. Drug interactions and effects on fertility are not known for this specific GnRH antagonist.
OK! Get busy before you put anything into your body and figure out your personal risk/benefit ratio.
Disclaimer: any and all material(s) presented herein are offered for informational purposes only. Such material is not intended to offer or replace medical advice offered by your personal physicians or healthcare professionals. No information herein should be considered as party to any doctor/patient relationship. All contents herein are © copyright by Robert B. Albee, Jr., MD except where otherwise explicitly noted. All rights reserved. This material may not be reproduced or utilized in any form, including electronic or mechanical, photocopying, recording, or by any information storage and retrieval system except for personal or teaching use with prior permission. Thank you.