Wednesday, August 8, 2012

Opioids on Trial, But Where’s the Evidence?

Editor's NotebookA recent Citizen Petition to the United States Food and Drug Administration (FDA) by Physicians for Responsible Opioid Prescribing, or PROP, requests labeling changes for all opioid analgesics when it comes to their prescription for noncancer pain. The changes would limit the dose, impose time limits, and restrict opioid use for only severe pain.

The Petition raises some important questions about the safety and efficacy of opioid analgesics as they are currently FDA-approved and prescribed. And, the urgency of an investigation was heightened by the fact that a Congressional committee has joined the petitioners in demanding action from the FDA. But, a critical question is whether there is sufficient evidence of reasonable quality for the FDA to act on the Petition at this time.

A Crisis of Confidence in Evidence

At every turn these days, opioid analgesics seem to be on trial, whether in the court of public opinion fueled by mass media, in the U.S. Congress and state legislatures, in various government agencies, and among select groups of healthcare professionals. Yet, what may be most at stake here is a crisis of confidence in scientific methods of inquiry and the reliance on valid research evidence as proof when it comes to making judgments that guide clinical practice in pain management.

Since our inception in late 2005, the mission of Pain Treatment Topics has been to focus on principles of evidence-based pain management. In Part 11 of our ongoing series, “Making Sense of Pain Research” [here], we examined several questions: What qualifies as evidence? What are the requirements of evidence as proof? How much proof is necessary for reaching valid and just clinical decisions?

We reminded readers, “Just as juries need good evidence to reach prudent verdicts, healthcare providers need good evidence as a guide for better decision-making in treating patients with pain.” However, due to the nature of scientific inquiry and research methods, absolute certainty is an illusion and research outcomes must be used circumspectly and wisely for reaching judicious conclusions affecting patients’ health and well-being.

We say all of this because, as much as anything, the PROP Petition [available here] raises questions about how pain research evidence could and should be interpreted and used for influencing decision-making and change. And, it also raises questions regarding the quality, quantity, relevance, and validity of evidence necessary for establishing an acceptable level of proof in pain management.

In previous UPDATES, we have dissected, discussed, and/or challenged much of the evidence that is used in the PROP Petition to support their requested changes to opioid-product labeling. This and additional evidence also is discussed in a recent guest author UPDATE [here] by Bob Twillman, PhD, FAPM, and further opinions debating claims of the Petition are offered elsewhere by clinical pharmacy specialist, Jeffrey Fudin, RPh, PharmD, DAAPM, FCCP [here].

In short, there does not appear to be a body of good, clear, and convincing evidence at this time to support the requests in the Petition, let alone any evidence beyond reasonable doubt for passing judgment. However, this is not to say that the petitioners’ assertions are frivolous or unworthy of further investigation and discussion.

In fact, the FDA has posted the Petition at the U.S. government site — www.Regulations.gov — and is accepting public commentary. The URL link is: http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-0818-0001

Document Name: Physicians for Responsible Opioid Prescribing - Citizen Petition
Document ID: FDA-2012-P-0818-0001
Docket ID: FDA-2012-P-0818

We should note that commenting is not limited to Americans, and persons from all parts of the world may have much at stake here. Changes to opioid labeling and prescribing in the U.S. may inspire other countries to re-examine how these medications should best be prescribed in their own populations. We would encourage any and all persons with something to say on this matter, pro or con, to submit a comment.

Here is the text of the public comment letter that we submitted to the FDA on August 6, 2012; Tracking ID# 810c2f4b….

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TO: FDA Docket ID: FDA-2012-P-0818 at www.Regulations.gov
RE: Physicians for Responsible Opioid Prescribing - Citizen Petition
FR: Stewart B. Leavitt, MA, PhD, on behalf of Pain Treatment Topics

On July 25, 2012, Physicians for Responsible Opioid Prescribing (PROP) and allied signatories submitted a Citizen Petition to the U.S. Food and Drug Administration (FDA) requesting certain changes to opioid analgesic labeling. These would limit opioid dosing, impose time limits, and restrict opioid use in noncancer conditions to only severe pain.

The Petition appears to be most concerned with opioid analgesia for chronic noncancer pain, and excludes cancer-related pain, but there is some confusion as to whether the label changes would apply also to acute pain. In any event, it seems that the broad and implicit hypothesis underlying the Petition might be stated as this:

Compared with opioid analgesic prescribing practices following indications on current product labeling, patients would be afforded superior effectiveness and safety if opioids were restricted to a dose of ≤100 mg/day of morphine or its equivalent for no more than 90 continuous days and only for severe pain in the case of noncancer conditions.

If this hypothesis is true, countless patients are possibly being mistreated or harmed by current prescribing practices, and it would be important to know if any or all of the Petition’s recommendations should be adopted. As it presently stands, however, there are some serious concerns regarding acceptance of the Petition and its implicit hypothesis:

  • The hypothesis has not been directly tested by adequate, prospective clinical research trials of any quality or sufficient quantity.

  • Current best evidence submitted by the petitioners under their “Statements of Scientific Basis for Petition” has been challenged in terms of its relevance, adequacy, and/or validity [Twillman 2012, ref below].

  • Limited clinical evidence presented at a recent FDA-sponsored Workshop last May, 2012, to assess analgesia for chronic pain was largely of lower quality — observational or epidemiological — and generally equivocal or inconclusive regarding the absolute benefits vs risks of long-term opioid therapy at any dose for various types of pain conditions [FDA 2012].

Therefore, the Petition proposes a hypothesis that raises important questions but, in itself, is untested and unproven. And, it seems apparent that, at this time, changing opioid-product labeling in accordance with the Petition’s requests could be tantamount to enrolling millions of persons with pain — unknowingly and non-consenting — as participants in a clinical experiment to test an unfounded medical theory.

Certainly, the clinical, scientific, ethical, and legal implications of this are daunting, and memory of egregiously cruel human experiments in history would seem to preclude the labeling change at present. Unintended consequences of the label change could possibly be significantly adverse and harsh.

Still, in the court of scientific inquiry there seems sufficient evidence for reasonable suspicion that some, if not all, of the Petition’s perspectives could merit further investigation. Government research-oriented agencies might be encouraged to examine these issues further and to fund the necessary well-designed clinical investigations.

First, however, it would be necessary to operationally define what is specifically meant in the Petition by such terms as: safety, effectiveness, noncancer, and severe pain. And, to better justify for testing the assignation of ≤100 mg/day morphine or equivalent and 90 days duration as threshold points.

Surely, opioid analgesics are not the only or best solution for all types of pain, whether acute or chronic, cancer or noncancer, and in all patients. Ultimately, the goal is to afford patients the best possible pain management, and to identify those patients who might benefit most from opioid analgesia at any dose and/or for any length of time.

References:
> Twillman R. Group Petitions FDA to Change Opioid Label. Pain-Topics UPDATES. 2012(Aug 2); available online at:
http://updates.pain-topics.org/2012/08/group-petitions-fda-to-change-opioid.html
> FDA (U.S. Food and Drug Administration). Assessment of Analgesic Treatment of Chronic Pain: A Scientific Workshop. 2012(May); available at: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM309444.pdf

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Our purpose in commenting was not to challenge particular research referenced in the Petition or the specifically requested changes; rather, to address issues of scientific method and the uses of evidence as proof. Quite simply, a new clinical hypothesis requires some basis in science or prior evidence to justify testing — which might be met by the limited evidence cited in the Petition — but the hypothesis itself should not be not put into practice until it has been tested and proven valid. Essentially, if opioid labeling were changed at this time in accordance with the Petition it would be “putting the cart before the horse” from an evidence-based medicine perspective.

In his recent guest author Pain-Topics UPDATE, Dr. Twillman, PhD, FAPM, did a thorough job of discussing and questioning the evidence base behind the Petition. In fair balance, immediately after we posted the Twillman UPDATE, we alerted Andrew Kolodny, MD, of the article; he is president of PROP and a principal signer of the Petition. We extended to Dr. Kolodny, and any fellow cosigners of the Petition, an open invitation to submit for publication a rebuttal UPDATE article commenting on Twillman’s critique and/or further presenting their own perspectives. [ADDENDUM: Dr. Kolodny did respond to us later today: available here.]

Congress Embraces the Petition

US CongressOn July 26, 2012 — just one day after the Petition was filed with the FDA — Congresswoman Mary Bono Mack and 5 fellow members of the Congressional Caucus on Prescription Drug Abuse sent a public letter [available here] to Margaret Hamburg, MD, FDA Commissioner, essentially endorsing the Petition and embracing all of its recommended labeling changes. The letter concludes:

“We believe that if a labeling change were made to opioid analgesics to reflect the uncertainty and lack of evidence surrounding safety and effectiveness of these drugs for treatment of chronic non-cancer pain, physicians would think twice before prescribing these highly addictive narcotics for ‘moderate’ pain such as a toothache or sore knee. While those who seek treatment for cancer pain and other diseases that cause “severe” pain would not be affected, the number of individuals prescribed opiate painkillers without evidence of the long-term safety and effectiveness may decrease and limit those susceptible to developing opioid dependence.”

To our knowledge, none of these elected officials has extensive medical training or expertise in the assessment of research evidence. Their statement reflects some bias in the use of emotion-laden terms — eg, “highly addictive narcotics” and “painkillers” [discussed previously in an UPDATE here] — and, they appear to advocate against even the short-term use of opioids for acute pain, such as a toothache, which is an unclear aspect of the Petition. The Caucus members also seem to have accepted the false argument of the petition, that a lack of evidence is, in itself, acceptable evidence for advocating against the long-term effectiveness and safety of opioids for noncancer pain.

Still, this letter commands the attention of the FDA, since it ends with, “For these reasons, we request an expedited review of the Citizen Petition submitted to FDA, and look forward to a timely response.”

What Happens Now?

FDAIn fairness, the letter from Congresswoman Mack and colleagues was merely instructing the FDA to look into the matter and report back. The FDA already held a Workshop last May exploring analgesia for chronic pain, but this letter probably motivated the agency to accept and post the Petition at the government regulations website on July 30, 2012, for further public comment. Again, that site can be accessed [here].

We have from time to time been critical of the FDA; yet, we know that the agency performs a vital function and is staffed with well-trained and dedicated physicians and scientists. They understand the ins and outs of pain research and are unlikely to be swayed by low-quality, biased, or inadequate evidence.

In our opinion, there is more at stake here than the fate of opioid analgesics prescribed for chronic noncancer pain. Conflicts of dogma versus science are at the core of many practices in the pain management field; yet, low-quality evidence and fallacies of logical thinking sometimes appear to be winning the battle.

Furthermore, some of the nuances and ramifications of the petitioned label change must be considered:

  • Some have argued that changing the label would stop pharmaceutical companies from promoting opioids for uses beyond the new, more limited indications, but, if deemed necessary, practitioners could still prescribe the medications off-label at any dose and for any duration of time in noncancer pain.

    However, off-label applications of medications are usually discouraged and can be risky; prescribers know that they could face regulatory scrutiny or liability issues if something goes wrong and they have not followed FDA-approved indications on labeling. The Congressional Caucus members are aware of this when they state, “…physicians would think twice before prescribing these highly addictive narcotics.”

  • This further raises the question of addiction to opioid analgesics among legitimate patients with pain. Evidence regarding this is discussed by Twillman in his UPDATE, and this still appears to be an unresolved issue needing further definition, investigation, and clarification. Yet, the Caucus members seem to accept the notion that restricting opioid prescribing, “may decrease and limit those susceptible to developing opioid dependence.” By dependence, we presume they mean “addiction” here, rather than the physiological dependence on opioids that naturally develops in many cases; although, whether or not they fully understand the distinctions seems unknown.

  • In reaction to the Petition, some professionals have questioned whether public and private healthcare insurance plans would continue to pay for opioid prescriptions that did not adhere to new restrictions indicated on labeling. If not, patients with chronic pain would need to personally absorb the financial burden associated with off-label opioid prescribing, which in many or most cases could preclude or curtail their ongoing access to these medications. Any answers to insurance coverage questions at this time would be speculative.

  • Most worrying are questions not even raised and addressed in the Petition or by Congressional Caucus members. What should take the place of opioid analgesics for chronic noncancer pain? What are the better, safer, tried and proven therapies?

There are no easy answers to questions and evidentiary dilemmas posed by the Petition. Our own recommendation is that, if the Petition is to be serously considered and judged, there first must be an objectively thorough review and critical assessment of all relevant evidence regarding this issue — pro and con. And, hopefully, these inquiries and further dialogue will be fair-balanced and steered by science — embracing principles of evidence-based medicine — rather than driven by dogma and demagoguery.

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11 comments:

Anonymous said...

So,what happens to chronic non-cancer pain patients after 90 days? How was it determined that 90 days is sufficient to treat chronic pain? PROP claims that the pharmaceutical companies are making claims without substantial proof, but it looks like PROP is being hypocritical. Where is the evidence or reasons for a 90 day limit? Where is the evidence for a max dosage 100 mg of morphine per day?

According to Dr.Kolodny's reasoning and logic, it is PROP's responsibility to prove these claims.

Anonymous said...

I have RSD/CRPS. For the last seven years I've taken morphine for the pain. It is the only thing that allows me to participate in my life and in the lives of my family. The only effect it has on me is a reduction in pain and sometimes mild fatigue.

Naturally it is very frightening when I read that the government is considering taking away the medication that helps me deal with my pain. What are they thinking? Ever heard "if it isn't broke? ..."

Anonymous said...

I am a Lupus/Sjogrens/Degenerative Disc Disease/ Bone Death of the femoral heads patient. My life had become a living hell of vicious, unrelenting pain. Every non-narcotic treatment known to exist was tried to control my pain to no avail. Under the strict supervision of several physicians I was started on Fentanyl patches, a hydrocodone/APAP combination tablet and Percocet for breakthrough pain. My life has been given back to me!!! I went from being suicidal bedridden to a functioning member of society. I do not get a buzz or high or any other effect deemed dangerous to me. I simply get a big reduction in the amount of excruciating pain I deal with 24/7. I also have radiofrequency ablation and steroidal epidural injections on a very regular basis to augment the opiate therapy. I am no danger to society or to myself. I follow my doctors directions to the exact letter or even take less than prescribed on good days. Please, for the sake of chronic pain patients everywhere, do not restrict the use of these type medications any more than they already are! Don't hurt us even more than we are already hurting please! My life has been given back to me...please don't take it away again!

Anonymous said...

of all the things people need to do is limit something that helps people who have or do not have cancer. Pain is pain and if you were needing it you would not be fighting it. To ask the FDA who has been under fire for letting even more dangerous drugs out to the public is even worse. If they let out these drugs, but limit a kind of medicine to that point then they need to limit how they let out these dangerous drugs they approve. Read and learn before you go ans open your mouth about what is good or bad for people. I know for a fact that I took a drug that almost could have killed me and I take pain medicine as prescribed which helps my pain a lot. It is not the stronger pain med either. Am going to be penalized for that, or should the FDA be asking me about the med I took which rendered me almost helpless and suicidal. Think on that people. I would rather take something that helps me not hurt. I took both meds as prescribed by the way. I can;t stand the people who think they know it all and don't

Anonymous said...

After giving this much thought I've come to the conclusion Dr. Kolodny needs some of his own medication he prescribes because this is crazy saying 100 mgs of morphine a day and the equivalent is enough for anyone suffering from severe chronic pain. And to keep it to 90 days like chronic pain is going to go away come day 90, I think all that signed this petition needs their head examined.
Everyone of you including Dr. Kolodny needs a reality check because you’ve lost it.
I don’t wish chronic pain upon anyone after I've suffered for many years.
But I forgive you for your ignorance, for I cant hate anyone,its against my religion.
Please find another hobby, because your stressing pain patients out, like the never ending pain is not enough.

Sam

Anonymous said...

Thing is you cant stress me out I don't let ignorance upset me anymore,this is actually comical.
What's next, lets keep insulin away from all diabetics.
I've seen and heard things like this for many years and in a few months everyone will look back on this and say
what where they thinking. Lets make all pain patients suffer their life away. One way or another if one suffers
they will find relief even if it means going to the streets so this is just great.
If this happens and I know it will not, all pain patients will be buying illegal pain meds off the streets.
See what your doing PROP.

Sam

Anonymous said...


I too have severe chronic intractable Pain issues. The medication helps get me through a long day working. I've been on the same dose for many years. So yes there could be a very good debate, being that the concerns being raised are cherry picked, and it is not true that a pain patient will always need an increase. Once you have pain control your good to go, and safe.

There are far worse issues in America than a patient trying to get by, go to work, take care of family members ect...

My injury's were mainly sport's related, and severe. Hope to have contributed, May God Bless!

Anonymous said...

The problem is that a lot of these prescribed pain pills and patches are KILLING our children. When another persons pain Meds cause death of another person, then WHO is responsible? We need to figure that out. You all commenting on here may keep tight control of your Meds, but I can tell you that MANY get into the wrong hands. The law that if you provide a drug to a person and they die is not being enforced......just ask us bereaved parents!

Anonymous said...

To the last comment from the parent. I am sorry for your loss and am not saying anything was your fault.But I think people need to take a real hard look at the TRUTH!!! I just don't think parents are participating enough in our youths lives.Our children are too hooked on video games and junk food.They grow up without supervision and are given video games instead of parent/child interaction.I have seen many things in my life and our youth is apathetic due to the reasons I stated. I have also witnessed happy children that have adults interacting with them, raising them, teaching them.These children rarely do drugs. It is the children that have to raise themselves that are in the most danger. With that said I think it is wrong to make people live with severe chronic pain that can be successfully treated with medication. I had my whole life taken away, I can no longer work due to chronic pain that my physician will no longer treat. I am almost homeless because I can't pay my bills anymore. I was born with a very painful birth defect, extra ribs in my neck that had to be removed. Now I have severe nerve pain. I still put myself through college and I am a registered nurse. I think it is inhumane to allow people to suffer like this. This is just wrong. The reason for all the opiates on the street is due to pill-mills, not all pain management clinics are responsible. Lets close down the pill-mills and allow our good pain management doctors do their job without being afraid!!!! Wake up people.

Anonymous said...

How much I enjoy reading all the articles and comments on this site! I am a 71 year old woman with intractable pain due to Pudendal Neuropathy, a condition that most doctors do not believe exist. I have had it for seven years. I had Pudendal surgery, which was not successful. I spent two of the last few years in bed until I realized that I would rather be dead than live like that, so I learned to walk again through sheer perseverance. I am in excellent health except for the pain. I also have a twisted coccyx due to the one and only fall I had while learning to walk. I found a wonderful pain management doctor who is two hours away, but so worth the trip. He has tried everything he could possibly do for me, until narcotics was the only choice. My pain is severe, but manageable with the narcotics and muscle relaxers. I had a bad experience last week with a very prominent spine doctor who gave me an injection into my coccyx. The whole time he was doing the procedure, he said there was no condition called Pudendal Neuropathy, and that I was nothing but an addict. When is this thinking going to change! Even the nurses in surgery were uncomfortable. I am just trying to have a little bit of life with the few years I have left.

Myron Shank, M.D., Ph.D. said...

To the woman with pudendal neuropathy and a "twisted" coccyx: I am a physician who has successfully treated several patients with severe pain due to coccygeal deviation. I did so by combining two techniques: (1) applying steady firm pressure toward the natural midline curvature, and (2) having the patient hold his breath and bear down (known as the Valsalva maneuver) as hard as he could.
While I do not have any experience treating pudendal neuralgia, I did find intriguing websites describing treatment options for this condition ( http://www.spuninfo.org/index_files/PhysiciansPerspectiveTreatment.htm and http://www.beyondbasicsphysicaltherapy.com/sexual-dysfunction ).
The former site points out that pudendal neuralgia is often associated with sacroiliac joint dysfunction. If your physician is not comfortable with evaluating or manipulating the sacroiliac joint, he should be able to refer you to a good physical therapist. In spite of your unfortunate experience with coccygeal injection therapy, I have had good experience with sacroiliac injections. Your physician can order an x-ray- guided injection into the joint, which can confirm or exclude it as a source for your pain and may provide relief.
You have apparently already tried them, but tricyclic "antidepressants" and neuroleptics ("antiseizure" drugs) sometimes help.
Your case points up another fallacy prevalent in pain management: The idea that the reason people travel to physicians for pain management is that they are inappropriately drug-seeking. Unfortunately, I have first-hand experience with this, courtesy of the State Medical Board of Ohio. I hope that your physician will be spared the injustice that I have experienced.
So long as you need "narcotics" for your chronic pain, I fully support your right to receive them in whatever dose and for whatever length of time that is required to provide you with relief and improve your functioning without unacceptable side effects and in the absence of evidence that you are misusing them. Period.
Myron Shank, M.D., Ph.D.