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With the country in the throes of the opioid epidemic, the Food and Drug Administration started a risk evaluation and mitigation strategy (REMS) in 2012 to restrict prescribing of quick-absorbing fentanyl to appropriate patients. At the time, these were the most potent and riskiest opioid-based medications available. The program should have worked, but was undermined by one company, Insys, whose top executives were convicted last week of bribing doctors to prescribe this type of painkiller to people who weren’t supposed to get it.

These fast-acting fentanyl medications, also known transmucosal immediate-release fentanyl (TIRF), are taken by mouth. They were approved to treat breakthrough cancer pain. In the months after the risk evaluation and mitigation strategy known as TIRF-REMS was launched, there were large decreases in prescribing this type of fentanyl. But as we and colleagues reported in JAMA Network Open, what then followed is a cautionary tale that’s emblematic of the influence the pharmaceutical industry can have over physicians’ clinical decisions.

While some TIRF products were already part of restricted-use programs, most of those prescribed in the U.S. were older, generic products and not restricted. These drugs were only supposed to be prescribed to patients with cancer pain, but were being widely prescribed for those without cancer. And warnings issued by the FDA had linked several deaths to their use.

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The FDA program included the strongest protective action the agency could have taken short of banning the drugs. Doctors who wanted to prescribe these powerful medications needed to pass a test to demonstrate they knew which patients were appropriate candidates for them (those with cancer for whom less powerful opioids were not effective). Patients needed to review information on the risks of TIRF. Pharmacies had to commit to dispense this kind of fentanyl only to verified patients with prescriptions from participating prescribers. And drug distributors had to commit to sell these products only to approved pharmacies.

It was, and still is, the strictest risk evaluation and mitigation strategy the FDA has undertaken related to opioids, and at first it seemed to work.

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We evaluated the impact of the program on Medicare beneficiaries who received prescription drug benefits through Medicare’s Part D program from 2010 through 2014 — approximately two years before the program started and two years after. In its first months, there was a 27% decline in fentanyl prescriptions. After a year, though, prescribing rebounded to pre-program levels.

We can’t be sure why the rebound occurred, but we have some ideas. It might simply have taken time for prescribers, patients, and pharmacies to sign up and adjust to the program before everyone returned to the status quo. That explanation doesn’t really fit, though, because there were large decreases in both the number of prescribers and the number of prescriptions after the TIRF-REMS was implemented, yet there was no subsequent increase in the number of prescribers when fentanyl prescriptions rebounded.

A more likely explanation was the 2012 approval of Subsys, a quick-absorbing fentanyl spray that soon dominated the market. Its maker, Insys, used fake medical lectures, bribes, and even falsifying patients’ medical histories to make it look like they had cancer. Several people have been convicted, and some are already in prison for these schemes, including doctors, physician assistants, and former and current Insys executives, including CEO John Kapoor. As researchers who study the promotion of prescription drugs, we found the Insys actions to be eye-opening, but not shocking.

Payments for fake lectures may be attention-grabbing, but most drug marketing is far more mundane, like a drug company representative bringing lunch to a doctor’s office to promote the company’s products. Most payments by pharmaceutical manufacturers to doctors are for meals and beverages, and average just $13 in value. Yet even small payments for lunch are associated with changes in prescribing.

In a study of prescriptions for oral anticoagulants and non-insulin diabetes drugs, we found that an average $13 payment from a drug maker was associated with an additional 100 days of prescribing of the promoted drug. Other studies have found correlations between payments and prescribing for cholesterol and eye medications. We also found that payments from opioid manufacturers were associated with patients receiving higher doses of opioids.

Outrage over what Insys did to boost Subsys sales of won’t fix the underlying problem of influence peddling by pharmaceutical manufacturers, just like the outrage over Martin Shkreli jacking up the price of a generic medication did not fix the underlying problems that contribute to high drug prices. Instead, what’s needed is bold action to curtail the legal world of prescriber influencing.

First, we believe all payments to prescribers that are not related to research should be banned so clinicians can care for their patients without the burden of potentially being influenced by pharmaceutical manufacturers. Second, when implementing risk reduction programs such as the TIRF-REMS, real-time monitoring is needed. That way, if the program is not achieving its intended goals, rapid modifications can be made, including penalties for those subverting it. Third, for dangerous drugs such as opioids, we believe the FDA should be more aggressive in investigating and penalizing companies that illegally market their products for off-label use. Fourth, we urge Congress to ensure that the FDA and law enforcement have adequate resources for faster, more aggressive responses to bad actors like Insys.

In March, the FDA announced plans to strengthen the TIRF-REMS program by requiring prescribers and pharmacies to verify and document patients’ tolerance for opioids (based on their prior opioid prescriptions) before each prescription is written and filled. Also planned is a  new database that will follow patients taking these drugs and enable better monitoring for safety issues. We applaud these efforts, and hope these changes, along with the increased scrutiny of past, present, and future marketing efforts by pharmaceutical manufacturers, will better protect patients’ and the public’s health.

William Fleischman, M.D., is the director of quality and implementation science in the Department of Patient Safety and Quality at Hackensack Meridian Health and previously served as a medical officer in the Center for Program Integrity at the Centers for Medicare and Medicaid Services. Joseph S. Ross, M.D., is an associate professor of medicine and public health at Yale University and receives research funding from the Food and Drug Administration. The views expressed here are those of the authors and do not necessarily represent the views of their employers, CMS, or the U.S. government.

  • I will do anything to get life back and I can live alife.Please guit making people hurt!

  • Correction: My last statement should read: They tax them and partake of both products. And the last name of Deborah Howdy should read: Deborah Houry.

  • I have to correct something Michael stated (and don’t feel bad Michael because this is the media’s fault). The CDC is almost as corrupt as the DEA, and spew one lie after another. First of all, it is not the CDC’s job to write Guidelines for prescribing opioids, that is the FDA’s job. But when recovering alcoholic psychiatrist (who has never practiced–no patients, just another idiot intelectual at Brandeis University), when he along with PROP which he directs, petitioned the FDA in 2010 to write the Guidelines which he and PROP came up with, THEY REFUSED!
    So when the Trump administration put the pressure on the CDC, they held a secret meeting with no pain patients, no pain doctors or specialists, just Addiction Treatment people and came up with these 2016 Guidelines even though the authors listed are Roger Chou and Deborah Howdy.
    THE LIE:. THE CDC CAME OUT AND SAID 70,000 PEOPLE OVERDOSED ON OPIOIDS! THE MEDIA KEPT REPEATING THIS AD NASEUM. THEN THE CDC RETRACTED THAT AND SAID NO WE WERE WRONG, IT WAS ONLY 42,0000. IT WAS FURTHER RETRACTED TO 17,000 WHICH IS STILL FALSE, BUT THE MEDIA KEEPS SAYING 70,000!
    The reason the 17,000 figure is still erroneous is because they counted as overdoses, people who drank alcohol and took benzo’s and other drugs along with opioids, so it wasn’t the opioids that killed them, IT WAS THE COMBINATION OF ALCOHOL AND SEDATIVES!!!!! You can Google the retracted number by asking: Did the CDC retract the overdose deaths.

    PLEASE MY FELLOW PAIN FRIENDS WHO I LOVE, PLEASE HONE UP ON THE FACTS AND DON’T GIVE THE CDC THE SATISFACTION OF SPREADING THEIR LIES!
    You made a great point Michael of showing the real culprits of alcohol and tobacco deaths! They will never do to alcohol and tobacco what they’ve done to opioids because they had them and partake of both of these products themselves!

    • Don’t know alot about laws on it, but it almost seems like they are all accessories to the deaths of thousands of innocent chronic pain patients, shirley. Similar to depriving someone of food and water..life giving pain medicines? I’m sure alot of lawyers are aware of it. If ever there were justifiable law suits to be filed…definitely for pain patients and their loved ones who have suffered tremendously.

  • The kicker to all this is the most effective treatment for opioid addiction is methadone. I was a heroin addict from 16 – 26, in that time I went to rehab over 30 times. The majority of the time I would relapse within hours of getting home. The longest time I managed was 3 days and that was after a 90 day stay inpatient. Treatment centers are a joke AA is ineffective and has never shown effective in any medical study.

    Methadone saved my life 8 years sober it took me a year after I started methadone to get 100% clean, due to the ridiculous laws they have around titration of methadone. It takes forever to get to a dose that keeps you stable and craving free.

    Opiates aren’t evil. Alcohol is the real issue yet we turn a blind eye

    • AA is not supposed to be helpful for addicts to substances other than alcohol. It certainly is not effective for everybody. It was created by middle class middle western white protestant men, and it’s not even effective for many of them, but it is effective for some. At one time there was much discussion about excluding persons who were addicted to other substances, but in the end they reverted to Tradition Three, any person who wants to quit drinking is a member of AA. That can include heroin addicts, and I’ve known a few of those who it helped. I think all the rehab programs have a success rate of about 5%, which is the same as the people who quit using their preferred substance on their own. I’m glad you finally found a routine that worked for you. I was lucky that I was among the 5% that AA worked for.

  • I am a terminal cancer patient under a hospice care. This is my 2nd hospice because the 1st one insisted that I take fentanyl which I declined. Next they raised my morphine to 270 mg. a day although I had not complained about additional pain. I got fed up and left them. I do know that they are now out of business. Doctors should listen to their patients especially when that patient is t turning down excessive amounts of opioids.

  • I’m in pain now everyday. I have fibermyalga and degenerating disc disease. Opiods stop the pain. In way I was told no more. Went through withdrawals by myself. You die your heart gives out. The shock on my body messed up my thyroid. I went through major surgury with three days of pain meds. Had to go back to the hospital. They took my blood did a $900. Dollar blood test without permission for opiods than harrassed me for having in my system. I said I just was operated on yesterday. The doctor gave them to me. There is a solution. Become a libertarian vote for them. They will fix it. All these laws are not what out forfounders wanted. The people in charge have walked over us made a mockery of freedom. If drugs are legalized crime will drop by prisons won’t be filled to the max. This opiod epidemic is total made up war I can’t believe people aren’t revolting. Tylonal is biggest killer of people by a drug. It caused liver failure. You help C can die taking it. There’s nothing left that helps a lot of pain that we are all suffering. Vote for libertarians be the Democrats and Republicans are working together. Nothing will change with them in power my news reporters need to get some morals they have helped the opiod war. It wouldn’t have gone anywhere without them demonizing it . And their false reports .

  • The people whose idea to limit opiate medications due to the “opioid crisis”does little to stem the tide of heroin and Chinese fentynal. It does restrict access to legitimate chronic pain patients, why doctors are intimidated and write fewer opiate prescriptions for fear of losing their license and reputation. Furthermore opioid addiction is a Psychological problem, o e that is overlooked in the hysteria to correct this problem

    • Exactly. People are addicted to opioids for nonmedical reasons, aren’t going to simply get it as easy as buying a candy bar downtown corner Shop. All this does is to make the lives of people suffering with for fatal and non-fatal chronic pain even more horrific, like my father. And the thing is that completely legal alcohol and tobacco products kill 10 times (680,000/yr) as many people every year as opioids, and opioids when the politicians did not get involved, we’re only killing about 7000 people a year, in 2010. Now it is 70,000 people, because of state restrictions on doctors prescribing what they believe is medically necessary and people can’t get proper pain management, and I have even seen people who are dying of cancer, having to buy heroin/fentanyl. Just legalize the damn stuff, make treatment programs available, and don’t make people who have a year to live have to jump through hoops just so they can make it through the day.

  • I would say that at least one of the authors has a conflict of interest in receiving money from the FDA. As an Intractable Pain Patient with CRPS Complex Regional Pain Syndrome caused by a crush injury to both legs and feet 20 years ago and this Pain Syndrome is the highest rated pain on the McGill Pain Scale above cancer, amputation and childbirth and known as the SUICIDE Disease, I believe I am more qualified than either of these physicicians to talk about opioids! They are NOT dangerous drugs first and foremost! They have been around since millenia in the form of the poppy plant and used for pain for thousands of years. LESS THAN ONE HALF OF 1 PERCENT OF PEOPLE WITH MODERATE TO SEVERE PAIN EVER BECOME ADDICTED TO OPIOIDS PERIOD!!!! The President, the government (CDC, FDA, DEA and Congress) have been co-opted by the Addiction Treatment Centers lies about opioids, because they want everyone OFF OF OPIOIDS and into their own ATC’s to make money! The big, fat lie by psychiatrist Andrew Kolodny is that “All Opioids are little heroin pills that make addicts out of everyone!” Well, if that were true we would have more like 150 million addicts (from surgeries) instead of the puny 2 million we have in actuality!
    The 2nd big lie is that “There are no longer term studies showing the effectiveness of opioids for chronic pain” and that “Studies have shown opioids have been proven ineffective for Chronic Pain.” That is because the studies were only done on inflammatory pain for the back, etc. and opioids don’t work for inflammatory pain! I would know because I also have back, hip and joint pain which my high dose of Fentanyl doesn’t touch. But, OMG, Fentanyl is the ONLY THING THAT ALLEVIATES MY NERVE PAIN!!!
    There are many types of pain (muscle nerve Soma nociceptive inflammatory bone,etc) but doctors don’t know this because they only get 9 hours on the study of pain while veterinarians get 45. The Government has demonized opioids so that after having them taken away, chronic Intractable Pain Patients can’t live in excruciating agonizing unrelenting pain 24/7, so we commit SUICIDE (rate is up 50%) and save the POLITICIANS 1 TRILLION A YEAR IN HEALTHCARE!
    The other thing that infuriates pain patients is when physicicians (like these two), make CANCER PAIN seem different than other types of pain! Cancer pain involves muscle, nerve and bone, BUT SO DOES AMPUTATION!
    THE ONLY REASON CANCER WAS SUPPOSED TO BE EXEMPT FROM THE 2016 CDC GUIDELINES WAS BECAUSE EVERYONE FEARED THAT THEY WOULD GET CANCER AND DIDN’T WANT TO BE DENIED OPIOIDS!! Well, guess what? The DOJ pays bonuses to the DEA investigators like bounty hunters to check the Prescription Drug Monitoring Databases and target any physician who writes a prescription for opioids and then takes a SWAT TEAM and kicks in the office door (with NO WARRANT), seizes the computers with the patient’s records violating the HIPPA ACT and tells the office staff and nurses that if they don’t testify against the doctor and say he/she was prescribing opioids illegally, then they will be going to prison along with the doctor! So the jury doesn’t know that the witnesses have been threatened and intimidated by the DEA, and they find the doctor guilty. So he/she not only loses their license but they face a jail sentence of 20-150 years, JUST SO THE DEA CAN DO A CIVIL ASSET FORFEITURE WHICH IS OUTRIGHT THEFT & BURGLARY! They take every asset the doctor owns and if there is a wife/husband and children, they are left homeless and destitute!
    BUT MORE HORRIFIC IS THE GENOCIDE BEING COMMITTED AGAINST 126 MILLION CHRONIC INTRACTABLE PAIN PATIENTS! WE ARE HITLER’S GERMANY AND THE DEA IS THE GESTAPO!

    ANOTHER LIE BEING PROPAGATED IS THAT PHYSICICIAN OVERPRESCRIBING CAUSED THE OPIOID EPIDEMIC! PLEASE GOOGLE : THE LAWHERN FILES–FACE FACTS

    WE DON’T HAVE AN OPIOID EPIDEMIC—–WE HAVE WHAT WE’VE ALWAYS HAD– A HEROIN AND ILLEGAL DRUGS COMING OVER THE BORDER AND THROUGH THE POST OFFICE PROBLEM. I’M OLD ENOUGH TO KNOW (67).

    WAKE UP AMERICA, THIS IS NO LONGER THE LAND OF THE FREE! BOTH PARTIES WANT TO OWN YOUR HEALTHCARE, AND UNTIL THEY PASS A LAW REMOVING THE AUTHORITY OF THE DEA TO SUE DOCTORS, NOTHING WILL CHANGE!
    A little post note: The Government is now paying hospitals to stop using opioids for SURGERIES, so if you have to have an operation, get ready to take a Tylenol or Ibuprofen, or in some cases nothing at all!

    • Well said. The opioid epidemic is not driven by physicians. A small percentage of patients become psychologically and physically addicted to opioids. This does not hold the medical community blameless, but it’s not the primary driver of serious addiction.

      I’m allergic to NSAIDS and find Tramadol as effective as lemon water. The only choice I have is opioids. The small does I take is enough to allow me to stand upright and walk. Yet, every day I see the false propaganda about all opioids. I’m made to feel guilty when I renew my RX’s. I have to get short term pre-approvals from my insurer, just to walk.

      Rather than put up with all of that nonsense, I often pay my pharmacy cash. I cannot imagine the suffering patients have with your diagnosis. It’s time for the insurance companies to get the hell out of our physicians offices.

      It’s also time for the right wing crazies to stop pandering to victims of the opioid crisis, and provide funds for better alternatives. More people need these drugs than abuse them.

      I believe in prevention of opioid overdoses by spending the real funds it takes to make a difference.

    • What a wonderful surprise to read a comment written by a fellow Pain Warrior! I wish that more people would read this and comment.

    • The anti pain med scare commercials make me sick. Most people who OD are taking black market “prescription” pills that are actually counterfeit and are laced with fentanal! They look like the real thing. THIS is why the percentage is so high, and the numbers are super inflated!

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