It’s been way too long since there was a new class of drugs to treat depression. Ketamine might be the solution.
By Moises Velasquez-Manoff
In May of 2017, Louise decided that her life was just too difficult, so she’d end it. In the previous four years, three siblings and a half-sibling had died, two from disease, one from fire and one from choking. Close friends had moved away. She felt painfully, unbearably alone. It would be the fourth time Louise (I’m using her middle name to protect her privacy), then 68, would attempt suicide, and she was determined to get it right.
She wrote a letter with instructions on where to find important documents and who should inherit what. She packed up her jewelry and artwork, addressing each box to particular friends and family members. Then she checked into a motel — homes where people have committed suicide lose value and she didn’t want hers to sell below market — put a plastic sheet on the bed, lay down and swallowed what she figured was an overdose of prescription pills with champagne.
A few days later, she woke up in a psychiatric ward in Albuquerque. The motel maid had found her. “I was very upset I had failed,” she told me recently. So she tried to cut her wrists with a bracelet she was wearing — unsuccessfully.
The suicide rate has been rising in the United States since the beginning of the century, and is now the 10th leading cause of death, according to the Centers for Disease Control and Prevention. It’s often called a public health crisis. And yet no new classes of drugs have been developed to treat depression (and by extension suicidality) in about 30 years, since the advent of selective serotonin reuptake inhibitors like Prozac.
The trend most likely has social causes — lack of access to mental health care, economic stress, loneliness and despair, the opioid epidemic, and the unique difficulties facing small-town America. These are serious problems that need long-term solutions. But in the meantime, the field of psychiatry desperately needs new treatment options for patients who show up with a stomach full of pills.
Now, scientists think that they may have found one — an old anesthetic called ketamine that, at low doses, can halt suicidal thoughts almost immediately.
Depression ran in Louise’s family. It had afflicted all her siblings, both of her parents and her grandmother. Prozac had helped Louise for a time, but stopped working for her in the late 2000s, as it sometimes does. No other drug seemed able to lift her dark moods.
After her suicide attempt, Louise’s psychiatrist suggested she try ketamine. She agreed, and received an infusion intravenously. Within hours, her sense of well-being improved. The hospital discharged her. Back home, she discovered that going to the market was no longer a “herculean task.” Getting her car washed wasn’t an insurmountable chore. “Life was better,” she said. “Life was doable.”
Using ketamine to treat depression and suicidality is somewhat controversial. Numerous small studies suggest that it holds great promise, but it’s only now being tested in placebo-controlled trials with hundreds of patients. It is also popular as a club drug in some circles. Like morphine, it may operate on the opioid system, and it can induce feelings of euphoria. Occasionally ketamine abusers develop severe symptoms, including brain damage, persistent hallucinations and a painful inflammation of the bladder called cystitis.
Nonetheless, if proven safe and effective in small doses, ketamine stands to transform how doctors deal with suicidal patients and depression generally.
The drug seems to address a longstanding problem in emergency psychiatry. Sedation and physical restraint aside, doctors have few ways to quickly stop suicidal ideation, or thoughts of killing oneself. The current crop of anti-depressants can take weeks and sometimes months to work, if they work at all. They may also, paradoxically, increase suicidality in some patients. Talk therapy takes time to help as well (assuming it does). Here’s a sobering fact: Some studies indicate that suicide risk peaks soon after patients have been discharged from a medical facility.
Researchers at Yale discovered ketamine’s potential as an antidepressant in the late 1990s and scientists at the National Institute of Mental Health confirmed it the mid 2000s. Numerous studies followed suggesting that the drug helps precisely with that subset of depressive patients — about a third — for whom nothing else works. It doesn’t work for everyone in this group, but when it does, it works within hours, not weeks.
Suicidality doesn’t perfectly overlap with depression. Many people attempt suicide not because they’re clinically depressed, but rather impulsively, because they’ve been fired or they’ve broken up with girl- and boyfriends, or sometimes because they’re just really drunk. I’ve heard people who show up in the hospital in this state — despondent, angry and uninhibited more than depressed — described as “drunkicidal.”
Many are fine once they sober up. For those who aren’t, ketamine may help independent of its effect on depression. And because ketamine is already approved by the Food and Drug Administration, doctors can prescribe it off-label. Meaning that not only does a drug exist right now that could help with depression and suicidality, it’s theoretically available to patients.
I kept thinking about this during the recent spate of high-profile suicides: the chef Anthony Bourdain, the designer Kate Spade, the actress Margot Kidder. Could ketamine have saved any of them? Did they know about it? Did their psychiatrists?
More patients should be aware of this,” Louise told me. “It really is a godsend.”
Earlier this year, I wrote about ketamine and depression for Wired, and patients I interviewed told me some version of the same thing — that ketamine changed their lives and, in some cases, saved it.
Ketamine works differently from other antidepressants. The prevailing theory is that it affects the brain’s glutamate system, which scientists now realize may be involved in depression, rather than the better-known serotonin pathway used by drugs like Prozac. Animal research suggests that partly blocking certain glutamate receptors increases brain plasticity — the ability of the brain to make new neuronal connections — and corrects some of the abnormalities that result from chronic stress. These salutary effects on the brain, coupled with how quickly ketamine works, have inspired a flurry of research. A number of drugs either derived from ketamine, or based on how scientists think it works, are in development. The pharmaceutical company Janssen is working on a nasal spray.
But ketamine has what many view as a major flaw. It can produce dissociative and hallucinatory side effects while it is being administered. Patients can feel as if they’ve left their bodies or that they’re dying. Louise described her first ketamine experience as being like Picasso’s painting “Guernica” — disjointed and unpleasant. But subsequent treatments, she said, were “wonderful” — full of images of birds, fish and whales.
Questions also remain about the safety of long-term use. Depressed patients often have to return for “booster” treatments (Louise finds that she needs an infusion once a month). The drug is considered safe when given once, but no one is sure how repeated doses may affect the brain. And ketamine can be addictive, too.
Nonetheless, dozens of clinics have opened around the country offering ketamine infusions as an off-label treatment for depression. Views on these clinics run the gamut from concerns about profiteering (Louise’s treatments cost $500 out-of-pocket; most insurance companies don’t cover ketamine when it is prescribed off-label) to acknowledgment that they may be helping desperately ill patients.
Dr. Jeffrey Lieberman, the psychiatrist in chief of Columbia University Medical Center, told the health care news site STAT that some patients may be “getting fleeced.”
Dr. Samuel Wilkinson, a Yale psychiatrist who studies ketamine, worries that some of these clinic operators forgo more established treatments to try ketamine. Case in point: Louise refused electroconvulsive therapy, because she remembers it making her mother and grandmother into “living zombies.” In Dr. Wilkinson’s view, patients should strongly consider all other reasonable possibilities before moving to ketamine. (And electroconvulsive therapy, which retains a gruesome reputation, has in fact improved greatly, he said.) He also worries that patients’ suicidal impulses could seem to disappear after ketamine treatment, leading to discharge from the hospital, but then rebound after the ketamine is stopped or tapered — something he’s seen happen in a research setting.
The deeper issue here is one of weighing the risks of new treatment that hasn’t been fully vetted and has unclear long-term side effects against a condition whose primary symptom is the urge to kill oneself.
Dr. Michael Grunebaum, a Columbia psychiatrist who studies ketamine, thinks the drug should no longer be relegated to a last-line treatment. “It makes sense that it move up in the treatment algorithm in E.R.s and inpatient units,” he told me. (Although if emergency rooms everywhere began offering ketamine, it could create new problems, he adds. As has occurred with opioids, people might claim to be suicidal when, in reality, they’re trying to get high.)
The most ringing endorsement of ketamine may come from those on the front lines of medicine: E.R. doctors. I met Louise through a doctor friend, Lowan Stewart, who works at the emergency room in Santa Fe, N.M., where she was first admitted after overdosing. He also treats patients at the ketamine clinic where Louise ended up going. Generally speaking, the protocol in emergency rooms doesn’t include giving suicidal patients ketamine, and he argues that this should change.
His view, informed by the extreme backdrop of the E.R., is worth considering. He regularly sees patients with gunshot and knife wounds, people experiencing psychotic episodes, car accident and drug overdose victims — and of course suicidal patients. Sometimes these patients beg him to kill them. Other times they threaten or attack police officers — an attempt at “suicide by cop.” Once he stabilizes them, he often has to lock them in a padded room for up to 24 hours dressed only in tearable paper pajamas, perhaps sedated, until a psychiatrist arrives. “It’s horrible,” he told me. The reality of a busy E.R. is that these patients often end up crying alone, he said.
E.R. doctors are often quite familiar with ketamine; Dr. Stewart uses it as an anesthetic regularly on children precisely because it’s considered so safe. Now that research has revealed its potential to treat depression and stop suicidal impulses, he thinks that doctors should offer it to suicidal patients in the E.R. “We could help so many people,” he said.
Moises Velasquez-Manoff, the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases” and an editor at Bay Nature magazine, is a contributing opinion writer.
Peter Grinspoon went to rehab for his opioid addiction—and realized that current faith-based abstinence programs often lack scientific research.
Kathy Jean Schultz
11.27.18 5:04 AM ET
We’re in the midst of an opioid epidemic. In the U.S., deaths spiked from 10,000 in 2002 to more than 49,000 in 2017. Canada’s steady uptick in opioid-linked deaths is highest for ages 30-39.
Treatments vary, and most of them use faith-based initiatives to attempt to stem addiction in the bud, and rely on an abstinence-only method.
The problem, say a growing number of scientists, is that these faith-based options don’t work—especially given new knowledge about how addiction affects our bodies through our brains.
The movement to redefine and understand opioid use disorder, or OUD, is welcomed by Peter Grinspoon.
A little more than a decade ago, Grinspoon had the veneer of success. He had a medical degree, a family, and was doing well in his practice. But, as he chronicled in his 2016 memoir, Free Refills: A Doctor Confronts His Addiction, he was hiding a secret: he was addicted to opioids.
Now Grinspoon, who is 11 years sober, is advocating for medication-assisted treatment, called MAT, which combines behavioral therapy with FDA-approved medications to help stem addiction.
Last month, Grinspoon published a post on Harvard Health Blog that questioned the very medical basis of addiction. Titled “Does Addiction Last a Lifetime?,” the post questions what mental health professionals understand about an “addictive personality,” a concept that he argues saddles people with lifelong vulnerability to relapse, or to re-addiction to new substances.
For one thing, he supports the use of buprenorphine. Drugs like buprenorphine lessen withdrawal symptoms and the cravings that lead to relapse and overdose.
While in rehab, Grinspoon was told, ‘A drug is a drug is a drug.’ “This mentality does not allow for a difference between the powerful opiate fentanyl, which kills thousands of people every year, and buprenorphine, which is a widely-accepted treatment for OUD,” he posted.
Grinspoon also sees a problem with the abstinence-only approach many rehabilitation centers have adopted.
“I have come to believe that an uncompromising ‘abstinence-only’ model is a holdover from the very beginnings of the recovery movement, almost 100 years ago, and our understanding has greatly evolved since then,” Grinspoon said. “The concepts of addiction and recovery that made sense in 1935, when Alcoholics Anonymous was founded, and which have been carried on by tradition, might not still hold true in the modern age of neurochemistry and functional MRIs.”
Given the opioid-overdose death rate, “uncompromising” is the key word.
“It seems as if it’s just what we’ve been doing since 1935 because there was nothing else,” he told the Daily Beast. “Now we have multi-faceted approaches to treatment, including the use of drugs like buprenorphine, which fuels OUD recovery.”
The problem, according to Grinspoon, is the very basis by which we think about and treat opioid addiction. “You treat opiate withdrawal differently than you treat alcohol withdrawal,” he said. “Yet the rehabs tend to treat every addiction the same. Most rehab centers are not using cutting-edge science.”
MAT could change that. It includes not only buprenorphine for opioid addiction, but also acamprosate for alcoholism, and naltrexone for opiates and/or alcohol. None of these drug treatments were discovered until recently, and definitely weren’t known in 1935.
But implementing change here is difficult, thanks to court-mandated NA and AA meeting attendance. Courts and probation officers, as well as police, prosecutors and local, state and federal agencies, often order OUD-related offenders to attend abstinence-only, faith-based NA or AA meetings, and have done so for decades. Yet people within the U.S. criminal justice system experience high rates of OUD and overdose, according to a recent Johns Hopkins University study.
That study, published last December in the journal Health Affairs, looked at 72,000 adults in an OUD treatment program, including 17,000 referred by criminal justice agencies.
The researchers found that less than 5 percent of OUD-related offenders ordered into treatment received MAT. In contrast, 40 percent of people referred by employers or healthcare providers received MAT.
That potentially set them up for failure. The study authors found that MAT’s behavioral therapy-fueled approach could decrease overdose risk within the court-ordered population, many of whom lack homes, jobs, medical care or other factors that contribute to OUD upon release from jail. Despite its promise, researchers found that courts were unlikely to refer misusers to MAT.
That doesn’t surprise Grinspoon.
“Judges are vastly under-educated about modern addiction, both the disease and the treatment,” Grinspoon said. “I was forced, by my professional medical society, into a pretty religious 12-step rehab program for 90 days and, as an atheist, I found it counterproductive at best. Judges need to enable people to access modern treatments, not the old-fashioned, non-evidence-based mush that is called ‘treatment’ at many rehab centers.”
Nora Volkow, the Director of the U.S. National Institute on Drug Abuse, agrees. “In general, studies show abstinence-only programs do not work with opioids,” Volkow told the Daily Beast. “There may be some misusers for whom it does work, but in the majority of cases it does not. People with OUD have a very high rate of relapse in abstinence-only programs, and the death rate during relapse can be as high as 90 percent.”
Volkow said that many treatment options don’t take into account the fact that OUD acts differently from that of other disorders from common addictive substances. “What opioids do is to kidnap the system that drives our motivation for survival,” she explained. “For example, if you have not eaten for days your brain will make getting food a priority, for survival. But when you are opioid-addicted your brain is not able to do any of the things we normally do to survive.”
Laura Schmidt is a University of California San Francisco School of Medicine professor who recently wrote a paper published in Drug and Alcohol Review on alternative methods of opioid addiction treatment. She says addiction remains surprisingly misunderstood.
“The addictive-personality concept has pretty much been debunked by research,” Schmidt told The Daily Beast. “The biggest problem now is capacity. We simply don’t have enough treatment slots for everyone who needs them.” Analyses have shown OUDs far exceed treatment need: in 2017, more than 450,000 people with OUD were unable to access treatment.
Schmidt, like Grinspoon, points out that addiction has been freighted by history, ever since the 19th century temperance movement that saw alcohol consumption as abhorrent. “With that framework in place, treatment providers strategically deploy what’s called a moral/medical model, depending upon the patient,” Schmidt explained. “When providers decide patients need to be held morally accountable, they get patients to stay sober by shaming them.
“In the very process of doing that, they continue to promulgate the idea that addiction is the addicts’ fault,” Schmidt added. “Providers think by shaming patients they can get them clean.”
That approach is problematic, and leads to a vicious circle of further stigmatization, which Schmidt said could also lead to the significant barrier to funding treatment patients face in dealing with insurance companies.
It’s something Schmidt has, in fact, seen in her own work.
“I worked on a study of a healthcare organization offering OUD treatment to their members,” Schmidt said. “There was a waiting list, and while people were waiting to enroll in our study, a few were able to receive MAT. They told others on the waiting list that MAT had helped them stay off opioids, and eventually through word-of-mouth, OUD misusers began asking us if they could get into MAT. So the word spread that it helped to quell craving and withdrawal sickness.
“This was really notable to me,” Schmidt continued. “The misusers themselves were more open-minded about treatment alternatives than NA suggestions. They wanted what works.”
Advances in MAT grew out of investigation into the science of brain imaging. Scientists were able to see inside the brain of an addicted person and pinpoint parts affected by drug abuse. The discovery of brain circuits underlying addiction has resulted in development of effective medications — including buprenorphine, naloxone, and acamprosate. One study actually mapped out what appear to be relapse pathways in the brains of opiate-dependent users.
New research has shown how those neural circuits are detectable via functional magnetic resonance imaging, or fMRI. fMRI can show whether oxygen levels and electricity flows inside a misuser’s brain are normal or abnormal. fMRIs have shown how craving contributes to cocaine relapse, for example. Cocaine users’ own feelings of craving matched their fMRI images, which showed activity in the craving area of their brains.
It’s a critical discovery in the science of addiction, one that Schmidt said was “hard to deny.”
Multi-pronged approaches that combine fMRI, recovery program meetings and MAT, along with other new techniques, are beginning to gain acceptance. They’re already in place in states from Washington to Vermont.
But will that actually stem the deaths resulting from the opioid crisis? “There is a pervasive bias in the rehab network against this kind of medicine-assisted treatment,” Grinspoon said—but he’s optimistic that MAT and other medically based treatments might help reverse the upward spike of opioid deaths every year.
Emergency Regulations Effective Immediately
Temporary ID Cards Will be Available for Certified Patients to Purchase Products More Quickly
ALBANY, NY (July 12, 2018) – The New York State Department of Health today announced the filing of emergency regulations adding any condition for which an opioid could be prescribed as a qualifying condition for medical marijuana.
Effective immediately, registered practitioners may certify patients to use medical marijuana as a replacement for opioids, provided that the precise underlying condition for which an opioid would otherwise be prescribed is stated on the patient’s certification. This allows patients with severe pain that doesn’t meet the definition of chronic pain to use medical marijuana as a replacement for opioids.
In addition, the regulation adds opioid use disorder as an associated condition. This allows patients with opioid use disorder who are enrolled in a certified treatment program to use medical marijuana as an opioid replacement.
Plans to add opioid replacement as a qualifying condition for medical marijuana were first announced last month.
“Medical marijuana has been shown to be an effective treatment for pain that may also reduce the chance of opioid dependence,” said New York State Health Commissioner Dr. Howard Zucker. “Adding opioid replacement as a qualifying condition for medical marijuana offers providers another treatment option, which is a critical step in combatting the deadly opioid epidemic affecting people across the state.”
Opioid replacement joins the following 12 qualifying conditions under the state’s Medical Marijuana Program: cancer; HIV infection or AIDS; amyotrophic lateral sclerosis (ALS); Parkinson’s disease; multiple sclerosis; spinal cord injury with spasticity; epilepsy; inflammatory bowel disease; neuropathy; Huntington’s disease; post-traumatic stress disorder; and chronic pain.
These emergency regulations went into effect on a temporary basis on July 12, 2018. The Department also filed a Notice of Proposed Rulemaking on July 12, 2018, commencing the process of permanently adopting the regulations. The permanent regulations will be published in the New York State Register on August 1, 2018, and will be subject to a 60-day public comment period.
In addition, within the next week, certified patients and designated caregivers will be able to print temporary registry ID cards. This will allow them to purchase medical marijuana products more quickly after registering for the program. Patients may use the temporary registry ID card in conjunction with a government issued photo identification to purchase medical marijuana products from a registered organization’s dispensing facility. Prior to this enhancement to the Medical Marijuana Data Management System, it could take 7 to 10 days for patients and their caregivers to receive their registry identification cards after their registration was approved.
Other recent enhancements to New York’s Medical Marijuana Program include adopting new regulations to improve the program for patients, practitioners and registered organizations; authorizing five additional registered organizations to manufacture and dispense medical marijuana; adding chronic pain and PTSD as qualifying conditions; permitting home delivery; and empowering nurse practitioners and physician assistants to certify patients.
As of July 10, 2018, there are 62,256 certified patients and 1,735 registered practitioners participating in the program.
For more information on New York’s Medical Marijuana Program, visit: https://www.health.ny.gov/regulations/medical_marijuana/.
I feel obligated to share the results of my five-year-long investigation into the medical benefits of the cannabis plant. Before I started this worldwide, in-depth investigation, I was not particularly impressed by the results of medical marijuana research, but a few years later, as I started to dedicate time with patients and scientists in various countries, I came to a different conclusion.
Not only can cannabis work for a variety of conditions such as epilepsy, multiple sclerosis and pain, sometimes, it is the only thing that works. I changed my mind, and I am certain you can, as well. It is time for safe and regulated medical marijuana to be made available nationally. I realize this is an unconventional way to reach you, but your office declined numerous requests for an interview, and as a journalist, a doctor and a citizen, I felt it imperative to make sure you had access to our findings.
Mr. Sessions, there is an added urgency, as we are in the middle of a deadly opioid epidemic that has been described as the worst self-inflicted epidemic in the history of our country.
The drug overdose scourge claimed about 68,000 US lives in 2017, just over 45,000 of them from opioids alone. Every day, 115 Americans die from opioid overdoses. It has fueled a decline in an entire country’s life expectancy and will be remembered as a sad and tragic chapter in our collective history.
These are desperate times, and while some may consider making medical marijuana widely available to be a desperate measure, the evidence has become increasingly clear of the important role cannabis can have.
We have seen real-world clues of medical marijuana’s benefits. Researchers from the Rand Corp., supported by the National Institute on Drug Abuse, conducted “the most detailed examination of medical marijuana and opioid deaths to date” and found something few initially expected. The analysis showed an approximately 20% decline in opioid overdose deaths between 1999 and 2010 in states with legalized medical marijuana and functioning dispensaries.
It’s not the first time this association between medical marijuana and opioid overdose has been found. Though it is too early to draw a cause-effect relationship, these data suggest that medicinal marijuana could save up to 10,000 lives every year.
The science of weed
Cannabis and its compounds show potential to save lives in three important ways.
Cannabis can help treat pain, reducing the initial need for opioids. Cannabis is also effective at easing opioid withdrawal symptoms, much like it does for cancer patients, ill from chemotherapy side effects. Finally, and perhaps most important, the compounds found in cannabis can heal the diseased addict’s brain, helping them break the cycle of addiction.
Mr. Sessions, there is no other known substance that can accomplish all this. If we had to start from scratch and design a medicine to help lead us out of the opioid epidemic, it would likely look very much like cannabis.
A better, and safer, way to treat pain
The consensus is clear: Cannabis can effectively treat pain. The National Academies of Sciences, Engineering, and Medicine arrived at this conclusion last year after what it described as the “most comprehensive studies of recent research” on the health effects of cannabis.
Furthermore, opioids target the breathing centers in the brain, putting their users at real risk of dying from overdose. In stark contrast, with cannabis, there is virtually no risk of overdose or sudden death. Even more remarkable, cannabis treats pain in a way opioids cannot. Though both drugs target receptors that interfere with pain signals to the brain, cannabis does something more: It targets another receptor that decreases inflammation — and does it fast.
have seen this firsthand. All over the country, I have met patients who have weaned themselves off opioids using cannabis. Ten years ago, attorney Marc Schechter developed a sudden painful condition known as transverse myelitis, an inflammation of the spinal cord. After visiting doctors in several states, he was prescribed opioids and, according to our calculations, consumed approximately 40,000 pills over the next decade. Despite that, his pain scores remained an eight out of 10. He also suffered significant side effects from the pain medication, including nausea, lethargy and depression.
Desperate and out of options, Schechter saw Dr. Mark Wallace, head of University of California, San Diego Health’s Center for Pain Medicine, where he was recommended cannabis. Minutes after he took it for the first time, Schechter’s pain was reduced to a score of two out of 10, with hardly any side effects. One dose of cannabis had provided relief that 40,000 pills over 10 years could not.
I have seen this firsthand. All over the country, I have met patients who have weaned themselves off opioids using cannabis. Ten years ago, attorney Marc Schechter developed a sudden painful condition known as transverse myelitis, an inflammation of the spinal cord. After visiting doctors in several states, he was prescribed opioids and, according to our calculations, consumed approximately 40,000 pills over the next decade. Despite that, his pain scores remained an eight out of 10. He also suffered significant side effects from the pain medication, including nausea, lethargy and depression.
Desperate and out of options, Schechter saw Dr. Mark Wallace, head of University of California, San Diego Health’s Center for Pain Medicine, where he was recommended cannabis. Minutes after he took it for the first time, Schechter’s pain was reduced to a score of two out of 10, with hardly any side effects. One dose of cannabis had provided relief that 40,000 pills over 10 years could not.
Using marijuana to get off opioids
For Schechter, as with so many others, the seemingly insurmountable barrier to ending his opioid use was the terrible withdrawal symptoms he suffered each time he tried. When a patient stops opioids, their pain is often magnified, accompanied by rapid heart rate, persistent nausea and vomiting, excessive sweating, anorexia and terrible anxiety.
Here again, cannabis is proven to offer relief. As many know, there is longstanding evidence that cannabis helps chemotherapy-induced symptoms in cancer patients, and those symptoms are very similar to opioid withdrawal. In fact, for some patients, cannabis is the only agent that subdues nausea while increasing appetite.
Why we can’t ‘just say no’ to opioids
Finally, when someone is addicted to opioids, they are often described as having a brain disease. Yasmin Hurd, director of the Addiction Institute at Mount Sinai in New York City, showed me what this looks like in autopsy specimens of those who had overdosed on opioids. Within the prefrontal cortex of the brain, she found damage to the glutamatergic system, which makes it difficult for neural signals to be transmitted. This is an area of the brain responsible for judgment, decision-making, learning and memory.
Hurd told me that when an individual’s brain is “fundamentally changed” and diseased in this manner, they lose the ability to regulate opioid consumption, unable to quit despite their best efforts — unable to “just say no.”
It is no surprise, then, that abstinence-only programs have pitiful results when it comes to opioid addiction. Even the current gold standard of medication-assisted treatment, which is far more effective, still relies on less-addictive opioids such as methadone and buprenorphine. That continued opioid use, Hurd worries, can cause ongoing disruption to the glutamatergic system, never allowing the brain to fully heal. It may help explain the tragic tales of those who succeed in stopping opioids for a short time, only to relapse again and again.
This is precisely why Hurd started to look to other substances to help and settled on nonpsychoactive cannabidiol or CBD, one of the primary components in cannabis. Hurd and her team discovered that CBD actually helped “restructure and normalize” the brain at the “cellular level, at the molecular level.” It was CBD that healed the glutamatergic system and improved the workings of the brain’s frontal lobes.
This new science sheds lights on stories like the one I heard from Doug Campbell of Yarmouth, Maine. He told me he had been in and out of drug rehab 32 times over 25 years, with no success. But soon after starting cannabis, he no longer has “craving, desire and has not thought about (opioids) at all, period.”
For the past 40 years, we have been told that cannabis turns the brain into a fried egg, and now there is scientific evidence that it can do just the opposite, as it did for Campbell. It can heal the brain when nothing else does.
I know it sounds too good to be true. I initially thought so, as well. Make no mistake, though: Marc Schechter and Doug Campbell are emblematic of thousands of patients who have successfully traded their pills for a plant.
These patients often live in the shadows, afraid to come forward to share their stories. They fear stigma. They fear prosecution. They fear that someone will take away what they believe is a lifesaving medication.
Where do we go from here?
Mr. Sessions, Dr. Mark Wallace has invited you to spend a day seeing these patients in his San Diego clinic and witness their outcomes for yourself. Dr. Dustin Sulak could do the same for you in Portland, Maine, as could Dr. Sue Sisley in Phoenix. Staci Gruber in Boston could show you the brain scans of those who tried cannabis for the first time and were then able to quit opioids. Dr. Julie Holland in New York City could walk you through the latest research. All over the country, you will find the scientists who write the books and papers, advance the science and grow our collective knowledge. These are the women and men to whom you should listen. They are the ones, free of rhetoric and conjecture, full of facts and truth, who are our best chance at halting the deadly opioid epidemic.
Making medicinal marijuana available should come with certain obligations and mandates, just as with any other medicine. It should be regulated to ensure its safety, free of contamination and consistent in dosing. It should be kept out of the hands of children, pregnant women and those who are at risk for worse side effects. Any responsible person wants to make sure this is a medicine that helps people, not harms.
Recently, your fellow conservative John Boehner changed his mind after being “unalterably opposed” to marijuana in the past. If you do the same, Mr. Attorney General, thousands of lives could be improved and saved. There is no time to lose.
For readers of our newsletter, this post might feel “different” from the others. Usually we like to talk about what you can do to help yourself or your loved one when it comes to addressing substance issues and finding support or treatment that will help changes last. In this post we are going to do something different because we are angry and scared about the misinformation that consumers are faced with everyday as they look for treatment for themselves or someone they care about.
An estimated 2 million Americans are dependent on opioids. The Centers for Disease Control reports that 115 Americans died daily in 2016 from opiate overdoses (42,249 deaths, five times higher in 2016 than 1999), and that 40% of these deaths involved a prescription opiate. Despite this deepening crisis, there is hope that a number of FDA approved, evidence-based Medication Assisted Treatments (e.g., buprenorphine, naltrexone/Vivitrol, methadone) for opioid use disorders can help. Studies have found that these medications support long-term change (including abstinence from opiates) and significantly reduce overdose rates. Yet the traditional drug and alcohol treatment industry has been shockingly slow to support their use. Even more astounding is that many doctors in the treatment industry have not been educated about their effectiveness or trained to use them despite comprehensive efforts such as the Surgeon General’s Report last year reiterating the important role of these treatments.
Why the delay? There continues to be a strong belief in the public and among many treatment providers that if you utilize medication to recover from a drug problem, you are not “really sober”. This bias persists even though mountains of evidence from well-conducted research studies demonstrate that medication-assisted treatments (MATs, like buprenorphine and naltrexone) save lives. Despite their benefits, MATs have been adopted in less than half of private treatment programs. Even in programs that do offer MAT options, only about a third of patients receive them.
In an effort to understand this at the ground level, we decided to do a little experiment. We know that when a family reaches out looking for treatment for a loved one, they are usually vulnerable, scared, and desperate for someone to offer advice and some hope. And often, in their fear, they will take the advice of the first person they speak to, assuming reasonably that that person is educated in substance use and has a clear understanding of current effective treatments. So we did what many people do: an internet search! Just like many desperate families do when they are looking for help. We typed in “top rehabs in the US” and “best rehabs in the country”, created a list of 34 rehabs that came up on these searches, and called them.
We called looking for treatment for “our brother” who was “in trouble with heroin”. In these calls we asked each program the same series of questions about their use of MATs like Vivitrol and Naltrexone (opiate blocking medications), and Suboxone (an opiate maintenance medication), including their treatment policies and stance on these medications. (We asked them a bunch of other questions but that is for another post)! Our mission? To see if the treatment landscape was changing now that multiple studies (over many years!) have found these medications to be life-saving. What we found is disturbing.
Out of the 34 residential programs called, less than 40% (n = 13) of the programs would consider maintaining someone on Suboxone (buprenorphine) or discharging a patient on suboxone. The rest (n = 19) only used Suboxone during detox as a taper medication, while 2 rehabs “never use suboxone”. One of these programs said, “we want to get them off everything, otherwise he would be a hopeless opiate addict for life.”
Hopeless addict for life? Really? Buprenorphine, which is a partial opioid agonist, does activate opioid receptors in the brain but does not produce the maximal effects that full opioid agonists (e.g., heroin) do. It does not produce feelings of euphoria, but it will produce enough effect to quell cravings, provide relief from withdrawal, and satisfy the brain into thinking it is receiving a full agonist. It is protective in lowering overdose risk as it blocks the receptor sites in the brain that opiates would otherwise attach to. It allows many opiate users to build a stable life without fighting off cravings to use everyday and protects them from overdosing if they relapse to opiate use (both “street” opiates like heroin and prescription opiates) while on the medication.
In these 34 contacted programs (“best of the best”!), openness to using Vivitrol was a little higher, with 65% of the rehabs saying that they could consider discharging someone on it. Vivitrol is the intramuscular injection (like a flu shot, for example) of Naltrexone, a medication that blocks opioids from binding with the opioid receptors in the brain, thereby eliminating any sense of a high. It last approximately 4 weeks and multiple studies have found that it contributes to reduced overdose rates among opiate users. It is not an opioid itself (unlike suboxone or methadone), which may account for it’s slightly more positive reception in our surveyed rehabs, by countering some of the (unfounded and stigmatizing) beliefs that an opiate user wanting to be on opioid medication is “just a drug user looking for another drug”.
Unfortunately, of the 12 programs that did not discharge clients on Vivitrol, 4 of them did not even know what it was! One of the programs we called said “We really try and get patients off of everything and we would not want to discharge him on Vivitrol” and another said “I don’t know what that is, but if you spell it for me I can look it up and see if we will use it”. We ask you: does your diabetes doctor not know what insulin is? Does your cancer doctor not believe in chemotherapy?
Many of the inpatient/residential facilities we talked to made comments that showed they do not understand these life-saving medications, that they do not value clients’ experiences or wishes, and that they are using fear and scare tactics to pressure people into treatments that may not be appropriate for them. One intake coordinator said after a 5 minute description of the potential referral, “I don’t want to sound aggressive, but he could die today…” This kind of statement, made after a short phone call and aimed at a scared family, is preying on their fears in an effort to book a client. This is what you’d expect when you’re buying a used car, not what you’re hoping for when you’re looking for help for a life-threatening problem. Several of the programs used other tried and true sales techniques, like transferring callers to many different programs without explanation, or making suggestions that they close the deal and “get on a plane right now.” And others said the fictional brother clearly “needs a lot of treatment, possibly a year,” without offering to speak with him or gathering more information. And “he could die today”? The refusal to consider use of MATs will leave clients treated at these facilities more vulnerable to dying.
In fact, if you seek treatment for an opioid use problem, there is a significant risk that the treatment professional you speak with will either not offer these medications or have ideologically-based opinions about them that negatively influence how you feel about being prescribed them. As many opioid users will attest, there is a sense that you are “just an addict looking for another drug.”
We’ve had countless people come to us at CMC who have been in multiple rehabs and never once were encouraged to be on medicatIon assisted treatments. This is in spite of the data that suggests as many as 90 percent of people detoxed completely off opiates relapse within the first 1-2 months unless treated with these medications.
The takeaway? If you or someone you love is one of the two million Americans estimated to be dependent on opioids, please demand better. Our nation’s opioid struggle is an undeniable tragedy, and is one of the worst public health crises in the nation’s history. It is made all the more tragic by the fact that there are many viable, proven treatments for the problem yet treatment programs continue to refuse to look at the science. This must change if we are to stem the tide of opioid addiction in this nation and prevent more loss of life.
Anyone looking for treatment needs to really investigate the different programs and ask lots of questions. Many people do more research about which car to buy than which treatment program to attend. That needs to be reversed. And clients should enter this process expecting their questions to be answered and answered well! If you’re not sure about something you heard, then it’s probably not right (or the right place for you). Demand better service, and you will have a better experience.
A bipartisan group of senators is introducing legislation Tuesday to address the opioid epidemic, framing it as a follow-up bill to the Comprehensive Addiction and Recovery Act (CARA) signed into law in 2016.
Dubbed CARA 2.0, the legislation includes a host of policy changes, such as establishing a three-day initial prescribing limit on opioids for acute pain, beefing up services to promote recovery and aiming to increase the availability of treatment.
The legislation is a mixture of policy changes and increased funding authorizations, in light of a two-year budget deal passed earlier this month that includes $6 billion for the opioid and mental health crises.
The bipartisan bill includes some measures similar to those removed from the original CARA bill passed in 2016, such as an initiative to bolster youth recovery support services and a provision requiring physicians and pharmacists to use their state prescription drug monitoring program before prescribing or dispensing opioids.
Additionally, the legislation would let states waive the cap on the number of patients a physician can prescribe buprenorphine — a medicine used to treat opioid addiction — and increase penalties for opioid manufacturers failing to report suspicious orders.
CARA 2.0 authorizes $1 billion in additional funding. Some $10 million would fund a national education campaign on opioids; $300 million would increase training for first responders and their access to an opioid overdose reversal drug; another $300 million would expand medication-assisted treatment; and $200 million would help build more recovery support services, for example.
To draft the first CARA bill, Portman and Whitehouse helped convene five national forums comprised of experts on prevention, treatment, law enforcement and recovery.
The opioid epidemic hasn’t shown signs of abating, as overdose deaths increased nearly 28 percent from 2015 to 2016, according to the latest data from the Centers for Disease Control and Prevention (CDC).
On the other side of the Capitol, the House Energy and Commerce Committee is working on legislation aimed at combating the opioid epidemic. Chairman Greg Walden (R-Ore.) hopes to pass the measures out of the House by Memorial Day weekend.
Health and Human Services Secretary Alex Azar is touting medication-assisted treatment (MAT) as a crucial component of stemming the opioid crisis plaguing the nation.
In his first extensive remarks on the opioid epidemic, set to be delivered Saturday, Azar announces two measures aimed at increasing this form of treatment.
“Medication-assisted treatment works,” Azar says in prepared remarks for a session of the National Governors Association’s winter meeting that were shared with The Hill. “The evidence on this is voluminous and ever growing.”
Addiction experts have long touted medication-assisted treatment — which aims to couple medicine with therapy — as a gold standard of treatment for an opioid addiction.
Azar’s remarks Saturday point to the challenge in obtaining this form of treatment. He said that about one-third of speciality substance abuse treatment programs offer MAT, calling failing to do so “like trying to treat an infection without antibiotics.”
“Under this administration, we want to raise that one-third number—in fact, it will be nigh impossible to turn the tide on this epidemic without doing so,” Azar says.
The Trump official says that the Food and Drug Administration (FDA) will release two new draft guidances “soon.”
Buprenorphine is one form of medication-assisted treatment. In November, the FDA approved the first monthly injection of Buprenorphine, aimed at making it easier to adhere to the medication.
The FDA will draft guidance to clarify what kind of evidence manufacturers that are trying to develop new forms of the medication need in order obtain approval for monthly injectable forms of buprenorphine.
The agency will also draft guidance aimed at “encourag[ing] more flexible and creative designs of MAT studies.” Researchers will be tasked with developing new ways to evaluate the effects of MAT formulations.
The opioid epidemic has ravaged areas across the country, and has shown no sign of stopping. Deaths from opioid overdoses increased nearly 28 percent from 2015 to 2016, according to the latest data from the Centers for Disease Control and Prevention.
In late October, President Trump declared the epidemic a public health emergency. Months later, however, some advocates had expressed frustration that it hadn’t led to much concrete action. In mid-January, the administration extended the emergency declaration another 90 days.
Advocates had also been pushing for more funding, saying a robust infusion of federal dollars is needed to curb the crisis.
A budget deal passed earlier this month included $6 billion over two years for the opioid and mental health crises. Trump’s budget proposed $10 billion in funding to address the opioid epidemic for fiscal 2019.
Congress will also examine bills aimed at curbing the epidemic, as the House Energy and Commerce Committee will kick off its legislative push on Wednesday.
The anesthesia medication ketamine has shown promise in treating depression, but its exact effects on the brain are unclear. Now, researchers have discovered that the drug changes the firing patterns of cells in a pea-size structure hidden away in the center of the brain. This could explain why ketamine is able to relieve symptoms of depression so quickly—and may provide a fresh target for scientists developing new antidepressants.
“It’s a spectacular study,” says Roberto Malinow, a neuroscientist at the University of California, San Diego, who was not involved in the work. “It will make a lot of people think.”
In clinical trials, ketamine appears to act much faster than existing antidepressants, improving symptoms within hours rather than weeks. “People have tried really hard to figure out why it’s working so fast, because understanding this could perhaps lead us to the core mechanism of depression,” says Hailan Hu, a neuroscientist at Zhejiang University School of Medicine in Hangzhou, China, and a senior author on the new study.
Hu suspected the drug might target a tiny region in the middle of the brain called the lateral habenula, the so-called “anti–reward center.” This region inhibits nearby reward areas, which can be useful in learning; for example, if a monkey pulls a lever expecting a treat but never receives it, the lateral habenula will reduce the activity of reward areas, and the monkey will be less likely to pull the lever in the future. But research over the past decade has suggested that the area may be overactive in depression, dampening down those reward centers too much.
In a series of experiments using mouse and rat models of depression reported today in Nature, Hu and her colleagues found that ketamine did affect the lateral habenula—but it was the pattern of firing, rather than the overall amount of activity, that proved crucial. A small proportion of the neurons in the lateral habenula fire several times in quick bursts, rather than firing once at regular intervals; the team found that “depressed” rodents had a lot more of these quick burst cells. In brain slices from normal rats, only about 7% of cells were the bursting type, but in rats bred to display depressionlike behavior, the number was 23%.
Direct recordings from the neurons of live mice showed the same pattern: Animals that had gone through a stressful procedure had more bursting cells in the lateral habenula. And, importantly, this bursting behavior appeared to cause depressionlike states. When researchers used optogenetics—a technique that allows cells to be switched on and off with light—to increase the amount of bursting in the lateral habenula, mice behaved in a more “depressed” way, remaining motionless when forced to swim in a container of water, for example. This kind of despair is thought to be similar to the feelings of hopelessness experienced in depression.
When “depressed” mice and rats were given ketamine, the number of bursting cells was much lower, similar to the number in normal animals, Hu’s team found. And even when the researchers forced the neurons to fire in bursts, animals that had been given ketamine no longer showed depressionlike behaviors.
Hu says that neurons firing several times in quick succession produce a more powerful signal. This means that bursting cells may be sending particularly strong messages to dampen down activity in reward areas, which could lead to depression. “Bursting has a special kind of signaling power,” Malinow says. “You get more bang for your buck.”
The findings could also explain why ketamine acts so quickly. By immediately blocking bursts in the lateral habenula, the drug releases the reward areas from those strong signals. This suggests that other drugs that reduce burst firing could also alleviate depression, whether they act on the same receptors or different ones. “Anything that can block the bursting … should be a potential target based on our model,” Hu says. In an accompanying paper, her team reports that a protein found on astrocytes, another type of brain cell that interacts closely with neurons, could be one of these targets.
Panos Zanos, a neuropharmacologist at the University of Maryland in Baltimore, says the immediate effects of the drug in the lateral habenula were interesting. “I’m very excited … to see whether this [also] applies to the long-lasting antidepressant effects of ketamine,” he says. “This is a great study that adds to the literature on how ketamine might work.”
The British Journal of Psychiatry, Volume 2 February 2018, pp. 103-111
Depression contributes to persistent opioid analgesic use (OAU). Treating depression may increase opioid cessation.
To determine if adherence to antidepressant medications (ADMs) v. non-adherence was associated with opioid cessation in patients with a new depression episode after >90 days of OAU.
Patients with non-cancer, non-HIV pain (n = 2821), with a new episode of depression following >90 days of OAU, were eligible if they received ≥1 ADM prescription from 2002 to 2012. ADM adherence was defined as >80% of days covered. Opioid cessation was defined as ≥182 days without a prescription refill. Confounding was controlled by inverse probability of treatment weighting.
In weighted data, the incidence rate of opioid cessation was significantly (P = 0.007) greater in patients who adhered v. did not adhered to taking antidepressants (57.2/1000 v. 45.0/1000 person-years). ADM adherence was significantly associated with opioid cessation (odds ratio (OR) = 1.24, 95% CI 1.05–1.46).
ADM adherence, compared with non-adherence, is associated with opioid cessation in non-cancer pain. Opioid taper and cessation may be more successful when depression is treated to remission.
Long-term prescription opioid analgesic use (OAU) for chronic non-cancer pain is defined as ‘daily or near-daily’ use for >90 days.1,2 Between 1.4 and 10% of patients with a new opioid prescription develop chronic OAU,2,3 and a majority, 65–80%, of patients who have >90 days OAU, are still taking opioids 3–5 years later.4,5 These patients are more likely than those who take opioids short term to develop opioid use disorder and overdose. Chronic OAU is also associated with new depressive episodes (NDEs)3,6,7 and treatment-resistant depression.6 Because depression and OAU are mutually reinforcing,8 these patients may be in a cycle of persistent OAU, depression and pain. Research on treating depression to improve outcomes for chronic non-cancer pain is sparse. In Kroenke et al‘s9 Stepped Care for Affective Disorders and Musculoskeletal Pain (SCAMP) study, where patients were randomised to optimal depression treatment v. usual care, treating depression led to reduced pain severity and anxiety, improved functioning and better health-related quality of life.9 Although SCAMP was not designed to measure change in OAU, the findings raise the possibility that depression treatment could reduce use of opioids, possibly from reduced pain or improved functioning.9–11 Improved functioning can occur independent of pain11 and should follow depression treatment. Independent of changes in pain severity, the need for OAU to self-regulate mood should dissipate following reduction in depression.
We are not aware of any studies that report changes in OAU following adherence to antidepressant medication (ADM) treatment in patients with chronic non-cancer pain. Using a retrospective cohort design, it is possible to test the hypothesis that adherence to ADM treatment v. non-adherence is associated with OAU cessation without the ethical barrier of randomising to inadequate treatment. Adherence serves as an indicator of depression improvement because patients who are non-adherent are less likely to have decreasing depression symptoms.12 Among patients initiating ADMs, response to treatment by 24 weeks is much lower in non-adherent v. adherent patients (55.8 v. 82.5%).13 Although it would be ideal to have 9-item Patient Health Questionnaire (PHQ-9)14 scores for all patients at the time of ADM initiation and opioid cessation, such data was available from only a subset of patients. Therefore, we used adherence as a proxy for depression improvement. In a large cohort of Veterans Health Administration patients with NDE following >90 days of OAU, we tested the hypothesis that depression treatment adherence was associated with OAU cessation. Specifically, the objective of the current study was to determine whether patients who developed depression following chronic OAU were more likely to stop using opioids if they adhered to ADM treatment compared with patients who did not adhere to ADM treatment. In addition, exploratory analysis in a subset of patients with sufficient data was computed to assess the change in depression symptoms and pain scores over time in patients adherent to treatment with ADM compared with those who were non-adherent who did and did not stop OAU.
This retrospective cohort analysis used patient data extracted from the Veterans Health Administration electronic medical record for 1 Jan 2000 to 31 Dec 2012. Data included ICD-9-CM diagnostic codes,15 in-patient stays, out-patient visits, prescriptions dispensed records, vital signs and demographic information.
A random sample of 500 000 patients was taken from a cohort of 2 910 335 identified with at least one out-patient visit in both fiscal years 1999 and 2000, and aged 18–80 years. We excluded patients over 80 because they are more likely to receive prescription opioids for end-of-life pain management and cancer pain and the risk of misclassifying depression increases because of the greater prevalence of vascular depression and depression related to dementia. From this sample, we excluded 151 500 patients with a cancer and/or HIV diagnosis. Patients must have had at least one yearly visit in the 2-year ‘washout’ period (2000–2001) during which they must have been free of a medical record depression diagnosis (n = 266 901). We then selected patients with a NDE beginning in 2002–2011 and not occurring on the last out-patient visit date (n = 31 224). Because our previous reports indicate >90-day OAU is associated with up to twice the risk of NDEs,3,7 we limited the cohort to patients with >90 days of OAU or by the date of the NDE (n = 3075).
NDE was defined by the presence of a primary diagnosis (ICD-9-CM: 296.2, 296.3, 311) of depression in at least one in-patient stay or two out-patient visits within the same 12-month period. This algorithm has been shown to be a valid measure of depression when compared with self-report or written medical record information.16,17 Patients without ADM treatment on or after the NDE were excluded (n = 138). Patients must have had >3 months follow-up after NDE diagnosis to allow for the possibility of the occurrence of least one acute-phase depression treatment period (≥84 days)18 (n = 2843). The final sample included patients with complete demographic data (n = 2821). The cohort selection process is shown in Fig. 1.
Outcome – opioid cessation
Opioids included codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, oxycodone, oxymorphone, morphine and pentazocine. Both short-acting and long-acting formulations were included. Opioid prescription information included days supplied, quantity (e.g. pills or liquid volume) and unit dose (mg). OAU cessation was defined as a gap of at least 182 days from the end date of the last prescription.5 OAU cessation date was the first day of this gap.
Exposure – ADM adherence
ADMs included monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclics (TCAs) and non-classified ADMs. ADM adherence was defined using proportion of days covered (PDC) from NDE to opioid cessation or censor date.19,20 ADM prescriptions dispensed were used to create time arrays to identify days of follow-up that an ADM was available. If multiple ADMs were available in a day, that particular day was only counted once as a covered day. The PDC was calculated by taking the total number of covered days in follow-up by the total number of days in follow-up. PDC was dichotomised to standard thresholds for adherence (≥80%) and non-adherence (<80%).19–21 To determine if patient adherence was correlated with duration of ADM treatment, we computed the number of continuous weeks of treatment. ADM use was considered continuous if there was no gap of >30 days between prescriptions dispensed and duration for all periods of continuous use in follow-up were assessed to categorise duration as ever ≥24 weeks, 12 to <23 weeks or <12 weeks.
We included an OAU duration variable to control for duration of use at the date of NDE (3–6 months, >6 to 12 months, >12 to 24 months, >24 months). Duration was computed from the months of continuous OAU (no gap >30 days between prescriptions dispensed). The opioid morphine equivalent dose (MED) was calculated using standard conversion tables. Days supplied and quantity variables were used to calculate daily MED in follow-up. We modelled the maximum daily MED before the end of follow-up (1–50 mg, 51–100 mg, >100 mg). We controlled for comedication with benzodiazepines, which are associated with long-term opioid use,22 and muscle relaxants, which could improve pain and functioning. Benzodiazepines included alprazolam, clonazepam, diazepam, lorazepam, chlordiazepoxide and clorazepate. Muscle relaxants included carisoprodol, cyclobenzaprine, baclofen, dantrolene, metaxalone, methocarbamol, chlorzoxazone, tizanidine and orphenadrine. Demographic variables included age, gender, ethnicity (white v. other), marital status (married v. other) and insurance coverage (Veterans Health Administration only v. other sources).
To control for detection bias related to more healthcare encounters, we created a healthcare utilisation variable defined as average number of out-patient clinic visits per month in follow-up. The distribution of the mean was then dichotomised into high utiliser, >75th percentile, v. low utiliser, ≤75th percentile. We controlled for psychiatric and physical comorbidities associated with depression23 and/or OAU.24–26 Comorbidities were defined using ICD-9-CM diagnostic codes. Psychiatric comorbidities included post-traumatic stress disorder and any other anxiety disorder, a composite of panic disorder, generalised anxiety disorder, social phobia, obsessive–compulsive disorder and anxiety disorder not otherwise specified. We controlled for alcohol misuse or dependence; illicit drug misuse or dependence, including opioids; and nicotine dependence. Chronic physical conditions included type 2 diabetes mellitus, hypertension, cerebrovascular disease, obesity, low testosterone, sleep apnoea and cardiovascular disease. Cardiovascular disease was a composite of hyperlipidaemia, ischaemic heart disease, disease of pulmonary circulation, other heart disease, hypertensive heart disease and myocardial infarction.
Five separate pain condition variables were created based on over 900 ICD-9-CM codes.7,24 These conditions were arthritis, back pain, musculoskeletal pain, headaches and neuropathic pain. Pain scores, collected during routine care in the Veterans Health Administration, were on a numerical rating scale ranging from 0 to 10, with higher scores indicating greater pain intensity. In propensity score models, we adjusted for a time invariant maximum pain score before the end of follow-up to control for the highest pain level. As variability in pain scores in the Veterans Health Administration have been previously reported,27 a time-varying pain score for each month of follow-up was used in final survival models. For the time-varying pain score assessment, the pain score was assumed to be consistent across subsequent months until a new monthly assessment was available.
Propensity scores and inverse probability of treatment weighting (IPTW) were used to balance potential confounders listed in Table 1 between ADM adherent and non-adherent treatment groups to reduce the effect of bias by indication and other sources of confounding. The propensity score is the probability of ADM adherence, given covariates and was calculated using a binary logistic regression model. Propensity scores were used to apply IPTW approaches using stabilised weights.28–33 A stabilised weight is the marginal probability of ADM adherence divided by the propensity score for the adherent group, and (1 – marginal probability of ADM adherence) divided by (1 – propensity score) for the non-adherent group. It helps reduce bias associated with extreme weights of either individuals in the ADM adherent group with low propensity scores or those in the non-adherent group with high propensity scores. Extreme weights are associated with increased variability of the exposure effect, thus, stabilising weights helps reduce type II error rate.34 Stabilised IPTW also preserves original sample size (i.e. does not inflate sample size in pseudo-data) in analysis thereby also preserving the type I error rate.33 Stabilised weights were trimmed if they were ≥10, as well-behaved weights have a mean close to 1 and a maximum <10.30,35 The mean of stabilised weights should be close to 1, extreme values indicate the propensity-score model poorly specified predictors of treatment exposure. IPTW resulted in pseudo-populations for ADM adherence groups such that covariates balanced across the two groups. Covariate balance was assessed by comparing covariate distributions between ADM adherence groups. Balance is indicated with no significant differences in the distribution of covariates between groups and by standard mean differences <10%.34,36
Table 1 Characteristics of patients with long-term opioid use with a new depression episode (NDE) by antidepressant medication (ADM) adherence status in unweighted data, 2002–2012 (n = 2821)
Results in bold are significant.
SMD %, standardised mean difference per cent.
a.Other anxiety disorders: panic disorder, obsessive–compulsive disorder, social phobia, generalised anxiety disorder, anxiety not otherwise specified.
b.Cardiovascular disease, hyperlipidaemia, ischaemic heart disease, diseases of pulmonary circulation, other heart disease, hypertensive heart disease, myocardial infarction.
Analyses were performed with SAS v9.4 at an alpha of 0.05. Bivariate analyses, using independent samples t-tests for continuous variables and chi-square tests for categorical variables, assessed the relationship of covariates with ADM adherence in unweighted and weighted data. A Poisson regression model was used in unweighted and weighted data to compare opioid cessation incidence rate (person-years) between ADM adherence groups. Unweighted and weighted Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for the relationship of ADM adherence and time to opioid cessation. Weighted analyses used stabilised weights in probability weighting. Confidence intervals and P-values in weighted analyses were calculated using robust, sandwich-type variance estimators. Follow-up time was defined as months from date of NDE to date of OAU cessation or censor date, which was the last available Veterans Health Administration encounter.
The final model included variables to control for pain diagnoses and changing pain score after the initiation of ADM treatment. All pain variables and ADM adherence were modelled as time dependent. This allows ascertainment of exposure status over the multiyear observation period and permits new diagnoses and change in pain scores to contribute to the outcome. Initial evaluation of each interaction term of each covariate and follow-up time confirmed that the proportional hazards assumption was met for ADM adherence (P = 0.11) and pain covariates (P > 0.05).
This project was approved by the institutional review boards of participating institutions.
In unweighted data, the average monthly change in PHQ-9 score and pain score across follow-up was computed using random intercept longitudinal mixed models (Proc Mixed, SAS v9.4) for four groups; (a) ADM adherent with OAU cessation (n = 5 PHQ-9; n = 213 pain scores), (b) ADM adherent without OAU cessation (n = 96 PHQ-9; n = 864 pain scores), (c) ADM non-adherent with OAU cessation (n = 14 PHQ-9; n = 354) and (d) ADM non-adherent without OAU cessation(n = 147 PHQ-9; n = 1390 pain scores). Because of the lack of PHQ-9 data prior to 2008, monthly changes in PHQ-9 scores in follow-up were computed for a subset of 262 patients with NDE occurring in 2008–2012 and with at least one PHQ-9 score before end of follow-up. Time was modelled as months since NDE and models included all available pain and PHQ-9 data in follow-up.
In unweighted data, a Fisher’s exact test of independence revealed ADM adherence and duration were highly related (P < 0.0001, results not shown). Among 1077 patients who were adherent, 0.2% received continuous ADM for less than 12 weeks, 4.4% received an ADM for 12 to <24 weeks and 95.5% for at least 24 weeks. Among 1744 patients who were non-adherent, 15.0% received ADM for less than 12 weeks, 19.0% for 12 to <24 weeks and 66.1% for at least 24 weeks.
Figure 2 shows that the overall unweighted incidence rate for OAU cessation was 48.4 per 1000 person-years, with no significant differences between ADM adherent (50.2/1000 person-years) and non-adherent (47.4/1000 person-years) groups (P = 0.496). However, after weighting data using IPTW techniques, the incidence rate of OAU cessation was higher for ADM adherent (57.2/1000 person-years) compared with non-adherent (45.0/1000 person-years ) groups (P = 0.007).
ADM, antidepressant medication.
Fig. 2 Antidepressant adherence, non-adherence and prescription incidence of opioids.
Unweighted distributions of covariates by ADM adherence are shown in Table 1. Among those individuals taking opioids for >90 day with a NDE receiving ADM treatment, almost half (46.9%) had taken opioids for more than 2 years (>24 months) at the time of the NDE. Almost two-thirds (63.0%) reached a maximum MED of >100 mg. Maximum dose achieved was similar (P = 0.704) in ADM adherent and non-adherent groups. Benzodiazepine comedication with ADM was significantly more prevalent among ADM adherent (59.0%) v. non-adherent (53.6%) groups. Comorbidities that were significantly more prevalent among ADM adherent compared with non-adherent groups were post-traumatic stress disorder, type 2 diabetes, hypertension, cardiovascular disease, low testosterone and sleep apnoea. Alcohol and illicit drug misuse/dependence were more prevalent among the non-adherent group. Patients in the ADM adherent compared with the non-adherent group were significantly older, White, married, more likely to have other insurance in addition to Veterans Health Administration insurance and have higher healthcare utilisation.
After applying IPTW, all covariates balanced and were not significantly different between the ADM adherent and non-adherent groups (Table 2). IPTW stabilised weights ranged from 0.54 to 3.15, with a mean of 1.00 (s.d. = 0.25) and median of 0.95 (interquartile range (IQR) = 0.83–1.11). The standardised mean differences (SMDs) after weighting were all <10%. Good balance was achieved given differences between treatment groups were all non-significant and all SMDs were <10%.
Table 2 Weighted association of covariates with antidepressant medication (ADM) treatment adherence, weighted by inverse probability of ADM treatment adherence, in patients with chronic opioid use (>90 days) at time of new depression episode (NDE, 2002–2012; n = 2821)
SMD %, standardised mean difference per cent.
a.Other anxiety disorders: panic disorder, obsessive–compulsive disorder, social phobia, generalised anxiety disorder, anxiety not otherwise specified.
b.Cardiovascular disease, hyperlipidaemia, ischaemic heart disease, diseases of pulmonary circulation, other heart disease, hypertensive heart disease, myocardial infarction.
Results of unweighted and weighted Cox proportional hazards models estimating the association between ADM adherence and time to OAU cessation are shown in Table 3. In unweighted data, there was no relationship of ADM adherence and time to OAU cessation (hazard ratio (HR) = 1.05, 95% CI = 0.88–1.24). However, after weighting and adjusting for changes in pain scores and pain diagnoses that could occur after ADM initiation, adherence was associated with a 24% increased likelihood of OAU cessation compared with non-adherence (HR = 1.24, 95% CI = 1.05–1.46)
Table 3 Results from Cox proportional hazards models estimating the association between antidepressant medication (ADM) adherence and opioid cessation among patients with chronic opioid use ( (>90 days) with a new depression episode (NDE, 2002–2012) (n = 2821).
Results in bold are significant.
b.Inverse probability of adherence weighted data to control for confounding factors shown in Table 1.
c.Additional adjustment for painful conditions and pain scores after date of ADM initiation.
Longitudinal linear growth curves for PHQ-9 score among a subset of 262 patients by ADM adherent and OAU cessation groups are shown in Fig. 3(a). At time of NDE, mean PHQ-9 scores were not significantly different between groups (P = 0.995). Overall, there was a trend for a monthly decrease in PHQ-9 score (P = 0.08). Average monthly decrease in PHQ-9 scores was largest for the ADM adherent group with OAU cessation (β = −0.60, 95% CI −1.33 to 0.12) followed by the ADM non-adherent group with OAU cessation (β = −0.21, 95% CI −0.53 to 0.10), ADM adherent group without OAU cessation (β = −0.13, 95% CI = −0.21 to −0.04), and ADM non-adherent group without OAU cessation (β = −0.06, 95% CI −0.12 to 0.01). However, time trend slopes were not statistically different (P = 0.23).
The four study groups were antidepressant medication (ADM) adherent, opioid continuation; ADM adherent, opioid cessation; ADM non-adherent, opioid continuation; and ADM non-adherent, opioid cessation.
Fig. 3 Change in (a) 9-item Patient Health Questionnaire (PHQ-9) scores and (b) pain scores over time in the study groups.
Longitudinal linear growth curves for pain scores in follow-up among the entire sample of 2821 patients are shown in Fig. 3b. The ADM non-adherent group with OAU cessation had significantly higher pain scores than the other three groups at time of NDE (P = 0.0003). Results indicated there was an overall significant monthly decrease in pain score across follow-up (P = 0.002) and that these monthly changes were different between groups (P = 0.01), however, these changes were relatively flat (β range −0.0004 to 0.009).
In a cohort of 2821 Veterans Health Administration patients who developed NDE after >90 days of prescription OAU and who received at least one ADM prescription, we observed adherence v. non-adherence to ADM treatment was associated with a 24% greater likelihood of opioid cessation. The ADM adherent v. non-adherent group had a significantly greater incidence rate of OAU cessation (57.2/1000 v. 45.0/1000 person years; P = 0.007). These results were observed after balancing factors associated with ADM. We also controlled for confounding by pain that could persist during ADM treatment.
Exploratory analysis indicates that the ADM adherent group who stopped taking opioids experienced a rapid and greater decline in depression symptoms compared with patients who did not stop taking opioids, regardless of adherence; however, these results are preliminary because cell sizes were very small for OAU cessation groups. Monthly pain scores were significantly higher among the ADM non-adherent group with OAU cessation compared with the other ADM adherent, non-adherent/opioid cessation-no cessation groups, but the size of the difference was not clinically meaningful. Adjusting for maximum pain scores after ADM initiation in the full Cox proportional hazard models did not change the association between ADM adherence and opioid cessation. Together, these results provide preliminary evidence that a reduction in depression may lead to OAU cessation. Stronger evidence indicates change in pain scores does not explain the association between ADM adherence and opioid cessation.
Interestingly, ADM adherent and non-adherent groups who stopped OAU had the steepest reductions in depression symptoms across follow-up. Because response to antidepressant treatment is markedly greater in those individuals who are adherent v. non-adherent,12,13 we speculate people who are ADM non-adherent may have decreased PHQ-9 scores because of OAU cessation. This would be consistent with the evidence for a bidirectional relationship between OAU and depression.8 Prospective studies are warranted to verify this finding.
Patients with comorbid pain and depression may remain on opioids in an attempt to self-medicate mood37 and to avoid depression during opioid withdrawal.38 Patients with depression are more likely to drop-out of opioid taper, and withdrawal symptoms are exacerbated in patients with current depression.38 Thus, another explanation for our findings may be related to improved depression leading to decreasing attempts to self-medicate mood and greater probability of completing opioid taper.
ADM adherence may be a proxy for overall adherence to medical treatment, the ‘healthy adherer’ effect.39 These patients may adhere to physician instructions to end OAU, adhere to other forms of pain management or begin opioid substitution treatment.
It is possible that unmeasured confounders were not included in the propensity score and we violated the exchangeability assumption.34 For instance we do not have personality measures or indicators of an orientation toward health that might predict both adherence to antidepressants and contribute to opioid cessation. Thus, unmeasured confounding is a limitation. The cohort was a majority male, Veterans Health Administration patient population, which could limit generalizability to non-Veterans Health Administration patients. However, we have previously found that the association between duration of OAU and NDEs in Veterans Health Administration patients was replicated in two private-sector cohorts,3 and the association between opioid use v. no use and risk of depression recurrence in Veterans Health Administration patients was replicated in a private-sector cohort.40 This suggests our findings could be replicated in private-sector cohorts. OAU was based on prescriptions dispensed and we were unable to determine whether patients took their medication as prescribed. Some OAU could be misclassified if patients transitioned to non-Veterans Health Administration or illicit sources for opioids.
Some antidepressants such as TCAs and duloxetine are used in pain management,41,42 but ADM management for analgesia is not designed to treat depression. Our conclusions were consistent in post hoc analysis comparing adherence to TCAs/duloxetine only v. adherence to other ADMs, indicating our findings were not as a result of adherence to only ADMs commonly used in pain management.
ADM adherence was associated with increased likelihood of OAU cessation in individuals with chronic use of opioids and this association was independent of duration of opioid use, maximum MED, pain and numerous comorbid conditions. Several studies have reported that the majority of people who take opioids for >90 days remain on opioids for 3–5 years.4,5 In our cohort, 47% took them for >2 years. Thus, OAU cessation following adherent ADM treatment occurred in a patient cohort with a low probability of OAU cessation. We computed the number-needed-to-treat and found for every 20 patients adherent to ADMs, one patient will stop OAU who would not have stopped if they were non-adherent.
Treatment of opioid dependence in patients with comorbid depression may be successful following effective depression treatment. Preliminary evidence suggests OAU cessation may also contribute to improvement in depression. Therefore, opioid taper paired with ADM could result in a faster reduction of depression symptoms and increase likelihood of successful OAU cessation. Prospective data collection to obtain detailed depression and functioning measures, change in OAU and treatment trials are needed to confirm our findings.
This study was supported by the National Institute of Mental Health, Prescription Opioid Analgesics and Risk of Depression, R21MH101389. The funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The views expressed in this paper do not necessarily reflect those of the Veterans Health Administration.
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APA Releases New Practice Guideline on AUD Pharmacotherapy
APA today released a new practice guideline for the pharmacological treatment of alcohol use disorder (AUD). Despite the high prevalence of AUD and its significant public health consequences, patients with this disorder remain undertreated.
“This new guideline is an important step in bringing effective, evidence-based treatments for alcohol use disorder to many more people and in helping address the public health burden of alcohol use,” APA President Anita Everett, M.D., said in a press release.
The guideline aims to increase physician and public knowledge on the effectiveness and risks of the five medications that may be used for the treatment of AUD: acamprosate, disulfiram, gabapentin, naltrexone, and topiramate.
Of these five, naltrexone and acamprosate have the best available evidence related to their benefits, and both have minimal side effects. As such, they should be considered the preferred pharmacological options for patients with moderate to severe AUD who want to reduce drinking or achieve abstinence. However, acamprosate should be avoided in patients with significant renal impairment, and naltrexone should be avoided in patients with acute hepatitis or liver failure, or in patients currently taking opioids or who may be expected to take opioids.
Disulfiram, gabapentin and topiramate are also options for treatment of AUD but should typically be considered after trying naltrexone and acamprosate, unless the patient has a strong preference for one of these medications. Disulfiram is a special case as it does cause a series of adverse reactions if alcohol is consumed within 12 to 24 hours of taking the medication; the reactions include elevated heart rate, flushed skin, headache, nausea, and vomiting. Therefore, disulfiram is suggested only to patients who wish to achieve abstinence from drinking. Patients taking topiramate are at an increased risk of cognitive dysfunction, dizziness, and loss of appetite, whereas patients taking gabapentin may experience fatigue, insomnia, and headache.
While the guideline focuses specifically on evidence-based pharmacological treatments for AUD, it also includes recommendations and suggestions related to psychiatric evaluation of patients with AUD and developing a person-centered treatment plan. Evidence-based psychotherapeutic treatments for alcohol use disorder also play a major role in treatment and peer support groups such as Alcoholics Anonymous, and other 12-step programs can be helpful for many patients. However, specific recommendations related to these treatments are outside the scope of this guideline.