Something New: Tianeptine




One of my doctor friends called me to ask if I’d seen any patients addicted to tianeptine. No, I had not. This was a new one for me, so I did some internet research for my readers.

Tianeptine is a medication used to treat depression, though some sources say it can be used for asthma and irritable bowel syndrome. Though structurally similar to tricyclic antidepressants, it exerts its action in a different way, via glutamate receptors. Other antidepressants are thought to work because they increase serotonin and norepinephrine levels, so tianeptine is novel in this sense.

Scientists know depression causes structural and functional changes in the brain, and some articles about tianeptine say this medication can reverse some of the stress-induced changes seen in depressed brains. We don’t fully understand all aspects of neurotransmitters and mood, and this medication shows us that serotonin and norepinephrine are not the only determiners of mood. [1, 2]

It’s an interesting medication, but not available in the U.S., Canada, or the United Kingdom. It is sold in Europe under the brand names Coaxil and Stablon. It appears to be more toxic to the liver than traditional antidepressants. And of course, if you Google tianeptine, you will see websites offering to sell it, with the fine of print of “not for human consumption,” with a wink and a nod, to protect the sellers, I assume. Mostly sites sell it in a powder form.

But what about this medication’s addictive potential? Why would people take it compulsively?

When I want to know how people are using various drugs, I go to several websites, including erowid, bluelight, and drugs-forum ( , , On these sites, people record their experiences with various medications used for euphoria, and occasionally for other reasons too.

On these sites, people described a euphoria similar to opioids, though the described dose was usually far in excess of the recommended 12.5mg three times daily. One person took 500mg and described euphoria. Other people mixed it with other drugs, so it’s hard to know what effect the tianeptine had. Other people described a difficult withdrawal from tianeptine.

Kesa et. al., 2007, says tianeptine has some stimulating activity at the mu opioid receptors, thought it has a low affinity for those receptors. Apparently it takes high doses to produce euphoria, moderated through those opioid receptors.

In the Annals of Internal Medicine, 2003, Leterme et al describe five cases of tianeptine abuse. Withdrawal was said to be difficult, due mostly to anxiety.

Bence et al, Pediatrics, 2016, published a case study about a pregnant woman who was taking tianeptine, more than 650mg per day. Unexpectedly, her newborn had a withdrawal syndrome indistinguishable from opioid withdrawal, which was when her doctors discovered her tianeptine use. The baby was treated with morphine, and no mention is made of treatment for the mother until her next pregnancy, when she was admitted to a residential detox unit in her seventh month of pregnancy. Other than low birth weight, her second infant was delivered at full term with no withdrawal. Both children appear to have normal development.

From the collective experiences I read, it seems tianeptine is a weak opioid agonist, but at high doses gives an opioid effect. It sounds like people describe a typical opioid addiction after using these high doses daily for more than a few weeks. They described classic signs and symptoms of opioid withdrawal.

The doctor friend who first called me about this drug worked at an opioid treatment program. The tianeptine-consuming patient he was seeing wanted to be started on buprenorphine or methadone to treat tianeptine withdrawal. I told my friend I didn’t know enough about the drug to feel it was OK to try buprenorphine or methadone.

Since then I’ve done more research, and I suspect buprenorphine or methadone could help treat these patients, but I didn’t see any studies about their use for this addiction.

Particularly with methadone, if we prescribe it to people without a clear indication, they could later get nasty and angry about being started on methadone, a difficult drug to taper off of.

I’d like a need for a study of tianeptine-addicted patients, to see if using classic opioid use disorder treatment medications work for these patients.

Tianeptine could become the latest fad drug. Some drugs fade in and out of popularity, like the latest style of dress or music. I think this one could be a harmful fad, and we have no research about treatment.

  1. Kasper et. al., “Neurobiological and clinical effects of the antidepressant tianeptine,” CNS Drugs, 2008;22(1);15-26.
  2. McEwen et. al., “The neurobiological properties of Tianeptine (Stablon): From hypothesis to glutamatergic modulation,” Molecular Psychiatry 2010 March;15(3): 237-249.

Suboxone Manufacturer Sued for Anticompetitive Practices

Pharma Lies




I read a brief news item online about the drug manufacturer getting sued, but I didn’t get detailed information until I read last week’s issue of Alcoholism and Drug Abuse Weekly (ADAW).

Here’s the scoop: the Attorneys General for thirty-six states are suing Reckitt-Benckiser (RB, now called Indivior), because the company attempted to block generics from entering the market after RB’s patent for sublingual buprenorphine products expired.

Reckitt-Benckiser manufactured Suboxone and Subutex, which were the initial buprenorphine products that came to market in 2002, after the DATA 2000 law was passed.

As a reminder, before DATA 2000 was passed, it was illegal to treat opioid use disorder in an office setting with an opioid prescription. Doctors have gone to jail for this. Before DATA 2000, opioid treatment programs (OTP) were the only setting where prescribing (methadone was the only approved medication) for opioid addiction was permitted, and these OTPs have always been strictly regulated by multiple governmental agencies.

The FDA has approved only one medication, buprenorphine, to be used under DATA 2000, and only the sublingual form was approved. Then earlier this year, a second form of buprenorphine was approved to treat opioid addiction: the six-month, sustained release implantable rods impregnated with buprenorphine, known as Probuphine.

Buprenorphine taken by other routes of administration aren’t covered by DATA 2000, and therefore can’t be used to treat opioid addiction. These forms include the name brands Butrans patch, Belbucca oral film, and IV/IM buprenorphine used for pain control.

Reckitt-Benckiser’s patent for sublingual buprenorphine tablets was set to expire around 2008. Years before that, RB worked on finding a different delivery system, and the film version of Suboxone came out in mid-2010. This new form had its own patent, so that RB was the only company that could manufacture and sell that form of their medication.

However, since their sublingual tablet had come off patient, other drug companies could make generics, which would bring down the price to consumers of this life-saving medication.

But the Attorneys General allege RB tried to block the release of the generic tablets. RB told their drug salespeople to tell doctors that children were dying from ingesting buprenorphine tablets, and that the risk of prescribing this form of treatment was too great. They said the safest way to treat patients was with the film, which comes individually wrapped in a foil packet. And remember, only RB manufactured this film.

On May 12, 2012, I blogged about Reckitt-Benckiser’s attempt to persuade me to prescribe only the film. In that blog post, I describe how the drug representative told me that sublingual tablets were now suddenly too dangerous to prescribe, due to pediatric overdoses. She also told me it was much better for patients to be prescribed the film, since people addicted to pills could be triggered by tablets.

Her credibility took a big hit that day, because she’d promoted the hell out of her company’s tablet form of Suboxone and Subutex to me for years. I called her out on the inconsistency and disingenuousness of her statements, promulgated by her company, and I blogged about it.

At her next visit, she told me she was “disappointed that I chose such a public forum to describe our conversation.”

It was the first time someone chastised me for something I wrote on my blog, and I was elated. I felt like a real journalist!

She hasn’t visited my office since, and I haven’t missed her. She’s a nice lady, which is the only reason I put up with her in the first place. Right or wrong, I‘ve always found drug reps to be tedious.

I harbor no illusions about what drug reps do. Their job is to sell their product. When I worked in primary care, I was lied to on a regular basis by drug reps. For example, when the drug rep for a company that sold Prempro told me that estrogen replacement therapy reduced the risk of breast cancer. I remember being shocked into silence as I frowned at him, wondering if he thought I was really, really stupid.

Back to the point of this blog. So in 2012, R-B tried to prevent the generic from coming onto the market by saying the pediatric overdose problem was so bad that only the films (still under patent with R-B) should be prescribed

The lawsuit alleges consumers had to pay higher prices due to RB’s efforts to block generic tablets. These states want Indivior, formerly Reckitt-Benckiser, to pay back billions of dollars of profit obtained through unfair practices.

The lawsuit alleges the company manufactured claims of pediatric safety as a way to manipulate doctors into switching their patients over to the film, instead of continuing to prescribe the tablet form of the medication, which would have generic versions coming onto the market soon.

The drug company, as well as the company that developed the film technology, both say they did nothing wrong, and that their product has saved countless lives.

So…what is the price difference for different forms of buprenorphine? I did some current comparisons for my area on, recording the lowest price on the site for people with no insurance. Here are the results:

Generic buprenorphine: dose of 16mg per day, #60 tabs: $133

Generic combination product, buprenorphine/naloxone, dose of 16mg per day, #60 tabs: $243

Name brand Suboxone Film, same dose of 16mg per day, #60 films: $455

Name brand Zubsolv, dose of 5.7mg, two per day, #60 tabs: $455

Name brand Bunavail buccal film, 4.2mg, two per day (highest recommended maintenance dose) #60 films: $455

I’m sure readers find it remarkable, as I do, that all three of the name brand forms are the same price. It’s also interesting that the cheapest form, generic buprenorphine monoproduct, is only 28% of what the name brands all cost.

Here’s something more fascinating – BlueCross/Blue Shield of NC requires prior authorization for every one of their covered patients who are prescribed buprenorphine. For years, this insurance company will ONLY authorize payment for the name brand Suboxone in film form. They refuse to pay for the cheaper generic, either mono or combination forms.

I don’t know why BC/BS decided to only cover the name brand Suboxone films.

I could understand if they wouldn’t pay for the monoproduct, due to concerns that it’s more desirable on the black market, and the insurance company may not want to contribute to this problem. But why do they object to the generic combo product? Perhaps they worked out a special, cheaper deal, or perhaps they were swayed by drug manufacturer patter.

It’s hard for me to see that Reckitt-Benckiser/Indivior did anything different than what other drug companies do routinely. Of course their drug salespeople exaggerated the danger of pediatric exposure to buprenorphine tablets in an effort to influence doctors to prescribe only the films. But their claims were so weak and transparent that it would be a gullible doctor indeed who fell for the company line.

And since when do doctors accept what a drug company salesperson tells them at face value? I’m not saying outright lying by drug company representatives should ever be OK, but…it happens.

The drug companies make big bucks, but they counter by saying they spend so much money in research and development of new drugs, and if it weren’t for their work, we wouldn’t have all these new medications that we have that are extending peoples’ lives.

That’s somewhat of a legitimate point, but at what point do we say the drug companies are making adequate profits or excessive profits? And at what point does an exaggeration about a medication become a lie?


Bad Science: “Miracle” Cures for Addiction

snake oil



Addiction is hard to treat. Like other chronic illnesses, relapses are common, and frustrating to both the patient and the family. Substance use disorders cause considerable disability and even death. Treatments do help many people, especially medication-assisted treatment for opioid use disorder, but still aren’t as successful as we’d like.

Scoundrels looking to make a quick buck often prey on patients with diseases that are difficult to treat, like cancer, multiple sclerosis, substance use disorders, and the like. Sometimes bogus treatments have no basis in science at all. Sometimes minimally helpful treatments are touted as being more successful than science shows that they are. In all these cases, bad science is used to cover questionable, usually financial, motives.

I hate bad science. For the purposes of this blog post, I’m defining bad science as when people attempt to give their treatment, or method, or viewpoint, a sheen of scientific validity by using or misusing data, or by having no relevant data at all.

Some examples are more outrageous than others, and bad science has been used for decades.

Charles B. Towns, together with Dr. Alexander Lambert, declared the Towns-Lambert cure for alcohol and drug addiction to be 90% effective. The Towns-Lambert cure was a mixture of belladonna, hyoscyamine, and herb called prickly ash, castor oil, and mercury. Patients were also given chloral hydrate, a sedative similar to a barbiturate, along with morphine and paraldehyde. It fact, it was while he was a patient in Towns’ New York hospital that Bill Wilson, co-founder of Alcoholics Anonymous, had his vision that lead to his spiritual awakening, which in turn lead to the formulation of the Twelve Step program of AA.

Eventually, the number of repeat patients undermined claims of the cure rates of the Towns-Lambert method. Despite his lack of evidence, Towns’ claims became ever more extravagant, leading Dr. Lambert eventually to disassociate himself from Townes. Eventually, the Towns cure was discredited and disappeared.

This wasn’t the first treatment with better marketing than science, and it certainly wasn’t the last.

I had the displeasure of seeing a product being promoted at a recent conference I attended. This device, and I’m not going to give the name since I don’t want to give the promoter any free publicity, generates electrical pulses to the head. Three electrodes are placed just under the skin, and the device is worn for five days while the patient receives intermittent electrical stimulation. This supposedly gets rid of opioid withdrawal symptoms.

The person peddling this new invention shot himself in the foot in my view as soon as he said this device worked 100% of the time. When I asked for studies which had been published in peer-reviewed journals, he said they had loads of studies. Sadly, none were yet published that had been done in humans. He did have human data, but it wasn’t published yet, since an IRB (internal review board) hadn’t approved the study design before they undertook the study, so they had to find someone to approve the study after it was done.

Huh? No, that’s not the way review boards work. Review boards review studies before they are done, to assure no patient will be put in danger needlessly. I’ve never heard of a post-study review board.

So anyway, their human data hadn’t yet been published.

I hinted (oh OK, I came right out and said it) that perhaps it was a bit unethical to promote and expensive treatment ($500, not covered by insurance) unless they had human data, approved and reviewed by the research community, showing efficacy. The promoter of the item countered by saying it was unethical NOT to provide this device, given the benefit it provides.

He didn’t understand that my objection was to the lack of scientific process that all new treatments should undergo, to show they are of at least some benefit prior to use in clinical practice. This should be done before the treatment is marketed. But he pointed to all the success stories on their website, testimonials by patients of how effective this treatment was at preventing opioid withdrawal.

These testimonials are called anecdotal data in the scientific community. Anecdotal data isn’t nothing. It is a type of information that can suggest a potential effective treatment. But anecdotal data alone isn’t sufficient to claim efficacy. It’s only a potential starting point.

People tend to give testimonial type of anecdotal information more credence than they deserve. Hearing a story of miraculous healing touches our hearts. If we are also desperate for a similar cure, we risk making emotional decisions rather than rational ones.

I wasn’t trying to tell this salesman his product didn’t work. For all I know it will be the greatest breakthrough in addiction medicine in the last one hundred years. What I’m saying is that we don’t yet know if it works, because it hasn’t yet been properly tested. And therefore, I thought it was unethical to sell it before testing it.

Does anyone remember Prometa? It was all the rage ten years ago. News articles asked if it was the big breakthrough in addiction treatment. Anecdotal stories from former methamphetamine addicts were heart-warming. The company that supplies Prometa, Hythiam, was created by a former junk bond salesman, which could have been a red flag. That salesman heavily promoted Prometa with the anecdotal stories from addicts who had lost everything but were now drug free and happy.

The medications that made up Prometa are hydroxyzine (an antihistamine with sedating properties), gabapentin (an anti-seizure medication also used for neuropathy) and flumazenil ( a benzodiazepine antagonist). All three are FDA approved for uses other than addiction, but the proprietary combination of these made up Prometa, and it was sold as an addiction treatment cure without FDA approval. This is perfectly legal, by the way.

One drug treatment court, in Tacoma, Washington, paid $400,000 to buy Prometa for its participants. When it was discovered that several of the people making decisions for the drug court also owned stock in Hythiam, it left some people believing there was a conflict of interest. And after results from that drug treatment court were available, Prometa performed no better than traditional (and much cheaper!) treatments. [1]

Ten years later, I rarely hear the word Prometa. Hythiam changed its name to Catasys. Dr. Walter Ling, a very respected scientist in the addiction treatment world, completed a double-blind placebo-controlled studies showed Prometa to be no more effective than placebo.

But all this happened after that former junk bond trader made up to $15,000 for every Prometa patient treated. All those patients and their families were disappointed by another treatment that promised much and delivered nothing better than placebo.

I think it’s unethical for a company to bring a product to market before there’s adequate science to prove that it works. This rather rigorous process is what makes a product or procedure or methadone evidence-based.

Until you’ve got something that’s evidence-based, please don’t waste my time by trying to sell it to me.

When the marketing of a medication outpaces the research supporting it, watch out. We are in snake oil territory.

If a salesman blathers about how good his product is, but can’t hand you a good study published in a peer-reviewed journal, beware. With science, you’re supposed to do the studies first, then present at a conference of your peers, or in a peer-reviewed journal. The data should be able to be replicated by other facilities before we can see it is an evidence-based treatment. Barring that, it’s only a possible treatment among many possible treatments.

  1. “Prescription for Addiction,” 60 Minutes, CBS News, December 9, 2007
  2. Ling et. al., “Double-blind placebo-controlled evaluation of the PROMETA program,” Addiction, 2012 Feb;107(2):361-9

Black Box Warning

black coffin



Last month the FDA (Food and Drug Administration) announced their decision to require black box warnings on opioid and benzodiazepine prescribing information. This warning will state that co-prescribing these two classes of medications increases the risks to patients of death, coma, sleepiness, and respiratory depression. The FDA also said they would require medication guides for patients, describing these risks.

Black box warnings are the strongest warnings issued by the FDA. These warnings are literally placed in a bold black box at the top of the prescribing, where the information is most noticeable.

I applaud the FDA’s action. I think FDA’s statement will make physicians and other providers think twice before blithely writing a benzodiazepine prescription for a patient already prescribed opioids. A black box means, “Take this seriously!”

Ten years ago, co-prescribing of opioids and benzodiazepines was commonplace for primary care physicians in my area. Earlier this year, our state medical board announced they would investigate the top prescribers of opioids and benzodiazepines together. Since then, I have noticed some prescribers appear to be backing away from the routine prescribing of benzodiazepines..

Most opioid treatment centers have policies in place to address benzodiazepine use, both licit and illicit. There are still a few OTPs who approve benzodiazepines to be prescribed for methadone or buprenorphine patients, but I think they are in the minority. Most opioid treatment program physicians feel that besides the dangers of sedation and overdose, there are few medical indications for long-term (more than three months) benzodiazepine prescriptions, and much better long-term treatments for anxiety disorders.

An article In the April 16th, 2016 issue of the American Journal of Public Health underlined how important it is to evaluate benzodiazepine prescribing in the U.S., particularly when prescribed along with opioids. [1]

The authors begin the article by stating that benzodiazepines were found to be involved in nearly a third of opioid overdose deaths in 2013. The authors wished to investigate nation trends in benzodiazepine prescribing and in fatal overdoses involving benzodiazepines.

The authors found the percentage of U.S. adults filling benzodiazepine prescriptions increased significantly over past years. They also found that among people who filled benzodiazepine prescriptions, the amount, defined as lorazepam equivalent doses, also increased significantly. Simultaneously, overdose deaths rates involving benzodiazepines rose nearly four-fold, though deaths appear to have plateaued since 2010.

Another study, this time in Canada, evaluated the risk of death in polysubstance users. In a prospective cohort study of IV drug users, done from 1996 through 2013, benzodiazepine use was more strongly associated with death than any other substance of abuse. [2

Many patients ask why they can’t take benzodiazepines while on methadone or buprenorphine. I tell them I’m mainly worried about the increased risk for overdose death, but I also tell them benzodiazepines are over-prescribed. Prescribing information suggests benzodiazepines are most beneficial when prescribed for no more than three or four weeks. Long-term prescribing of benzodiazepines is generally discouraged, due to serious side effects seen even in patients with no substance use disorders.

Benzodiazepines are associated with increased risk of auto accidents, increased risk of completed suicide, worsening of mood disorders like depression, increased risk of drug-induced dementia, and increased risk of daytime fatigue. Benzodiazepines are also associated with increased risk of cancer, falls, and pneumonia.

Although an association of benzodiazepines with these conditions doesn’t necessarily mean benzodiazepines cause these conditions, it’s a good reason to be conservative when prescribing benzodiazepines and other sedatives, pending further studies.

Sedative medications including benzos can make undiagnosed sleep apnea worse, even to the point of causing death. Obesity increases the risk of sleep apnea, and with more adults becoming obese, the risks of benzodiazepines in such patients may be overlooked.

As for my patients, many of whom are prescribed methadone or buprenorphine, the risk of drug interaction and overdose with the hypnotics usually outweighs all of the benefits, and I recommend that patients do not mix these two types of medications.

  1. Bachhuber et. al., “Increasing Benzodiazepine Prescription and Overdose Mortality in the Unites States, 1996-2013,” American Journal of Public Health, April 16, 2016.
  2. Walton et. al., “The Impact of Benzodiazepine Use on Mortality Among Polysubstance Users in Vancouver, Canada,” Public Health Rep., 2016 May-June;13(3)491-9.

September is National Recovery Month!


September is National Recovery Month, so it’s a good time to come back from my blogging break. Following are some things that recovery means to me, and I hope my readers will write in with their own definition of recovery.

Recovery means…

….taking the worst and most embarrassing thing in my life and turning it into my greatest asset.

….becoming less judgmental of other people.

….remaining teachable.

….having more free time, after the burden of looking for the “next one” has been lifted.

…looking in the mirror, and feeling content at what I see.

….being satisfied with the small pleasures in life.

….developing a thicker skin for judgmental people. They aren’t going to ruin my day.

….re-connecting with the human race.

….re-connecting with the God of my understanding.

…reconnecting with myself.

….doing what I need to do for my well-being, even if other people don’t approve.

….being happy when I make progress, no longer expecting perfection.

….understanding it’s more important what I think of me than what other people think of me.

….talking frequently with other people who share my passion for recovery.

Recovery goes beyond 12-step programs or medication-assisted treatment. Recovery can apply to issues other than drug addiction. It can apply to eating disorders, co-dependency, gambling problems, sex addiction, or any other compulsive activity that is bad for our health. We can be in good recovery in one area of our life and be in active addiction in other areas. We have good and bad days. We relapse, and we try again, and we stop listening to the voice of addiction that tells us we should give up because we will always fail. We learn from our failures and come to look at them as opportunities for growth. We turn stumbling blocks into stepping stones. We lift up our fellow travelers when they weaken and they do the same for us.

We do recover.


Recovery Rocks


Methadone Overdose Deaths: First Two Weeks



Methadone is a tricky drug to start, due to the narrow margin between therapeutic dose and fatal dose. Making it more difficult, people vary a great deal in the rate at which they metabolize methadone.  Some people have a methadone half -life as short as 15 hours, while others have half- lives as long as 60hours. The average is 22 hours. So even for people with a high tolerance to other opioids, increasing methadone too quickly can be deadly.

Methadone’s long half-life makes it good for a maintenance medication, since after stabilization, there’s not much fluctuation in the blood levels. However, the long half-life makes it more difficult to adjust the dose. The change I make in a patient’s dose today may not be fully experienced by the patient for five or more days.

The tolerance to the anti-pain effect of methadone builds faster than the tolerance to respiratory suppression, adding to the danger. When methadone is used inappropriately, patients may take more methadone to relieve pain, but by the time the pain is gone, they could easily have taken a methadone overdose.

All of this explains why the first two weeks of methadone maintenance treatment are the most dangerous. According to some studies, death rates for patients starting methadone at opioid treatment programs are actually higher during the first two weeks than when using illicit opioids. (1, 2)

Even so, it’s a risk worth taking, given the proven life-saving benefits of methadone (and buprenorphine) maintenance

Patient overdose during the first two weeks is a serious concern for doctors working at opioid treatment programs. We must do all we can to keep patients safe. It’s a fine line; if we start at too low of a dose or go up too slowly, we risk having our patients drop out of treatment. And if we increase the dose too quickly, it increases the risk of overdose…

The American Society of Addiction Medicine (ASAM) recently updated their methadone induction guidelines. In past years, doctors working at opioid treatment programs (OTPs) tended to start patients at 30-40mg and increase the dose rather quickly. Now, the expert ASAM panel recommends a starting dose of 10-30mg. If that dose isn’t sufficient to suppress withdrawal, a second dose can be given after three hours, so long as the total dose is not greater than 40mg. The expert panel recommends increasing the dose no more quickly than every five days, and no more than five milligrams at a time.

Some patients are more susceptible to overdose, and physicians should consider lower methadone starting doses for these people:

-Age over 60

-Using sedating drugs like benzodiazepines

-Regularly consume alcohol

-Are on prescription medications which can interact with methadone

-Medically fragile patients, for example patients with coronary artery disease, morbid obesity, -chronic obstructive pulmonary disease (COPD), or sleep apnea

-Have risk factors for prolonged QT interval, such as a recent heart attack, personal history of heart rhythm problems, or family history of heart disease

-Patients who have been abstinent from opioids for five or more days (e.g. recent incarceration, recent detoxification or hospitalization). These patients lose some of their tolerance and might be more prone to overdose with any opioid.


Interestingly, the degree of withdrawal that the patient has when entering treatment does not correlate with the dose of methadone they will need to get rid of withdrawal symptoms. In other words, one person in terrible withdrawal may need a smaller dose than another person with milder withdrawal. The degree of withdrawal that a patient feels is only partly due to opioid tolerance. Genetic makeup may be the reason why some people have more severe withdrawal than other people.

While I always ask my new patients how much opioid they have been using per day, that alone doesn’t determine methadone starting doses. There’s incomplete cross-tolerance between other opioids and methadone, meaning we can’t use the table of equianalgesic doses.

Last week I found an interesting article describing a large study of Canadian methadone patients, which will contribute even more to what we already know about risk during the first two weeks of methadone. This study showed which patient characteristics are associated with overdose death.

The study was done in Canada from 1994 until 2010, and covered over 43,000 patients enrolled in an opioid treatment program in those years. The study looked at all overdose deaths in this patient population and found 175 deaths deemed to be from opioids. These cases were matched with patients who entered treatment around the same time as the patient who died, creating a nested case-control study.

This study found, as expected, a higher degree of risk in the first few weeks on treatment. In this study, patients in the first two weeks of treatment were 16 times more likely to die in the first two weeks of treatment than any other time in treatment.

Psychotropic drugs were associated with a two-fold risk of overdose death overall, with antipsychotics associated with a 2.3-fold risk and benzodiazepines a 1.6-fold increased risk. Antidepressants were not associated with increased risk of overdose death. Alcohol use disorder diagnosis was also associated with a two-fold increase risk of overdose death.

Even more interesting, heart disease was associated with over five times increased risk of overdose death, and serious lung disorders (sleep apnea, COPD) were associated with a 1.7 times increase in overdose death.

This is a powerful study because it was so large.

This is information I can use. I’ve been stressing about patients whom I thought were at increased risk – those who use alcohol and benzodiazepines, and those with severe lung disease. While these patients are at higher risk, from this study it appears patients on anti-psychotics are at even higher risk. And I need to do a better job of getting patients to see primary care doctors, to screen for heart disease, which gave the highest risk of all.

As time goes on, I think we’ll get more information about which patients are at higher risk. Those patients need a higher degree of interaction with treatment center staff, and better coordination of care with mental health providers and primary care doctors. I know I plan to implement a system at the OTP where I work to make sure I see patients more often if they have the risk factors described.

Obviously any patient death is a terrible thing. Of course it’s worst for the family, but it also affects the treatment team. I feel badly for the families of those 175 patients in the Canadian study who died, but they gave us information that can hopefully help us provide better care for future patients.


  1. Caplehorn et al, “Mortality Associated with New South Wales Methadone Programs in 1994: Lives Lost and Saved,” Medical Journal of Australia, 1999 Feb 1;170(3):104-109
  2. Cousins et al, “Risks of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study,” Journal of Substance Abuse Treatment, October 2011, Vol 41(3); pp252-260.
  3. Leece et al, “Predictors of opioid-related death during methadone therapy,” Journal of Substance Abuse Treatment, Oct 2015,