Buprenorphine Overdose After Naltrexone Treatment

Naltrexone induces mu-receptor hypersensitivity.  Buprenorphine’s protective ‘ceiling effect’ may not prevent overdose in patients with this ‘reverse tolerance’.

A new patient described his recent history of respiratory failure several days into buprenorphine treatment.  He was told by his doctors that he experienced an allergic reaction to Suboxone. The rarity of buprenorphine or naloxone allergy led me to look deeper into his history, and my conclusion differs from what he was told by his last treatment team.
The patient, a man in his mid-50s, has a history of significant opioid use over the past 20 years.  He used a variety of opioid agonists over the past year, mostly prescription opioids, with an average daily dose greater than 200 mg of oxycodone per day.
Three months ago he went through hospitalization and detox, and after a week he was discharged on oral naltrexone.  He sought further treatment at a different institution that offered buprenorphine.  He was told to stop the naltrexone two weeks before induction with buprenorphine.
He avoided all opioids for that two weeks, and then started buprenorphine, 2 mg twice per day as directed by his physician.  The patient became progressively sleepier after each dose of buprenorphine, and after 24 hours could barely maintain wakefulness.  His complaints resulted in his admission to the hospital intensive care unit.
In the ICU he had a rocky course that included several episodes of apnea, hypoxemia and bradycardia.  The patient does not currently have the records from the hospitalization, so the course of events is based only on his recollections from several weeks ago.  He blacked out several times, and was told by doctors and nurses that his ‘heart stopped on the monitor’ during those times.  He says that his oxygen level was very low at those times according to the monitors, and according to what he was told.
After the episodes when he lost consciousness, he was told that since his heart stopped he needed emergency implantation of a pacemaker.  He said that a short time later those concerns were dropped, and no pacemaker was inserted.  He was discharged from the hospital in good condition after several days.  Follow-up with a cardiologist was not deemed necessary. He was told by his hospital physician that the episodes of lost consciousness were caused by an allergic reaction to Suboxone.  He had no rash or pruritus (itching).
I’m writing about this patient’s care in the form of a ‘case report’.  The patient does not have access to his records.  If he did, I would review them and write a formal case report for publication.  Since I’m relying on the patient’s perceptions and memories, I’ll use this blog.  I will say that I have no axe to grind, and my purpose in sharing this case is to help people avoid a similar situation.  And, of course, to keep readers of this blog entertained!
As the patient shared his story, I assumed that he had an opioid tolerance well-below the ceiling actions of buprenorphine.  When I mentioned my hypothesis, the patient smiled, and told me he had been using over 200 mg of oxycodone each day, blowing that theory to pieces.
But I returned to the same theory when he said that he followed the doctor’s orders very closely, including avoiding opioids completely for two weeks before induction.  I wondered, could a 2-week interval of abstinence lower tolerance so dramatically that buprenorphine resulted in overdose? Then the patient mentioned, in an offhanded way, that ‘he even stopped the naltrexone’.
I’ve written about the increased incidence of opioid overdose following treatment with naltrexone, a risk that is unreported and largely unknown beyond brief reports from Australia cited in the linked post.   Opioid antagonists, including naltrexone (the drug that makes up Vivitrol injections), induce ‘reverse tolerance’ in mu opioid receptors to cause a heightened response, and heightened respiratory depression, from subsequent exposure to opioid agonists.  Anyone close to the field of opioid dependence notices the increased frequency of overdose in patients newly released from confinement, whether in jail or in abstinence-based treatment.  The increased risk of death after a period of abstinence is related to the resetting of tolerance during abstinence.  A return to ‘normal’ use creates significant risk of overdose.
That risk is multiplied if the period of abstinence includes treatment with naltrexone.   Imagine a person who is using six ‘30s’ of oxycodone—180 mg—every 24 hours.  If that person waits a week and then goes on naltrexone, tolerance drops to zero and then to negative levels.  After a couple of weeks on naltrexone, a tablet of Vicodin has the potency of a tablet of Percocet.  That 180 mg of oxycodone now has the potency to cause respiratory arrest and death.
Buprenorphine is a partial agonist with a ceiling effect that prevents overdose in almost all patients who have even small degrees of opioid tolerance.   Almost all deaths from buprenorphine occur in people with limited or no tolerance to opioids.  In the presence of inverse or negative tolerance, the ceiling on buprenorphine’s opioid effect has less protective value.  Such was the case in the patient who is the subject of this discussion.
So what would have been a better plan?  Buprenorphine induction is always more dangerous in patients with low opioid tolerance, so careful patient selection will mitigate that risk.  In patients with low tolerance, reducing the starting dose buprenorphine to low-milligram levels does little to reduce the risk of respiratory depression because of the ceiling effect, which reflects the minimal difference in strength between 2 or 16 mg of buprenorphine.   Much lower doses of buprenorphine, on the order of 0.5-1 mg, are required to reduce risk of respiratory depression and overdose in patients with inverse tolerance to mu opioid agonists.
A second option would be to continue naltrexone through the induction process, and afterward gradually reduce the dose of naltrexone over a week or two.  As the block from naltrexone decreases, buprenorphine bound to mu receptors would gradually increase, allowing opioid tolerance to grow more slowly.  Precipitated withdrawal would not be a problem, as PW occurs when bound agonist is suddenly displaced by buprenorphine—  not when antagonists are displaced by agonists or partial agonists like buprenorphine.
Thankfully, the patient is now doing well, with no lingering problems caused by his course of treatment.  But the incident also relates to another common problem, i.e. the erroneous blaming of symptoms on medication ‘allergies’.  In an era of electronic medical records, that mistake often removes, permanently, a patient’s access to medication that may someday be helpful—and in the case of buprenorphine, irreplaceable.

Suboxone Detox is a Sucker’s Bet

First Posted 10/6/2013
I attended the US Psychiatric and Mental Health Congress meeting last week and actually attended the meetings (the event was held in Las Vegas), but I was disappointed by the absence of lectures about addiction.  There are other mental health groups geared more toward addiction, but one would think that psychiatry would maintain a strong presence in the field.  This was my first time at the annual meeting for this group, and so I can’t say that I’m witnessing a trend away from addiction by psychiatry—which would be a real shame.
At any rate, I had a very busy Friday and Saturday catching up with the office work I put off for a few days. So today I had to cram in a lot of non-work activities, to make sure that my life remains well-balanced.  That meant watching the entire Packer game, going to the movie ‘Gravity’ complete with 3-D glasses, and then catching the latest episode of Homeland, where psychiatrists continue to gain a bad name.  Thorazine injection, anyone?
So I’m beat…  but I’ve been intending to write something for the past couple weeks, and I think I can knock it off fairly quickly.  Readers know that I get many emails from across the country describing atrocious behavior by physicians.  The latest scam?  It appears that everyone with a medical clinic has a secret recipe for tapering off Suboxone.
I received an email from a person who wanted to stop Suboxone/buprenorphine for months, if not years.  For people who don’t know my attitude, I tend to believe my own eyes, and also what the research shows—that over 9 out of 10 of the people who stop buprenorphine are using opioids again within one year.  When people moan that ‘it is hard to stop buprenorphine’, I remind them that the reason they are TAKING buprenorphine is because they were unable to stop opioids.  Why would they expect that to change?  Oh- I know— counseling!  That’s the line from all of the addiction insiders—that patients take buprenorphine and do ‘counseling’, and the addiction goes away.
There are two scientific findings that keep trickling out these days that are driving some people crazy— and I admit to a bit of amusement with each headline.  The first set of findings concern the troubling lack of global warming over the past 8 years—including the recent headlines that polar icecaps, predicted by Gore et al. to be completely gone by now, have grown by almost a third in the past year.  The other interesting findings are the several studies that failed to demonstrate an increase in sobriety in buprenorphine patients engaged in ‘counseling.’    There is real danger for people who borrow science just in order to hide behind It for an argument or two; they risk getting caught naked when the science moves in an unexpected direction!
Anyway, the person wrote to tell me that after multiple failed efforts to taper off buprenorphine on her own, she had gone to a rapid-detox clinic that promised to ‘heal’ her receptors over a few days. The $7 grand was spent, and I had no desire to ruin whatever placebo effect she would gain from the silly cocktail of nutritional supplements she purchased.  So I told her that I hoped she felt better soon, not adding that she will feel better at about the same time she would have felt better without the rapid detox and nutritional supplements.
She wrote again a week later, struggling from withdrawal, and then again a few days after that to say that she went back on buprenorphine.  But the good news was that she found a different doctor who SPECIALIZES in getting people off buprenorphine.
A few days later she wrote to tell me about the hundreds of dollars the visit cost— and asked if his taper schedule appeared reasonable.  ‘He’s your doctor’, I explained, trying to sound neutral.  I shared my belief, though, that it was a conflict of interest for doctors to sell nutrient products that they themselves prescribed, and that opioid receptors are able to return to health without the addition of trace nutrients.
A week later she wrote about yet another specialist, who this time took $800 to tell her to take 3 mg for a few days, then 2 mg for a few days, then 1 mg for a few days.  She said she had to go back for another appointment for him to tell her what to do after that.
I know it sounds like I’m joking, but sadly, I’m not.  More sadly, I’ve read similar messages a number of times over the past few years.  I’ve stated that I would try to point out things I write that are based on science, vs. things based on personal experience, vs. what I’ve witnessed as a clinician.  What I’m about to say is based on all three.
I had my own nightmare withdrawal from potent opioids when I was in treatment 13 years ago.  I lost 30 pounds from my already-skinny frame at that time, having no appetite and without taking nutrient supplements.   But my withdrawal ended and my receptors healed in about 6-8 week, just as in every opioid addict who I’ve assisted through detoxification.  And when I’ve seen people go away for rapid detox, they complain about feeling lousy— the same amount of complaining over the same lousiness—for the same 6-8 weeks.  One would think that all of this would be enough to outrage the FDA, who usually get irritated at stories about high-cost, low-yield medical procedures.  But once again, the truth is even worse.  For those who do manage to white-knuckle through 6-8 weeks of withdrawal, guess how many are still clean a year later?  Wanna bet?
As for the warming of the planet, I’ll continue to read the science with an open mind.  Maybe Gore will be right in the long run, which would be bad for the planet but good for those who give out Nobel Prizes.  But we know one thing for certain now; that asserting the ice caps would be gone by 2014 was a sucker’s bet.  And the same is true about promises for a rapid or gentle path through opioid withdrawal.