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Tapering off Buprenorphine or Suboxone, Pt 2

In the last post we discussed some of the misconceptions about tapering off opioids. Today we will discuss a couple basic principles, and then describe the approach I recommend for my patients tapering off buprenorphine.
Opioids act at receptors that normally bind endorphins, which are released by neurons in response to a range of stimuli including trauma and rewarding behaviors such as eating a good meal or using addictive drugs. Endorphin pathways elevate mood, reduce sensation of pain, and impact urine production, immune function, intestinal motility, and other bodily functions. Endorphin pathways have a certain baseline activity or ‘opioid tone’ that is directly related to opioid tolerance. When opioid stimulation is greater than one’s tolerance, opioid tone is increased. When opioid stimulation drops below one’s tolerance, opioid tone is reduced, causing withdrawal symptoms.

The goal of any taper off opioids is to recover original or native opioid tolerance. Some people focus on getting rid of the opioid, and even use substances or behaviors to ‘flush buprenorphine from the body’. Products marketed as detox agents have minimal impact on the clearance of buprenorphine or other substances. And even if they could increase the rate of clearance, they would only make detox harder by increasing the severity of withdrawal symptoms. The relatively slow metabolism and clearance of buprenorphine provides a cushion by slowing the loss of opioid tone.

Prolonged use of any opioid changes opioid receptors. The changes are not fully understood but include a decrease in number of receptors and changes in binding properties that reduce receptor sensitivity to opioids, including endogenous opioids (endorphins). Recovery from a state of tolerance takes 2-3 months, and is initiated by reduced opioid tone. Withdrawal symptoms reflect the reduced opioid tone that provokes eventual recovery of native tolerance.

Recovery of native tolerance is the rate-limiting step when tapering off any opioid, including buprenorphine. When the dose of buprenorphine is reduced, the amount of buprenorphine at opioid receptors decreases over the next 5 days and then stabilizes at a lower level. In response, opioid tone (the summation of current flow through opioid receptors) drops below normal. If the dose of buprenorphine is maintained at that level, opioid tone will recover to normal in about 2-3 months. If buprenorphine is suddenly and completely discontinued, opioid tone will decrease to very low levels and cause severe withdrawal that lasts for 2-3 months. If buprenorphine dose decreases more slowly, opioid tone will decrease more slowly, lessening the severity of withdrawal. But it still takes 2-3 months for opioid tone to return to normal. So for any taper, patients must decide whether to decrease their dose quickly and be done in 2-3 months, at the cost of greater withdrawal, or instead to taper more slowly to reduce the severity of withdrawal.

The relationship between buprenorphine dose and opioid activity is linear up to about 2-6 mg. Beyond that point further increases in dose have less impact on opioid tone. The reverse occurs when tapering, so that opioid tone decreases only slightly as dose is reduced from 16 mg per day to 4 mg per day. The non-linear dose/response relationship allows for rapid decreases in dose early in the taper process with limited or no physical withdrawal symptoms. Since the early challenge is mostly psychological, I use the early part of a taper to help assess whether a patient is truly ready to take on the tapering process.

I like to have patients lead the way in tapering off buprenorphine. I’ve found that if I lead and reduce the amount of prescribed buprenorphine for the next month, patients often fail to make reductions and end up out of medication before the end of the month. So instead I ask patients to tell me when they are certain that they are ready to stay at the lower dose.
During a taper, I recommend dosing buprenorphine twice per day. Patients start by removing 2 mg from the evening dose. After at least two weeks 2 mg can be removed from the morning dose. This sequence is repeated at intervals of at least 2 weeks until the total dose is 4 mg per day. In my experience patients who get to that point are usually in a good mental position to begin the second, more difficult part of the taper.

Most people will be able to continue working when opioid dose is reduced by 5% or less every 2 weeks, or 10% every month. That number is a good general guideline when deciding how fast to taper. Suboxone film makes tapering relatively easy. Patients purchase a weekly med organizer, and start the week by opening and stacking 7 films. A scissors or razor is used to cut a millimeter from the end of the stack, and one film is placed in each compartment of the organizer for that day’s dose. When the patient is comfortable with that dose, slightly more is removed for the next week. The process continues every 2-4 weeks, eventually changing to the 2 mg films. I recommend that patients continue tapering until the dose is 300 micrograms (0.3 mg) per day or less before stopping buprenorphine completely. It is fairly easy to guesstimate where to cut the film in order to reduce by 10%; just measure half, then half of that, then half of that.

Buprenorphine tablets, of course, are much harder to divide. Zubsolv did people a favor by coming out with a range of doses, and hopefully other brand and generic manufacturers will eventually follow suit. For now I usually have patients use the tablets to taper as far as possible, using the 2 mg tablets in the lower dose range, and then pay the extra cost for the film for the final month or so. A 12 mg film can be divided into 24 half-milligram pieces without too much effort, so the cost doesn’t have to be prohibitive.

I have had many patients taper successfully off buprenorphine. Fear is common and normal for a number of reasons, but the fear usually gives way to a sense of confidence and optimism when a taper is done correctly.
Things to keep in mind:

Be patient. Tapering by too much, or too quickly, causes withdrawal symptoms that lead to ‘yo-yos’ in dose.
Buprenorphine products are very potent. A sliver of Suboxone Film may contain enough buprenorphine to harm or kill an animal or small child. Take care to divide the medication in a well-lit setting, and clean up very carefully.
Buprenorphine is used to treat pain in microgram doses. If you jump from 1 mg, you will have considerable withdrawal symptoms.
If you are still running out of medication early, it is not time to taper off the medication.
People on buprenorphine for a year or less have rates of relapse over 90%. In my experience patients are more successful tapering off buprenorphine if they have been on the medication for 2-5 years or more.
If you struggle in tapering down to 8 mg, consider going back to your stable dose, waiting 6 months, and trying again.
People addicted to opioids often substitute other drugs for their drug of choice. Do not start a new addictive substance in order to get off buprenorphine.

Good luck!

Tapering Off Buprenorphine or Suboxone pt. 1

Many patients taking buprenorphine live in fear of a dark world around the corner where they will have to taper off the medication. They see horror stories on YouTube posted by people who, for some reason, abruptly stopped the medication and kept a video log of their experiences. My own patients sometimes ask, nervously, if I plan to retire some day. Some have asked what they should do if I ever, say, drop dead.

It needn’t be all that bad. Yes, sudden discontinuation of a typical dose of buprenorphine will result in withdrawal symptoms. But if you taper correctly, your body will slowly reset your tolerance without putting you through the wringer. In this post I’ll describe my typical approach to helping a person through that process. But first we should correct some of the misconceptions about buprenorphine and opioid dependence.

It does NOT get harder and harder to stop buprenorphine the longer you take the medication. I have heard that idea over and over in one form or another, and I presume it comes from the experience people have with active addiction where use tends to grow with time, and other facets of life gradually fade away. But the opposite occurs in patients treated with maintenance agents like buprenorphine or methadone, where use of the medication does not trigger a reward or relieve the ‘punishment’ of withdrawal. The conditioning that occurred during active addiction is slowly extinguished, and most people gradually lose the desire to use opioids. I’ve witnessed this process literally hundreds of times over the past 12 years in patients on buprenorphine or methadone. Patients of successful treatment also develop interests and accomplishments that help them avoid returning to opioids. And after a few years away from ‘using friends’, people no longer see themselves as part of the using scene. Patients get to a point where they have too much to lose to get close to that world again.

Opioid withdrawal has physical and psychological dimensions. During short-term detoxes, minor physical symptoms trigger fears that magnify the perception of those symptoms. A bead of sweat on the neck signals that hot flashes, diarrhea, and depression are on the way. Patients who have been away from the cycle of using and withdrawal don’t seem to have as many emotions about their physical symptoms. I see the change very clearly in methadone-assisted treatment, where the minor withdrawal at the end of the day is a big deal to people starting treatment, but a minor inconvenience in patients tapering off methadone after several years of treatment.

Does buprenorphine ‘get in your bones’? YES, of course! Bones are living tissue, so anything in the bloodstream gets in the bones. Glucose gets in your bones. Aspirin gets in your bones. But so what? When you taper off buprenorphine, the buprenorphine in your body will be metabolized and removed. It does not accumulate or stay in bones or other tissues beyond what occurs with other fat-soluble molecules.

Is buprenorphine or Suboxone ‘the hardest opioid to stop’? No. The brain keeps no record of the molecules that pushed opioid tolerance higher. The challenge during a taper is that opioid receptors have become down-regulated by opioid stimulation, resulting in reduced endorphin tone as the opioid is removed. Opioids that leave the body quickly tend to have more-intense discontinuation effects than those that leave more slowly because the latter mimics a taper, where opioid activity decreases over time. The longer half-life of buprenorphine also slightly extends the total period of withdrawal by a few days.

I’ve heard people claim that ‘heroin was much easier to stop’, and rather than tell people what they should think I’ll let them have their opinions on the issue. But that opinion is not supported by studies comparing withdrawal from different opioids. Usually the claim is followed by the comment that ‘with heroin I was fine after 4 days’ or something along that line. But it takes longer for tolerance to reset, after ANY opioid. I suspect that perception comes from the severity of early heroin withdrawal, making subsequent weeks easier by comparison. Again, the brain doesn’t care which opioid you used to take; it only cares that the opioid stimulation that was there is now gone.

In a few days I’ll share the approach I recommend to patients tapering off buprenorphine.

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.

Cannabinoid Hyperemesis: How Rare?

I recently read a CBS news story about CHS, or Cannabinoid Hyperemesis Syndrome, describing a 100% increase in cases in Colorado since the legalization of marijuana there. A search for ‘THC’ and ‘CHS’ pulls stories from a range of sources including High Times, Wikipedia, Fusion.net, and Current Psychiatry. A broader search reveals articles calling the disorder ‘fake news‘.

Most articles about CHS describe the condition as rare, but becoming less rare as the legalization movement takes root and grows. The syndrome occurs in heavy, long-time users of marijuana who first notice reduced appetite, mild nausea, and sometimes weight loss. Those symptoms, and the symptoms that follow, are relieved by smoking marijuana, leading those with the condition to become heavier users who come to see marijuana as beneficial to their health.

Over time the symptoms worsen to include paroxysms of severe abdominal pain, nausea, and vomiting. Patients often seek help from a number of health practitioners, including alternative health treatments. Tests come up negative, and patients continue to turn to marijuana to treat the symptoms– along with hot baths and showers, which for some reason make the pain and nausea more-tolerable.

Since we live in an era of social media I’ll point out that I have no strong feelings toward marijuana. I don’t kick people off buprenorphine products for testing positive for THC, as it makes little sense to stop treating a potentially fatal disease because the patient smokes pot. I doubt doctors would withhold cancer treatment because of marijuana use either. I’m describing my observations only to get the word out about something that doctors are missing. Over the past 2-3 years I’ve had several patients with symptoms identical to those described in stories about CHS, so I suspect the condition is more common than thought.

The Current Psychiatry article describes possible mechanisms for symptoms of CHS. The nausea and vomiting may be caused by accumulation of cannabinoids in the lipid tissue of the gut, causing activation of the CB1 receptor in the intestine to override the anti-emetic effects of CB1 activation in the hypothalamus. Activation of CB1 receptors in the gut slows peristalsis (the motion of the intestines that propels food forward) and dilates the blood vessels to the intestinal system. Hot baths and showers may provide relief by dilating blood vessels in the skin and redirecting blood flow away from the gut. Other possible causes relate to the effects of specific cannabinoids, or perhaps herbicides or pesticides.
One of my patients had classic symptoms of CHS for several years. A year ago I had not yet heard of the condition, but noticed that he repeatedly talked about marijuana being a ‘wonder drug’ for disabling stomach pain and nausea, even as he lost weight and his general health deteriorated. When I asked if he considered that marijuana may actually be harming his health he became angry and defensive, and never returned for follow-up.

Another patient talked about his spouse’s health problems, hoping I would have ideas about the cause of her symptoms that weren’t found through visits to many specialists. Marijuana wasn’t even part of the discussion as he described her severe pain and nausea over the past year that caused her to go to the ER several times each month. At his last appointment, armed with new knowledge about CHS, I asked him if his wife smoked marijuana.

He said that she not only smoked it, she recently got her ‘medical marijuana’ card because smoking was the only thing that relieved her nausea. I asked if she ever felt better after a shower, and he said “oh my gosh, she is in the shower for three hours or more every day with the hot water turned up!”

The big question, of course, will be whether people with similar symptoms will try going without pot for a month, the length of time required for symptoms to fade, and whether clearing their systems of THC actually relieves their symptoms. But other heavy marijuana users with pain and nausea should read up on CHS, and consider a trial off THC. One month without pot isn’t going to kill you.

Post-op Pain on Suboxone

Many patients on Suboxone or buprenorphine eventually require pain treatment, just like people who aren’t on buprenorphine products. I’ve written about post-op pain control several times, but I continue to get emails from patients who haven’t seen my comments and who view an upcoming surgery with the same fear experienced by patients before the early 1900’s, when the OR was correctly seen as a horror-chamber.
These patients are often torn between following the treatment plan vs. doing what they have learned may work better. In all cases, I tell patients that they cannot act in ways counter to what their physician prescribes. But I often support their intent to ask their doctors to clarify or modify their treatment plans.

Patients write about ‘the look’– the way doctors, nurses, and pharmacists react when patients ask about pain control. As a recovering addict myself, I know what they are referring to. Doctors encourage other patients to discuss concerns about pain control, and as long as they have no piercing or tattoos, patients will usually be comforted with assurances that their doctors will take their pain seriously. But people on buprenorphine often see their doctors roll their eyes, or even say that the opposite is true– that if they have pain, they had better not bother the doctor about it! Doctors who act that way are asses, of course, and I urge patients to avoid them if possible. This post is not for those doctors, as they are not likely to ‘get it’ after reading the comments of another doctor— if they would ever read them in the first place!

I’m writing for the doctors who are open to hearing about new ways to help their patients. I intend to use this post, going forward, to answer the emails from patients about this topic If you are a physician who received this from a patient, please consider my comments– as I have found the approach described below far more helpful for surgical patients on buprenorphine products than the alternatives described elsewhere. There was an NIH consensus paper a few years ago for example that described several alternatives, but mostly focused on discontinuing buprenorphine before surgery, then restarting buprenorphine at some point through a standard induction that includes 24 hours of withdrawal in patients already weakened by surgery. Standard doses of opioid agonists were recommended for pain. That approach was also described in a flashy article in one of the throw-away journals a month or two ago (i.e. Autumn of 2015).

There are so many problems with that approach:

Patients forced to stop buprenorphine before surgery and enter surgery dehydrated and weakened (IF they even managed to stop, as many patients end up staying on buprenorphine covertly– NOT a good situation for surgery.)
Buprenorphine discontinuation not an option for emergency surgeries;
Constant opioid levels are necessary to avoid withdrawal, before even considering pain control;
Buprenorphine is erroneously considered gone, when the long half-life actually assures that buprenorphine is still present;
Patients fret and argue over pain control every time the nurses change shifts;
Buprenorphine re-induction at some point after surgery, requiring patients to go through withdrawal symptoms;
Agonist treatment alone causes tolerance to rise very rapidly, requiring high doses of narcotic at hospital discharge;
An increased risk of overdose from narcotic pain medication in patients off buprenorphine;
And many other reasons. Using the ‘discontinuation’ approach, patients end up on a Hellish roller-coaster ride where pain is grossly under-treated and withdrawal symptoms are only 4 hours away, day after day.

I’ve read emails from people whose buprenorphine doctors recommended taking more buprenorphine for post-op pain, or dosing more often. I’ve read about suggestions to use Tramadol for pain after major surgery(!)
Earlier today I sent a letter in response to a woman who is planning a series of painful procedures. I’ll share that letter to spare myself some time:

Dear A,

You’ve been through enough misery, and I hope you convince your physician to consider a different approach to your pain. I’ve had patients on buprenorphine go through many surgeries including thoracotomy, nephrectomy, open cholecystectomy, total knee replacement, and rotator cuff repair– all very painful surgeries. My experience as an anesthesiologist piques my interest in post-op pain control.

My favored approach is very simple. Maintain buprenorphine, and use oxycodone or other agonists to out-compete buprenorphine at the mu receptor as needed for pain relief. The benefits of the approach are obvious once the prescriber opens his/her mind to the realities of ligand competition. There is no need to go through withdrawal, no need for ‘comfort meds’ to tolerate the withdrawal, and no need to enter surgery in an already-weakened state. As you know, even minor withdrawal causes people to feel very depressed, lose their appetites, stop sleeping…. is that really any way to go into surgery?

As an aside, buprenorphine alone does not provide ‘real’ pain control in patients who take chronic buprenorphine. Yes, buprenorphine seems to reduce pain in people with minor pain issues. But it is of no use for the pain of major surgery. Of course in theory, why would buprenorphine treat chronic pain in patients with complete mu tolerance to a medication with a ceiling effect?

A few years ago, an NIH consensus paper described a few approaches to acute pain in patients on buprenorphine. I don’t know who was on that panel, but the paper suggested stopping buprenorphine for several days before surgery and then using agonists. The panel mentioned the approach that I favor near the end of the paper. I also described my favored approach at an annual meeting of ASAM, in a talk that was very-well received. I was optimistic that the discussion would open enough minds among prescribers to follow the neurochemistry, instead of focusing on the misplaced fear of combining an agonist and a partial agonist. There are other papers out there– and book chapters– about the effects gained by combining an agonist with a partial agonist. You can find my ASAM slides at www.slideshare.net by searching for ‘junig’ and ‘uncoupling analgesia’.
The ‘uncoupling’ part BTW is what makes my favored approach so valuable, but that gets into the area of chronic pain, which is not entirely relevant to this discussion. In short, opioid analgesia has always been limited by tolerance and dependence. I believe that those limits can be removed by combining mu receptor agonists with partial agonists, allowing for pain relief from agonists while partial-agonists prevent euphoria and anchor tolerance at a lower level.

My approach is to reduce buprenorphine to about 4 mg per day. Higher doses in my experience get in the way of pain control. I then treat post-op pain as I would in any patient, but using 4 times more agonist (warning– see * below). I typically prescribe oxycodone, 15 mg tabs,* and direct patients to take one tab every 4 hours as needed. When patients no-longer needs narcotic analgesia, I stop the agonist and have them resume their regular doses of buprenorphine. That’s it. No tapering, and no withdrawal… just treating patients as I would any other patients, but realizing that mu receptors are competitively blocked, and effective doses of oxycodone must out-compete buprenorphine.

Dilaudid or fentanyl are not necessary. You could approach post-op pain in a very elegant way in a hospital using sublingual buprenorphine, fentanyl infusion, and PCA, but that gets a bit complicated. Oxycodone works fine. In rare cases my patients required higher doses of oxycodone, but I’ve never had reason to use more than 30 mg. Oxycodone is typically used every 4 hours. My buprenorphine patients have found good pain relief from total daily doses of 60-120 mg of oxycodone. The patients who went to a hospital where I couldn’t control their analgesia, who were told to stop buprenorphine, ended up on much higher doses of oxycodone at discharge.

Advantages of Combined Approach:

There are many advantages to maintaining buprenorphine throughout the perioperative period. The entire process is much simpler, and the patient’s experience is better because there is no euphoria, and no warm rush from oxycodone to rekindle addiction. The pain is relieved, but the reinforcing effects of oxycodone are eliminated. I assume the that the limits on mu effects by buprenorphine are like a ‘governor’ that limits the speed of fleet vehicles. You can get only so much opioid effect in the presence of buprenorphine, and not enough to cause a ‘high.’

The combined approach also prevents tolerance, which is a greater issue with chronic pain than with post-operative pain. Buprenorphine anchors tolerance at the level yielded by the ceiling effect, allowing agonist effects to continue over time. I’ve treated people with the combination of buprenorphine and oxycodone for over 2 years, and the combination continues to work as well as it did on the first day.

Some prescribers and pharmacists worry about ‘precipitated withdrawal’, but that is not an issue as long as buprenorphine is continued every day. The only way to precipitate withdrawal would be to stop buprenorphine for at least a few days, boost tolerance higher with an agonist, and then give buprenorphine– which would ‘yank’ tolerance back down again. Patients who stay on buprenorphine can add agonists without fear of precipitated withdrawal.

I’ve convinced a few doctors to try this approach, and I’ve received a number of positive reports about the approach. I’ve described the idea to several pharmaceutical companies as an approach that would revolutionize pain treatment. Can you imagine pain relief without addiction, without tolerance, and without euphoria? I realize that the large number of deaths caused by opioid overdose limits interest in opioid analgesia. But I suspect that a product that combines buprenorphine and an agonist would go a long way to reducing opioid dependence, providing that the two medications were irreversibly bonded together in a combination product. I have some thoughts about how to do that… but that’s for another day.

It is NEVER safe to prescribe one’s self opioids or other controlled substances, so this discussion is intended to provoke discussion between patients and their doctors. Patients must realize that there are many things that go into decisions about post-operative analgesia, and NO approach is the right approach for everyone. Any individual patient may have features to his/her history that make the combination approach inappropriate, or even dangerous.

*Doses described in this post are intended as approximations for consideration by trained and licensed medical professionals. Doses described may not be safe in some patients, including patients at the extremes of age, patients with respiratory or other chronic illness, patients with central nervous system disorders, or patients on other respiratory depressant medications.

NEVER use opioids except as directed by your own physician.

Media Bias Against Suboxone

First Posted 2.8.2014
After Philip Seymour Hoffman’s death, I anticipated a flood of articles describing the ineffectiveness of non-medication treatments for opioid dependence. I assumed the media would finally report on the need for long-term treatment of a long-term illness. Instead we read more articles describing Suboxone (i.e. buprenorphine) as a ‘bad drug’, since Hoffman may have used the drug to reduce withdrawal between heroin binges.
Taking buprenorphine within a few days of using heroin blocks most of heroin’s effects and makes overdose much less likely– a fact rarely reported. Out of about 400,000 overdose deaths over the past ten years, only 400 deaths included buprenorphine as one drug in the fatal mix– a stunning statistic that calls out for more life-sustaining buprenorphine treatment, not less. In most of those cases, death would not occurred had there been more buprenorphine in the victim’s bloodstream.
Vivitrol is the brand name for a monthly, injectable form of naltrexone that appeals to a superficial approach to opioid dependence. Naltrexone advocates focus on the months of abstinence when patients are taking the medication, often during forced compliance mandated by drug courts. Rarely questioned is the long-term effectiveness (or lack thereof) of naltrexone for reducing the morbidity and mortality of opioid dependence.
The uncritical acceptance of naltrexone by some prescribers begs some important questions. If short-term use of a treatment causes an increase in long-term mortality, is the treatment ethical? If patients mandated to receive a course of treatment only relapse and reoffend a year later, is the treatment an efficient use of resources?
Naltrexone appeals to the same people who push abstinence programs that have long-term success rates well below 10%. Current abstinence treatments often center around programs developed in the 1920′s, that ignore the advances in our understanding of neuroscience and addiction since that era. Abstinence programs blame failures on patients rather than recognizing failed treatment approaches. The case of Philip Seymour Hoffman should call out for a new paradigm, where patients are treated with medication that works and continues to work over the years of a person’s life.
Naltrexone is a ‘blocker’—a great thing for the anti-drug attitudes in all of us. But does it matter that people treated with naltrexone die from overdose at a rate 7-fold higher than people on methadone? Proponents of naltrexone ignore the long-term nature of opioid dependence. And whether naltrexone is administered by shot or by tablet, patients inevitably stop taking it. The ‘naltrexone paradigm’ calls for only 6-12 months on the medication, and many patients drop out even sooner, when their probation ends.
Many patients learn from the internet or elsewhere that naltrexone increases their sensitivity to heroin, a ‘reverse tolerance’ effect that makes relapse impossible to resist. The same hypersensitivity causes greater risk of death, making ‘one last time’ a self-fulfilling prophecy.
On the other hand, headlines that decry ‘abuse of buprenorphine’ greatly exceed true harm from buprenorphine. Most buprenorphine abuse consists of self-treatment by addicts who have no access to the medication, because of limits on patient enrollment and regulations that discourage physicians from prescribing the medication. ‘Abuse’ of buprenorphine is far more likely to prevent overdose than to cause harm. Even one dose of 8 mg buprenorphine prevents death for several days by blocking opioid receptors.
Given the safety of buprenorphine, it is hard to justify the use of temporizing measures or ineffective step treatments. Addiction deserves proper medical treatment—not superficial approaches that delay death for a year or so.

Does Suboxone Stop Working Over Time?

First Posted 12/31/2013
Buprenorphine is relatively unique among opioids in having a ‘ceiling’ to mu opioid effects. There are other known molecules that act as partial agonists at mu opioid receptors, but buprenorphine is the most useful, at this point, because of other traits of the molecule– such as having few side effects from actions at non-mu receptors.
As most opioid users soon realize, opioid agonists increase tolerance over time to what appears to be an infinite degree. The mechanisms of tolerance are complicated. I often describe tolerance as a process where receptors become less and less sensitive to opioids with stimulation, to the point where native opioids (endorphins and enkephalins) no longer activate opioid pathways. Some of the change in sensitivity is caused by the binding of phosphate molecules to the intracellular portion of receptors, causing changes in conformation. Tolerance development is likely far more complicated, though, and includes other changes in synaptic transmission through different mechanisms.

The best model to understand the effects of buprenorphine, in my opinion, is to plot the curve with ‘mu effects’ on the y axis and ‘blood drug level’ or ‘dose’ on the x axis. Opioid agonists yield a straight line with a slope that correlates with drug potency. Buprenorphine yields a straight, sloped line in microgram doses and low blood levels, but a horizontal line in high doses. At a sufficient blood level, buprenorphine essentially sets the tolerance at the degree of opioid effect predicted by that horizontal line.
We could also graph the development of tolerance over time, to high doses of opioids. Agonists would yield a sloped line that eventually flattens, providing the dose of drug is held constant. In increase in dose of agonist would cause the line to slope upward for more time, and flatten at a higher level. With buprenorphine, on the other hand, the slope would flatten at a level that remains constant, even if dose of buprenorphine was increased.
This second graph answers the question of whether buprenorphine or Suboxone stop working at some point in time. From a theoretical standpoint– which is mirrored by clinical experience– tolerance from high-dose buprenorphine does not change beyond the increase in tolerance over the first few weeks of use—- or beyond the decrease in tolerance that was caused by higher amounts of an opioid agonist. If we graphed the development of tolerance to high dose buprenorphine (say 16 mg per day) vs. time, the graph would be different for opioid-naive persons than for people taking high doses of agonists. In the former group, the line would slope upward and flatten in days to weeks. In people taking high doses of opioid agonists, the line would slope steeply downward over the course of minutes, and flatten at the same level as for the first group of patients. The steep, downward-sloping line would represent the forced-lowering of tolerance by buprenorphine, which is experienced as precipitated withdrawal. In precipitated withdrawal, buprenorphine is ‘yanking’ tolerance down suddenly. The graph would be similar for the mu antagonists naltrexone or naloxone, but the point of leveling off would be lower– theoretically at the level of zero, if enough antagonist is used.
I realize that it is difficult to develop mental images from another person’s written descriptions… but I encourage people who want a better understanding of buprenorphine to give the mental images a try. Once a person can picture the flattening of opioid effect with increased dose or blood level of buprenorphine, the mechanism of action of buprenorphine is easily understood. As long as the blood level remains above the point where the line becomes horizontal, the opioid effect does not decrease– and so from the brain’s perspective nothing wears off, and nothing ‘comes on’. Tolerance develops to that level of opioid effect within days to weeks, removing any subjective opioid effect.
After the initial days to weeks on buprenorphine, the tolerance level remains constant– even if the dose of buprenorphine is raised or lowered, as long as the dose remains above the critical level that yields the ceiling effect of the drug.
For those who want ‘just the facts’, the response of opioid receptors to high-dose buprenorphine does not change over time. Buprenorphine and Suboxone therefore do NOT stop working over time, and there is no need for the dose to change over time. If anything, my patients tend to move to a lower dose with time, as they find the minimum dose necessary to produce the ceiling effect of buprenorphine throughout the entire dosing interval.
The graphs also explain why there is no truth to the common internet comment that ‘the longer you take buprenorphine, the harder it is to stop’. Tolerance remains constant, so from a physical standpoint the journey off buprenorphine is the same in three months or three years. My own clinical experience suggests that people find it progressively easier to stop buprenorphine the longer they take the medication. I have no proof for if or why that occurs, but I suspect that a number of psychological factors are responsible—including the transformation to a new, non-using identity that allows withdrawal symptoms to act aversively and remind people of their desire to stop opioids.
In other words, I suspect that being on buprenorphine for a long time reduces the cravings during withdrawal, instead causing cravings

Toward Understanding Ibogaine

First Posted 12/30/2013
Paul Dessauer, Outreach Coordinator at WASUA, the Western Australian Substance Users’ Association, often adds insight to issues that come up on my blog. He shared a few comments in response to my post about ibogaine, and at my request gave permission to post his remarks here. His comments include a summary of the receptor actions of ibogaine known to date, a description of the legal status of ibogaine ‘down under’, and several links to further information.
The information provides a good example of how knowledge is gained about psychoactive substances through combining research data from different areas of study. Psychologists assess the effects of the drug on different aspects of behavior. Neurochemists identify the actions of the substance at different receptor systems, with an understanding of the anatomy and interconnections of those receptor systems. Neurophysiologists identify the effects of the substance on firing patterns in different brain regions. All of this knowledge is added to the things we already know about brain function, to push our understanding a bit further. Neuroscience is inefficient, as single studies rarely provide significant gains, and some studies yield results counter to the findings of other studies. But little by little, over years, we gain an understanding of how a substance affects brain function.
I thought it appropriate to share some information about WASUA:
WASUA Vision:
To improve the health and social circumstances of substance users, utilising a framework underpinned by harm reduction and peer education.
Mission Statement:
To provide support, education and advocacy and to reduce transmission of Blood Borne Viruses and the harms and hazards associated with substance use amongst people in Western Australia.
His Comments:
We should always be skeptical in the extreme of any treatment modality that is presented as a universal “cure” or “magic bullet”, but at the same time we must be careful that the blind zeal of enthusiasts doesn’t cause us to dismiss potentially useful tools out of hand.
Pharmacologically, Ibogaine is a very interesting substance, as it’s a psychedelic tryptamine that is an agonist at 5-HT2A (serotonin receptors) but also acts as an antagonist at NMDA receptors, is an agonist for kappa-opioid receptors and also non-competitively inhibits nAChR (nicotinic acetylcholine receptors).
Serotonin agonists include LSD and a great many other hallucinogenic drugs.
Like dopamine and glutamate, NMDA (N-methyl-D-aspartate) is heavily implicated in the development and maintenance of dependence to many drugs.
Nicotine binds to nAChR (nicotinic acetylcholine receptors), and the drug Zyban (bupropion), which is used as a smoking cessation treatment, blocks acetylcholine receptors.
Just to complicate this pharmacological profile further, Ibogaine is metabolized in the liver (via CYP450 2D6) to produce a psychoactive metabolite noribogaine (12-hydroxyibogamine).
Noribogaine is most potent as a serotonin reuptake inhibitor, reinforcing the serotonergic effects of the parent molecule. It also acts as a moderate κ-opioid receptor antagonist and a weak µ-opioid receptor full agonist, (mu-opioid receptors mediate the euphoric effect of opioids).
(Opioid receptors come in three classes- kappa, mu, and delta. Ibogaine binds most strongly to κ- opioid receptors, shows less affinity for μ receptors, and no affinity for δ receptors. Noribogaine binds to all three classes more strongly than Ibogaine does). http://www.ibogaine.desk.nl/ch05.pdf
It is possible that this action of noribogaine at the κ-opioid receptor may contribute to the psychoactive effects; the hallucinogenic plant Salvia divinorum contains the chemical salvinorin A which is a highly selective kappa opioid agonist.
As an opioid receptor agonist, Ibogaine actually potentiates opioids. It’s been demonstrated in a couple of small studies that co-administering Ibogaine with morphine stops the development of tolerance and decreases the chance of dependence- but no-one has used this effect clinically, apparently because the dangers of overdose due to potentiation.
Animal studies show that Ibogaine appears to reduce or repress the urge to self-administer morphine in some, but not all, rats who are morphine-dependent, eg;http://www.sciencedirect.com/science/article/pii/0014299991904745
It also inhibits cocaine self-administration, eg;http://www.sciencedirect.com/science/article/pii/001429999390212Z
Both of those rodent studies show a dose-response relationship, with more of the rats ceasing or reducing self-admin if they were given three doses over a three week period, than from a single dose.
More; http://jpet.aspetjournals.org/content/288/1/88.short andhttp://jpet.aspetjournals.org/content/275/2/753.short
Although Ibogaine treatment is apparently not illegal in Australia, Ibogaine is a very strictly controlled substance.
The import of ibogaine is specifically prohibited under Schedule 4 (import regulations) of the Customs Act. Under the definition of the law ANY material containing the listed substance is deemed to be that substance. Hence, all ibogaine containing material is a drug prohibited import. However, there are no restrictions on possessing ibogaine containing material, seed or live plants in Australia, except that pure ibogaine may not be sold or possessed as a therapeutic product without prescription.
NOTE: Under customs law the importation of 1g of ibogaine is equivalent to importing 1g of heroin. The importation of 100g of iboga bark is equivalent to importing 100g of heroin. The importation of 1g of ibogaine dissolved in 100ml of water/alcohol (eg a tincture) is equivalent to importing 100g of heroin.
Legal status in Australia; http://shaman-australis.com.au/shop/tabernanthe_spp_cp_110.php andhttp://www.shaman-australis.com/forum/index.php?showtopic=26958.
New Zealand’s regulators decided to classify Ibogaine and its primary metabolite as a prescription medicine, but this actually makes it more difficult to legally source, as previously it was unregulated. Interestingly, in their review they mention that Ibogaine in NZ as an un-regulated drug was associated with about the same number of deaths per annum as the most strictly regulated prescription drug, methadone. Here is the decision; http://www.medsafe.govt.nz/Profs/class/mccMin03Nov2009.htm
Scroll all the way down the page to item 10. “General Business”, and you’ll see that Ibogaine is Item 10.1 There is actually a good, concise summary of what we know about this drug at 10.1, – well worth a quick read if you are interested in Ibogaine.
There is a native Australian Ibogaine Shrub, containing extractable quantities of the drug, although there appears to be no surviving tradition of Aboriginal people ever using it. (Although just because there is no surviving evidence of current or pre-European-settlement Aboriginal cultures using it, doesn’t mean none have ever done so during the 60,000 years or more that they’ve populated Australia. Other psychoactive plants, like Pitjuri (contains nicotine and scopolamine) and Psilocybin mushrooms were exploited ritually and recreationally by traditional Aboriginal peoples, and Pitjuri was traded all over the continent).
Australian Ibogaine (or Iodine) Bush ;http://www.somemagneticislandplants.com.au/index.php/plants/87-tabernaemontana-orientalis
I’ve met a handful of people who have used Ibogaine to treat drug dependency, but not a large or broad enough sample to have a strong opinion about its effectiveness. (In a similar fashion, I’ve met a couple of Americans and one Mexican guy who, every six to nine months, go out in the desert with Huicol people and eat peyote, and all three swear this is what has allowed them to overcome serious drug addictions). Because of the ambiguous legal status in Australia, only 1 or two places advertise Ibogaine treatment, I don’t know how many customers they get, and I don’t know how professional these outfits are.
Ibogaine treatment centres in Australia and New Zealand; http://www.ibogaine.co.uk/options.htm#Aus
Testimonials about Ibogaine treatment; http://www.iboga.com.au/testimonials.html
More; http://shaman-australis.com.au/Website/Constituents/Ibogaine.html
Hope this is a useful info.
Regards,
Paul

A Letter from Drug Court

I recently received a note from an area drug court, asking for help tapering one of my patients off buprenorphine. The patient came to me 4 years ago after being treated for a congenital pain condition. He had been treated with 150 mg of methadone per day, becoming dependent on the medication after taking it for several years.
He did great on buprenorphine for the past four years, but when a buddy offered him some surprisingly-potent heroin he decided to see what all the excitement was about. He overdosed and almost died, and was charged for heroin possession as he recovered in the hospital. I’m convinced he would be dead if not for the buprenorphine circulating in his system.
I thought I’d share my conversation between the person taking his case at drug court. Names have been left out so that I don’t aggravate my patient’s situation:
Hi Dr. Junig,
I am the ZZZZ County Treatment Drug Court Coordinator and am writing to you in order to get your input and expertise on a taper down plan for XXXX involving his Suboxone. XXXX began an Intensive Outpatient Program this week with the ZZZZ County Health & Human Services Department. XXXX’s therapist is YYYYY. Our understanding is that XXXX currently takes Suboxone three times a day for pain. Our goal would be for XXXX to be clean and no longer on Suboxone in the future. Please feel free to contact me or email me regarding this matter.
I appreciate your time.
Thank you.
My Response:
Dear Ms. AAAA,
I will be as helpful as I can.   I ask that you consider my hesitance to endorse the plan, though, after reading my comments below.
Understand that while XXXX messed up recently, he did well on buprenorphine since 2011. Before that time, he was taking over 100 mg of methadone per day for pain related to PPPP syndrome, and taking narcotics from physicians before he went on methadone.   I moved him to my AODA group from the pain group since his last appointment, providing a different intensity of observation for abuse of other substances, and requiring him to avoid other substances entirely, including alcohol.
As you know after meeting XXXX, people on buprenorphine are not impaired. They have complete mu tolerance, and look and feel normal. They also have an extremely low incidence of death by overdose.   In the past ten years, on average, 40 people per year in the US  have died with buprenorphine in their bloodstream— the same as the number of people who died from lightning strikes (they didn’t die from buprenorphine; they died from other drugs, and happened to have traces of buprenorphine in their bloodstream). It is VERY hard to overdose when buprenorphine is in the body; XXXX would certainly be dead had he taken what he did a few months ago, and NOT been on buprenorphine.
The 40 deaths per year on average in people with buprenorphine in their system compares to over 35,000 deaths per year in people who have no buprenorphine in their system. Because of the very strong protective effect that buprenorphine has against death, I am always reluctant to stop buprenorphine maintenance or pain treatment, as doing so leaves patients unprotected— while relying on traditional AODA treatment, which as you likely know has a very low success rate.
I have had six patient who were forced off buprenorphine or Suboxone by PO’s, drug courts, or family members, who died within a couple years of stopping buprenorphine.    For that reason, I think that XXXX should receive informed consent that if he uses drugs while not on buprenorphine, he will have a much higher risk of death by overdose. That fact is pretty clear from the data about overdose in the US.
As for the process of tapering, be sure to check out my forum at www.suboxforum.com where people discuss all sorts of methods, ranging from tapering all the way down to zero, versus stopping ‘cold turkey’. The best approach in my opinion is to taper relatively quickly down to 4-8 mg per day, as a taper in that dose range causes minimal or no withdrawal symptoms.    From there, I recommend reducing his dose each week by a small amount, i.e. from 4 mg, to 2 mg, to 1 mg per day, dropping each week. Below 1 mg per day, the specific pharmacodynamics of the drug makes it difficult to taper, because the ceiling effect that allows people to feel relatively even between higher doses becomes irrelevant, as people drop below the ceiling effect and feel sick between dosing.
The best option may be to stop buprenorphine completely when he gets below one mg per day, and put up with the withdrawal for about 6 weeks. The misery starts to get less severe at about the 3 week mark.   Clonidine is a blood pressure med that reduces the intensity of opioid withdrawal, and I would be happy to prescribe it for him if he sets up an appointment to plan all of this out at some point.
Again, please plan on following his progress after he stops, because I want you, and anyone else who is involved with this approach, to be aware of what usually happens.   I was med director of QQQQ (a long-term residential treatment program) for several years, until I tired of watching people pay $7000, get cleaned up, die from overdose a month after discharge. I think that XXXX has a less-severe addiction than many people, so I won’t send a real angry letter your way (believe it or not, I sometimes get even more annoying on this topic!).   But I do worry for XXXX’s sake after working with him for the past 4 years. If my son were ever addicted to opioids, I would sleep much better knowing he was protected from death by taking buprenorphine.
Feel free to write if I can be of help.
Jeff J

Wasting Resources on Suboxone

Originally posted 1/26/2013
Readers of this blog know that I have often questioned whether there is any clinical difference between Suboxone and generic buprenorphine. Naloxone is an opioid-blocking chemical added to buprenorphine, supposedly in order to reduce intravenous diversion of the medication. The combination of buprenorphine plus naloxone is branded as Suboxone. I’ve pointed out over the years that the high affinity of buprenorphine at the opioid receptor is too great to be overcome by the amount of naloxone in a tablet or two of Suboxone, making naloxone unnecessary for anything except to create profits from Suboxone.
Because of the low number of doctors who obtain certification to prescribe buprenorphine and the limits on number of patients per doctor, many people who want treatment with buprenorphine are unable to find it. While sitting on wait lists, some people opt to treat themselves with ‘street Suboxone, rather than continue to use oxycodone or heroin.
When taken through the proper sublingual route, about 25-33% of the buprenorphine in Suboxone reaches the bloodstream. Because of the scarcity and high cost of Suboxone, patients who engage in self-treatment sometimes choose to inject the medication, since doing so reduces their costs by 70%.
I have treated patients who described injecting buprenorphine or Suboxone while waiting for a treatment spot to open up. The patients always claim the same thing; that they could detect no difference between injecting Suboxone, with the medication’s naloxone component, vs. injecting plain buprenorphine.
I am not advocating injecting Suboxone by any means; injecting any substance not intended to be used intravenously is very dangerous, particularly in people who are not clinically monitored, by people who are not trained in aseptic techniques. My point is that in an era of limited healthcare resources, should insurers and state health agencies use a medication that costs four times more than the clinically-identical generic?
The reasoning behind Suboxone makes sense on the surface. Naloxone is poorly absorbed from the mouth, whereas buprenorphine dissolves through cell membranes and enters the circulation when Suboxone is placed under the tongue. Naloxone is swallowed, absorbed by the intestine, and destroyed at the liver. But if injected, the naloxone is not destroyed, and instead binds to opioid receptors, blocking the effects of buprenorphine.
But what if naloxone doesn’t do what everybody thinks? I’ve done binding studies of other neural receptors back in my grad school years, and I’ve wondered, from those experiences, just how well a loose-binding drug like naloxone would interfere with the binding of a very tightly-binding drug like buprenorphine?
A study in human volunteers from 2006 does nothing to reduce my curiosity (1). In the study, adult volunteers received 0.2 mg of intravenous buprenorphine and the respiratory effects were measured. The volunteers then received different doses of intravenous naloxone, and the ability of varying doses of naloxone to block the effects from buprenorphine were measured.
The study found that 2 mg of naloxone, the amount in a standard tablet of Suboxone, blocked the respiratory effects of 0.2 mg of buprenorphine. But the study found that lower ratios of naloxone had no effect on buprenorphine. A tablet of Suboxone contains 40 times more buprenorphine than was used in the study.
According to the 2006 study, naloxone had no effect on buprenorphine when administered intravenously in the ratio of 4:1. In fact, naloxone became effective only at doses over 10:1. But when a person injects Suboxone, the ratio of naloxone to buprenorphine is much, much smaller— equal to 0.25:1. According to the 2006 study, a dose of Suboxone would have to include 80 mg of naloxone in order to block the respiratory effects of 8 mg of buprenorphine!
To restate the findings, blocking the effects of buprenorphine requires a dose of naloxone ten times higher than the dose of buprenorphine. Suboxone contains only 2.5% of the naloxone that would be necessary—-an amount that isn’t even in the ballpark of what is needed to block the effects of buprenorphine.
If naloxone isn’t doing anything, why do insurers demand that people spend the insurers’ money on it?

Van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006;105(1):51–57