Tag: Suboxone withdrawal

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.

Opioid Withdrawal Treatments

A post on the Forum asked about the best remedies for opioid withdrawal.   I will review the medications and other treatments for opioid withdrawal that I have heard discussed by physicians or by people on the internet.  Hopefully readers will leave comments about medications or approaches that they have found useful.  Likewise, if you are a physician, please weigh in with the approaches that you have found to be useful.
For readers, it is very important to understand a couple things about this post.  First, the medications listed here are not FDA approved for treating opioid withdrawal.  They have not been systematically tested for that purpose. Most of the medications that I will list are available only by prescription— and must be taken ONLY by prescription.  They all have interactions with other medications, and they all have toxicity in certain doses, and in people with certain conditions.  Do NOT take them other than through guidance by your doctor.  This post is intended to spark discussion with your doctor— and to help doctors learn about approaches that they have not heard about elsewhere.
I will encourage doctors or other contributors to this post to avoid discussion specific dosages.  These medications must be prescribed by physicians who understand them, or who know how to become knowledgeable about them.
One problem for doctors is that CME meetings generally discuss treatments that are FDA indicated.  I do not know of any medications that have been approved or marketed specifically for opioid withdrawal, and I do not have the sense that the field of medicine views opioid withdrawal as a pressing issue.  But I am aware that for buprenorphine patients, the treatment of withdrawal symptoms has the highest priority of any medical concern.
With those caveats, here are the medications that I have heard the most about, roughly in the order of what consider their usefulness:
– Clonidine:  Available by tablet or by patch.  The medication reduces CNS excitability, and relieves all opioid WD symptoms to some extent.  Side effects include sedation (which may be useful), dry mouth, and hypotension.
– Gabapentin:  An anticonvulsant that some people find relieves anxiety and perhaps the sweating during withdrawal.
– Benzodiazepines: A controversial topic.  They are potent sedatives, but they are also potent respiratory depressants when combined with opioids.  Most overdose victims have these drugs on board.  They relieve anxiety, insomnia, and muscle tension, and cause fatigue.  Should NEVER be combined with opioids unless under very careful supervision (i.e. ‘self treatment’ = NO treatment).
– Phenobarbital: A Forum participant wrote that his/her doc prescribed phenobarbital for opioid withdrawal with great success.  All barbiturates act similarly to benzodiazepines, and have potent respiratory depression, especially with opioids.  Again, must NOT be used except under close supervision.  Have effects similar to benzodiazepines.  Dangerous if combined with alcohol.
– Quetiapine: AKA Seroquel.  A potent sedative, used to treat psychosis, bipolar mania, depression… and off label, insomnia.  Side effects include dry mouth and sleepiness.
– Natural ‘remedies’: A variety of withdrawal remedies are advertised on opioid-related web sites.  I’ve had patients who tried most of them, and I’ve never heard anyone say they were useful. Some come in ‘daytime formula’ and ‘nighttime formula’.  Always read the ingredients– and if you see a long list of herbs and roots, realize that there is NO oversight of the claims that are made.  You could put bundles of dandelions into empty capsules and sell them over the internet, making the same claims.  How hard do you think it would be to find a people to write ‘testimonials’ for twenty bucks? Or you could just write them yourself! Buyer beware.
– Amino acids:  Again, advertised on the internet, and offered at steep cost by ‘select’ doctors.  One of the ‘pioneers’ of amino acid treatments for withdrawal was convicted of fraudulent practice in Texas, and now offers the same as he did in Texas, but safely across the border, in Mexico.  He has clinics in the US, run by other doctors, who boast of using his methods.  The appeal of buying into a treatment that was proven fraudulent in court escapes me.  But the treatment of opioid dependence is strongly influenced by perception, and so is strongly subject to placebo effects.  The appeal of snake-oil remedies has created a living for many, many charlatans over the years, and a sucker is born (at least) every minute.
– General sedatives:  Insomnia is such a big problem that anything that helps with sleep will help during opioid withdrawal.  Meds include diphenhydramine and hydroxyzine (antihistamines), zolpidem and zopiclone (short-term sleep meds), and trazodone and mirtazapine (sedating antidepressants).   Cyproheptadine is a sedating antihistamine that reduces nightmares, and stimulates the appetite.
– Stimulants:  I’ve read of people using them to fight the depression and fatigue during withdrawal.  That use of a schedule II medication may be illegal in some states, and is probably frowned-upon by agencies that regulate medical practice.  The energy and mood effects from stimulants are temporary, and must be ‘paid back’ with fatigue and depression when the stimulants are discontinued.
– Naltrexone: An opioid antagonist that has been used to speed the reduction of opioid tolerance.  Naloxone and naltrexone are used during rapid detox, under strong sedation or anesthesia, but I believe that some have used naltrexone in very low doses in awake patients.  If you are a doc who knows about this approach, I’m all ears…
– Antidepressants:  Depression is one of the worst aspects of opioid withdrawal.  Antidepressants would seem appropriate… but I know of no antidepressant medications that have a chance against the severe depression caused by opioid withdrawal.  I’ve used them for patients after the withdrawal ends, when depression lingers… but I see little use for them during acute withdrawal.
Gosh, I thought my list would be longer.  Given how many people suffer through discontinuation of opioids, our approach to easing misery is pretty limited.   I will remind readers–  most of the medications listed above will cause serious harm, if taken without doctor supervision.
If you are a doctor who has found success with other medications, or if you are a patient of such a doctor, leave a comment to help spread the knowledge.  If you are not comfortable with leaving a post, send me an email, or a message through LinkedIN.
 

A New Way to Stop Suboxone?

Originally Posted 10/27/2013
I usually have my wife/business partner review my posts and provide her opinion whether my arguments are sound.  For the record, she tells me that this post is technical and boring.  I disagree, but we aren’t planning to separate over the issue.  A valid criticism, I think, is that I’m doing a lot of guessing and wondering in this post.  This post is an example of the things I waste time wondering about.   I try to avoid writing things that are somewhat speculative, but I wanted to give it a shot for two reasons.  First, because there may actually be something to the idea I am about to describe.  But more important, I wish to point out some of the many ideas in the addiction world worth exploring…. And I hope that pharma continues to search for answers (i.e. spend money) in this area of medicine.
So I’ve been thinking more about ALKS 5461, the Alkermes pipeline medication that is a combination of buprenorphine and ALKS 33, which is a mu opioid antagonist also called Samidorphan with the structure shown at the left. ALKS 5461 is being developed by Alkermes for the treatment of major depression.  I don’t know much about the clinical actions of ALKS 33, (a proprietary molecule), except that it comes from a family of drugs that bind with high affinity and specificity to mu or other opioid receptors.  Samidorphan, a mu receptor antagonist, allows investigation of buprenorphine’s potential therapeutic effects at kappa and delta opioid receptors by blocking effects at the mu receptor.  Drugs with actions at other opioid receptors have be developed, and in some case patented.Until recently, theories about depression revolved around abnormalities in brain monoamine pathways or deficiencies of monoamine neurotransmitters.  Monoamines include serotonin, melatonin, and the catecholamines (noradrenaline, dopamine, and adrenaline). Most modern antidepressants act at serotonin or catecholamine receptors or reuptake sites. The new Alkermes medication ALKS 5461 is the first serious effort that I am aware of to treat depression from the opioid perspective.
Our brains contain natural opioids called endorphins and enkephalins.  Endorphins and enkephalins are neurotransmitters in pathways with a wide range of actions, including blocking pain and raising mood during injury or sexual activity. Pain pills such as oxycodone displace endorphins and hijack the natural endorphin pathways, providing euphoria without the trouble of buying flowers.  Of course, a relationship with self-administered opioids always becomes more destructive than even the most codependent partnership!
As an aside, when I presented for addiction treatment 13 years ago I told the addictionologist about my background in neurochemistry, and went on to explain that I was fairly certain that I suffered from a deficiency of natural opioids.  That doctor got a kick out of my story, and I would enjoy a sense of justification if my hypothesis someday proved to be correct.
When one considers using treating depression with buprenorphine, the obvious deal-breaker is the same issue that has prevented every other serious consideration of treating depression with opioids, namely the development of tolerance at the mu opioid receptor.  Because of tolerance, anyone who finds relief from depression with buprenorphine would be cursed by the need for eventual withdrawal, as well as other consequences of opioid dependence. I assume that Samidorphan is added to ALKS 5461 to prevent mu activation and tolerance.  Beyond partial agonist effects at the mu receptor, buprenorphine antagonizes (blocks) delta and kappa opioid receptors.  These blocking actions are not subject to tolerance, and may provide avenues for treating pain and/or depression.
Depression causes significant morbidity throughout the world, so there are huge profit incentives for new antidepressant medications. Addiction creates a large market as well, but companies rarely go as far out on a limb for addiction products as they do for other diseases. The need for new antidepressants is acute, but in an alternate universe where pain and addiction treatment take priority, Samidorphan and related opioid molecules might have a number of benefits. I’ve posted, for example, about my experience treating severe chronic pain by combining buprenorphine with an opioid agonist.  I expect the combination to be exploited eventually given the need for effective pain treatments, perhaps using an analog of Samidorphan.
Doctors use buprenorphine to treat opioid dependence.  The goal of buprenorphine treatment is to block the cycle of use and reward for some period of time, and to allow patients to create support systems, establish self-sufficiency, regain self-esteem, and practice living ‘life on life’s terms.’  The amount of time that it takes to accomplish these goals likely varies depending on the individual’s premorbid function, life experiences, insight, genetics, and other factors, but studies suggest that a year is not long enough to make meaningful headway.   It is possible that for some people, opioid dependence is a relatively permanent condition that is best controlled with life-long maintenance treatment.   But for those who would like to try to maintain sobriety off buprenorphine, the tapering process reignites the circuits that were set up by the initial addiction, causing cravings, withdrawal, and the constant obsession to delay the taper and resume the prior day’s dose of opioid.
If ALKS 33 has a long half-life and blocks buprenorphine in a dose-dependent manner, I could picture an alternate strategy for stopping buprenorphine where the antagonist (ALKS 33) is introduced to buprenorphine patients at a gradually-increasing dose.  The goal would be to eventually have the person on a daily dose of Samidorphan sufficient to block all of buprenorphine’s effects at the mu receptor, at which point the person could discontinue buprenorphine without withdrawal.  I suspect that the patient would experience withdrawal in response to each increase in dose of Samidorphan, although withdrawal would be reduced by introducing the drug at a measured pace.
What is the value in tapering in such a ‘reversed’ way?  Why would adding an antagonist be preferable to the current process, i.e. simply reducing the dose of buprenorphine over time?  The answer comes from an understanding of the nature of addiction.  A person stopping buprenorphine by gradually adding Samidorphan would face the decision once per day, whether to take the next dose of Samidorphan.  Compare that once-per-day decision to the current method of tapering buprenorphine, where the person must decide, thousands of times per day, to NOT take more buprenorphine.  I would expect that deciding to take an antagonist once per day would be more likely to succeed then CONSTANTLY deciding NOT to take buprenorphine all day long, throughout all of life’s ups and downs—times when the patient was conditioned to take opioids.
We will learn more about Alkermes new medication in coming months. I hope that someone in a power position will consider some of the other diseases that might respond to these interesting chemicals, including opioid dependence.

Withdrawal Work-Up II

First posted 11/11/2012
In my last post, I wrote about the work-up of a patient who experiences symptoms similar to opioid withdrawal that start about an hour after each dose of Suboxone. We decided that the symptoms were signs of withdrawal—i.e. reduced activity of mu-opioid pathways—and that the symptoms were triggered by taking a daily dose of Suboxone (buprenorphine/naloxone).
Note that I wrote that the symptoms seemed to be caused by reduced mu activity, i.e. not necessarily by reduced mu-receptor binding. Endogenous opioid pathways are very complex. Decreased activity in opioid pathways may arise from decreased binding of agonist at the receptor, or from changes in a number of other chemical or neuronal pathways.
This diagram shows the processes that are triggered by mu-receptor binding in humans before and after opioid tolerance. The diagram only shows the complexity of processes within one type of neuron with opioid receptors; realize that each neuron 1. Has receptors for many other neurotransmitters as well, and 2. Receives input from thousands of other neurons. As we sort through possible causes of our patient’s symptoms, keep in mind the complexity of neural pathways.
While we are on the subject of complexity, the web site linked above is an incredible resource for those interested in biochemistry. The site includes diagrams of a number of metabolic pathways that describe how different molecules, including neurotransmitters, are manufactured by the human body. I encourage people to browse the site. You will gain insight into why the actions of substances are difficult to fully predict.
The withdrawal symptoms experienced by our patient might arise from dysfunction in any one of the many chemical pathways that affect opioid tone. But since a dose of Suboxone contains naloxone, a mu-receptor inverse agonist, it is possible, maybe even likely, that the naloxone is related to symptoms.
Naloxone is less lipid-soluble than buprenorphine and so only a small portion—about 3%– of a dose is absorbed through mucous membranes. The rest of the naloxone is swallowed, consciously or inadvertently, and eventually absorbed from the small intestine, to pass to the liver via the portal vein. The entire dose is usually metabolized by the liver before gaining access to the general circulation, a process called ‘first pass metabolism.’ If our patient’s withdrawal symptoms are caused by naloxone, we have to find a way for the naloxone to enter the general circulation, so that it can displace buprenorphine from mu receptors in the brain.
Absorption through oral mucosa is unlikely to vary from one person to the next. Some molecules become more lipid-soluble in acidic or basic pH environments, but not naloxone. I suppose that absorption might be increased by removing layers of the oral mucosa by vigorous brushing, but I doubt we could get a significant increase in absorption without considerable painful damage to the oral mucosa.
Likewise, there is little difference in the absorption of molecules by the small intestine in the absence of significant disease processes affecting the GI tract. Absorption and liver metabolism of some drugs may be changed by surgeries, such as gastric bypass. But our patient has neither gastro-intestinal disease nor history of surgery to his GI tract.
Naloxone is metabolized by a liver enzyme called UDP-glucuronyl transferase. The enzyme attaches a molecule called glucuronic acid to naloxone, creating a larger molecule that is easily excreted by the kidneys. I have been reading up on glucuronidation, suspecting that something may be interfering with that process in our patient to cause an increased blood level of naloxone. Biochemists are invited to correct me if I am wrong, but from my reading, the glucuronidation process is not limited to specific cytochromes. Whereas buprenorphine is metabolized by CYP3A4 and CYP2C8, two groups of enzymes that are inhibited by certain medications, the glucuronidation of naloxone is not blocked by other medications.
In layperson’s terms, I suspected that the patient was taking a medication that blocked the breakdown of naloxone at the liver, causing an increased blood level of naloxone that then interfered with buprenorphine activity. There are a number of medications that block the breakdown of buprenorphine, but none that I could find that block the breakdown of naloxone. Dead end.
The patient was taking an antihistamine, cetirizine, which is excreted mostly unchanged at the kidneys, but I have not found any evidence that the excretion of cetirizine interferes with the metabolism or excretion of naloxone. Likewise for the Lexapro he was also taking. Dead end again.
It would have been cool had I discovered a precise explanation for the patient’s symptoms. Had I found a logical explanation for his symptoms, I would have suggested changes in his medications and submitted the drug interaction to a peer-reviewed journal as a case report. The patient would feel better, and fame and fortune would be one step closer…
But the true outcome is more instructive, as it is more consistent with what usually happens. I will explain to the patient that I do not have a good explanation for his symptoms, and whatever we do going forward will be ‘educated guesswork.’ But I hope that after reading this, people will understand that even when we can’t find the answers, it isn’t from lack of trying. And like other doctors I will continue to read the literature, as our knowledge of med/med interactions, while complex, still has a long way to go.

Withdrawal Symptoms on Suboxone

Originally posted 11/7/2012
I struggle with the length of my posts. I shoot for 1000 words—an amount of reading that most people can knock off in a typical trip to the bathroom— but I find it difficult to limit posts to that size. So as I have done in the past, I will break this post into a couple of sections. In the first, I’ll lay the groundwork for investigating symptoms of withdrawal in a patient taking buprenorphine. The second post will go into greater detail.
A patient recently contacted me to complain that he was experiencing withdrawal symptoms for several hours after each dose of Suboxone. I will describe my thought process, in case the description helps someone else experiencing similar symptoms.
My first decision point is whether or not the person is truly experiencing symptoms of withdrawal. Some people will misinterpret symptoms from excess opioid stimulation as withdrawal symptoms, for example. Nausea is a not-uncommon complaint among people taking buprenorphine, and patients often assume that nausea is the result of insufficient opioid activity, and so take higher doses of buprenorphine. But nausea is actually more common in opioid overdose than during opioid withdrawal, along with constipation, whereas withdrawal primarily causes diarrhea.
Pupil diameter is a good indicator of withdrawal vs. overdose; small or ‘pinpoint’ pupils suggest an excess of opioid activity, whereas withdrawal is associated with very large pupil diameter.
Other symptoms are also misinterpreted as withdrawal. Many opioid addicts develop a strong fear of withdrawal over years of using, and so ‘withdrawal’ is often the first thing to come to mind, during unpleasant symptoms. I also believe that the experience of withdrawal becomes learned in a way that allows the symptoms to re-occur after certain triggers. I remember an experience years ago, when I awoke from a dream experiencing significant withdrawal symptoms, even though I had not taken an opioid agent for years. I feel back asleep, and was grateful to find that the symptoms were gone, when I woke the second time.
People are angered by the notion that their symptoms have ‘psychological’ origins. But as a psychiatrist, I have seen people blinded or paralyzed by conversion disorder. If the mind can cause paralysis (and it can), I have little doubt that the mind can cause other physical symptoms.
If, after these considerations, the symptoms seem consistent with symptoms of opioid withdrawal, the next step is to compare the timing of the symptoms with what would be expected from various causes. For example, withdrawal symptoms occurring shortly before the next dose of buprenorphine (or Suboxone) suggest that the dose is not quite high enough. Buprenorphine eliminates cravings if kept at a blood level above that necessary to maximally occupy mu opioid receptors, because then fluctuations in blood level have no effect on opioid activity. But if the blood level of buprenorphine decreases below that threshold, cravings and/or withdrawal symptoms will occur.
If the symptoms occur shortly before dosing, the solution would be to increase the daily dosage of buprenorphine, decrease the dosing interval, or increase the efficiency of dosing. I have discussed ways to increase dosing efficiency here.
This particular patient describes symptoms of withdrawal beginning about an hour after taking Suboxone. Absorption of buprenorphine takes 1-2 hours, and so the timing could suggest that the dose needs to be increased. But if dosage is truly the problem, we would expect even worse symptoms if he delays his daily dose by several hours—as that would allow the blood level of buprenorphine to fall even further. But in this person’s case, delaying the dose of Suboxone delays the withdrawal symptoms. The symptoms continue to occur about an hour after taking the medication, suggesting that the dosing itself is causing the symptoms.
I cannot imagine a scenario where a sublingual dose of buprenorphine would cause true symptoms of withdrawal, an hour after the dose. At this point we need to look at the naloxone component of the medication, and determine whether the naloxone is causing unpleasant symptoms— and if so, why.
To be continued…