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 Medications

I owe it to readers to make it clear that I do not endorse any product sold for the expressed purpose of reducing opioid withdrawal. I have PPC ads on the site, but I have no control over the ads that run in them. I am not saying that the products that often appear in ads do NOT work– only that I have not prescribed or advised people to use them, and know of no peer-reviewed studies showing them to be effective or ineffective.
As always, caveat emptor.

Rapid Opioid Rip-Off

While I’m on the subject of rip-offs, I’ll mention an extreme form of ‘detox capitalism’; a process called rapid opioid withdrawal, rapid detox, or ‘the Waismann Method.’
The name of the process supposedly comes from a certain ‘Dr. Waismann’ who helped Israeli soldiers get off opioids after they were treated for various injuries.  It sounds like a pretty exciting history, but to be honest there is nothing in the technique that takes a rocket scientist to figure out.  The basic idea is to precipitate withdrawal using an opioid antagonist— something that is done many times over every day in emergency rooms across the U.S.—but to do it while the person is sedated with non-opioid medications.

Put me out, Doc!

I never expected to admit this back when it occurred, but I had the bright idea of putting myself through ‘rapid opioid detox’ shortly before entering treatment ten years ago, when I was desperately searching for a way to free myself from opioids.
Like any typical addict I wanted to do it entirely by myself, figuring that I knew as much about opioids and medicine as anyone else.  I loaded up on naltrexone (an oral form of naloxone) thinking that the antagonist would block my receptors, lower my tolerance, and prevent me from using for as long as I took the naltrexone.
I simplified things a bit by omitting the sedation—a good idea since there was no other doctor monitoring me, but a bad idea because I experienced about a week of withdrawal condensed into several intensely-miserable hours.  I remember being shocked at just how much sweat my body could produce in such a short time, as liquid beaded on my skin as fast as I could wipe it off!
After the real horrible period—the period that I would have slept through had I come up with $15,000 plus airfare—I remained quite ill for a matter of weeks.  And of course that is what happened, since it takes weeks for tolerant mu receptors to be replaced by new, normal mu receptors.  Until the receptors are replaced, the brain’s endorphin pathways remain quiet, causing hypersensitivity to pain—not to mention diarrhea, restless legs, cramping, gooseflesh, and depression.
There are several variations of rapid detox, but the principles are the same for all of them:
–          The addict is given a strong sedating medication or anesthetic
–          While heavily sedated, the addict is given an intravenous infusion of the opioid antagonist naloxone to precipitate withdrawal.
–          After a period of time that varies with the name of the facility, the addict wakes up;  one day of withdrawal gone, and only two more months of withdrawal to go!
–          The process costs from five to ten thousand to tens of thousands of dollars.
–          Different options are tossed in for different programs, everything short of an extended warranty: amino acid cocktails, ‘vital nutrients,’ or long-term sedatives.
–          In some cases a chip of naltrexone is implanted that slowly releases over weeks, supposedly preventing a high from using—provided the addict doesn’t become desperate and use very high doses of heroin, or dig the implant from his/her body using a fork!
Web sites for the procedure point out that opioid dependence is a relapsing illness and that people who use Suboxone relapse when they stop Suboxone (no argument from me), but go on to claim a 70% one-year sobriety rate after their rapid-detox procedure—without any explanation for how they get better numbers than Suboxone patients.  I have never seen peer-reviewed studies showing such success rates.
Speaking of peer-reviewed studies, I have seen a study of rapid detox showing what is intuitively obvious—that since it takes a number of weeks for the body to adjust to the lack of opioids, one day of sedation avoids only a tiny portion of the misery of withdrawal.  Is it worth ten grand to avoid one day of withdrawal, knowing that several more weeks of withdrawal are yet to come?  I suppose it depends on one’s checking account.
But the bigger issue is the poor long-term outcome for these people—a problem similar to what I described in my post about Sneetches.  Early in the spiral of addiction, addicts and their families are under the mistaken belief that the hardest part of ‘kicking opioids’ is to get through physical withdrawal.
They eventually they learn that they are wrong, and that it is much more difficult and rare to STAY clean than it is to GET clean—but ‘rapid detox’ makes money off their ignorance in the meantime.  Quitting opioids by rapid detox, amino acids, magic crystals, hypnosis, or a host of other expensive, highly-promoted methods reminds me of the story about the guy boasting about how easy it was to quit smoking—so easy that he’s done it over 20 times!

Withdrawal from Suboxone

I often receive e-mails asking for advice on tapering Suboxone, or asking how long Suboxone withdrawal should last.  People who read my blog know my approach to stopping Suboxone; I see it as an exercise in futility even in the rare cases where the person is successful, because of a relapse rate that verges on 100%.
A couple myths to get out of the way… there is NO evidence that withdrawal becomes more difficult the longer a person is on buprenorphine.  In fact, from my experience the opposite is true.  The feelings and emotions during withdrawal are aggravated by the guilt and shame of active using, and the further from active using a person gets, the less the suffering during withdrawal—and the better able the person is to keep some perspective on what is happening, rather than drowning in despair.  I believe that the severity of withdrawal is subject to a ‘kindling effect’, a phenomenon that affects seizure disorders and other neural activity as well.  In other words, the pathways of the brain that are used the most frequently are the pathways that are most likely to fire again.  So a person who has been through very severe withdrawal is likely to experience withdrawal as very severe, no matter what agent the person is stopping.  It would make sense that the more time that goes by in between episodes of withdrawal, the less powerful would be the kindling effect—sort of like ruts in a muddy road being erased by repeated cycles of weather over time.
Many people write on blogs or forums that Suboxone withdrawal is worse than coming off opioid agonists.  This is simply ‘poppycock!’  I have seen many, many people go through opioid withdrawal, and have experienced it myself (gratefully, many years ago!).  People going through withdrawal from agonists are very miserable; they tend to stay in bed, getting up only to race to the bathroom because of severe diarrhea.  Their legs shake involuntarily—a very uncomfortable experience that is similar to severe ‘restless legs.’  The mental effects are perhaps the worst; most people have severe depression and thoughts of suicide.  Eventually, when the person attempts to get out of bed, he/she faces weeks of profound fatigue and weakness.  During my own detox ten years ago I remember my family visiting after a week or two, and being able to walk about half a block before needing to sit and catch my breath.  Appetite is gone for weeks as well, and most people lose significant weight during detox.
Withdrawal from buprenorphine, on the other hand, rarely forces addicts into bed for more than a day or two.  I’m not saying that they don’t FEEL like staying in bed, but they will still usually get to work and engage in the activities of daily living—eating, showering, getting dressed, etc.  A simple look at the forums shows a profound difference between Suboxone and agonist withdrawal; people coming off Suboxone write about how bad they are feeling, whereas people coming off agonists are nowhere to be found— and are certainly not able to sit at the computer and type!
There are two basic approaches to stopping Suboxone.  One is to taper slowly, and the other is to just ‘jump’ and handle the withdrawal as best as possible, sometimes with the help of clonidine, benzos, or other substances.  Some people find that THC helps, but I can’t really recommend that approach—at least not in states where there are no laws allowing the use of ‘medical marijuana.’  There are a couple taper methods described here and there on the web; I described something called the ‘liquid taper method’ on the forum that uses tiny doses of dissolved buprenorphine, administered by an eye dropper.  As I mentioned in an earlier post there is a new transdermal buprenorphine system hitting the market soon, and that should make things considerably easier.  The main problem with any taper is that the person usually gets to a certain point and then realizes that a full dose would cause a ‘buzz’—and that buzz is almost impossible to say ‘no’ to, especially after being in minor withdrawal for several days or weeks!  The transdermal approach is appealing because it would allow the person to get rid of all tablets that could be used to bail out of the taper.  I can’t imagine that there is much chance of success if the person has 8 mg of tablets stashed away in the house somewhere!
Because of the tendency to bail out of a taper, most people who start out tapering end up ‘jumping’ at some point—raising the question of whether people should just jump from the start, planning to be miserable for a good few weeks, and then just tolerating it.  For those taking that approach, the main thing is to STICK WITH IT.  In order for your receptors to return to normal, you MUST be miserable— that misery is what causes the neurons to manufacture new receptors.  If you take a break from the misery by using for a day, you turn off the forces that are moving you toward feeling better, delaying the process by days to weeks.  To be direct, the quickest way to stop Suboxone and get back to zero opioid tolerance is to avoid opioids completely until you feel better.
Again, in my opinion, all of this is folly because the chance of staying clean is low. At minimum, a person must be completely free of any contacts who are using or who have access to opioids.  The person should be actively involved in some time of recovery program.  The person should have someone in his or her life who can act as a ‘reality check’ to speak up if the person starts to harbor resentments, or if the ego begins to grow out of control.  If you don’t have these things at a minimum, consider just sticking on buprenorphine.  You will save yourself a great deal of money, time, embarrassment, and who knows what else.
If you do stop buprenorphine, expect withdrawal to peak at about 4-7 days after you finally discontinue taking Suboxone, followed by slow recovery that accelerates each week.  By four weeks, you will be done with the creepy crawly legs, and your energy will be starting to return.  By two months, your sleep should be coming back—unless you are also stuck on benzos, which make sleep a big problem if you use them for more than very short-term.
By three months, you should be back to normal—assuming that you did not use opioids at all.  And you will recover fastest if you get some exercise, eat right, and stay as active as possible, even when you don’t feel like it!

Treatments for Opioid Withdrawal

I have written about this topic multiple times, but perhaps a summary is appropriate.  More and more evidence and clinical experience suggest that buprenorphine is best considered a long-term ‘remission agent’ for opioid dependence.  Such a conclusion would have been obvious years ago if not for the hesitancy to do what has been suggested by addictionologists for decades, and treat opioid dependence as a DISEASE.  While many people pay lip service to addiction being a chronic illness, the reluctance, particularly by AODA counselors, to fully accept a medication for the condition is clear evidence of the stigma that continues to force addiction into the realm of ‘character.’   AODA counselors would do well to do some serious soul-searching on this issue– at least in my opinion.
While remission therapy with buprenorphine will likely become the standard treatment for opioid dependence, there will be some cases where tapering off buprenorphine is appropriate.  The problem in such cases is that the taper process causes withdrawal, which stirs up all of the self-disgust, fear, and shame that predispose an addict toward relapse.  As I have discussed, a long-term injectable formulation (such as Probuphine, currently in the FDA approval process) would be useful for tapering off buprenorphine.  The final piece of the equation would be effective treatments for opioid withdrawal. 
A number of medications are rumored to help reduce the symptoms of opioid withdrawal.  I’ll mention a few of the medications that I have used to treat withdrawal, or that I have read about in scientific studies or case reports.
– Clonidine is the ‘standby’ agent for treating opioid withdrawal.  The medication reduces CNS excitation by effects at alpha-2 adrenergic receptors, causing less release of epinephrine and norepinephrine by central and peripheral nerve terminals.  Symptoms of withdrawal are reduced by about a third, and the primary side effect is sedation.
– Some medications target specific components of withdrawal;  Imodium (generic name loperamide) reduces bowel cramping and diarrhea; benzodiazepines reduce anxiety (but are themselves addictive); ibuprofen and acetaminophen reduce muscle aches and headache; stimulants or wellbutrin reduce fatigue (perhaps for severe symptoms, but use of stimulants would be considered controversial at best).
– Proglumide is an antagonist of two classes of receptors for a gastro-intestinal hormone called ‘cholecystokinin’, or CCK.  Proglumide used to be used in the US and elsewhere to treat gastric ulcers, before more effective medications like histamine blockers were developed (e.g. cimetadine).  There are a number of chemicals structurally related to proglumide that have similar actions, that include enhancing analgesia caused by opioids, treating Parkinsons disease, and enhancing the release of growth hormone.  Proglumide appears to ‘reset’ tolerance to opioids in people who are physically dependent, and also to reduce symptoms of withdrawal.  Proglumide appears to have dropped of the face of the planet;  if you search for the medication you will find it available in chemical supply houses in China, but not available through pharmaceutical companies.  I recently received contact from a person claiming that  proglumide is available through a company based in Pakistan, but I have not yet verified the information.  Stay tuned.
– I recently came across an article with some fairly convincing evidence that symptoms of withdrawal are reduced by the anti-anxiety medication buspirone.  A study found that self-reported withdrawal symptoms of opioid addicts were greatly reduced by treatment with buspirone, which is a pretty safe, inexpensive medication that is not itself addictive.
– Ondantreson is an anti-nausea medication used during chemotherapy and surgery.  I have seen several studies demonstrating a reduction in opioid withdrawal from the medication, which like buspirone is fairly safe and is not addictive.  Ondantreson is, however, more costly.
I have treated patients in withdrawal using gabapentin, specifically to reduce sweating and hot flashes.  I do not know if it works, or if the people who liked it were getting a placebo response.  I have not seen reports in the literature showing this benefit.
– I have mentioned the recent approval of transdermal buprenorphine, called ‘BuTrans.’  This formulation provides a lower range of doses of buprenorphine, in the tens to hundreds of micrograms (one tablet of Suboxone contains 8000 micrograms of buprenorphine).  This lower dosed formulation may find usage for tapering.
Do you have other suggestions for treating opioid withdrawal?  If so, please share them in the comments below or over at SuboxForum.  Of course, these medications must NOT be taken ‘on the street,’ but rather should be discussed with your physician if and when the time comes to taper off buprenorphine.
Thanks all,
JJ

Opiate withdrawal: hell beyond words– does your doctor care?

I am often told by opiate addicts that they would kill themselves rather than go through withdrawal again.  I assume  that the comments are  exaggerations to make a point.   But a recent nightmare helped me realize that the comments are not hyperbole– but rather are serious attempts by addicts to describe just how horrible their experiences were.  I remember my own detox only when I force myself to remember it (0r after the occasional bad dream);  I have a tendency to repress the memory, perhaps as people do with traumatic memories.  But when I really think about my experience during those 5-7 days at the end of that horrible hall in that horrible ward, I cannot imagine going through the experience again, for any reason.  I hate to say it as a psychiatrist who knows the damage done to the survivors of suicide, but I understand the logic of choosing death instead. 

The loneliness is the worst part

When I discuss addiction and detox with other doctors, one frustration is that there are no words to express the horror of severe withdrawal.  (The other frustration, by the way, is that few doctors seem interested in knowing about the experience– but I’m not going to fix that problem with my blog!)  Opiate withdrawal is not a matter of physical pain, although physical pain is surely a part of the experience.  The term  ‘depression’ likewise do not capture the experience.  Nobody has the energy or wherewithall to write during the experience, and so it is unlikely that we will read a great description recorded in ‘real time’.  But when I meditate on the experience in order to improve my memory, I am struck by the utter despair, the self loathing, the hopelessness, and the complete isolation that I felt during detox.  I remember thoughts of being ‘cursed’, or of being possessed by demons of death– I felt as if the world I had known was long gone, and I was left alone with demons.  I had no vision of hope for the future.  I remember trying to take my mind off of the horrible thoughts by directing my attention on the clock, which seemed to move backwards, it was going so slow.
I am writing this somewhat self-effacing description of the experience because of a thread in SuboxForum earlier today, from a woman who was trying to make it through 24 hours in order to get induced with buprenorphine.  She was asking whether she could use anything to help her make it, such as tylenol, ibuprofen, or the Xanax that she has been prescribed for the past year.  For the record, yes– you CAN take all of those things.  In fact, ideally a person going through the 24 hours of hell will be given sedatives, clonidine, anti-emetics, and anti-diarrheals to make the process a little more bearable. 
For any doctors who are reading this and thinking that doing so is a waste of time, or who takes refuge in saying ‘I don’t know the person well enough to prescribe those things,’ shame on you– because withdrawal really, really stinks.   To the writer on the forum this morning, I hope you made it.  If not, don’t give up.  It is hard to see in the middle of all that horror, but it will be worth it.