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.

Clonidine and Opiate Withdrawal

For those of you who like to do some scientific reading, a recent meta-analysis looked at clonidine’s efficacy in reducing the symptoms of opiate withdrawal.  A meta-analysis, by the way, is when someone takes a number of studies that sometimes didn’t reach significant conclusions and combines the numbers, creating a larger study group that sometimes shows significant results that were missed in the smaller study.  There are limitations to such an approach, but it is still a common approach to looking at infrequent things.    The infamous ‘black box warnings’ on SSRIs about suicidal ideation in children came from meta-analysis of old studies of antidepressants.

Alpha2-adrenergic agonists for the management of opioid withdrawal

SuboxDoc

Zofran for Coming Off Suboxone? (etc)

Thank you to Heather Hajek for the following report. I found the report on several health pages with RSS feeds, but unfortunately there is no byline to the article that says where ‘Heather Hajek’ writes– I did a Google search for her name and came up with a few more health articles, so I assume she is a health reporter for some newspaper. But if you find this, Heather, thanks– and I suggest you add a line to your articles stating where you are writing, as your articles are placed in newsfeeds without any identifying information.  The article:

Nausea Drug Can Help Reduce Symptoms in Opiate Withdrawal

Opioid addiction, whether illegal heroin or legally prescribed medications, is a growing problem in the United States. There are companies that are working on opioid substitutes or tamper-proof opioids, but as of now morphine is still the painkiller most prescribed by doctors after surgery, and codeine is in many prescriptions, including cough suppressants. In 2007, 12.5 million Americans 12 or older were using prescription opioid medications for non-medical purposes according to the National Survey on Drug Use and Health.
Larry F. Chu, M.D., assistant professor of anesthesia at the School of Medicine, Stanford University, said that opioid abuse is rising at a faster rate than any other illicit drug use, but only about a quarter of those who are opioid dependent seek treatment. Chu said that one barrier to treatment is that when a person stops taking the drugs suddenly it is like “bad flu” with agitation, insomnia, diarrhea, nausea and vomiting.


Chu was among a group of Stanford University researchers looking for ways to prevent the symptoms of withdrawal and was the lead author of the study on their research published in the Journal of Pharmacogenetics and Genomics. The researchers say that a drug already approved by the FDA appears to avoid some of the problems that accompany withdrawal. The drug, ondansetron, is approved to treat nausea and vomiting for those receiving chemotherapy. The scientists warned that the drug will not solve the problems that occur with the continued use of the opioids, but in tests with mice it reduced the symptoms of their addiction, jumping and pain sensitivity.
Since the drug was already approved for use in humans, the scientists then used the drug in eight healthy humans who were not opioid dependent. The group received a single large dose of morphine and in another session at least a week later they took ondansetron in combination with the morphine. The participants then completed questionnaires to assess their withdrawal symptoms. Similar to the mice, humans receiving ondansetron with the morphine had a significant reduction in withdrawal symptoms.
Ondansetron is completely different from other treatments used to treat addiction. One drug, clonidine, causes severe side effects and requires close medical supervision. Methadone and buprenorphine are not satisfactory because they replace the opioid addiction with their own addiction. “It’s like replacing one drug with another,” said co-investigator Gary Peltz, M.D., Ph.D., professor of anesthesia.
A clinical study to test another ondansetron-like drug for opioid withdrawal is planned in a larger group of healthy humans, and the research team will continue to test ondansetron in the treatment of opioid addiction. The scientists warn that ondansetron will not resolve the problems of continued use of painkillers. It will treat the symptoms of withdrawal, but not the addiction.
We now have a number of medications to help with opiate withdrawal.  I will certainly be offering Zofran to my patients who are tapering off Suboxone (those who have been on Suboxone for a sufficient length of time to extinguish the conditioning from addiction, and who are taking Suboxone once per day in an ‘automatic’ way– not ‘as needed’).  I will write back with the experiences of my patients with Zofran, which has the generic name odantreson.  Ironically, I gave many people Zofran back in my anesthesia days, as it is a good treatment for post-operative nausea.  And here I am prescribing it once again, as a psychiatrist… Who would have thought?!
As for the ‘etc’: I am receiving more and more comments and questions from people out there as the blog has become higher ranked on the search engines.  I am very grateful for the readership, and for the nice comments from people.  I am also flattered that people come to me with their questions– that you trust me with your questions.  I realize that there are many doctors out there who do not take the time to understand the issues involved in addiction, and doctors who do not take the time to talk to their patients.  I enjoy writing back to people and hearing a bit about their lives.  BUT…  tonight my wife said ‘you sure are always on that computer’… which all married people know translates into ‘it is pissing me off that you are always on that computer’.  And when I told my 14-y-o daughter that she was on the computer too much, she pointed out that I am too.  And I couldn’t really argue with her.   So…  please forgive me for not writing back as much going forward.  I feel bad about it, but I just cannot keep up.  I have said this before, and hesitate a bit… but if you have something that you really cannot find by searching the blog (most answers to questions are in here somewhere), if you drop me a $20 donation you will make me feel so guilty that I will have to respond.  I get an e-mail notice of any donation;  I’ve had 3 donations in the past year– I just add that because if I don’t someone will write and accuse me of ‘making a fortune off this blog’.  I AM happy to say that the Google ads are bringing in about 3 bucks per day– not quite enough to retire…
Thank you for your understanding.  If there is a topic you think I am missing here, always be sure to let me know!

It (gasp!) IS Hard to Stop Suboxone. Here is why.

Yes, you heard it here fir…. fourth…  it is hard to stop Suboxone.  As anyone pausing at this web site knows, it is hard to stop ANY opiate.  There are many forces at work against you when you are tapering off opiates; physical withdrawal, mental withdrawal, cravings for opiates, and the unconscious mental effects of addiction– the conditioning of your mind to see opiates as the solution to all of those uncomfortable feelings.  With all of that going on, it is no wonder that most ‘opiate tapers’ end unsuccessfully, leaving the addict more discouraged than he was before.

Suboxone is clearly different than other opiates, and the differences profoundly influence the tapering process.  I will mention my good friend Brian over at suboxonetaper.com, where he walks through his own experiences and helps a person know what to expect during the taper of Suboxone.  I have mentioned a number of times how the ceiling effect of the drug affects the tapering process;  there is minimal withdrawal going from 16 to 12 to 8 to 4 mg, but then the withdrawal kicks in during the last part of the taper.  This is probably why people leave messages here and there on internet health boards about Suboxone being ‘the worst thing to stop’;  the early stages are a cake-walk, and then the person tapering the drug gets hit with a brick at the end of the process.

What we really could use, to help people taper off Suboxone, is a tablet that is as large as the 8 mg tablet, but that contains less buprenorphine.  It would be helpful to be able to dose people with 1 mg, then 0.5 mg, then 0.25 mg, then 0.125 mg, then off.  Buprenorphine is a very potent drug;  when used for pain relief it came in solution for IV administration in microgram doses, and a dose of 50 micrograms was a potent dose;  the smallest pill form available is 2000 micrograms!  So tapering requires the use of tiny chips of a tablet during the final stages, making accuracy impossible.  In fact, if you wanted to do a proper taper with the drug you would want doses of about 50 micrograms each… and that amount is in one fortieth of one quarter of an eight mg tab.  Do you know anyone with tiny tiny fingers and macroscopic vision?

Since we don’t have a formulation that allows slow, accurate reduction in dose, we are left with doing the best that we can under the circumstances.  I think it is useful, knowing what to expect, so you don’t become too discouraged when hit with the withdrawal at the end.  One thing that seems to be different about Suboxone is that people seem to have less ‘pull’ to take more during the taper.  I don’t know if that is a real difference in the drug, or if it is just that people coming off Suboxone in my practice have taken it long enough for the conditioning that is so prevalent during active use has faded at least to a large extent.  I believe in medicating the taper off Suboxone;  I was criticized on one site for suggesting the medication Vyvanse to deal with the horrible fatigue.  But there is a ‘balance of risks’, and I believe that it is safer to use everything we can to get a person through the taper without re-igniting all of those thoughts and memories of using, even if it means using a stimulant or benzo for a week.

People need to understand that the issue with addiction, and with all of these things related to addiction, is NOT THE DRUG… THE ISSUE IS THE RELATIONSHIP WITH THE DRUG.  Some people hear the word ‘amphetamine’ and they go crazy– ‘that’s addictive!’ they say.  Yes, it is.  So is clonidine, when used in the prison environment.  There are safe ways to use addictive medications;  unfortunately modern medicine demands ten minute appointments, where safe prescribing is an impossibility.  Why do patients keep putting up with it?  Shouldn’t it take longer to figure out your problem and educate you, than it takes to make a hamburger?

The problem with any opiate taper, including Suboxone, is the loss of motivation after a few days of pain, weakness, and depression.  You all tell me– would motivational tapes help?  I have mentioned my web site sober after Sub, where I have tapes describing the state of mind you want to be in…  you can get in that state of mind in a few ways that I know of, including going to meetings.  I am eventually going to have tapes that will hopefully help a person feel support during the four or five days at the end of the taper…  the days when everything appears hopeless and the clock moves in half-time, or even slower.

As for medications, I have been surprised at the effectiveness of gabapentin in relieving the ‘hot flashes’ that are such a pain during withdrawal.  Clonidine is helpful, but it is such a drain on energy that it is sometimes hard to decide if a person is better with or without it.  I tend to recommend it for nighttime use only.  And then there is Vyvanse, an interesting molecule consisting of lysine bound to amphetamine…  it is impossible to abuse, and a short course can really help a person keep working.

For those people who have a problem with the use of a stimulant, picture my patient in the final few days of tapering off Suboxone.  He is tired and discouraged, and despite my encouragements I know that the ‘addict inside’ is now awake, and about to use the self-pity to turn the person away from his good intentions.  That is what happens, by the way– the addict inside the person waits for these opportunities, and once active the addict inside will actually change a person’s insight!  And once it changes, it is impossible to change it back… at least not until there is some negative consequence that wakes the ‘real’ person.  Crazy description, I know…. but addicts will recognize what I am saying.  I strongly recommend all addicts learn to recognize their own ‘addict inside’.  One value of twelve step groups is that you get to hear about everyone’s addict inside, and you learn that the addict inside everyone is the SAME PERSON– the SAME ADDICT.  Watch it in others, and learn about it in yourself.

Where was I…. this patient of mine is on the fence, and I am in danger of losing him.  He won’t go off and relapse, but he will go back to the full dose of Suboxone for another six months before trying again.  So if instead of all that, I can give a week of a stimulant to get his energy and mood up a bit, and help him kick through those last few days… where is the harm?  As it turns out, many opiate addicts have ADD as well;  they were in that common path of poor student identified by the school and the parents, leading to anger, shame, discouragement, and drug use.  And so I have seen a number of patients start reading for enjoyment for the first time in their lives…  pretty cool.

I think I’ve covered the major points:
Yes, it is hard to stop Suboxone… just like anything else.  The ceiling effect results in the withdrawal symptoms being ‘back loaded’– all at the very end of a tapering process.  It is very hard to taper because of the potency of buprenorphine;  a tiny fragment of a tablet of Suboxone contains a very potent amount of buprenorphine, which is usually dosed in micrograms when used to treat pain.  Remember when tapering that stopping 16 mg of buprenorphine is like stopping 30 mg of methadone… and stopping 2 mg of buprenorphine is like stopping… 30 mg of methadone!  THAT is the ceiling effect in action– great for holding addiction in remission, but a pain when it comes to eventually tapering off Suboxone.

One last comment:  tapering off the opiate is the EASY part;  the hard part is not picking back up again.  And that takes a great deal of work over the rest of your life.  Before Suboxone, getting clean literally required changing one’s personality.  I honestly don’t know if people going through a year on Suboxone, learning some things, then tapering the drug will be able to stay clean long term.  I try to offer things that I believe will help, things I picked up through a long residential treatment and years of twelve step immersion.  I really hope I am helping at least some people- not only helping them feel ‘not alone’, but also helping them keep opiates from destroying their lives.  BUT… if you are not doing well, don’t rely on my blog to turn it around.  Do what I did, and open your mind and ask for help at a treatment center.  I will say this again, because if you hear it I will save you tons of money you would otherwise waste:  open your mind before stepping in the door.  Treatment is NOT education– it requires you to change, and to do that you must drop all of your resistance to change.  Avoid thinking that you have the answers; after all, it was your own best thinking that got you to where you are today.

Suboxone (buprenorphine) and Opiate Withdrawal in Newborns

I received an e-mail today related to an article I had placed on a different web site about using Suboxone during pregnancy:
My son was born November 19th 2008 and is still in the hospital because the mother is on Suboxone. He has tremors, has trouble sleeping and is excessively strong and ‘tight’. The doctors placed him on methadone to treat these symptoms and they are weaning him off the methadone. It is a very emotionally frustrating, confusing and strained time for us all. I see the side effects of the Suboxone and they are real and do happen. For more info. on my case email me. I would be happy to fill you in on more. I am dealing with it right now.
I am frequently frustrated by the lack of knowledge about Suboxone among physicians;  the manufacturer of Suboxone sponsors educational seminars and courses, but doctors tend to see addiction as something other than a fatal illness that deserves their best efforts.  In just my own collection of patients I have had several encounters with physicians who were literally just ‘guessing’ over their management of patients on Suboxone;  they weren’t reading the literature (which there is plenty of), they weren’t asking for consultation from other doctors (who would guess that doctors have egos!); and worst of all, in some cases they were treating the patients on Suboxone with patronizing or disdainful attitudes.

Methadone is harder for newborns to kick than Suboxone.
Methadone is harder for newborns to kick than Suboxone.

As a Suboxone patient you bear the burden of educating yourself and perhaps educating your physician.  Do not assume that every doctor knows what he or she is doing in regard to buprenorphine;  you may want to seek second opinions, particularly if your doctor recommends something that isn’t consistent with what you have learned about the actions of Suboxone and buprenorphine.
My response to the e-mail about the newborn with tremors:
Thank you for writing, and I am sorry about your son.  I don’t know how you will take what I am about to say, but I am not interested in an argument so please don’t reply with one—I would not read it even if you did, as the issue is your son—not my opinions.

For your own interest, and for your own concerns taking care of your son and finding your son the best care, understand that there is a vast amount of information on buprenorphine, the active ingredient in Suboxone.  Unfortunately, there are also more and more examples of improper diagnosis and care related to doctors not knowing enough about buprenorphine.  I have seen a number of mistakes made by physicians because of their lack of knowledge about buprenorphine, including mistakes by obstetricians and neonatologists.  I don’t know where your son is, but to be frank, their use of methadone to treat ‘Suboxone withdrawal’ is so improper that I have to think that your son is not where he should be.  I am sharing some articles with you that will likely make you more knowledgeable than your son’s doctors;  I encourage you to read and learn about buprenorphine so that someone can lobby for proper treatment of your son.

I am someone who does know about buprenorphine;  I have worked with it for over 10 years, and buprenorphine has been around for over 30 years.  In fact, before epidurals buprenorphine was used to treat pain DURING LABOR, as it doesn’t carry the same risk of respiratory depression as other opiates.  So understand that buprenorphine has been used for years as a ‘good medication’ for treating pregnant women in labor.  It is NOT a ‘new drug’—only the patent and formulation are new.

I keep current in the literature about buprenorphine and Suboxone.  There are a number of articles that provide information about the medication, although simply understanding the typical actions of opiate agonists and antagonists is sufficient to understand that it makes no sense to treat Suboxone withdrawal with methadone.  You can read the articles, but one pertinent conclusion from the review article is:

From these reports it appears that buprenorphine use during pregnancy induces a more mild withdrawal syndrome in neonates, when compared with methadone.

From another of the attached papers:

Regarding Subutex and buprenorphine:  it does not seem to be teratogenic in humans or animals. Administered in monotherapy form as Subutex, it has been used successfully in opioid-dependent pregnant women as a maintenance replacement opioid.  A 2003 review of the available clinical studies has been published covering approximately 300 pregnancies. Compared with methadone, a lower incidence of NAS (neonatal abstinence syndrome) has been reported in buprenorphine-exposed neonates. The severity of NAS is reduced as assessed by total opiate required to treat and length of hospital stays. Some data suggest that the placental transfer of this opioid may be limited in comparison with others, such as methadone, thereby limiting fetal exposure and the development of dependency. Deshmukh and colleagues have demonstrated that a large proportion of buprenorphine is metabolized to Norbuprenorphine, the only metabolite formed as determined by high-performance liquid chromatography and mass spectrometry, by placental aromatase (CYP 19) within the microsomal fraction of the trophoblast.

From the attached case report:

If methadone cannot be withdrawn before birth, mild to strong withdrawal signs in the newborn are frequent.4 The present case suggests that buprenorphine might be considered for the treatment of pregnant women addicted to heroin because (1) it does not induce teratogenic or embryotoxic effects in animals, (2) it apparently induces only a weak withdrawal syndrome in the newborn, and (3) the dose absorbed through maternal milk is negligible.

I don’t know the cause of your son’s tremors, but I strongly doubt they are related to the mother’s use of Suboxone or Subutex.  Attributing the tremors to those medications would require tossing out all of what we know about the medications—which is a large amount of data.  One thing that we absolutely DO know is that methadone causes a much greater ‘abstinence syndrome’ than does buprenorphine—and so if anything, the tremors are likely due to the methadone withdrawal!  Since neither buprenorphine nor methadone harm the fetus, however, I would be most concerned that your son’s doctors are doing what is unfortunately typical—focusing on the buprenorphine since it is something they don’t know enough about, and perhaps overlooking the real cause of your son’s tremors.  I encourage you to print and share the attached papers with your son’s doctors.

SuboxDoc

The papers I mentioned in my message:

Elkader A and B Sproule. Buprenorphine: Clinical Pharmacokinetics in the Treatment of Opioid Dependence. Clin Pharmacokinet 2005; 44 (7): 661-680.

Marquet P, J Chevrel, P Lavignasse, L Merle, and G Lachltre. Buprenorphine withdrawal syndrome in a newborn. Clinical Pharmacol Ther 1997; 62(5): 569-571.

Helmbrecht G, and S Thiagarajah. Management of Addiction Disorders in Pregnancy. J Addict Med 2008; 2: 1–16.