Addiction Treatment 'Science' and Dead Rats

In my last post I teased that I would write about fake science.  I’ll try to make it interesting.
The internet allows everyone to do research about symptoms and treatments for any condition. If not for need for prescriptions, people could act as their own doctors.  But a huge dose of caution is necessary before anyone takes that path.
Realize first that doctors don’t treat themselves or even their family members.  The saying that ‘a person representing himself in court has a fool for a lawyer’ applies double in healthcare.  Treating someone close to one’s self introduces a bias that is hard to explain, but easy to notice.  As an example, I see a doctor annually to monitor a progressive condition that threatens my vision.  I would like to know the answer to a simple question:  how bad is it?  If I have a patient with that condition I can look at images of his/her retina and have an immediate, rough sense about what the person is facing.  But when I look at my own images and test results I sense nothing beyond fear or relief.  The problems with self-assessment are of course greater in the field of psychiatry and addiction.  After my relapse in 2001 I was told I needed treatment, and my assessment called for a brief refresher course on the twelve steps.  Three months later, still in residential treatment, I recognized how wrong I was.
A larger problem is that research on the internet is nothing like the research used by doctors or scientists.  There are a few sites that offer true research, such as Pub Med, where you can search my name and see the articles from my PhD work in the 1980s.   Doctors at academic hospitals or institutions often have access to an electronic database including thousands of peer-reviewed journals.  In grad school I spent time each morning in the library, reading the Science Citation Index for new stories about vasopressin and then searching the stacks for the article (medical libraries have so many journals that they take up 4 or 5 floors or more of a large building, with narrow halls between floor-to-ceiling shelves).  In the stacks I sometimes realized I was standing amidst the results of the hard work of millions of scientists over the past 50 years.
The information on the internet is useful because it helps patients ask the right questions.  But it is a mistake to consider it as research, or even to assume it is correct.  Doctors and scientists (and any good health practitioners) rely only on peer-reviewed literature.  And even then, a good scientist gathers a sense, over time, of the better peer-reviewed journals vs. the ones with less credence.  What is peer review?  When a scientist submits research for publication, the article is sent to 3 or 4 independent reviewers who work in the same field but have no connection to the author of the study.  I am a peer-reviewer for a couple of journals.  When I receive an invitation to review a study I have to disclose any bias or connection to the study or authors.  If I accept the invitation I have several weeks to carefully review the study, noting if the findings are valuable, whether the groups were sufficiently randomized and blinded, whether the statistics are correct or if a statistician should be involved, and whether the findings support the conclusions.  I then tell the journal editor my opinion, including whether the study should be accepted, rejected, or accepted with certain revisions.  Peer reviewers are not paid;  they provide the service because they recognize that the process is necessary and valuable.
The FDA regulates medications based on the results of research studies.  Some of the studies reviewed by the FDA are already published, and some may never end up in a formal publication.  But their process for evaluating medications is similar to the work of a peer-reviewer in that they determine whether the science is ‘good’ – double blinded, properly randomized, good statistics, etc.  Any claims about a medication MUST be deemed accurate by the FDA.
This post was inspired by an ad for Declinol, a supplement marketed to ‘treat’ alcoholism.  Supplements are not medications, and not subject to the same rules. Read the FAQ on the Declinol web site and note the answer about FDA approval.  Declinol is not subject to FDA approval because it is a nutrient, not a medication.  The FDA allows greater latitude for promotional claims about nutrients, but even makers of supplements are not allowed to lie.  The acrobatics of marketers of such products are sometimes funny, at least to us nerds, and Declinol is a classic example.  Note that the web page doesn’t say that it treats alcoholism or cravings;  it is a ‘SUPPORT for physical cravings, calmness, and overall well-being’.  What is a ‘support’?  Your guess is as good as mine.
Instead of making claims that can be found to be false, nutrients often show quotes by ‘satisfied customers’.  If the FDA believes that the quotes are misleading, that’s on ‘Bob from California’, not on the marketer of the nutrient.  Instead of describing how the nutrient works, nutrient marketers provide citations about the nutrient that support whatever the marketers want you to think.  So with Declinol we see ingredients like folic acid, with broad generalizations about the value of that substance.  Yes, Folic acid is valuable.  You can’t live without it.  But that’s a far cry from saying that taking extra folic acid has any value, let alone value in reducing alcohol intake.  We give folate to alcoholics in detox because they sometimes have dietary deficiencies caused by consuming nothing but alcoholic beverages.  If you eat meals a couple of times per day you almost surely have plenty of folic acid in your body, and any extra is metabolized and excreted..
Must nutrient ‘treatments’ or supplements contain a blend of vitamins.  It is very easy to write reassuring and positive statements about vitamins because by definition, vitamins (the term comes from ‘vital amines’) are molecules critical to normal function.  But many studies have shown that a typical diet provides adequate amounts of vitamins, even if that diet includes fast food.
Many nutrient ‘treatments’ also contain a couple special ingredients we’ll call ‘secret sauce’.  One secret sauce in Declinol is Kudzu, and support for Kudzu in reducing alcohol consumption can be found on Pub Med.  Like similar products, Declinol’s marketers take a finding about a substance and grossly generalize the findings to create an impression that was never part of the original finding.  According to the study about Kudzu, 20 people in a ‘natural settings laboratory’ (is that an oxymoron?) were given water, juice, and up to six beers, and told to drink at will.  And (wow) when people were given 2 grams of Kudzu first, they drank beer more slowly, and opened fewer bottles.
A couple of problems, though, in concluding relevance to treating alcoholism.  Were the 20 subjects alcoholics? It doesn’t say, but I would guess not because I don’t know if a study giving beer to alcoholics would pass the ethical review board.  Beyond that, WHY did they drink less alcohol?  If I gave you syrup of ipecac, you would probably drink less alcohol.  If I gave you a tablet of oxycodone, you would probably drink less alcohol.  That doesn’t mean that the substances are useful in treating alcoholism or alcohol cravings.  Why did the Kudzu group drink less alcohol? Did it truly reduce interest in alcohol in a study with very few subjects who may or may not have alcohol problems? Or did it leave a nasty taste in their mouths or destroy their taste buds?  Did it cause nausea or dizziness that made alcohol less enticing? Did it reduce vision so they couldn’t find the beer bottles as easily?
As for the title of this post, when I researched vasopressin one hot idea was that vasopressin enhanced learning and memory.  We measured that improvement in studies using ‘passive avoidance.’  We placed rats in a cage that had dark cubbies in one corner, and when rats invariably went into a certain cubby they received an electric shock.  We repeated the task with or without putting vasopressin into the rats’ brains and some rats ‘learned’ to avoid the electric cubby, supposedly by remembering the shock better than other rats.  There is a major flaw in the study that can often be applied to other ‘experiments’, including the one I cited about Kudzu:  the best performer in a passive avoidance task is a dead rat.
I have no idea whether Declinol reduces cravings or generates ‘well being’, whatever that is.   But nothing on their website pushes me toward that conclusion.  I hope readers will keep some of these comments in mind when the next big cure comes along.

Leadership on Opioids

Anyone who proposes an easy solution to the overdose epidemic is either a simpleton or a politician.  But far too many people entrusted with the power and responsibility to set priorities decry the number of overdose deaths, then stigmatize and demonize every effort to save lives.   “Suboxone can be diverted.”   “Someone might drive impaired after methadone.”  “Needle exchange programs attract drug dealers.”    Meanwhile the number of deaths from overdose make clear that current solutions are not working.  Small community newspapers have story after story about the increasing number of deaths, but the silence in Washington is deafening.    I picture a cruise ship leaving  one after another drowning passenger in it’s wake, while the ship’s captain dines at the captain’s table, pausing between bites to tell dinner guests that all is well.
Statistics and numbers don’t tell a story unless put into context, so some simple comparisons help demonstrate the magnitude of the ‘opioid problem.’  My perception is skewed after sitting with so many people affected by addiction, but we seem to have a huge blind spot for one of the leading killers of young people.  Consider the issues our country’s leaders talk about and our news reporters write about.   I think we all know the things that get our President’s undies in a bundle… but did I miss the Presidential Summit on Opioid Dependence?  This would not be the first time that our leaders missed the elephant in the living room, of course— but it may be one of the first times a President has been given a pass after missing this big an elephant for this long.  I’m old enough to remember the media soundly criticizing Reagan for failing to create a sense of urgency over AIDS.  And so I wonder… When is Obama going to express urgency about opioids?  Where is the media criticism of his lack of urgency?   Today he told reporters he ‘will leave everything on the field during his last year in office,’ just before he took off for another Christmas in Hawaii.  Will that time on the field include some concern for people killed by overdose?
I don’t get the impression that our President lies awake all night worrying about overdose deaths.  But maybe he should.  We heard a great deal from Obama about the need to bring troops home from Iraq a few years ago.  And all of the networks kept a running tally of US deaths in Iraq in the lower right corner of the screen during the evening news.   So let’s compare priorities.  Let’s add up all of the deaths of US troops during Iraq II during two administrations of Bush and the 1 and 3/4 Obama administrations.  Let’s add the deaths from the World Trade Center attacks, the recent terrorist attacks in France and California, and the mass shootings at Sandy Hook and Columbine.  How does that number compare to the impact of opioid dependence?
I don’t intend to lessen the honor of fallen military servicemen and women, or downplay the horror experienced by victims of 911 and other violent attacks.   I chose these numbers because the horror of each situation prompted speeches by our leaders, rallies by our citizens, and headlines in National news media.   The speeches and commitments of our President and the coverage by news anchors are supposed to be a reflection of what our citizens care about.
The number of deaths from overdose in 2013 alone– one year– was over four times greater than the complete count of US deaths in Iraq, plus all of the horrible events listed above.   US deaths in the Iraq war?  About 4500.  The Trade Center attacks killed almost 3000 people.   In 2013, over 30,000 US citizens died from overdose.  Surprised?  I was.  On average about 100 people in the US die from overdose every day– day after day.
As I wrote above, I remember the reporters calling out Reagan over AIDS.  Activists claimed that Reagan avoided talking about HIV because of the stigma associated with ‘homosexuals’, the people hit the hardest by the initial outbreak of HIV.   They say that the people who died were ‘second class citizens’ who didn’t have a voice, and it was easier for Reagan to pretend that the problem didn’t exist.  Many people believe that if Reagan spoke about AIDS in his speeches or directed National attention toward the outbreak of the virus, that fewer people would have died.   Maybe those people were right.
If they were, what’s Obama’s excuse?

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.
 

Broken Bones on Suboxone; Need Pain Relief

Originally Posted 1/11/2014
I received the following email from a Suboxone patient (from another practice) after he experienced a painful injury.  He shared what happened at the hospital when he was trying to get relief from pain, while taking Suboxone (the active component is buprenorphine).
Hey there.  Just to let you know, i was on 24 mg of Suboxone when I jumped off a fence and crushed bones in both feet.  The injury was among the most painful things I have gone through in my life.  At the hospital they did not understand Suboxone even though I tried to explain to them how it worked.  They couldn’t get a painkiller to break through and I was nearly passing out from the pain.  They finally used Ketamine and it worked immediately.  However, they only used it 3 times and its effect don’t last more than about 20 minutes in my case.  Then they switched to IV Fentanyl….I’m not sure of the dose but I know it was high and after a few injections they hooked me up to a drip bag.  Just wanted to share this info in case anyone finds themselves in a situation like mine where I was ready to strangle a doctor because they tried all of the regular oxycodone, hydromorphone, morphine, etc. all the while I was almost (or maybe even) in a state of shock from the pain.
Hope this can help someone out in the future.
I wrote back the following message, with a few minor changes:
Thank you for sharing your story.  As you may know, I was an anesthesiologist for ten years before developing my own addiction to pain medications.  I have been in the position, many times, of treating pain in patients after surgeries or accidental injuries.  Pain relief is possible in every case, if a competent doctor takes the time and effort to control the pain.  There are arguments within the field of medicine over the use of narcotics for chronic pain, but those arguments do not extend to acute pain.  There are no reasons a person should be allowed to suffer from pain in a US hospital—beyond incompetence or failure of the system.
Buprenorphine complicates pain treatment in two ways; by blocking mu receptors and by contributing to a higher opioid tolerance. Opioid agonists (pain medications) compete with buprenorphine for binding at mu opioid receptors.  Larger doses of buprenorphine cause greater blockade of mu receptors, requiring larger amounts of agonist to treat pain.  When I read your description of the different things tried, my impression was that your pain control was delayed by your doctors trying too many things, instead of sticking with one thing until it worked.
Some opioids (notably morphine) trigger histamine release, which causes hives, lowers blood pressure, and limits the dose that can be given in a short amount of time.  Large doses of high-potency opioids like fentanyl or sufentanil cause muscles to tighten, and in rare cases cause rigidity of the chest that interferes with breathing.  But that side effect is rare, and not a major concern in modern acute care facilities.
For the most part, oxycodone (oral) or hydromorphone or fentanyl (IV) could be given in almost infinite amounts, and at some dose either medication will provide pain relief.  Doctors should remember their training from medical school, when they learned to focus on the patient rather than the numbers.  In your case, nasal oxygen and pulse oximetry should have been applied, and attention directed to your respiratory rate. Oxycodone (oral) or hydromorphone (IV) should have been titrated upward until your respiratory rate was 12-14 breaths per minute.  At that point you would have been relatively comfortable.
Anesthesiologists regularly use respiratory rate to determine whether additional narcotics are indicated in patients near the end of surgery.  The dose of hydromorphone (Dilaudid) necessary in your case may have been high, but respiratory rate decreases gradually as opioid effect increases and pain is relieved, allowing for safe use of virtually any amount of narcotic. The term for this type of care is ‘titrating to effect.’ With appropriate monitoring (present in every ER, OR, recovery room, or ICU), titrating in this way is very effective.  Some hospitals place limits on intravenous opioid doses on general med/surg units, but there are no such limits in units with 1:1 nursing, oxygen, and pulse-oximetry.
There were other ways to provide pain relief, depending on whether you were the hospital CEO, a major donor, or a guy labelled a ‘drug addict.’  They could have placed an epidural and run local anesthetic at a dose low-enough to allow you to walk with assistance while greatly reducing your pain.  Or they could have used a higher dose of anesthetic that provided complete pain relief.  Higher doses of anesthetic cause temporary muscle weakness that may have kept you from walking, but you probably weren’t walking anyway, given the injuries you described.
Readers are invited to use the ‘share’ button to create a print-friendly version, and to place a copy in your wallet—in case you ever find yourself in a buprenorphine knowledge-free zone!

Short Term Suboxone

Firsted Posted 1/8/2014
I received an email today containing an angry comment about Suboxone/buprenorphine that I’ve read a number of times before on forums about addiction.  The essence of the comment was that Suboxone has caused tons of problems, including diversion, people stuck on the medication, and buprenorphine abuse. He wrote that the reason for all these problems was because Suboxone was ‘never intended for long-term use’, but rather was originally intended for detox only.
I could address the nonsense of his email by pointing out that the ‘problems’ he listed are infinitely better than the death that results from untreated addiction, but I’ve made that point already in a number of posts. Instead I’ll address his claim that the addiction community has hijacked a medication intended for short-term use and used it, incorrectly, for long-term treatment.
Let’s first presume, for the sake of the argument, that buprenorphine WAS originally intended for detox and not for maintenance, back in the year 2000 when the FDA considered approval of the drug.  That was not the case—but so what if it was? Over the past ten years we’ve gained knowledge about addiction that we didn’t have back then.  Studies that have shown, quite clearly, that use of buprenorphine for a year or less does little to ‘cure’ addiction.  We’ve also gained clinical experience with buprenorphine.  This gain in knowledge is not unique to buprenorphine, or to addiction.  All fields of medicine progress in a non-linear manner, as medications or procedures are honed to perfection over years of trial and error
.
I remember taking care of people going through autologous bone marrow transplants in the mid-1980’s when I was an intern in medicine.  Back then, bone marrow transplant patients were the sickest patients in the hospital, and many of them died.  I remember one young man in particular who had metastatic testicular cancer. We talked at the same time each night, when I was summoned to inject medications that helped him tolerate the side effects of platelet transfusions. I was moved by what he was doing, subjecting himself to horrible pain and nausea in order to get through a procedure that at the time was rarely successful. He died from a fungal infection during the stage of treatment when his own bone marrow had been destroyed by chemo, but before the transplanted bone marrow grew back to defend against the many organisms in our environment that can kill people who are immunocompromised.
Autologous bone marrow transplants have changed in many ways over the years, including how the marrow is harvested, how the marrow is cleaned of malignant cells, how the marrow is stored and re-introduced, the timing of each step in the process, the meds and techniques used to prevent fatal fungal infections, and the types of cancer appropriate for such treatment.  The current procedure bears little resemblance to the original—which is a good thing.
The same can be said of every aspect of medicine, from liver transplants to laparoscopic surgeries to running ACLS ‘code blues’.   In the latter case, we added calcium.  When we learned that brain damage was made worse by calcium, and we removed calcium.  We added bicarb, and took away bicarb.  It’s interesting to look back over 30 years at the number of things ‘we knew were right’ that proved to be wrong.  That’s how medicine worked—and still works today.
In the same way, if buprenorphine WAS ‘intended for detox’, so what?  We now know that short-term detox yields long-term sobriety in less than 5% of patients.  Even in the residential treatment centers that use buprenorphine only temporarily, to aid detox, success rates are poor.  Like meetings, buprenorphine works when you work it.  Like meetings, its value ends when you stop taking it.
In reality, buprenorphine was never ‘just a detox agent.’  I became certified about three years into the use of Suboxone in the US, and for a short time served as a ‘treatment advocate’, teaching other doctors how to treat patients with Suboxone.   We didn’t set time limits on treatment.  I suppose there were people who had a mystical view of how medication works, who hoped that buprenorphine somehow erased all of the psychopathology that accumulates during active addiction… but there were no official recommendations to use Suboxone only in that way.  Short-term detox was not the ‘intended use’ for Suboxone.
I’m left wondering: Where do these statements come from, that “Suboxone was never intended as a maintenance agent”, or that “it gets in your bones”, or “it is the worst opioid to come off”, or “it made me gain weight”, “it rotted my teeth”, “it is dangerous long-term”, etc.? Is it like the old ‘telephone game’, where stories take gain details as they are passed from person to person?  For that matter, why do some people spend their time trash-talking buprenorphine on sites intended to help people understand buprenorphine?  The forum is often visited by trolls who are obsessed with other people taking buprenorphine. Do people go on forums for illnesses other than addiction, and taunt patients with bogus information?
As I wrote to the angry person earlier today—if you don’t want or need the medication, move on already.  To some, this is serious business.  Surely you must have something better to do.
Addendum: Since this post, attitudes toward buprenorphine seem to have changed to some extent. We have far-fewer people coming to the forum just to attack buprenorphine. I’m hoping the difference is because of a better understanding of the medication, and not because of less use of the medication.

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

Buprenorphine Diversion: Beyond a Superficial Understanding

First Posted 11/19/2013
In ‘Addiction Treatment with a Dark Side’, Deborah Sontag of the New York Times shared her observations of the clinical use of buprenorphine for treating opioid dependence, warts and all.  Readers of the Talk Zone know my bias—that buprenorphine/Suboxone is one of the only effective treatments for opioid dependence, and many patients are best-served by long-term, perhaps life-long treatment with buprenorphine.   But I read the article the article with interest because I know that Ms. Sontag ‘did her homework’, including visiting a number of practices, speaking with a number of patients, and reviewing hundreds of studies about buprenorphine and Suboxone over the course of many months.
From my perspective, the article overstates the diversion problem.  In my last post I asked if the fear of diversion should be a factor in whether buprenorphine-based medications become the leading edge of addiction treatment.    I stated my opinion—that if overdose deaths don’t pull acetaminophen from pharmacy shelves and diversion doesn’t keep hydrocodone off the market, then diversion of buprenorphine deserves little discussion relative to the value of buprenorphine treatment for addiction.
With the wave of stories describing buprenorphine as ‘controversial’, every discussion of the medication seems to revolve around diversion.   Do the numbers support the association? Deaths from Suboxone—deaths where buprenorphine was one of the drugs that caused death—amounted to several hundred over the past ten years, compared to 38,000 drug overdose deaths in 2010 alone.  The magnitude of the difference is so staggering that it deserves repetition; 400 deaths in ten years, vs. 38,000 deaths in one year.  The total number of deaths linked to buprenorphine over the past ten years is about equal to the number of people who die from acetaminophen– EACH year.
Diversion of buprenorphine is a complex issue.   Words like ‘diversion’ and ‘overdose’ are loaded with so much emotion that one word seems to tell the whole story.   A Google search of Suboxone brings up news reports such as ‘Suboxone found at overdose scene’, or ‘man arrested with cocaine, heroin, and three Suboxone tablets.’  The stories create an ugly image, with buprenorphine/naloxone as one more drug of abuse, found at ‘an increasing rate’, according to other headlines. But a superficial look at diversion yields a superficial understanding of the diversion problem.
Take as example a patient has not used illicit substances for 3 years while taking prescribed Suboxone, who relapses to heroin and dies from overdose.  News stories will describe a scene littered with needles, heroin, and Suboxone tablets.  That description creates a misleading impression of the patient’s history, and a misleading impression of buprenorphine.  Even if the story provides more detail, the headline alone will fill the tweet—the ‘news’ of the modern era.
Is the nature of diversion, the reason for diversion, or the consequence of diversion relevant to discussions about the diversion of buprenorphine?  If someone tries to hold life together by purchasing street Suboxone in a geographic region void of certified physicians, should that ‘diversion’ be included in the category as the sale of oxycodone?
What if the powerful mu-receptor blocking effects of buprenorphine have positive effects?  What if studies found a lower rate of overdose deaths in communities with greater diversion of buprenorphine?   Would that be relevant to the diversion discussion?
I do not know of any evidence that diversion of buprenorphine correlates with fewer overdose deaths.  But many public health experts predict that encouraging ‘street use’ of naloxone would reduce overdose deaths, so expecting the same from buprenorphine, a stronger and longer-lasting mu antagonist, is not unreasonable.
Patients on buprenorphine awaiting elective surgery discover that the blocking effects of buprenorphine last for weeks.  The same patients report that even after several weeks off buprenorphine, significant doses of oxycodone will relieve post-op pain, but won’t provide the ‘euphoria’ oxycodone used to provide.  Patients who could never make a week’s script for oxycodone last longer than a day can often control use of opioid agonists after surgery if kept on a small dose of buprenorphine.    Considering these findings, it is not unreasonable to wonder if there is a lower risk of death by overdose in people who ‘divert’ buprenorphine.  Buprenorphine has a much longer half-life than oxycodone or heroin, so diverted buprenorphine intended for use ‘in between’ acts as a blocker during periods of active heroin use.  Is it possible that traces of diverted buprenorphine in the bloodstream saves lives?  If so, is that relevant to discussions about diversion?
The worst diversion scenario is if opioid-naïve people take buprenorphine or Suboxone and becoming addicted to opioids as a result, i.e. diverted buprenorphine serving as a gateway drug to opioid dependence.  Nobody should take that situation lightly.  But stories from the streets bring to mind biological programs where sterile males of an invasive species are released into the wild in effort to eliminate the invasive mosquito, lamprey eel, or fruit fly.  What if the spread of buprenorphine functions as an ‘addiction moderator’ where the more buprenorphine in a community, the lower the rate of overdose deaths?
I realize that I am out on a limb— but as the saying goes, that’s where the fruit is.   If buprenorphine diversion is investigated in a superficial manner, we will collect nothing but superficial results.  The diversion of a medication with the potential to save as many lives as buprenorphine deserves a deeper level of understanding.

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.

Codeine Never Works for Me

Originally published 10/29/2012
The FDA recently released a Drug Safety Announcement about the use of codeine in young children after tonsillectomy/adenoidectomy surgery for obstructive sleep apnea.  I was somewhat surprised to see a safety announcement on a medication that has been in use for decades, but the release underscores our improved knowledge of drug metabolism, and the broadening demographics of the United States.
Codeine has little activity at opioid receptors.  The analgesic effects of codeine are actually caused by morphine, after the conversion of codeine to morphine at the liver.  The conversion is catalyzed by an enzyme called CYP2D6, part of the cytochrome system of enzymes that are involved in the metabolism of a number of compounds.
I have written about the addictiveness of narcotic pain medications.  People addicted to opioids often go to significant lengths to obtain prescriptions for narcotic pain relievers from healthcare practitioners.  Emergency room physicians and nurses become aware of the efforts of ‘narcotic-seekers’, which range from faking pain symptoms or dental injuries to self-catheterization and instilling blood into the bladder to fake kidney stones.  Distinguishing those with real pain from those who are addicted and not experiencing pain is a serious situation, but doctors roll their eyes at some of the more-typical presentations.  One such situation is the patient who reports an ‘allergy’ to all of the weaker narcotics, and claims that ‘the only drug that works is (insert Dilaudid, morphine, oxycodone, or another potent opioid here).
Codeine is one drug that is commonly rejected as ‘ineffective’ as part of a request for something stronger.  When I was a medical student, we assumed that requests for something other than codeine were disingenuous.  But at some point, maybe 15 years ago, I remember reading an article that described the conversion of codeine to morphine by the liver.  The article reported that the enzyme that performs the conversion exists in varying forms across the population, with some ethnic groups having more active forms of the enzyme than others.  Some people have very low levels of CYP2D6, and so get very little analgesia from codeine.  In other words, some of the people who claimed that ‘codeine never works for me’ were probably less disingenuous than doctors thought!
The latest FDA warning describes three deaths in children between the ages of 2 and 5.  The effected children were ‘ultra-rapid CYP2D6 metabolizers’ who were given typical doses of codeine for post-operative pain control, who converted the codeine to morphine more efficiently than expected.  The respiratory depressant effects of morphine, combined with some degree of post-operative respiratory obstruction, caused the death of those children and the near-death of a fourth.
About 6% of the people in the US are ultra-rapid metabolizers.  About the same number are poor metabolizers and have a reduced analgesic response to codeine.  In some ethnic groups there are greater numbers of rapid metabolizers, particularly people from Greek or African/Ethiopian ancestry.  If you are someone who gets little pain relief from codeine or on the other hand if you get a very strong effect from codeine, you may want to look into G6PD testing, which can be ordered by physicians.  The enzyme activity is heritable to some extent, so your own enzyme activity may bear relevance to the activity of the enzyme in your children.
Expect similar issues to arise with other medications, as we learn more and more about how our bodies metabolize medications, and about the effects of those metabolites on enzyme systems.  The lesson also reminds doctors that there is wisdom to be gained by listening to our patients.

Up and Running

I apologize for the hiatus. For some reason, all of the posts from the past year suddenly disappeared… and backup files, which would normally be used to restore the site, were corrupt. At least one of the IT experts I consulted believed that the site was infected by a malicious robot… but I’m not sure if I agree, since I don’t have any robots that I’m enemies with.
I was able to pull the posts from the database files… the process reminds me of the movie Argo, where photos of embassy workers were reconstructed from shredded documents, but without the help of hundreds of small children. I am going to start posting those older posts, and hopefully Google will eventually index them properly, so that searches at SuboxSearch.com will point in the right direction.
I appreciate your patience… please feel free to read the old installments, and watch for the new entries that will be coming out now and then!
J