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.