Today I read about the stereotactic brain surgery used to treat opioid dependence in China over the past ten years.   The procedure is relatively straightforward; the patient’s skull is clamped in place while small holes are drilled, guided by computerized, 3-dimensional maps of the brain.  Probes are inserted deeply through brain tissue to the nucleus accumbens, where electric current destroys varying amounts of brain tissue.   Patients are awake and talking during the procedure, so that surgeons know if the probes are too close to brain regions that control speech or other functions.

A large number of ablations for the treatment of addiction were performed in China about ten years ago.  The rapid growth in popularity of the technique, before full knowledge of the risks and long-term effects, led to a ban on the procedures by the Chinese Ministry of Health in 2004.  Still, ablations were performed as part of research studies, with over 1000 people treated by ablation since 2004.

The scientific community outside of China overwhelmingly condemns the technique, and medical journals are pressured to withhold publication of ablation studies.  Human rights advocates claim that such experiments are performed on people who are not fully aware of the risks, or who are pressured to participate in the studies to avoid harsh punishments for drug offenses.  The veracity of the results from ablation studies has also been challenged. Ablation treatment of opioid dependence is in the news lately because of a recent paper describing the five-year follow-up of opioid addicts treated by the procedure.

Neuroscientists distinguish between DBS (deep brain stimulation by electric current) vs. procedures where brain tissue is destroyed.  I’m surprised by the intensity of the distinction, given the similarity of the procedures.  In both cases long probes are passed through brain tissue, risking hemorrhage, stroke, or seizures.  For DBS, wires are left behind and connected to power-packs that release different patterns of electrical current.  In the ablation studies, small areas of tissue at the end of the probes are destroyed, and the probes removed.  If there is a future for addiction treatment using stereotactic brain surgery, DBS is likely to become the procedure of choice, given the preference by the scientific community for non-permanent interventions.

The recent follow-up study found that about half of those treated by ablation of the nucleus accumbens were sober from heroin after five years.  But about a quarter of the patients who had ablation were found to have long-term neuropsychiatric side effects including memory loss, loss of motivation, mood disturbances, and loss of sexual desire.

I found the studies and results interesting in a number of ways.  Throughout the latest paper, the authors point out the severe consequences of opioid dependence and the lack of effective treatment options.  Opioid dependence is noted to be a permanent, progressive, fatal condition, with a prognosis poor enough to warrant drilling holes in the skull and destroying brain tissue.  Even as record numbers of young people die from overdose, I don’t have the sense that US citizens recognize the severity of the problem.

I find it interesting how society’s perceptions influence what is considered appropriate or inappropriate brain procedures.  SingularityHub points out the popularity of frontal lobotomies after 1949, when António Egas Moniz won the Nobel Prize for Physiology or Medicine for inventing the procedure.  Over 20,000 lobotomies were performed in the US by 1951, but the procedure was discredited and eventually banned in the US.  Who says the Nobel Prize people always get it right?

The recent study’s introduction points out that the most stringent addiction treatments in China– compulsory detoxification, mandatory labor, education, and skills training for as long as 3 years– have one-year abstinence rate of 44% and 3-year abstinence rates of only 15%.

Drilling holes deep into the brain to destroy the pleasure centers might bring the sobriety rates up to 50%, but at the cost of loss of memory and motivation.

And then there is buprenorphine (brand name Suboxone), a medication that has success rates over 50%, with fewer risks or side effects than drilling holes in the brain– but that remains limited by US law.

Which approach would you prefer for your son or daughter?

Doctor with brain photo available from Shutterstock

People who read this blog are aware of the shortage of physicians who can prescribe buprenorphine to treat people addicted to pain pills, even as an epidemic of addiction to heroin and pain pills devastates the heartland of the country.  In order to prescribe buprenorphine, physicians take a short course and obtain special certification.  To obtain certification, physicians must promise to treat no more than 30 patients at one time, a number that can be increased to 100 patients after one year.

If you only have a few minutes, please take the time to go to the White House web site and add you name to a petition to allow individual doctors to treat more than 100 patients using buprenorphine.  The whole process is fast and easy, and only requires your name and email address through this link: http://wh.gov/QR6K

If you have more time, need convincing, or just like hearing a 52-y-o rage against the machine, continue reading my thoughts about limiting treatment for this one health condition.

The reason for the patient cap, according to cap proponents, is to prevent pill-mill practices where patients could obtain narcotic medications without adequate care for their underlying addiction.  That concern is reasonable, I suppose, but I often discover that proponents of the cap have other motives to keep the limits in place.  For example, one person at a ‘linked in’ group argued that individual physicians don’t provide the all-encompassing care that he provides… to the 800+ patients he ‘counsels’ at the methadone clinic where he works!  According to that counselor, all people addicted to opioids need years of counseling—largely from other people with addictions, who after a couple years of school have all the answers.

He would be surprised to see just how well people can do on buprenorphine, a medication that selectively removes craving for opioids.  After years of treating and knowing patients on buprenorphine I realized that ‘character defects’ are largely maintained by active craving.  Yes– people with antisocial tendencies before and during active addiction have the same antisocial tendencies on buprenorphine.  But people who lost good lives to opioid dependence often do remarkably well when their addictions are placed in remission by buprenorphine, regaining their good lives and more.  In fact patients with opioid dependence, when treated with buprenorphine and a bit of human decency, do as well as ‘normal’ people, if there is any such thing.  They just don’t look all that great when standing in line at 6 AM!

Another concern by counselors at residential treatment programs or methadone treatment centers is that doctors who prescribe buprenorphine are in it for the money— never mind that fewer and fewer doctors are willing to work in the relatively low-reimbursement field of addiction medicine.  To those worried about profiteering, I can only suggest a glance in the mirror.  I write from the standpoint of a Board Certified Psychiatrist with 100 patients on buprenorphine who make up less than a third of his practice, who cringes at the flow of emails from patients begging for help.

I’m not certain whether the limit on patients was originally intended to protect patients with addictions or to safeguard society at large.    But no matter the intent, the cap doesn’t make much sense when viewed critically.  Let’s assume that the cap was intended to protect patients treated for addictions, to make sure that doctors don’t see unmanageable numbers of patients.  Does anyone believe that treatment of addiction is uniquely difficult, requiring limits that are not necessary for the treatment of other complex illnesses such as childhood cancer?

Arguments that the limits protect the general public also fall apart under examination.  Buprenorphine can be abused, similar to medications used for treating anxiety, pain, or attention deficit disorder. But nobody believes that buprenorphine is more likely to be diverted than other scheduled medications, including medications that are prescribed without any thought of patient limits. For example, individual pain physicians treat hundreds or even thousands of patients using opioid agonists that pose much greater risk for addiction or overdose than buprenorphine.

The operational reason for the cap is because patients with addictions to opioids treated with buprenorphine are being prescribed opioids, an action prohibited by the Harrison Act.  People have a hard time getting their head around using opioid medications to treat opioid dependence, no matter how effective that treatment may be.  Is it unfair that people addicted to opioids should get off so easy with a medication that actually works, rather than face repeated, ineffective trips to residential treatment centers?

In reality the cap exists for one reason:  because it can.  Congress does not have the ability to make similar decisions in regard to other illnesses, and would not likely gain such power through legislative action.  Limiting the number of operations performed by cardiac surgeons might be a good idea, for example, but society realizes that surgeons themselves are best-positioned to decide when their practices reach maximum capacity.  But buprenorphine treatment was allowed through specific legislative action, as an exception to the Harrison Act.  In this unique setting, Congress was able to set practice parameters in a way that is impossible in other area of medicine.  The result was typical of settings where the government has control; physicians in the trenches of addiction treatment are told what they can or cannot handle, rather than allowed to practice according to their own best judgment.

To the patients on my buprenorphine wait list it goes something like this:

I’m from the government and I’m here to help.  There are no spots for you.

Please add your name after mine, at this site: http://wh.gov/QR6K

Pills in hand photo available from Shutterstock

Several of my patients have warned me about the world ending in a few days, on December 21, 2012.  There are variations on the theme, but the basic idea is that the Mayans, who were accomplished mathematicians and astronomers, used an advanced calendar to measure planetary cycles… and that calendar ends at the end of this week.   Some patients tell me that the end of the Mayan calendar coincides with predictions by the French seer Nostradamus, although the definitive authority on everything, Wikipedia, holds that Nostradamus did not make such a prediction.

I’ve browsed internet sites about this topic in order to prepare this post and found that there are about as many different versions as there are web sites about the prediction.  I suspect that some versions have more adherents than others, and I have no idea which web sites are the most authoritative.  I’ve read, though, that the world will end as described in the Book of Revelation in the Bible, or that instead, humanity will be erased, leaving the Earth unscathed.  I’ve read that the Earth and Sun will line up in a way that eclipses the energy flowing from the center of the Milky Way Galaxy, causing humanity to die off and be replaced by aliens from outer space.

Like any good prediction, this one has plenty of wiggle-room.  Comparisons between our modern calendar and the Mayan calendar require assumptions about how the Mayans determined months and years, so December 21^st is only one best guess for the end of times.  Some interpretations place the date a year or so ago, and others place the date a year or so in the future.  In other words, things are not quite as tidy as they were at the millennium, when people only had to figure out which time zone marked where midnight would spell disaster.

Talk about the end of the world carries a certain levity, but like anything conjured by humans has a dark side.   In 1997, 39 members of the religious group Heaven’s Gate committed suicide in order to join the UFO that they thought was hidden in the path of Hale-Bopp, a comet that was uniquely visible from Earth for a few weeks.  And more recently the slain mother of the man who committed the atrocious shootings in Connecticut was reported by some news outlets to be preparing for a doomsday scenario.

Something about the fleeting nature of our lives, I believe, makes us want to live in special times or own a unique slice of history.  If we can’t each have fifteen minutes of fame, then at least we can live in uniquely famous (or infamous) times.  We want to believe that this (insert event here) is different from the thousands of similar occasions that have occurred through history.

If our internal pressure is not enough, we are pushed into believing in the uniqueness of our times by the media.  Some people who are by all means ‘mainstream’ believe that the Earth is in trouble right now, and that warming skies and oceans will bring dire ills to humanity.  The scientists most supportive of global ‘climate change’ repeatedly inform us that regional warm winters are unrelated to long-term climate change, and point out that Sandy was a weak hurricane by weather standards, made devastating by the concentration of people where it happened to make landfall.  But a popular mayor used the tragedy to argue how uniquely horrible the climate has become right now, even though much larger hurricanes travelled the same route decades ago.

At the same time, we read about the impending debt bubble that is consuming our future or the perils of China holding mountains of US debt.   Like others my age, I remember the same concerns in the 1980s over Japan owning too much of our real estate.  But in case the debt issue isn’t frightening enough, newspapers splash color charts about the latest challenge facing our politicians, not-reassuringly called the fiscal cliff.

I’ve lived through quite a few fateful eras.  As a kid I worried about the coming nuclear war as I walked past the familiar fallout shelter signs in the stairwells of my school; the signs are still there, even as the definition of ‘fallout’ has been forgotten.    In my early teens I read about the population explosion that would use up the Earth’s resources in short order; nobody predicted that in some parts of the world (i.e. Japan and Western Europe), lack of population growth would cause problems.  When I was 14, Newsweek and Time magazine carried stories about the coming ice age and the famines sure to occur as a result.  Thankfully, nobody took the actions that some thought were necessary to avert crisis:  to cover the ice caps with soot in order to warm, and save, the Earth!

I never bought into the Red Menace, but I believed what my high school teachers said about peak oil, and all of the world’s oil being gone within 30 years.  Now, 30 years later, stores of oil and natural gas in the US alone are estimated to last 300 years, not counting the resources sure to lie off our coastlines, yet unexplored.  The image of the future painted in the 1970’s included smog-filled skies and rivers thick with chemicals.  Nobody predicted what happened: that air and rivers would be cleaner in most parts of the US than they were in the 1970’s.

I’m certainly not arguing that nothing lies ahead but endless sunshine.  I worry, for example, about a nuclear Iran, and I always worry what our politicians might fail to do. But I doubt a time ever existed when people woke up with no worries.  As for the Mayan calendar and the end of the week, let’s just say I’m not losing any sleep.

December calendar photo available from Shutterstock

Lately it seems as if I’ve been hearing more calls to change US marijuana laws.  The legalization of marijuana has been a cause for some citizens for decades, and efforts to change marijuana laws have waxed and waned since I was a teenager in the 1970’s.  Some people believe that this time around, attitudes are truly changing.  A recent Quinnipiac University poll  showed that as of November 2012, a majority of US voters favor legalization of the drug for recreational use.

The current status of marijuana laws are confusing, to say the least. Marijuana is regulated at multiple jurisdictional levels, so a person in any one location is subject to state, federal, and sometimes local statutes.  These statutes are often at odds with each other, so the legality of marijuana depends largely on the employer of the agent or officer making the arrest.

There are also multiple forms of legality. In November, Colorado and Washington State legalized the possession of up to one ounce of marijuana.  Another dozen-or-so states decriminalized marijuana over the past 20 years, so that possession of the drug is punishable by citation, not prison time.  Another 20 or so states have laws allowing for the medical use of marijuana, including in some cases provisions to grow marijuana for personal use or for a small number of patients.

By federal law, marijuana continues to be illegal in virtually all settings.  The DEA classifies marijuana as ‘Schedule I’, the same status as heavy-hitters like LSD or Heroin.  Smoking marijuana can be reason enough for most employers to terminate employment.  And violation of marijuana laws, even the possession of small amounts of marijuana, can result in permanent banishment from federal financial aid programs for higher education.

I have no pressing personal opinion on this issue.  I don’t have a ‘marijuana problem’, and I never really had a problem with the drug.  I smoked it as a teen, and note that the year of my high school graduation, 1978, was the peak year for marijuana use in this country.  But I never enjoyed smoking pot as much as some people appear to.  I always had things that I wanted to do or accomplish, and smoking marijuana, as I grew older, got in the way of those things.

Marijuana was a much less potent drug in the 1970’s than it is today.  In my teens, people talked about ‘smoking a joint or two.’  Now that the THC content is much greater, people have ‘hits.’  I just realized, by the way, how ‘square’ I sound right now.

It is difficult to know whether perceptions surrounding marijuana are accurate or based in fantasy.   Last night I saw a Facebook post from one of my HS classmates that included a picture of my geography teacher in 1976, wearing extra-long, extra-wide, plaid bell-bottom slacks.  It is hard to remember 1970’s marijuana without remembering all of the other silly things that we did in the 1970s, that seem so harmless in retrospect.  On the other hand, I remember the fallout shelters and nuke drills back then, which on paper seem every bit as serious as any ‘fiscal cliff.’   Clearly, dangerous things in the past seem less frightening than dangerous things now.

Is marijuana a ‘gateway drug’ that leads to use of more dangerous substances? There is no doubt that marijuana smokers are more likely to use heavier drugs than are non-marijuana-users, but correlation is not causation.  I’m reluctant to conclude that marijuana use ‘causes’ people to use pain pills or heroin. At the same time, I don’t buy the arguments by some pot smokers that marijuana keeps them sober from alcohol or illicit substances.

My Klout score isn’t so high as to impact the likelihood of legalization of marijuana, but I will share a few thoughts anyway about my clinical experiences and observations:

• Many of my patients can smoke marijuana without apparent negative impact on their lives.
• Many patients have shared with me their desire to stop smoking, but are unable to leave the drug behind.
• The biggest downside of marijuana use from my perspective is the complacency that some users develop.  Some marijuana smokers seem to accept miserable circumstances that they would be more likely to change if forced to endure them without smoking pot.
• Medical marijuana, at least in some cases, is a system rife for abuse.  I meet patients from neighboring Michigan who are prescribed marijuana to treat pain from cancer and side effects from chemotherapy.  I see other patients prescribed marijuana for headaches, fibromyalgia, anxiety, depression, irritable bowel, Crohn’s disease, and a host of other symptoms and disorders.  For all other medications, the FDA provides guidelines on the proper indications for the drug.  Medical marijuana, on the other hand, has been embraced as a panacea for so many symptoms and conditions that it is difficult to accept any specific treatment as ‘clinically indicated.’  The illegal status of marijuana, of course, prevents the FDA from considering the drug as medically indicated for any condition.  So we have the worst of both worlds;  a drug without proper vetting by the FDA, only-legal-enough to allow for use of the drug in the absence of good clinical study.
• Proponents of marijuana legalization compare marijuana to alcohol from the perspective of fairness, but when doing so often neglect to consider the huge societal costs from use of alcohol.  Or as grandma says, ‘two wrongs don’t make a right.’

Many young people have been led to believe that the Obama administration is on ‘their side’ in regard to legalizing marijuana.  I wonder, though, if legalization of marijuana will require the lead of a traditional antagonist—as Clinton participated in welfare reform, and Nixon opened relations with China.  In other words, I’m not expecting big changes on the federal level anytime soon.

Marijuana plant photo available from Shutterstock

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 the 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.

Neuron image available from Shutterstock

I struggle with the length of my posts. I shoot for 1000 words—an amount of reading that most people can knock off in a typical trip to the bathroom— but I find it difficult to limit posts to that size. So as I have done in the past, I will break this post into a couple of sections. In the first, I’ll lay the groundwork for investigating symptoms of withdrawal in a patient taking buprenorphine. The second post will go into greater detail.

A patient recently contacted me to complain that he was experiencing withdrawal symptoms for several hours after each dose of Suboxone. I will describe my thought process, in case the description helps someone else experiencing similar symptoms.

My first decision point is whether or not the person is truly experiencing symptoms of withdrawal. Some people will misinterpret symptoms from excess opioid stimulation as withdrawal symptoms, for example. Nausea is a not-uncommon complaint among people taking buprenorphine, and patients often assume that nausea is the result of insufficient opioid activity, and so take higher doses of buprenorphine. But nausea is actually more common in opioid overdose than during opioid withdrawal, along with constipation, whereas withdrawal primarily causes diarrhea.

Pupil diameter is a good indicator of withdrawal vs. overdose; small or ‘pinpoint’ pupils suggest an excess of opioid activity, whereas withdrawal is associated with very large pupil diameter.

Other symptoms are also misinterpreted as withdrawal. Many opioid addicts develop a strong fear of withdrawal over years of using, and so ‘withdrawal’ is often the first thing to come to mind, during unpleasant symptoms. I also believe that the experience of withdrawal becomes learned in a way that allows the symptoms to re-occur after certain triggers. I remember an experience years ago, when I awoke from a dream experiencing significant withdrawal symptoms, even though I had not taken an opioid agent for years. I feel back asleep, and was grateful to find that the symptoms were gone, when I woke the second time.

People are angered by the notion that their symptoms have ‘psychological’ origins. But as a psychiatrist, I have seen people blinded or paralyzed by conversion disorder. If the mind can cause paralysis (and it can), I have little doubt that the mind can cause other physical symptoms.

If, after these considerations, the symptoms seem consistent with symptoms of opioid withdrawal, the next step is to compare the timing of the symptoms with what would be expected from various causes. For example, withdrawal symptoms occurring shortly before the next dose of buprenorphine (or Suboxone) suggest that the dose is not quite high enough. Buprenorphine eliminates cravings if kept at a blood level above that necessary to maximally occupy mu opioid receptors, because then fluctuations in blood level have no effect on opioid activity. But if the blood level of buprenorphine decreases below that threshold, cravings and/or withdrawal symptoms will occur.

If the symptoms occur shortly before dosing, the solution would be to increase the daily dosage of buprenorphine, decrease the dosing interval, or increase the efficiency of dosing. I have discussed ways to increase dosing efficiency here.

This particular patient describes symptoms of withdrawal beginning about an hour after taking Suboxone. Absorption of buprenorphine takes 1-2 hours, and so the timing could suggest that the dose needs to be increased. But if dosage is truly the problem, we would expect even worse symptoms if he delays his daily dose by several hours—as that would allow the blood level of buprenorphine to fall even further. But in this person’s case, delaying the dose of Suboxone delays the withdrawal symptoms. The symptoms continue to occur about an hour after taking the medication, suggesting that the dosing itself is causing the symptoms.

I cannot imagine a scenario where a sublingual dose of buprenorphine would cause true symptoms of withdrawal, an hour after the dose. At this point we need to look at the naloxone component of the medication, and determine whether the naloxone is causing unpleasant symptoms— and if so, why.

To be continued…

Withdrawal poster image available from Shutterstock

The FDA recently released a Drug Safety Announcement regarding 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 breakdown 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 therefore 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.

Sleeping child photo available from Shutterstock

A couple weeks ago the manufacturer of Suboxone, Reckitt-Benckiser, filed a Citizens Petition with the FDA, announcing a voluntary recall of one of the company’s signature products, Suboxone Tablets.  Suboxone was sold in tablet form for almost ten years, and the patent ran out on Suboxone Tablets last year.  A couple years ago the same company began making Suboxone Film; a rapidly-dissolving form of the medication that comes with each dose individually packaged.

Suboxone is used to treat opioid dependence, and the medication has been a vital, albeit expensive, tool for saving the lives of patients addicted to narcotic pain medications or heroin.

Last week I expressed anger at the company for their actions. Uninsured patients treated for opioid dependence pay a high cost for the medication that helps keep them safe, and have been looking forward to a generic form of the medication for years.   It appeared to me that Reckitt Benckiser was trying to tarnish the tablets, perhaps to reduce insurance or Medicaid coverage of the tablets when they inevitably (?) hit the market.

I have carefully read through the entire Citizens Petition, and I now have a better understanding of what, exactly, was accomplished by that action by the manufacturer of Suboxone.  It turn out that I underestimated the people at Reckitt-Benckiser.

The Citizens Petition explains that Reckitt-Benckiser (RB) hired an independent group, RADARS (Researched Abuse, Diversion, and Addiction-Related Surveillance), to investigate the exposure of small children to Suboxone tabs and Suboxone Film.  The results of the RADARS findings are spelled out in detail in the Petition.

RADARS showed an increase in exposure to Suboxone Tabs over the past ten years.  They also show an increased rate of exposure, i.e. number of exposures, divided by the number of tabs prescribed.  Reckitt-Benckiser wrote that they instituted REMS over the past few years to counter that increase. What are REMS, you ask?

From the FDA site:  The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks.  To meet that requirement, RB claims that they instructed their sales force to be double, extra-especially careful to tell doctors to remind patients to avoid giving Suboxone tablets to their children.  No, I’m not making this stuff up… although the ‘double, extra-especially’ part is my own hyperbole.  I don’t remember exactly how it was worded in the petition.

RB wrote that the warning is actually part of their mitigation strategy—that they expect an impact on pediatric exposure, if their salespeople tell doctors to tell patients to keep the pills out of the hands of children.  Gosh—good thing they did that!  I’m picturing all those people who having their 2-year-old kids managing their Suboxone!

But telling doctors to tell patients this ridiculous bit of information did not solve the problem, so RB claims they needed to do more.  They decided that every dose of Suboxone must be individually packaged.  But they had problems with the stability of naloxone while producing individually-packaged Suboxone Tabs, leading them to make the Film form of the drug.

To read the petition, the expiration of their patent on the tabs had nothing to do with anything.  And the long, new patent on the Film has nothing to do with anything.

I have a couple questions at this point.  First, the obvious one—did RB REALLY have a discussion about having their salespeople remind doctors to remind patients to protect their children?  Do they really think that patients and doctors are that stupid—that their salespeople can make a difference in that regard?

Second, do they really find it necessary to individually wrap each dose of Suboxone, a combination of an opioid partial agonist plus an opioid antagonist, when oxycodone, hydromorphone, hydrocodone, and other potent opioid agonists are sold by the bottle?  I could go on and on about this issue… most patients on Suboxone guard each tablet carefully, as they are prescribed to match up with the number of days in each month… whereas opioid agonists are usually prescribed to take ‘as needed’, meaning the tabs are much more likely to end up in kitchen cupboards or otherwise unaccounted for.

Why would a company hire another company to find fault with their product?  One might think that the manufacturer of a substance would be, if anything, pointing out the safety of their product—not arguing that it is unsafe.  This is where cynicism starts to set in.  I’m supposed to believe, according to RB, that they discovered a problem with their product, hired a company to assess that problem, and then voluntarily withdrew the product from the market.

But to believe the RB story, I have to accept a number of ‘coincidences’.  They wrung profits out of the tabs for almost ten years, and just happened to figure out this danger within a year after patent expiration—just when generic pharmaceutical companies were able to manufacture cheaper forms of buprenorphine.  The company has been dreading the flow of generics for years;  heck, their reps spend more time talking about THAT issue than they do about pediatric exposures!  It is also an odd coincidence that RB just happened to be pushing the Film like crazy to insurers and Medicaid agencies, well before their ‘discovery’ of the danger of pediatric exposure to tablets.

To really understand the situation, you must read all the way to the top of page 29 of the Citizens Petition.  There, the attorneys for RB point out to the FDA that if a manufacturer voluntarily withdraws a medication for safety reasons, the FDA is not allowed to approve any new drug application for a generic that is based on the withdrawn medication.

Wow.  They have some darn good attorneys at RB.

Pills photo available from Shutterstock

Message from a reader:

I am trying to determine what my best course of action might be in dealing with protracted withdrawals from a number of drugs, including benzodiazepines.

My history is as follows:  I was snorting Oxycontin for about 6 months and went into treatment to stop.  Before entering the rehab hospital they put me on Clonidine .2 mgs, Ambien 12.5 mg and Sertraline 50mgs for about 1-2 weeks. Once hospitalized they switched me to Mirtazapine 15 mg, Clonazepam 1 mg and Cymbalta 20 mg., and I was on these for 5-6 months.

I took myself off all three of the last meds over a week or two, becoming free from all drugs. I believe stopping these medications cold turkey affected my CNS.  I don’t drink alcohol or smoke pot. I basically stopped interacting with all of my friends to stay away from all drugs and alcohol.

I still feel awful. My primary symptoms are anxiety, depression, foggy-headed and depersonalization.

I have read posts from a woman who goes by username “Polenta,” from a site called benzo buddies,  who is nearly 80 and has been in withdrawal for 20 years.

Will I fully heal? Does everybody heal no matter how far out they are? This Polenta woman says she knows of people who are as far out as her, or farther. My big question that plagues me is whether these people recover mentally? I’m aware there are physical and mental symptoms; I only suffer from mental symptoms. Polenta said in another post that Una had said there were people out even farther out who recovered, even a person 25 yrs. out. I’m wondering if that person was like Polenta and suffered from mental issues and still recovered to have quality of life.

Would I benefit from starting a low dose of an antidepressant and then tapering very slowly off to help stabilize my CNS? I greatly appreciate any advice that you can offer me. I’ve been in a lot of pain these last couple years and believe that someone with your professional and personal experiences can help me find some answers.

Tom

My Thoughts:

Hi Tom,

I hear similar complaints frequently.  Just today I saw a person who has been struggling to get off psychiatric medications, including benzodiazepines, for several years.  He is not able to stop cold turkey because when the diazepam level in his bloodstream drops too low, his anxiety and panic become unbearable.

There is a split between what you will read on the internet* vs. what you will be told by most physicians.  Horror stories about permanent structural damage to the GABA receptor complex have little or no basis in scientific research.

The common medical opinion is that benzodiazepines act at GABA receptors in a reversible manner, and that while withdrawal is very unpleasant for some people, there are no permanent symptoms caused by benzodiazepine intoxication or withdrawal.  Benzodiazepines have been prescribed fairly commonly for 40 years or so, and the collective experience suggests that they are quite safe, beyond an increased risk of miscarriage in the first trimester of pregnancy and the well-known problems of tolerance, dose escalation and addiction.  That said, I am no fan of routine use of benzodiazepines, as I point out here.

I suspect that most physicians who hear your story will write the symptoms off as psychiatric or psychological.  There will be homeopathic or naturopathic physicians who will use your symptoms as reason to sell you all sorts of ‘cleansing’ products, or gadgets that ‘rebalance the body’ in some way, or bizarre-sounding therapies that adjust your ‘energy fields.’

I’m sure I sound skeptical, because I AM skeptical.  Since you are writing to it me, I’ll share my opinion, and you can decide who to believe.  I am a scientist at heart.  One thing that getting a PhD teaches a person is how to critically assess the scientific literature.  I am a reviewer for two publications—Academic Psychiatry and Journal of Addiction—where I am occasionally called upon to review articles that have been submitted, suggest changes, and help determine whether the study described in the article contains bias or statistical errors that should prevent publication.  I know very well how easily we humans can misperceive things by seeing what we want to see, or by automatically believing what we suspect to be true.

The supplements used to treat opioid or benzodiazepine withdrawal are essentially worthless.  There are many plants that have folklore attached to them, and in many cases that folklore has been copied in some bogus ‘encyclopedia of natural remedies’ and then claimed by other people to be true— because it is in a book.  People write all sorts of nonsense in home medicine ‘references’;  many such books are self-published, so there is not even an editor putting his/her reputation on the line—or if there is, the lure of quick cash has erased concerns about leading people astray.  My patients have used many of the remedies, including products that advertise on my web sites. I’ve never witnessed relief beyond the expected placebo effect.  Realize that the placebo effect has a huge impact on psychological symptoms such as depression and anxiety.

There is a bizarre tendency among people to accept what is described as ‘natural.’  Many people are afraid of FDA-approved medications that have been through years of testing, yet gobble down supplements from China that were never inspected by anyone.  I’m off topic, but I think that the general attraction of things described as ‘natural’ must be called out for the silly charade that it is.  Your body has no way of knowing what is ‘natural’ and what isn’t;  your intestine takes on the breakdown and absorption of ingested chemicals regardless of whether that chemical was made by a factory or by a mushroom.

The products hyped to ‘cleanse’ the body are simply bogus—with the exception of a few medications with very specific binding properties such as chelating agents that bind heavy metals, or chemicals that draw ammonia from the bloodstream into the colon.  When someone is given naltrexone, opioids are NOT flushed from the system.  Naltrexone competes for binding at the mu receptor and causes withdrawal, but the molecules being antagonized are still in the body, and are eliminated at the same rate whether or not naltrexone is present.  Yet the ‘rapid detox’ people love to write about ‘cleansing’ the body of opioids.  Hogwash!

Back to your case… from a scientific, evidence-based perspective it is difficult to see how withdrawal would cause permanent damage to neurons, provided there were no seizures or lack of oxygen at some point in the process.  While some people have long-term symptoms like you describe, the vast majority of people suffer insomnia for several weeks, but then return to normal as the receptors lose their tolerance.  Why would your brain be different?  Realize that dividing physical vs. mental causes for symptoms creates an unnatural dichotomy.  Mental symptoms are caused by physical changes in the brain.  If you are having depression and anxiety, there are neurons in your brain that are firing in a certain pattern to make you to feel that way.

So if I’m correct, why do some people experience symptoms like yours for years after stopping benzodiazepines?

I suspect that in some people, psychological symptoms and physical or emotional feelings become ‘imprinted’ on the brain, as memories that play back over and over in response to certain cues, until they are replaced by other memories and imprinting.  Memories form because the neural pathways that get used become more likely to be used again, like ruts in a muddy field.  The pathways that make you feel anxious, for example, fire strong signals over and over during true withdrawal, and from that point forward, those pathways are easily set off again by certain cues, or perhaps even spontaneously.

I see more evidence for this phenomenon in people addicted to opioids, whose thoughts can generate symptoms of withdrawal months or years after the last use of opioids.  As one thinks about it, if memories of a pleasant vacation can generate smiles for weeks afterward, doesn’t it make sense that memories of withdrawal can generate anxiety and depression?

The answer for your situation then becomes forgetting those miserable experiences, best done by replacing the bad memories with layers and layers of better memories.  That may mean doing your best to ‘act as if’;  to ‘fake it ‘til you make it’, force a smile, and keep on truckin’ day after day until you feel better.  Keep your mind open to change, and do your best to see the positive side of things.  Practice gratitude whenever you remember to.  Exercise is always helpful, I think because it forces us to replace thoughts of despair and impotence with the experience of pushing forward despite those feelings.

I wish I knew an easier, faster way to feel better.  But if there is one, I haven’t discovered it yet.

I wish you well,

J

* References to a certain UK physician have been removed.  I admit that my knowledge of that physician’s body of work comes from what I have read from others– not directly from the source.