Subox Docs: Analyze This!

People on buprenorphine or Suboxone often write to me with complaints about lab testing.  I received an email last week that mirrors my personal experience with lab testing companies.
Here is what it said:
Dr. Junig:
I thought you might find this interesting. I continue to see (name withheld) for addiction treatment using buprenorphine. I see the doctor every three months, and I’m prescribed a low dose of Suboxone film (below 4 mg per day). I recently got an insurance denial for over $2000 in lab charges, for ONE urine test! Evidently someone sent my tests to (lab name withheld for patient privacy) who billed for 23 tests!  This is on a test that was negative for any substances other than the proper amount of buprenorphine.   This is like a license to print money! The same thing happened three or four years ago with (a National lab provider), but that was ‘only’ $600 and it eventually got written off. I have no idea if (withheld) will come after me– but there is no way I’ll pay them a dime.
Is there any wonder health costs are so out of control? How can a company get away with this? I have a feeling this is just routine and someone on the staff sent it by mistake as after the first incident with the other lab.   My doctor doesn’t usually send my tests into a lab, but instead just does the immune point-of-care test in the office.
Have you heard of charges this high? Just thought I’d pass it to you in case it’s good info for a blog post. Talk about crazy–  How in the hell, even seeing a doctor 4 times a year, could I remain in recovery on buprenorphine with total annual costs near $12,000?  Plus, doing these expensive tests on negative samples?  I can maybe see on a positive result – but negative?  This is so wrong.
I wrote this email in response (I’ve edited my remarks for grammar and privacy):
I wrote about this issue a couple of years ago, and I understand your anger.  I used the same lab company a few years ago for about a month, after their salesperson promised they would never charge anything beyond what insurance paid.  But they did charge some patients, and then other patients complained that one lab test used up their entire annual mental health coverage!   Now I only use point-of-care tests (which cost $3 each), unless there is a clear reason for confirmatory testing.
(Note—Wisconsin health insurers used to commonly limit mental health expenses to two or three thousand dollars.  Now, because of mental health parity laws, insurers must provide the same coverage for mental health expenses, including drug testing, as they do for other types of healthcare.  I guess it’s good that the care is no longer treated differently… but one very ugly result has been an explosion in lab testing costs—which increase EVERYONE’S insurance rates).
Back to my email:
In the past few years representatives from two pain clinics asked for meetings, and told me the same thing: that insurers were tightening payments for ‘injections’ by paying only for injections that actually worked (what a concept!).  The pain clinics now make more money from lab testing than from their bogus injections.  The problem?  Insurance would only cover one urine test per month unless an addiction doc was on staff, which would allow them to do unlimited numbers of tests.  They said that lab companies set up turn-key operations for docs providing equipment, technicians, billing codes, etc—and they could bill over $1000 for a test that used $4 in raw materials.   Even Medicaid paid over $500 for one urine test!
I would love to blow the whistle on this garbage, but every agency seems to have the attitude that doctors need to test people more, not less—no matter the cost.  Talk about a situation ripe for abuse!
Comments:
Opioid agonists are a Godsend to patients with severe pain, whether the pain is acute or chronic.  Opioid agonists are also highly-abused, so some degree of monitoring is appropriate.  I wonder about the motives of some doctors, who prescribe ever-increasing doses of potent opioids, and then suddenly stop prescribing when a urine test shows traces of THC.  Those doctors know, or at least should know, that acutely stopping opioids results in severe withdrawal.    About ¾ of my addiction patients turned to street pain pills when a doctor, often the same doc who started them on pain meds, kicked them out of treatment for testing positive for THC or for running out of medicine early after treating a flare-up of their pain.
Even for the sadistic docs who practice that way, it doesn’t take a thousand-dollar test to discover a drug habit.  If society is truly concerned about healthcare costs, is it appropriate to spend $2700 testing for non-existent metabolites of non-existent substances, when one $3 test will detect the presence or absence of cocaine, buprenorphine, oxycodone, hydrocodone, amphetamine, THC, propoxyphene, PCP, heroin, or benzodiazepines?  Is the extra $2697 justified on every routine follow-up visit?  Inexpensive or free measures, such as pill counts or random 3$ point of care tests– are far more useful to determine if someone is selling or sharing a prescription.
Opioid agonists cause tens of thousands of deaths each year, so maybe someone could argue for that type of overkill with those medications. But this degree of drug testing for patients treated with buprenorphine?!   Buprenorphine is identified in fewer than 50 overdose victims per year in the US–  the same number of people killed by lightning.  Even in those few cases, buprenorphine didn’t cause death, but rather was present because the person used a buprenorphine product at some point in the days or weeks before overdose.  In fact, most of those 50 overdose deaths would have been prevented had MORE buprenorphine been present.
I find it bizarre that more and more ‘PA’s’ for buprenorphine products ask the question, ‘are you doing drug testing’?  I’m curious– what do the people who create those forms WANT to happen with their patients?  I’ve thought about writing back…. “Yes, I did drug testing.  He tested positive for marijuana, so I kicked him out of my practice, and he died of a heroin overdose last week.”  Would the insurer see that as a good outcome?  Would I get a pat on the back– “Great job!  That’s some GREAT drug testing you’re doing!”
Why So Much Testing?
When did doctors stop trusting their patients?  Doctors used to provide a confidential refuge for troubled people.  Med school ethics courses questioned whether doctors should take any action that interfered with patient autonomy.  Doctors must go against their patients’ wishes in certain situations, such as cases of child abuse.  But when did we start assuming that people voluntarily seeking treatment were lying?
I wonder why my colleagues are so eager to get behind aggressive testing.  I’ve already suggested one motivator—i.e. greed.  But that doesn’t explain the entire phenomenon, because many docs get just as excited about testing while leaving all the profit for the testing companies.  In those cases I’ve wondered if their willingness to distrust their patients relates to their backgrounds as addiction doctors.
Many addiction docs are psychiatrists, a specialty that attracts the most risk-averse medical students.  Consider the risks that doctors in other specialties accept as a matter of course.  A neurosurgeon speaks with a patient a couple of times, and then opens that person’s skull and removes part of the person’s brain.   Consider the CT surgeon who meets with a patient, reviews the tests, and then splits the sternum to sew grafts into arteries that supply blood to the heart.  Those doctors are entrusted to cut people open, remove diseased tissue, and provide appropriate follow-up care.
But when you talk to addiction docs about drug testing, they all say the same thing:  They have to do the testing ‘or they will lose their license.’   They claim that they don’t have the power or autonomy to decide which patients need to be treated like criminals, and which patients have proven themselves as trustworthy and stable.  They have no choice, they say, other than to test every single patient on every visit.
Then there is the true cynic in me, who wonders of some doctors just ‘get off’ on catching people.  Patients who come in for addiction treatment are in dire straits, and have a lot of work to do.   After living like animals, they are taking on the challenges of giving up their drugs of choice, learning to trust their physicians, giving up self-medicating, and learning to tolerate their emotions.   Many new patients struggle with giving up marijuana, a drug they’ve used to treat withdrawal for years, and a drug associated with mixed signals from a couple states (and from the President).   Kicking a heroin addict out of treatment for smoking marijuana is the worst type of of bullying I can imagine.
I admit that I drug-test patients.  But I don’t use drug tests to kick someone out of my practice, any more than an endocrinologist would stop prescribing insulin for a diabetic patient who can’t stay on a diet.  My patients know that I don’t kick people out for struggling, so I usually hear, at the start of the appointment, if a patient has relapsed.    I’m sure there are docs who think I’m naïve, who believe that patients are getting away with something ‘on my watch’.  But I can live with that.   In return I get to be a doctor who treats people like human beings, not criminals.
If buprenorphine was causing death (it isn’t), serving as a gateway drug (it isn’t), or was used in some nefarious way similar to GHB (it isn’t), I would likely think differently.  But honestly—the docs and DA’s who spout that ‘buprenorphine is just like heroin’ are idiots.  I suggest that they learn a bit of neurochemistry before spreading such nonsense.  In fact, just pay for my travel and I’ll walk you through the science, and show you WHY you’re idiots.
To the doctors who aren’t yet making a profit from lab testing but considering jumping on the bandwagon, reconsider. What type or relationship do you want with your patients?
To the doctors who gave in to the slick sales pitch from a lab company’s salesperson who brought you a nice lunch, and promised to only bill insurance so that ‘nobody loses’, stop kidding yourself.  You are a big part of the problem.
And to the docs who make money from treating all patient like liars, driving up insurance rates for the rest of us…  Shame on you.

On Biodelivery and Norbuprenorphine

Over the past few months, I’ve read a few posts at the forum that are worth sharing.  I’ve been torn whether to share them with the general buprenorphine community, or only with doctors who prescribe the medication.  I’ve decided that since the ideas came from a layperson community, I’m not opening the floodgates to irresponsible behavior by repeating what I’ve read.  Feel free to comment if you believe I’ve made the wrong decision.
But first, a word of warning to persons taking buprenorphine:   Do NOT take steps to deliberately alter drug delivery beyond the things that your doctor approves of, such as avoiding drinking liquids right after dosing, or placing the film against your cheek instead of under the tongue—a useful step particularly for someone with dentures.  Do NOT try to increase the effects of buprenorphine by taking substances that block metabolism of the drug.  Such actions risk turning a lifesaving medication into just one more drug of abuse, putting you back into the miserable condition where you existed before buprenorphine treatment!
Bioavailability has become a significant issue for differentiating buprenorphine products.  Late-generation products have increased bioavailability— from 25% with Suboxone Film to 40% and 50% in Zubsolv and Bunavail, respectively.  One result of higher bio-availability is that lower doses of buprenorphine are needed to create identical buprenorphine blood levels.  A second result is lower blood levels of buprenorphine’s primary metabolite, norbuprenorphine, resulting in less constipation during buprenorphine treatment.
Some buprenorphine patients have learned about bioavailability, and have used the forum to describe their efforts to maximize delivery of buprenorphine to the bloodstream.  Over the past few weeks two discussions popped up that relate to different aspects of the same general issue.   And while similar discussions have come and gone over the years, there seems to be a growing sophistication to the discussions.
One recent discussion focused around the use of grapefruit juice to boost the actions of buprenorphine by delaying drug metabolism at CYP3A4, a cytochrome enzyme found in the liver.  Several writers described feeling a boost in mu-receptor activity when they dosed their buprenorphine after drinking grapefruit juice, a side effect that I considered unlikely given the ‘ceiling effect’ of buprenorphine and the rather limited impact of delaying metabolism in a medication that already has a long half-life.  But I realized, during the discussion, that grapefruit juice may be doing far more than reducing the breakdown of sublingually-absorbed buprenorphine.
When a person takes a buprenorphine product, 50% (Bunavail) to 75% (Suboxone Film) of the buprenorphine is swallowed, absorbed at the intestine, and converted to norbuprenorphine at the liver via ‘first pass metabolism.’  But blocking CYP3A4 may allow swallowed buprenorphine to escape first pass metabolism, causing swallowed buprenorphine appear in the inferior vena cava as buprenorphine rather than norbuprenorphine.  In such a case, blood levels of buprenorphine would increase not by the small factor expected from delayed metabolism of a long-half-life drug, but instead by a very large amount—doubling or even tripling the blood levels of buprenorphine.
I have not researched the issue, so I don’t know whether the effects of grapefruit juice on CYP3A4 are strong enough to eliminate or reduce the second-pass effect on swallowed buprenorphine.   But the topic is worth a look—a hint to some aspiring grad student out there!
In another discussion, a patient wrote that he is about to be kicked out of treatment because his doctor doesn’t think he is taking the buprenorphine that he is prescribed.  The patient wrote that he is not only taking the medication, he is INJECTING the medication, ‘so there should be even more buprenorphine in his system than normal.’
Lost on the patient, besides the general  folly of injecting non-sterile, non-IV-grade substances, is that many doctors measure levels of norbuprenorphine to make sure that their patients didn’t just ‘dose’ on the day of their appointments.  I suspect that this patient delivers far less buprenorphine to his liver by dosing intravenously, resulting in very little production of norbuprenorphine.
Why does he inject, by the way?  Like most people who inject buprenorphine, he says he doesn’t really know the answer to that question.  He says that injecting is a means of drug delivery that he has become used to, and that he is hesitant to give up. He is used to getting everything that he can out of heroin…. and he wants to get everything he can now, out of buprenorphine.  He says he doesn’t experience any ‘high’ when he injects buprenorphine.  I explained to him that by behaving so foolishly, he opens the door to huge risks – including the risk of losing access to buprenorphine.
Hope everyone had a nice Thanksgiving.

Quantitative Urine Drug Testing and Buprenorphine: Tainted Motives?

First Posted 11/23/2013
As fear of buprenorphine diversion sweeps the nation, some states have passed legislation adding more rules for practices that treat addiction using buprenorphine.    Never mind that buprenorphine is linked to about 400 deaths over ten years, one tenth of the number of deaths from acetaminophen during that same time, and 0.1% of the number of overdose deaths overall.

Many parts of the country have seen a reduction in number of buprenorphine-certified physicians over the past few years.  Many rural areas have no buprenorphine prescribers at all.  The lack of prescribers, combined with the limit of 100 patients per prescriber, leaves opioid addicts with one legitimate treatment option— the early morning line for methadone or buprenorphine at methadone clinics.  I’m not against the clinics, but the need to report each morning is a significant barrier to employment in many patients who would do just as well with a prescription for the medication—and a first-shift job. Their other option is to do what all the news stories have been reporting—use buprenorphine without a doctor’s supervision and attempt to stop heroin or pain pills on their own, aka diversion.

One clue about your own state’s buprenorphine policies is whether your doctor is still prescribing buprenorphine products, or has instead moved to an area of medicine where doctors make decisions according to clinical judgment.  As the number of buprenorphine/naloxone prescribers in my part of the country has decreased, the amount of diversion has increased.  I predict that policies that discourage doctors from treating opioid dependence will increase the number of addicted people trying to treat themselves.

Sometimes it is easy to predict unintended consequences.

Regulatory agencies of at least one state prevent insurers from covering specific, FDA-approved medications.  Other states require doctors to follow specific practice patterns instead of their best clinical judgment.  One example of oversight that demonstrates the folly of lawmakers playing doctor is the push to require ‘quantitative urine testing’ in all patients at frequencies determined at the state capital, rather than by the doctors treating the patients.  The expectation is for quantitative testing to reduce diversion.  Note that 30,000 overdose deaths per year from non-buprenorphine products never prompted such oversight, nor did the well-known ‘pill-mill’ pain clinics that have flourished for the past decade.  But an average of 40 deaths per year related to buprenorphine has demanded action by lawmakers!
There are times when quantitative testing is useful, but I suspect that legislators who voted to require such testing heard only the half of the story told by people with vested interests.  After all, quantitative testing is one of the more lucrative areas in all of healthcare.  Even Medicaid agencies that pay pennies on the dollar for office visits pay generously for testing with the right billing codes.  Turn-key testing businesses can be purchased by entrepreneurial doctors to grow revenue at pain clinics, leasing out testing equipment and training techs in return for a piece of the action.

What legislators SHOULD know:

Quantitative urine tests for standard drugs of abuse in just one patient can cost well over $1000.  Costs over $500 per test are the norm.  The costs are paid by insurers, Medicaid, or patients, increasing insurance premiums and taxes and blocking treatment for some patients.

‘Point of care’ test strips that use immunoassay methodology are sensitive and accurate.  A standard test kit shows the presence/absence of trace amounts of specific opioids (methadone, oxycodone, or heroin/morphine derivatives), amphetamine, benzodiazepines, cannabinoids, cocaine, PCP, barbiturates, and buprenorphine.  Typical test kits give all the results for a total price of $5-$10.

Almost all the decisions related to testing rely on the presence or absence of substances—not the number of nanograms of a substance.   The point is whether a patient used heroin or cocaine—not how many milligrams of heroin or cocaine were used.  Test companies claim that measurement of buprenorphine’s first breakdown product, norbuprenorphine, can determine if a patient took buprenorphine only recently to fool the doctor. But I receive dozens of emails each year from patients with nothing to gain by describing their experience in those cases, swearing that they were taking the medication correctly, and asking how they can prove their truthfulness after what is called ‘flipped levels’ in such testing.  Besides, anyone with knowledge of addiction knows how difficult it would be to pull of such a scam. The scammer’s urine would still contain the drug of abuse, unless we suppose the unlikely scenario where scammers successfully stop all opioids for a week each month and experience withdrawal each time, all for the sake of a script for Suboxone.  Beyond the misery, few addicts would be able to control use of narcotics to that extent.  That’s why they are addicted in the first place!

‘Quantitative urine testing’ measures the concentrations of substances in a patient’s urine.   But urine concentrations of substances are not accurate reflections of blood concentrations of the substances.  The first part of kidneys (the glomeruli) act like sieves with very large pores, spilling gallons of dilute liquid that contains drug metabolites and other molecules.  The largest parts of our kidneys consist of tubules that reabsorb water and reabsorb or secrete other molecules and ions.  When that liquid finally reaches the exit from the kidneys at the ureters, the original filtrate has been concentrated by several orders of magnitude, and has had a range of molecules removed from or secreted into it.  Water reabsorption depends on hydration status, circadian rhythms, diuretic and other medications, stress hormones, diet, and other factors.  As a result, concentration of a substance in the urine is not related to concentration in the blood—let alone to the use of the substance.  Blood levels provide far-more-accurate information, but even blood levels vary from differences in metabolism of substances between individuals.
Quantitative testing tries to overcome the gap between blood and urine levels by using levels of other substances, such as creatinine or urea, to estimate the extent of concentration performed by the kidneys.  But there are enough variables to make the results far from reliable.  But frankly, the inaccuracies don’t really matter—since in most cases the presence or absence of a chemical is the issue, not the concentration.

In an era when costs are a concern, why would states become involved in testing processes that force a dramatic increase in treatment costs?   Doctors who know their patients are in better position to decide when such testing is valuable.   In medical school 25 years ago, I learned about the inefficiency of shotgun approaches to lab testing—that instead of ordering routine chemistry panels for every patient, doctors should decide which specific tests are necessary and order accordingly.  To mandate such expensive testing, someone is deciding ‘yes that’s true, but….’.   The annual climb in the cost of healthcare is largely due to those and other ‘buts.’

The only reason the state would think that they know better—from hundreds of miles away, without meeting the patients—is if they assume that doctors treating addiction don’t care what their patients are doing, or are inept.  But if the same inept doctors are the people interpreting the results of mandated quantitative testing, what does the mandate add, exactly?  And why the selective oversight of doctors who treat addiction, when most of the harm from drug diversion comes from opioid agonists prescribed by doctors who don’t work in the addiction field?

Other mandates include the rules found on standard opioid treatment contracts.  The rules themselves are not unreasonable.   But I take issue with the double standard applied to addiction physicians.  Expensive residential treatment programs have abysmal success rates.  Should they be regulated?   People who have too much plastic surgery look ridiculous—should that be regulated?  Everybody talks about the epidemic of opioid overdose deaths— deaths caused 99.9% of the time by something other than buprenorphine, the most effective treatment for opioid dependence.  But it’s buprenorphine that needs regulating?

A New Way to Stop Suboxone?

Originally Posted 10/27/2013
I usually have my wife/business partner review my posts and provide her opinion whether my arguments are sound.  For the record, she tells me that this post is technical and boring.  I disagree, but we aren’t planning to separate over the issue.  A valid criticism, I think, is that I’m doing a lot of guessing and wondering in this post.  This post is an example of the things I waste time wondering about.   I try to avoid writing things that are somewhat speculative, but I wanted to give it a shot for two reasons.  First, because there may actually be something to the idea I am about to describe.  But more important, I wish to point out some of the many ideas in the addiction world worth exploring…. And I hope that pharma continues to search for answers (i.e. spend money) in this area of medicine.
So I’ve been thinking more about ALKS 5461, the Alkermes pipeline medication that is a combination of buprenorphine and ALKS 33, which is a mu opioid antagonist also called Samidorphan with the structure shown at the left. ALKS 5461 is being developed by Alkermes for the treatment of major depression.  I don’t know much about the clinical actions of ALKS 33, (a proprietary molecule), except that it comes from a family of drugs that bind with high affinity and specificity to mu or other opioid receptors.  Samidorphan, a mu receptor antagonist, allows investigation of buprenorphine’s potential therapeutic effects at kappa and delta opioid receptors by blocking effects at the mu receptor.  Drugs with actions at other opioid receptors have be developed, and in some case patented.Until recently, theories about depression revolved around abnormalities in brain monoamine pathways or deficiencies of monoamine neurotransmitters.  Monoamines include serotonin, melatonin, and the catecholamines (noradrenaline, dopamine, and adrenaline). Most modern antidepressants act at serotonin or catecholamine receptors or reuptake sites. The new Alkermes medication ALKS 5461 is the first serious effort that I am aware of to treat depression from the opioid perspective.
Our brains contain natural opioids called endorphins and enkephalins.  Endorphins and enkephalins are neurotransmitters in pathways with a wide range of actions, including blocking pain and raising mood during injury or sexual activity. Pain pills such as oxycodone displace endorphins and hijack the natural endorphin pathways, providing euphoria without the trouble of buying flowers.  Of course, a relationship with self-administered opioids always becomes more destructive than even the most codependent partnership!
As an aside, when I presented for addiction treatment 13 years ago I told the addictionologist about my background in neurochemistry, and went on to explain that I was fairly certain that I suffered from a deficiency of natural opioids.  That doctor got a kick out of my story, and I would enjoy a sense of justification if my hypothesis someday proved to be correct.
When one considers using treating depression with buprenorphine, the obvious deal-breaker is the same issue that has prevented every other serious consideration of treating depression with opioids, namely the development of tolerance at the mu opioid receptor.  Because of tolerance, anyone who finds relief from depression with buprenorphine would be cursed by the need for eventual withdrawal, as well as other consequences of opioid dependence. I assume that Samidorphan is added to ALKS 5461 to prevent mu activation and tolerance.  Beyond partial agonist effects at the mu receptor, buprenorphine antagonizes (blocks) delta and kappa opioid receptors.  These blocking actions are not subject to tolerance, and may provide avenues for treating pain and/or depression.
Depression causes significant morbidity throughout the world, so there are huge profit incentives for new antidepressant medications. Addiction creates a large market as well, but companies rarely go as far out on a limb for addiction products as they do for other diseases. The need for new antidepressants is acute, but in an alternate universe where pain and addiction treatment take priority, Samidorphan and related opioid molecules might have a number of benefits. I’ve posted, for example, about my experience treating severe chronic pain by combining buprenorphine with an opioid agonist.  I expect the combination to be exploited eventually given the need for effective pain treatments, perhaps using an analog of Samidorphan.
Doctors use buprenorphine to treat opioid dependence.  The goal of buprenorphine treatment is to block the cycle of use and reward for some period of time, and to allow patients to create support systems, establish self-sufficiency, regain self-esteem, and practice living ‘life on life’s terms.’  The amount of time that it takes to accomplish these goals likely varies depending on the individual’s premorbid function, life experiences, insight, genetics, and other factors, but studies suggest that a year is not long enough to make meaningful headway.   It is possible that for some people, opioid dependence is a relatively permanent condition that is best controlled with life-long maintenance treatment.   But for those who would like to try to maintain sobriety off buprenorphine, the tapering process reignites the circuits that were set up by the initial addiction, causing cravings, withdrawal, and the constant obsession to delay the taper and resume the prior day’s dose of opioid.
If ALKS 33 has a long half-life and blocks buprenorphine in a dose-dependent manner, I could picture an alternate strategy for stopping buprenorphine where the antagonist (ALKS 33) is introduced to buprenorphine patients at a gradually-increasing dose.  The goal would be to eventually have the person on a daily dose of Samidorphan sufficient to block all of buprenorphine’s effects at the mu receptor, at which point the person could discontinue buprenorphine without withdrawal.  I suspect that the patient would experience withdrawal in response to each increase in dose of Samidorphan, although withdrawal would be reduced by introducing the drug at a measured pace.
What is the value in tapering in such a ‘reversed’ way?  Why would adding an antagonist be preferable to the current process, i.e. simply reducing the dose of buprenorphine over time?  The answer comes from an understanding of the nature of addiction.  A person stopping buprenorphine by gradually adding Samidorphan would face the decision once per day, whether to take the next dose of Samidorphan.  Compare that once-per-day decision to the current method of tapering buprenorphine, where the person must decide, thousands of times per day, to NOT take more buprenorphine.  I would expect that deciding to take an antagonist once per day would be more likely to succeed then CONSTANTLY deciding NOT to take buprenorphine all day long, throughout all of life’s ups and downs—times when the patient was conditioned to take opioids.
We will learn more about Alkermes new medication in coming months. I hope that someone in a power position will consider some of the other diseases that might respond to these interesting chemicals, including opioid dependence.

New Bupe News Section

Wanted to take a second or two to point out a new section to the blog, called ‘Bupe News’.  You’ll see the link at the tope of the page, along with an ever-growing list of links.  The point, of course, is to keep y’all reading, since Google knows EVERYTHING, including how many seconds each and every one of you spends on this (and every other) web site.  Understand that I don’t GIVE that information;  that information is simply that is there for the taking on the internet.  Even I can see the average time people spend on the site, the order they went to one page or another, etc.    I do not ‘collect data’ about any reader, meaning that I do not have information about who any individual is or isn’t…   but I DO get reports on my collective audience.
Check the page out, along with the other new section, and of course tell me what you think.  Positive suggestions are ALWAYS welcome!
Thank you for hanging with me,  by the way, for some tough I.T. times.  I’ve got about 3/4 of the ‘lost’ posts back, and then I’ll be back to firing off the NEW things I’m angry about, rather than replaying the things that irritated me a year ago!
J

Who Pays For Health Care? (Hint: We ALL Do)

First Published 4/20/2013
I realize that practice patterns differ between practices, even those treating the same condition (opioid dependence) with the same medication (buprenorphine).  Differing patient characteristics result in different regional standards of care, for example.  And some areas have access to services (e.g. group treatments or laboratory testing) that may not be as available somewhere else.
Is Anyone Trying to Reduce Costs?
Physicians also have differing opinions and attitudes toward relapse and personal responsibility.  Some docs are more paternalistic than others. Some are quicker to dump ‘difficult’ patients. For most medical problems, patients are able to find doctors whose practice patterns match their personal preferences.
Shortages of buprenorphine prescribers in some parts of the country force patients onto waiting lists, and to take whatever open space comes along, whether or not they consider the physician to be personable or competent.  I resist finding fault in how other docs run their practices, as I have no way of knowing the considerations that any physician takes in regard to his/her patients.  But I sometimes hear about practice styles that make me wonder if patients need a wider range of options.

Per Capita Healthcare Costs
Per Capita Healthcare Costs

A patient in my buprenorphine program is trying to find treatment for his wife.  I’m at the cap, so I can’t take more patients.  At a recent visit, he described the practice where his wife receives buprenorphine treatment.  I realize that I’m hearing only ‘his side’, but he had little to gain by misleading me…. beyond, I suppose, having an interesting story.
He said that his wife has done well on buprenorphine/Suboxone for over two years.  She hasn’t relapsed or missed appointments, and she hasn’t tested positive for any other psychotropic substances.
She is required to attend weekly psychotherapy sessions with a counselor employed by her physician.  If she misses a psychotherapy appointment, she is subject to discharge from treatment.  Even after two years of doing well, she is required to continue weekly psychotherapy.  She must attend at least one AA or NA meeting per week.  She must see the prescribing physician every month.  And every month she undergoes urine testing.
Her prescriber accepts Medicaid, so her financial burden is not all that high, other than needing to take time off from work five times per month for appointments.  But her husband described the invoices that she receives for charges to Medicaid.  The charges for doctor appointments are significantly discounted, so they make up less than half of the total bill.  But the lab bills add up.
The clinic charges Medicaid a couple hundred dollars for each ‘point of care’ urine test.  Without Medicaid, the charge is paid by the insurer or by patients themselves.  I showed her husband the kits I use that test for the presence or absence of amphetamines, cocaine, buprenorphine, THC, methadone, oxycodone, mixed opioid (e.g. heroin), and PCP.  I purchase the test kits through internet suppliers, complete with collection vials, for about $5 per test— total, for a test that measures simultaneously for all of the substances.  The $5 kits are just as sensitive and accurate as the $200 tests. The only difference is that I do the testing myself in about 3 minutes, rather than send the urine to the lab.
People with ‘indeterminate’ tests at his wife’s clinic— something that he says occurs about 30% of the time— undergo ‘quantitative’ drug testing.  I’ve written about the boondoggle of quantitative urine testing in the past, about why the tests are not an accurate reflection of blood levels of substances.  In short, blood is filter at the kidney through sieve-like structures.  That filtrate goes through a series of tubules where water is re-absorbed in varying amounts, depending on the balance between fluid intake and fluid loss through sweating, respiration, etc.  Because of the varying concentration of urine, the concentration of a drug in the urine is not directly related to the concentration of that drug in the bloodstream.  Further confounding the tests, some substances are specifically transported out of the filtrate, and others are specifically excreted into the filtrate.
Quantitative tests measure the amount of each substance in the patients’ urine, but tell little about the amount of each substance in the bloodstream.  Labs try to correct for concentration effects by measuring the specific gravity and applying a correction factor.  But the resulting value must be taken with a grain of salt (no pun intended) because of the essential flaw in using urine to determine drug levels.
I have used quantitative testing, and I understand the value in knowing, for example, the ratio between excreted buprenorphine and excreted norbuprenorphine, the chief breakdown product.  But in an era of limited resources, I cannot rationalize making a patient, insurer, or taxpayer pay the $800 – $1200 charged for EACH test!
I dropped the quantitative test company that I was using after I learned about their charges.  The reps for the company paid me a visit over lunch, and asked me why it mattered.  ‘Everybody else is using us,’ they said.  ‘Besides— the patient never even sees it.  We just take it from the insurance company, or from Medicaid.  The patients don’t really pay for it.’
Then one of them added a comment that summarizes why healthcare costs are out of control:  ‘I see your point about the problems with the test, but if you don’t use it, you could get in trouble with the state.’
To translate, the $1000 test adds very little information to the $5 test, but the people on state medical boards doesn’t necessarily understand the reasons why the tests are not worth the money, so I should order them just to make sure that I LOOK like I’m doing as much testing as everybody else.
When I was in med school (way back in the mid-1980’s), my professors at the University of Rochester made a big deal about healthcare costs.  We were taught to know the price of tests that we ordered, and to consider the value of each test, in light of the cost. With everybody bemoaning the cost of health care, seems to me that now would be a good time to get back to some of those considerations.

Urine Drug Testing on Suboxone

First Posted 2/15/2013
A recent exchange with a reader:
I have been on buprenorphine for 5 yrs.  Recently my doctor stated that my u/a t looked like I have been ‘loading my meds.’  He said my levels where ‘backwards’ and that would happen if I took just a few doses just before my appt.   My doc had me come back in two weeks to go over my next u/a, and again it came back funky.  So my doc starts having me take my meds in front of the nurses on a daily basis.  Two weeks later with supervised u/a’s, my urine comes back the same.  My doc looked perplexed but kind of ignored the results like I was still doing something to mess with the results.  I had to come in again for another urine test and it finally came back normal.  My numbers were fine after that, and all was good until last week.
I went to my normal monthly check up and the u/a showed NO buprenorphine in my system.  My doc looked at me like I am the biggest liar.  I am perplexed.  I am taking my meds daily.  I don’t know what is going on and I need to figure it out soon before my doc kicks me out of the program. What could be wrong with the test, that is says that I have no buprenorphine in my body?
My response:
There are several directions we could go with this issue.  One aspect is whether it is always fair to believe the results of drug tests over the word of our patients.  I understand the reasons for testing, but I think that doctors sometimes lose the forest (the patient’s addiction problem) on account of the trees (quantitative testing).  This patient has been on buprenorphine for five years; I would hope to have sufficient trust established with patients after that period of time, such that the lab results wouldn’t be seen as the only answer.  There can be problems with any laboratory test.  Drug tests are one tool– not the ultimate arbiter of truth.
Most people metabolize buprenorphine a certain way, leading to the build-up of a chemical called norbuprenorphine.   I assume that by ‘backwards’ the doctor is saying that the buprenorphine level is higher than the norbuprenorphine level, whereas with daily use of buprenorphine the opposite would be true. As your doctor said, if a person takes one dose of buprenorphine and is tested an hour later, buprenorphine would be present, with only small amounts of the metabolite norbuprenorphine.
Urine tests for any substance are affected by many variables, including the actions that different parts of the kidney have on certain substances.  Some substances are concentrated at the kidneys, making urine testing more sensitive than blood testing.  But other substances might be re-absorbed by the kidneys to a varying degree, depending on hydration status, nutritional and dietary factors, hormonal factors, and personal genetics.  Because of concentration and reabsorption effects, the drug levels from urine tests are not accurate indicators of drug levels in the bloodstream.
In addition, the metabolic pathways for certain substances might be changed by the presence of other substances.   For example, if the enzyme that turns buprenorphine into norbuprenorphine is blocked or occupied by other substances, the pathway may change such that metabolites other than norbuprenorphine are formed—- including metabolites that won’t show up unless they are specifically tested for.
I asked the patient:
Are you taking any other medications?  Are you able to get the actual lab results showing the details of the test?
She replied:
I thank you for responding to me.  I am on many medications because I have fibromyalgia among many other things.  My list of meds:
Prozac 20 mg; Provigil 200 mg; Clonidine 0.1 mg 4x’s a day; Amlodipine 5mg once a day; Nabumetone 500mg 2x’s a day; omeprazole 20mg once a day; Ambien 10mg per day; Relpax when I have a migraine; Buspirone 10mg about 2x’s a day; Subutex 16 mgs per day. I also take diphenhydramine 50 mgs at bedtime when needed to help sleep, and Vitamin D3-1000 iu once per day.  I take this because my blood tests showed it was low.
I asked to see my results and my doctor told me that I didn’t need to see them; that he had told me what it said and that it should be enough for me to know.
The receptionist in the office is getting the number to the lab for me.  Do you have any questions that I should ask?  What should I know?  I am going to ask for a copy of my labs at my next visit.  I am nervous that my doc will just stop prescribing.  This medication has saved my life and I don’t know where I would be without it.  Please help me make my doctor believe in me again.  I know that is a lot to ask but I’m in trouble.  Where can I turn?  There aren’t any Suboxone docs in my area taking new patients.
(A couple thoughts)
Over my 20 years as a physician, I’ve come across times when tests were mistakenly trusted over the word of patients.  At a maximum security prison for women where I worked as a psychiatrist, for example, many women were disciplined for diverting clonazepam, until a call to the lab revealed that testing wasn’t reliable for that medication.
Over time, we learn more and more about how the metabolism of one medication impacts other medications.  One such interaction was apparent in this person’s case.
My comments:
The most obvious interaction from your list is that Provigil is an ‘inducer’ of cytochrome 3A4, the enzyme that breaks down buprenorphine.  A person taking Provigil develops greater amounts of that enzyme in the liver, which results in faster metabolism of buprenorphine.  The first step in metabolism of buprenorphine is conversion to norbuprenorphine, so levels of buprenorphine and norbuprenorphine would be affected by Provigil, in unpredictable ways.
From the program that I use to search for interactions: buprenorphine ↔ modafinil
Coadministration with modafinil (the racemate) may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil and armodafinil are modest inducers of CYP450 3A4, and pharmacokinetic studies suggest that their effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, lovastatin, midazolam, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, calcium channel blockers). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.
That is just one of many possible interactions. When a person takes multiple medications, there are often other, less predictable interactions.  Some medications also interfere with the testing of other medications.  You may know that there are chemicals available on the internet to block the testing for certain compounds;  some medications do the same thing.
She answered:
I can’t thank you enough for even responding to me……  You are a very kind man!  I hope this helps me.  I am very scared my doctor will take me off my meds.
But then she wrote again:
I wanted to send you an update.  My doctor wouldn’t even look at the conversation we had.  I guess for whatever reason, he refuses to look deeper into the issue.  It is sad when a doctor has had a patient for over 5 yrs and he won’t look into this further.  I don’t ever have dirty u/a’s.  I don’t drink, I don’t smoke marijuana, I only take what he prescribes to me.  He refuses to look further into the matter so much that it is clouding his judgment.  He won’t even test me another way.  He states urine test are the most accurate but there is something wrong because I know that I take my meds.  He refuses to do another supervised dosage week because he doesn’t have the manpower.  
I know in his eyes that all I am is a drug addict but I deserve respect. Why would a man who believes in science have such a closed-minded view?  I would think he would at least want to discover what is happening.  There has to be more patients like me that are being thrown away because we don’t fit a certain mold.  When he throws me out of treatment on Monday, I have nowhere to go.  There are large waiting lists to see a doctor in my area. I can’t go back on the streets for medication.  I don’t have any of those friends left in my life.  I am in so much trouble.
I don’t know why I felt the need to vent to you but my hope was to find one person that believes me in hopes that this problem could be addressed someday, somehow.  Thank you for listening.  I do appreciate it.

Questions, Excuses, Krokodil

I’ve been in more of a chatty mood lately, as regular readers have likely noticed.  I find it interesting that weeks will pass when I have little or nothing to say… and at other times, I have all sorts of random thoughts to discuss.
Excuses first– I’ve been tinkering with ads for the past few days, and I apologize to those of you who tried to read a post while I was activating and deactivating Wordpress plug-ins.  After experimenting with different colors I’ve decided that basic grayscale is the best.  For those who don’t blog, ‘plug-ins’ are small, add-on programs that add a range of functions to a blog.  There are literally thousands of them out there;  some free, some for a small charge.  A couple dozen plug-ins are designed to add the code for Google Adsense to a blog, with a range of features including adding ads randomly to old posts, etc.  I’ve found that some work better than others; a couple of them really messed up the other blog functions, causing the top banner to appear at the bottom and vice versa.  I THINK I have things working OK now;  if you are having trouble, please send me an email (drj at Suboxonetalkzone dot com) and tell me the nature of the problen, and the browser and operating system you are using.  Thanks!
Another neat feature of WordPress is that you can review a number of different statistics for a blog, including the keyword that each viewer searched for before arriving at the site.  I see certain questions posted over and over;  I presume those questions are about things that come up often in the lives of people on Suboxone.  I used to do ‘questions and answers’ on a regular basis;  I’ll try to get back to those now and then, using the most popular queries as starting points.
Yesterday, several people searched for phrases related to buprenorphine and workplace drug testing.  I’ve received a number of questions by email about that same topic.  People wonder if Suboxone (buprenorphine) shows up in drug testing, and whether they should disclose that they take the medication before the test.  This is a very tough issue.  I believe that people who take Suboxone properly are NOT impaired by the medication.  There was an article from the Mayo Clinic Proceedings recently that claimed that people ARE impaired by Suboxone, and therefore certain occupations– notably physicians and nurses– should not work at those jobs, if taking Suboxone.
There were at least two things that made their conclusions… ridiculous.  First, the authors wrote that doctors’ work is so uniquely difficult, that it challenges gray matter so much more heavily than other occupations, that doctors should avoid buprenorphine treatment.  To that, I say that a recovering anesthesiologist taking Suboxone is much safer than a recovering anesthesiologist, holding fentanyl in his/her hand, not on Suboxone!  Even if you take away the risk that the non-Suboxone doctor is using, one must consider the effects of cravings on vigilance.  I’ll take the doc on Suboxone, who is placing all of his attention on ME, over the guy reciting the serenity prayer to himself and pondering the decision over what can be ‘changed’ and what can’t!  Of course, that’s just me…
I was also impressed by the ego of the writers, who think that a pediatrician or radiologist has greater need for an ‘unmedicated brain’ than a jet pilot, or a welder ten stories up, or a long-haul trucker, or a nuclear physicist. Yes– doctor jobs are ‘uniquely’ difficult!  (add sarcasm here).
The conclusions were deeply flawed in other ways.  To determine the effects of Suboxone on performance, they looked at studies that gave people opioid agonists or buprenorphine, and concluded that the effects were similar.  I mean really– people who are not on Suboxone regularly, without a tolerance to opioids, taking buprenorphine?  OF COURSE the people were messed up!  Suboxone has potent opioid effects;  there is no argument to that point.  But the unique ceiling effects of buprenorphine allow the subjective effects to go away, as tolerance is established.  That’s the whole point of Suboxone treatment!
I’m off on a tangent, right?  Back  to drug testing…  I do not think that people on Suboxone, who take it properly, are impaired in any way.  So I do not believe that people should have to disclose their treatment, and their history, to their potential employers.  But my opinions on the matter are irrelevant, unless the new/old President-elect appoints me as Attorney General… and odds are not in favor of that happening.
I can say that I’ve received 20-30 emails over the years, asking about employee drug testing.  In each case I asked the writer to follow-up and let me know what happened.  Some ended up disclosing that they were on Suboxone, and most did not.  To date, nobody has written back to say that they were denied the job over the issue.  I therefore conclude that most employers are ignoring buprenorphine, at least at this point.  That’s the best answer I have;  I can’t recommend any specific course of action.
Finally… today I came across an old post on my forum about a drug that was sweeping across Russia last year, called Krokodil.  The drug apparently is made from over-the-counter codeine tablets, in a process that creates a cheap concoction of opioids in a toxic sludge.  Users of the drug describe withdrawal more severe than opioid withdrawal, that includes seizures.  And within days of starting a habit, users slough off large sections of skin and other tissue from their arms, legs, torso– even from the face.  Not for the faint of heart— if you search the name of the drug under Google Images, you will find horrifying photographs of the damage inflicted on people addicted to the substance.
If anyone really thinks that drug addiction is a ‘choice,’ please tell me what, exactly, those tragic people were thinking.

Relapse in an Era of Buprenorphine

A recent experience with a patient helped me realize some of the dramatic differences in the treatment of opioid dependence, in an era of buprenorphine.
I drug-test patients who are treated with buprenorphine or Suboxone.  The point of testing is not to catch someone messing up, but rather to determine when a person is in trouble.  It would be great if we could simply rely on the word of our patients, but once a person is using opioids, his/her own ability to know what is true falls apart. All of us who treat addiction have heard patients rationalize relapse as something they ‘had to do’ for one reason or another, for example.  The effects of active using on insight are why I like the use of ‘DENIAL’ as a mnemonic for ‘Don’t Even Notice I Am Lying.’
The effects of relapse on telling the truth are part of the profound impact of using on a person’s insight.  Insight disappears very quickly during active using, as the mind abandons the broad view and becomes focused on one goal. Before buprenorphine, drug testing was in some ways more, and other ways less important.  It was more important because after relapse, the person was immediately thrown back into the world of desperate scrambling, where risks for consequences are high.  On the other hand, testing was less important—or maybe necessary– because experienced addictionologists (and spouses) could see the effects of using, including the loss of insight, in the active addict’s eyes.
I was one of those people who experienced that rapid loss of insight after my relapse, back in 2000. For years I had attended AA and NA; hundreds if not thousands of meetings over seven years.  I remember comforting myself that ‘if I ever get off track, at least I now know where the door is to get back.’  I didn’t realize that at the instant one relapses, that door becomes nowhere to be found.
In retrospect, I don’t know if the door actually disappeared. I suspect that with the right attitude, that same door would have opened for me.  But the honesty and humility that I needed, in order to ask for help in finding and passing through the door, were suddenly replaced by the need for secrets—secrets about everything.  As soon as I relapsed, nobody could be trusted. Nobody would understand me.  I was on my own.
Contrast that with the experiences of patients on buprenorphine who relapse with opioid agonists. As I compare their experiences to mine, I realize that I am using the experiences of a couple people to make broad generalizations.  But I have seen a number of examples that support these generalizations, that have consistently followed the paths that I’m about to describe.
One patient—call him ‘Paul’—told me about his relapse before I even mentioned that I would be asking for a urine test.  In fact, he was eager to tell me about his experience, as if he looked forward to getting it off his conscience.  “I have to tell you that I really screwed up last week,” he said. When I asked him what happened, he said that a friend who he hadn’t seen for several months came through town and stopped by his house.  With little warning, his friend pulled out a bag of heroin and a couple clean needles, tossed them on the table, and said ‘let’s fire up.’
After shooting the heroin, Paul immediately felt disappointed in himself.  Unlike in the old days, he felt nothing from the heroin.  While his old friend nodded off next to him, Paul wondered what the heck happened—and immediately wanted to talk to me about the situation.
His desire to talk is an amazing thing—and worth noting.  Without buprenorphine, a person who relapses is not generally eager to speak to his/her sponsor, let alone counselor or physician.  In those cases, the mind reels from an avalanche of shame, and the need to keep secrets—even from one’s own awareness—becomes paramount.
There are many buprenorphine programs that would discharge a person for one relapse—and in such cases, I would not expect the same type of honesty from patients.  I don’t get the logic of those programs, and I become angry when I think about them.  As I’ve said before, if a person relapses, that person NEEDS help—not abandonment!  I believe that the proper approach to treating addiction can be found in almost all cases simply by considering opioid dependence to be another chronic illness.  And if someone with heart disease overexerts himself and comes in with chest pain, we don’t boot him from treatment!
Paul made an appointment to talk about his experience.  He explained how he felt when his old buddy contacted him, and we discussed ways to avoid meeting up with ‘old friends’ in the future.  He discussed the urge to escape when he saw the paraphernalia—to escape from life’s responsibilities—and we talked about how difficult it can be to simply tolerate life sometimes, and the powerful effects of triggers and cues.  Most interesting to me, as a psychodynamic psychiatrist, he talked about a complicated set of thoughts and feelings that came up when he saw the drugs—questions about who he was, about shame, about the heavy load that comes with doing the right thing, and about the pressure of not letting people down.  Those are all big issues, I said as I agreed with him.  How much easier, at least for a few moments, to just be ‘nothing’—to have no expectations about one’s self!
We talked about the challenge of being ‘someone’– of being proud of one’s self.  It feels good to do the right thing– but it may also feel bad.  Am I letting my old friends down, if I do better? I suggested that he might watch the old movie, Ordinary People, where a younger brother struggles after surviving an accident that claimed the life of his brother.
Before buprenorphine, people struggled with opioid dependence largely on their own.  Yes, we had twelve step groups—and still do—but twelve step groups place the responsibility to get one’s act together squarely on the back of the using addict.  Many people in AA or NA will say that “AA is a selfish program.”  It has to be.  When one relapses, one is left with his own distorted insight, accumulating consequences until, hopefully, he finds his way back to the pathway established by the simple program of the steps.
On buprenorphine, relapse doesn’t necessarily cause instant loss of insight.  I don’t mean to minimize relapse, as bad things can always happen.  For example, I have had patients stuck in a pattern of chronic relapse that was difficult to straighten out, even though there was little or no psychic effect from the drug being abused.  But from an optimistic standpoint, relapse on buprenorphine stimulates a deeper investigation into what is missing from the person’s life, and a renewed effort to gain what is missing.
This assumes, of course, that the person is not simply tossed from treatment for the relapse.  In that case, other people are left trying to figure out what happened—when the obituary appears a few months later.

The REAL Future of Partial Agonist Treatment— Pharma are you Listening?

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980’s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)
Hi ——,
(private chit chat that would bore everyone)
Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.
The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.
The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.
The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.
Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.
A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.
Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?
I figured you’re the person to ask!
Thanks ——–
Jeff