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?

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.