The False Matching of the Buprenorphine Dose

Kenneth Blum

The False Matching of the Buprenorphine Dose

Faced with a devastating opiate/opioid epidemic the Food and Drug Administration (FDA) has approved some Medication-Assisted Treatments (MATs) for the treatment of alcoholism, opiate, and nicotine dependence, but nothing for psychostimulant and cannabis abuse. These pharmaceuticals are important and have relevance short-term for the acute induction of “psychological extinction,”
[taking the drug no longer causes a high]. However, our sense of
“well-being” relies on healthy dopamine function and caution is necessary when the chronic (long-term) use of MAT favors blocking dopaminergic function. The two institutions devoted to alcoholism and drug dependence (NIAAA & NIDA) realize that MAT is not optimal and continue to seek better treatment options.

Opioid Substitution Therapy (OST)
From our experience and observations, Medication-Assisted Treatment (MAT), in practice, is the use of FDA approved medications – many of which are opioids – for the treatment of opiate/opioid addiction. The two primary opioids used in opioid substitution therapy (OST) to treat opiate/opioid addiction are methadone and buprenorphine. Buprenorphine is up to 50 times more potent than morphine. These narcotics have FDA approval for use in opiate/opioid addiction treatment, are habit forming, addictive just like any other opiate or opioid, are subject to the same abuse as any other prescription or illicit narcotic, and are potentially just as deadly.

Previous work from our laboratory found that, like opiate use, long-term Suboxone® [Buprenorphine/naloxone] use led to blunted emotional responses in its users. They had less self-awareness of being happy, sad, and anxious. In layman terms, over time, Suboxone® users feel zombie-like. Other work showed that in comprehensive treatment programs, that include talk therapies, compliance with taking OST medication was high, and abstinence rates improved over time. Short-term treatment was successful
(psychological extinction).

Although methadone and buprenorphine diversion by patients in OST is a poorly understood phenomenon, recent drug addiction policy plans include allowing for greater availability and use of Buprenorphine/Naloxone combinations in addiction treatment have been published. Despite the problem of expanded office-based buprenorphine opioid dependence treatment being associated with medication misuse and diversion consequences, to help with treatment accessibility, Blum and associates have recently advocated raising the patient limit per doctor to 200. Genetic addiction risk testing and rigorous urine drug monitoring were also recommended. The purpose of this white paper is to discuss and clarify a claim made by some laboratories that result ranges from urine drug screens can predict clinical responses to drugs and quantify diversion.

Can reported ranges from urine drug screens predict clinical response or diversion?

Obviously, a major concern in the United States about the treatment of pain and addiction is the possibility of both street diversion
and clinical response to buprenorphine alone or in combination with naloxone. There are also the problems of mortality and even suicidal intent especially in the elderly. Clearly, it would be of benefit to a practicing physician to be able to accurately predict from urine drug screens the actual ideal dose of buprenorphine needed to treat the patient. This would allow the clinical team to determine treatment response, possible diversion, or abuse. However, there is no way to match the quantity of buprenorphine or any drug consumed with the reported range from a urine drug screen, even using sophisticated detection instruments such as LC/MS/MS.

Unfortunately, there is no relationship between Buprenorphine dosage, and the urine drug screen results reported from the laboratory. Many factors can change the urine drug result ranges. Some of the biological factors that would prohibit this unsupported claim are explained below.

Factor one: Genetic defects in metabolism
It is widely known that the cytochrome P450 (CYP450) enzyme system is crucial for the metabolism of some opioids. In fact, many patients who require high doses of opioids may have a genetic defect that can alter their ability to metabolize these agents. There are at least three specific CYP defects—2D6, 2C9, and 2C19. The cytochrome P450 could be called the “drug metabolizing enzyme system.” The CYP450 enzymes are primarily found in the liver, but can exist in the intestine, lungs, brain, and kidney. Many opiates/opioids are metabolized via the CYP enzymes system. They include codeine, hydrocodone, oxycodone, tramadol (Ultram), fentanyl, methadone, and buprenorphine. Laboratories will identify patients as Extensive Metabolizer (EM; normal enzyme), rapid or Ultra-Rapid Metabolizer (UM; overactive enzyme), Intermediate Metabolizer (IM; underactive), or Poor Metabolizer (PM; inactive or minimally active). The IM and PM have decreased function

Buprenorphine is metabolized by P450-3A4 in N-dealkylation in the liver and therefore is subject to varying degrees of metabolism as suggested above. The end products of metabolism measured in the urine drug screen will also vary, for example, the same amount of drug taken at the same time by an EM vs. an IM would produce different amounts of residue in the urine. The results as determined by LC/MS/MS or any other detection methods would differ.

Factor Two – Absorption & Distribution
Oral dosing leads to “first-pass metabolism” in the liver that breaks down both buprenorphine and naloxone preventing good absorption. Additionally, some opioids will act without biotransformation at the opioid receptor, and provide pain relief without being metabolized by the CYP enzyme or glucuronidation system. Together these differences explain the increasing utilization of sublingual, buccal, patch, subcutaneous and intravenous injection, and intrathecal routes of opioid administration since these non-oral routes allow either greater opioid effect or reach the central nervous system (CNS) before entering the liver. The drugs Suboxone® and Zubsolve® are designed to be taken ‘trans-mucosally’, i.e. absorption into the bloodstream via the (mucosal) lining of the oral cavity. The passage of molecules through the oral mucosa is affected by many factors, like the size of the molecule, the lipid solubility of the molecule, the concentration of molecules, and the pH of the solution. For example, if the pH of the oral mucosa is 6.5 at the time of administration of sublingual Buprenorphine the absorption rate is 55%. Lower pH becomes more acid, and less absorption occurs if the pH becomes more basic more is absorbed. The remaining 46% Buprenorphine will be absorbed through “first pass” metabolism.

While naloxone is poorly absorbed through the mucosa, buprenorphine is better absorbed through this site. However, these and possibly other factors would also influence the ability of buprenorphine to enter through the blood brain barrier. Buprenorphine can also be metabolized in the kidneys. This alternative metabolic system known as glucuronidation may also have an effect on the therapeutic level of buprenorphine.

These various types of absorption and distribution influenced
by each individual’s metabolic-function ensure that ranges of buprenorphine metabolites will have little to no meaning.

Factor Three: Opioid Receptor sensitivity
Opioids can act at the opioid receptor, and provide pain relief without being metabolized. Although this seems like a way to match buprenorphine dosing with urine range, it does not take into account a crucial pharmacologic principle that receptor sensitivity (response to a drug) is altered by the ability of a drug to bind to a receptor. Better opiate receptor(s) availability for drug binding results in better response to the drug. So, for example, if a patient carries a gene variant that influences the brain to produce either higher or lower numbers of opiate receptors the resultant urine range will likewise vary and have little to no relevance to dose response and therapeutic value., Another example is a patient who has the A1 variant of the dopamine, D2 receptor gene (DRD2), will have 30-40 percent fewer D2 dopamine receptors than a patient with the A2 variant. This means that naloxone (the diversion/abuse deterrent) is less efficient because it cannot bind to opiate receptors in many brain regions reducing its ability to regulate opiate activity. Another genetic effect is that carriers of the so-called 9 variant of the dopamine transport gene (involved in rapidly clearing dopamine from the synapse-resulting in low dopamine) respond well to buprenorphine. So knowledge of urine range once again cannot help the clinician predict any useful information related to clinical response or diversion issues.

Make no dubious claims –first, do no harm
The claim that Buprenorphine dosage can accurately be determined by drug urine range is false. The only determination that can be made by a urine drug test is either the presence or absence of the drug.

Some clinical laboratories are making these claims proposing that they possess an advantage of their urine drug test compared to other laboratories that do not ascribe to this tactic for sales purposes. Such claims are worthless and false, and worse could confuse the practicing physician and clinical team. Unfortunately, there is no way to match buprenorphine or any other drug with the reported range even using sophisticated detection instruments such as LC/MS/MS.

In summary, based on these and numerous others factors not discussed in this white paper, laboratories claiming that- “knowing the drug urine range provides the clinician with an accurate dosage match” are not supported scientifically. With that said I would encourage these laboratories to rethink and change their false claims and “first, do no harm.”

Kenneth Blum, B.Sc. (Pharmacy), M.Sc., Ph.D. & DHL; received his Ph.D. in Neuropharmacology from New York Medical College and graduated from Columbia University and New Jersey College of Medicine. He also received a doctor of humane letters from Saint Martin’s University Lacey, WA. He has published more than 550 abstracts; peer-reviewed articles and 14-books.