Pharmacokinetics and the fallacy of One Size Fits All

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By R Carter

Definitions:

Fallacy fal·la·cy /ˈfaləsē / noun – a mistaken belief, especially one based on an unsound argument.

Pharmacokineticsphar·ma·co·ki·net·ics /ˌfärməkōkəˈnediks / noun – the study of the way in which drugs move through the body during absorption, distribution, metabolism and excretion. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body.

In 2016 the CDC published its prescribing guidelines for chronic pain. By the CDC’s own admission the guidelines were based on the then current research for treatment of acute pain in opiate native patients. Research based on long term chronic pain with opiates was inconclusive. Reason for being inconclusive, out of its $37 Billion annual budget, the NIH funds less than $200 Million annually on chronic pain. Until this changes; public health officials will continue to use this as an excuse for making policy based on opiate naïve patients with acute pain.

Traditional standards of care used by government and insurance view medical treatments as experimental when there is no research based evidence to support them.

One Size Fits All

Without research evidence to back them the CDC published caps and limits on the use of opiates in treating chronic pain. Those limits consist of an initial 50 MME of for opiate naïve patient and a recommendation not to exceed 90 MME for any other individual, this is a one-size-fits-all guideline.

So what does one-size-fits-all really mean? The term is a euphemism which points out a fallacy from a medical perspective, with regards to treating patients without taking into consideration the pharmacokinetics and mass distribution of the medication. To explain this for non-medical types a brief lesson is required in pharmacology, physiology and a definition for poisoning is needed.

Poison Definition

Poison – A substance that is capable of causing the illness or death of a living organism when introduced or absorbed.

What most people don’t realize is that any substances can be a poison, even the air we breathe. Air is roughly 20% oxygen, 70% nitrogen, 5% carbon dioxide and 5% other gases. Increase any of these at the expense of another and the individual will begin suffering symptoms. Give a person too much water by mouth and they will show signs of fresh water drowning. Each substance causes a unique set of symptoms and side effects, but any substance if given in sufficient amounts is a poison.

The CDC guidelines operate from this perspective, that opiates are first and foremost a poison and should be treated as such regardless of their medical benefits. This approach also assumes doctors are not capable of making this distinction; therefore the government must do it for them.

The CDC guidelines are therefore an effort to promote safety but in doing so, they must propagate several lies and convince Americans to buy into them.

  1. A fixed amount of medication is sufficient for all types and causes of pain.
  2. A fixed amount of medication has the same effect in all people.
  3. A fixed amount of medication has fewer adverse outcomes.
  4. A fixed amount of medication provides the same benefits in all people.

The following scientific facts will dispel these myths.

Pharmacology – Opiates as a poison

Give a large enough single dose of opiate and an individual will show signs of opiate toxicity. Nausea, vomiting, profound sedation or somnolence, slowed respirations, the accumulation of carbon dioxide and a drop in oxygen levels, eventually sleep and asphyxiation due to a depressed respiratory system.

But opiate toxicity can occur in a slower more subtle way. Persistent daily dosing which is not adequately cleared from the body can result in a slow accumulation of medication over time; this is particularly true with Methadone and such cases are not necessarily an overdose but a reaction based on changing conditions over time.

The signs and symptoms are less obvious and vary. They may appear as sleep disturbances, frequently waking up after being asleep for short periods of time, roughly 10-60 minutes; the symptoms are similar to sleep apnea. The slow accumulation of carbon dioxide and a drop of oxygen levels cause the brain to attempt a forced waked up. Other symptoms could be a feeling of tightening in the abdomen or chest wall, this is known as chest wall rigidity and is a combination of paralysis of the diaphragm plus muscle rigidity of the intercostal muscles in the chest, both can lead to asphyxiation. In such situations the individual should go to an ER as quickly as possible, especially if taking Methadone.

Other less obvious warning signs would be waking with a headache; due to high carbon dioxide levels in the brain, or waking with a productive cough even though you’re not a smoker. Notice there are no symptoms of nausea, vomiting, drowsiness or somnolence, this is because the accumulation of medication occurs much slower over an extended period, days, weeks or months and because most individual on long term opiates, have a tolerance to the medication which eliminates some of these symptoms.

Physiology – The metabolizing and elimination of opiates

For oral medications the body has a two step process of uptake and elimination. The first step is absorption through the stomach and small intestine, medications are absorbed into the blood stream and make a first pass through the liver for detoxification and conversion into active metabolites.

Depending on the substance, first pass elimination can remove as much as 50% of a drug. Fist pass elimination is also responsible for converting most of an opiate into its active metabolite which are lipophilic (fat soluble) and more easily absorbed by fatty tissues, nerves and the brain are high in fatty proteins. Individuals with liver problems may have an unpredictable response to a variety of medications not just opiates.

Second pass elimination occurs after mass distribution of a drug throughout the body and as active metabolites in the blood stream make a second pass through the liver where they are broken down into water soluble by-products which can be excreted by the kidneys. Those with kidney disease may also have problems eliminating medications.

It’s important to note that some active metabolites from first pass elimination produce by-products which are more potent than the actual medication prescribed and taken. These active metabolites also have different elimination profiles, some are eliminated faster some slower, depending on the chemical makeup of the substance and its fat solubility.

Lipid Solubility and Protein Binding

Drugs which have a high affinity for fatty tissues bind to proteins in the nervous system more readily than drugs which are water soluble. Generally speaking, the more water soluble a substance the faster it is eliminated from the body through the kidneys.

Opiate metabolism is affected primarily by an enzyme system in the liver known as the Cytochrome P450 enzyme system. There are hundreds of subsystems but only a few which effect opiate metabolism. Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. Phase 2 metabolisms conjugate the drug to hydrophilic substances which are water soluble and therefore easily excreted by the kidneys.

Most tissues in the human body have a high fat content; muscles which make up a large portion of our body mass have high concentrations of fat in them as do nerves and nervous tissues such as the brain. Medications which are fat soluble (lipophilic) are deposited into fatty tissues and reside there for longer periods of time. Fentanyl and its analogs are the most lipid-soluble while heroin, morphine, hydrocodone and oxycodone are less so.

Phase 1 metabolism of opioids in the Cytochrome P450 system mainly involves CYP3A4 and CYP2D6 enzymes. The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug to drug interactions. The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk for drug to drug interactions. Drugs that undergo phase 2 conjugations into water soluble substances have little or no involvement with the CYP system and have minimal interaction potential with other drugs.

Osmosis and Mass Distribution

Most people should be familiar with this term from their junior high school physics class. Simply put osmosis is the propensity of a solid dissolved in a liquid to equalize itself across a barrier. The concentration of a substance on either side of a barrier is further affected by its lipid solubility and in cells, by active transport mechanisms which are designed to restrict or facilitate the movements of substances across a cell membrane. All of these work together to maintain an equilibrium of a substance within a container such as the human body. As a substance is metabolized into by-products there’s a constant movement of substance and its by-products across barriers as the body and physics attempt to equalize concentrations and as they are eliminated by the kidneys.

Mass distribution refers to how a substance distributes itself within a container. Mass distribution is a measurement of how well osmosis is occurring. Basic physics tells us that all substance want to equally distribute themselves within a space. This fact is an important concept when speaking to the one-size-fits-all approach of the CDC.

If you give 50 mg of medication to a person who weighs 120 pounds and the same 50 mg to a person who weighs 240 pounds, the concentration per cu/mm is half that in a person weighing 240 pounds as compared to a person weighing half that amount.

The medication is therefore diluted in one person as compared to another. This dilution does not affect half-life which I will discuss next, but it does make less medication available for binding to fatty proteins, which includes nerves and nervous tissue. With less medication to bind to proteins a person weighing twice as much as another will only have half the amount of drug needed to produce the same clinical effect and as everyone knows, you can’t produce the same effect with half the medication available.

Access any book which discusses specific dosing guidelines and you’ll see that a medication is always given in milligram or micrograms per kilogram of body weight. This simple calculation allows a doctor to prescribe an amount which will produce the same clinical effect for each person regardless of their size and weight.

Mass distribution is also the single biggest reason for why the CDC guidelines are an assault on patients treated for pain and why they should be rejected by every medical board who has adopted them in treating patients with pain.

Traditionally, any doctor who prescribed a medication without considering mass distribution and who has a bad outcome as a result of this failure, that doctor would be subject to malpractice litigation. Yet this is exactly what the CDC has encourage doctors to do and state medical boards, under the guidance of doctors, are turning into laws. The fact that attorneys and litigators can’t see this as malpractice is mystery for another post.

Imagine what would happen if doctors suddenly began prescribing fixed dosages of insulin for diabetics. If a diabetic died as a result of being under medicated, wouldn’t this be considered malpractice? I put the same question before seven different attorneys in the last four months and none of them could respond with an appropriate answer.

The factors discussed so far which affect the absorption, distribution, conversion and elimination of drugs are basic concepts every healthcare professional is taught during their training. They are used in every treatment decision made for every patient for every medical condition known to medical science. Yet for the treatment of chronic pain they have been conveniently thrown aside because the guidelines are not about treating chronic pain as proposed, but are about eliminating the risk of abuse. In my opinion this constitutes malpractice.

These facts mean only one thing. The CDC guidelines are a lie, perpetrated by politics through our public healthcare system to deceive Americans at the expense of health and wellbeing, placing thousands of chronic pain patients at risk for unknown complications for which there is no research or evidence to support.

Pharmacokinetics – Drug Half Life

All of the systems listed so far produce what is known as a half-life for a medication. Half-life is the amount of time it takes for half of an active form of a medication to be eliminated from the body.

Medication absorption, conversion from inactive to active and back to inactive metabolites, fat and water solubility, osmosis, active transportation and elimination all work together to produce a half-life profile for a medication. When determining half-life in a biological system, measurements don’t take into consideration faulty organ systems such a liver or kidney disease, so half-life is always expressed in terms of a healthy biological system.

Lipid solubility has a large impact on half-life, the more fat soluble a drug, the longer it will hang around in your body. For this reason, drugs such as morphine, hydrocodone and oxycodone have short half-lives, typically about 2.3 to 2.6 hours.

Half-life works in this way. If the half-life is say 2 hours then at the end of that time, half of the active substance is eliminated from the body. At the end of another 2 hours half of what was there 2 hours ago is eliminated, meaning at the end of 4 hours, 75% of the substance has been eliminated. Another 2 hours and 87.5% has been eliminated.

Another way of looking at half-life is to imagine as bell curve with the peak being that point in time where a medication is producing its peak effects. As time goes by the amount of active drug decreases according to its half-life profile, if a second dose is taken at two hours, half way through the dose of the first half-life, the next bell curve will have a higher peak than the previous and a longer duration as it is eliminated from the body.

This is an important concept for chronic pain patients who have some level of physical tolerance to these medications. When a larger dose is taken over a longer period of time, say 10 mg over 6 hours, a person experiences a higher peak 1 hour after dosing and a longer trough as it wears off over the next 5 hours. A chronic pain patient is more likely to experience breakthrough pain during this 5 hour period and can’t take more medication without the risk of using more than they should and being in a worse set of circumstance 10 hours later.

Understanding how half-life works can make managing medication and its benefits easier and safer for chronic pain patients. For example, short acting preparations such as hydrocodone and oxycodone when taken in smaller amounts, for example ¼ tablet at more frequent intervals, every 2 hours,  produces a lower peak and lower trough, but it allows the individual to take the same dose sooner. The net effect produces a stable blood level of medication, giving a chronic pain patient a steady state of pain management.

When to use a Half-Life approach to opiate usage

With some doctors acting out of fear and forcing patients to taper or eliminate opiates, patients should consider this concept of half-life while tapering or using the last of the medication they have after being forced off. For some who have been on opiates for years, this could make the difference between surviving a forced taper and not surviving it.

Alternatively, chronic pain patients who continue to use opiates still must address the physical tolerance that develops during long term use. For this reason I routinely perform a self-imposed taper every 4-6 months. In doing so, I continually push back on the problem of physical tolerance and when I resume my normal dose, get better results from my prescribed dosage.

Forced Tapering or Elimination of Pain Medication

Although the CDC guidelines were designed to improve the safe use of opiates, the rush to judgement without evidence based research has led to a classic failure in medical treatments, the loss of life.

Without research to discover outcomes, limits of safe use. risks and benefits a medical treatment is considered experimental. So since 2016 when the guidelines were released, healthcare agencies, clinic and the doctors who have adopted them, have for all practice purposes, been experimenting on a patient population without consent for such experiments.

The results have been predictable and horrific. As VA hospitals, state medical boards, clinics and individual prescribers adopted these guidelines, forcing some patients to taper down to CDC guidelines and in some cases, terminating care for others, some went to the blackmarket while others chose suicide, still others succumbed to complications aggravated by such actions and died from those complications.

While such adverse complications and outcomes were predictable, they were ignored even discredited by policy makers and it easy to see why. Carefully reading the CDC guidelines it is quite clear that this publication is first and foremost about preventing abuse more than anything else. 

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