Clean Enough, Chapt. 3: A Primer on Suboxone

What is Suboxone?
Suboxone is the trade name for a medication that contains buprenorphine and naloxone. A similar medication, Subutex, contains buprenorphine without naloxone.  Both are manufactured and sold by Reckitt-Benckiser, a company based in the UK with operations world-wide. Suboxone is FDA indicated for the treatment of opioid dependence.  Both medications are also used ‘off label’ (**see footnote ), or without FDA indication, to treat chronic pain and more controversially,  refractory depression.  Because of longstanding regulations in the United States that prohibit treating opioid dependence with narcotics, a waiver from the DEA is required in order for doctors to prescribe buprenorphine for that indication.  Buprenorphine can be used to treat other conditions, including chronic pain, without special waiver or permission, provided the doctor has current DEA registration for Schedule III medications and a valid state medical license.
The use of buprenorphine to treat opioid dependence in the US was made possible by the Drug Abuse Treatment Act of 2000 (DATA 2000).  In order to become certified to use buprenorphine, a physician must have his/her credentials approved by the DEA and must take an 8-hour course that describes proper uses and regulations related to buprenorphine.  Even after the passage of DATA 2000, the use of buprenorphine for treating opioid dependence was not possible until 2003, when the FDA approved Suboxone for that indication.  Buprenorphine, which had been a Schedule V drug for many years, was moved up to Schedule III by the DEA.  To differentiate the use of microgram doses of buprenorphine for treating pain from the use of milligram doses of buprenorphine for treating opiate dependence, some authors who have written about studies of buprenorphine have used the term ‘high dose buprenorphine’ or HDB for the latter.  I will try to use HDB to refer to the use of buprenorphine in milligram doses, except when the specific brand medication is discussed.
Naloxone is not necessary
The naloxone in Suboxone has no significant action when the medication is used properly, and is not responsible for the ‘ceiling effect’ of Suboxone. Suboxone is taken by dissolving the tablet in the mouth; buprenorphine enters the bloodstream via capillaries that flow just beneath the lining of the oral cavity. To get into the capillaries the dissolved buprenorphine must stick to the surfaces inside the mouth and then diffuse through those surfaces. Naloxone is a large molecule that is less soluble in fatty tissues, and so is less likely to stick to the oral surfaces (cell membranes consist of fatty molecules, so molecules that dissolve in fats pass through the membranes more easily). Since naloxone doesn’t stick to, or pass through, the cell membranes lining the mouth, little or no naloxone enters the bloodstream.  Eventually the non-absorbed molecules are swallowed, and the naloxone and the remaining buprenorphine are absorbed into the bloodstream from the intestine.  The anatomy of the circulatory system has important effects on Suboxone at this point; the blood that drains the small intestine flows into the portal vein, which takes newly-absorbed substances directly to the liver. Some substances—including buprenorphine and naloxone—are destroyed so efficiently by the liver that few molecules survive to enter the general circulation. This phenomenon, the efficient breakdown of an absorbed medication by the liver, is called the ‘first pass effect.’  The first pass effect for buprenorphine makes the medication ineffective if the tablets are swallowed, and the first pass effect for naloxone prevents oral naloxone from reaching the systemic circulation and causing withdrawal.
The reason naloxone was added to Suboxone is probably more theoretical than medical.  Buprenorphine has been used for thirty years as an intravenous pain medication, and so there are concerns over diversion and abuse of the substance.  If Suboxone is injected, the naloxone would be active (injected naloxone bypasses the first pass effect).  Naloxone blocks opioid receptors and is used clinically to reverse opioid effects during overdose, so an addict who dissolves and injects Suboxone will experience withdrawal rather than euphoria. 
I should point out that the withdrawal from naloxone that occurs when Suboxone is injected is completely different from the withdrawal that can occur when Suboxone is taken too soon after opioid use.  In the latter case, called ‘precipitated withdrawal,’ the buprenorphine is responsible for the withdrawal symptoms, NOT.  The mechanism behind precipitated withdrawal will be discussed later in this text.  I should also point out that naloxone is sometimes confused with naltrexone, which is an opioid blocker that is active when taken orally.  Naltrexone is indicated, curiously enough, to reduce cravings for alcohol in alcoholics.  It is sometimes used ‘off label’[1]  in opioid addicts in early sobriety to prevent the possibility of a ‘high’ from opioids; it has this effect by blocking receptors for opioids in the brain.  Naltrexone causes withdrawal in people who have a high tolerance to opioids, even if opioids haven’t been used for weeks.  The brain and nerve cells take up to 8 weeks to return to normal tolerance after stopping opioid agonists, and so naltrexone is generally started only after a prolonged period of sobriety.  The exception is a form of opiate detox called ‘medicated withdrawal’ or ‘rapid opiate detox.’  In this procedure the addict is given an almost-general anesthetic, and then a large dose of intravenous naloxone.  Sometimes a slow-dissolving piece of naloxone is also implanted under the skin to prevent the addict from getting high for weeks following the procedure.  The procedure sounds good in theory, but in reality the procedure costs up to $10,000 and the benefit questionable, both in terms of avoiding misery and maintaining sobriety.
Opiate receptors and opioid effects
The use of HDB for opioid dependence stems from the actions of the drug at opiate receptors.  There are many opiate receptor types and subtypes; mu, kappa, sigma, delta, and others.  The actions of most pain medications, including buprenorphine, occur at mu opiate receptors.  To provide some background, neurons communicate with each other when one neuron releases chemicals called ‘neurotransmitters’, which cross a space or ‘synapse’ and attach to ‘receptors’ on the cell membrane of another neuron.  Endorphins are naturally-occurring chemicals in our brains that act as neurotransmitters.  Endorphins (and smaller molecules called enkephalins) are released during severe trauma, activate mu receptors on neurons, and cause those neurons to block signals from pain receptors.  The teleologic reason for such a system is because during severe injury, pain serves no adaptive advantage, but rather gets in the way of survival of the injured animal.  Pain-fighting chemicals like oxycodone and hydrocodone mimic endorphins, attaching to mu receptors and causing neurons with those receptors to fire at a rate even greater than the firing caused by endorphins.  The extra activity of these neurons causes analgesia, euphoria, relaxation, energy… good feelings for the most part.  When the chemicals leave the receptors the neurons stop firing, and the good feelings go away, and so the person wants to take the pain pills again– and again.
Most parts of our bodies, including neurons, have some ability to repair themselves. The neurons stimulated by endorphins and pain pills recognize that they are firing at an abnormal rate, and make changes to bring the firing rate back down to normal.  They do this by changing the receptors, essentially making the receptors less sensitive to the chemicals that activate them.  It then takes larger levels of chemicals to get the same effect– something called ‘tolerance’.  Over time, the receptors become less and less sensitive in response to increasing doses of pain pills.  That is why patients with chronic pain can end up taking huge doses of pain pills yet get little benefit from them.  A person in this situation must take large doses of pain pills just to get the neurons to fire normally! The person is now ‘physically dependent’ on opioids.  The receptors have become so insensitive that the person’s own endorphins no longer activate them.  And without activation of the receptors, the neurons become quiet, allowing pain input from everywhere to flood the brain.  This situation is experienced as ‘withdrawal’—a miserable state of affairs that opioid addicts learn to avoid at any cost.  As before, the neurons can ‘fix themselves’; they recognize that they are firing at an abnormally slow rate and adjust the receptors, this time making them more sensitive to stimulation.  The sensation of withdrawal will go away when the neurons have made the receptors normal again, so that native endorphins will activate them– a process that takes days, weeks, or even months, depending on a number of factors.
**
The term ‘off label’ refers to the prescribing of medications for purposes other than those approved by the FDA.  A pharmaceutical company will submit evidence to the FDA that a given drug, say ‘drug X’, is effective for treating depression.  If the FDA gives approval, the drug is then ‘indicated’ for that use.  The company can run ads and market the medication for that use, provided they also list the risks of the medication in the commercials—those fast words at the end about how the medication might kill you.  If a few years later drug X is found to cure something else, say baldness, doctors can prescribe the drug to treat baldness without needing any special FDA permission.  This is called ‘off label prescribing’, and is actually very common.