The Real Reason Fentanyl is So Dangerous

Fentanyl plays a role in more and more opioid overdose deaths. Most fentanyl used ‘on the streets’ starts in China, with precursors shipped to California or Mexico before distribution throughout the US. Fentanyl acts very potently at the same receptors as heroin, morphine, and oxycodone. Reports of overdose deaths caused by fentanyl usually blame potency, but the real reason for fentanyl’s outsized role in overdose is rarely mentioned – at least outside operating rooms.

Fentanyl is as ubiquitous in the medical industry as it is on the street, in 50 microgram per cc, sterile vials rather than the small rocks ground up by drug dealers and added to heroin. Operating rooms are full of the stuff, as are dental offices, cardiac cath labs, and colonoscopy suites (why, by the way, do we call rooms used for THAT procedure ‘suites’?).

When an anesthesiologist puts morphine into a patient’s IV, the patient’s rate or breathing slows down over a span of about 10 – 15 minutes. The patient keeps breathing, and blood oxygen level might fall slightly if nasal oxygen isn’t provided. But when the anesthesiologist injects fentanyl into the IV, the patient will sometimes stop breathing as soon as the drug hits the brain – in about 20 seconds. That ‘apnea’ occurs when there is no drive to breathe, and results in a fall in blood oxygen levels – hypoxemia – which can trigger cardiac arrest.

The difference is due to the difference in lipid (fat) solubility. The morphine molecule dissolves in water. The fentanyl molecule, on the other hand, dissolves in fat. That small difference in characteristics is behind the current flood of overdose deaths.

All addictive opioids have certain effects in common. One effect is to reduce the sensitivity of our respiratory centers to carbon dioxide. Every cell in our bodies uses oxygen as fuel to produce energy, with carbon dioxide as the main byproduct. When we exercise, we use more oxygen and produce more CO2. Our brain maintains a precise level of CO2, a level of 40 mm mercury, over a wide range of activity, by speeding or slowing our breathing.

Opioids change that response. Under opioid effects the setpoint is higher, up to 50-60 mm mercury. People under the influence of opioids breathe more slowly because it takes less respiration to maintain the higher level of carbon dioxide.

Morphine crosses the blood brain barrier over 10-15 minutes. Respiration gradually slows, but doesn’t stop, as the brain level of morphine rises. Oxygen levels are maintained, especially if a small increase in oxygen is provided. Fentanyl, on the other hand, crosses into the brain almost instantly. Drive to breathe disappears, completely, until carbon dioxide build up to the new setpoint. In the absence of respiratory drive, breathing stops. Oxygen levels in the blood fall, even when nasal oxygen is provided . The lack of oxygen causes problems in the organs that need oxygen the most, the heart and brain.

The difference in response to different opioids is reflected in hospital policies. Many hospitals allow morphine to be administered to patients intramuscularly, or even intravenously, on a general medical floor. But fentanyl is usually confined to ‘monitored beds’ like the ICU, where patients have respiratory monitoring, ECG and pulse-oximetry (the latter to follow blood oxygen levels).

Anesthesiologists are familiar with the different actions of fentanyl and other lipid-soluble opioids. During colonoscopy or other procedures under ‘IV conscious sedation’ patients will often pause their breathing after a small dose of fentanyl. Opioids stop breathing in doses lower than those required to block consciousness, so those patients will often breathe when instructed to ‘take a deep breath’.

Before fentanyl hit the streets, overdose often occurred when patients were home sleeping, sometimes hours after opioids were injected or swallowed, when the mixture of drugs and alcohol in the stomach passed into the intestine to be absorbed into the blood. Fentanyl overdoses are different, occurring within seconds or minutes of drug use. I wonder if recognizing the difference in pharmacology might lead to public campaigns that could reduce overdose risk. For example, a ‘buddy approach’ would be helpful if one person waited, before using, for about 15 minutes, until the peak effects of injection have passed in the other user. Each ‘buddy’ could have Narcan at the ready in case apnea occurred. And if Narcan isn’t available, a strong sternal rub with the instruction to ‘take a deep breath’ might save a life!

Ending Constipation from Suboxone and Buprenorphine

Constipation is one of the few potential side effects caused by buprenorphine medications, including Suboxone Film and Zubsolv. Fortunately, ‘binding up’ can be managed by making minor changes to your lifestyle.

Constipation from buprenorphine is caused by activation of mu opioid receptors in the small and large intestine, reducing the sequential squeezing and relaxation (called peristalsis) that pushes bowel contents forward. All opioids have similar effects, mimicking our natural endorphins throughout the body. Endorphins are released during trauma to naturally block pain and to divert blood flow to areas where it is needed most — and the bowel is relatively shut down during those periods to conserve energy.

Constipation problems from buprenorphine (I’ll use that term for Suboxone, Zubsolv, Bunavail, or any other form of buprenorphine) often occur in people who are already having some constipation problems, where the medication makes things worse. The first few ideas I’ll offer will help anybody, regardless of whether they take buprenorphine or other opioids.

Diet and Hydration

The function of the large intestine is primarily to reabsorb water. The amount of water reabsorbed is related to the time that contents spend in transit. This will be a bit graphic… but that’s why the first part of a bowel movement is generally hard and drier than what follows. That first part has been through the ascending colon, the transverse colon, the descending colon, and the sigmoid colon, and has hardened into something like adobe bricks. After that has been pushed out of the way, the remaining stool passes through more quickly, with less drying.

The most important step to avoid constipation is to keep things moving. If nature gives you a chance to go, take it! If you manage to skip the chance, it would only be harder to go tomorrow.

Many people fail to drink enough liquids, especially those who live in hot environments. If your body is relatively dehydrated, your colon will work harder to conserve water. Staying hydrated — to the point where you urine is light-colored — will reduce constipation.

Diet, of course, plays an even larger role. Those of you who work with concrete know that certain additives will make the mix more strong or dense. Throw in a bale of hay, and the opposite happens. So add food to your diet that contains fiber, which reduces concretion and adds bulk, making it easier for you colon to compress and push the mass forward.

Certain foods like prunes and plums have chemicals (as well as fiber) that keep the bowel moving. Other foods — e.g. cheese and processed foods — can slow things down.

Medications

Add medications only when the ideas listed above aren’t working. Consider softening agents first, as they have less effect on colon function and are less likely to create a dependence. Medications with docusate pull water into the feces to soften them. Drugs that contain sorbitol, magnesium, or polyethylene glycol pull water back into the colon, increasing the volume of feces which then stimulates a bowel movement.

Senna and bisacodyl stimulate the colon to increase peristalsis. I usually recommend Senokot to my patients, as it comes in liquid form that can be added to juice in measured amounts. With all of these over-the-counter products, be sure to follow the directions on the bottle. ALL of them can do harm if taken in excess. Stimulant laxatives and cathartics can also create tolerance and dependence, so avoid using that approach for more than 2 days in a row.

Nothing Works!!

It is possible for constipation to block the colon completely. The last things on the list are enemas and suppositories, which work from the other end of the obstruction and aren’t, obviously, something to use routinely. Glycerin suppositories lubricate and also stimulate the colon. Bisacodyl suppositories stimulate the colon to provoke a bowel movement. Enemas stimulate peristalsis, lubricate, and soften feces. Many people, though, are uncomfortable doing enemas at home.

If you are completely blocked up, stimulant cathartics will cause pain and vomiting. In that case, you may have to bite the bullet and go to the ER.

if none of the convenient options are working, you might consider ‘dosing and spitting’. At the liver, buprenorphine is metabolized to norbuprenorphine, an opioid agonist that does not cross into the brain. When you take 8 mg of buprenorphine, about 30% of the dose is absorbed into the bloodstream and the other 70% is swallowed and metabolized to norbuprenorphine. If you dose for 10 minutes and then spit out the remaining saliva, you will reduce the formation of norbuprenorphine, and reduce constipation. It takes about 5 days to start seeing results because norbuprenorphine builds up in your system over time. The practice might turn off your friends so try to do it in private!

Keep in mind that solving the constipation problem will require making a change that you can continue going forward. Drinking more water and eating more fresh fruits and vegetables are great places to start.

Dr. J

Stopping Buprenorphine in Three Steps

Readers will sometimes ask for my thoughts about buprenorphine. I’m always happy to respond, time permitting. I’ve described how my patients taper off buprenorphine in prior posts, but the interest out there warrants revisiting the topic.

Most people who become dependent on opioids become very fearful of withdrawal. That fear continues on buprenorphine medications like Suboxone, Zubsolv, and generic buprenorphine. Patients should strongly consider using buprenorphine to keep their addictions in remission for at least a year or two before starting a taper, and those prone to relapse to opioid use should consider life-long medication. Doctors regularly use medications with higher risk-profiles than buprenorphine to prevent illnesses with lower associated morbidity!

But some people feel trapped by their fear of withdrawal. Such an attitude is completely unnecessary, because most people can taper off without too much trouble. Over the years, hundreds of my patients have tapered off buprenorphine.

Are You Ready?

The first thing to do is to consider whether you are ready to taper. Stopping buprenorphine IS difficult when tried too early, before the mental connections to opioid use have faded. To assess readiness, I make sure that the patient has been dosing once or twice per day, ‘as needed’, which reinforces the behaviors that treatment aims to eliminate. You should be doing well with prescriptions, and not running out early.

Make sure the odds against relapse are running in your favor. Several studies have shown that relapse rates are very high – over 95% – in people who have been on a maintenance agent for less than 12 months. Relapse is also more common in people who are frequently exposed to their drug of choice, so if you’re still hanging with the same crowd, consider staying on buprenorphine. Finally, your odds are improved by being busy. If you’re not working, consider holding off on tapering until you are.

Just Do It!

If you’re ready by those standards, I recommend dosing twice per day during a taper.  Dosing twice, rather than once, will be helpful when you get to blood levels that dip below the ‘ceiling effect’ during a 24-hour day.

So you’re taking 8 mg in the AM, and 8 mg in the PM.  They don’t have to be 12 hours apart;  many people choose around 7 AM and then around dinnertime.
The first step is to remove 2 mg from the PM dose.  Take that amount, 14 mg/d, for two weeks.  Then remove 2 mg from the AM dose and stay at 12 mg/d for the next two weeks.  Then remove another 2 mg from the PM dose, wait two weeks, and then remove another 2 mg from the AM dose.  It takes about 2 months do do all that, and now you’re at 8 mg/day.   Unless you have an unusual metabolism, you won’t have significant withdrawal during this first part.

The second half of the taper takes more time, and works best if you have the film.  You do the same as you did in the first part – i.e. remove a little bit from alternating doses – but you will need to remove less than 2 mg.   There are three things that make the second half of the taper more difficult:

  1. It is harder to consistently divide smaller pieces.
  2. The dose/response relationship is now a steep diagonal line rather than the horizontal line present at ‘ceiling effect’ doses.
  3. Your body’s response to a dose reduction is based on percent change, not the change in amount.   Taking 2 mg from 16 is 12%, but taking 2 mg from 4 is 50%.

As you start the second half of the taper, tear off about 40% from one end for the morning dose.   At night, tear off a similar amount.  Keep doing that amount for 2 weeks, then change to tearing off a little less. Repeat.

Within a couple months you’ll be down to about 2-4 mg buprenorphine per day.  At this point you will want to get more precise.  Get a razor or a sharp scissors and cut the film into quarters, lengthwise.  Now when you tear off pieces, the pieces will be 25% of the dose that you would get from tearing an entire strip.  Better yet, have your doc prescribe the 2 mg films.   However you do it, you just keep slowing reducing the dose, and keep dosing twice per day.  ALWAYS wait a couple weeks between dose changes to allow your body to adjust.

When you get down to less than 0.3 mg per day, you can ‘jump’ without too much discomfort.  Some people taper lower, but if you’ve been at 0.3 mg for at least a couple weeks, you shouldn’t have too much trouble.

There will be times when you find that you have reduced by too much too fast.  When those times come, go back a tiny amount, but avoid giving up all of the gains you made.  And now and then, give yourself a reward – maybe get a massage (if that even happens during a pandemic!), or go out with a friend and get a good meal.

Tapering off Suboxone will NOT be the hardest thing you’ve ever done.  As you make progress you’ll see that all of those people on the internet were wrong when they said ‘it is the hardest opioid to stop’! Good luck, and check out the forum too (suboxforum.com)!

Dr. J

Suboxone Forum Upgrade

Regular readers know that I’m a psychiatrist and addiction doc – not a computer guy. When I started writing about Suboxone and buprenorphine twelve years ago, there were few other people writing about the medication. Of course heroin addiction was just taking off, and fentanyl was confined to operating rooms.

I put together a couple sites that skyrocketed in readers. The most-used was SuboxForum, where we discussed controversial issues like ‘is Suboxone a drug for a drug’, and ‘do the films hurt your teeth?’

I did not work on SEO stuff, because (in case I didn’t say) I’m a psychiatrist. I watched my sites fall below sites that had almost no content, that only advertised spa-like treatment programs that have been proven not to work for treating opioid addiction. Many web sites ‘scraped’ my posts and content, or took feeds from the forum, and posted them as content on their own sites – that scored above the native sites.

Google always says ‘don’t worry about SEO; just have good content and we’ll find you!’ I can attest that in this corner of the internet, they don’t do a good job of separating the posers and scammers from real content.

There are a couple other forums out there that were big in the past, and now sit dormant or dead. They still rank for questions about buprenorphine. I’ve decided that I need a hobby, so I’m going to try to get the numbers up at SuboxForum. If you haven’t been there for a while, stop by! We are still at the same place, with some software upgrades… but we have many of the same people you knew years ago. Our main mission, of course, is to help the newcomer learn about an important medication… so if you’re wondering how the medication works or other questions, stop by.

I’m a psychiatrist (if I didn’t say that before). So I don’t collect info and sell it to spammers. The software needs you to give your email to sign up, but get a free anonymous one and use that.

Hope to see you there.

Tapering off Buprenorphine or Suboxone, Pt 2

In the last post we discussed some of the misconceptions about tapering off opioids. Today we will discuss a couple basic principles, and then describe the approach I recommend for my patients tapering off buprenorphine.
Opioids act at receptors that normally bind endorphins, which are released by neurons in response to a range of stimuli including trauma and rewarding behaviors such as eating a good meal or using addictive drugs. Endorphin pathways elevate mood, reduce sensation of pain, and impact urine production, immune function, intestinal motility, and other bodily functions. Endorphin pathways have a certain baseline activity or ‘opioid tone’ that is directly related to opioid tolerance. When opioid stimulation is greater than one’s tolerance, opioid tone is increased. When opioid stimulation drops below one’s tolerance, opioid tone is reduced, causing withdrawal symptoms.

The goal of any taper off opioids is to recover original or native opioid tolerance. Some people focus on getting rid of the opioid, and even use substances or behaviors to ‘flush buprenorphine from the body’. Products marketed as detox agents have minimal impact on the clearance of buprenorphine or other substances. And even if they could increase the rate of clearance, they would only make detox harder by increasing the severity of withdrawal symptoms. The relatively slow metabolism and clearance of buprenorphine provides a cushion by slowing the loss of opioid tone.

Prolonged use of any opioid changes opioid receptors. The changes are not fully understood but include a decrease in number of receptors and changes in binding properties that reduce receptor sensitivity to opioids, including endogenous opioids (endorphins). Recovery from a state of tolerance takes 2-3 months, and is initiated by reduced opioid tone. Withdrawal symptoms reflect the reduced opioid tone that provokes eventual recovery of native tolerance.

Recovery of native tolerance is the rate-limiting step when tapering off any opioid, including buprenorphine. When the dose of buprenorphine is reduced, the amount of buprenorphine at opioid receptors decreases over the next 5 days and then stabilizes at a lower level. In response, opioid tone (the summation of current flow through opioid receptors) drops below normal. If the dose of buprenorphine is maintained at that level, opioid tone will recover to normal in about 2-3 months. If buprenorphine is suddenly and completely discontinued, opioid tone will decrease to very low levels and cause severe withdrawal that lasts for 2-3 months. If buprenorphine dose decreases more slowly, opioid tone will decrease more slowly, lessening the severity of withdrawal. But it still takes 2-3 months for opioid tone to return to normal. So for any taper, patients must decide whether to decrease their dose quickly and be done in 2-3 months, at the cost of greater withdrawal, or instead to taper more slowly to reduce the severity of withdrawal.

The relationship between buprenorphine dose and opioid activity is linear up to about 2-6 mg. Beyond that point further increases in dose have less impact on opioid tone. The reverse occurs when tapering, so that opioid tone decreases only slightly as dose is reduced from 16 mg per day to 4 mg per day. The non-linear dose/response relationship allows for rapid decreases in dose early in the taper process with limited or no physical withdrawal symptoms. Since the early challenge is mostly psychological, I use the early part of a taper to help assess whether a patient is truly ready to take on the tapering process.

I like to have patients lead the way in tapering off buprenorphine. I’ve found that if I lead and reduce the amount of prescribed buprenorphine for the next month, patients often fail to make reductions and end up out of medication before the end of the month. So instead I ask patients to tell me when they are certain that they are ready to stay at the lower dose.
During a taper, I recommend dosing buprenorphine twice per day. Patients start by removing 2 mg from the evening dose. After at least two weeks 2 mg can be removed from the morning dose. This sequence is repeated at intervals of at least 2 weeks until the total dose is 4 mg per day. In my experience patients who get to that point are usually in a good mental position to begin the second, more difficult part of the taper.

Most people will be able to continue working when opioid dose is reduced by 5% or less every 2 weeks, or 10% every month. That number is a good general guideline when deciding how fast to taper. Suboxone film makes tapering relatively easy. Patients purchase a weekly med organizer, and start the week by opening and stacking 7 films. A scissors or razor is used to cut a millimeter from the end of the stack, and one film is placed in each compartment of the organizer for that day’s dose. When the patient is comfortable with that dose, slightly more is removed for the next week. The process continues every 2-4 weeks, eventually changing to the 2 mg films. I recommend that patients continue tapering until the dose is 300 micrograms (0.3 mg) per day or less before stopping buprenorphine completely. It is fairly easy to guesstimate where to cut the film in order to reduce by 10%; just measure half, then half of that, then half of that.

Buprenorphine tablets, of course, are much harder to divide. Zubsolv did people a favor by coming out with a range of doses, and hopefully other brand and generic manufacturers will eventually follow suit. For now I usually have patients use the tablets to taper as far as possible, using the 2 mg tablets in the lower dose range, and then pay the extra cost for the film for the final month or so. A 12 mg film can be divided into 24 half-milligram pieces without too much effort, so the cost doesn’t have to be prohibitive.

I have had many patients taper successfully off buprenorphine. Fear is common and normal for a number of reasons, but the fear usually gives way to a sense of confidence and optimism when a taper is done correctly.
Things to keep in mind:

  • Be patient. Tapering by too much, or too quickly, causes withdrawal symptoms that lead to ‘yo-yos’ in dose.
  • Buprenorphine products are very potent. A sliver of Suboxone Film may contain enough buprenorphine to harm or kill an animal or small child. Take care to divide the medication in a well-lit setting, and clean up very carefully.
  • Buprenorphine is used to treat pain in microgram doses. If you jump from 1 mg, you will have considerable withdrawal symptoms.
  • If you are still running out of medication early, it is not time to taper off the medication.
  • People on buprenorphine for a year or less have rates of relapse over 90%. In my experience patients are more successful tapering off buprenorphine if they have been on the medication for 2-5 years or more.
  • If you struggle in tapering down to 8 mg, consider going back to your stable dose, waiting 6 months, and trying again.
  • People addicted to opioids often substitute other drugs for their drug of choice. Do not start a new addictive substance in order to get off buprenorphine.

Good luck!