Paul Janssen, Janssen Pharmaceutica’s founder originally synthesized Fentanyl back in early 1960s. It is a opioid drug, which is synthetic. This drug got popular initially as an anesthetic under the Sublimaze brand, which is a compound comprising citric and Fentanyl acid. Not until the 1990s, was Fentanyl approved by the FDAfor using it clinically as a transdermal patch and it was branded as Duragesic. Once it got approved by the PDA, the transdermal patches of Fentanyl got hugely popular for treating pain – be it moderate or severe. Now, it is also available in the market in several forms – lozenges, or even intravenously. For eliciting analgesic effects, the Fentanyl gets bounded to MOR (mu-opioid receptors) as agonist for the stimulation of release of enkephalins and beta-endorphin. This MOR is also linked with mood improvement and neurophysiologic relaxation. However, the usage of Fentanyl also causes some side effects, including – dizziness, constipation, nausea, compromised motor skills, brain fog, sedation, and/or nausea. Due to these side effects, many users tend to discontinue Fentanyl and would understandably be curious to know as to how long it can stay in our bodies.
How Long Does Fentanyl Stay In Your System ?
First things first, you should know that if you have stopped taking Fentanyl completely, you’re going to face some sever withdrawal effects. These symptoms are mostly caused due to the readapting that your neurophysiology has to do, to learn to function in the absence of mu-receptor agonism, which was earlier provided by Fentanyl. Since you’ll be facing these symptoms, you’d want to know how long you will be suffering from these and how much time it will take for your body to be completely detoxified. To know for how long it will stay in your body once you have discontinued, you need to know about its elimination half life. Fentanyl’s elimination half life is actually a subject to a few variations depending on the mode of its administration. Intravenous Fentanyl administration will have a quicker elimination from your body as compared to transmucosal and transdermal forms. Intravenous Fentanyl has an elimination half life about 2 hours to 4 hours for adults. It means that it would somewhere in between 11 hours to 22 hours to get it out from the concentration of the plasma. Lozenges (transmucosal Fentanyl) and patches (transdermal Fentanyl) have elimination half lives of about 7 hours. This means that both of them can be out from the plasma in about 1.6 days once the drug is discontinued.
According to many sources, there has been observed a bigger discrepancy between transmucosal and transdermal Fentanyl, when we talk about elimination half lives. According to a source, the elimination half life of transdermal Fentanyl (17 hours, in the range of about 13 hours to 22 hours) is longer than the elimination half life of transmucosal Fentanyl (6.6 hours, in the range of about 5 hours to 15 hours). If this is correct, for the elimination of Fentanyl administered transdermally, it should take about 3.89 days and for the one administered transmucosal, it should take about 1.51 days. To summarize, it can be said that Fentanyl which is transmitted intravenously will be out of your system much faster compared to any other mode. The other two modes – transdermal and transmucosal formats will take a bit longer, but even they will be out of your body within 5 days once you have discontinued.
Factors influencing the stay of Fentanyl in the system
Even though for many individuals would eliminate Fentanyl out of their bodies at the same rates, the exact time for the drug to be eliminated is variable. This variation occurring as the difference in elimination speed is due to many factors. These are – dosage, Fentanyl format, individual factors, term and frequency of administration, co administered drugs, etc. Let’s take a look at how each of these factors affects the stay of Fentanyl in the body in details:
The amount of dosage:
It’s a simple thing – the greater your dose of Fentanyl you administer consistently, the longer it is going to stay in the system. The Fentanyl patches get manufactured in different doses, varying from 12 mcg per hour to 100 mcg per hour. Transmucosal Fentanyl citrate comes in doses varying from 200 mcg per hour to 1600 mcg per hour. High doses can cause a huge burden on CYP3A4 enzymes of the hepatic function. This leads to a delay in the metabolism of the drug and thereby causing a delayed elimination from the body. Moreover, increased doses also cause significant amount of exogenous substances getting circulated in the body. Fentanyl is extremely lipophilic, hence, higher doses can leads to higher amount of accumulation in the fat tissues.
You should also note that taking a high dose would take a longer time to get it excreted out of the body through urine, because they exist in the form of numerous broken metabolites as compared to the lower doses. If you take lower doses of Fentanyl, it would be metobilized and excreted out with a greater efficiency and even lesser amount of it will get accumulated in the fat tissues. This leads to quicker plasma elimination. Since lesser number of metabolites are formed due to lower doses, the speed of the excretion would also be faster as compared to the higher doses.
Drugs co-administered along with Fentanyl
If you happen to take some other drugs simultaneously with Fentanyl, it could influence the metabolism of Fentanyl and would eventually also affect the excretion from the body. Fentanyl gets metabolized by CYP3A4 isoenzymes present in the liver. Hence, any drug which is co administered that might influence the function of CYP3A4 isoenzymes in any way, either by inhibiting it or by inducing it, they will ultimately affect of how long Fentanyl could be there in your body. A co administered drug that could interfere the function of CYP3A4 isoenzymes in a way that it decreases the elimination speed of Fentanyl, it is called a CYP3A4 inhibitor. Some of the common examples of CYP3A4 inhibitors are Ritonavir, Clarithromycin, Ketoconazole, Nelfinavir and Indinavir. If you take any of these along with a dose of Fentanyl, the metabolism of Fentanyl will be altered as well as it will lead to a longer time for its elimination. However, the drugs which could enhance CYP3A4 enzymes’ functions are known as CYP3A4 inducers. They could help in expedition of the Fentanyl elimination process. Some common examples of CYP3A4 inducers are – Phenytoin, Oxcarbazepine, Carbamazepine, St. John’s wort, Phenobarbital, Rifampicin and Modafinil. Hence, if you take any of these together with Fentanyl, it would get metabolized quickly and eliminated quicker than usual. It is important to note that the effect of inhibitors or inducers could vary on the basis of the type of the drug and its dosage.
The administration route of Fentanyl
There are different formats for Fentanyl and each one of them is administered into the body through different routes. The primary routes for Fentanyl administration are transdermal (patch), intravenous (IV) and transmucosal (lozenge). It has been known that intravenous administration leads the elimination process to be the fastest, whereas transdermal and transmucosal administration processes eliminate the drug comparatively slowly. Here’s how each mode of administration impacts the elimination process:
- Transdermal (Patch): A major number of sources state that Fentanyl administered this way has an elimination half life of about 7 hours, while many other sources state that it has an elimination half life of about 13 hours to 22 hours, an average half life of 17 hours. Hence, for the users who have chosen this mode will have this drug in their system for about 2.98 days to 5.04 days once it is discontinued, the average time being 3.9 days.
- Intravenous (IV): according to pharmacokinetic reports, Fentanyl which is administered intravenously would have an elimination half life of about 2 hours to 4 hours for adults. This means that it should be out of the body within 24 hours once it is discontinued. If you have administered Fentanyl intravenously, it should be excreted out from your plasma anywhere between 11 hours to 22 hours after the dose. This mode of administration leads to the fastest excretion of Fentanyl as compared to any other methods.
- Transmucosal (Lozenge): According to many sources, the elimination half life of this mode of administration is about 7 hours. Some other sources also suggest that the elimination half life for this mode of administration of Fentanyl is about 6.6 hours and it can vary from about 5 hours to 15 hours. Hence, for the people using this method, once they have discontinued, the drug should be excreted out of their bodies in about 1.5 days. However, for many users, the elimination rate is slower and they have shown to take up to about 3.44 days.
Frequency and term of the dosage
The time period of your dosage along with for how long you have taken it should influence on how long it will be there in your body. For the users who take it regularly and that too for a longer term, there is a peak level of accumulation of Fentanyl in the concentrations of the body tissues as compared to the ones who are infrequent users or have used it for shorter terms. For instance, for someone who has taken a dose and removes it in 10 hours, he or she is highly unlikely to get an accumulation and will also excrete it out faster.
If someone has applied Fentanyl patches for 72 hours consecutively, they would attain the steady state plasma concentration. They would have also accumulated the drug in their tissues. Such long term, consistent administrations are linked with a tolerance development, which is why increase in dosages need to maintain the therapeutic efficacy. Such increase also means an increased level of the drug’s plasma concentration, which in turn leads to increased elimination time. For the users who aren’t frequent or who have taken it for a short term, they tend to take lower Fentanyl doses because their body hasn’t developed a tolerance for it. Hence, these doses can be metabolized and eliminated efficiently without any accumulation.
Other individual factors:
- If two people have simultaneously administered the same dose of Fentanyl over the same period of, let’s say, 72 hours, one person would retain the drug for a longer period in their body as compared to the other person. This difference in the elimination half lives could be mild or drastic and it entirely depends on the individual factors of both the people. Let us study how each of these individual factors influence the elimination rate in detail:
- Hepatic function: for people who have an impaired hepatic function or have conditions such as cirrhosis, they are known to eliminate the drug out a slower rate as compared to people with normal hepatic function. The hepatic impairment in a person can interfere with CYP450 (cytochrome P450) enzymes’ function, like CYP3A4. This reduced function due to the hepatic impairment can cause poor metabolism of the drug, an increase in plasma concentration and an elongation in the elimination half life. The severe the hepatic impairment is, the longer it is going to take for the drug to be out from the system. For someone with a milder impairment, it will be out comparatively quicker than for someone with a significant impairment. This is the reason why dosage limits are set for people with impaired hepatic function.
- Genetics: Primarily, Fentanyl gets metabolized by isoenyzymes CYP3A4. The conversion to norfentanyl metabolites through dealkylation from Fentanyl is facilitated by this. A small number of people might be not able to metabolize Fentanyl efficiently due to a poor functioning of CYP3A4 from the alleles of CYP3A4 gene. A lot of CYP3A4 alleles are responsible for poorer Fentanyl metabolism as compared to the average. For the people who are poor metabolizers of Fentanyl due to this reasons tend to have elongated level of Fentanyl in their plasma. Conversely, some other CYP3A4 gene alleles could acts as rapid metabolizers. They help a quicker elimination of the drug as compared to the average.
- Percentage of body fat: Fentanyl’s pharmacokinetics can be affected by the fat percentage and mass of the user. The people with high percentage body fat tend to retain the drug for a longer period of time in their system as compared to those who have lower body fat percentages. This happens because of the fact that Fentanyl is extremely lipophilic, which means it is fat soluble. Since obese people have lots of fatty tissue, the accumulation of fentanly becomes easier in them. People with lower fat percentage will excrete the drug out faster for this very reason.
- Metabolic rate: A person’s BMR (basal metabolic rate) can also affect the stay of the drug in the body. People with a higher BMR burn greater amount of energy as compared to the ones with a lower BMR. At rest, if more energy is burned due to a higher BMR, the process of metabolism and excretion will be done faster. Now, if at rest, lesser energy is spent, it will be the opposite. Here, it is also important to understand the influence of BMR on fat percentage. People with high BMR mostly have low body fat and how that affects the elimination rate has already been discussed in the above point.
- Age: Research shows that Fentanyl stays for longer and takes longer to get eliminated for elder people than younger people. It has also been said that for IV administration, the elimination half life was 15.75 hours for elder people whereas it was 4.42 hours your younger people. This suggests that for elders, it would take 3.61 days for the drug to be out and for the younger people; it would take about 1.6 days only. Yet another study showed that for Fentanyl patches’ elimination half life with regards to old people (64-82 years) was 11.1 hours, while it was 11.1 hours for young people (25-38 years). Fentanyl stays in the body after discontinuation for double the time in elders as compared to that in younger people. Some age related factors play a role here – diminished hepatic function, decreased tissues perfusion, lower physiologic efficiency and lesser plasma proteins.
- Hydration: the metabolites of Fentanyl are excreted out of the body in the form of urine once it is discontinued. Hence, staying properly hydrated would lead to an increase in the flow rate of urine, leading to efficient excretion of the drug. Hence, for someone who stays well hydrated post discontinuation will definitely excrete out the drug quicker than someone who does not.
The process of absorption, metabolism and excretion of Fentanyl explained
- After the transmucosal or the transdermal Fentanyl administration, the gets absorbed efficiently. This efficiency would increase if it is administered intravenously for the people who experience analgesic effects almost immediately after infection. The effects peak in just several minutes after an intravenous Fentanyl dose is injected, and they last for about 30 to 60 minute. For Fentanyl that is intramuscularly administered, there is a minor delay in the effects as compared to the IV administration. They occur after 7 to 15 minutes post ingestion and last for about 1 hour to 2 hours. For transmucosal Fentanyl, it gets absorbed rapidly through the mucous membranes of the cheeks.
- Absorption through buccal mucosa ends up in 25% Fentanyl being available. The remaining part, 75% of it is swallowed by the saliva and slowly absorbed through the GI tract. Out of that 75%, about 25% gets available post hepatic metabolism. Hence, the bioavailability of transmucosal Fentanyl is about 50%. For transdermal administration through a patch, the bioavailability of Fentanyl is 92%. Either way, about 85% Fentanyl gets bounded to the plasma proteins, especially alpha-1-acid glycoprotein. Later, it is distributed to heart, lungs, brain, spleen and kidneys. Since it is highly lipophilic, it can get accumulated in the fatty tissues easily.
- Post ingestion, through the CYP3A4 isoenzymes, hepatic metabolism of Fentanyl is carried out. The metabolite norfentanyl is formed from Fentanyl through N-dealkylation with the help of CYP3A4. Moreover, it also gets metabolized by mucosa of the intestine and then is subjected to hydroxylation for the formation of inactive metabolites – propionic acid and 4-N-anilinopiperidine before excretion. About 90% Fentanyl gets excreted out in the form of urine – as metabolites. About 7 to 10% gets excreted out in the form of unchanged Fentanyl. Very small amount is thrown out through feces and from this, less than 1% is unchanged Fentanyl. Study shows that about 70% to 75% Fentanyl gets excreted out through urine in just 4 days post discontinuation.
Clearing Fentanyl quickly from the system
- After you have discontinued taking Fentanyl, you would want to have your body detoxified from it as soon as possible. Though the good thing is, Fentanyl has an elimination half life which is much shorter than most of the drugs and it gets excreted out as it is. However, if you still want to speed up the process, you could consider the tips given below. It is important for you to discuss any of these with your doctor before you try. Have a look:
- Reducing the body fat: this can be done only by exercising. Since Fentanyl is lipophilic, if you have a high body fat percentage, it will get accumulated in the body. You can burn some fat and help the process of elimination to get over quickly.
- Activated charcoal: once you have fully stopped taking Fentanyl, you can use activated charcoal. Note that it can’t be used until Fentanyl is out from the plasma. Though it does help in the detoxification of Fentanyl from the body, along with its metabolites and other endotoxins created in the process. Talk to the doctor to know about the safe time and method of taking it.
- Calcium-D-Glucarate: this substance is known for being a cellular detoxifier that helps in the removal of toxins from the kidneys and liver. Hence, it could be possibly that it may help in removal of the metabolites and Fentanyl.
- Stop taking Fentanyl: the best way to know for sure that it is out from your system is to avoid taking it altogether. As you keep taking it, it will keep getting accumulated in your tissues and won’t really get completely removed. It could take many days to be out of your system and many more days to be completely excreted out.
Kinds of drug tests for Fentanyl
- Even though Fentanyl is quite more potent as compared to other opioids, it isn’t assessed on drug tests commonly. The standard drug test for detecting opioids metabolizing into morphine is SAMHSA-5. Now we know that Fentanyl doesn’t get metabolized into morphine, it won’t get detected by this procedure, unless a Fentanyl specific screening is used. Let’s take a look at other tests in detail:
- Hair test: one way to look for Fentanyl ingestion is by collecting hair follicles to analyze them. The concentration of Fentanyl in hair can range from 0.1 ng per mg to 0.5 ng per mg post ingestion, according to research. Actually, small concentrations of Fentanyl can be found for even months after it is administered. Since there is a long detection window for hair test, and the fact that happen to be minimally invasive as well as highly convenient, they are generally preferred for testing Fentanyl. Fentanyl is present in greater amounts in the roots rather than the tips of the hair. The only reason why they can’t be completely relied upon is that the amount of Fentanyl present cannot be determined.
- Urine test: it is understandably easier for detection of Fentanyl from a urine sample with the use of gas chromatography or mass spectrometry (GC/MS). A study found out the level of Fentanyl and the metabolite norfentanyl for Fentanyl patches users. On the basis of the dosage, the levels of metabolites and its parent compound were documented. Here is what was found – the 25 mcg per hour patch yielded 175 ng per ml norfentanyl along with 47 ng per ml Fentanyl. The 50 mcg per hour patch generated 247 ng per ml norfentanyl and 74 ng per ml Fentanyl and in the urine. The 75 mcg per hour patch yielded 328 ng per ml norfentanyl and 107 ng per ml Fentanyl. The 100 mcg patch generated 373 ng per ml norfentanyl and 100 ng per ml Fentanyl in urine. According to a study done back in 1993, the unchanged Fentanyl can be detected in the urine quickly post administration, but till what duration it will be detected changes from person to person. Some people excrete the Fentanyl out quickly, so it won’t be detected in a day. For others, it can be detected even till 72 hours after ingestion. The norfentanyl metabolites get accumulated to a much greater extent and may be detected even up to 96 hours or 4 days in many people after the ingestion through a GC/MS urinalysis.
- Blood test: if a person is unable of being tested for Fentanyl by a urine test, one can always go for a blood test. Through a blood test, Fentanyl can be detected minutes after the administration and can stay for even days based on the format of Fentanyl. IV Fentanyl can allow the detection in just a few minutes post administration, but it has to be done with a day, that is, 24 hours. The transmucosal Fentanyl or transdermal Fentanyl can be detectable for up to 4 days in your plasma concentration based on its dosage and the question if the person did attain a steady state concentration. However, since blood tests are invasive and a very small window of time is there to detect, they are not preferred much. Though they are used for postmortem analyses and for other scientific researches.
- Saliva test: most of the drugs can be easily detected from the saliva, but not Fentanyl. It is really difficult to be able to detect Fentanyl from the saliva, and even more so, if it was an IV administration or a transdermal administration. If Fentanyl is administered through oral lozenge, the drug remnants can be retained in the oral mucosa post administration, thereby increasing the chances of detection. Back in the ‘90s, it was difficult to do saliva tests for Fentanyl, but now, the tests can extract the absorbed Fentanyl from CDB (cotton dental bud) on a salivette testing device. This can be done by using the chemical acetonitrile along with reverse phase chromatographic separation and HPLC (high-performance liquid chromatography). Both norfentanyl and ff will appear in small amounts on the saliva tests. In the future, such testing devices are thought to improve the ability of detecting Fentanyl. Even though the saliva test is convenient and minimally invasive, it is not accurate like the urine test and even fails to give a longer window for detection. For the same reason, they are not widely used.
