Promethazine is a first-generation antihistamine of the “phenothiazine” classification often prescribed for the treatment of postoperative nausea, vomiting, and motion sickness. It is commonly utilized as an adjunct to narcotic analgesics to increase their efficacy among those experiencing acute or chronic pain. Additionally, promethazine is sometimes administered for the treatment of the common cold and allergy symptoms (e.g. itchiness, runny nose, skin rash).
As an antihistamine, promethazine functions primarily as an H1 receptor competitive antagonist, thereby blocking the effect of histamine on H1 receptor sites. It also acts as an anticholinergic drug via binding to muscarinic receptors and inhibiting their responses to acetylcholine. Promethazine’s antiallergenic properties are likely derived from its histaminergic action, whereas its antiemetic properties are associated with its central anticholinergic effects.
Despite the significant therapeutic benefit that can be attained from promethazine when utilized properly, it may provoke unwanted side effects such as: brain fog, confusion, fatigue, dizziness, drowsiness, dry mouth, irritability, and tardive dyskinesia. Furthermore, some users are concerned with the fact that promethazine and other anticholinergics are linked to dementia. For this reason, many individuals discontinue treatment only to wonder how long promethazine stays in their system.
How long does Promethazine stay in your system?
If you recently discontinued treatment after a prolonged term, you may notice the onset of some uncomfortable promethazine withdrawal symptoms. You may also notice that certain side effects associated with promethazine treatment such as cognitive impairment may linger for days after you’ve stopped the drug. This may lead you to question whether any promethazine is still in your system, and if so, how long it will remain in circulation.
To determine how long promethazine is likely to stay in your system after your final dose, it is important to understand its elimination half-life. The average elimination half-life of promethazine reportedly falls within the range of 9 to 16 hours when administered intravenously or intramuscularly. With this information, we can estimate that promethazine is likely to remain in your system for 2.1 to 3.67 days after administration (assuming “IV” or “IM” routes).
Should you have administered promethazine orally or rectally, the range of its elimination half-life falls between 16 and 19 hours. This indicates that oral and rectal users will have fully eliminated promethazine from systemic plasma circulation between 3.67 and 4.35 days post-ingestion. In other words, regardless of the route by which you administer promethazine, it should be out of your system within 5 days of your final dose.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/promethazine
Variables that influence how long Promethazine stays in your system
It is important to realize that although systemic elimination of promethazine is likely to occur within 3 and 5 days of a user’s final dose, some users will eliminate it quicker from their systems than others. Not everyone will necessarily eliminate promethazine from their system in an “average” amount of time. Therefore it is necessary to consider some variables that will likely affect promethazine elimination including: route of administration, individual attributes, dosage, term of administration, and co-ingested drugs.
Route of Administration
There are multiple modalities in which promethazine may be administered. These modalities influence the pharmacokinetics of promethazine and ultimately how long it is likely to stay in your system. Users that administer promethazine via intravenous or intramuscular injection tend to eliminate the drug (and its metabolites) faster from their systems than those who administer promethazine orally or rectally.
Intravenous / Intramuscular: As was mentioned above, the half-life for promethazine when administered intravenously and/or intramuscularly is between 9 and 16 hours – considerably less than that associated with oral and/or rectal administration. This implies that promethazine is likely to be eliminated from systemic circulation between 2.1 and 3.67 days post-administration. Since most drugs are eliminated quicker when administered intravenously (IV) compared to intramuscularly (IM), it is likely that intravenous users will have cleared promethazine in just over 48 hours, whereas intramuscular users may take over 72 hours to clear it from their systems.
Oral / Rectal: Both oral and rectal administration of promethazine are associated with a half-life of 16 to 19 hours. This implies that the drug is likely to remain in a user’s system for 3.67 to 4.35 days after administration. It is unclear as to whether elimination speed is likely to be quicker either orally or rectally (compared to the other). That said, orally and rectally administered promethazine should be out of a user’s system within 5 days after their final dose.
- Source: http://www.medicine.virginia.edu/clinical/departments/pediatrics/education/pharm-news/2006-2010/201003.pdf
Two promethazine users could administer a single-dose of 25 mg simultaneously, yet one user would likely eliminate the drug (and its metabolites) faster than the other individual. Differences in elimination speed of promethazine from a person’s system may be a result of individual factors. These factors include things like: a user’s age, body mass, genetics, hepatic function, and renal function.
Age: Elderly individuals (over the age of 65) tend to eliminate most drugs slower than younger adults. This is primarily due to the fact that distribution, metabolism, and elimination processes are altered among elderly as a result of age-related physiologic decline. Specifically, altered concentrations of plasma proteins, declining hepatic function, and diminishing renal function among elderly are thought to prolong promethazine elimination.
In addition, elderly individuals are more likely to be taking medications and/or have other health conditions that could interfere with the efficiency of promethazine metabolism and elimination. Though formal studies haven’t investigated the elimination half-life of promethazine among elderly patients, it is likely to be longer than it is among younger adults – especially when administered orally.
Body mass index (BMI): It is likely that the distribution and pharmacokinetics of promethazine are affected by a user’s BMI. Someone with a high BMI taking a single dose of 25 mg promethazine is likely to eliminate it quickly compared to someone with a low BMI. Individuals with a high BMI respective to the dose of promethazine administered have a larger system to efficiently process and eliminate the drug, especially when administered at a single dose.
However, when administered consistently for a long duration at a dosage appropriate for a person’s size, promethazine and its metabolites may have a greater propensity to accumulate within the body of a high BMI user. This is due to the fact that there is a greater area for distribution and an increased number of fat stores for accumulation. This may lead to a prolonged elimination term among a person with a high BMI after steady state concentrations have been attained.
Genetics: It is understood that promethazine is metabolized via enzymes in the liver, principally CYP2D6 isoenzymes. The alleles associated with your CYP2D6 gene will dictate the function of hepatic CYP2D6 isoenzymes. An individual with certain CYP2D6 polymorphisms (as occurs in 3% to 10% of the population), will exhibit suboptimal function of CYP2D6 isoenzymes, leading to poor metabolism of promethazine.
This poor metabolism ultimately results in increased plasma concentrations and a prolonged elimination period of promethazine. On the other hand, someone with optimal function of CYP2D6 isoenzymes (as dictated by their CYP2D6 gene) will metabolize promethazine efficiently, leading to quick systemic elimination. To determine whether you are an efficient or poor metabolizer of promethazine, and ultimately predict how long it is likely to remain in your system upon cessation, you could consider a test like “GeneSight.”
Hepatic function: Individuals with compromised hepatic function may retain promethazine and its metabolites for a longer duration than those with normative liver function. This is due to the fact that hepatic impairment decreases function of CYP2D6 isoenzymes within the liver. This leads to poorer-than-average metabolism of promethazine, increased plasma concentrations, and a longer elimination half-life.
Typically the degree to which an individual is hepatically impaired will determine how long promethazine stays in his/her system. Someone with severe impairment is likely to retain the drug for a longer duration than a person with minor impairment. Furthermore, it is necessary to account for the endogenous function of CYP2D6 isoenzymes as a result of the CYP2D6 gene; a CYP2D6 poor metabolizer with hepatic impairment may be affected more substantially than a CYP2D6 extensive metabolizer with the same degree of impairment.
Metabolic rate: It is possible that a person’s BMR (basal metabolic rate) may affect how long promethazine (and its metabolites) stay in systemic circulation. Individuals with high BMRs are thought to metabolize and eliminate certain drugs faster than those with low BMRs. This is perhaps best evidenced by cases of individuals with hyperthyroidism who often exhibit extremely short half-lives of drugs compared to those with the polar opposite, hypothyroidism.
If you have a high BMR, your body is burning more energy at rest, and may be more likely to metabolize promethazine (and other exogenous substances) quicker. If you have a low BMR, your body is utilizing less energy in a resting state, which may contribute to a slower metabolism and elimination of drugs like promethazine.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/797503
Renal function: Promethazine is excreted principally through the urine, which is facilitated by the kidneys. Individuals with renal impairment or suboptimal renal function may be more likely to accumulate promethazine metabolites prior to elimination. Increased accumulation and decreased clearance of promethazine within the kidneys stems from the fact that they may not be functioning properly.
Suboptimal renal function leads to reabsorption of the drug throughout a user’s system, leading to prolonged elimination. While minor renal impairment may not have a significant effect on the elimination speed of promethazine metabolites, moderate or severe impairment may lead to a large increase in elimination half-life. That said, if you have normative renal function, excretion of promethazine metabolites via urine should be efficient.
Dosage (High vs. Low)
Usually the greater the dosage a person ingests of promethazine (especially relative to their body size), the longer it’ll take to eliminate from systemic circulation. When administered at large doses, CYP2D6 isoenzymes in the liver will need to work harder to metabolize the increased quantity of promethazine. This increased enzymatic burden leads to less efficient metabolism of the drug, ultimately prolonging the process of metabolite formation.
Once the promethazine is fully metabolized after a large dose, a greater number of metabolites are formed. The high dosage ingested of promethazine, along with the increased number of metabolites formed means that a heightened level of the drug will be circulating throughout the plasma. Administration of 50 mg promethazine will therefore linger in greater quantity, for a longer duration than a 12.5 mg dose.
Assuming the drug has a half-life of 19 hours, the 50 mg user would be down to 25 mg promethazine in the plasma after 19 hours, whereas the 12.5 mg user would be down to just 6.25 mg in systemic circulation; this is considerably less. Additionally, it is necessary to consider that renal elimination among those taking high doses may be less efficient due to the fact that there’s more metabolites that necessitate elimination. This may lead to metabolite accumulation within the kidneys, ultimately prolonging excretion compared to a low dose user.
If you are taking a high cumulative daily dosage of promethazine, you’ll be likely to retain it for a longer duration than someone taking a low cumulative daily dosage. The less of an exogenous substance you ingest (e.g. promethazine), the easier it will be for your hepatic enzymes to metabolize it, and your kidneys to excrete it efficiently. In cases of an overdose or supratherapeutic dose, elimination of promethazine is likely to be considerably longer than the slower range of the “norm.”
Frequency/Term of administration
The more frequently you use promethazine, the more likely you are to have ingested a larger daily dosage than an infrequent user. Consider an infrequent user taking just 25 mg, whereas a frequent user may take 12.5 mg three times per day for a daily total of 37.5 mg; this is 12.5 mg more than the 25 mg user. Furthermore, frequent users will be administering new doses before their previous dose was metabolized and eliminated.
This taxes hepatic enzymes to a greater extent, leads to increased plasma concentrations of promethazine metabolites, and decreases renal efficiency. For this reason, the more frequently you use promethazine on a daily basis, the longer it will likely stay in your system. Additionally, it may also be necessary to consider the total term over which you’ve consistently administered promethazine.
Someone that’s been taking it several times per day for a full year will likely retain the drug for a longer duration upon discontinuation than a user that’s been taking it for just a few days. In part this is due to the fact that long-term users are more likely to be taking higher doses of promethazine as a result of developing tolerance over a prolonged term of administration. Additionally, it is possible that the drug may accumulate in bodily tissues of long-term users to a greater level than short-term users.
Co-administered drugs (CYP2D6)
If you’ve took promethazine along with any other drugs (or supplements), it is necessary to acknowledge that the co-administered agents may have altered promethazine’s metabolism and half-life. Since promethazine is metabolized mostly via CYP2D6 isoenzymes, any agent that affects CYP2D6 isoenzyme function will either expedite or prolong metabolism of promethazine. Drugs that are classified as “CYP2D6 inhibitors” are known to interfere with CYP2D6 isoenzyme function.
This interference leads to poorer promethazine metabolism and a longer elimination half-life. Examples of such CYP2D6 inhibitors include: Bupropion, Cinacalcet, Fluoxetine, Paroxetine, Quinidine, and Ritonavir. If you were taking any of the aforementioned agents along with promethazine, realize that promethazine may stay in your system for longer than expected.
Drugs classified as “CYP2D6 inducers” are known to enhance CYP2D6 isoenzyme function. This enhancement increases the efficiency of promethazine metabolism and may expedite its elimination. Examples of CYP2D6 inducers include: Dexamethasone, Glutethimide, and Rifampicin. Keep in mind that potency of CYP2D6 inhibition/induction is reflective upon the specific drug and the dosage at which it was ingested.
Promethazine: Absorption, Metabolism, Excretion (Details)
When administered parenterally (via intravenous or intramuscular injection), promethazine is absorbed by the gastrointestinal tract and is 75% to 93% bound to plasma proteins. Sedation typically occurs within 5 minutes of intravenous administration and within 20 minutes of intramuscular administration. When administered orally or rectally, promethazine is also absorbed through the gastrointestinal tract and is subject to extensive hepatic metabolism.
First-pass hepatic metabolism is facilitated by CYP450 (cytochrome P450) enzymes, primarily CYP2D6 isoenzymes. CYP2D6 converts promethazine to its predominant metabolite N-desmethylpromethazine and various promethazine sulfoxides. Promethazine is distributed widely throughout bodily tissues and organs. The duration of promethazine’s therapeutic effects reportedly ranges between 2 and 8 hours post-ingestion and is largely contingent upon route of administration.
Peak plasma concentrations of promethazine are known to be greater among those ingesting promethazine orally (in the form of syrup) compared to those administering it rectally (via a suppository). Among oral promethazine users, peak plasma levels reached 19.3 ng/ml, whereas among rectal users, peak plasma levels reached 9.04 ng/ml. Time to reach peak concentration is also shorter among syrup users (~4.4 hours) compared to suppository users (~7.65 hours).
The elimination half-life of promethazine following parenteral administration is 9 to 16 hours, whereas following oral or rectal administration, half-life is 16 to 19 hours. The range of half-lives suggests that promethazine may be eliminated from plasma circulation in as early as 2.1 days and as late as 4.35 days – depending upon route of administration. A majority of promethazine is processed by kidneys and excreted via urine. Less than 1% is excreted as unchanged promethazine, while the majority appears as N-desmethylpromethazine and promethazine sufloxide metabolites.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/promethazine
Types of Promethazine Drug Tests
Many people taking promethazine are worried that it may cause them to fail a mandatory drug test such as the SAMHSA-5. In most cases, promethazine isn’t anything to worry about on a drug screening simply because it’s not considered a “controlled-substance.” Really the only time you may need to worry about promethazine usage is if it is concomitantly administered with codeine.
Urine tests: If you are tested for promethazine, the most common assessment is that of a urinalysis. This involves collecting a fresh urine sample and analyzing it for concentrations of promethazine metabolites. Solid phase extraction via chromatographic methods can detect promethazine and its primary metabolites within the urine such as: promethazine sulfoxide, monodesmethyl promethazine sulfoxide, and monodesmethyl promethazine.
The duration these metabolites will remain detectable in a user’s urine will depend upon the dosage he/she took, frequency of administration, and route of administration. Orally ingested promethazine should remain detectable for a longer duration within the urine than intravenously administered promethazine. Urinalyses can detect promethazine metabolites above 2.5 ng/ml and promethazine above 3.75 ng/ml.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/11710587
Blood tests: Another way to determine how much promethazine was ingested is to collect a blood sample. Blood testing is more invasive than urine testing, and for this reason, is less preferred. Additionally, promethazine doesn’t remain in the plasma for as long of a duration as promethazine metabolites within the urine.
Unless an individual is participating in a scientific study and/or hospitalized and unable to take a urine test, a blood test is unlikely to be administered. That said, a blood sample will be highly accurate in determining the amount of promethazine present within plasma.
Hair tests: Though not common, a hair test can be taken to determine whether someone has ingested promethazine. Hair tests are advantageous over blood tests and urine tests in that they provide a long window of detection. In some cases, the parent compound (promethazine) and its metabolites may linger in hair follicles for over a month after discontinuation.
The quantity of promethazine in a user’s hair will be dependent upon the dosage ingested as well as whether they were an acute or chronic user. Hair follicles are unlikely to be accurate in determining whether promethazine was ingested recently, but can be accurate in assessing usage over a long-term. Most promethazine is likely to appear in the proximal segments of follicles, but may appear in medial and distal segments if chronically used.
Saliva tests: An oral fluid sample may accurately detect whether an individual ingested promethazine. Saliva testing isn’t yet very common for promethazine because it isn’t considered a drug of abuse – it is merely an antihistamine. However, devices are being engineered to accurately assess an intoxicated individual’s saliva sample to determine whether they had ingested any illicit or prescription drugs.
Oral fluid samples are easy to collect and relatively low cost to analyze. The window of detection is likely reduced compared to urine and/or hair samples. That said, as oral fluid drug detection devices improve in accuracy, salivary assessment for promethazine may be more frequently utilized by law enforcement agents.
Tips to clear Promethazine from your system
If you’ve used promethazine and are concerned that it may still be in your system after discontinuation, there may be some steps you can take to expedite its elimination. Prior to implementing any of the suggestions below, be sure to verify safety and alleged efficacy with a medical professional. Realize that regardless of whether you take additional steps to quickly eliminate promethazine from your system, your body will eventually detoxify itself from the drug.
- Activated charcoal: A supplement that is invaluable in regards to expediting detoxification is that of activated charcoal. Should you have any unmetabolized promethazine and/or metabolites circulating throughout your system, administration of activated charcoal can ensure their elimination. Activated charcoal works by binding to exogenous drugs via adsorption, thereby efficiently ushering them out of your system.
- Calcium-D-Glucarate: Promethazine metabolites are eliminated via renal detoxification pathways and excreted through urine. If you experience renal impairment and/or have accumulated a large quantity of toxins in renal pathways, detoxification speed may be suboptimal. To ensure efficient urinary elimination of promethazine, you may want to take calcium-d-glucarate. Calcium-d-glucarate acts as a beta-glucuronidase inhibitor to clear molecules from detox pathways in your kidneys which may speed up metabolite clearance.
- Hydration: Staying hydrated is important for many physiologic processes within your body, including hepatic and renal function. Elimination of promethazine metabolites may be quicker among those who are optimally hydrated due to the fact that hydration increases urinary flow rate. In turn, urinary flow rate may expedite the renal excretion of exogenous substances such as promethazine metabolites.
How long has Promethazine stayed in your system after stopping?
If you’ve stopped taking promethazine, share a comment regarding how long you believe it stayed in your system after your final dose. Do you think that promethazine metabolites remained in systemic circulation for longer-than-average? Or do you think that you were able to metabolize the drug efficiently and eliminate it from your body in a short amount of time.
Understand that route of administration will affect how long promethazine stays in your system, with parenterally administered promethazine getting eliminated faster than oral or suppository administration. Promethazine is unlikely to stay in your system for longer than 5 days after your final dose, and extremely unlikely to remain in systemic circulation after a full week of cessation. Only if you are hepatically/renally impaired, are a CYP2D6 poor metabolizer, took a ridiculously high dose, and/or co-administered a CYP2D6 inhibitor – would you be likely to retain promethazine for a significantly longer duration.