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W2997156856 abstract "Although the Food and Drug Administration (FDA) has approved several medications for the treatment of opioid use disorder (OUD), patients with OUD who are not in established care will often attempt to self-treat their withdrawal symptoms with opioid agonists or other pharmacologic therapies. These treatments, along with the medications commonly prescribed for opioid withdrawal, have unique adverse effects that present a risk both to the patient and to others who may experience an inadvertent exposure. This review will discuss the toxicities of OUD therapies, including both prescribed and patient-initiated agents. Because of societal stigma, patients with OUD often present for care without disclosing their underlying disorder or associated withdrawal remedies. For this reason, our review will take a case-based approach. We will present 5 clinical scenarios, and for each case, we will describe potential causal therapies, with special attention to the epidemiology, pharmacology, and unique toxicity of each agent. The classic opioid toxidrome of coma, miosis, and bradypnea due to full agonist therapy at the µ-opioid receptor will not be discussed in this review. Case 1: syncope A 50-year-old woman with OUD presents with syncope. In the emergency department (ED), she is initially hemodynamically stable, but becomes transiently unresponsive while resting on the hospital gurney. On the cardiac monitor, this episode corresponds with a run of nonsustained polymorphic ventricular tachycardia, or torsades de pointes (TdP). After 30 seconds, she regains consciousness and the cardiac monitor shows sinus rhythm. Syncope in patients with OUD carries with it a broad differential of both benign and life-threatening processes. One should consider the typical causes of syncope, including but not limited to congenital arrhythmogenic disorders, myocardial infarction, valvular disease, aortic catastrophe, pulmonary embolism, intracranial hemorrhage, ectopic pregnancy, seizure, orthostatic hypotension, and vasovagal syncope. A toxicologic differential for syncope also includes poisoning from agents including beta blockers, calcium channel blockers, cardiac glycosides, clonidine, lofexidine, opioids, toxic alcohols, sodium channel antagonists, and potassium channel antagonists. In addition, the patient with active intravenous (IV) drug use is at risk for bacterial endocarditis, septic shock, and cardiac valvular dysfunction, all of which can present with syncope. After regaining consciousness, the patient expresses to her clinician that she has been attempting to “get clean” from her OUD; however, insurance and transportation issues have kept her from enrolling in a treatment program that offers buprenorphine or methadone. While methadone can prolong the QT interval and induce TdP, our patient is not in established treatment and methadone is not the causative agent in her case. Instead, she states that she has been taking large doses of the over-the-counter antidiarrheal loperamide, which she read online could help reduce the side effects of opioid withdrawal. Loperamide, a peripherally acting µ-opioid receptor agonist, is intended to reduce intestinal peristaltic activity without the typical central nervous system (CNS) effects of analgesia, euphoria, sedation, or respiratory depression. Initially classified as a Schedule V drug in 1977, loperamide has been available over the counter since 1982.1 Since the early 2000s, loperamide, taken at large doses, has received attention as an affordable alternative for those looking to treat chronic pain, treat opiate withdrawal symptoms, or get high.2–6 The National Poison Data System (NPDS) has shown a 91% increase in intentional misuse of loperamide in the United States from 2010 to 2015.7 Available both online and in stores across the United States, loperamide is widely available to the public. Loperamide is a synthetic phenylpiperidine opioid that primarily agonizes µ-opioid receptors in the alimental mesenteric plexus, thereby reducing intestinal peristalsis and transit time. Unlike other opioids, it is also believed to reduce diarrhea via increased intestinal fluid absorption through calmodulin antagonism.8–11 At therapeutic doses, loperamide lacks central opioid effects; loperamide has minimal bioavailability (<2%) due to poor enteric uptake and active first-pass metabolism by hepatic CYP3A48,12, and it is a substrate for the P-glycoprotein transmembrane efflux pump (Pgp), which actively prevents it from crossing the blood-brain barrier (BBB) despite its lipophilicity.10,13,14 At therapeutic dosing, loperamide reaches peak plasma concentrations at 2.5 to 5 hours, has a plasma half-life of 11 hours, and has an onset of action of 1 hour with maximum effect at 16 to 24 hours.8 However, toxicokinetics are varied: a case report of loperamide overdose demonstrated serum concentrations >6 times higher than therapeutic peak concentrations even 70 hours after ingestion.15 Although therapeutic loperamide dosing of less than 16 mg daily results in effective antidiarrheal activity, the supratherapeutic ingestion in the range of 32 mg up to 100s of mg daily can overcome the aforementioned low bioavailability and poor BBB penetration to cause central µ-opioid agonism. Some users further accentuate CNS effects through concomitant ingestion of CYP3A4 inhibitors to reduce hepatic loperamide metabolism, or Pgp inhibitors to impede active efflux at the BBB.3–5,10,14,16 Loperamide overdose can cause euphoria, analgesia, somnolence, and respiratory depression. In a patient suffering from opiate withdrawal, the central effects of loperamide overdose can drastically subdue the symptoms of agitation, insomnia, abdominal pain, vomiting, diarrhea, and hyperhidrosis.2–6 However, large doses of loperamide can cause life-threatening cardiotoxicity, predominantly from inhibition of the inward rectifying potassium channel (Ikr) responsible for Phase 3 myocardial repolarization.17–19 Ikr inhibition prolongs the QT interval, increases early afterdepolarizations (“R-on-T” phenomenon), and results in TdP. There is also evidence that high doses of loperamide inhibit myocardial Nav1.5 sodium channels, thereby prolonging Phase 1 myocardial depolarization, widening the QRS interval, and inducing monomorphic ventricular tachycardia (mVT).18 These QT and QRS prolongation effects have been seen clinically, with numerous published case reports documenting wide-complex dysrhythmias for up to 5 days and interval prolongation for up to 10 days after loperamide overdose.9,20,21 Management of loperamide cardiotoxicity follows standard resuscitation protocols for cardiotoxicity and wide complex tachydysrhythmias. After identification of loperamide-induced QT or QRS prolongation, the local Poison Control Center (PCC) should be consulted and the patient must be placed on continuous cardiac monitoring. If an acute ingestion occurred fewer than four hours before presentation, activated charcoal (AC) should be administered (assuming that the patient has an intact sensorium). There is a longer window for AC administration in loperamide overdose compared with other overdoses because of the delayed intestinal transit time caused by loperamide. Those with concomitant respiratory depression would benefit from naloxone. Any sustained or hemodynamically significant mVT or TdP should be treated immediately with defibrillation, magnesium (TdP), and Advanced Cardiac Life Support (ACLS) protocols. In otherwise stable patients, an attempt should be made to narrow the QRS interval with sodium bicarbonate (50 meq ampule IV pushes as needed, followed by an infusion of 150 meq in a liter of D5W infused at 150 mL/h). For a persistently wide QRS or recurrent nonsustained mVT, an infusion of 3% sodium chloride can also be considered. To narrow the QT interval, we recommend maintaining magnesium and potassium within their normal ranges by repletion as necessary. For patients whose rhythm repeatedly devolves to TdP, induced tachycardia with isoproterenol or overdrive cardiac pacing has been effective. Rescue therapies with minimal supporting data, but with reasonable mechanisms of action, include lipid emulsion therapy and venous-arterial extracorporeal membrane oxygenation (VA ECMO) (lipid emulsion therapy is approved in the United States for parenteral nutrition; use in loperamide toxicity is off-label). Given high protein binding, hemodialysis is unlikely to effectively clear loperamide.9–11,16,20,21 All patients with an acute overdose or with prolonged QT or QRS intervals should be admitted either to a telemetry floor or the intensive care unit, depending on the hospital’s comfort with identifying and managing acute malignant dysrhythmias. Our patient was found to have a QTc of 610 ms. She was hypomagnesemic, and was administered magnesium sulfate 4 g IV. She was admitted to the intensive care unit, where she fortunately had no further dysrhythmias and her QTc returned to normal over 3 days. On discharge, she was initiated on buprenorphine for her OUD. It should be noted that methadone and lofexidine, both medications used for treating OUD, would not be ideal therapies for this patient as they are both known to prolong the QT interval.22,23 As patients are attempting to treat their OUD, loperamide has become a readily accessible and affordable alternative to traditional MAT. In addition to the expected central opioid toxidrome, loperamide misuse can result in potentially lethal wide-complex tachydysrhythmias that may persist for several days. In addition to loperamide, large doses of methadone in therapeutic dosing and overdose can cause QT interval prolongation and TdP. Case 2: somnolence, miosis, and normal respiration A 38-year-old woman is brought to the ED by ambulance for altered mental status. She has had 2 previous ED visits for opioid overdose. In the field, she was hypertensive; however, on arrival to the ED, her vital signs are notable for hypotension, bradycardia, mild hypothermia, and normal respirations. Her examination demonstrates somnolence, confusion, and reactive miosis. An electrocardiogram shows sinus bradycardia with a first-degree AV delay and a point-of-care glucose was normal. The patient is administered IV naloxone; however, it is ineffective. This patient’s clinical presentation generates a broad differential. Patients with hypotension, hypothermia, and encephalopathy are in a shock-like state; thus, emergent resuscitative measures and work-up of distributive, cardiogenic, obstructive, and hypovolemic causes are indicated. Given that this patient was initially hypertensive, one should also consider the triad of altered mental status, bradycardia, and hypertension, which may suggest intracranial hemorrhage or other causes of increased intracranial pressure.24 From a toxicologic perspective, opioid overdose is reasonable to consider given the somnolence and miosis; however, a feature of the opioid toxidrome is bradypnea, which this patient did not exhibit.25 Other toxicities that may cause bradycardia, hypotension, and hypothermia include beta blockers, calcium channel blockers, and α2 agonists. Coupled with the patient’s history of OUD, miosis, euglycemia, and normal respirations, this case is highly suggestive of an α2 agonist overdose.26,27 Notably, opioids and α2 agonists such as clonidine and lofexidine can produce overlapping toxidromes. Distinguishing them can be made more difficult by the fact that the patient population most likely to misuse opioids is also at risk of α2 agonist overdose as these medications are used both to treat opioid-withdrawal symptoms and amplify opioid-induced euphoria.28–31 Fortunately, our patient’s vital signs began to normalize with atropine, crystalloid fluid, and a low-dose norepinephrine infusion. The patient’s boyfriend arrived and stated that she was prescribed clonidine to help her stop using heroin; however, it had been only modestly effective, and she had been taking extremely large doses. Clonidine and lofexidine, both imidazolines, are central α2 agonists commonly used to treat opioid withdrawal. Clonidine, an antihypertensive and attention deficit hyperactivity disorder medication, is often prescribed off-label for opioid withdrawal symptoms, and lofexidine became the first FDA-approved nonopioid medication for opioid withdrawal in 2018.32–34 Multiple mechanisms of action have been hypothesized to explain the role of α2 agonists in treating opioid withdrawal. First, it is believed that opioids suppress adrenergic signaling in the pontine locus ceruleus, from which the resultant increase in adrenergic activity during opioid withdrawal contributes to the associated symptoms of autonomic hyperactivity including anxiety, chills, elevated heart rate, blood pressure, and piloerection.28,35 As such, α2 agonism in the locus ceruleus decreases the offending hyperadrenergic signaling; furthermore, similar signaling in the medulla oblongata decreases heart rate and blood pressure.36,37 Second, it is possible that imidazoline-1 receptor agonism may also play a role in sympathetic downregulation, and that peripheral catecholaminergic suppression is also occurring.38 Third, clonidine may reduce withdrawal symptoms by causing endogenous opioid release.39–41 Irrespective of the mechanism, clonidine and lofexidine have been found to be valuable tools to control the symptoms of opioid withdrawal. Clonidine has an oral bioavailability of 70% to 80%, with peak plasma levels at 1 to 3 hours after administration of therapeutic dosing. Protein binding is 20% to 40% and the elimination half-life is 12 to 16 hours. Clearance depends equally on hepatic metabolism and renal excretion.32,42 Lofexidine has a bioavailability of 72%, with peak plasma concentration at 3 to 5 hours after ingestion. It is 55% protein bound, has an elimination half-life of 12 hours, and is almost entirely renally excreted.23 Clonidine and opioid toxidromes are substantially overlapping, and include CNS depression, bradycardia, miosis, hypotension, transient hypertension, and hypothermia.43 A significant distinguishing characteristic is the lack of respiratory depression seen with adult clonidine overdose. Bradycardia, CNS depression, and hypotension appear to be the most common presenting features of clonidine overdose; however, bradycardia and hypotension may be less common in pediatric populations.26,44 Miosis may be seen in fewer than a quarter of cases.45 Although not classically a component of α2 agonist toxicity, respiratory depression occurs in 5% of adult overdoses and 15% of pediatric overdoses; this may be due in part to α2 agonist-induced release of endogenous opioids.26,44,45 Transient hypertension can be seen early after ingestion, and is likely mediated by peripheral α1 receptor stimulation, which is eventually overwhelmed by the central agonist effects.43 Minimal data exist on lofexidine overdose; however, the clinical presentation is considered to be similar. Lofexidine is less likely to cause hypotension, and can cause dizziness and dry mouth.29 Lofexidine has also been reported to prolong the QT interval and increase the risk of TdP; thus, it should not be co-administered with methadone or other QT-prolonging agents without strict monitoring.23 As seen in our case, assessment and urgent management of the airway, respiration, and circulation must take priority in any clonidine overdose. Although most patients will protect their airway, in previous studies 5% of adults and 12.5% of children required intubation.44,46 Those with symptomatic bradycardia should be treated with ACLS protocols, including atropine. Increasing the heart rate will also improve the blood pressure in many cases.44 Hypotension usually responds to crystalloid fluids, and vasopressors are needed infrequently; in one case, the administration of epinephrine as a vasopressor paradoxically worsened hypotension.43,44,47 Hypertension should be treated with caution as the duration is typically short, and there is a potential risk of causing unopposed α1 stimulation with beta blockade and precipitating profound hypotension once the initial transient hypertension resolves.48,49 Treatment with AC can be considered in patients presenting with a known α2 agonist overdose <1 hour before presentation who are protecting their airway. That said, many α2 agonist overdoses may appear clinically similar to opioid overdoses, thus making it difficult to rapidly determine the appropriateness of AC as an intervention.47,48 Naloxone use has been described to reverse the depressed mental status, hypotension, and bradycardia of α2 agonist toxicity. Large doses of naloxone are typically required: a 10 mg IV push of naloxone appears to be efficacious and safe in pediatric patients, and decreases the risk of intubation.50,51 However, it is somewhat controversial whether it is the effect of naloxone itself or time to administer such large doses that truly results in the improved mental status. Noxious stimulation alone is sometimes adequate for improving respiratory status sufficiently to avoid intubation in the sedated patient.49 The α2 antagonist yohimbine and the nonspecific α antagonist tolazoline have been used as reversal agents for clonidine. However, clinicians are unlikely to be familiar with their usage and they have inconsistent and only anecdotal reports of success. Furthermore, they can induce hypertension, tachycardia, arrhythmias, and anxiety, and are thus not considered first-line therapy.52 Clonidine and its newly available analog lofexidine are frequently used to treat the symptoms of opioid withdrawal. In overdose, patients present with decreased responsiveness, cardiovascular suppression, and occasionally miosis. Treatment is largely supportive and these ingestions are well tolerated. Rarely, respiratory depression can occur with clonidine and lofexidine, and QT prolongation may be seen with lofexidine overdoses. Case 3: lethargy, miosis, and respiratory depression in a child A 2-year-old boy who lives with his mother presents to the ED after being found minimally responsive in the living room of their home. His mother noted that he appeared pale, limp, with small pupils, and was breathing very slowly. She immediately called for an ambulance, and on their arrival, paramedics administered 0.1 mg/kg of intranasal naloxone, with moderate improvement. On arrival to the ED, the patient was mildly tachycardic and bradypneic, and his blood pressure and temperature were normal. Children between 1 and 3 years old have high rates of toxin ingestion, often termed “unintentional” or “exploratory” ingestions. This high incidence is due to their curious nature, development of a pincer grasp, and tendency to explore the world around them with their mouths. One and 2-year-olds collectively made up 28.5% of all human exposures reported to US poison centers in 2017.53 There are several factors that make children particularly vulnerable to the effects of OUD treatment medications. First, the weight-based dose of any ingestion will be much higher than for the same ingestion in an adult. Second, infants and children have less Pgp, the aforementioned efflux transporter, along the BBB as compared with adults.54 Pgp actively prevents xenobiotics from crossing the BBB, protecting the brain from potential toxins. Finally, physiologic differences in minute ventilation, metabolism, and distribution of opioid receptors may make children more prone to respiratory depression and resultant adverse events after opioid ingestion. The differential diagnosis is again broad, and includes head trauma, infection, and toxic exposure. The toxicologic differential includes many xenobiotics, including oral hypoglycemics, sedative hypnotics, central α2 agonists, ethanol, cannabis, opioids, and medications used for the treatment of OUD; many of these can be confused with an opioid toxidrome. Pediatric ingestion of oral hypoglycemics, most notably sulfonylureas, can cause delayed and profound hypoglycemia by stimulating endogenous insulin release from the pancreatic beta cells in the absence of post-prandial increases in glucose.55 Hypoglycemia in children and infants can present with depressed mental status, poor tone, and seizures. Treatment includes glucose supplementation and octreotide, a somatostatin analog that decreases insulin secretion from the pancreas. Sedative hypnotics including benzodiazepines, barbiturates, muscle relaxants, and ethanol can cause somnolence and respiratory depression. Flumazenil, a competitive inhibitor of benzodiazepines on GABA-A receptors, can be considered for the treatment of benzodiazepine-intoxicated children. Central α2 agonists such as clonidine and lofexidine are discussed elsewhere in this article. Small doses, as low as 0.3 mg or 0.015 mg/kg, may cause clinically significant respiratory depression in children.56 In fact, clonidine was the leading cause of intubation in poisoned children aged 0 to 5 years in the United States from 2002 to 2013.57 Methadone, buprenorphine, and other opioids can produce a similar toxidrome. Children co-living in households with adults who are prescribed these medications are at increased risk of unintentional exposures. After arriving in the ED, our patient received an additional 0.1 mg/kg of IV naloxone, with further improvement in his mentation and respiratory rate. He was admitted for 24 hours of observation. It was subsequently discovered that the patient’s father is currently receiving treatment for OUD with buprenorphine. Opioid replacement therapy, classically with methadone or buprenorphine, is considered part of the ideal treatment of OUD.58 Buprenorphine is a partial agonist of the µ-opioid receptor with high binding affinity (>1000 times that of morphine). Although available in the United Kingdom in 1978 and the United States by 1981, use in treatment of OUD was only approved by the FDA in 2002. It has been shown to be effective for treating withdrawal in the ED and in reducing illicit opioid use and injection use.59,60 Buprenorphine is being prescribed at increasing rates to help combat the opioid epidemic in the United States.61 Buprenorphine is available in tablet, sublingual film, and transdermal patch formulations. When used orally or sublingually, it is often formulated with naloxone in a 4:1 ratio. Although buprenorphine’s oral bioavailability is about 30%, naloxone’s oral bioavailability is negligible. As such, the naloxone deters illicit IV use, but has little effect when taken as directed. When administered buccally/sublingually, buprenorphine is absorbed within 5 minutes. Buprenorphine is 96% protein bound and is hepatically metabolized through CYP3A4 to norbuprenorphine, which can also bind to opioid receptors. Norburenoprhine, which is a substrate for Pgp, may be responsible for some of the respiratory depression associated with buprenorphine ingestions through reduction in efflux at the BBB.62 Buprenorphine and norbuprenoprhine are then eliminated in the urine (30%) and feces (69%), with the mean elimination half-life ranging from 24 to 42 hours.63 Buprenorphine is a partial agonist at the µ-opioid receptor; above a certain concentration, there is little additional effect. This “ceiling effect” is seen as protective against respiratory depression. Despite only a partial-agonist effect, buprenorphine has very high affinity for the mu-opioid receptor, displacing other opioid agonists from the µ-receptor. If buprenorphine is administered to a patient still under the effect of full opioid agonists, it can precipitate acute withdrawal. Nevertheless, it is able to prevent cravings and exerts analgesic effects, but has a low risk of respiratory depression. Unfortunately, the protective ceiling effect on respiratory depression is not observed in children. Even small doses of buprenorphine can cause clinically significant respiratory depression requiring naloxone or mechanical ventilatory support. In the United States, in children younger than 5 years old, the mortality rate from opioids increased linearly from 0.08 per 100,000 children in 1999 to 0.26 in 2016.64 Rates of pediatric exposures to OUD medications are less well defined, although exposures to buprenorphine are increasing and will likely continue to increase as medication-assisted treatment becomes more available.65,66 Implementation of strategies to limit unintentional pediatric exposures, such as unit-dose and child-resistant packaging, has decreased the rate of pediatric exposures for buprenorphine prescription in the United States.67 Treatment for buprenorphine toxicity includes supportive care, with particular attention to maintaining adequate respiratory status. Patients with little or no opioid tolerance, especially children, are at particular risk for respiratory depression. Although most patients exhibit respiratory depression within 4 hours, some children do not exhibit initial signs and symptoms until 8 hours after exposure.68 Therefore, we recommend overnight observation for any pediatric patient exposed to buprenorphine. Naloxone can be used to reverse respiratory depression. Children who are not opioid tolerant should receive 0.1 mg/kg IV or intranasal naloxone with the intent to completely reverse the effects of buprenorphine. Doses can be repeated as needed. Children exposed to buprenorphine may warrant evaluation for home safety. Although adults are at a much lower risk for respiratory depression due to the ceiling effect of buprenorphine, if an adult patient presents with clinically significant respiratory depression, the patient should also receive 2 to 4 mg of naloxone for reversal and be observed for recurrence of symptoms. Even though respiratory depression from buprenorphine is rare in adults, buprenorphine ingestion must be considered in a child who presents with an opioid toxidrome with respiratory depression living in a household with someone being treated for OUD. As a partial µ-opioid agonist, opioid-tolerant individuals are unlikely to have clinically significant adverse effects; however, children or opioid-naive adults can be at substantial risk for delayed respiratory depression. Children with buprenorphine ingestion should be observed overnight, and respiratory depression should be treated with naloxone. Case 4: seizure and hypoglycemia A 27-year-old woman with a history of OUD not in any established treatment program presents after a witnessed seizure with obtundation, hyperreflexia, and a fingerstick blood glucose level of 20. The patient was treated with 25 g of dextrose 50% solution, with improvement of her blood glucose. Her mental status gradually improved, but she remained hyperreflexive in her lower extremities and had sustained inducible clonus of her bilateral ankles. The differential diagnosis of hypoglycemia is broad. Hypoglycemia on its own can cause seizures and altered mental status. In the presence of hyperreflexia, agents that cause serotonin excess must also be considered. Agents that are pro-serotonergic include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, dextromethorphan, linezolid, meperidine, and tramadol. Antidepressants with a high affinity for the serotonin reuptake transporter, such as sertraline and fluoxetine, are associated with hypoglycemia.69 Hypoglycemia in the setting of a venlafaxine overdose has also been reported.70 However, as this patient was not reported to be taking any medications and has a history of OUD, tramadol use was the most likely cause of this patient’s presentation as it is associated with seizures, hypoglycemia, and sertonorgic excess. Tramadol was first synthesized by the pharmaceutical company Chemie Grunenthal GmbH in Stolberg, Germany, in 1946.71 The compound, however, was not introduced to the market as a pain-relieving medication until 1977.72,73 It was not approved in the United States until 1995 for the treatment of moderate to severe pain under the trade name of Ultram.74 Initially, tramadol was the only nonscheduled opioid available for use in the United States.75 However, shortly after its approval, there were increased reports of diversion and abuse, consistent with trends seen in other countries. Tramadol is currently a schedule IV medication in the United States.74 It is available in numerous formulations and used worldwide.73,75 Tramadol is a centrally acting analgesic medication. As a 1:1 racemic mixture, it works as an agonist at the µ-opioid receptor and by inhibiting the re-uptake of monoamines such as norepinephrine and serotonin.76,77 Importantly, tramadol is a pro-drug that is metabolized by the cytochrome P450 2D6 system into the major active metabolite o-desmethyltramadol (M1).76 The analgesic activity of tramadol is likely mediated by both opioid and nonopioid activity.77 The (+)-enantiomer of tramadol inhibits serotonin reuptake, the (−)-enantiomer of tramadol inhibits norepinephrine reuptake, and the M1 metabolite has weak agonist activity at the µ-opioid receptor.73 Compared with morphine, the affinity of tramadol at the µ-opioid receptor is 6000-fold less.77 However, the active M1 metabolite has a higher affinity to the µ-opioid receptor by 300-fold compared with tramadol.77 Because tramadol is a pro-drug, its analgesic activity is in part dependent on CYP2D6 activity.78 CYP2D6 is an important polymorphic enzyme responsible for half of CYP450 activity, while generally being considered the only drug-metabolizing enzyme system that is noninducible.79 As such, the activity of the medication is highly dependent upon the CYP2D6 phenotype. Depending on the combination of CYP2D6 alleles, the amount of metabolite produced by a prodrug can vary widely. In patients with poor metabolism, subtherapeutic concentrations of the metabolite are produced. For tramadol, CYP2D6 ultra-rapid metaboli" @default.
W2997156856 created "2020-01-10" @default.
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W2997156856 date "2020-01-01" @default.
W2997156856 modified "2023-09-25" @default.
W2997156856 title "Toxicity of agents used for opioid withdrawal: a case-based approach" @default.
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W2997156856 doi "https://doi.org/10.1097/aia.0000000000000265" @default.
W2997156856 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31904630" @default.
W2997156856 hasPublicationYear "2020" @default.
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