Sufentanil Citrat-Ketamine Hcl (sufentanil citrate/ketamine HCl)
Opioid Analgesics- IR (with all antitussive opiates) Nasal Aerosol, Spray With Pump (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Ketamine hydrochloride, an N-methyl-d-aspartate (NMDA) receptor antagonist, is a nonbarbiturate general anesthetic that also has analgesic and antidepressant properties.
Sufentanil citrate is a synthetic phenylpiperidine-derivative opiate agonist.
Ketamine is a nonbarbiturate general anesthetic that also has analgesic, amnestic, anti-inflammatory, and antidepressant properties. The drug is an arylcycloalkylamine derived from phencyclidine (PCP). Ketamine is commercially available in the US as a racemic mixture containing equal amounts of the R- and S-enantiomers.
S-Ketamine, which is commercially available as esketamine in the US and some other countries, has a higher binding affinity for N-methyl-d-aspartate (NMDA) receptors and has approximately 3-4 times greater anesthetic potency than R-ketamine. S-Ketamine also appears to be associated with more frequent psychotomimetic adverse effects compared with R-ketamine.
The pharmacologic effects of ketamine are dose dependent and mediated principally by its actions on the N-methyl-d-aspartate (NMDA) receptor, with contributory effects from other receptor interactions. The anesthetic, amnestic, analgesic, and psychotomimetic effects of ketamine have been attributed to the drug's noncompetitive antagonism of the NMDA receptor. The NMDA receptor is a ligand-gated channel complex that plays an important role in excitatory glutamate-mediated neurotransmission, which can affect cognition, chronic pain, opiate tolerance, and mood regulation.
The receptor is blocked at resting state by extracellular magnesium. Upon neuronal depolarization, magnesium is released, resulting in ligand-induced channel opening and calcium influx. Ketamine binds to the phencyclidine (PCP) site of the NMDA receptor channel, decreasing the frequency of channel opening and duration of time in the open active state, thereby inhibiting receptor activation and excitatory glutamatergic neurotransmission.
The NMDA receptor is closely involved in the development of opiate tolerance, opiate-induced hyperalgesia, and central sensitization (a condition closely related to the development of chronic pain). Activation of the NMDA receptor enhances neuronal excitability that can lead to hyperalgesia and allodynia. In the development of opiate tolerance and opiate-induced hyperalgesia, repeated activation of opiate receptors causes phosphorylation and opening of the NMDA receptor channel, leading to downregulation of opiate receptors and a reduction in opiate responsiveness.
In chronic pain states, prolonged nociceptive stimulation causes activation and upregulation of NMDA receptors at dorsal horn synapses, resulting in enhanced and amplified trafficking of pain signals to the brain (central sensitization). Therefore, antagonism of NMDA receptors by ketamine decreases amplification of the response to repeated opiate receptor stimulation and can also prevent or reduce central sensitization.
In addition to its effects on the NMDA receptor, ketamine also acts on a wide range of other targets, including opiate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid A (GABAA), cholinergic, nicotinic, and muscarinic receptors; L-type voltage-dependent calcium channels, hyperpolarization-activated cyclic nucleotide (HCN) channels, voltage-gated sodium channels, and large-conductance potassium (BK) channels; and the monoaminergic system.
Ketamine produces dissociative anesthesia as a result of a functional and electrophysiologic dissociation between the thalamocortical and limbic systems. The drug appears to selectively depress sensory association areas in the cortex, limbic systems, and thalamus without substantially obtunding the more primitive pathways (reticular-activating and limbic systems). At anesthetic doses, ketamine disrupts frontal-to-posterior corticocortical connectivity while maintaining thalamocortical somatosensory pathways.
Thus, sensory input may reach cortical receiving areas but fail to be observed in some of the association areas, effectively dissociating the CNS from outside stimuli. At subanesthetic doses, ketamine has been shown to alter functional connectivity between the subgenual anterior cingulate cortex and a network cluster involving the thalamus, hippocampus, and the retrosplenial cortex, without reported loss of consciousness.
At anesthetic doses, ketamine produces a dissociative, cataleptic state characterized by profound analgesia, sedation, and amnesia. Although there is some variability, ketamine dissociation usually occurs at a dosing threshold of approximately 1-1.5 mg/kg when given IV or 3-4 mg/kg when given IM. Plasma ketamine concentrations associated with dissociative anesthesia have been reported to range from approximately 1.2-3 mcg/mL; concentrations associated with hypnosis and amnesia during surgery range from 0.8-4 mcg/mL and awakening usually occurs at plasma concentrations of 0.5-1.1 mcg/mL.
At doses and plasma concentrations lower than those used for anesthesia, ketamine produces analgesia and sedation. Although there is some variability, doses less than 1 mg/kg generally have been considered subanesthetic. Following IV or IM administration, analgesic effects are associated with plasma ketamine concentrations ranging from 0.07-0.2 mcg/mL.
Analgesic effects following oral administration occur at plasma ketamine concentrations of 0.04 mcg/mL, possibly due to a higher ratio of norketamine.
The precise mechanism(s) of ketamine's antidepressant activity has not been clearly established. Considerable preclinical research suggests that the NMDA class of glutamate receptors plays a role in the pathophysiology of depression as well as in the mechanism of action of antidepressant treatments. In addition, NMDA receptor antagonists, including ketamine, have been shown to be effective in animal models of depression and in models that predict antidepressant activity in many studies.
Preclinical and clinical data suggest that the antidepressant effects of ketamine may be mediated by an increase in glutamate, which leads to a cascade of events that results in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly in the prefrontal cortex. Following IV infusion of 0.5 mg/kg of ketamine over 40 minutes in patients with treatment-resistant major depressive disorder, peak plasma ketamine concentrations of 0.07-0.2 mcg/mL are achieved. These concentrations usually are associated with antidepressant effects but not general anesthetic effects.
Like PCP, ketamine may cause psychotomimetic effects as a result of NMDA-receptor antagonism; such effects can occur following anesthetic or subanesthetic doses. At higher ketamine doses used for anesthesia, psychotomimetic effects appear to be dose related; however, a dose-related effect has not been clearly established at subanesthetic doses. The analgesic properties of ketamine are closely related to its psychotomimetic effects.
Psychotomimetic effects of ketamine may occur at IV doses in the range of 0.1-1 mg/kg or IM doses in the range of 25-200 mg.
Ketamine has a rapid onset of anesthetic action when given IV or IM. Following IV administration of the usual induction dose of 2 mg/kg, onset of surgical anesthesia occurs within 30 seconds and the duration of anesthetic effect is 5-10 minutes. Following IM administration of doses ranging from 9-13 mg/kg, onset of surgical anesthesia occurs within 3-4 minutes and the duration of anesthetic effect is usually 12-25 minutes.
Following IV administration of a 2.5-mg/kg dose, ketamine has an initial distribution phase (alpha) lasting about 45 minutes and a half-life of 10-15 minutes, which is associated with the duration of anesthetic effect (about 20 minutes). Norketamine, the main active metabolite of ketamine, appears in the blood 2-3 minutes following IV administration of the drug and reaches peak plasma concentration in approximately 30 minutes.
Peak plasma concentrations following oral administration of ketamine occur within 20-120 minutes. Bioavailability of ketamine following IM administration is 93% in adults; lower IM bioavailability has been reported in children. Due to extensive first-pass metabolism, bioavailability following oral or rectal administration is low (16-30 or 11-30%, respectively), with relatively higher concentrations of norketamine.
Bioavailability of ketamine following intranasal administration has been reported to be up to 45-50%, but can vary substantially. In children 4-10 years of age, plasma ketamine concentrations are similar to those observed in adults. Plasma concentrations of norketamine are higher in children than adults following equivalent weight-adjusted doses.
Ketamine is rapidly and widely distributed into highly perfused tissues, including the CNS, with a distribution half-life of 10-15 minutes. Animal studies have shown ketamine to be highly concentrated in body fat, liver, and lung. Because ketamine is lipophilic, it has a large volume of distribution.
Termination of the anesthetic effect of ketamine occurs partly via redistribution from the CNS to peripheral tissues and partly by hepatic biotransformation.
Ketamine crosses the placenta. Following an IM dose of 250 mg (approximately 4.2 mg/kg) in parturient patients, placental transfer rate of ketamine from maternal artery to umbilical vein was 47% at the time of delivery (average of 12 minutes from the time of injection to vaginal delivery). It is not known whether ketamine is distributed into milk.
Ketamine is less than 50% bound to plasma proteins (alpha1-acid glycoprotein or albumin). Ketamine is metabolized extensively in the liver, principally undergoing N-demethylation to the active metabolite norketamine, which has approximately one-third the anesthetic activity of the parent drug. N-demethylation of ketamine to norketamine is mediated principally by cytochrome P-450 (CYP) isoenzyme 2B6 and 3A4 and, to a lesser extent, by other CYP enzymes.
Norketamine is further metabolized to hydroxynorketamines and dehydronorketamine. Other biotransformation pathways of ketamine include hydroxylation of the cyclohexone ring, conjugation with glucuronic acid, and dehydration of the hydroxylated metabolites to form a cyclohexene derivative. About 90% of a parenteral dose of ketamine is excreted in the urine, mostly as conjugates of hydroxylated metabolites.
Less than 5% of a dose is excreted unchanged in feces and urine. Because ketamine is extensively metabolized prior to excretion, the effect of renal function on the pharmacokinetics of ketamine and norketamine is minimal. Plasma concentrations of ketamine have been reported to be 20% higher in individuals with acute renal failure than in those with normal renal function.
Ketamine is not appreciably removed by hemodialysis or hemofiltration (10 or 4%, respectively). The elimination half-life of ketamine is approximately 2-4 hours and is shorter in children (approximately 100 minutes) than in adults. The half-life of norketamine is 12 hours.
Sufentanil citrate is an opioid agonist with high affinity and selectivity for the micro-opiate receptor in the CNS; the drug reportedly is more selective and binds more tightly to this receptor than fentanyl. Partial occupancy of the micro-receptor by naloxone (an opiate antagonist) has been shown to substantially decrease the analgesic effect of sufentanil.
Sufentanil produces dose-related analgesia; at doses up to 8 mcg/kg, the drug has a potent analgesic effect. Higher doses usually produce substantial CNS depression resulting in hypnosis and anesthesia; however, hypnosis may occur at doses of 1.5 mcg/kg. The analgesic potency of sufentanil appears to be 5-12 times that of fentanyl on a weight basis.
Sufentanil doses of 8 mcg/kg or greater result in EEG patterns indicative of a deep level of anesthesia; the drug induces a shift to the left in EEG amplitude and frequency that is consistent with central anesthetic activity.
Following IV administration, sufentanil has a more rapid onset of action than does morphine or fentanyl. The onset of action of sufentanil as determined by time to unconsciousness (i.e., loss of response to voice command) reportedly ranges from 1.2-3 minutes following total mean doses of 4.9-30 mcg/kg. The mean duration of anesthesia is reportedly 40 minutes following initial doses of 0.4 mcg/kg of sufentanil; the mean duration of anesthesia of additional doses of 0.1 mcg/kg of sufentanil is reportedly 41-44 minutes.
Following a single sublingual administration, sufentanil has a bioavailability of approximately 53% relative to a 1-minute IV sufentanil infusion of 30 mcg. Compared to IV administration, sublingual maximum concentration values were 17-fold lower. The sublingual route of administration of sufentanil avoids intestinal and hepatic first-pass effects.
Following a single dose of sufentanil sublingual tablets, maximum concentrations occur at a median time of 1 hour. After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC0-60min) and maximum concentration values were increased by 3.7-fold and 2.3-fold greater compared to single-dose administration, respectively. Steady-state plasma concentrations were achieved after 7 doses.
Distribution of sufentanil injectioninto human body tissues and fluids has not been fully characterized; however, the drug is highly lipophilic and is rapidly and extensively distributed in animals. The drug is approximately 93% bound in plasma in healthy males, mainly to albumin; alpha-, alpha1-, beta-, and gamma-globulins; and alpha1-acid glycoprotein. Plasma concentrations of sufentanil decline rapidly secondary to redistribution and appear to decline in a triphasic manner.
In adults with normal renal and hepatic function, the plasma half-life of sufentanil citrate injectionin the initial (distribution) phase averages 0.72-1.2 minutes, the plasma half-life in the second (redistribution) phase averages 13.7-17 minutes, and the plasma half-life in the terminal (elimination) phase averages 140-158 minutes. The elimination half-life is longer (434 minutes) in neonates but shorter in infants and children (97 minutes), compared with adults (164 minutes). Following a single dose of sufentanil sublingual tablets, the mean terminal half-lfe is 13.4 hours.
The clearance of sufentanil in healthy neonates is approximately one-half that reported in adults and children, and the clearance may be further reduced by up to one-third in neonates with cardiovascular disease.
The major sites of biotransformation of sufentanil are the liver and small intestine via N-dealkylation at the piperidine nitrogen and O-demethylation. The O-demethylated metabolite appears to have about 10% of the analgesic activity of the unchanged drug. Sufentanil and its metabolites are excreted principally in urine and also in feces via biliary elimination; approximately 80% of the administered dose is excreted in urine and feces within 24 hours after administration.
Only 2% of the dose is excreted unchanged in urine and feces.
Ketamine hydrochloride was initially developed as an anesthetic agent; however, the drug can also produce profound analgesia and other pharmacologic effects, and is therefore used for a variety of other indications such as procedural sedation, pain management+, sedation and analgesia in the intensive care setting+, and some psychiatric indications, including treatment-resistant depression and suicidality+.
Generic name: sufentanil citrate/ketamine HCl
Drug class: Opioid Analgesics- IR (with all antitussive opiates)
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Sufentanil Citrat-Ketamine Hcl
Indications
No indications are available for this drug.
Dosing
Dosage of ketamine hydrochloride is expressed in terms of ketamine.
Dosage of sufentanil citrate is expressed in terms of sufentanil. Dosage must be carefully adjusted according to body weight, individual requirements and response, physical status and underlying pathologic condition, premedication or concomitant medication(s), the anesthetic(s) being used, and the nature and duration of the surgery.
Ketamine hydrochloride usually is administered by slow (e.g., over 60 seconds) IV injection, IV infusion, or IM injection. Ketamine also has been used in IV patient-controlled analgesia (PCA), either as the sole analgesic or in combination with opioids to improve pain control and reduce opioid-related adverse effects. Ketamine also has been administered by oral+, intranasal+, rectal+, subcutaneous+, and intraosseous (IO)+ routes. Because of extensive first-pass metabolism, the bioavailability of ketamine following oral or rectal administration is limited (approximately 20-30%). Although ketamine has been administered epidurally+ or intrathecally+, there have been concerns about potential neurotoxicity with these routes, and some experts state it may be prudent to avoid neuraxial administration of the drug.
Some experts state that IV administration of ketamine is preferred to IM administration when access can be obtained readily. IM administration is associated with a higher rate of vomiting and longer recovery times compared with IV administration. In addition, IV access can permit convenient administration of additional doses for longer procedures and allow for rapid treatment of adverse effects (e.g., IV benzodiazepines for emergence reactions). In certain patients (e.g., severely agitated or uncooperative patients, young children), IM administration may be preferred.
Store ketamine hydrochloride injection at controlled room temperature between 20-25degreesC (excursions permitted between 15-30degreesC) and protect from light.
Ketamine has been reported to be compatible with several drugs when administered as additives, simultaneously in the same syringe, or when a Y-type administration set is used; specialized references should be consulted for more specific information.
Sufentanil is administered IV or epidurally, oras sublingual tablets (Dsuvia(R)).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Ketamine principally undergoes N-demethylation to the active metabolite norketamine. N-Demethylation of ketamine to norketamine is mediated principally by cytochrome P-450 (CYP) isoenzyme 2B6 and 3A4 and, to a lesser extent, by other CYP enzymes.
Ketamine, and its active norketamine metabolite, are principally metabolized by CYP3A4 with lesser involvement by CYP2B6 and CYP2C9.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Opioid Analgesics/Opioid Antagonists
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Naltrexone, nalmefene, and samidorphan are opioid antagonists and thus inhibit the effects of opioid analgesics.(1-3)
CLINICAL EFFECTS: Concurrent administration or the administration of naltrexone within 7-10 days of opioids may induce acute abstinence syndrome or exacerbate a pre-existing subclinical abstinence syndrome.(1,4) Patients taking naltrexone may not experience beneficial effects of opioid-containing medications.(4) Samidorphan can precipitate opioid withdrawal in patients who are dependent on opioids. In patients who use opioids, delay initiation of samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids.(3) Concurrent use of nalmefene tablets with opioid agonists may prevent the beneficial effects of the opioid.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of naltrexone states that the administration of naltrexone concurrently with opioids or to patients dependent on opioids is contraindicated.(1,4) Patients previously dependent on short-acting opioids should be opioid-free for a minimum of seven to ten days before beginning naltrexone therapy. Patients previously on buprenorphine or methadone may be vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4) The manufacturer of naltrexone states that the naloxone challenge test, described in the naltrexone prescribing information, can be administered to determine if patients are opioid free.(1) The manufacturer of samidorphan states the concurrent use of samidorphan in patients using opioids or undergoing acute opioid withdrawal is contraindicated. Prior to initiating samidorphan, there should be at least a 7-day opioid free interval from the last use of short-acting opioids, and at least a 14-day opioid free interval from the last use of long-acting opioids.(3) The UK manufacturer of nalmefene tablets (for reduction of alcohol consumption) states the concurrent use of opioid analgesics is contraindicated.(2) Suspend the use of nalmefene tablets for 7 days prior to the anticipated use of opioids (e.g., elective surgery).(2)
DISCUSSION: A double-blind, randomized, placebo-control study evaluated pain relief and side effects of 35 opioid-naive patients undergoing cesarean section. All patients received spinal anesthesia (bupivacaine and morphine) and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone 6 mg. Patients treated with naltrexone experienced shorter duration of pain relief (not statistically significant), however incidence of opioid-induced side effects was reduced. Patients in the naltrexone 6 mg group had lower rates of pruritus, vomiting, and somnolence (all statistically significant) compared to the placebo group.(5) In a double-blind, randomized, placebo-control trial ten recreational opioid users were studied to determine the effects of hydromorphone (4 mg and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after pretreatment with naltrexone (50 mg) or placebo. Results show that lower doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone 16 mg alone caused euphoria and miosis which were blocked by naltrexone. Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared to hydromorphone. Naltrexone partially diminished the euphoria caused by tramadol, while it enhanced some of the unpleasant monoaminergic effects (flushing, malaise, vomiting).(6) A case report describes a 28 year-old ex-heroin addict who was stable on methadone 100 mg daily and simultaneously stopped using heroin and began drinking alcohol. He was admitted to the hospital for alcohol detoxification and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg. The patient experienced withdrawal symptoms including chills, agitation, muscle and abdominal pain, generalized piloerection, and dilated pupils. Treatment of withdrawal was titrated to treat symptoms and required administration 78 mg of parenteral hydromorphone, after which the patient experienced relief for the following six hours.(8) Intentional administration of an opioid antagonist, naloxone, with opioid analgesics has been performed with close monitoring to lower required opioid dose by inducing withdrawal. Three case reports describe patients who had improved pain relief on significantly reduced doses of opioid analgesics.(8) In a double-blind controlled trial, 267 trauma patients were randomized to receive 0.05 mg/kg intravenous morphine either alone or in combination with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction of pain and incidence of side effects. Results indicate that ultra-low dose naltrexone does not alter opioid requirements for pain control, but does lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9)
Selected Opioids/Mifepristone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil.(1)
CLINICAL EFFECTS: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are particularly susceptible to significant toxicity, including profound sedation, respiratory depression, coma, and/or death.(1,2)
PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity.
PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with CYP3A4 substrates with a narrow therapeutic range, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil, is contraindicated.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) If concomitant use is unavoidable, monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)
DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.(1) Mifepristone is a time- and concentration-dependent CYP3A4 inhibitor. Single dose mifepristone 200 mg may have a lower risk of inhibiting the metabolism of CYP3A4 substrates, including selected opioids.
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Agents That May Cause Respiratory Depression/Sodium Oxybate
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)
CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)
PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)
PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)
DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)
Anticholinergics; Opioids/Eluxadoline
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)
CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)
DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)
N-Methyl-D-Aspartate (Nmda) Antagonists/Memantine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine.(1,2)
CLINICAL EFFECTS: Concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of memantine states that the concurrent use of memantine with N-methyl-D-aspartate (NMDA) antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2)
DISCUSSION: Because N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine, concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects. Therefore, the UK manufacturer of memantine states that the concurrent use of memantine with NMDA antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2) In a study in 52 healthy subjects, concurrent memantine (20 mg daily) and dextromethorphan/quinidine (30/30 mg daily) resulted in no changes in dextromethorphan or memantine levels. There was a slight increase in dizziness as measured by the dizziness visual analog scale (VAS) when compared to memantine alone but not the combination of dextromethorphan/quinidine alone. For other pharmacodynamic assessments, there was either no effect or improvement on some subscales.(3)
Selected Opioids/Ceritinib; Crizotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ceritinib(1) and crizotinib(2) inhibit CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil.
CLINICAL EFFECTS: Concurrent use of ceritinib(1) or crizotinib(2) with alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil may lead to elevated drug levels and increased side effects of the opioid, including profound sedation, respiratory depression, coma, and/or death.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid coadministration of sensitive or narrow therapeutic window CYP3A4 substrates such as alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil with ceritinib and crizotinib. If concomitant use is unavoidable, dosage adjustments of the opioid should be considered when initiating or discontinuing ceritinib(1) or crizotinib.(2) Patients maintained on ceritinib or crizotinib may need lower initial doses of opioid medications. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for adverse affects, including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)
DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Crizotinib (250 mg twice daily for 28 days) increased the AUC of oral midazolam by 3.7-fold.(2) Thus, ceritinib(1) and crizotinib(2) are expected to increase levels of opioids metabolized by CYP3A4.
Selected Opioids/Maois
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Selected opioids inhibit neuronal reuptake of serotonin. Non-selective MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.
CLINICAL EFFECTS: The concurrent use of some opioids with MAOIs has resulted in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)
PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or inhibit the metabolism of serotonin are risk factors for serotonin syndrome. Higher opioid concentrations, as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for an interaction.
PATIENT MANAGEMENT: Use an alternative analgesic when possible. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: Although documentation is lacking for some opioids, the FDA recommends health professionals monitor and advise patients to report symptoms of serotonin syndrome in patients receiving analgesic opioids and serotonergic agents.(2) The interaction between meperidine and MAOIs has been well documented. There are two reports of potential interactions between MAOIs and dextromethorphan.(3,4) In another case report, the concurrent use of propoxyphene and phenylzine resulted in sedation and somnolence. The patient had previously taken both agents alone with no adverse effects.(5) Although some studies have shown that morphine does not interact with MAOIs,(6,7) other data indicates that MAOIs markedly potentiate the effect of morphine.(8) One study indicates that methadone does not interact with MAOIs;(7) however, the UK manufacturer of methadone states that concurrent use is contraindicated.(9) US manufacturers recommend sensitivity tests with small, incremental doses of methadone in patients maintained on MAOIs with careful observation of vital signs.(11) Selected opioids linked to this monograph include: alfentanil, anileridine (not available in US/CA), diphenoxin, meptazinol (not available in US/CA), pentazocine, phenoperidine (not available in US/CA), propoxyphene (not available in US/CA), remifentanil, and sufentanil. Linezolid is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(12,13)
Selected Opioids/Rasagiline; Selegiline
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Selected opioids may inhibit neuronal reuptake of serotonin. MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.
CLINICAL EFFECTS: The concurrent use of some opioids with MAOIs has resulted in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1-3)
PREDISPOSING FACTORS: High doses or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.
PATIENT MANAGEMENT: This combination should be avoided if possible. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: Although documentation is lacking for some opioids, the FDA recommends health professionals monitor and advise patients to report symptoms of serotonin syndrome in patients receiving analgesic opioids and serotonergic agents.(2) Selected opioids linked to this monograph include: alfentanil, anileridine (not available in US/CA), diphenoxin, meptazinol (not available in US/CA), pentazocine, phenoperidine (not available in US/CA), propoxyphene (not available in US/CA), remifentanil, and sufentanil.
Selected Opioids/Selected Cyp3a4 Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil.(6) Benzhydrocodone is a prodrug of hydrocodone.(3)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil,(6) including profound sedation, respiratory depression, coma, and/or death.
PREDISPOSING FACTORS: Heat.
PATIENT MANAGEMENT: Monitor patients receiving potent or moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of itraconazole states that concomitant administration of fentanyl is not recommended during and 2 weeks after itraconazole treatment.(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(6) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)
DISCUSSION: A nested-case control study of patients who were prescribed fentanyl patches, hydromorphone, or oxycodone and were hospitalized for opioid toxicity found that, among 70 cases and 120 control patients, CYP3A4-inhibiting macrolides (erythromycin and clarithromycin) were associated with a higher risk of opioid toxicity (aOR 3.80, 95% CI: 1.36-11.56 with fentanyl; aOR 3.38, 95% CI: 1.28-8.97 with hydromorphone; aOR 3.11, 95% CI: 1.05-9.51 with oxycodone).(10) In a randomized, placebo-controlled trial in 20 healthy subjects, clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) of a single oral dose of oxycodone (10 mg) by 2-fold and 2.3-fold in young and elderly subjects, respectively.(11) In a controlled cross-over study in 6 subjects, 7 days of pretreatment with erythromycin decreased the clearance of alfentanil by 25%. Alfentanil half-life increased by 56%.(12) Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(13) In a randomized, double-blind, placebo-controlled crossover study in 9 subjects, single doses of intravenous fluconazole (400 mg) and oral fluconazole (400 mg) decreased the clearance of a single dose of alfentanil (20 mcg/kg) by 58% and 55%, respectively. Alfentanil half-life almost doubled after both intravenous and oral fluconazole. Both intravenous and oral fluconazole increased subjective effects of alfentanil and increased alfentanil-induced respiratory depression.(14) In a cross-over study, pretreatment with itraconazole (200 mg daily for 4 days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(15) In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily for 5 days) increased the AUC and Cmax of a single oral dose of oxycodone (10 mg) by 144% and 45%, respectively. The AUC of noroxycodone decreased 49% and the AUC of oxymorphone increased 359% with concurrent itraconazole and oral oxycodone. Itraconazole increased the AUC of a single intravenous dose of oxycodone (0.1 mg/kg) by 51%.(16) In a randomized cross-over study in 12 healthy subjects, ketoconazole increased the AUC of oxycodone by 2-fold to 3-fold and also increased oxycodone-related nausea, drowsiness, and pruritus.(17) In a randomized cross-over study in 10 healthy subjects, ketoconazole increased the AUC of oxymorphone by 3-fold following a single dose of oxycodone (0.2 mg/kg). Increased side effects were also noted.(18,19) Ketoconazole has been shown to inhibit the metabolism of alfentanil,(20) fentanyl,(13) and oxycodone(21) in vitro. In a study of 11 subjects, ritonavir reduced the clearance of fentanyl 67% and increased the AUC 174%. Eight subjects reported nausea during the study.(22) In a randomized cross-over study in 16 healthy subjects, ritonavir (300 mg twice daily for 4 days) and lopinavir/ritonavir (400/100 mg twice daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg) by 3.0-fold and 2.6-fold, respectively. Oxycodone half-life increased 55% and 58%, respectively, with concurrent ritonavir or lopinavir/ritonavir. Both regimens also increased self-reported oxycodone effects.(23) The Australian manufacturer of ritonavir states that the AUC of fentanyl may be potentially increased 3-fold with concurrent ritonavir.(24) In a randomized cross-over study in 11 healthy subjects, telithromycin (800 mg daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg immediate-release) by 80%. The AUC of noroxycodone was decreased by 46%. There was a modest increase in the pharmacodynamic effects of oxycodone.(25) In a randomized cross-over study in 10 healthy subjects, troleandomycin increased the AUC of alfentanil by 135%.(26) In a randomized cross-over study in 12 healthy subjects, troleandomycin increased the AUC of a single dose of fentanyl (oral transmucosal, 10 mcg/kg) by 76%.(27) Troleandomycin has been shown to inhibit alfentanil(19) and fentanyl(28) metabolism in vitro. In a randomized, cross-over study in 12 healthy subjects, concurrent use of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and decreased its clearance by 85%.(25,29) In a randomized, cross-over study in 12 healthy subjects, voriconazole (400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400 mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(30) In a randomized cross-over study in 12 healthy subjects, pretreatment with voriconazole for 4 days increased the AUC, Cmax, and half-life of a single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold, respectively.(31) There are case reports of interactions between alfentanil and erythromycin,(32) fentanyl and clarithromycin,(33) fentanyl and fluconazole,(34) fentanyl and itraconazole,(35) and oxycodone and voriconazole.(36) In the case report with fentanyl and fluconazole, the patient died of respiratory depression.(34) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(2) In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(6) Strong CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone or would be expected to interact with these agents include: boceprevir, clarithromycin, cobicistat, elvitegravir, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, voriconazole.(37) Moderate CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone include: erythromycin and fluconazole.(37)
Selected Serotonergic Opioids/Metaxalone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of serotonergic opioids and metaxalone, a weak monoamine oxidase (MAO) inhibitor, may result in additive CNS depression and additive serotonergic effects.(1-4)
CLINICAL EFFECTS: Concurrent use of opioids and metaxalone may result in profound sedation, respiratory depression, coma, and/or death.(3,4) The concurrent use of some opioids with serotonergic properties with metaxalone may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1-2,5)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Treatment with multiple medications which increase serotonin levels or inhibit the metabolism of serotonin are risk factors for serotonin syndrome. Higher opioid concentrations, as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for an interaction.
PATIENT MANAGEMENT: Use an alternative analgesic when possible. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3,4) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3,4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)
DISCUSSION: Although documentation is lacking for some opioids, the FDA recommends health professionals monitor and advise patients to report symptoms of serotonin syndrome in patients receiving analgesic opioids and serotonergic agents.(4) In a case report, the concurrent use of propoxyphene and phenelzine resulted in sedation and somnolence. The patient had previously taken both agents alone with no adverse effects.(8) Metaxalone is a weak inhibitor of MAO.(1,2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Agents With Hyponatremia Risk/Desmopressin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)
CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)
PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).
PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)
DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)
Opioids (Immediate Release)/Benzodiazepines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)
Opioids (Immediate Release)/Cyclobenzaprine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and cyclobenzaprine may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as cyclobenzaprine, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Opioids (Immediate Release)/Muscle Relaxants
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Opioids (Immediate Release)/Selected Stimulants
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS.
CLINICAL EFFECTS: Opposing CNS effects of opioids and stimulants may compromise the effectiveness of both agents and mask opioid overdose symptoms such as drowsiness and inability to focus.
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).
DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)
Opioids (Immediate Release)/Sleep Drugs
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)
DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)
Opioids (Ir & Er)/Gabapentinoids
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Opioid-induced reduction in GI motility may increase the absorption of gabapentin and pregabalin.(1) Gabapentin and pregabalin may reverse opioid-induced tolerance of respiratory depression.(2) Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(3)
CLINICAL EFFECTS: Concurrent use of opioids may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-7)
PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an opioid analgesic, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)
DISCUSSION: In a study in 12 healthy males, administration of a single dose of morphine (60 mg sustained release) increased the area-under-curve (AUC) of a single dose of gabapentin (600 mg) by 44%.(1,3,4) There were no affects on the pharmacokinetics of morphine.(1,3,4) The combination of gabapentin plus morphine increased pain tolerance over the combination of morphine plus placebo. Side effects were not significantly different between morphine plus placebo and morphine plus gabapentin.(1) A retrospective, case-control study of opioid users in Ontario, Canada between August 1, 1997 and December 31, 2013 who died of an opioid-related cause matched cases to up to 4 controls who also used opioids. Use of gabapentin in the 120 days prior to death resulted in a significant increase in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared to opioid use alone. Use of moderate dose (900 mg to 1,799 mg daily) or high dose (>= 1,800 mg daily) gabapentin increased the odds of opioid-related death 60% compared to opioid use without gabapentin. Review of gabapentin prescriptions from calendar year 2013 found that 46% of gabapentin users received at least 1 opioid prescription.(3) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function.(7) A retrospective cohort study evaluated the risk of mortality among Medicare beneficiaries aged 65 and older who were taking gabapentin with or without concurrent use of opioids. All-cause mortality in gabapentin users compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per 1,000 person years, respectively. Adjusted for covariates, the risk of all-cause mortality among gabapentin users on high-dose opioids was more than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10)
Opioids/Buprenorphine; Pentazocine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opiate receptors, exhibiting a ceiling effect at which higher doses produce no further effect. Pentazocine is a mixed agonist-antagonist at opiate receptors.(1) Full mu-opioid agonists (e.g., morphine, methadone) continue to have increased effects at higher doses without ceiling effects.(2)
CLINICAL EFFECTS: Concurrent use of buprenorphine or pentazocine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.
PREDISPOSING FACTORS: Patients dependent on opioids or who take higher dosages of opioids may be more likely to experience withdrawal symptoms with concurrent use.
PATIENT MANAGEMENT: Use buprenorphine and pentazocine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. The manufacturer of Sublocade states buprenorphine may precipitate opioid withdrawal in patients who are currently physically dependent on full opioid agonists. The risk of withdrawal may be increased if buprenorphine is given less than 6 hours after short-acting opioids (such as heroin, morphine) and less than 24 hours after long-acting opioids (such as methadone).(3)
DISCUSSION: Concurrent use of buprenorphine with other opioids in opioid dependent patients could result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.(2) In clinical trials, administration of buprenorphine injection produced withdrawal symptoms in patients maintained on methadone (30 mg daily) when administered 2 hours post-methadone,(4) but not when administered 20 hours post-methadone.(5) In another study, sublingual buprenorphine produced withdrawal symptoms in patients maintained on methadone. Symptoms were more pronounced in patients maintained on 60 mg daily doses than in patients maintained on 30 mg daily doses.(6) In a study of 10 patients maintained on methadone (100 mg daily), only three were able to tolerate escalating sublingual doses of buprenorphine/naloxone up to 32/8 mg. Split doses produced less withdrawal symptoms than full doses.(7) In a case report, a heroin-user maintained in a buprenorphine-maintenance program began stockpiling his buprenorphine instead of ingesting it and began using heroin. He then decided to re-initiate treatment on his own and ingested between 80 and 88 mg of buprenorphine over a two day period and experienced extreme withdrawal symptoms, despite restarting heroin during these symptoms. Methadone relieved his withdrawal symptoms.(8)
Opioids/Butorphanol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Butorphanol antagonize mu-opiate receptors. Other opioids agonize mu-opiate receptors.(1)
CLINICAL EFFECTS: Concurrent use of butorphanol with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.
PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. Patients using higher doses of opioids may also be at a higher risk.
PATIENT MANAGEMENT: Use butorphanol with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects.
DISCUSSION: Because butorphanol antagonizes mu-opiate receptors and other opioids agonize mu-opiate receptors, concurrent use of buprenorphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.(1) In a study in patients maintained on methadone, butorphanol produced withdrawal symptoms comparable to naloxone.(2) In a case report, the use of remifentanil for conscious sedation in a patient maintained on butorphanol produced severe withdrawal symptoms.(3)
Opioids/Nalbuphine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Nalbuphine(1) antagonizes mu-opiate receptors. Other opioids agonize mu-opiate receptors.
CLINICAL EFFECTS: Concurrent use of nalbuphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.
PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. In opioid naive patients, higher doses of nalbuphine may result in decreased analgesic effects.
PATIENT MANAGEMENT: Use nalbuphine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. If nalbuphine is used to reverse opioid anesthesia, monitor patients for renarcotization.
DISCUSSION: Nalbuphine has been successfully used as an adjunct to morphine without decreasing analgesic effects.(2,3) However, other studies reported increased morphine requirements in patients who had initially received nalbuphine.(4,5) Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however, patients often required additional pain medication(5-7) and some studies reported renarcotization after the effects of nalbuphine wore off.(9,10) Nalbuphine has also been used to prevent epidural fentanyl,(13) morphine(14-16), and hydromorphone induced pruritus;(17-18) however, one study reported shortening of the duration of analgesia(16) and another reported increased PCA demands.(17) In methadone-dependent subjects, administration of nalbuphine produced withdrawal symptoms similar to naloxone.(19,20) Administration of nalbuphine to patients maintained on controlled-release morphine resulted in withdrawal symptoms.(20,21)
Selected Opioid Analgesics/Cimetidine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The metabolism of selected opioid analgesics may be inhibited by cimetidine.(1-15) At doses of 800-2400 mg daily, cimetidine is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2C19, CYP2C9, and CYP2D6.(16) Benzhydrocodone is a prodrug of hydrocodone.(12)
CLINICAL EFFECTS: The effect of selected opioid analgesics may be increased including profound sedation, respiratory depression, coma, and/or death. Opioid analgesics have been associated with histamine release and is dependent on dose, route of administration, and rate of administration. Histamine release can cause arteriole dilation and contribute to a profound decrease in systemic blood pressure. The cardiovascular effects of histamine release occurring with the opioid analgesics may be decreased by giving cimetidine concurrently.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Cimetidine use at higher doses of 200-400 mg four times daily would have an increased risk of inhibiting the metabolism of opioid analgesics. Lower doses and over-the-counter doses of cimetidine would be expected to have a diminished effect. Consider using alternative H2 antagonists when long-term concurrent therapy with opioid analgesics is indicated. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(15) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(17) Monitor the patient for increased adverse effects of the opioid analgesic including respiratory and central nervous system depression, unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(18)
DISCUSSION: Severe respiratory depression has been reported with the concurrent administration of opioid analgesics and cimetidine. Systemic levels of opioid analgesics metabolized by CYP3A4 may be increased during concurrent use with cimetidine, a CYP3A4 inhibitor.(1-15) In a study of 6 healthy subjects, the effects of ketoconazole (a strong CYP3A4 inhibitor) 400 mg daily for 3 days on alfentanil were studied. The maximum concentration (Cmax) and area-under-curve (AUC) of alfentanil were increased with both sequential and simultaneous dosing of alfentanil with concurrent ketoconazole.(19) In a study of 16 healthy subjects, the effects of ketoconazole 300 mg twice daily for 2 days on fentanyl 5 mcg/kg single dose were examined. Fentanyl AUC was increased by 133% and clearance was reduced to 78%. The metabolism of fentanyl to norfentanyl by CYP3A4 was delayed and partial metabolic clearance decreased by 18% with concurrent ketoconazole.(20) In vitro results of the effects of ketoconazole on hydrocodone confirmed CYP3A4 is responsible for the metabolism of hydrocodone to norhydrocodone.(21) A review discussed the metabolism of hydrocodone by CYP2D6 to O-demethylated hydromorphone and by CYP3A4 to N-demethylated norhydrocodone. CYP3A4 activity is reported as higher in women resulting in higher fractions of the norhydrocodone metabolite in women than in men.(22) A case report of a 46 year old hemodialysis patient was on routine therapy with phenytoin 100 mg three times daily and cimetidine 300 mg three times daily. Four days after starting cimetidine, morphine 15 mg IM every 4 hours was initiated for pain. After the sixth dose of morphine, the patient was apneic with a respiratory rate of 3 breaths/minute and had a grand mal seizure. The patient responded to naloxone 0.4 mg IV single dose with improvement in respiratory rate to 12 breaths/minute. Cimetidine was stopped and phenytoin decreased to 100 mg twice daily with improvement after 80 hours from initial episode. A month later the patient required surgery and was given cimetidine 150 mg twice daily followed by Pantopon 15 mg IM every 3-6 hours postoperatively for pain. The patient again became apneic, confused, and developed muscle twitching which responded to naloxone 0.4 mg for 4 doses over the next 24 hours with complete recovery.(23) In a study of 8 healthy subjects, the effects of cimetidine on morphine were studied. Subjects were evaluated in three study periods: morphine 10 mg IM single dose; cimetidine 600 mg oral given one hour before morphine 10 mg IM single dose; and cimetidine 600 mg oral single dose. Morphine reduced resting ventilation and increased end-tidal CO2 with peak effects at 120 minutes and resolution at 12 hours. Morphine with cimetidine pretreatment had similar effects on resting ventilation and end-tidal CO2, however the recovery ratio from 120 to 720 minutes was significantly different than morphine alone (p<0.05).(24) In a study of 7 healthy subjects, the effects of cimetidine 300 mg oral four times daily for 4 days on morphine 10 mg IV single dose were evaluated. No significant differences were found in morphine concentrations at any time point from zero to ten hours after dose administration with and without cimetidine. Morphine elimination half-life (t1/2), systemic clearance, volume of distribution, and AUC with and without cimetidine had no statistical differences.(25) In a study of 40 patients undergoing elective coronary artery bypass graft surgery were randomized to receive either cimetidine 4 mg/kg, diphenhydramine 1 mg/kg, a combination of both cimetidine and diphenhydramine, or placebo, followed by morphine 1 mg/kg. Patients were randomized to one of four groups: 1. placebo plus morphine; 2. cimetidine plus morphine; 3. diphenhydramine plus morphine; or 4. cimetidine plus diphenhydramine plus morphine. Patients in group 1 had a 10-fold increase in plasma histamine levels within 2 minutes of morphine with a decrease in mean BP, diastolic BP, and systemic vascular resistance (SVR). Group 2 has similar effects with a peak change in SVR and plasma histamine rise within 2 minutes of morphine. The change in SVR was significant when compared to placebo but less than group 1. Group 3 patients had an increase in heart rate (HR) from diphenhydramine alone as well as peak effects within 2 minutes of morphine with decreases in BP and SVR but were less than morphine alone. Group 4 patients had a 7-fold increase in histamine with a significant increase in HR, diastolic BP, and BP. When group 4 is compared to group 1, patients had a decrease in SVR and diastolic BP that was significantly less despite comparable increases in plasma histamine.(26) In vitro testing of oxycodone and methadone, cimetidine caused a greater than 50% inhibition in all pathways: CYP2B6, CYP3A4, CYP2C18, and CYP2D6. Cimetidine was found to be a weak reversible inhibitor in vitro. Extrapolation of the data to in vivo inhibition is unlikely to produce significant inhibition unless concentrations exceed normal doses by 10-fold.(27) Two studies examined the effects of CYP2D6 and CYP3A4 on the metabolism of oxycodone as well as genetic polymorphism influences. After concurrent administration of oxycodone with ketoconazole, the Cmax of the metabolites noroxycodone and noroxymorphone were decreased by 80% from baseline.(28,29) A review discussed the metabolism of oxycodone by CYP3A4 to noroxycodone, the major metabolite with weak antinociceptive properties, and by CYP2D6 to the active minor metabolite oxymorphone.(30) In a study of 8 male subjects, effects of cimetidine 600 mg twice daily for seven days on pethidine 70 mg IV single dose was evaluated. Concurrent use with cimetidine was associated with a 22% decrease in clearance, 11% decrease in elimination rate, and a 13% decrease in volume of distribution of pethidine. Changes were also seen in norpethidine, the primary metabolite, with a 23% decrease in AUC and 29% decrease in Cmax.(31) Opioid analgesics linked to this monograph include: alfentanil, benzhydrocodone, dihydrocodeine, fentanyl, hydrocodone, meperidine, meptazinol, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, and sufentanil.
Selected Opioids/Barbiturates; Phenobarbital; Primidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: There are two mechanisms involved in this interaction. Pharmacokinetic: alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are primarily metabolized by CYP3A4/5 and glucuronidation pathways.(1-8) Phenobarbital is an inducer of these pathways. Pharmacodynamic: both opioids and barbiturates are associated with respiratory depression; these effects may be additive.(1,3,9) Benzhydrocodone is a prodrug of hydrocodone.(2) Primidone is metabolized to phenobarbital.
CLINICAL EFFECTS: Short term or intermittent use of phenobarbital and opioids metabolized by CYP3A4 may be associated with respiratory suppression or other CNS depression. Continuous, longer term use of phenobarbital may result in decreased levels and effectiveness of the opioid. Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(6,10)
PREDISPOSING FACTORS: Patients with a history of alcohol or sedative abuse may be at risk for relapse and overuse or abuse of prescribed phenobarbital.(1,3,5,11) Individuals with significant obstructive pulmonary disease, the elderly, and debilitated patients are at greater risk for respiratory depression from either agent.(1,3) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients on chronic therapy with phenobarbital who are newly starting opioids metabolized by CYP3A4 may need higher than usual doses of the opioid for analgesia or opioid maintenance.(1,3,12) Opioid-treated patients newly started on phenobarbital should be monitored initially for additive CNS sedation or respiratory depression, particularly when predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. Continued use of phenobarbital leads to induction of the opioids' metabolism. The onset is gradual and may not peak for several weeks. Monitor patient for possible loss of efficacy or opioid withdrawal. If a patient has been maintained on concurrent treatment with an opioid metabolized by CYP3A4 and phenobarbital, and the phenobarbital is discontinued, opioid levels will gradually rise as induction effects diminish. Monitor for increased opioid effects and adjust the dose accordingly.(1,3,12) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(13) For patients receiving opioid maintenance treatment, it would be prudent to assure all controlled substance prescriptions are approved or written by the opioid provider. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(14)
DISCUSSION: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are metabolized by CYP3A4, and barbiturates, phenobarbital, and primidone would be expected to induce their metabolism.(1,2,4-6) Newer metabolites and minor metabolic pathways for buprenorphine have been recently described. Phenobarbital, an inducer of multiple enzyme pathways (e.g. CYP2B, CYP2C, CYP3A and UGT) could potentially lower systemic buprenorphine levels via major and minor pathways.(12)
Selected Opioids/Selected Moderate Cyp3a4 Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression.
PREDISPOSING FACTORS: Heat.
PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(4) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat.(1)
DISCUSSION: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)
Selected Opioids/Selected Strong Cyp3a4 Inducers
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of alfentanil, benzhydrocodone, buprenorphine,(1) fentanyl, hydrocodone, meperidine,(2-4) morphine,(5) oxycodone, papaveretum, and sufentanil.(6)
CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels of alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-6) Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(2,3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients maintained on alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil may require dosage adjustments if a strong CYP3A4 inducer is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer. Patients who transfer to Sublocade (extended release subcutaneous syringe buprenorphine) from transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level produced by Sublocade is adequate. If patients already on Sublocade require newly-initiated treatment with CYP3A4 inducer, the patient should be monitored for withdrawal. If the dose of Sublocade is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, the patient should be transitioned back to a formulation of buprenorphine that permits dose adjustment. If a patient has been stabilized on Sublocade with a CYP3A4 inducer and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of Sublocade administration, if the dose provided by Sublocade is excessive in the absence of the concomitant inducer, it may be necessary to remove the Sublocade and treat the patient with a formulation of buprenorphine that permits dose adjustments.(15) The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inducers is necessary, consider use of an alternate agent that allows dose adjustment.(6)
DISCUSSION: In a study in 12 opoid-dependent patients, rifampin (600 mg daily) decreased the area-under-curve (AUC) of buprenorphine by 70%. Half of the subjects experienced withdrawal symptoms. When compared to historical values, there was no effect on rifampin levels.(1) In a study of four healthy volunteers, phenytoin increased meperidine clearance from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min and decreased half-life from 6.4 hours to 4.3 hours. Phenytoin also increased normeperidine AUC by 1.53-fold after IV meperidine and by 1.25-fold after oral meperidine.(3) In a study in 10 healthy subjects, pretreatment with rifampin (600 mg daily) for 13 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of morphine by 28% and 41%, respectively. The AUCs of morphine-3-glucuronide and morphine-6-glucuronide were proportionally decreased as well. Following rifampin pretreatment, no analgesic effects of morphine were seen.(5) In a randomized controlled trial of 12 healthy participants St. John's wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination half-life, and decreased the self-reported drug effect of oxycodone compared to placebo.(7) In a study in 12 healthy subjects, pretreatment with rifampin had no effect on fentanyl Cmax or time to Cmax (Tmax) after administration of oral transmucosal fentanyl. However, fentanyl AUC decreased 62%.(8) In a study in 9 healthy subjects, rifampin increased the clearance of alfentanil by 169%. Alfentanil half-life decreased 61%.(9) In a study of patients undergoing craniotomy, higher fentanyl maintenance doses were required in patients receiving carbamazepine and phenytoin compared to control subjects not receiving enzyme-inducing agents.(10) There are case reports of decreased levels and effectiveness of oxycodone with concurrent phenytoin(11) and rifampin(12) and with concurrent fentanyl and rifampin.(13-14) Selected strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort.
Slt Opioids (Immediate Release)/Antipsychotics;Phenothiazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Slt Opioids (Immediate Release)/Ziprasidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics such as ziprasidone may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as ziprasidone may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including ziprasidone, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Contraindications
*Patients in whom substantial blood pressure elevation would constitute a serious hazard.
*Known hypersensitivity to ketamine or any ingredient in the formulation.
*Some experts state that relative contraindications may include history of airway instability, tracheal surgery, or tracheal stenosis; active pulmonary infection or disease; known or suspected cardiovascular disease (e.g., angina, congestive heart failure (CHF), hypertension); CNS masses, abnormalities, or hydrocephalus; elevated intraocular pressure (IOP) (e.g., glaucoma, acute globe injury); and porphyria, hyperthyroidism, or concomitant thyroid replacement therapy.
*Hypersensitivity to sufentanil.
*Significant respiratory depression (sufentanil sublingual tablets).
*Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (sufentanil sublingual tablets).
*Known or suspected GI obstruction, including paralytic ileus (sufentanil sublingual tablets).
- Acute decompensated heart failure
- Paralytic ileus
- Severe uncontrolled hypertension
- Cardiac decompensation
- Debilitation
- Delirium
- Disease of liver
- Drug abuse
- Familial dysautonomia
- Gastrointestinal obstruction
- History of opioid overdose
- Intracranial hypertension
- Lower seizure threshold
- Respiratory depression
- Sleep apnea
- Acute cognitive impairment
- Adrenocortical insufficiency
- Alcohol intoxication
- Alcohol use disorder
- Bradycardia
- Chronic disease of respiratory system
- Decreased cardiac function
- Increased cerebrospinal fluid pressure
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Ocular hypertension
- Seizure disorder
- Spasm of sphincter of oddi
Adverse reactions
The most common adverse reactions with ketamine are emergence reactions and elevated blood pressure and pulse.
The most common adverse reactions associated with sufentanil citrate injection were respiratory depression, apnea, rigidity, and bradycardia.
The most common adverse reactions (>=2%) associated with sufentanil sublingual tablets were nausea, headache, vomiting, dizziness and hypotension.
More Frequent
- Bradycardia
- Hypertension
- Hypotension
- Respiratory depression
- Tachycardia
Less Frequent
- Bradycardia
- Cardiac arrhythmia
- Hypotension
Rare or Very Rare
- Abnormal hepatic function tests
- Accidental fall
- Acquired dilation of bile duct
- Acute cognitive impairment
- Acute kidney injury
- Allergic dermatitis
- Anaphylaxis
- Apnea
- Bronchospastic pulmonary disease
- Cardiac arrhythmia
- Cholestasis
- Cholestatic hepatitis
- Cystitis
- Delirium
- Depression
- Disorder of adrenal gland
- Drug dependence
- Drug-induced hepatitis
- Excitement
- Hematuria
- Hepatic fibrosis
- Hepatocellular damage
- Hydronephrosis
- Increased cerebrospinal fluid pressure
- Laryngismus
- Laryngismus
- Paresthesia
- Pruritus of skin
- Respiratory depression
- Secondary sclerosing cholangitis
- Tonic clonic seizure
- Urinary tract obstruction
- Viral infection
More Frequent
- Acute cognitive impairment
- Delirium
- Drowsy
- Hallucinations
- Nausea
- Tremor
- Vomiting
Less Frequent
- Agitation
- Behavioral disorders
- Diplopia
- Dream disorder
- Drowsy
- Erythema
- Hypertonia
- Memory impairment
- Tachypnea
- Vomiting
Rare or Very Rare
- Accidental fall
- Anorexia
- Biliary spasm
- Blurred vision
- Chills
- CNS depression
- Constipation
- Diplopia
- Dysuria
- Erectile dysfunction
- Increased urinary frequency
- Infertility
- Injection site sequelae
- Libido changes
- Muscle spasm
- Nausea
- Nystagmus
- Ocular hypertension
- Orthostatic hypotension
- Skin rash
- Ureteral spasm
- Urinary urge incontinence
- Vasodilation of blood vessels
- Visual changes
Precautions
No enhanced messaging available.
Although the manufacturer states that safety and efficacy of ketamine have not been established in patients younger than 16 years of age, the drug has been used widely in pediatric patients+ in a variety of clinical settings for anesthesia, procedural sedation and analgesia, postoperative analgesia, and chronic pain management. Ketamine frequently is used in children to facilitate painful procedures in the emergency department and is considered a drug of choice for this use. Ketamine may be particularly useful in pediatric patients because the drug may be administered IM.
Repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, in children <3 years of age or during the third trimester of pregnancy may adversely affect neurodevelopment. In animals, use of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity leads to widespread neuronal apoptosis in the brain and long-term deficits in cognition and behavior when used for longer than 3 hours; however, the clinical relevance to humans is unknown.
Ketamine may be preferred for induction of anesthesia in children with congenital heart disease with right-to-left shunt+ because of its sympathomimetic effects and hemodynamic stability.
Ketamine generally should not be used in infants younger than 3 months of age because of the potential increased risk of airway complications (e.g., airway obstruction, laryngospasm, apnea) thought to be due to age-specific differences in airway reactivity and anatomy.
Safety and efficacy of sufentanil citrate injection in children as young as 1 day of age have been documented in a limited number of patients undergoing cardiovascular surgery. Safety and efficacy of sufentanil sublingual tablets in pediatric patients have not been established; use is not recommended in these patients because of the risk of noncompliance with sublingual dosing instructions.
The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life.
There are no adequate and well-controlled studies of ketamine in pregnant women. Although ketamine has been used for induction of anesthesia during vaginal delivery and caesarean sections, the manufacturer states that the drug is not recommended for use during pregnancy or delivery because safety has not been established. Some neonates exposed to ketamine at maternal IV doses of 1.5 mg/kg or higher during delivery have experienced respiratory depression and low Apgar scores requiring resuscitation. Marked increases in maternal blood pressure and uterine tone have been observed following administration of IV ketamine doses greater than 2 mg/kg.
In animal reproduction studies using IM ketamine doses approximately 0.3-0.6 times the usual human IM dose of 10 mg/kg (based on body surface area), developmental delays, skeletal hypoplasia, and increased fetal resorptions were observed.
Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.
Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome. Data on sufentanil in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal studies, embryolethality and maternal toxicity occurred in rabbits with IV sufentanil administration at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose. No malformations were observed in either rats or rabbits at doses below the human procedural dose. Sufentanil should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Sufentanil injectionis not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Epidural administration of sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. Sufentanil is not recommended for IV use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery.
It is not known whether ketamine is distributed into milk. Because the drug should be undetectable in plasma approximately 11 hours after administration, nursing after this time period should not expose the infant to clinically relevant amounts of ketamine.
Consider the developmental and health benefits of breastfeeding along with the mother's need for sufentanil and any potential adverse effects on the breastfed infant or from the underlying maternal condition. Monitor infants exposed to sufentanil through breast milk for excess sedation and respiratory depression.
The manufacturer recommends that dosages in geriatric patients should generally be started on the lower end of the dosing range to accommodate any underlying hepatic, renal, or cardiac dysfunction and any comorbidities or other drug therapy.
While reported clinical experience to date has not revealed age-related differences in response to ketamine when used as an anesthetic agent, clinical studies have not included sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. When ketamine is used as an anesthetic agent in geriatric patients, the dosage should be selected carefully, usually starting at the low end of the dosing range, because of the greater frequency of age-related decreases in hepatic, renal, and/or cardiac function, and of concomitant disease or other drug therapy.
In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Titrate the dosage of sufentanil injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression. Because the dose of sufentanil sublingual tablets cannot be titrated, monitor geriatric patients closely for signs of CNS and respiratory depression or consider an alternate medication that can be titrated.
Elderly patients may have increased sensitivity to sufentanil. No special population studies in geriatric patients have been performed for sufentanil sublingual tablets. In patients who received sublingual sufentanil, the overall rate of adverse events and most common adverse events tended to increase with age, although vomiting was less common in patients aged >=75 years than in younger patients.
In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Titrate the dosage of sufentanil citrate injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression. Because the dose of sufentanil sublingual tablets cannot be titrated, monitor geriatric patients closely for signs of CNS and respiratory depression or consider an alternate medication that can be titrated.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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