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Drug overview for MS CONTIN (morphine sulfate):
Generic name: MORPHINE SULFATE (MOR-feen SUL-fate)
Drug class: Opioid Analgesics- ER (with all antitussive opiates)
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Morphine sulfate is a phenanthrene-derivative opioid agonist; morphine is the principal alkaloid of opium and considered to be the prototype of the opioid agonists.
No enhanced Uses information available for this drug.
Generic name: MORPHINE SULFATE (MOR-feen SUL-fate)
Drug class: Opioid Analgesics- ER (with all antitussive opiates)
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Morphine sulfate is a phenanthrene-derivative opioid agonist; morphine is the principal alkaloid of opium and considered to be the prototype of the opioid agonists.
No enhanced Uses information available for this drug.
DRUG IMAGES
MS CONTIN ER 200 MG TABLET
MS CONTIN ER 15 MG TABLET
MS CONTIN ER 30 MG TABLET
MS CONTIN ER 60 MG TABLET
MS CONTIN ER 100 MG TABLET
The following indications for MS CONTIN (morphine sulfate) have been approved by the FDA:
Indications:
Severe chronic pain requiring long-term opioid treatment
Severe chronic pain with opioid tolerance
Professional Synonyms:
None.
Indications:
Severe chronic pain requiring long-term opioid treatment
Severe chronic pain with opioid tolerance
Professional Synonyms:
None.
The following dosing information is available for MS CONTIN (morphine sulfate):
Morphine sulfate should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.
Titrate the dose based on the individual patient's response to their initial dose of morphine sulfate to a dose that provides adequate analgesia and minimizes adverse reactions. Continually re-evaluate patients to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
Immediate-release tablets in adults: The recommended initial adult dosage of morphine sulfate immediate-release tablets is 15-30 mg orally every 4 hours as needed for pain; the lowest effective dosage should be used.
Immediate-release tablets in pediatric patients: The recommended initial dosage of morphine sulfate immediate-release tablets in pediatric patients weighing at least 50 kg is 15 mg every 4 hours as needed for pain; the lowest effective dosage should be used. Morphine sulfate immediate-release tablets are not recommended for pediatric patients weighing less than 50 kg.
Oral solution in adults: The recommended initial adult dosage of morphine sulfate oral solution is 10-20 mg every 4 hours as needed for pain; the lowest effective dosage should be used. Titrate the dose based upon the individual patient's response to their initial dose of morphine sulfate oral solution.
Oral solution in pediatric patients: The recommended initial dosage in pediatric patients 2 years of age and older is 0.15-0.3 mg/kg every 4 hours as needed for pain; the lowest effective dosage should be used.
Extended-release capsules: The recommended initial dose of morphine sulfate extended-release capsules in adult opioid-naive patients or in those who are not opioid tolerant is 30 mg orally every 24 hours. Adjust the dosage in increments no greater than 30 mg every 3 to 4 days. Patients who experience breakthrough pain may require a dosage increase or may need rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage of morphine sulfate. Because steady-state plasma concentrations are approximated within 2 to 3 days, dosage may be adjusted every 3 to 4 days. The daily dosage of morphine sulfate extended-release capsules must be limited to a maximum of 1600 mg/day; higher amounts contain a quantity of fumaric acid that has not been demonstrated to be safe, and which may result in serious renal toxicity.
Extended-release tablets: The recommended initial dose of morphine sulfate extended-release tablets in adult opioid-naive patients is 15 mg every 8 or 12 hours. The recommended initial dose of morphine sulfate extended-release tablets in adult opioid non-tolerant patients is 15 mg every 12 hours. Patients who experience breakthrough pain may require a dosage increase of morphine sulfate extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine dosage. Because steady-state plasma concentrations are approximated in 1 day, morphine sulfate extended-release tablets dosage adjustments may be adjusted every 1 to 2 days.
The recommended initial adult dosage of morphine sulfate rectal suppositories is 10-20 mg every 4 hours as needed for pain and at the lowest dose necessary to achieve analgesia.
The usual starting dosage of morphine sulfate injection in adults is 0.1-0.2 mg/kg every 4 hours as needed by slow IV injection.
An initial adult IV dosage range of 2 -10 mg based on a patient's weight of 70 kg has been recommended by some manufacturers.
The initial IM dose of morphine sulfate is 10 mg every 4 hours as needed to manage pain (based on a 70 kg adult).
When the 0.5 mg/mL or 1 mg/mL morphine sulfate injection is administered epidurally, the recommended initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within 1 hour, carefully administer incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness.
Do not administer more than 10 mg per 24 hours.
When the 10 mg/mL or 25 mg/mL morphine sulfate injection is administered as a continuous epidural infusion, the recommended initial dosage in adults who are not tolerant to opioids is 3.5-7.5 mg/day.
Based on limited experience, the usual initial epidural dosage for continuous infusion in adults with some degree of opioid tolerance is 4.5-10 mg/day. Epidural dosage requirements may increase substantially during chronic therapy, frequently to 20-30 mg daily; the upper daily limit must be individualized for each patient.
When the 0.5 mg/mL or 1 mg/mL morphine sulfate injection is administered intrathecally, the recommended initial injection of 0.2-1 mg may provide satisfactory pain relief for up to 24 hours.
For the morphine sulfate injection (Duramorph(R)) preparation, this is only 0.4 to 2 mL of the 5 mg/10 mL ampul or 0.2 to 1 mL of the 10 mg/10 mL ampul.
Do not inject more than 2 mL of the 5 mg/10 mL ampul or 1 mL of the 10 mg/10 mL ampul intrathecally. Repeated intrathecal injections are not recommended. If pain recurs, consider alternative routes of administration.
A constant IV infusion of naloxone 0.6 mg/hr for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.
When the 10 mg/mL or 25 mg/mL morphine sulfate injection is administered as a continuous intrathecal infusion, the recommended initial lumbar intrathecal dose range in adult patients with no tolerance to opioids is 0.2 to 1 mg/day. The published range of doses for individuals who have some degree of opioid tolerance varies from 1 to 10 mg/day.
The upper daily dosage limit for each patient must be individualized.
To relieve pain in adults with ST-segment-elevation myocardial infarction (STEMI), an initial morphine sulfate dose of 2-4 mg IV is recommended; additional doses of 2-8 mg may be administered every 5-15 minutes as needed. In patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) who continue to experience pain despite maximally tolerated anti-ischemic therapy, experts state that a morphine sulfate dose of 1-5 mg IV may be administered during IV nitroglycerin therapy; additional doses may be given every 5-30 minutes to relieve symptoms and maintain patient comfort.
For the management of neonatal opiate abstinence syndrome+, use of protocols that base initiation, adjustment, and tapering of morphine sulfate dosage on standardized patient assessments performed at regular intervals is recommended. The most commonly used tool for assessing severity of withdrawal in term neonates is the Finnegan scoring system (original or modified versions) performed every 3-4 hours. Treatment protocols vary in recommended dosages, thresholds for initiation of therapy, incremental changes and thresholds for dosage adjustment, and tapering strategies.
Under various protocols, treatment with morphine sulfate oral solution is initiated at a dosage of 0.04-0.05 mg/kg every 3-4 hours based on Finnegan score (e.g., score exceeds 8 on at least 2 or 3 occasions, the sum of 3 consecutive scores is 24 or greater, a single score or 2 consecutive scores are 12 or greater); under other protocols, initial dosage may vary depending on the severity of withdrawal manifestations, with higher initial dosages recommended for neonates with higher Finnegan scores.
Some clinicians state that initial dosage usually ranges from 0.03-0.1 mg/kg every 3-4 hours.
If Finnegan score remains elevated (e.g., a single score or 2 consecutive scores are 12 or greater, 2 consecutive scores are 8 or greater, the sum of 3 scores is 24 or greater), dosage may be increased, generally by 0.02-0.05 mg/kg per dose or by 10-20% depending on the protocol and/or Finnegan score, to achieve stabilization.
Some clinicians have recommended a usual maximum dosage of 1.2-1.3 mg/kg daily or 0.2
mg/kg per dose. Once patients are stable (generally, no score exceeds 8 ) for at least 48 hours, morphine sulfate dosage typically is tapered in decrements of approximately 0.02 mg/kg per dose or approximately 10% of the highest (stabilization) dose at intervals of approximately 24-48 hours.
Protocols vary in terms of the dosage at which morphine sulfate can be discontinued. However, neonates should be monitored for at least 48 hours after the drug has been discontinued. Specialized protocols should be consulted for further information on morphine sulfate dosage and monitoring of Finnegan scores in neonates with opiate abstinence syndrome.
Further study is needed to define optimal dosing strategies.
Discuss the availability of naloxone for the emergency treatment of opioid agonist overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate preparations. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants,history of opioid use disorder, or prior opioid agonist overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.
If naloxone is prescribed, educate patients and caregivers onuse of the drug.
Dosing errors can result in accidental overdose and death. A boxed warning regarding this risk has been included in the prescribing information for morphine. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine sulfate oral solutions of different concentrations, when prescribing, dispensing, and administering morphine sulfate oral solution.
Ensure that the dose is communicated clearly and dispensed accurately.
Instruct patients and caregivers on how to measure and take or administer the correct dose of morphine sulfate oral solution and to use extreme caution when measuring the dose. Instruct patients and caregivers to always use a graduated oral syringe when administering the oral solution to ensure the dose is measured and administered accurately. Instruct patients to never use a household teaspoon or tablespoon to measure a dose because these are not adequate measuring devices.
Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.
Titrate the dose based on the individual patient's response to their initial dose of morphine sulfate to a dose that provides adequate analgesia and minimizes adverse reactions. Continually re-evaluate patients to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
Immediate-release tablets in adults: The recommended initial adult dosage of morphine sulfate immediate-release tablets is 15-30 mg orally every 4 hours as needed for pain; the lowest effective dosage should be used.
Immediate-release tablets in pediatric patients: The recommended initial dosage of morphine sulfate immediate-release tablets in pediatric patients weighing at least 50 kg is 15 mg every 4 hours as needed for pain; the lowest effective dosage should be used. Morphine sulfate immediate-release tablets are not recommended for pediatric patients weighing less than 50 kg.
Oral solution in adults: The recommended initial adult dosage of morphine sulfate oral solution is 10-20 mg every 4 hours as needed for pain; the lowest effective dosage should be used. Titrate the dose based upon the individual patient's response to their initial dose of morphine sulfate oral solution.
Oral solution in pediatric patients: The recommended initial dosage in pediatric patients 2 years of age and older is 0.15-0.3 mg/kg every 4 hours as needed for pain; the lowest effective dosage should be used.
Extended-release capsules: The recommended initial dose of morphine sulfate extended-release capsules in adult opioid-naive patients or in those who are not opioid tolerant is 30 mg orally every 24 hours. Adjust the dosage in increments no greater than 30 mg every 3 to 4 days. Patients who experience breakthrough pain may require a dosage increase or may need rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage of morphine sulfate. Because steady-state plasma concentrations are approximated within 2 to 3 days, dosage may be adjusted every 3 to 4 days. The daily dosage of morphine sulfate extended-release capsules must be limited to a maximum of 1600 mg/day; higher amounts contain a quantity of fumaric acid that has not been demonstrated to be safe, and which may result in serious renal toxicity.
Extended-release tablets: The recommended initial dose of morphine sulfate extended-release tablets in adult opioid-naive patients is 15 mg every 8 or 12 hours. The recommended initial dose of morphine sulfate extended-release tablets in adult opioid non-tolerant patients is 15 mg every 12 hours. Patients who experience breakthrough pain may require a dosage increase of morphine sulfate extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine dosage. Because steady-state plasma concentrations are approximated in 1 day, morphine sulfate extended-release tablets dosage adjustments may be adjusted every 1 to 2 days.
The recommended initial adult dosage of morphine sulfate rectal suppositories is 10-20 mg every 4 hours as needed for pain and at the lowest dose necessary to achieve analgesia.
The usual starting dosage of morphine sulfate injection in adults is 0.1-0.2 mg/kg every 4 hours as needed by slow IV injection.
An initial adult IV dosage range of 2 -10 mg based on a patient's weight of 70 kg has been recommended by some manufacturers.
The initial IM dose of morphine sulfate is 10 mg every 4 hours as needed to manage pain (based on a 70 kg adult).
When the 0.5 mg/mL or 1 mg/mL morphine sulfate injection is administered epidurally, the recommended initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within 1 hour, carefully administer incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness.
Do not administer more than 10 mg per 24 hours.
When the 10 mg/mL or 25 mg/mL morphine sulfate injection is administered as a continuous epidural infusion, the recommended initial dosage in adults who are not tolerant to opioids is 3.5-7.5 mg/day.
Based on limited experience, the usual initial epidural dosage for continuous infusion in adults with some degree of opioid tolerance is 4.5-10 mg/day. Epidural dosage requirements may increase substantially during chronic therapy, frequently to 20-30 mg daily; the upper daily limit must be individualized for each patient.
When the 0.5 mg/mL or 1 mg/mL morphine sulfate injection is administered intrathecally, the recommended initial injection of 0.2-1 mg may provide satisfactory pain relief for up to 24 hours.
For the morphine sulfate injection (Duramorph(R)) preparation, this is only 0.4 to 2 mL of the 5 mg/10 mL ampul or 0.2 to 1 mL of the 10 mg/10 mL ampul.
Do not inject more than 2 mL of the 5 mg/10 mL ampul or 1 mL of the 10 mg/10 mL ampul intrathecally. Repeated intrathecal injections are not recommended. If pain recurs, consider alternative routes of administration.
A constant IV infusion of naloxone 0.6 mg/hr for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.
When the 10 mg/mL or 25 mg/mL morphine sulfate injection is administered as a continuous intrathecal infusion, the recommended initial lumbar intrathecal dose range in adult patients with no tolerance to opioids is 0.2 to 1 mg/day. The published range of doses for individuals who have some degree of opioid tolerance varies from 1 to 10 mg/day.
The upper daily dosage limit for each patient must be individualized.
To relieve pain in adults with ST-segment-elevation myocardial infarction (STEMI), an initial morphine sulfate dose of 2-4 mg IV is recommended; additional doses of 2-8 mg may be administered every 5-15 minutes as needed. In patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS) who continue to experience pain despite maximally tolerated anti-ischemic therapy, experts state that a morphine sulfate dose of 1-5 mg IV may be administered during IV nitroglycerin therapy; additional doses may be given every 5-30 minutes to relieve symptoms and maintain patient comfort.
For the management of neonatal opiate abstinence syndrome+, use of protocols that base initiation, adjustment, and tapering of morphine sulfate dosage on standardized patient assessments performed at regular intervals is recommended. The most commonly used tool for assessing severity of withdrawal in term neonates is the Finnegan scoring system (original or modified versions) performed every 3-4 hours. Treatment protocols vary in recommended dosages, thresholds for initiation of therapy, incremental changes and thresholds for dosage adjustment, and tapering strategies.
Under various protocols, treatment with morphine sulfate oral solution is initiated at a dosage of 0.04-0.05 mg/kg every 3-4 hours based on Finnegan score (e.g., score exceeds 8 on at least 2 or 3 occasions, the sum of 3 consecutive scores is 24 or greater, a single score or 2 consecutive scores are 12 or greater); under other protocols, initial dosage may vary depending on the severity of withdrawal manifestations, with higher initial dosages recommended for neonates with higher Finnegan scores.
Some clinicians state that initial dosage usually ranges from 0.03-0.1 mg/kg every 3-4 hours.
If Finnegan score remains elevated (e.g., a single score or 2 consecutive scores are 12 or greater, 2 consecutive scores are 8 or greater, the sum of 3 scores is 24 or greater), dosage may be increased, generally by 0.02-0.05 mg/kg per dose or by 10-20% depending on the protocol and/or Finnegan score, to achieve stabilization.
Some clinicians have recommended a usual maximum dosage of 1.2-1.3 mg/kg daily or 0.2
mg/kg per dose. Once patients are stable (generally, no score exceeds 8 ) for at least 48 hours, morphine sulfate dosage typically is tapered in decrements of approximately 0.02 mg/kg per dose or approximately 10% of the highest (stabilization) dose at intervals of approximately 24-48 hours.
Protocols vary in terms of the dosage at which morphine sulfate can be discontinued. However, neonates should be monitored for at least 48 hours after the drug has been discontinued. Specialized protocols should be consulted for further information on morphine sulfate dosage and monitoring of Finnegan scores in neonates with opiate abstinence syndrome.
Further study is needed to define optimal dosing strategies.
Discuss the availability of naloxone for the emergency treatment of opioid agonist overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate preparations. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants,history of opioid use disorder, or prior opioid agonist overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.
If naloxone is prescribed, educate patients and caregivers onuse of the drug.
Dosing errors can result in accidental overdose and death. A boxed warning regarding this risk has been included in the prescribing information for morphine. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine sulfate oral solutions of different concentrations, when prescribing, dispensing, and administering morphine sulfate oral solution.
Ensure that the dose is communicated clearly and dispensed accurately.
Instruct patients and caregivers on how to measure and take or administer the correct dose of morphine sulfate oral solution and to use extreme caution when measuring the dose. Instruct patients and caregivers to always use a graduated oral syringe when administering the oral solution to ensure the dose is measured and administered accurately. Instruct patients to never use a household teaspoon or tablespoon to measure a dose because these are not adequate measuring devices.
Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.
Morphine sulfate is administered by the oral, rectal, IV, IM, intrathecal, or epidural routes.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| MS CONTIN ER 15 MG TABLET | Maintenance | Adults take 1 tablet (15 mg) by oral route every 12 hours |
| MS CONTIN ER 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route every 12 hours |
| MS CONTIN ER 60 MG TABLET | Maintenance | Adults take 1 tablet (60 mg) by oral route every 12 hours |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| MORPHINE SULF ER 15 MG TABLET | Maintenance | Adults take 1 tablet (15 mg) by oral route every 12 hours |
| MORPHINE SULF ER 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route every 12 hours |
| MORPHINE SULF ER 60 MG TABLET | Maintenance | Adults take 1 tablet (60 mg) by oral route every 12 hours |
| MORPHINE SULF ER 100 MG TABLET | Maintenance | Adults take 1 tablet (100 mg) by oral route every 12 hours |
| MORPHINE SULF ER 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 12 hours |
The following drug interaction information is available for MS CONTIN (morphine sulfate):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Opioid Antagonists/Opioid Analgesics 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) |
CONTRAVE, LOTREXONE, LYBALVI, NALTREX, NALTREXONE BASE MONOHYDRATE, NALTREXONE HCL, NALTREXONE HCL DIHYDRATE, NALTREXONE HCL MICRONIZED, OPVEE, VIVITROL |
There are 5 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Chronic Opioids/Nalbuphine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Nalbuphine antagonizes mu-opiate receptors.(1) 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 or taking higher doses of 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) |
NALBUPHINE HCL |
| Sodium Oxybate/Agents that May Cause Respiratory Depression 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. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| Chronic Opioids/Butorphanol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Butorphanol antagonizes mu-opiate receptors.(1) Other opioids agonize mu-opiate receptors. 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, decreased opioid side effects, and/or renarcotization. PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses of opioids may be more likely to experience withdrawal symptoms with concurrent use. 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: 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) |
BUTORPHANOL TARTRATE |
| Chronic Opioids/Buprenorphine; Pentazocine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Buprenorphine antagonizes mu-opiate receptors.(1) Pentazocine is a mixed agonist-antagonist at opiate receptors.(2) Other opioids agonize mu-opiate receptors. 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, decreased opioid side effects, and/or renarcotization. PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses 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: 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) |
BELBUCA, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, PENTAZOCINE-NALOXONE HCL, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Eluxadoline/Anticholinergics; Opioids 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) |
VIBERZI |
There are 12 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| 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. |
BRAFTOVI, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, ORKAMBI, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFADIN, RIFAMPIN, TEGRETOL, TEGRETOL XR, TIBSOVO, XTANDI |
| Gabapentinoids/Opioids (IR & ER) 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER |
| Opioids (Extended 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| Opioids (Extended 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
AMBIEN, AMBIEN CR, BELSOMRA, DAYVIGO, EDLUAR, ESZOPICLONE, LUNESTA, QUVIVIQ, RAMELTEON, ROZEREM, ZALEPLON, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Opioids (Extended 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
BACLOFEN, CARISOPRODOL, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHLORZOXAZONE, DANTRIUM, DANTROLENE SODIUM, FLEQSUVY, LORZONE, LYVISPAH, MEPROBAMATE, METHOCARBAMOL, NORGESIC, NORGESIC FORTE, ORPHENADRINE CITRATE, ORPHENADRINE CITRATE ER, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OZOBAX, OZOBAX DS, REVONTO, ROBAXIN, RYANODEX, SOMA, TANLOR, TIZANIDINE HCL, VANADOM, ZANAFLEX |
| Opioids (Extended Release)/Antipsychotics; Phenothiazines 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
ABILIFY, ABILIFY ASIMTUFII, ABILIFY MAINTENA, ADASUVE, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, ARISTADA, ARISTADA INITIO, ASENAPINE MALEATE, BARHEMSYS, CAPLYTA, CHLORPROMAZINE HCL, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, COMPAZINE, COMPRO, DROPERIDOL, ERZOFRI, FANAPT, FLUPHENAZINE DECANOATE, FLUPHENAZINE HCL, HALDOL DECANOATE 100, HALDOL DECANOATE 50, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, LATUDA, LOXAPINE, LURASIDONE HCL, MOLINDONE HCL, NUPLAZID, OLANZAPINE, OLANZAPINE ODT, OLANZAPINE-FLUOXETINE HCL, OPIPZA, PALIPERIDONE ER, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PERSERIS, PHENERGAN, PIMOZIDE, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, REXULTI, RISPERDAL, RISPERDAL CONSTA, RISPERIDONE, RISPERIDONE ER, RISPERIDONE ODT, RYKINDO, SAPHRIS, SECUADO, SEROQUEL, SEROQUEL XR, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, THIOTHIXENE, TRIFLUOPERAZINE HCL, UZEDY, VERSACLOZ, VRAYLAR, ZYPREXA |
| Desmopressin/Agents with Hyponatremia Risk 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) |
DDAVP, DESMOPRESSIN ACETATE, NOCDURNA |
| Opioids (Extended 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: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, 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 inadequate. 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. Consider this risk when using concurrently with stimulants.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. 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) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE SULFATE, APTENSIO XR, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DESOXYN, DEXEDRINE, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, FOCALIN, FOCALIN XR, JORNAY PM, LISDEXAMFETAMINE DIMESYLATE, METADATE CD, METADATE ER, METHAMPHETAMINE HCL, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), MYDAYIS, PROCENTRA, QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN, RITALIN LA, VYVANSE, XELSTRYM, ZENZEDI |
| Selected Opioids (Extended Release)/Metaxalone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and metaxalone may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as the muscle relaxant metaxalone, 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 the muscle relaxant metaxalone to patients for whom alternatives are inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
METAXALONE |
| Opioids (Extended 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
AMRIX, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, FEXMID, NOPIOID-LMC KIT |
| Select Opioids (Extended Release)/Select Tranquilizers 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 or tranquilizers may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as tranquilizers 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 tranquilizers to patients for whom alternatives are inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
PENTOBARBITAL SODIUM |
| Opioids (Extended 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 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 ziprasidone to patients for whom alternatives are inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE |
The following contraindication information is available for MS CONTIN (morphine sulfate):
Drug contraindication overview.
*Significant respiratory depression. *Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. *Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
*Known or suspected GI obstruction, including paralytic ileus. *Hypersensitivity to morphine (e.g., anaphylaxis). *Neuraxial administration of morphine sulfate injection (Duramorph(R)) in patients with infection at the injection microinfusion site, concomitant anticoagulant therapy, uncontrolled bleeding diathesis, or the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration especially hazardous.
*Significant respiratory depression. *Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. *Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
*Known or suspected GI obstruction, including paralytic ileus. *Hypersensitivity to morphine (e.g., anaphylaxis). *Neuraxial administration of morphine sulfate injection (Duramorph(R)) in patients with infection at the injection microinfusion site, concomitant anticoagulant therapy, uncontrolled bleeding diathesis, or the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration especially hazardous.
There are 2 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute asthma attack |
| Paralytic ileus |
There are 17 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute pancreatitis |
| Alcohol intoxication |
| Alcohol use disorder |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Drug abuse |
| Exacerbation of chronic obstructive pulmonary disease |
| Familial dysautonomia |
| Gastrointestinal obstruction |
| History of opioid overdose |
| Hypotension |
| Inflammatory bowel disease |
| Intracranial hypertension |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Respiratory depression |
| Shock |
| Sleep apnea |
| Systemic mastocytosis |
There are 12 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Adrenocortical insufficiency |
| Benign prostatic hyperplasia |
| Biliary tract disorder |
| Cachexia |
| Constipation |
| Cor pulmonale |
| Debilitation |
| Lower seizure threshold |
| Seizure disorder |
| Severe hepatic disease |
| Untreated hypothyroidism |
| Urinary retention |
The following adverse reaction information is available for MS CONTIN (morphine sulfate):
Adverse reaction overview.
Common adverse effects reported in adults receiving morphine include constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, headache, and sweating. Serious adverse effectsinclude apnea, circulatory depression, respiratory depression or arrest, shock, and cardiac arrest. Common adverse effects reported in pediatric patients (>5%) receiving morphine include nausea, vomiting, constipation, decreased oxygen saturation, and flatulence.
Common adverse effects reported in adults receiving morphine include constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, headache, and sweating. Serious adverse effectsinclude apnea, circulatory depression, respiratory depression or arrest, shock, and cardiac arrest. Common adverse effects reported in pediatric patients (>5%) receiving morphine include nausea, vomiting, constipation, decreased oxygen saturation, and flatulence.
There are 40 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Allergic dermatitis Angioedema Atelectasis Bradycardia Bronchospastic pulmonary disease Dyspnea Involuntary muscle movement Laryngeal edema Laryngismus Pruritus of skin Skin rash Tachycardia Urticaria |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Accidental fall Acute generalized exanthematous pustulosis Acute respiratory failure Adrenocortical insufficiency Anaphylaxis Androgen deficiency Anemia Apnea Cardiac arrest Coma Drug dependence Drug-induced psychosis Hallucinations Hypothalamic-pituitary insufficiency Ileus Intracranial hypertension Lethargy Muscle rigidity Myoclonus Osteopenia Pancreatitis Respiratory depression Seizure disorder Shock Sleep apnea Urinary retention |
There are 61 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Constipation Dizziness Drowsy Hyperhidrosis Hypotension Nausea Sedation Syncope Vomiting |
Anorexia Biliary spasm Blurred vision Diplopia Gastrointestinal irritation General weakness Headache disorder Malaise Nervousness Peripheral edema Ureteral spasm Xerostomia |
| Rare/Very Rare |
|---|
|
Acute cognitive impairment Agitation Amenorrhea Anticholinergic toxicity Ataxia Delirium Depression Disorder of ejaculation Dream disorder Dry skin Dyspepsia Dysphagia Dysphoric mood Dysuria Edema Elevated serum amylase Erectile dysfunction Euphoria Gait abnormality Hiccups Infertility Insomnia Libido changes Memory impairment Ocular pain Opioid dependence Opioid induced allodynia Opioid induced hyperalgesia Orthostatic hypotension Palpitations Polydipsia Symptoms of anxiety Toxic amblyopia Tremor Urinary hesitancy Vasodilation of blood vessels Vertigo Visual changes Voice change Weight loss |
The following precautions are available for MS CONTIN (morphine sulfate):
Safety and effectiveness of morphine in pediatric patientsvary based on the route of administration and characteristics of the preparation. The safety and effectiveness of immediate-release morphine sulfate tablets administered orally have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. Use of the immediate-releasetablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with postoperative acute pain.
The safety and effectiveness of immediate-release morphine sulfate tablets have not been established in pediatric patients weighing less than 50 kg because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg. The safety and effectiveness of morphine sulfate oral solution (2 mg/mL and 4 mg/mL) have been established for the management of pediatric patients 2 to 17 years of age with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate.
The safety and effectiveness of the oral solution have not been establishedin pediatric patients younger than 2 years of age. The safety and effectiveness of morphine sulfate oral solution 20 mg/mL have not been established in pediatric patients. The safety and effectiveness of morphine sulfate oral solution have not been established for the management of pediatric patients 2 years of age and older with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.
The safety and effectiveness of continuous IV infusion of morphine have been established for the management of pain in pediatric patients of all age groups. Such use is supported by evidence from randomized controlled studies in pediatricpatients. Monitor cardiorespiratory function in children younger than 3 months of age.
Adjust the infusion rate based on clinical signs of inadequate pain relief and/or increased somnolence. For premature infants and former premature infants with chronic lung disease and up to 5 to 6 months of age, careful monitoring for depressed hypoxic drive is required following continuous IV infusion of the opioid. Safety and efficacy of morphine sulfate suppositories in pediatric patients have not been established.
Safety and efficacy of epidural or intrathecal injection of morphine in pediatric patients have not been established and such injections are not recommended. Safety and efficacy of patient-controlled analgesia (PCA) have not been established in pediatric patients. Safety and efficacy of morphine sulfate extended-release capsules in children younger than 18 years of age have not been established.
In addition, the manufacturers state that commercially available strengths of morphine sulfate extended-release capsules are not appropriate for children and that the contents of the capsules should not be sprinkled onto applesauce for administration to children. Safety and efficacy of morphine sulfate extended-release tablets in children have not been established.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
The safety and effectiveness of immediate-release morphine sulfate tablets have not been established in pediatric patients weighing less than 50 kg because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg. The safety and effectiveness of morphine sulfate oral solution (2 mg/mL and 4 mg/mL) have been established for the management of pediatric patients 2 to 17 years of age with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate.
The safety and effectiveness of the oral solution have not been establishedin pediatric patients younger than 2 years of age. The safety and effectiveness of morphine sulfate oral solution 20 mg/mL have not been established in pediatric patients. The safety and effectiveness of morphine sulfate oral solution have not been established for the management of pediatric patients 2 years of age and older with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.
The safety and effectiveness of continuous IV infusion of morphine have been established for the management of pain in pediatric patients of all age groups. Such use is supported by evidence from randomized controlled studies in pediatricpatients. Monitor cardiorespiratory function in children younger than 3 months of age.
Adjust the infusion rate based on clinical signs of inadequate pain relief and/or increased somnolence. For premature infants and former premature infants with chronic lung disease and up to 5 to 6 months of age, careful monitoring for depressed hypoxic drive is required following continuous IV infusion of the opioid. Safety and efficacy of morphine sulfate suppositories in pediatric patients have not been established.
Safety and efficacy of epidural or intrathecal injection of morphine in pediatric patients have not been established and such injections are not recommended. Safety and efficacy of patient-controlled analgesia (PCA) have not been established in pediatric patients. Safety and efficacy of morphine sulfate extended-release capsules in children younger than 18 years of age have not been established.
In addition, the manufacturers state that commercially available strengths of morphine sulfate extended-release capsules are not appropriate for children and that the contents of the capsules should not be sprinkled onto applesauce for administration to children. Safety and efficacy of morphine sulfate extended-release tablets in children have not been established.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
There are no available data with morphine use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Clinical studies of morphine use during pregnancy have not reported a clear association between morphine and major birth defects. Based on findings from animal studies, advise pregnant women of the potential risk to a fetus.
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphineis not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.
Opioid analgesics, including morphine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression.
Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphineis not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.
Opioid analgesics, including morphine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression.
Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.
Morphine should be used with caution in nursing women, since the drug has been reported to distribute into humanmilk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for morphine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. Because of the potential for serious adverse reactions, including excessive sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules or tablets.
Monitor infants exposed to morphine through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.
Monitor infants exposed to morphine through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.
Patients 65 years of age or older may have increased sensitivity to morphine. In general, use caution when selecting 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. Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after administration of large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other drugs that depress respiration.
Titrate the dosage of morphine sulfate slowly in geriatric patients and frequently reevaluate the patient for signs of CNS and respiratory depression. Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection;regular evaluation of renal function should occur.
Titrate the dosage of morphine sulfate slowly in geriatric patients and frequently reevaluate the patient for signs of CNS and respiratory depression. Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection;regular evaluation of renal function should occur.
The following prioritized warning is available for MS CONTIN (morphine sulfate):
WARNING: Morphine has a risk for abuse and addiction, which can lead to overdose and death. Morphine may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of morphine that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have naloxone available to treat opioid overdose. Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Be sure you know how to take morphine and what other drugs you should avoid taking with it.
See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up. Do not break, crush, chew, or dissolve this medication.
Taking broken, crushed, chewed, or dissolved forms of extended-release morphine could cause a fatal overdose. Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away.
Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits. Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed.
It may slightly increase the risk of birth defects if used during the first two months of pregnancy. Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time.
Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms. Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight.
WARNING: Morphine has a risk for abuse and addiction, which can lead to overdose and death. Morphine may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of morphine that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have naloxone available to treat opioid overdose. Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Be sure you know how to take morphine and what other drugs you should avoid taking with it.
See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up. Do not break, crush, chew, or dissolve this medication.
Taking broken, crushed, chewed, or dissolved forms of extended-release morphine could cause a fatal overdose. Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away.
Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits. Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed.
It may slightly increase the risk of birth defects if used during the first two months of pregnancy. Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time.
Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms. Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight.
The following icd codes are available for MS CONTIN (morphine sulfate)'s list of indications:
| Severe chronic pain requiring long-term opioid treatment | |
| G89.2 | Chronic pain, not elsewhere classified |
| G89.21 | Chronic pain due to trauma |
| G89.22 | Chronic post-thoracotomy pain |
| G89.28 | Other chronic postprocedural pain |
| G89.29 | Other chronic pain |
| G89.4 | Chronic pain syndrome |
| Z79.891 | Long term (current) use of opiate analgesic |
| Severe chronic pain with opioid tolerance | |
| G89.2 | Chronic pain, not elsewhere classified |
| G89.21 | Chronic pain due to trauma |
| G89.22 | Chronic post-thoracotomy pain |
| G89.28 | Other chronic postprocedural pain |
| G89.29 | Other chronic pain |
| G89.3 | Neoplasm related pain (acute) (chronic) |
| G89.4 | Chronic pain syndrome |
| Z79.891 | Long term (current) use of opiate analgesic |
Formulary Reference Tool