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Opioids (Alfentanil, Butorphanol, Codeine, Diamorphine, FeOxycodonentanyl)
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Pharmacology
The opioid analgesics act primarily on the CNS and the intestines. The perception of and emotional response to pain is modified when opioid analgesics bind with stereospecific receptors in the CNS. Five major groups of opioid receptors are known: mu, kappa, sigma, delta and epsilon. Opioid analgesic activity occurs at the mu, kappa and sigma receptors. Opioid agonists such as morphine exert their activity mainly at the mu receptor. Mixed agonist-antagonists such as butorphanol, nalbuphine and pentazocine act primarily at the kappa receptors (thought to mediate analgesic effects) and sigma receptors (may produce subjective and psychotomimetic effects).
In addition to analgesia, opioid agonist activity in the CNS may cause suppression of the cough reflex, respiratory depression, change in mood such as euphoria or dysphoria, and EEG changes. Nausea and vomiting, probably caused by stimulation of the chemoreceptor trigger zone, can also occur. Peripheral vasodilation, reduced peripheral resistance and the inhibition of baroreceptors can result in orthostatic hypotension and fainting.
Effects of opioids on the gastrointestinal tract include decreased gastric, biliary and pancreatic secretions, and inhibition of peristalsis leading to constipation. Opioids can affect smooth muscle tone in the urinary tract, leading to dysuria or urinary retention.
Methadone: Methadone is a synthetic diphenylheptane-derivative opioid agonist with pharmacologic properties qualitatively similar to those of morphine. In equianalgesic doses, methadone may produce a similar or slightly higher degree of respiratory depression and less sedation, euphoria and constipation than morphine.
Methadone prevents withdrawal symptoms and reduces opioid cravings in individuals who are opioid-dependent.
Pharmacokinetics: Opioid analgesics are absorbed after administration by many different routes including the oral, rectal, intramuscular, intravenous, epidural, intrathecal, subcutaneous, intranasal and transdermal routes. They are metabolized by the liver and eliminated primarily by the kidney. Dosage adjustment in the presence of renal or hepatic disease is usually indicated. A comparison of pharmacokinetic parameters can be found in TableI.
The opioid analgesics act primarily on the CNS and the intestines. The perception of and emotional response to pain is modified when opioid analgesics bind with stereospecific receptors in the CNS. Five major groups of opioid receptors are known: mu, kappa, sigma, delta and epsilon. Opioid analgesic activity occurs at the mu, kappa and sigma receptors. Opioid agonists such as morphine exert their activity mainly at the mu receptor. Mixed agonist-antagonists such as butorphanol, nalbuphine and pentazocine act primarily at the kappa receptors (thought to mediate analgesic effects) and sigma receptors (may produce subjective and psychotomimetic effects).
In addition to analgesia, opioid agonist activity in the CNS may cause suppression of the cough reflex, respiratory depression, change in mood such as euphoria or dysphoria, and EEG changes. Nausea and vomiting, probably caused by stimulation of the chemoreceptor trigger zone, can also occur. Peripheral vasodilation, reduced peripheral resistance and the inhibition of baroreceptors can result in orthostatic hypotension and fainting.
Effects of opioids on the gastrointestinal tract include decreased gastric, biliary and pancreatic secretions, and inhibition of peristalsis leading to constipation. Opioids can affect smooth muscle tone in the urinary tract, leading to dysuria or urinary retention.
Methadone: Methadone is a synthetic diphenylheptane-derivative opioid agonist with pharmacologic properties qualitatively similar to those of morphine. In equianalgesic doses, methadone may produce a similar or slightly higher degree of respiratory depression and less sedation, euphoria and constipation than morphine.
Methadone prevents withdrawal symptoms and reduces opioid cravings in individuals who are opioid-dependent.
Pharmacokinetics: Opioid analgesics are absorbed after administration by many different routes including the oral, rectal, intramuscular, intravenous, epidural, intrathecal, subcutaneous, intranasal and transdermal routes. They are metabolized by the liver and eliminated primarily by the kidney. Dosage adjustment in the presence of renal or hepatic disease is usually indicated. A comparison of pharmacokinetic parameters can be found in TableI.
Indications
The Opioid Analgesics Act Primarily On The CNS And The Intestines. The Perception Of And Emotional Response To Pain Is Modified When Opioid Analgesics Bind With Stereospecific Receptors In The CNS. Five Major Groups Of Opioid Receptors Are Known: Mu, Kappa, Sigma, Delta And Epsilon. Opioid Analgesic Activity Occurs At The Mu, Kappa And Sigma Receptors. Opioid Agonists Such As Morphine Exert Their Activity Mainly At The Mu Receptor. Mixed Agonist-antagonists Such As Butorphanol, Nalbuphine And Pentazocine Act Primarily At The Kappa Receptors (thought To Mediate Analgesic Effects) And Sigma Receptors (may Produce Subjective And Psychotomimetic Effects).
In Addition To Analgesia, Opioid Agonist Activity In The CNS May Cause Suppression Of The Cough Reflex, Respiratory Depression, Change In Mood Such As Euphoria Or Dysphoria, And EEG Changes. Nausea And Vomiting, Probably Caused By Stimulation Of The Chemoreceptor Trigger Zone, Can Also Occur. Peripheral Vasodilation, Reduced Peripheral Resistance And The Inhibition Of Baroreceptors Can Result In Orthostatic Hypotension And Fainting.
Effects Of Opioids On The Gastrointestinal Tract Include Decreased Gastric, Biliary And Pancreatic Secretions, And Inhibition Of Peristalsis Leading To Constipation. Opioids Can Affect Smooth Muscle Tone In The Urinary Tract, Leading To Dysuria Or Urinary Retention.
Methadone: Methadone Is A Synthetic Diphenylheptane-derivative Opioid Agonist With Pharmacologic Properties Qualitatively Similar To Those Of Morphine. In Equianalgesic Doses, Methadone May Produce A Similar Or Slightly Higher Degree Of Respiratory Depression And Less Sedation, Euphoria And Constipation Than Morphine.
Methadone Prevents Withdrawal Symptoms And Reduces Opioid Cravings In Individuals Who Are Opioid-dependent.
Pharmacokinetics: Opioid Analgesics Are Absorbed After Administration By Many Different Routes Including The Oral, Rectal, Intramuscular, Intravenous, Epidural, Intrathecal, Subcutaneous, Intranasal And Transdermal Routes. They Are Metabolized By The Liver And Eliminated Primarily By The Kidney. Dosage Adjustment In The Presence Of Renal Or Hepatic Disease Is Usually Indicated. A Comparison Of Pharmacokinetic Parameters Can Be Found In TableI.
The Opioid Analgesics Act Primarily On The CNS And The Intestines. The Perception Of And Emotional Response To Pain Is Modified When Opioid Analgesics Bind With Stereospecific Receptors In The CNS. Five Major Groups Of Opioid Receptors Are Known: Mu, Kappa, Sigma, Delta And Epsilon. Opioid Analgesic Activity Occurs At The Mu, Kappa And Sigma Receptors. Opioid Agonists Such As Morphine Exert Their Activity Mainly At The Mu Receptor. Mixed Agonist-antagonists Such As Butorphanol, Nalbuphine And Pentazocine Act Primarily At The Kappa Receptors (thought To Mediate Analgesic Effects) And Sigma Receptors (may Produce Subjective And Psychotomimetic Effects).
In Addition To Analgesia, Opioid Agonist Activity In The CNS May Cause Suppression Of The Cough Reflex, Respiratory Depression, Change In Mood Such As Euphoria Or Dysphoria, And EEG Changes. Nausea And Vomiting, Probably Caused By Stimulation Of The Chemoreceptor Trigger Zone, Can Also Occur. Peripheral Vasodilation, Reduced Peripheral Resistance And The Inhibition Of Baroreceptors Can Result In Orthostatic Hypotension And Fainting.
Effects Of Opioids On The Gastrointestinal Tract Include Decreased Gastric, Biliary And Pancreatic Secretions, And Inhibition Of Peristalsis Leading To Constipation. Opioids Can Affect Smooth Muscle Tone In The Urinary Tract, Leading To Dysuria Or Urinary Retention.
Methadone: Methadone Is A Synthetic Diphenylheptane-derivative Opioid Agonist With Pharmacologic Properties Qualitatively Similar To Those Of Morphine. In Equianalgesic Doses, Methadone May Produce A Similar Or Slightly Higher Degree Of Respiratory Depression And Less Sedation, Euphoria And Constipation Than Morphine.
Methadone Prevents Withdrawal Symptoms And Reduces Opioid Cravings In Individuals Who Are Opioid-dependent.
Pharmacokinetics: Opioid Analgesics Are Absorbed After Administration By Many Different Routes Including The Oral, Rectal, Intramuscular, Intravenous, Epidural, Intrathecal, Subcutaneous, Intranasal And Transdermal Routes. They Are Metabolized By The Liver And Eliminated Primarily By The Kidney. Dosage Adjustment In The Presence Of Renal Or Hepatic Disease Is Usually Indicated. A Comparison Of Pharmacokinetic Parameters Can Be Found In TableI.
Contraindications
Hypersensitivity to opioid analgesics. Diarrhea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract. Acute respiratory depression, acute asthma attack, and upper airway obstruction.
For Epidural or Intrathecal Use: Infection at or near site of administration, clotting defects due to anticoagulant therapy or hematological disorders.
See individual product monographs for comprehensive information, with attention to the following: Diamorphine, morphine or pethidine should not be used concurrently with MAO inhibitors, or within 2weeks of such therapy.
Hypersensitivity to opioid analgesics. Diarrhea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract. Acute respiratory depression, acute asthma attack, and upper airway obstruction.
For Epidural or Intrathecal Use: Infection at or near site of administration, clotting defects due to anticoagulant therapy or hematological disorders.
See individual product monographs for comprehensive information, with attention to the following: Diamorphine, morphine or pethidine should not be used concurrently with MAO inhibitors, or within 2weeks of such therapy.
Safety Information / Warning
Opioid analgesics have the potential for abuse. Psychological dependence or physical dependence and tolerance may follow repeated administration. Opioid analgesics should be prescribed and administered with caution, especially in cases of severe hepatic insufficiency, severe CNS depression or coma, in patients with head injuries or conditions in which intracranial pressure is increased, myxedema, Addison's Disease, acute alcohol intoxication, delerium tremens, convulsive disorders and in patients taking MAO inhibitors. Opioid analgesics can cause severe hypotension in individuals whose circulation is already compromised by hypovolemia, shock, drugs producing hypotension or other conditions that interfere with ability to maintain normal blood pressure. These drugs may produce orthostatic hypotension in the ambulatory patient.
Rapid i.v. injection of opioid analgesics increases incidence of adverse reactions such as severe respiratory depression, apnea, hypotension, peripheral circulatory collapse and cardiac arrest. The patient should be lying down during i.v. administration. These drugs should not be administeredi.v. unless an opioid antagonist and the facilities for assisted or controlled respiration are immediately available.
Opioid analgesics should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve and patients with preexisting respiratory depression, hypoxia or hypercapnia. Refer to individual product monographs for specific warnings with attention to the following:
Nalbuphine: Commercial preparation contains sodium metabisulfite which may cause allergic reactions (e.g., hives, itching, wheezing, anaphylaxis) in susceptible individuals. Prevalence of sensitivity in the general population is probably low; it is seen more frequently in asthmatics or atopic non-asthmatic patients.
Pentazocine: Acute CNS manifestations (e.g., hallucinations, disorientation, confusion) have been reported in patients receiving therapeutic doses.
Methadone: Overdose and death can occur when methadone is ingested by individuals for whom it has not been prescribed, or who are not opioid-dependent.
Opioid analgesics have the potential for abuse. Psychological dependence or physical dependence and tolerance may follow repeated administration. Opioid analgesics should be prescribed and administered with caution, especially in cases of severe hepatic insufficiency, severe CNS depression or coma, in patients with head injuries or conditions in which intracranial pressure is increased, myxedema, Addison's Disease, acute alcohol intoxication, delerium tremens, convulsive disorders and in patients taking MAO inhibitors. Opioid analgesics can cause severe hypotension in individuals whose circulation is already compromised by hypovolemia, shock, drugs producing hypotension or other conditions that interfere with ability to maintain normal blood pressure. These drugs may produce orthostatic hypotension in the ambulatory patient.
Rapid i.v. injection of opioid analgesics increases incidence of adverse reactions such as severe respiratory depression, apnea, hypotension, peripheral circulatory collapse and cardiac arrest. The patient should be lying down during i.v. administration. These drugs should not be administeredi.v. unless an opioid antagonist and the facilities for assisted or controlled respiration are immediately available.
Opioid analgesics should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve and patients with preexisting respiratory depression, hypoxia or hypercapnia. Refer to individual product monographs for specific warnings with attention to the following:
Nalbuphine: Commercial preparation contains sodium metabisulfite which may cause allergic reactions (e.g., hives, itching, wheezing, anaphylaxis) in susceptible individuals. Prevalence of sensitivity in the general population is probably low; it is seen more frequently in asthmatics or atopic non-asthmatic patients.
Pentazocine: Acute CNS manifestations (e.g., hallucinations, disorientation, confusion) have been reported in patients receiving therapeutic doses.
Methadone: Overdose and death can occur when methadone is ingested by individuals for whom it has not been prescribed, or who are not opioid-dependent.
Precautions
General: Opioid analgesics should be used with caution in elderly and debilitated individuals because of the danger of cardiac or respiratory depression, as well as those patients with hemorrhage and those with severe impairment of hepatic, pulmonary or renal function. Careful consideration should be given before using opioid analgesics in the presence of the following conditions: myxedema or hypothyroidism (increased risk of CNS and respiratory depression); adrenocortical insufficiency; toxic psychosis; CNS depression; prostatic hypertrophy or urethral stricture; kyphoscoliosis; acute alcohol intoxication and delerium tremens; severe inflammatory bowel disease; gallbladder disease. Due to their cholinergic effects, opioid analgesics should be used with caution in patients with cardiac arrhythmias.
Opioid analgesics may obscure the diagnosis or clinical course in patients with acute abdominal conditions and may induce or exacerbate seizures.
Hypersensitivity: Opioids cause histamine release from mast cells in blood and tissues to varying degrees. Histamine release seems to be related to the dose and route of administration of the opioid, with the oral, rectal and transdermal routes less likely than parenteral administration to result in a reaction. The propensity for an individual opioid to cause anaphylactoid or anaphylactic reactions appears to be related (inversely) to its analgesic potency, rather than to its chemical structure. Pethidine (meperidine) has a higher propensity to cause histamine release than does fentanyl, for example. Switching to a structurally unrelated opioid is not helpful in preventing subsequent reactions.
It is important to determine the exact nature of the reaction in patients reporting allergy to opioids, as many patients believe they are allergic after experiencing an exaggerated pharmacologic response to opioids such as nausea, drowsiness or constipation.
Methadone: Patients established on methadone maintenance therapy for opioid dependence develop tolerance to the analgesic, sedative and euphoric effects of methadone. The established maintenance dose of methadone in these patients will consistently prevent withdrawal symptoms, but will not, by itself, meet their analgesic requirements in the event of surgery or pain of another cause. If pain is not severe, nonopioid analgesics such as NSAIDs can be used. For severe pain, pure opioid agonists may be used. The use of agonist-antagonists should be avoided because of the possibility of precipitating withdrawal. See TableI for a list of opioid agonists and agonist-antagonists.
The use of opioid analgesics in patients on methadone maintenance must be closely supervised, with appropriately frequent reassessment of their pain control needs. Similar precautions are recommended for the use of drugs such as benzodiazepines or CNS stimulants in these patients.
Drug Interactions : Anticholinergics: Concomitant use of drugs with antimuscarinic activity may increase the risk of severe constipation and/or urinary retention.
Cimetidine: Concurrent administration of cimetidine may lead to increased effect or toxicity of opioid analgesics.
CNS Agents: Concomitant administration of other CNS drugs such as sedatives, hypnotics, phenothiazines, anesthetics and alcohol may increase the sedative and depressant effects of opioid analgesics. If the concomitant use of these drugs is considered necessary, their doses should be reduced accordingly.
MAO Inhibitors: Serious adverse reactions have been reported in patients who receive MAO inhibitors with pethidine. Other opioid analgesics should be used with extreme caution, in patients taking MAO inhibitors (including selegiline) or within 14days of such therapy.
Neuromuscular Blocking Agents: Opioid analgesics may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Opioid Antagonists: Naltrexone and agonist-antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol) should not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist-antagonists may reduce the analgesic effect or may precipitate withdrawal symptoms.
Other Opioids: The use of more than one opioid agonist at a time is usually inappropriate; additive CNS depressant, respiratory depressant and hypotensive effects may occur if 2or more agonists are used concurrently. Potentiation of effects may occur with a previously administered long-acting opioid analgesic.
Tricyclic Antidepressants: Tricyclic antidepressants may enhance opioid-induced respiratory depression.
Warfarin: Opioid agonists may potentiate the anticoagulant effects of coumarin anticoagulants.
Drug-Laboratory Test Interactions : Opioid analgesics may interfere with certain diagnostic procedures, by increasing plasma amylase and lipase concentrations and by increasing CSF pressure. Gastric emptying is delayed by these drugs so gastric emptying studies will not be valid.
Pregnancy: Safety for use has not been established, although certain opioid analgesics are sometimes used to relieve pain during labor and delivery.
As opioid analgesics cross the placental barrier, potential benefits must be weighed against possible hazards. Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. Withdrawal signs include: irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting and fever.
Methadone: Methadone is sometimes used during pregnancy in opioid-dependent women, even though the fetus will be exposed to the drug and may experience withdrawal after delivery. The use of methadone in pregnancy is often considered to be a safer and more manageable option than the possibility of continued illicit drug use, especially if the mother is likely to engage in high-risk behaviors associated with procuring and using street drugs.
Lactation: The extent to which opioids are excreted in breast milk is controversial. This should be taken into consideration when breast-feeding. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped.
Methadone: Methadone is distributed into breast milk in variable amounts but is generally considered to be compatible with breast-feeding.
Breast-feeding may prevent withdrawal symptoms in addicted neonates.
Children: Opioids are used in children of all ages for the management of pain associated with medical or surgical procedures, as an adjunct to general anesthesia, for postoperative pain and for the treatment of painful medical conditions. Specialized references should be consulted for specific information on dosage and management of adverse effects.
Neonates: Agents known to compromise respiratory function should be administered only by persons experienced in neonatal airway management and in settings with the capacity for continuous monitoring.
Geriatrics: Elderly patients may be more susceptible to adverse effects, especially respiratory depression and constipation. Caution is advised; the initial dose should be reduced and effects monitored. Elimination and metabolism may be slowed; lower doses or longer dosing intervals may be required.
Occupational Hazards: Patients should be warned against driving or operating machinery if they become drowsy or show impaired mental and/or physical abilities.
Headache: Limited clinical experience appears to suggest patients with migraine headache may be more susceptible to adverse reactions with butorphanol use.
Myocardial Infarction: Opioid analgesics must be used with caution in patients with MI who are experiencing nausea or vomiting.
General: Opioid analgesics should be used with caution in elderly and debilitated individuals because of the danger of cardiac or respiratory depression, as well as those patients with hemorrhage and those with severe impairment of hepatic, pulmonary or renal function. Careful consideration should be given before using opioid analgesics in the presence of the following conditions: myxedema or hypothyroidism (increased risk of CNS and respiratory depression); adrenocortical insufficiency; toxic psychosis; CNS depression; prostatic hypertrophy or urethral stricture; kyphoscoliosis; acute alcohol intoxication and delerium tremens; severe inflammatory bowel disease; gallbladder disease. Due to their cholinergic effects, opioid analgesics should be used with caution in patients with cardiac arrhythmias.
Opioid analgesics may obscure the diagnosis or clinical course in patients with acute abdominal conditions and may induce or exacerbate seizures.
Hypersensitivity: Opioids cause histamine release from mast cells in blood and tissues to varying degrees. Histamine release seems to be related to the dose and route of administration of the opioid, with the oral, rectal and transdermal routes less likely than parenteral administration to result in a reaction. The propensity for an individual opioid to cause anaphylactoid or anaphylactic reactions appears to be related (inversely) to its analgesic potency, rather than to its chemical structure. Pethidine (meperidine) has a higher propensity to cause histamine release than does fentanyl, for example. Switching to a structurally unrelated opioid is not helpful in preventing subsequent reactions.
It is important to determine the exact nature of the reaction in patients reporting allergy to opioids, as many patients believe they are allergic after experiencing an exaggerated pharmacologic response to opioids such as nausea, drowsiness or constipation.
Methadone: Patients established on methadone maintenance therapy for opioid dependence develop tolerance to the analgesic, sedative and euphoric effects of methadone. The established maintenance dose of methadone in these patients will consistently prevent withdrawal symptoms, but will not, by itself, meet their analgesic requirements in the event of surgery or pain of another cause. If pain is not severe, nonopioid analgesics such as NSAIDs can be used. For severe pain, pure opioid agonists may be used. The use of agonist-antagonists should be avoided because of the possibility of precipitating withdrawal. See TableI for a list of opioid agonists and agonist-antagonists.
The use of opioid analgesics in patients on methadone maintenance must be closely supervised, with appropriately frequent reassessment of their pain control needs. Similar precautions are recommended for the use of drugs such as benzodiazepines or CNS stimulants in these patients.
Drug Interactions : Anticholinergics: Concomitant use of drugs with antimuscarinic activity may increase the risk of severe constipation and/or urinary retention.
Cimetidine: Concurrent administration of cimetidine may lead to increased effect or toxicity of opioid analgesics.
CNS Agents: Concomitant administration of other CNS drugs such as sedatives, hypnotics, phenothiazines, anesthetics and alcohol may increase the sedative and depressant effects of opioid analgesics. If the concomitant use of these drugs is considered necessary, their doses should be reduced accordingly.
MAO Inhibitors: Serious adverse reactions have been reported in patients who receive MAO inhibitors with pethidine. Other opioid analgesics should be used with extreme caution, in patients taking MAO inhibitors (including selegiline) or within 14days of such therapy.
Neuromuscular Blocking Agents: Opioid analgesics may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Opioid Antagonists: Naltrexone and agonist-antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol) should not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist-antagonists may reduce the analgesic effect or may precipitate withdrawal symptoms.
Other Opioids: The use of more than one opioid agonist at a time is usually inappropriate; additive CNS depressant, respiratory depressant and hypotensive effects may occur if 2or more agonists are used concurrently. Potentiation of effects may occur with a previously administered long-acting opioid analgesic.
Tricyclic Antidepressants: Tricyclic antidepressants may enhance opioid-induced respiratory depression.
Warfarin: Opioid agonists may potentiate the anticoagulant effects of coumarin anticoagulants.
Drug-Laboratory Test Interactions : Opioid analgesics may interfere with certain diagnostic procedures, by increasing plasma amylase and lipase concentrations and by increasing CSF pressure. Gastric emptying is delayed by these drugs so gastric emptying studies will not be valid.
Pregnancy: Safety for use has not been established, although certain opioid analgesics are sometimes used to relieve pain during labor and delivery.
As opioid analgesics cross the placental barrier, potential benefits must be weighed against possible hazards. Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. Withdrawal signs include: irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting and fever.
Methadone: Methadone is sometimes used during pregnancy in opioid-dependent women, even though the fetus will be exposed to the drug and may experience withdrawal after delivery. The use of methadone in pregnancy is often considered to be a safer and more manageable option than the possibility of continued illicit drug use, especially if the mother is likely to engage in high-risk behaviors associated with procuring and using street drugs.
Lactation: The extent to which opioids are excreted in breast milk is controversial. This should be taken into consideration when breast-feeding. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped.
Methadone: Methadone is distributed into breast milk in variable amounts but is generally considered to be compatible with breast-feeding.
Breast-feeding may prevent withdrawal symptoms in addicted neonates.
Children: Opioids are used in children of all ages for the management of pain associated with medical or surgical procedures, as an adjunct to general anesthesia, for postoperative pain and for the treatment of painful medical conditions. Specialized references should be consulted for specific information on dosage and management of adverse effects.
Neonates: Agents known to compromise respiratory function should be administered only by persons experienced in neonatal airway management and in settings with the capacity for continuous monitoring.
Geriatrics: Elderly patients may be more susceptible to adverse effects, especially respiratory depression and constipation. Caution is advised; the initial dose should be reduced and effects monitored. Elimination and metabolism may be slowed; lower doses or longer dosing intervals may be required.
Occupational Hazards: Patients should be warned against driving or operating machinery if they become drowsy or show impaired mental and/or physical abilities.
Headache: Limited clinical experience appears to suggest patients with migraine headache may be more susceptible to adverse reactions with butorphanol use.
Myocardial Infarction: Opioid analgesics must be used with caution in patients with MI who are experiencing nausea or vomiting.
Side Effects / Adverse Effects
Adverse Effects: Major: respiratory depression and respiratory arrest. To a lesser degree circulatory depression, shock and cardiac arrest.
Most Commonly Requiring Medical Attention: sedation, nausea and vomiting, constipation and sweating. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated if the patient lies down.
Cardiovascular: supraventricular tachycardia, bradycardia, palpitations, faintness, syncope, postural hypotension and hypertension, and phlebitis following i.v. injection.
CNS: drowsiness, sedation, euphoria, dysphoria, weakness, headache, agitation, seizures myoclonus, uncoordinated muscle movements, alterations of mood, dreams, hallucinations and disorientation, visual disturbances, insomnia, miosis, toxic psychoses.
Constipation: Practically all patients become constipated while taking opioid analgesics on a persistent basis. In some instances, particularly the elderly or bedridden, patients may become impacted. It is essential to caution patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged therapy.
Gastrointestinal: dry mouth, nausea, vomiting, constipation, biliary tract spasm, anorexia, diarrhea, cramps, dyspepsia, taste alterations.
Genitourinary: urinary retention or hesitance, antidiuretic effect, reduced libido and/or potency.
Hypersensitivity: See Precautions.
Nausea and Vomiting: occur frequently after single doses of narcotics or as an early unwanted effect of regular opioid analgesic therapy.
Withdrawal Syndrome: Physical dependence with or without psychological dependence tends to occur with chronic administration. An abstinence syndrome may be precipitated when an opioid analgesic is abruptly discontinued or opioid antagonists are administered. The following withdrawal symptoms may be observed after abrupt discontinuation of an opioid analgesic: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, sleep disturbances, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate medical use and gradual withdrawal from opioid analgesics, these symptoms are usually mild.
Other: abnormal liver function test results (propoxyphene), flushing/warmth, pain at injection site, local tissue irritation and induration following s.c. injection, particularly when repeated.
Adverse Effects: Major: respiratory depression and respiratory arrest. To a lesser degree circulatory depression, shock and cardiac arrest.
Most Commonly Requiring Medical Attention: sedation, nausea and vomiting, constipation and sweating. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated if the patient lies down.
Cardiovascular: supraventricular tachycardia, bradycardia, palpitations, faintness, syncope, postural hypotension and hypertension, and phlebitis following i.v. injection.
CNS: drowsiness, sedation, euphoria, dysphoria, weakness, headache, agitation, seizures myoclonus, uncoordinated muscle movements, alterations of mood, dreams, hallucinations and disorientation, visual disturbances, insomnia, miosis, toxic psychoses.
Constipation: Practically all patients become constipated while taking opioid analgesics on a persistent basis. In some instances, particularly the elderly or bedridden, patients may become impacted. It is essential to caution patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged therapy.
Gastrointestinal: dry mouth, nausea, vomiting, constipation, biliary tract spasm, anorexia, diarrhea, cramps, dyspepsia, taste alterations.
Genitourinary: urinary retention or hesitance, antidiuretic effect, reduced libido and/or potency.
Hypersensitivity: See Precautions.
Nausea and Vomiting: occur frequently after single doses of narcotics or as an early unwanted effect of regular opioid analgesic therapy.
Withdrawal Syndrome: Physical dependence with or without psychological dependence tends to occur with chronic administration. An abstinence syndrome may be precipitated when an opioid analgesic is abruptly discontinued or opioid antagonists are administered. The following withdrawal symptoms may be observed after abrupt discontinuation of an opioid analgesic: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, sleep disturbances, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate medical use and gradual withdrawal from opioid analgesics, these symptoms are usually mild.
Other: abnormal liver function test results (propoxyphene), flushing/warmth, pain at injection site, local tissue irritation and induration following s.c. injection, particularly when repeated.
Overdose
Symptoms: Respiratory depression (reduced respiratory rate and/or tidal volume; Cheyne-Stokes respiration; cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold or clammy skin, and sometimes hypotension and bradycardia. Severe overdosage may result in apnea, circulatory collapse, cardiac arrest and death. Miosis can be one characteristic of morphine derivative overdose. Mydriasis can take place in terminal narcosis, severe hypoxia or as a toxic effect of pethidine or its congeners.
In addition to the effects of opioid analgesic overdose in general, focal and generalized seizures constitute a prominent feature in most cases of severe propoxyphene poisoning. Nephrogenic diabetes insipidus and ECG abnormalities may also occur.
Treatment: In cases of oral ingestion, activated charcoal should be administered. Vomiting should not be induced because of the risk of rapid onset of CNS depression. Establish adequate respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation. Naloxone, a pure opioid antagonist, is used as a specific antidote to reverse the effects of opioid agonists and agonist-antagonists. An appropriate dose of naloxone should be administered, preferably by the i.v. route, simultaneously with efforts at respiratory resuscitation. The usual initial adult dose of naloxone is 0.4to 2mg i.v.; children: 0.01mg/kg i.v. (see product monograph). Since the duration of action of the opioid may exceed that of the antagonist, the patient should be under surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration. A neuromuscular blocking agent may be required if respiratory depression is related to muscular rigidity. In propoxyphene overdose, in addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant such as diazepam, bearing in mind the potential additive respiratory depressant effects.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be used as indicated. In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of such a syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in patients with physical dependence on opioids, the antagonist should be administered with extreme care by using dosage titration, commencing with 10to 20% of the usual recommended initial dose.
Methadone: The relatively long duration of action of methadone compared to that of naloxone may necessitate repeated doses of naloxone to counteract respiratory depression. A continuous i.v. infusion of naloxone may be used following the initial bolus, at a rate of two-thirds the bolus dose per hour.
The possibility of precipitating withdrawal must also be considered. Naloxone should not be used in the absence of clinically significant respiratory or cardiovascular depression.
Symptoms: Respiratory depression (reduced respiratory rate and/or tidal volume; Cheyne-Stokes respiration; cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold or clammy skin, and sometimes hypotension and bradycardia. Severe overdosage may result in apnea, circulatory collapse, cardiac arrest and death. Miosis can be one characteristic of morphine derivative overdose. Mydriasis can take place in terminal narcosis, severe hypoxia or as a toxic effect of pethidine or its congeners.
In addition to the effects of opioid analgesic overdose in general, focal and generalized seizures constitute a prominent feature in most cases of severe propoxyphene poisoning. Nephrogenic diabetes insipidus and ECG abnormalities may also occur.
Treatment: In cases of oral ingestion, activated charcoal should be administered. Vomiting should not be induced because of the risk of rapid onset of CNS depression. Establish adequate respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation. Naloxone, a pure opioid antagonist, is used as a specific antidote to reverse the effects of opioid agonists and agonist-antagonists. An appropriate dose of naloxone should be administered, preferably by the i.v. route, simultaneously with efforts at respiratory resuscitation. The usual initial adult dose of naloxone is 0.4to 2mg i.v.; children: 0.01mg/kg i.v. (see product monograph). Since the duration of action of the opioid may exceed that of the antagonist, the patient should be under surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration. A neuromuscular blocking agent may be required if respiratory depression is related to muscular rigidity. In propoxyphene overdose, in addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant such as diazepam, bearing in mind the potential additive respiratory depressant effects.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be used as indicated. In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of such a syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in patients with physical dependence on opioids, the antagonist should be administered with extreme care by using dosage titration, commencing with 10to 20% of the usual recommended initial dose.
Methadone: The relatively long duration of action of methadone compared to that of naloxone may necessitate repeated doses of naloxone to counteract respiratory depression. A continuous i.v. infusion of naloxone may be used following the initial bolus, at a rate of two-thirds the bolus dose per hour.
The possibility of precipitating withdrawal must also be considered. Naloxone should not be used in the absence of clinically significant respiratory or cardiovascular depression.
Recommended Dosage
Some basic analgesic dosing information on morphine and methadone is provided in this monograph. Specific product monographs should be consulted for more detailed information. See TableII for approximate analgesic equivalences.
Morphine: Adults: Oral: 10to 30mg every 4hours; Extended-release: Dose should be individualized in the treatment of cancer pain or chronic pain.
Dosing and administration of all opioids should be individualized taking into account the following: the nature and severity of pain and medical status of the patient (e.g., renal and hepatic function), daily dose and potency of other opioids or other medication given previously or concurrently, and the degree of tolerance experienced. The use of potent opioid analgesics for the management of persistent pain should be preceded by a thorough assessment of the patient and diagnosis of the pain and its cause.
Methadone: The dosage of methadone in opioid dependence must be individualized, with the aim of controlling abstinence symptoms without causing respiratory depression or excessive sedation. Generally, initial dosage ranges from 15to 30mg once daily. Maintenance dosage is usually in the range of 50to 120mg daily, but may be higher or lower in some patients.
The usual oral dose of methadone for the relief of severe pain ranges from 5 to 20 mg every 4 to 8 hours. Dosage should be individualized and some patients may require dosages outside that range. When switching from other opioids to methadone in the management of severe pain, careful consideration of the methadone dosage is recommended. Several recent studies have reported that methadone's relative analgesic potency may be significantly higher than previously believed and that the appropriate dose of methadone, when switching from other opioids, can vary greatly depending on the patient's previous opioid dosage.
The specific guidelines pertaining to the prescribing and dispensing of methadone are described in the Health Canada publications cited in the Indications section.
Some basic analgesic dosing information on morphine and methadone is provided in this monograph. Specific product monographs should be consulted for more detailed information. See TableII for approximate analgesic equivalences.
Morphine: Adults: Oral: 10to 30mg every 4hours; Extended-release: Dose should be individualized in the treatment of cancer pain or chronic pain.
Dosing and administration of all opioids should be individualized taking into account the following: the nature and severity of pain and medical status of the patient (e.g., renal and hepatic function), daily dose and potency of other opioids or other medication given previously or concurrently, and the degree of tolerance experienced. The use of potent opioid analgesics for the management of persistent pain should be preceded by a thorough assessment of the patient and diagnosis of the pain and its cause.
Methadone: The dosage of methadone in opioid dependence must be individualized, with the aim of controlling abstinence symptoms without causing respiratory depression or excessive sedation. Generally, initial dosage ranges from 15to 30mg once daily. Maintenance dosage is usually in the range of 50to 120mg daily, but may be higher or lower in some patients.
The usual oral dose of methadone for the relief of severe pain ranges from 5 to 20 mg every 4 to 8 hours. Dosage should be individualized and some patients may require dosages outside that range. When switching from other opioids to methadone in the management of severe pain, careful consideration of the methadone dosage is recommended. Several recent studies have reported that methadone's relative analgesic potency may be significantly higher than previously believed and that the appropriate dose of methadone, when switching from other opioids, can vary greatly depending on the patient's previous opioid dosage.
The specific guidelines pertaining to the prescribing and dispensing of methadone are described in the Health Canada publications cited in the Indications section.
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