Version July 2025
Opioid use disorder, maintenance treatment: Note: Individualize dosing regimen based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals. Patients may receive supplemental oral opioid agonist therapy or transition to methadone to minimize withdrawal symptoms between doses. Patients may administer the injections, however, patients must be supervised by health care providers experienced in the treatment of severe opioid use disorder and trained in the administration of injectable opioid agonist therapy; patients must be monitored for 15 to 30 minutes after diamorphine administration for signs of withdrawal, overdose, respiratory depression, or sedation in health care settings where emergency naloxone or nalmefene and resuscitation equipment is available and cardiopulmonary resuscitation can be performed.
IM, IV: Initiate therapy over several days and titrate to response (see "Example Initiation Regimens" below).
Example initiation regimens:
Initiation:
Two Doses per Day (Ref)
Day 1:
Dose 1: IM, IV: 30 mg, then observe for 15 minutes; if no intoxication symptoms, administer 60 mg based on clinical judgement and discussion with patient; observe for 15 minutes. Administer next dose in 3 to 12 hours. Total possible dose = 90 mg.
Dose 2: IM, IV: If dose 1 is well tolerated, administer 90 mg and observe for 15 minutes; if no intoxication symptoms, administer 60 mg based on clinical judgement and discussion with patient; observe for 15 minutes. Administer next dose the following day. Total possible dose = 150 mg.
Day 2:
Dose 1: IM, IV: Administer 100 mg and observe for 15 minutes; if no intoxication symptoms, administer 60 mg based on clinical judgement and discussion with patient; observe for 15 minutes. Administer next dose in 3 to 12 hours. Total possible dose = 160 mg.
Dose 2: IM, IV: Administer 160 mg and observe for 15 minutes; if no intoxication symptoms, administer 40 mg based on clinical judgement and discussion with patient; observe for 15 minutes. Administer next dose the following day. Total possible dose = 200 mg.
Day 3: Administer maximum tolerated single dose given during day 2 every 12 hours; observe for 15 minutes following every dose.
Three Doses per Day (Ref)
Day 1:
Dose 1: IM, IV: 15 mg, then observe for 15 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose in 3 to 8 hours. Total possible dose = 45 mg.
Dose 2: IM, IV: If dose 1 is well tolerated, administer 45 mg and observe for 15 to 30 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose in 3 to 8 hours. Total possible dose = 75 mg.
Dose 3: IM, IV: If previous doses are well-tolerated, administer 75 mg and observe for 15 to 30 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose the following day. Total possible dose = 105 mg.
Day 2:
Dose 1: IM, IV: Administer 40% of total daily dose at day 1 (up to a total of 90 mg if all doses on day 1 were tolerated) and observe for 15 to 30 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose in 3 to 8 hours. Total possible dose = 120 mg.
Dose 2: IM, IV: Administer maximum tolerated amount of dose 1 (up to 120 mg) and observe for 15 to 30 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose in 3 to 8 hours. Total possible dose = 150 mg.
Dose 3: IM, IV: Administer maximum tolerated amount of dose 2 (up to 150 mg) and observe for 15 to 30 minutes; if no intoxication symptoms, administer 30 mg based on clinical judgement and discussion with patient; observe for 15 to 30 minutes. Administer next dose the following day. Total possible dose = 180 mg.
Day 3: Administer maximum tolerated single dose given during day 2 every 8 hours; observe for 15 to 30 minutes following every dose.
Maintenance: IM, IV: Adjust dosage once a week based on response and tolerability. Maximum single dose: 400 mg; maximum daily dose: 1 g/day.
Missed dose: If treatment is interrupted, re-initiation of dose titration may be needed, starting at a decreased dose.
Conversion to oral methadone: During transition to or from diamorphine, ensure dose of methadone is properly calculated so patient receives the same degree of saturation of opioid receptors.
Discontinuation of therapy: When indicated, gradually taper under medical supervision.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 20 to 50 mL/minute: Administer 75% of usual initial dose; titrate cautiously to response.
CrCl 10 to 20 mL/minute: Administer 50% of usual initial dose; titrate cautiously to response.
CrCl <10 mL/minute or hemodialysis: Use not recommended.
Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Initiate treatment at the lowest possible dose and titrate slowly with extended dosing intervals.
Severe impairment: Use is not recommended.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).
Initiate at a lower dose and slowly titrate to effect.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults and may include concomitant methadone.
>10%:
Dermatologic: Skin rash (4% to 43%)
Local: Application-site pruritus (30%), injection-site reaction (43%; including injection-site pruritus and urticaria at injection site)
1% to 10%: Nervous system: Drowsiness (9%), seizure (3% to 5%)
Frequency not defined:
Cardiovascular: Circulatory depression, shock
Gastrointestinal: Constipation, decreased gastrointestinal motility, nausea, vomiting
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, local hypersensitivity reaction, and severe hypersensitivity reaction)
Nervous system: Drug abuse, opioid dependence
Postmarketing:
Cardiovascular: Peripheral edema, presyncope, syncope
Dermatologic: Pruritus, urticaria
Endocrine & metabolic: Altered hormone level (decreased luteinizing hormone and follicle stimulating hormone), amenorrhea, increased serum glucose, increased serum prolactin, loss of libido
Gastrointestinal: Biliary colic, decreased appetite, delayed gastric emptying, paralytic ileus
Genitourinary: Urinary hesitancy, urinary retention
Hepatic: Increased liver enzymes
Nervous system: Agitation, anxiety, asthenia, chills, confusion, disorientation, dysphoria, emotional lability, euphoria, fatigue, feeling abnormal, hallucination, increased intracranial pressure, lethargy, malaise, myoclonus, neonatal withdrawal, nervousness, nightmares, paresthesia, serotonin syndrome, tremor, withdrawal syndrome
Neuromuscular & skeletal: Dyskinesia, laryngospasm
Ophthalmic: Blurred vision, diplopia, miosis, nystagmus disorder, visual impairment
Respiratory: Bronchospasm, dyspnea, respiratory depression
Miscellaneous: Drug tolerance
Hypersensitivity to diamorphine, other opioid agonists, or any component of the formulation; patients without opioid use disorder and who are not currently taking high doses or high concentrations of opioids; known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures); diseases/conditions that affect bowel transit (eg, ileus of any type); acute or severe bronchial asthma; chronic obstructive airway; status asthmaticus; acute respiratory depression; elevated carbon dioxide levels; cor pulmonale; acute alcohol use disorder; delirium tremens; seizures; severe CNS depression; increased cerebrospinal fluid; increased intracranial pressure; head injury; concomitant use with monoamine oxidase inhibitors or within 2 weeks of their discontinuation; patients with signs of intoxication, including due to centrally acting sedatives, stimulants, or other acute condition that would increase the risk of adverse effects; bipolar disorder, schizophrenia, or other psychiatric disorders with active psychotic symptoms refractory to medical management.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hypersensitivity: Generalized and localized hypersensitivity reactions may occur at the injection site.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction), circulatory shock, or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Avoid use in patients with circulatory shock. Avoid rapid IV injection.
• Respiratory depression: [Canadian Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants [TCAs]), lithium, St John's wort, agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Symptoms may include mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile BP, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Coagulation disorders: Use with caution in patients with coagulation disorders.
• Infection: Use with caution in patients with injection-related infections (eg, sepsis, endocarditis, pneumonia, infective osteomyelitis).
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Respiratory disease: Use with caution in patients with decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages.
• Seizure disorders: [Canadian Boxed Warning]: Use with caution in patients with seizure disorders or at risk for seizures (eg, head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections, concurrent use with other medications that reduce seizure threshold).
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and central nervous system depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines or other CNS depressants: [Canadian Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, somnolence, respiratory depression, coma, and death. Antidepressants (eg, TCAs) may increase risk of arrhythmias, seizures, and affect thyroid levels. Reserve concomitant prescribing of morphine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Consider prescribing naloxone or nalmefene for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.
• Ethanol use: Patients should not consume alcoholic beverages or medication containing ethanol while taking diamorphine; ethanol may increase plasma levels, resulting in a potentially fatal overdose.
Special populations:
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Neonates: Neonatal withdrawal syndrome: [Canadian Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening. Signs and symptoms include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Older patients: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and central nervous system depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]).
Other warnings/precautions:
• Abrupt discontinuation/withdrawal: Abrupt discontinuation or missed doses in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Diacetylmorphine interruption may require starting at a decreased dose for patient safety as rapid loss in tolerance may result in increased risk of overdose.
• Abuse/misuse/diversion: [Canadian Boxed Warning]: Diamorphine exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Store securely to avoid theft and diversion.
• Accidental exposure: [Canadian Boxed Warning]: Use care to reduce risk of accidental exposure during reconstitution; ensure all syringes are properly and securely stored.
• Appropriate use: [Canadian Boxed Warning]: For use only in opioid-tolerant patients requiring high concentrations of opioid agonists under a health care provider trained in the treatment of opioid use disorder and the provision of opioid agonist therapy. Initiate treatment slowly. Assess patient to determine readiness to leave the health care setting and ensure safe transportation is available. Do not inject into the jugular or femoral vein; jugular vein thrombosis, deep neck infections, pneumothorax, endocarditis, and sepsis may occur. Should only be administered in facilities equipped and staffed to immediately recognize severe adverse reactions (eg, respiratory depression, seizures); resuscitative equipment, oxygen, naloxone, and other resuscitative drugs should be available for immediate use. Use with caution in patients who cannot safely self-inject medication (eg, poor venous access, poor injection technique).
• Naloxone/nalmefene access: Discuss the availability of naloxone or nalmefene with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone or nalmefene to patients prescribed medications to treat OUD; patients at risk of opioid overdose, even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone or nalmefene (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone or nalmefene, and getting emergency help.
Not available in the United States.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection, as hydrochloride:
Generic: 200 mg (1 ea); 5000 mg (1 ea)
C-I
Only available through controlled distribution.
IM, IV: May administer by supervised self-injection IM or IV; do not inject into the jugular or femoral vein. Use proper injection techniques to minimize risk of infection.
Note: Not approved in the United States.
Opioid use disorder, maintenance treatment: Maintenance treatment of opioid use disorder in adult patients who use injectable opioids and have failed previous attempts at opioid agonist therapy (including methadone); in conjunction with an individualized, comprehensive, opioid dependence treatment program (eg, medical, psychological, social support).
Diamorphine may be confused with morphine or hydromorphone.
Diamorphine may be confused with Diamox brand name for acetazolamide (various countries), Dimorf brand name for morphine (Brazil), and Duramorph brand name for morphine (United States).
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See "Warnings/Precautions" section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Significant differences exist between dosing diamorphine and morphine or diamorphine oral and IV dosing. Use caution when converting from one drug to the other or from one route of administration to another.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor
Alcohol (Ethyl): May increase CNS depressant effects of Diamorphine. Risk X: Avoid
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alvimopan: Opioid Agonists may increase adverse/toxic effects of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider Therapy Modification
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor
Antiplatelet Agents (P2Y12 Inhibitors): Diamorphine may decrease antiplatelet effects of Antiplatelet Agents (P2Y12 Inhibitors). Diamorphine may decrease serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CNS Depressants: May increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Desmopressin: Opioid Agonists may increase hyponatremic effects of Desmopressin. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Eluxadoline: Opioid Agonists may increase constipating effects of Eluxadoline. Risk X: Avoid
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Gastrointestinal Agents (Prokinetic): Opioid Agonists may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors: May increase adverse/toxic effects of Diamorphine. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nalfurafine: Opioid Agonists may increase adverse/toxic effects of Nalfurafine. Opioid Agonists may decrease therapeutic effects of Nalfurafine. Risk C: Monitor
Nalmefene: May decrease therapeutic effects of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider Therapy Modification
Naltrexone: May decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid
Nirmatrelvir and Ritonavir: May decrease serum concentration of Diamorphine. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxitriptan: Diamorphine may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
QuiNIDine: May increase active metabolite exposure of Diamorphine. Management: Use caution and reduce the diamorphine dose during coadministration with quinidine. Risk D: Consider Therapy Modification
Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor
RifAMPin: May decrease active metabolite exposure of Diamorphine. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ritonavir: May decrease serum concentration of Diamorphine. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid
Serotonergic Agents (High Risk): Opioid Agonists may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification
Somatostatin Analogs: Opioid Agonists may decrease analgesic effects of Somatostatin Analogs. Opioid Agonists may increase analgesic effects of Somatostatin Analogs. Risk C: Monitor
Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid
Tryptophan: Diamorphine may increase serotonergic effects of Tryptophan. This could result in serotonin syndrome. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Patients who could become pregnant should be offered pregnancy screening prior to injectable opioid agonist treatment (iOAT) (CRISM 2019).
Amenorrhea has been reported following diamorphine use. Chronic opioid use may cause hypogonadism and hyperprolactinemia, which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).
Contraception should be discussed with patients undergoing iOAT (CRISM 2019).
Opioids cross the placenta.
Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]).
Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]).
Opioid agonist pharmacotherapy is recommended for pregnant patients with an opioid use disorder (CRISM 2018; SOGC [Ordean 2017]). However, data related to injectable opioid agonist treatment (iOAT) during pregnancy are limited and oral treatment should be considered prior to initiating or continuing iOAT in pregnant patients (CRISM 2019).
Monitor neonates for symptoms of withdrawal (SOGC [Ordean 2017]).
Opioids are present in breast milk; the amount of diamorphine in breast milk is not known.
Infants exposed to diamorphine via breast milk are at risk for life-threatening respiratory depression. Consider the potential benefit to the mother and the potential risk to the breastfed infant prior to use in breastfeeding patients.
Monitor for signs of withdrawal, overdose, respiratory depression, and sedation during administration and for 30 minutes following administration; signs of intoxication, withdrawal, and to avoid diversion prior to initiation, during, and after injection; signs of injection-related infections; symptoms of hypotension following initiation or dose titration; signs of serotonin syndrome; signs of misuse, abuse, and substance use disorder.
A potent morphine opiate derivative with CNS depressant effects, increases smooth muscle tone, and causes the release of histamine and catecholamines.
Onset: IV: 0.3 minutes; IM: 5 minutes.
Duration: IV: 1 to 3 hours.
Absorption: IM: 5 minutes diacetylmorphine, metabolite 6-monoacetylmorophine peaks within 6 minutes, and morphine within 17 minutes.
Distribution: IV: 37 ± 16 L; active metabolite: 60 to 100 L.
Protein binding: 20% to 40% to albumin.
Metabolism: Rapidly hydrolyzed to active metabolites 6-monoacetylmorphine (further metabolized to morphine) by serum and liver esterases; some morphine-glucuronides are excreted in the bile and are hydrolyzed into morphine in the colon resulting in enterohepatic recirculation and additional contribution to total bioavailability of morphine.
Bioavailability: IM: 380% ± 157%; ≥3 to 4 times greater than IV administration; metabolite 6-monoacetylmorophine mean 120% ± 30% and morphine 134% ± 54% compared to IV administration.
Half-life elimination: Active metabolites: Terminal: 2 to 6.4 hours.
Time to peak: IM: 5 minutes; active metabolites: 6 to 17 minutes; IV: 0.7 to 5.1 hours; active metabolite: 0.3 minutes.
Excretion: Urine (70%; 55% as conjugated morphine).
