Natural opium alkaloids
ATC code: N02AA01 (Morphine)
Brand names
MS Contin, Avinza, Kadian
Full μ-opioid receptor agonist in the CNS, activating descending pain-inhibitory pathways. Reduces pain perception and emotional response. At therapeutic doses produces analgesia, sedation, euphoria, miosis, and respiratory depression. The comparator for all opioid analgesics — oral morphine 30 mg = 10 mg IV = 100 mg oral codeine. About 5–7 % of Europeans have genetically reduced μ-opioid receptor activity.
First line
Standard for severe acute pain in hospital. IV 2–5 mg every 5–10 minutes to analgesia. In postoperative patients, patient-controlled analgesia (PCA) is used. Per CDC 2022, outpatient courses for acute pain should not exceed 3–7 days.
In severe acute pain (MI, major trauma, postoperative pain) in hospital settings.
First line
First-line for moderate-to-severe cancer pain per Cancer Pain Ladder and ESMO 2018. In cancer patients, opioids are used without upper dose ceiling when properly titrated and tolerated. Opioid-naive starting dose: 5–10 mg orally every 4 hours (immediate release) or 1–2 mg IV. After stabilization, switch to extended-release twice daily. Duration is not capped.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Morphine is not used in mild-to-moderate non-cancer pain. Opioids in chronic non-cancer pain per CDC 2022 are the exception, not the rule. Foundation: paracetamol, NSAIDs, gabapentinoids, antidepressants tailored to pain type, and non-pharmacological measures.
15 pairs found. Sorted from critical to minor.
Mechanism
Alprazolam and morphine depress the central nervous system and respiratory centre through different routes (GABA-A and μ-opioid). Effects are additive – risk of fatal respiratory depression rises several-fold. boxed warning applies to all opioid + benzodiazepine combinations since 2016.
Symptoms
Drowsiness, slowed and shallow breathing (respiratory rate below 12/min), cyanosis of lips and nail beds. Severe cases progress to respiratory arrest and death. Symptoms are easy to miss, so the patient and family are warned in advance.
Management
Avoid the combination. For anxiety on opioid therapy, use non-benzodiazepine anxiolytics: gabapentinoids, hydroxyzine, or SSRIs for long-term control. For panic disorder with palliative cancer pain, minimal doses of both under respiratory monitoring with naloxone available.
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Boxed warning
FDA boxed warning: high risk of addiction, abuse, and severe respiratory depression, especially with benzodiazepines or other CNS depressants. Neonatal exposure can cause withdrawal syndrome. Concomitant alcohol use is potentially fatal.
Long-term use in the third trimester is associated with neonatal abstinence syndrome. In pregnant patients with severe pain, use is justified at the minimum effective dose. In opioid-dependent pregnant women, methadone or buprenorphine maintenance is the standard — not abrupt discontinuation.
Morphine is evaluated for the following indications with varying evidence strength: Chronic cancer pain (evidence tier A), Acute moderate-to-severe pain (evidence tier A), Mild to moderate pain in adults (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Morphine (≥ 1 in 100): Constipation (in 90 % of patients), Nausea, vomiting (especially in the first days), Sedation, drowsiness, Pruritus, Dry mouth, Urinary retention. See the Safety section for uncommon and serious reactions.
FDA category C. Long-term use in the third trimester is associated with neonatal abstinence syndrome. In pregnant patients with severe pain, use is justified at the minimum effective dose. In opioid-dependent pregnant women, methadone or buprenorphine maintenance is the standard — not abrupt discontinuation.
Transfers into breast milk in small amounts. Short-term standard-dose use is compatible with breastfeeding per LactMed. Long-term high-dose therapy requires pediatric consultation.
Morphine is contraindicated in: Respiratory depression, respiratory failure; Acute or severe bronchial asthma; Paralytic ileus; Acute abdomen of unknown etiology; Concurrent or recent MAOI (within 14 days). Full list in the Safety section.
Mechanism
Morphine and diazepam act on different receptors (μ-opioid and GABA-A) but both depress the central nervous system and the medullary respiratory centre. Effects are additive – risk of fatal respiratory depression rises several-fold. expanded the boxed warning to all opioid + benzodiazepine pairs in 2016.
Symptoms
Drowsiness, slowed and shallow breathing (respiratory rate below 12/min), cyanosis of lips and nail beds. Severe cases progress to respiratory arrest and death. Symptoms are easy to miss, so the patient and family are warned in advance.
Management
Avoid where possible. In palliative care and cancer pain, use minimal doses of both with continuous respiratory rate and saturation monitoring. Provide the patient and family with naloxone (opioid antidote) and train them in its use. Alternative anxiolytics without respiratory depression: gabapentin, pregabalin, hydroxyzine.
Sources
Mechanism
Phenazepam is a long-acting benzodiazepine with an active metabolite persisting for several days. Morphine and phenazepam together depress the CNS and respiratory centre. Effects are additive – risk of fatal respiratory depression rises. boxed warning applies to all opioid + benzodiazepine pairs since 2016.
Symptoms
Drowsiness, slowed and shallow breathing (respiratory rate below 12/min), cyanosis of lips and nail beds. Severe cases progress to respiratory arrest and death. Symptoms are easy to miss, so the patient and family are warned in advance.
Management
Avoid the combination. In palliative care for cancer pain, minimal doses of both with saturation monitoring and naloxone available. For long-term anxiolytic support, choose gabapentinoids or hydroxyzine.
Mechanism
High morphine doses cause opioid-induced myoclonus, raising seizure risk. Bupropion lowers the seizure threshold. Particularly dangerous in chronic pain patients on high opioid doses.
Symptoms
Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.
Management
Avoid bupropion on long-term opioid therapy. Alternative antidepressants in chronic pain: duloxetine or sertraline (no proconvulsant effect). For smoking cessation on morphine: nicotine replacement or varenicline.
Mechanism
Gabapentin reduces morphine clearance and potentiates CNS depression. issued a 2019 warning about increased respiratory depression risk with the combination.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
The combination is possible in neuropathic or palliative pain. Keep doses minimal, start low. Provide naloxone to the patient and family. Monitor respiratory rate and saturation.
Mechanism
Additive CNS depression and sedation. Severe hypotension and respiratory depression have been reported, especially in older patients.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
Avoid the combination in older patients. For opioid-induced nausea, use ondansetron (no QT issue in short courses in older patients) or metoclopramide. For acute delirium, dexmedetomidine (no respiratory depression).
Mechanism
Pregabalin acts via the α2δ subunit of calcium channels and depresses the central nervous system. Morphine suppresses the respiratory centre via μ-opioid receptors. Effects are additive.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
The combination is possible in neuropathic pain or palliative cancer pain with careful titration. Keep doses minimal, provide naloxone to the patient and family, monitor respiratory rate and saturation.
Mechanism
Additive CNS and respiratory depression. Quetiapine potentiates opioid sedation. Older patients: fall and aspiration risk.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
The combination is possible in palliative care with careful monitoring. Keep doses minimal. Older patients: cap quetiapine at 25–50 mg at night. Alternative antipsychotic for delirium: dexmedetomidine or low-dose haloperidol.
Mechanism
Additive CNS and respiratory centre depression. Tramadol is also serotonergic and lowers seizure threshold.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
Avoid the combination. To strengthen opioid analgesia on tramadol, switch to a pure opioid agonist (morphine, oxycodone) and stop tramadol. Dual opioid therapy is only used in palliative care with careful respiratory monitoring.
Mechanism
Additive CNS depression, sedation, and anticholinergic effect (constipation, urinary retention). Older patients: delirium and fall risk.
Symptoms
Deep sedation, drowsiness, confusion. Constipation and urinary retention (amitriptyline anticholinergic effect amplified by opioid constipation). Older patients: delirium risk.
Management
The combination is common in cancer pain with depression or neuropathic pain. In older patients and palliative care: constipation prophylaxis (lactulose, polyethylene glycol) and urine output monitoring. Alternative antidepressant without anticholinergic effect: mirtazapine or agomelatine.
Mechanism
Additive hypotension and sedation. Morphine reduces sympathetic tone; amlodipine dilates vessels. Older patients: fall risk.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
The combination is acceptable in palliative care and acute coronary syndrome. Titrate morphine from a low dose; monitor pulse, blood pressure, and saturation. Older patients: enhanced fall monitoring.
Mechanism
Additive bradycardia and hypotension. Morphine reduces sympathetic tone via μ-opioid receptors.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).
Management
The combination is acceptable in palliative care and acute coronary syndrome (standard practice). Titrate morphine from a low dose; monitor pulse, blood pressure, and saturation.
Mechanism
Cetirizine penetrates the blood-brain barrier at higher doses. With opioids, additive CNS depression and sedation occur.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On the combination, cap cetirizine at 10 mg/day (at bedtime). Avoid the combination in older patients — fall risk. In palliative care, alternatives: loratadine (minimal sedation) or bilastine (minimal sedation and no sedating metabolites). With marked sedation, stop the antihistamine.
Mechanism
Linezolid is a reversible MAO inhibitor and may mildly potentiate opioid CNS depression. Morphine does not cause serotonin syndrome directly (minimal serotonergic effect).
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Possible sedation increase and respiratory rate decrease.
Management
On the combination, do not raise morphine until linezolid ends (10–14 days). On a stable maintenance morphine dose (chronic pain, palliative care), adjustment is usually not needed. If marked sedation or bradypnoea develops, reduce morphine by 25%. Alternatives if available: fentanyl or hydromorphone (no serotonergic risk).
Mechanism
Loratadine is a second-generation antihistamine with minimal blood-brain barrier penetration. With opioids, mild additive CNS depression is possible, especially in older patients.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
No dose adjustment needed. In older patients and palliative care, watch for sedation signs. Loratadine is preferred over cetirizine or chlorpheniramine on concurrent opioid therapy — minimal sedation. With marked sedation, stop the antihistamine.
Transfers into breast milk in small amounts. Short-term standard-dose use is compatible with breastfeeding per LactMed. Long-term high-dose therapy requires pediatric consultation.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
FDA boxed warning: high risk of addiction, abuse, and severe respiratory depression, especially with benzodiazepines or other CNS depressants. Neonatal exposure can cause withdrawal syndrome. Concomitant alcohol use is potentially fatal.