Morphine

Mechanism

Besides its antibacterial action, linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO), so it belongs to the MAO inhibitors (linezolid SmPC). The US Food and Drug Administration (FDA) morphine labels warn that MAO inhibitors may potentiate the effects of morphine, including respiratory depression, coma and confusion, and that MAO inhibitor interactions with opioids may present as serotonin syndrome or opioid toxicity. The linezolid SmPC also reports serotonin syndrome when linezolid was combined with serotonergic drugs, including opioids.

Symptoms

Increasing drowsiness, confusion, slow and shallow breathing, up to coma (FDA morphine labels). Signs of serotonin syndrome: agitation, high fever, heavy sweating, tremor, muscle jerks and rigidity, exaggerated reflexes, impaired thinking and coordination (linezolid labels).

Management

The combination is contraindicated. Spanish SmPCs for oral morphine contraindicate morphine with monoamine oxidase (MAO) inhibitors and within two weeks of stopping them, and the linezolid SmPC classes linezolid as an MAO inhibitor. The US Food and Drug Administration (FDA) morphine labels set the same 14-day ban and name linezolid among MAO inhibitors. The linezolid SmPC contraindicates its use with serotonergic drugs, opioids included, unless the combination is absolutely necessary. If it cannot be avoided, the patient is closely watched for signs of serotonin syndrome: cognitive dysfunction, high fever, exaggerated reflexes, poor coordination; if they appear, stopping one or both drugs is considered (linezolid SmPC).

Mechanism

Alprazolam and morphine act on different receptors (GABA-A and mu-opioid), but both depress the central nervous system and the respiratory centre, and the effects add up. The labels of both drugs warn that together they can cause profound sedation, respiratory depression, coma and death. The US Food and Drug Administration (FDA) puts this risk in the boxed warning of the alprazolam and morphine labels and cites observational studies: with benzodiazepines, the risk of drug-related death is higher than with opioids alone (FDA labels).

Symptoms

Severe drowsiness, reduced alertness, confusion, slow and shallow breathing, low blood pressure; in severe cases coma and death (alprazolam and morphine labels). The patient and caregivers are taught in advance to recognise these signs (alprazolam and morphine labels).

Management

The combination is not prohibited, but the alprazolam and morphine labels allow it only for patients who have no other treatment options. Both drugs are then given at the lowest effective dose for the shortest possible time, and the patient is closely watched for respiratory depression and sedation (alprazolam and morphine labels). The alprazolam and morphine labels approved by the US Food and Drug Administration (FDA) add: in a patient already on morphine, start alprazolam at a lower dose than usual; when morphine is added to alprazolam, lower the starting dose of morphine. Explain the risk and the signs of respiratory depression to the patient and caregivers, advise against driving until the effect of the combination is known, and if the combination is warranted consider prescribing naloxone, the opioid antidote (FDA labels). Alprazolam is given for no longer than 2–4 weeks, at a lower dose in older or debilitated patients and in chronic respiratory insufficiency, and it is contraindicated in severe respiratory insufficiency and sleep apnoea syndrome (alprazolam SmPC); morphine is also given at a lower dose to older patients and in chronic kidney or liver disease (morphine SmPC).

Mechanism

Amitriptyline increases the sedative effect of other central nervous system depressants (amitriptyline SmPC), and morphine combined with such drugs can cause respiratory depression, low blood pressure, deep sedation and coma (morphine SmPC). The second mechanism is the anticholinergic effect of amitriptyline: with morphine it raises the risk of severe constipation, paralytic ileus and urinary retention (morphine SmPC). The third is serotonergic: the US Food and Drug Administration (FDA) warns about serotonin syndrome when opioids are combined with tricyclic antidepressants (morphine FDA label).

Symptoms

Deep sedation, drowsiness, confusion, slow or shallow breathing, low blood pressure. Severe constipation, bloating and abdominal pain, urinary retention. In older people: confusion, delirium, falls. With serotonin syndrome: changes in mental state, swings in blood pressure and pulse, sweating, fever, tremor and muscle twitching, nausea and diarrhoea.

Management

The morphine SmPCs require reduced doses and the greatest caution in patients who take tricyclic antidepressants (morphine SmPCs). The oral morphine SmPC lists antidepressants among central nervous system depressants and requires limiting the dose and duration of concomitant use (oral morphine SmPC). Morphine is not recommended with drugs that have anticholinergic action unless strictly necessary; if they are combined, reduce the dose of the other drug and monitor the patient closely (injectable morphine SmPC). Watch the patient for respiratory depression and excessive sedation, urinary retention and slowed bowel movement (morphine SmPCs). The US Food and Drug Administration (FDA) asks for frequent evaluation of the patient, especially at the start of treatment and after dose changes, and for stopping morphine if serotonin syndrome is suspected (morphine FDA label).

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

Morphine and diazepam act on different receptors (mu-opioid and GABA-A), but both depress the central nervous system and the respiratory centre, and the effects add up. The labels of both drugs warn that together they can cause profound sedation, respiratory depression, coma and death. The US Food and Drug Administration (FDA) puts this risk in the boxed warning of the morphine and diazepam labels and cites observational studies: with benzodiazepines, the risk of drug-related death is higher than with opioids alone (FDA labels).

Symptoms

Severe drowsiness, reduced alertness, confusion, slow and shallow breathing, low blood pressure; in severe cases coma and death (morphine and diazepam labels). The patient and caregivers are taught in advance to recognise these signs (morphine and diazepam labels).

Management

The combination is not prohibited, but the morphine and diazepam labels allow it only for patients who have no other treatment options. Both drugs are then given at the lowest effective dose for the shortest possible time, and the patient is closely watched for respiratory depression and sedation (morphine and diazepam labels). The morphine and diazepam labels approved by the US Food and Drug Administration (FDA) add: in a patient already on morphine, start diazepam at a lower dose than usual and titrate to response; when morphine is added to diazepam, lower the starting dose of morphine. Explain the risk and the signs of respiratory depression to the patient and caregivers, advise against driving until the effect of the combination is known, and if the combination is warranted consider prescribing naloxone, the opioid antidote (FDA labels). Diazepam is contraindicated in severe respiratory insufficiency and sleep apnoea syndrome, its dose is reduced in chronic respiratory insufficiency, and older patients start at 2–2.5 mg (diazepam SmPC); morphine is also given at a lower dose to older patients and in chronic kidney or liver disease (morphine SmPC).

Mechanism

Morphine and gabapentin both depress the central nervous system, and the effects add up: the risk of profound sedation, respiratory depression, coma and death rises. The kinetic effect goes one way: controlled-release morphine taken 2 hours before gabapentin raised gabapentin AUC by 44%, while gabapentin did not change morphine pharmacokinetics. In December 2019 the FDA warned about serious breathing problems when gabapentinoids are combined with opioids.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

The US morphine label reserves the combination for patients whose alternative treatment options are inadequate, and the Spanish label requires limiting the dose and duration of concomitant use. Start gabapentin at a low dose. If drowsiness or slowed breathing appears, reduce the gabapentin or morphine dose per the label. Monitor respiratory rate, oxygen saturation and level of consciousness, with extra care in older adults and in patients with lung disease or renal impairment. Prescribe naloxone and teach the patient and family the signs of overdose.

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

Phenazepam is a benzodiazepine. The morphine SmPC warns that with benzodiazepines and related sedatives morphine can cause sedation, respiratory depression, coma and death because of additive central nervous system depression (morphine SmPC). The US Food and Drug Administration (FDA) puts this risk in the boxed warning of the morphine label and cites observational studies: with benzodiazepines, the risk of drug-related death is higher than with opioids alone (morphine FDA label). Phenazepam is not authorised in Spain or the US and has no centralised EU authorisation, so these agencies have no label for it.

Symptoms

Severe drowsiness, reduced alertness, confusion, slow and shallow breathing, low blood pressure; in severe cases coma and death (morphine labels). The patient and caregivers are taught in advance to recognise these signs (morphine labels).

Management

The combination is not prohibited, but the morphine SmPC allows morphine with benzodiazepines only for patients who have no other treatment options. Both drugs are then given at the lowest effective dose for the shortest possible time, and the patient is closely watched for respiratory depression and sedation (morphine SmPC). The morphine label approved by the US Food and Drug Administration (FDA) adds: in a patient already on morphine, start the benzodiazepine at a lower dose than usual; when morphine is added to a benzodiazepine, lower the starting dose of morphine. Explain the risk and the signs of respiratory depression to the patient and caregivers, advise against driving until the effect of the combination is known, and if the combination is warranted consider prescribing naloxone, the opioid antidote (morphine FDA label). Older patients and patients with chronic kidney or liver disease receive a lower morphine dose (morphine SmPC).

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 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

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.