Benzodiazepines. Short-to-medium-acting anxiolytics
ATC code: N05BA12 (Alprazolam)
Brand names
Xanax, Xanax XR
Allosteric modulator of the GABA-A receptor. Potentiates GABA action through the benzodiazepine site. Increases chloride channel opening frequency and enhances inhibitory neurotransmission. Rapid onset (30-60 minutes), half-life 11-13 hours. Metabolised via CYP3A4. Among benzodiazepines, alprazolam has one of the highest potentials for misuse and dependence.
Second line
Alprazolam is - and -registered for panic disorder. Recommended as a second-line option after SSRIs and SNRIs. 2023, CG113, and WFSBP list SSRIs (escitalopram, , ) as first-line due to a more favourable long-term profile: no dependence risk or withdrawal syndrome. Benzodiazepines are discussed as a 'bridge' during the first 4-6 weeks of treatment while SSRIs reach therapeutic effect, or when SSRIs are not tolerated.
Long-term use (> 4-6 weeks) is not recommended due to dependence risk. If continuation is required, alternatives are sought – another drug class or psychotherapy.
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
For GAD, international guidelines ( 2023, CG113) recommend SSRIs and SNRIs as first-line. Benzodiazepines are considered only briefly for severe symptoms that prevent waiting for SSRI onset. Long-term alprazolam use in GAD is associated with cognitive impairment in older adults, dependence, and a difficult withdrawal syndrome.
Not recommended
Alprazolam is not recommended for chronic insomnia. When pharmacotherapy is needed, 2021 recommends melatonin agonists (ramelteon), orexin antagonists (suvorexant, lemborexant), and low-dose doxepin. Benzodiazepines are acceptable only short-term (< 2-4 weeks) and preferentially as longer-acting agents (temazepam), not alprazolam. 'For flights' or 'holiday' use is dangerous due to dependence risk.
43 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.
Sources
Mechanism
Additive CNS depression, sedation, and anticholinergic effect. In older patients: high delirium and fall risk.
Symptoms
Deep sedation, drowsiness, ataxia, confusion (especially in older patients). Dry mouth, constipation, urinary retention (anticholinergic effect).
Management
Avoid the combination in older patients. If needed, use the minimum effective dose of both with a short course. Alternative anxiolytic when a TCA is needed: hydroxyzine or gabapentinoids.
Mechanism
Carbamazepine induces CYP3A4; alprazolam plasma levels fall by 50%. Loss of anxiolytic effect and withdrawal symptoms (anxiety, insomnia, tremor) are possible.
Symptoms
Return of anxiety, insomnia, tremor, sweating, tachycardia (withdrawal). With high carbamazepine doses, full return of panic disorder symptoms is possible.
Management
During carbamazepine therapy, increase alprazolam by 50% or switch to lorazepam/oxazepam (glucuronidated, no CYP3A4 dependence). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.
Mechanism
Clarithromycin blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 2- to 3-fold, with prolonged and stronger effect.
Symptoms
Prolonged sedation, drowsiness, dizziness, ataxia. Falls and fracture risk in older patients. Symptoms appear within 1–2 days.
Management
During clarithromycin therapy, halve the alprazolam dose. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 impact). Alternative benzodiazepines without CYP3A4 dependence: lorazepam, oxazepam.
Mechanism
Dronedarone is a strong CYP3A4 inhibitor, the main alprazolam metabolic route. Alprazolam plasma levels may rise 2- to 4-fold. Deep sedation, fall risk in older patients.
Symptoms
Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear within 1–2 days.
Management
During dronedarone therapy, halve alprazolam or use lorazepam/oxazepam (glucuronidated, no CYP3A4 dependence).
Mechanism
Fluconazole at 200 mg/day or above blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 2- to 3-fold, with stronger and longer effect.
Symptoms
Deep sedation, drowsiness, ataxia. Particularly dangerous in older patients – fall and fracture risk. Symptoms appear within 1–2 days.
Management
During fluconazole therapy, halve the alprazolam dose. Alternative antifungals: terbinafine or echinocandins. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam.
Sources
Mechanism
Fluoxetine and its active metabolite norfluoxetine moderately block CYP3A4. Alprazolam plasma levels rise by 30–50%; deep sedation and fall risk in older patients emerge.
Symptoms
Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear within 1–2 weeks of combination.
Management
Reduce alprazolam by 30–50% when combined. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 3- to 4-fold. Particularly dangerous in older patients: deep sedation and fall risk.
Symptoms
Deep sedation, drowsiness, marked ataxia, cognitive impairment. In older patients: fall and fracture risk. Symptoms appear within 1–2 days.
Management
Avoid the combination. Alternative antifungals: terbinafine (no CYP3A4 effect) for dermatophytosis or echinocandins for systemic mycoses. Alternative benzodiazepines without CYP3A4 dependence: lorazepam, oxazepam.
Mechanism
Ritonavir is the most potent CYP3A4 inhibitor available – the main alprazolam metabolic route. Alprazolam plasma levels rise 4-fold. Marked sedation, ataxia, and respiratory depression risk emerge.
Symptoms
Deep sedation, drowsiness, marked ataxia. Older patients: fall and fracture risk. With high alprazolam doses and high ritonavir doses: respiratory depression risk.
Management
Avoid the combination. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam (metabolised by glucuronidation, weakly affected by ritonavir). If alprazolam is needed, reduce the dose 4-fold.
Mechanism
Alprazolam and tramadol depress the central nervous system and respiratory centre. Tramadol additionally lowers the seizure threshold and raises serotonergic activity. Fatal overdoses have been reported.
Symptoms
Drowsiness, sedation, slowed breathing. Seizures may occur (tramadol) and syncope from orthostatic hypotension. Older patients: fall risk.
Management
Avoid the combination. For analgesia on alprazolam, use paracetamol, an NSAID, or morphine/oxycodone (with respiratory depression warning). Alternative anxiolytics: hydroxyzine or gabapentinoids.
Mechanism
Additive bradycardia and hypotension. Alprazolam sedation may mask early symptoms of excessive blood pressure drop.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).
Management
The combination is acceptable for short alprazolam use with pulse and blood pressure monitoring. In older patients, lorazepam at minimum doses is preferable with fall risk warning.
Mechanism
Bupropion lowers seizure threshold, especially at high doses (above 300 mg/day) or in predisposition. Abrupt alprazolam withdrawal further raises seizure risk via GABAergic rebound.
Symptoms
Tremor, jitters, severe cases: seizures. Symptoms appear with bupropion up-titration or abrupt alprazolam withdrawal. In epilepsy or prior head trauma, risk is maximal.
Management
Avoid in epilepsy and prior head trauma. If unavoidable (nicotine dependence with anxiety), start bupropion at 150 mg in the morning and do not exceed 300 mg/day. Do not stop alprazolam abruptly — taper over 4–8 weeks.
Mechanism
Additive hypotension. Alprazolam sedation may mask early orthostatic symptoms.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after start. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive hypotension and sedation. Carvedilol's α/β-blockade causes fatigue and dizziness on its own; alprazolam adds GABAergic CNS depression.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
On starting the combination, begin alprazolam at the minimum dose (0.25 mg at bedtime). In older patients, cap at 0.5 mg/day. Check standing/sitting BP at one week. With pronounced sedation, consider non-drug options for anxiety (CBT, breathing exercises) or switch to buspirone (no sedation).
Mechanism
Additive sedation. Cetirizine is a second-generation antihistamine with minimal blood-brain barrier penetration, but the effect adds up with alprazolam.
Symptoms
Drowsiness, sedation, ataxia. Older patients: fall risk. Symptoms appear in the first 1–2 days.
Management
Warn the patient about drowsiness, especially with the first dose. Alternative antihistamines with minimal sedation: fexofenadine or bilastine. In patients needing alprazolam, take antihistamines during the day, not at bedtime.
Mechanism
Additive CNS depression. Citalopram does not inhibit CYP3A4 — no pharmacokinetic interaction with alprazolam. The effect adds up at GABA and serotonin receptors.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On starting the combination, begin alprazolam at the minimum dose. In older patients, cap citalopram at 20 mg/day (QT risk) and alprazolam at 0.5 mg/day. For long-term anxiety treatment, plan CBT as the core therapy with gradual benzodiazepine taper.
Mechanism
Additive CNS depression and hypotension. Clonidine is a central α2-agonist with sedative effect; alprazolam is a GABAergic sedative.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Pronounced morning hypotension and bradycardia possible.
Management
On starting the combination, begin both at minimal doses with time-separated dosing (e.g. clonidine in the morning, alprazolam at bedtime). Avoid the combination in older patients — fall risk. In anxiety disorders with hypertension, alternative: a beta-blocker (metoprolol) plus buspirone.
Mechanism
Diltiazem moderately inhibits CYP3A4; alprazolam is a CYP3A4 substrate. Alprazolam AUC rises by 30–50%, prolonging sedation.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Morning sedation is especially pronounced (alprazolam half-life is extended).
Management
On starting the combination, reduce alprazolam by 25–50%. In older patients, start at 0.125 mg at bedtime. Antihypertensive alternatives: amlodipine or a beta-blocker without CYP3A4 effect (metoprolol, bisoprolol). Anxiolytic alternatives: lorazepam or oxazepam (CYP3A4-independent), or buspirone.
Mechanism
Additive CNS depression. Duloxetine weakly inhibits CYP2D6 with no CYP3A4 effect — no pharmacokinetic interaction with alprazolam.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On starting the combination, begin alprazolam at the minimum dose. In anxiety with chronic pain (neuropathy, fibromyalgia), the combination is reasonable, but for long-term therapy assess feasibility of benzodiazepine discontinuation via CBT. Avoid the combination in older patients — fall risk.
Mechanism
Additive hypotension. Alprazolam sedation may mask orthostatic symptoms.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after start. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive sedation. No direct pharmacokinetic interaction – escitalopram does not significantly block CYP3A4.
Symptoms
Additional drowsiness, ataxia in the first 1–2 weeks. Older patients: fall risk.
Management
Widely used in anxious-depressive disorders. Alprazolam is given for a short course (4–6 weeks) with gradual taper after escitalopram's effect stabilises. In older patients: minimum alprazolam dose; monitor cognition.
Mechanism
Fluvoxamine inhibits CYP3A4 and CYP1A2. Alprazolam is a CYP3A4 substrate. Alprazolam AUC rises by 50–100%; half-life doubles.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Morning sedation is especially pronounced.
Management
Avoid the combination. If unavoidable, halve the alprazolam dose and give only at bedtime. Do not prescribe in older patients. Anxiolytic alternatives: buspirone, lorazepam, or oxazepam (CYP3A4-independent). Antidepressant alternatives: sertraline or escitalopram (minimal CYP3A4 effect).
Sources
Mechanism
Additive hypotension and fall risk in older patients. No direct pharmacokinetic interaction.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after starting alprazolam. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive CNS depression via different mechanisms: alprazolam (GABAergic) and gabapentin (α2δ calcium channel inhibition). Sedation, ataxia, and fall risk amplify.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Ataxia and fall risk are especially pronounced in older patients.
Management
On starting the combination, begin both at minimal doses. Avoid the combination in older patients — fall and fracture risk. In neuropathic pain and anxiety, alternative: low-dose amitriptyline (10–25 mg at bedtime) with buspirone. If unavoidable, watch for sedation signs and check heart rate and BP at one week.
Mechanism
Additive CNS depression and sedation. In older patients: high delirium and fall risk.
Symptoms
Deep sedation, drowsiness, ataxia, confusion (especially in older patients). Orthostatic hypotension possible (haloperidol blocks α1-adrenoceptors).
Management
The combination is used briefly in acute agitation or psychotic episodes. In older patients: lorazepam at minimum dose with olanzapine or aripiprazole (less α1-blockade than haloperidol) is preferable.
Mechanism
Additive hypotension and fall risk. No direct pharmacokinetic interaction.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after start. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive hypotension and fall risk in older patients. Additional delirium risk with diuretic-induced hypovolaemia.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after start; assess fluid and electrolyte balance. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive CNS depression and sedation. No direct pharmacokinetic interaction – levetiracetam is not CYP-metabolised.
Symptoms
Drowsiness, sedation, ataxia. Older patients: fall risk.
Management
The combination is acceptable when anticonvulsant and anxiolytic therapy are both needed. In older patients, monitor cognition and fall risk. Alternative anxiolytic with minimal sedation: a gabapentinoid (low-dose pregabalin) for anxiety.
Mechanism
Additive hypotension. Alprazolam sedation may mask orthostatic symptoms.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after start. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive bradycardia and sedation. Fall risk in older patients.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check pulse and blood pressure 1–2 weeks after starting alprazolam. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive sedation and fall risk in older patients. No direct pharmacokinetic interaction.
Symptoms
Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear in the first 1–2 weeks.
Management
Widely used in anxious-depressive disorders. Alprazolam is given for a short course (4–6 weeks) with gradual taper after mirtazapine's effect stabilises. In older patients: minimum alprazolam dose; monitor cognition.
Mechanism
Additive hypotension with sublingual nitroglycerin. Alprazolam sedation may worsen dizziness.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
The patient takes the first nitroglycerin dose sitting or lying down. Warn the patient about fall risk after nitroglycerin while on alprazolam.
Mechanism
Omeprazole weakly blocks CYP3A4; alprazolam plasma levels may rise slightly. The effect is clinically weak.
Symptoms
Minimal changes: mild additional sedation in some patients. Older patients: rare ataxia.
Management
Dose adjustment is usually unnecessary. In older patients and prolonged therapy, monitor cognition and fall risk.
Sources
Mechanism
Additive CNS depression via different mechanisms (GABAergic for alprazolam, α2δ calcium channel blockade for pregabalin). Sedation, ataxia, and fall risk amplify, especially in older patients.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Ataxia and fall risk are especially pronounced in older patients.
Management
On starting the combination, begin both at minimal doses. Avoid the combination in older patients — fall and fracture risk. In neuropathic pain and anxiety, alternative: low-dose amitriptyline with buspirone, or duloxetine with CBT. If unavoidable, give alprazolam only at bedtime.
Mechanism
Additive bradycardia, hypotension, and sedation. Propranolol is non-selective (blocks β1 and β2); risk higher than with bisoprolol.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
In older patients, check pulse and blood pressure 1–2 weeks after start. In asthma or COPD, a selective beta-blocker (bisoprolol, metoprolol) is preferable. Alternative anxiolytic: hydroxyzine or a short lorazepam course.
Mechanism
Additive CNS and respiratory depression. Both are sedating; the combination raises paradoxical respiratory suppression risk in older patients and in COPD.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. In COPD: dyspnoea, hypercapnia. Pronounced morning sedation possible.
Management
Avoid in older patients and in COPD. If unavoidable (anxiety with bipolar depression), cap alprazolam at 0.5 mg at bedtime and use the minimum quetiapine dose. In patients on stable quetiapine for sedation, adding alprazolam is not justified — increase quetiapine alone instead.
Mechanism
Tacrolimus is a weak CYP3A4 inhibitor; alprazolam is a CYP3A4 substrate. Alprazolam levels may rise moderately. Additive sedative effect.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On starting the combination, begin alprazolam at 0.25 mg at bedtime. In transplant patients, prefer buspirone or CBT for anxiety over benzodiazepines. If unavoidable, tacrolimus monitoring is unchanged, but check sedation at 1 and 2 weeks after starting alprazolam.
Mechanism
Additive orthostatic hypotension. Tamsulosin (α1-blocker) directly vasodilates; alprazolam mildly lowers BP and amplifies the orthostatic response.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk. Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On starting the combination, take tamsulosin in the evening (to minimise daytime weakness) and alprazolam at bedtime. In older patients, start alprazolam at 0.125 mg. Check standing/sitting BP at 1 and 2 weeks. With pronounced orthostatic hypotension, consider switching tamsulosin to silodosin (minimal BP effect).
Mechanism
Additive hypotension. Benzodiazepines have weak hypotensive effect; the main one comes from the ARB. In most patients, clinically minor.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk. Morning weakness possible at standard doses.
Management
No dose adjustment usually needed. In older patients on starting telmisartan, check standing/sitting BP at one week. With pronounced morning hypotension, move alprazolam from night to morning or switch to buspirone.
Mechanism
Valproate weakly suppresses hepatic alprazolam metabolism; alprazolam plasma levels may rise slightly. Plus additive sedation.
Symptoms
Additional drowsiness, ataxia. Older patients: fall risk. Symptoms appear in the first 1–2 weeks.
Management
Reduce alprazolam by 25% if needed. In older patients and prolonged therapy, monitor cognition and fall risk. Alternative anxiolytic without CYP dependence: lorazepam or oxazepam.
Mechanism
Additive CNS depression (minimal for venlafaxine, mainly from alprazolam). High-dose venlafaxine (above 150 mg/day) also raises BP.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On starting the combination, begin alprazolam at the minimum dose. For long-term anxiety treatment, prioritise antidepressant monotherapy with CBT and gradual benzodiazepine taper. In arterial hypertension, check BP 2 weeks after starting venlafaxine.
Mechanism
No direct pharmacokinetic or pharmacodynamic interaction. Isolated reports of slight digoxin elevation in older patients, without clinical significance.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
No dose adjustment needed. In older patients on digoxin, watch for alprazolam sedation signs.
Mechanism
No direct interaction. Mild additive hypotension and fall risk in older patients during hypovolaemia or on starting the combination.
Symptoms
Possible mild morning hypotension and sedation. In older patients: fall risk.
Management
No dose adjustment needed. In older patients, start alprazolam at 0.125 mg at bedtime. In dehydration or acute illness, temporarily stop spironolactone.
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Boxed warning
FDA black-box warning (2020): combining benzodiazepines with opioids significantly increases the risk of profound sedation, respiratory depression, coma, and death.
FDA category D. Use in the third trimester causes neonatal withdrawal and 'floppy infant' syndrome. Contraindicated.
Passes into breast milk and can cause infant sedation. Not recommended during breastfeeding.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Alprazolam is evaluated for the following indications with varying evidence strength: Panic disorder (evidence tier B), Generalized anxiety disorder (evidence tier C), Insomnia (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Alprazolam (≥ 1 in 100): Drowsiness, ataxia, Cognitive impairment, coordination disturbance, Headache, Dry mouth, Reduced libido. See the Safety section for uncommon and serious reactions.
FDA category D. FDA category D. Use in the third trimester causes neonatal withdrawal and 'floppy infant' syndrome. Contraindicated.
Passes into breast milk and can cause infant sedation. Not recommended during breastfeeding.
Alprazolam is contraindicated in: Hypersensitivity to benzodiazepines; Acute closed-angle glaucoma; Myasthenia gravis; Severe respiratory failure, sleep apnoea syndrome; Severe hepatic impairment. Full list in the Safety section.
FDA black-box warning (2020): combining benzodiazepines with opioids significantly increases the risk of profound sedation, respiratory depression, coma, and death.