chapter
Opioids
Pages 9

Consider using a formulation with a lower dose of ethinylestradiol

NSAIDs PERIPHERAL VASODILATORS

Risk of bleeding when pentoxifylline is given with ketorolac post surgery

Possibly additive antiplatelet effect Avoid co-administration

NSAIDs PROGESTOGENS ≠ risk of hyperkalaemia Drospirenone (component of the Yasmin brand of combined contraceptive pill) is a progestogen derived from spironolactone that can cause potassium retention

Monitor serum potassium weekly until stable, and then every 6 months

OPIOIDS

OPIOIDS ALCOHOL ≠ sedation Additive effect Warn patient OPIOIDS ANTIARRHYTHMICS

METHADONE, TRAMADOL

FLECAINIDE, PROCAINAMIDE, PROPAFENONE

Possible ≠ flecainide, procainamide and propafenone levels

Methadone and tramadol inhibit CYP2D6

Monitor PR and BP closely

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ANALGESICS OPIOIDS

2. Methadone may ≠ mexiletine levels

1. Uncertain but thought to be due to an opioid-induced delay in gastric emptying 2. Methadone inhibits CYP2D6-mediated metabolism of mexiletine

1. Watch for poor response to mexiletine; consider starting at a higher or using the intravenous route 2. Monitor PR, BP and ECG closely; watch for mexiletine toxicity

OPIOIDS ANTIBIOTICS

OPIOIDS CIPROFLOXACIN 1. Effects of methadone ≠ by ciprofloxacin 2. ↓ levels of ciprofloxacin with opioids

1. Ciprofloxacin inhibits CYP1A2-, CYP2D6-and CYP3A4-mediated metabolism of methadone 2. Uncertain

1. Watch for ≠ effects of methadone 2. Avoid opioid premedication when ciprofloxacin is used as surgical prophylaxis

OPIOIDS MACROLIDES Effects of alfentanil ≠ by erythromycin

Erythromycin inhibits metabolism of alfentanil

Be aware that the effects of alfentanil (especially when given as an infusion) may be prolonged by erythromycin

OPIOIDS RIFAMPICIN ↓ effect of alfentanil, codeine, methadone and morphine

Rifampicin ≠ hepatic metabolism of these opioids (alfentanil by CYP3A4, codeine by CYP2D6, morphine unknown). Rifampicin is also known to induce intestinal P-gp, which may ↓ bioavailability of oral morphine

Be aware that alfentanil, codeine, methadone and morphine doses may need to be ≠

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DRUGS – CYTOTOXICS

effects of codeine, dextromethorphan, hydroxycodone, methadone, morphine, oxycodone, pethidine and tramadol 2. Unpredictable reactions may occur associated with hypotension and respiratory depression when procarbazine is co-administered with alfentanil, fentanyl, sufentanil or morphine

1. Imatinib is a potent inhibitor of CYP2D6 isoenzymes, which metabolize these opioids 2. Opioids cause hypotension due to arterial and venous vasodilatation, negative inotropic effects and a vagally induced bradycardia. Procarbazine can cause postural hypotension. Also attributed to accumulation of serotonin due to inhibition of MAO

1. Monitor for clinical efficacy and toxicity. Warn patients to report ≠ drowsiness, malaise and anorexia. Measure amylase and lipase if toxicity is suspected. Tramadol causes less respiratory depression than other opiates, but need to monitor BP and blood counts and advise patients to report wheezing, loss of appetite and fainting attacks. Need to consider reducing dose. Methadone may cause Q-T prolongation; the CSM has recommended that patients with heart and liver disease on methadone should be carefully monitored for heart conduction abnormalities such as Q-T prolongation on ECG, which may lead to sudden death. Also need to monitor patients on more than 100 mg methadone daily, and thus ≠ plasma concentrations necessitates close monitoring of cardiac and respiratory function 2. Recommended that a small test dose (one-quarter of the usual dose) be administered initially to assess response

OPIOIDS ANTICOAGULANTS – ORAL Cases of ≠ anticoagulant effect with tramadol

Unknown Monitor INR at least weekly until stable

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ANALGESICS OPIOIDS

Additive effects on NMDA receptors

Avoid co-administration

OPIOIDS MAOIs Additive depression of CNS ranging from drowsiness to coma and respiratory depression

Synergistic depressant effects on CNS function

Necessary to warn patients, particularly regards activities that require attention, e.g. driving or using machinery and equipment that could cause self-harm

PETHIDINE, MORPHINE, PHENOPERIDINE, DEXTROMETHORPHAN

MAOIs Two types of reactions are reported: 1. Risk of serotonin syndrome with dextromethorphan, pethidine or tramadol and MAOIs 2. Depressive – respiratory depression, hypotension, coma

Type I reactions are attributed to an inhibition of reuptake of serotonin; this more common with pethidine, phenoperidine and dextromethorphan. Type II reactions, attributed to MAOI inhibition of metabolism of opioids, are more common with morphine

Avoid co-administration; do not give dextromethorphan, pethidine or tramadol for at least 2 weeks after cessation of MAOI

OPIOIDS SSRIs 1. Possible ↓ analgesic effect of oxycodone and tramadol 2. ≠ serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are co-administered with SSRIs (fluoxetine, sertraline) 3. SSRIs may ≠ codeine, fentanyl, methadone, pethidine and tramadol levels

1. Uncertain. Paroxetine inhibits CYP2D6, which is required to produce the active form of tramadol 2. Uncertain 3. SSRIs inhibit CYP2D6-mediated metabolism of these opioids

1. Consider using an alternative opioid 2. Look for signs of ≠ serotonin activity, particularly on initiating therapy 3. Watch for excessive narcotization

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phine 3. Cases of seizures when tramadol is co-administered with TCAs 4.TCAs may ≠ codeine, fentanyl, pethidine and tramadol levels

1. Additive effect 2. Uncertain; likely to ≠ bioavailability of morphine 3. Unknown 4. TCAs inhibit CYP2D6-mediated metabolism of these opioids

1. Warn patients of this effect. Titrate doses carefully 2. Warn patients of this effect. Titrate doses carefully 3. Consider an alternative opioid 4. Watch for excessive narcotization

OPIOIDS OTHER – DULOXETINE ≠ serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are given

Uncertain Look for signs of ≠ serotonin activity, particularly on initiating therapy

MORPHINE ANTIDIABETIC DRUGS – METFORMIN

≠ level of metformin and risk of lactic acidosis. The onset of lactic acidosis is often subtle with symptoms of malaise, myalgia, respiratory distress and increasing non-specific abdominal distress. There may be hypothermia and resistant bradyarrhythmias

Metformin is not metabolized in humans and is not protein bound. Competition for renal tubular excretion is the basis for ≠ activity or retention of metformin

Theoretical possibility. Requires ↓ of metformin dose to be considered or to avoid co-administration. Warn patients re hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

OPIOIDS ANTIEMETICS 1. Ondansetron seems to ↓ analgesic effect of tramadol 2. ↓ efficacy of domperidone on gut motility by opioids 3. Metoclopramide ≠ speed of onset and effect of oral morphine

1. Uncertain; tramadol exerts its analgesic properties via serotoninergic pathways in addition to stimulation of opioid receptors. Ondansetron is a serotonin receptor antagonist 2. Antagonist effect 3. Uncertain; possibly metoclopramide promotes absorption of morphine by increasing gastric emptying

1. Avoid co-administration. Although increasing the dose of tramadol restored the analgesic effect, it also caused a poor response to an antiemetic 2. Caution with coadministration 3. Be aware that the effects of oral morphine are ≠

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ANALGESICS OPIOIDS

2. ↓ carbamazepine, phenobarbital, phenytoin or primidone 3. Carbamazepine ↓ tramadol levels 4. Risk of pethidine toxicity

1. Additive sedative effect 2. ≠ hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 3. Carbamazepine ≠ metabolism of tramadol 4. Phenytoin induces metabolism of pethidine, which causes ≠ level of a neurotoxic metabolite

1. Monitor respiratory rate and conscious levels 2. Be aware that the dose of fentanyl and methadone may need to be ≠ 3. Watch for poor effect of tramadol. Consider using an alternative opioid 4. Co-administer with caution; the effect may be å by administering pethidine intravenously

OPIOIDS ANTIFUNGALS 1, Ketoconazole ≠ effect of buprenorphine 2. Fluconazole and itraconazole ≠ the effect of alfentanil 3. Fluconazole and possibly voriconazole ≠ effect of methadone; this is a recognized pharmacokinetic effect but of uncertain clinical significance

1. Ketoconazole ↓ the CYP3A4mediated metabolism of buprenorphine 2. ↓ clearance of alfentanil 3. ↓ hepatic metabolism

1. The dose of buprenorphine needs to be ↓ (by up to 50%) 2. ↓ dose of alfentanil 3. Watch for ≠ effects of methadone

OPIOIDS ANTIHISTAMINES Promethazine ≠ analgesic and anaesthetic effects of opioids. However, it has an additive sedative effect

Unknown Monitor vital signs closely during coadministration

OPIOIDS ANTIMALARIALS – QUININE

≠ codeine, fentanyl, pethidine and tramadol levels

Quinine inhibits CYP2D6 Watch for excessive narcotization

PETHIDINE, TRAMADOL ANTIPARKINSON’S DRUGS – RASAGILINE, SELEGILINE

1. Risk of neurological toxicity when pethidine is co-administered with rasagiline 2. Risk of hyperpyrexia when pethidine and possibly tramadol is co-administered with selegiline

Unknown 1. Avoid co-administration; do not use pethidine for at least 2 weeks after stopping rasagiline 2. Avoid co-administration

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seems to be particularly marked with clozapine

Additive effects Warn patients of these effects. Monitor BP closely. Titrate doses carefully

TRAMADOL ANTIPSYCHOTICS ≠ risk of fits Additive effects Consider using an alternative analgesic

OPIOIDS ANTIVIRALS

METHADONE NNRTIs Methadone levels may be significantly ↓ by efavirenz and nevirapine

≠ CYP3A4-and 2B6-mediated metabolism of methadone

Monitor closely for opioid withdrawal; ≠ dose as necessary. Likely to need dose titration of methadone (mean 22% but up to 186% ≠)

METHADONE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

↓ efficacy of methadone when co-administered with abacavir

Uncertain; possibly enzyme induction

Monitor for opioid withdrawal and consider increasing dose

ALFENTANIL, BUPRENORPHINE, FENTANYL, TRAMADOL

PROTEASE INHIBITORS Possibly ≠ adverse effects when buprenorphine is co-administered with indinavir, ritonavir (with or without lopinavir) or saquinavir

Inhibition of CYP3A4 (CYP2D6 in the case of tramadol)

Halve the starting dose and titrate to effect. For single injection of fentanyl, monitor sedation and respiratory function closely. If continued use of fentanyl, ↓ dose may be required. Concomitant use of ritonavir and transdermal fentanyl is not recommended

CODEINE, DIHYDROCODEINE

PROTEASE INHIBITORS ↓ efficacy of codeine and dihydrocodeine when given with ritonavir

Inhibition of CYP2D6-mediated metabolism of codeine to its active metabolites

Use an alternative opioid

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ANALGESICS OPIOIDS

nelfinavir, ritonavir (with or without lopinavir) or saquinavir

Uncertain; possibly due to induction of CYP3A4 and CYP2D6

Monitor closely for opioid withdrawal, and ≠ dose of methadone as necessary. This advice includes co-administration of methadone with low-dose ritonavir. Short-term use of pethidine is unlikely to cause a problem

OPIOIDS ANXIOLYTICS AND HYPNOTICS

OPIOIDS ANXIOLYTICS AND HYPNOTICS

1. ≠ sedation with BZDs 2. Respiratory depressant effect of morphine antagonized by lorazepam

1. Additive effect; both drugs are sedatives 2. Uncertain

1. Closely monitor vital signs during co-administration 2. Although this effect may be considered to be beneficial, risk of additive effects should be borne in mind if the combination of an opioid and BZDs is used for sedation for painful procedures

OPIOIDS ANXIOLYTICS AND HYPNOTICS – SODIUM OXYBATE

Risk of CNS depression – coma, respiratory depression

Additive effect Avoid co-administration

OPIOIDS BETA-BLOCKERS 1. Risk of ≠ plasma concentrations and effects of labetalol, metoprolol and propranolol; ≠ systemic effects of timolol eye drops 2. ≠ plasma concentrations of esmolol when morphine added 3. ≠ plasma concentrations of metoprolol and propranolol when dextropropoxyphene added

1. Methadone inhibits CYP2D6 which metabolizes these beta-blockers 2. Unknown 3. ↓ hepatic clearance of metoprolol and propanolol

1. Monitor BP at least weekly until stable 2. Monitor BP closely 3. Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

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Diltiazem inhibits CYP3A4mediated metabolism of alfentanil

Watch for the prolonged action of alfentanil in patients taking calcium channel blockers; case reports of delayed extubation in patients recovering from anaesthetics involving large doses of alfentanil in patients on diltiazem

OPIOIDS CARDIAC GLYCOSIDES ≠ concentrations of digoxin may occur with tramadol

Unknown Watch for digoxin toxicity; check levels and ↓ dose of digoxin as necessary

OPIOIDS CNS STIMULANTS – ATOMOXETINE

Risk of arrhythmias with methadone and possible risk of fits with tramadol

Uncertain Avoid co-administration of atomoxetine with methadone or tramadol

OPIOIDS DRUG DEPENDENCE THERAPIES – BUPROPION

≠ plasma concentrations of these substrates, with risk of toxic effects

Bupropion and its metabolite hydroxybupropion inhibit CYP2D6

Initiate therapy of these drugs at the lowest effective dose

OPIOIDS H2 RECEPTOR BLOCKERS

ALFENTANIL, FENTANYL, PETHIDINE, TRAMADOL

CIMETIDINE Cimetidine may ≠ fentanyl, pethidine and tramadol levels

Cimetidine inhibits CYP2D6-mediated metabolism of these opioids. Ranitidine weakly inhibits CYP2D6

Watch for excessive narcotization

CODEINE CIMETIDINE Cimetidine may ↓ efficacy of codeine

Cimetidine inhibits CYP2D6mediated conversion of codeine to its active metabolite. Ranitidine weakly inhibits CYP2D6

Watch for poor response to codeine. Consider using an alternative opioid or acid suppression therapy

OPIOIDS OESTROGENS Effect of morphine may be ↓ by combined oral contraceptives

Hepatic metabolism of morphine is ≠

Be aware that morphine dose may need to be ≠. Consider using an alternative opioid such as pethidine

OPIOIDS PROGESTOGENS Gestodene ≠ effect of buprenorphine

Gestodene ↓ the CYP3A4-mediated metabolism of buprenorphine

The dose of buprenorphine needs to be ↓ (by up to 50%)