Pain medicine therapeutics Flashcards
ADR of mu receptor activation
- Analgesic
- miosis
- respiratory depression
- bradycardia
- hypothermia
- indifference
- decreased flexor reflex
mu1 analgesia
mu2 ADR
ADR of kappa receptor activation
- Analgesic
- miosis
- respiratory depression
- depression
- dissociative/hallucinogenic effect
ADR of delta receptor activation
- analgesia
- physical dependence
- respiratory depression
Opioids mechanism
Modifies central perception of pain by binding to opioid receptors •Synergistic with non-opioids •Many are controlled substances •Roles: - Moderate to severe pain - Post-operative pain - Procedural pain - Obstetrical pain - Mainstay for cancer pain - Other uses: • antitussive, antidiarrheal, sedation, HA
Buprenorphine
Buprenorphine = Partial agonist
Pentazocin
Pentazocin (agonist at Kappa, antagonist at mu)
= mixed agonist antagonist
weak opioids
codeine
tramadol
moderate opioids
Tapentadol
Strong opioids
Morphine sulphate
Pethidine (NVR USE)
Fentanyl
Dont use much
Methadone
oxycodone
Codeine
- Availability:
- Equianalgesic dose:
weak opioids
Injection and tablet
•Equianalgesic dose: 200mg (oral) codeine = 10mg (IM/SC) Morphine or 100mg (IV) codeine
Indication and dose of codeine
weak opioids
Indication: Moderate pain (4-6)
- Dose: Usually orally 15mg - 60mg up to 6 times daily
- Dosing adjustment in renal impairment:
- Clcr 10-50 mL/minute: Administer 75% of dose
- Clcr <10 mL/minute: Administer 50% of dose
•Dosing adjustment in hepatic impairment:
- Probably necessary in hepatic insufficiency
Codeine DDI
weak opioid
DRUG INTERACTIONS –
- Substrate of CYP2D6 (major), 3A4 (minor);
- Inhibits CYP2D6 (weak)
- CYP2D6 inhibitors: May decrease the effects of codeine.
Example inhibitors include chlorpromazine, fluoxetine, miconazole, paroxetine, quinidine, quinine
Codeine ADR
weak opioid
ADVERSE REACTIONS — Incidence of some adverse effects may increase over time
• >10%:
Drowsiness
Constipation
Codeine PK
- Onset of action:
- Peak effect:
- Duration
- Absorption
- Distribution
Protein binding
Metabolism
Half-life elimination
Excretion
• Onset of action: - Oral: 0.5-1 hour; - I.M.: 10-30 minutes •Peak effect: - Oral: 1-1.5 hours; - I.M.: 0.5-1 hour • Duration: 4-6 hours • Absorption: Oral: Adequate •Distribution: Crosses placenta; enters breast milk
- Protein binding: 7%
- Metabolism: Hepatic to morphine (active)
- Half-life elimination: 2.5-3.5 hours
- Excretion: Urine (3% to 16% as unchanged drug, norcodeine, and free and conjugated morphine)
Weak opioid
TRAMADOL
Availability
Equianalgesic dose
weak opioid
•Availability: Injection and tablet
•Equianalgesic dose:
50mg of tramadol = 60mg of codeine
120mg of tramadol = 30mg of oral morphine
(2 tab codeine = 1 tab tramadol)
tramadol
indication
dose
weak opioid
- Indication: Moderate pain (4-6)
- Dose: 50 - 100mg every 4 to 6 hourly, max. of 400mg/day
- Dosing adjustment in renal impairment:
o Immediate release:
Clcr <30 mL/minute: Administer 50-100 mg dose every 12 hours (maximum: 200 mg/day)
o Extended release: Should not be used in patients with ClCr < 30 mL/minute - Dosing adjustment in hepatic impairment:
o Immediate release: Cirrhosis: Recommended dose: 50 mg every 12 hours
o Extended release: Should not be used in patients with severe hepatic dysfunction
Tramadol ADR
weak opioid
Lesser cardiovascular & respiratory side effects compared to other opiates; “Low” potential for abuse
ADVERSE REACTIONS— Incidence of some adverse effects may increase over time >10%:
- Dizziness, headache, somnolence
- Constipation, nausea
At high dosing, it lowers the seizure threshold (like tricyclic antidepressants) ——> It is prudent to avoid tramadol in patients predisposed to epileptic activity, such as those with brain tumors.
Tramadol DDI
weak opioid
DRUG INTERACTIONS — Substrate of CYP2D6 (major), 3A4 (minor)
– CYP2D6 inhibitors: May decrease the effects of tramadol. Example inhibitors include chlorpromazine, fluoxetine, miconazole, paroxetine, quinidine, quinine
– Carbamazepine: Decreases half-life of tramadol by 33% to 50%
– Naloxone: May increase the risk of seizures (if administered in tramadol overdose)
– Neuroleptic agents: May increase the risk of tramadol associated seizures and may have additive CNS depressant effects.
– SSRIs: May increase the risk of seizures with tramadol. Includes citalopram, fluoxetine, paroxetine, sertraline.
– Tricyclic antidepressants: May increase the risk of seizures.
– Warfarin: Concomitant use may lead to an elevation of prothrombin times; monitor
Tramadol PK
onset duration absorption bioavailable metabolism half life time to peak excretion
Weak opioid
Onset of action: Within1 hour
Duration of action: 9 hours
Absorption: Rapid and complete
Bioavailability: Immediate release: 75%; Extended release: 85% to 90% as compared to immediate release. Protein binding, plasma: 20%
Metabolism: Extensively hepatic via demethylation, glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)
Half-life elimination:
- Tramadol: ~6-8 hours;
- Active metabolite: 79 hours; prolonged in elderly, hepatic or renal impairment
Time to peak: Immediate release: 2 hours; Extended release: 12 hours
Excretion: Urine (30% as unchanged drug; 60% as metabolites)
Morphine
available form and Oral:parental ratio
strong opioid
Used as reference to compare other opioids; strong opioid of choice
May be given as PO, IV, IM, SC, I/T, epidural
Availability: Injection, mixture, tablet and capsule
Oral : Parenteral ratio of 2(3) : 1
Morphine dose and indication
strong opioid
•Indication: Moderate (4-6) to severe pain (7-10)
Dose: Variation
Dosing adjustment in renal impairment:
- Clcr 10-50 mL/minute: Administer at 75% of normal dose
- Clcr <10 mL/minute: Administer at 50% of normal dose
Dosing adjustment/comments in hepatic disease:
- Unchanged in mild liver disease; substantial extrahepatic metabolism may occur;
excessive sedation may occur in cirrhosis
morphine ADR
strong opioid
ADVERSE REACTIONS (>10%) - Cardiovascular: Palpitations, hypotension, bradycardia
- Central nervous system:
Drowsiness (48%, tolerance usually develops to drowsiness with regular dosing for 1-2 weeks);
dizziness (20%), confusion, headache (following epidural or intrathecal use)
- Dermatologic: Pruritus (may be secondary to histamine release)
- Gastrointestinal: Nausea (28%, tolerance usually develops to nausea and vomiting with chronic use); constipation (40%, tolerance develops very slowly if at all); xerostomia (78%)
- Genitourinary: Urinary retention (16%; may be prolonged, up to 20 hours, following epidural or intrathecal use)
- Neuromuscular & skeletal: Weakness
Morphine
DDI FDI
strong opioid
DRUG INTERACTIONS
• Antipsychotic agents: May increase hypotensive effects of morphine; monitor.
• CNS depressants: May increase the effects/toxicity of morphine; monitor.
• MAO inhibitors: May increase the effects/toxicity of morphine; some manufacturers recommend avoiding use within 14 days of MAO inhibitors
• Ethanol: Avoid ethanol (may increase CNS depression)
- Herb/Nutraceutical: Avoid valerian, St John’s wort, kava kava, gotu kola (may increase CNS depression).
- Food: Administration of oral morphine solution with food may increase bioavailability (ie, a report of 34% increase in morphine AUC when morphine oral solution followed a high-fat meal).
Morphine PK
Onset of action: Absorption Bioavailability protein binding metabolism half life excretion
Strong opioid
Onset of action:
- Oral (immediate release): ~30 minutes;
- I.V.: 5-10 minutes
Absorption: Variable
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability)
Protein binding: 30% to 35%
Metabolism: Hepatic via conjugation with glucuronic acid to morphine-3-glucuronide (inactive),
morphine-6-glucuronide (active),
and in
lesser amounts, morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and the 3-ethereal sulfate
Half-life elimination: Adults: 2-4 hours (immediate release forms)
Excretion: Mainly in urine, about 10% bile
FENTANYL
availability form and Equianalgesic dose
Strong opioid
- A semi-synthetic opioid (related to pethidine)
- Estimated to be about 100 times more potent than morphine
•Availability: Injection and dermal patch
•Equianalgesic dose: 100 mcg (IM) fentanyl = 10mg (IM) morphine
FENTANYL
indication and dose
- Indication: Severe pain (7-10)
- Dose: Usually 50 - 100mcg
- Dosing adjustment in renal impairment: Nil
- Dosing adjustment in hepatic disease: Monitor
Fentanyl PK Onset duration distribution metabolism Half life time to peak excretion
strong opioid
–Onset of action:
Analgesic:
I.M.: 7-15 minutes;
I.V.: Almost immediate
–Duration:
I.M.: 1-2 hours;
I.V.: 0.5-1 hour
–Distribution: Highly lipophilic, redistributes into muscle and fat
–Metabolism: Hepatic, primarily via CYP3A4
–Half-life elimination: 2-4 hours; Transdermal: 17 hours (halflife is influenced by absorption rate)
–Time to peak: Transdermal: 24-72 hours
–Excretion: Urine (primarily as metabolites, 10% as unchanged drug)
Fentanyl ADR
strong opioid
•Cardiovascular:
Hypotension, bradycardia
• Central nervous system:
CNS depression, confusion, drowsiness, sedation
- Gastrointestinal: Nausea, vomiting, constipation, xerostomia
- Respiratory: Respiratory depression
Fentanyl Transdermal —-> background info
indication
Strong opioid
•Transdermal (TD) fentanyl is a self-adhesive skin patch with a rate limiting membrane which allows a standardized amount of fentanyl to cross each hour from the patch into the skin
Indicated for patients with,
- intolerable undesirable side effects from morphine
- renal failure
- dysphagia
- tablet phobia’ or poor oral compliance
Fentanyl TD patch
Bioavailability time to steady state concentration half life duration of action elimination
With the TD patch,
- bioavailability >92%
- steady-state plasma concentrations of fentanyl are achieved after 36–48h
- after removal of a patch, the elimination plasma hal flife is 13–22h
- duration of action 72h; for some patients, 48h
• Elimination principally involves biotransformation in the liver by cytochrome P450 3A4 to inactive norfentanyl which undergoes urinary excretion
Fentanyl TD
caution
(withdraw, rate of absorption, removal)
• Some patients experience withdrawal symptoms when changed from morphine PO to TD fentanyl despite satisfactory pain relief, e.g. colic, diarrhoea and nausea together with sweating and restlessness.
This phenomenon is probably also accounted for by the differences between the two opioids in relation to their relative impact on peripheral and central µ-opioid receptors.
(Morphine less potent so [] is higher than fentanyl, thus sudden withdrawal of morphine for fentanyl can cause withdrawal)
- The rate of absorption of fentanyl from the patch may be increased in febrile patients, or if the skin under the patch becomes vasodilated because of an external heat source such as an electric blanket or heat pad.
- Used patch still contain drug; after removal, fold patch with adhesive side inward before disposal.
Hairy–> cut till short dont shave (damage epithelial –> increase rate of absorption)
Methadone MOA (receptor targets)
•Methadone is a synthetic strong opioid with mixed properties.
–a µ-opioid receptor agonist, an NMDA-receptor-channel blocker and a presynaptic blocker of serotonin re-uptake
a lipophilic drug
Methadone PK
Bioavailability onset time to peak half life duration of action metabolism Excretion
Strong Opioid
– Bio-availability 80% (range 40–100%) PO
– Onset of action 30min PO
– Time to peak plasma concentration 4h PO
– Plasma half-life 8–75h;longer in older patients; acidifying the urine results in a shorter half-life (20h) and raising the pH with sodium bicarbonate a longer halflife (>40h)
– Duration of action 4–5h PO; 6–12h repeated doses
– Metabolism: Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, and CYP2C19 to inactive metabolites – Excretion: Urine (<10% as unchanged drug); increased with urine pH <6
Methadone DDI
• Drug Interactions
- Substrate of CYP2C8/9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major);
- Inhibits CYP2D6 (moderate), 3A4 (weak)
–CYP3A4 inducers: CYP3A4 inducers may DECREASE the levels/ effects of methadone.
Example inducers include aminoglutethimide, carbamazepine, phenobarbital, phenytoin, and rifamycins.
–CYP3A4 inhibitors: May INCREASE the levels/effects of methadone.
Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nicardipine, propofol, quinidine, and verapamil.
• Agonist/antagonist analgesics (buprenorphine, butorphanol, nalbuphine, pentazocine): May decrease analgesic effect of methadone and precipitate withdrawal symptoms; use is not recommended
Methadone Food and herb interation
- Ethanol: Avoid ethanol (may increase CNS effects). Watch for sedation.
- Herb/Nutraceutical: Avoid St John’s wort (may decrease methadone levels; may increase CNS depression). Avoid valerian, kava kava, gotu kola (may increase CNS depression). Methadone is metabolized by CYP3A4 in the intestines; avoid concurrent use of grapefruit juice.
Methadone dose adjustment
• Dosage adjustment in renal impairment:
–Clcr <10 mL/minute: Administer 50% to 75% of normal dose
• Dosage adjustment in hepatic impairment:
–Avoid in severe liver disease
Methadone should only be used by specialist
Methadone side effects
• Side effects: Frequency not defined.
During prolonged administration, adverse effects may decrease over several weeks; however, constipation and sweating may persist.
– Cardiovascular: Bradycardia, peripheral vasodilation, HYPOTENSION, tachycardia, cardiomyopathy, flushing, heart failure, palpitation etc
– Central nervous system: Euphoria, dysphoria, headache, insomnia, agitation, disorientation, DROWSINESS, dizziness, lightheadedness, sedation, confusion, seizure
– Dermatologic: Pruritus, urticaria, rash
– Gastrointestinal: N/V, CONSTIPATION, anorexia, stomach cramps, xerostomia, biliary tract spasm, abdominal pain, glossitis, weight gain
– Genitourinary: Urinary retention or hesitancy, impotence
– Hematologic: Thrombocytopenia (reversible, reported in patients with chronic hepatitis)
– Neuromuscular
– Ocular: Miosis, visual disturbances
– Respiratory: Respiratory depression, respiratory arrest, pulmonary edema
Oxycodone pk
bioavailability onset time to peak half life duration of action metabolism excretion
•Oxycodone is a strong opioid with similar properties to morphine
- Bio-availability 75% PO (60–87%)
- Onset of action 20–30min PO
- Time to peak plasma concentration 1–1.5h; 3h m/r
- Plasma halflife 3.5h; 4.5h in renal failure
- Duration of action 4–6h; 12h m/r
- Metabolism: Hepatic (partly to oxymorphone)
- Excretion: Urine
oxycodone dose
strong opioid
- Starting Dose:
- Immediate release: Adults: 5 mg every 6 hours as needed
- Controlled release: Adults: (Opioid naïve) 10 mg every 12 hours
Normal-release oxycodone is used in the same way as morphine but q6h rather than q4h.
• Dosing adjustment in renal insufficiency:
–In renal impairment the clearance of oxycodone, noroxycodone and conjugated oxymorphone are reduced. Oxycodone plasma concentration increases by 50% and the half-life lengthens by 1h —> use with CAUTION
• Dosing adjustment in hepatic impairment:
–Reduce dosage in patients with severe liver disease
oxycodone ADR
–Central nervous system: Fatigue, DROWSINESS, dizziness, somnolence
–Dermatologic: Pruritus
–Gastrointestinal: N/V/C
–Neuromuscular & skeletal: Weakness
oxycodone DDI FDI HDI
•Drug Interactions - Substrate of CYP3A4 and CYP2D6
•CYP2D6 inhibitors: May DECREASE the effects of oxycodone.
Example inhibitors include chlorpromazine, fluoxetine, miconazole, paroxetine, quinidine, quinine…
- Ethanol: Avoid ethanol (may increase CNS depression).
- Food: When taken with a high-fat meal, peak concentration is 25% greater following a single OxyContin® 160 mg tablet as compared to two 80 mg tablets.
- Herb/Nutraceutical: Avoid valerian, St John’s wort, kava kava, gotu kola (may increase CNS depression)
Oxycodone metabolite is more active than parent drug.
__________ metabolizes oxycodone to the active metabolite oxymorphone •
CYP2D6 metabolizes oxycodone to the active metabolite oxymorphone
Oxymorphone is a potent opioid that has a ___ to ___ times higher μ-opioid receptor affinity than morphine
Oxymorphone is a potent opioid that has a 3 to 5 times higher μ-opioid receptor affinity than morphine
When compared to morphine, _________has a higher affinity for the μ-opioid receptor than the parent compound oxycodone
When compared to morphine, oxymorphone has a higher affinity for the μ-opioid receptor than the parent compound oxycodone
Tapentadol MOA
Moderate opioid
Synthetic, centrally active analgesic; structurally and pharmacologically related to tramadol
•Binds to μ-opiate receptors and inhibits the reuptake of norepinephrine
Tapentadol PK
Absorption
bioavailability
peak plasma [] time
______ meal increase AUC
Distribution
metabolism
half life
excretion
Moderate opioid
- Absorption: Rapid;
Bioavailability: ~32% after a single oral dose;
Peak plasma concentrations at ~ 1.25 hours after po;
High-fat, high-calorie meal increases tapentadol AUC by 25% - Distribution: Widely distributed throughout the body; May distribute into human milk; Protein binding: ~20%
- Metabolism: All metabolites pharmacologically inactive; metabolized primarily via phase 2 glucuronidation to glucuronides; minimal phase 1 oxidative metabolism; also metabolized to a lesser degree by CYP2C9, CYP2C19, and CYP2D6.
- Half-life elimination: Immediate release: ~4 hours; Long acting formulations: ~5-6 hours
- Excretion: Urine (99%: 70% conjugated metabolites; 3% unchanged drug)
Tapentadol administration
moderate opioid
• Administration: Administer orally with or without food; Long acting formulations must be swallowed whole.
tapentadol dose and indication
• Dosages exceeding 700 mg daily on the first day of therapy or 600 mg daily on subsequent days have not been evaluated and are NOT recommended.
• For the management of moderate to severe acute pain in adults,
the recommended dosage of tapentadol is 50–100 mg administered every 4–6 hours depending on the intensity of pain.
- No dosage adjustment is needed in patients with mild or moderate renal impairment
- No dosage adjustment is needed in patients with mild hepatic impairment
moderate opioid
tapentadol ADR
moderate opioid
Central nervous system: Dizziness, drowsiness, Gastrointestinal: Nausea , vomiting
pethidine PK
onset duration absorption distribution protein binding metabolism plasma halflife excretion
Strong opioid
- A synthetic opioid
- Clinical effect similar to morphine, but its effect on the CVS and GIT are less prominent
–Onset:
SubQ: 10-15 minutes;
I.V.: ~5 minutes
–Duration:
SubQ.: 2-4 hours
–Absorption:
I.M.: Erratic and highly variable
–Distribution:
Crosses placenta; enters breast milk
–Protein binding: 65% to 75%
–Metabolism: Hepatic; hydrolyzed to meperidinic acid (inactive) or undergoes Ndemethylation to normeperidine (active; has 1/2 the analgesic effect and 2-3 times the CNS effects of meperidine)
–Plasma half-life of about 3 hours
–Excretion: Urine (as metabolites)
pethidine
availability and equianalgesic dose and indication
strong opioid
•Availability : Injection •Equianalgesic dose: 75 mg (IV) pethidine = 10mg (IM/SC)morphine
•Indication: Acute pain
pethidine dose
strong opioid
•Dose: Usually IV 75mg - 100mg every 3 hourly
- Dosing adjustment in renal impairment:
- Avoid repeated administration in renal dysfunction:
- Clcr 10-50 mL/minute: Administer at 75% of normal dose
- Clcr <10 mL/minute: Administer at 50% of normal dose
- Dosing adjustment in hepatic disease:
- Increased effect in cirrhosis; may need to reduce dose
Pethidine ADR
strong opioid
•Side effects: Frequency not defined
–Cardiovascular: Hypotension
–Central nervous system: Fatigue, drowsiness, dizziness, nervousness, headache, restlessness, malaise, confusion, mental depression, hallucinations, paradoxical CNS stimulation, increased intracranial pressure, seizure (associated with metabolite accumulation), serotonin syndrome
–Dermatologic: Rash, urticaria
–Gastrointestinal: Nausea, vomiting, constipation, anorexia, stomach cramps, xerostomia, biliary spasm, paralytic ileus, sphincter of Oddi spasm
–Genitourinary: Ureteral spasms, decreased urination
–Local: Pain at injection site
–Neuromuscular & skeletal: Weakness
–Respiratory: Dyspnea
Why do we avoid Pethidine in Palliative Care?
- Quick onset, short duration of action (2-3h). Not good for regular analgesia, and increases risk of dependence
- Toxic metabolite (norpethidine) which accumulates if given regularly, esp. in RF
- Norpethidine decreases seizure threshold
- More emetogenic than morphine
tx for opioid ovedose
onset
halflife
metabolism
excretion
- Availability:
- Dose:
NALOXONE •An antagonist used for the treatment of opioids overdosage •Onset of action within 2 minutes (IV) •Plasma half life of about 1 hour •Metabolised in the liver •Excreted by the kidney
•Availability: Injection 400mcg/ml
•Dose:
Adult - IV 100 to 200mcg adjusted according to response, may repeated every 2 minutes.
Max. of 10mg if respiratory function does not improve.
Child - IV 5 to 10 mcg/kg, may be repeated every 2 minutes
opioid overdose guideline
IF Respiratory rate >= 8/min and the patient easily rousable and not cyanosed, adopt a policy of WAIT AND SEE; consider reducing or omitting next regular dose of morphine
if RR <8/min, patient barely rousable / unconscious and or cyanosed
- dilute a standard ampoule containing naloxone 400mcg to 10ml with saline for injection
- administer 0.5ml (20mcg) IV q2min until the patients respiratory status is satisfactory
- further boluses may be necessary because naloxone is shorter acting than morphine and other opioids.
