Indications
Management of breakthrough pain in cancer patients
18 yr old already receiving opioids and tolerant to
around-the-clock opioids for persistent cancer pain
(60 mg/day of oral morphine or equivalent).
Action
Binds to opioid receptors in the CNS, altering the response
to and perception of pain. Therapeutic Effects:
Decrease in severity of breakthrough pain.
Pharmacokinetics
Absorption: Buccal tablet—65% absorbed from
buccal mucosa; 50% is absorbed transmucosally, remainder
is swallowed and is absorbed slowly from the
GI tract. Buccal absorption is enhanced by an effervescent
reaction in the dose form; Nasal spray—Well absorbed
from nasal mucosa (bioavailability higher than
that of oral transmucosal lozenge); Oral transmucosal
lozenge—Initial rapid absorption (25%) from buccal
mucosa is followed by more prolonged absorption
(25%) from GI tract (combined bioavailability 50%);
Sublingual spray—76% absorbed through sublingual
mucosa; Sublingual tablets—54% absorbed from
oral mucosa following sublingual administration.
Distribution: Readily crosses the placenta and enters
breast milk.
Metabolism and Excretion: Mostly metabolized
in the liver and intestinal mucosa via the CYP3A4 enzyme
system; inactive metabolites are excreted in urine;
7% excreted unchanged in urine. Half-life: Buccal tablet—2.6–11.7 hr (qwith
dose); Nasal spray—15–25 hr (qwith dose); Sublingual
spray—5–12 hr; Sublingual tablet—5–10
hr (qwith dose); Transmucosal lozenge—7 hr.
TIME/ACTION PROFILE (p pain)
ROUTE ONSET PEAK DURATION
Buccal tablet 15 min 40–60 min 60 min
Nasal spray within 10 min unknown 2–4 hr
Oral transmucosal
lozenge
rapid 15–30 min several hr
SL within 30 min 30–60 min 2–4 hr
Contraindications/Precautions
Contraindicated in: Known intolerance or hypersensitivity;
Acute/postoperative pain including headache/
migraine, dental pain, or emergency room use;
Opioid—naive (nontolerant) patients; Concurrent use
of MAO inhibitors; OB: Labor and delivery; Lactation:
Avoid use during breast feeding; may cause infant sedation
and/or respiratory depression.
Use Cautiously in: Chronic obstructive pulmonary
disease or pre-existing medical conditions predisposing
to hypoventilation; Concurrent use of CNS active
drugs; History of substance abuse; Severe renal/hepatic
impairment (use lowest effective starting dose); Concurrent
use of CYP3A4 inhibitors (use lowest effective
dose); Bradyarrhythmias; OB: Use only if the potential
benefit justifies the potential risk to the fetus. Chronic
maternal treatment with opioids during pregnancy may
result in neonatal abstinence syndrome; Geri: May be
more sensitive to effects and may have anqrisk of adverse
reactions; titrate dosage carefully; Pedi: Safety and
effectiveness not established.
Exercise Extreme Caution in: Patients susceptible
to intracranial effects of CO2 retention including
those withqintracranial pressure, head injuries, or impaired
consciousness.
Adverse Reactions/Side Effects
Opioid side effectsqwithqdosage.
CNS: dizziness, drowsiness, headache, confusion, depression,
fatigue, hallucinations, headache, insomnia,
weakness. Resp: RESPIRATORY DEPRESSION, dyspnea.
CV: hypotension. Endo: adrenal insufficiency. GI:
constipation, nausea, vomiting, abdominal pain, anorexia,
dry mouth. Misc: allergic reaction including ANAPHYLAXIS,
physical dependence, psychological dependence.
Interactions
Drug-Drug: Should not be used within 14 days of
MAO inhibitors because of possible severe and unpredictable
reactions. Concurrent use of CYP3A4 inhibitors
including ritonavir, ketoconazole, itraconazole,
fluconazole, clarithromycin,
erythromycin, nefazodone, diltiazem, verapamil,
nelfinavir, and fosamprenavirqlevels and risk of
opioid toxicity; careful monitoring during initiation,
dose changes, or discontinuation of the inhibitor is recommended.
Concurrent use with CYP3A4 inducers
including barbiturates, carbamazepine, efavirenz,
corticosteroids, modafinil, nevirapine, oxcarbazepine,
phenobarbital, phenytoin, rifabutin, or
rifampin maypfentanyl levels and analgesia; if inducers
are discontinued or dosagep, patients should be
monitored for signs of opioid toxicity and necessary
dose adjustments should be made. Use with benzodiazepines
or other CNS depressants including other
opioids, non-benzodiazepine sedative/hypnotics,
anxiolytics, general anesthetics, muscle relaxants,
antipsychotics, and alcohol may cause profound
sedation, respiratory depression, coma, and
death; reserve concurrent use for when alternative
treatment options are inadequate. Drugs that affect serotonergic
neurotransmitter systems, including tricyclic
antidepressants, SSRIs, SNRIs, MAO inhibitors,
TCAs, tramadol, trazodone, mirtazapine, 5–HT3
receptor antagonists, linezolid, methylene blue,
and triptansqrisk of serotonin syndrome.
Drug-Natural Products: St. John’s wort is an inducer
of CYP3A4; concurrent use mayplevels and analgesia;
if inducers are discontinued or dosage decreased,
patients should be monitored for signs of
opioid toxicity and necessary dosage adjustments made.
Drug-Food: Grapefuit juice is a moderate inhibitor
of CYP3A4 enzyme system; concurrent use mayqlevels
and the risk of CNS and respiratory depression. Careful
monitoring and dose adjustment may be necessary.
Route/Dosage
Transmucosal Products Are Not Equivalent
on a mcg-to-mcg Basis
Buccal (Adults): Tablets—100 mcg, then titrate to
dose that provides adequate analgesia without undue
side effects.
Intranasal (Adults): One 100-mcg spray in one nostril
initially, then titrate in a step-wise manner (qto one
100-mcg spray in each nostril [200 mcg total], then a
total of three 100–mcg sprays (one in right nostril,
then one in left nostril, then last spray in right nostril),
then one 400-mcg spray in one nostril (or two 100–
mcg sprays in each nostril [400 mcg total]), then two
300–mcg sprays in each nostril [600 mcg total], then
one 400-mcg spray in each nostril [800 mcg total] to
provide adequate analgesia without undue side effects
(up to a maximum of one 400-mcg spray in each nostril).
Oral transmucosal (Adults): One 200-mcg unit dissolved
in mouth (see Implementation section) over 15
min; additional unit may be used 15 min after first unit
is completed. If more than 1 unit is required per episode
(as evaluated over several episodes), dose may be
qas required to control pain. Optimal usage/titration
should result in using no more than 4 units/day.
SL (Adults): Tablets—100 mcg initially, then titrate
using 100-mcg increments to provide adequate analge sia without undue side effects (not to exceed 2 doses
per episode; no more than 4 doses per day; separate by
at least 2 hr); Spray—100 mcg initially; if pain not relieved
within 30 min, repeat 100-mcg dose (do not take
more than 2 doses per breakthrough pain episode);
patients must wait 4 hr before treating another episode
of breakthrough pain. Dose may be titrated during
subsequent pain episodes to 200 mcg, then 400 mcg,
then 600 mcg, then 800 mcg, then 1200 mcg, and then
1600 mcg to provide adequate analgesia and undue
side effects.
Availability (generic available)
Buccal tablets: 100 mcg, 200 mcg, 300 mcg, 400
mcg, 600 mcg, 800 mcg. Cost: 200 mcg $1,006.04/28.
Nasal spray: 100 mcg/spray, 300 mcg/spray, 400
mcg/spray. Oral transmucosal lozenge on a stick
(berry flavor-sugar free): 200 mcg, 400 mcg, 600
mcg, 800 mcg, 1200 mcg, 1600 mcg. Cost: Generic—
400 mcg $599.93/30, 1200 mcg $799.93/30, 1600
mcg $1,155.89/30. Sublingual spray: 100 mcg/spray,
200 mcg/spray, 400 mcg/spray, 600 mcg/spray, 800
mcg/spray. Sublingual tablets: 100 mcg, 200 mcg,
300 mcg, 400 mcg, 600 mcg, 800 mcg.
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