N-demethylation (cytochrome P-450 3A4)
may increase the plasma concentrations of codeine's inactive metabolite
norcodeine. Drugs that are strong inhibitors of codeine O -demethylation (cytochrome P-450 2D6) may decrease the
plasma concentrations of codeine's active metabolites, morphine and
morphine-6-glucuronide. The contribution of these active metabolites to the
overall analgesic effect of codeine is not fully understood, but should be
7.6 Drug-Laboratory Test Interaction
Codeine sulfate tablets may cause an elevation of plasma amylase
and lipase due to the potential of codeine to produce spasm of the sphincter of
Oddi. Determination of these enzyme levels may be unreliable for some time after
an opiate agonist has been given.
Acute overdose of codeine is characterized by respiratory
depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes
respiration, cyanosis), extreme somnolence progressing to stupor or coma, miosis
(mydriasis may occur in terminal narcosis or severe hypoxia), skeletal muscle
flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In
severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may
Codeine sulfate may cause miosis, even in total darkness. Pinpoint pupils are
a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of
hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis
rather than miosis may be seen with hypoxia in overdose situations.
Primary attention should be given to the re-establishment of
adequate respiratory exchange through provision of a patent airway and
institution of assisted or controlled ventilation as necessary. Supportive
measures (including oxygen and vasopressors) should be employed in the
management of circulatory shock and pulmonary edema accompanying overdose as
indicated. Cardiac arrest or arrhythmias may require cardiac massage or
defibrillation. Induction of emesis is not recommended because of the potential
for CNS depression and seizures. Activated charcoal is recommended if the
patient is awake and able to protect his/her airway. In persons who are at risk
for abrupt onset of seizures or mental status depression, activated charcoal
should be administered by medical or paramedical personnel capable of airway
management to prevent aspiration in the event of spontaneous emesis. Severe
agitation or seizures should be treated with an intravenous benzodiazepine.
The opioid antagonist naloxone hydrochloride is a specific antidote against
respiratory depression resulting from overdosage or unusual sensitivity to
opiate agonists, including codeine. Therefore, an appropriate dose of naloxone
hydrochloride (see prescribing information for naloxone hydrochloride) should be
administered, preferably by the intravenous route, simultaneously with efforts
at respiratory resuscitation. Since the duration of action of codeine may exceed
that of the antagonist, the patient should be kept under continued surveillance
and repeated doses of the antagonist should be administered as needed to
maintain adequate respiration. A narcotic antagonist should not be administered
in the absence of clinically significant respiratory or cardiovascular
depression secondary to codeine sulfate overdose.
In an individual physically dependent on opioids, administration of the usual
dose of the antagonist will precipitate an acute withdrawal syndrome. The
severity of the withdrawal symptoms experienced will depend on the degree of
physical dependence and the dose of the antagonist administered. Use of an
opioid antagonist should be reserved for cases where such treatment is clearly
needed. If it is necessary to treat serious respiratory depression in the
physically dependent patient, administration of the antagonist should be
initiated with care and titrated with smaller than usual doses.
Codeine sulfate is contraindicated in patients with known
hypersensitivity to codeine or any components of the product. Persons known to
be hypersensitive to certain other opioids may exhibit cross-sensitivity to
Codeine sulfate is contraindicated in patients with respiratory depression in
the absence of resuscitative equipment.
Codeine sulfate is contraindicated in patients with acute or severe bronchial
asthma or hypercarbia.
Codeine sulfate is contraindicated in any patient who has or is suspected of
having paralytic ileus.
DRUG ABUSE AND DEPENDENCE
Codeine sulfate is an opioid agonist and is a
Schedule II controlled substance. Codeine sulfate can be abused and is subject
to criminal diversion.
Codeine is intended for oral use only. Abuse of codeine
poses a risk of overdose and death. The risk is increased with concurrent abuse
of alcohol and other substances. Parenteral drug abuse is commonly associated
with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment of the patient, proper prescribing practices, periodic
re-evaluation of therapy, and proper dispensing and storage are appropriate
measures that help to limit abuse of opioid drugs.
Infants born to mothers physically dependent on opioids will
also be physically dependent and may exhibit respiratory difficulties and
withdrawal symptoms. [see 8 USE
IN SPECIFIC POPULATIONS]
Tolerance is the need for increasing doses of opioids to maintain
a defined effect such as analgesia (in the absence of disease progression or
other external factors). Physical dependence is manifested by withdrawal
symptoms after abrupt discontinuation of a drug or upon administration of an
antagonist. Physical dependence and tolerance are not unusual during chronic
The opioid abstinence or withdrawal syndrome is characterized by some or all
of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other symptoms also may develop, including
irritability, anxiety, backache, joint pain, weakness, abdominal cramps,
insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
In general, opioids should not be abruptly discontinued.