Acetaminophen; Codeine Contraindications and Precautions
- abrupt discontinuation
- acetaminophen hypersensitivity
- breast-feeding
- alcoholism
- anemia
- asthma
- bladder obstruction
- bone marrow suppression
- cardiac arrhythmias
- cardiac disease
- children
- chronic obstructive pulmonary disease (COPD)
- constipation
- diarrhea
- driving or operating machinery
- elderly
- G6PD deficiency
- GI disease
- GI obstruction
- head trauma
- hepatic disease
- hepatitis
- hypotension
- hypovolemia
- ileus
- immunosuppression
- increased intracranial pressure
- infection
- inflammatory bowel disease
- oliguria
- opiate agonist hypersensitivity
- pregnancy
- prostatic hypertrophy
- pulmonary disease
- renal disease
- renal impairment
- respiratory depression
- salicylate hypersensitivity
- substance abuse
- ulcerative colitis
- urethral stricture
- urinary retention
Acetaminophen; Codeine Contraindications and Precautions
NOTE: This monograph discusses the contraindications/precautions of acetaminophen; codeine combination products. Clinicians may wish to consult the individual monographs for more information about each agent.
Acetaminophen; codeine combinations should not be used in a patient with a known acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Although true opiate agonist hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to codeine should not receive acetaminophen; codeine or other opioid agonists of the phenanthrene subclass including morphine, oxycodone and hydromorphone.
Due to the effects of opiate agonists on the gastrointestinal tract, acetaminophen; codeine should be used cautiously in patients with GI disease including GI obstruction or ileus, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Codeine is contraindicated in patients who have or are suspected of having paralytic ileus. Patients with acute ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.
Acetaminophen; codeine should be used cautiously in patients with asthma who also have salicylate hypersensitivity. Of 50 patients with aspirin-sensitive asthma, 17 had either a naso-ocular or bronchospastic reaction after ingestion of either 1000 mg or 1500 mg of acetaminophen. The magnitude of FEV1 decline after a mean aspirin dose of 47 mg was similar to the decline seen after a mean acetaminophen dose of 1227 mg. The lower the aspirin provocative dose, the more likely patients were to cross-react to acetaminophen. For example, 5 of 6 patients with aspirin-induced bronchospasm after a dose of 30 mg or less had cross-reactivity to acetaminophen whereas no patients had cross-reactivity when the provocative aspirin dose was at least 150 mg. The acetaminophen challenges were performed before any aspirin challenges and all patients had a measured FEV1 of at least 70% of predicted or best previously recorded value, an absolute value greater than 1.5 liters, and a fall of less than 15% in FEV1 from morning baseline during placebo challenges. In addition, codeine should be avoided in patients with severe pulmonary disease such as acute or severe bronchial asthma, chronic obstructive pulmonary disease (COPD), or upper airway obstruction, patients with decreased respiratory reserve or in patients with significant respiratory depression due to potential additive affects.
Abrupt discontinuation of prolonged acetaminophen; codeine therapy can result in withdrawal symptoms (see Adverse Reactions). Patients should be gradually tapered off acetaminophen; codeine to avoid a withdrawal reaction. Generally, a 50% decrease every 1 - 2 days of the daily acetaminophen; codeine dose will prevent withdrawal symptoms in patients who have been receiving large daily doses of codeine.
Due to potential toxicities and increased side effects, acetaminophen; codeine should be used cautiously in patients with hepatic disease. Patients with viral hepatitis or alcoholism may be at risk for acetaminophen-induced hepatotoxicity due to decreased conjugation with glucuronide or sulfate. Acetaminophen should not be used in patients who consume more than 3 alcoholic beverages per day. The maximum daily dose of acetaminophen is 4 g/day in patients with normal hepatic function. Health care providers need to consider other potential sources of acetaminophen in addition to acetaminophen; codeine products. Codeine may accumulate leading to a prolonged duration of action in patients with decreased liver function. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver or renal disease may require less frequent dosing intervals. Short courses of normal adult doses of acetaminophen have been administered safely in patients with stable chronic liver disease.
Because codeine is an opiate agonist, acetaminophen; codeine is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with acetaminophen; codeine. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Acetaminophen; codeine is not approved for the management of substance abuse (alcohol or drug dependence). The use of acetaminophen; codeine in patients with alcohol or drug dependence, either active or in remission, is for the treatment of pain requiring opiate agonist analgesia. Patients receiving opiate substitution therapy for opiate substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain, and will require higher and more frequent dosing to control their pain. Opiate substitution therapy does not adequately treat pain.
Patients with head trauma or with increased intracranial pressure should be given acetaminophen; codeine with extreme caution, because these drugs can make it difficult to evaluate neurologic parameters. Hypoventilation due to the codeine component can produce cerebral hypoxia and raise CSF pressure, exaggerating the injury.
Opiate agonists, such as codeine, produce cholinergic side effects (by stimulating medullary vagal nuclei) causing bradycardia and vasovagal syncope, and induce the release of histamine, causing peripheral vasodilatation and orthostatic hypotension. These effects can cause problems in patients with cardiac disease. Acetaminophen; codeine should be used with caution in patients with cardiac arrhythmias, hypotension, or hypovolemia.
Acetaminophen; codeine is classified as FDA pregnancy-risk category C drug. No well-controlled studies in pregnant women have been performed. The pregnancy risk factor increases to FDA category D if acetaminophen; codeine is used for prolonged periods during pregnancy or in high doses close to term. Neonates whose mothers have been taking acetaminophen; codeine chronically may show some respiratory depression and/or withdrawal symptoms at birth or within a few days. No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 infants exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.
Acetaminophen; codeine should be used with caution in breast-feeding, as codeine is distributed into breast milk at varying degrees depending upon the dose. Codeine is metabolized to morphine, which is also distributed into breast milk (see Pharmacokinetics). Breast-fed infants of women who quickly metabolize codeine (ultra-rapid metabolizer) may ingest dangerous amounts of morphine. A healthy, 13-day-old breastfed baby died from a morphine overdose; the baby’s blood morphine concentration was 70 ng/ml. The mother was taking codeine 30 mg and acetaminophen 500 mg tablets. The mother initially took 2 tablets every 12 hours for episiotomy pain, but she took half of this dose from day 2 to 14 because of somnolence and constipation. She stored her milk on day 10 because of poor neonatal feeding; the morphine concentration in the milk was 87 ng/ml. She was determined by genetic testing to be an ultra-rapid metabolizer of codeine (heterozygous for a CYP2D6*2A allele with CYP2D6*2x2 gene duplication). Ultra-rapid metabolizers have a specific CYP2D6 genotype and may change codeine to morphine more rapidly and completely than other people. Ultra-rapid metabolizers are more likely to have higher than normal blood and breast milk morphine concentrations after taking codeine. Ultra-rapid metabolism has only been reported as a problem with codeine, although ultra-rapid metabolism has the potential to affect other narcotics. Too much of any narcotic in breast milk can be fatal to a nursing infant. The estimated number of ultra-rapid metabolizers varies among different population groups from less than 1 per 100 people up to 28 per 100 people. Although a genetic test to identify ultra-metabolizers is available, the risk of having an adverse event when taking codeine is not known. The test result alone may not correctly predict if a mother’s milk will have too much morphine if she ingests codeine. Acetaminophen also crosses into breast milk, with a concentration ranging from 0.1 - 1.85% of the maternal dose. According to the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast feeding. The AAP regards acetaminophen as a maternal medicine that is usually compatible with breast feeding. If acetaminophen; codeine use by a breast-feeding mother is desired, prescribe the lowest dose for the shortest amount of time to relieve pain or cough. Also, educate nursing patients about the potential risks and the signs of morphine overdose in themselves and in their babies. Instruct patients to immediately call their physician or get emergency help if they are extremely sleepy, confused, or have shallow breathing or severe constipation or if the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, difficulty breathing, or limpness. Acetaminophen; codeine should not be used chronically during breast-feeding, as withdrawal symptoms may occur in the infant when the mother stops chronic acetaminophen; codeine therapy. Healthcare providers and other individuals are encouraged to report any acetaminophen; codeine side effects to the FDA by calling 1 - 800 - 332 - 1088.
Acetaminophen; codeine should be used cautiously in patients with renal impairment and renal failure; dosage adjustments may be required. Codeine can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with prostatic hypertrophy, urethral stricture, bladder obstruction or pelvic tumors. In addition, codeine may accumulate in these patients leading to a prolonged duration of action and potential increase in side effects. Chronic acetaminophen administration should be avoided in patients with underlying renal disease; however it may be used for episodic pain.
Elderly patients are more sensitive to the analgesic effects of opiate agonists as they experience higher peak serum levels and a longer duration of pain relief. In addition, elderly patients are more susceptible to adverse reactions from opiate agonists; especially sedation and respiratory depression probably as a result of altered distribution of the drug and decreased elimination. Initial doses of opiate agonists may need to be reduced and doses should be carefully titrated taking into account analgesic effects and adverse reactions.
Opiate agonists are may be used in children for moderate to severe pain; however, acetaminophen; codeine is not indicated for children < 3 years of age. Children weighing < 50 kg may be more sensitive to the effects of opiate agonists and require body weight dosing of opiate agonists. Whenever possible analgesia should be administered to a pediatric patient through a noninvasive route (i.e., orally or through an existing IV line). Intramuscular administration of analgesic medications, including opiate agonists, to children sends them the message that to achieve pain relief more pain must be given. This can lead to denial of pain by fearful children.
Patients with G6PD deficiency who overdose with acetaminophen; codeine may be at increased risk for drug-induced hemolysis due to the acetaminophen component. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.
Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen; codeine in patients who have bone marrow suppression or immunosuppression.
Any patient receiving acetaminophen; codeine should be warned about the possibility of sedation and to use caution when driving or operating machinery.
[ Last revised: 8/17/2007 4:02:00 PM ]
References
. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther 1983;33:95 - 101.
. Settipane RA et al. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995;96:480 - 5.
. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776 - 89.
. McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy. Analysis of the outcomes of 300 cases referred to the teratology information service. Reproductive Toxicol 1997;11:85 - 94.
. Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:704.
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