Codeine sulfate is an opioid analgesic, related to morphine, but with less potent analgesic properties. Codeine is selective for the mu receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.
Codeine is used to treat mild to moderate pain and to relieve cough. Codeine is also used to treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is available without a prescription for milder diarrhea), diphenoxylate, paregoric or even laudanum are more frequently used to treat severe diarrhea.
There is weak evidence that it is useful in cancer pain but it is associated with increased side effects. The American Academy of Pediatrics does not recommend its use in children due to side effects.
Furthermore, codeine has been found as an endogenous compound, along with morphine, in the brains of non human primates with depolarized neurons, indicating that codeine may function as a neurotransmitter or neuromodulator in the central nervous system.
Evidence does not support its use for acute cough suppression in children or adults. In Europe it is not recommended as a cough medicine in those under twelve years of age. There is some tentative evidence it can reduce a chronic cough in adults.
Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1,2,4); with aspirin (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy).
Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin(Emprazil with codeine No. 1, 2, 3, 4 and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above.
Codeine-only products can be obtained with a prescription as a time release tablet. Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated.
Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated as this can result in non-immune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries.
Common adverse effects associated with the use of codeine include drowsiness and constipation. Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, euphoria, dysphoria, and coughing. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis, and respiratory depression. As with all opiates, longer-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as the swelling of skin and rashes.
Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.
A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby. In August 2012, the United States Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy; this warning was upgraded to a black box warning in February 2013.
Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients: use the drug in the lowest amount that can control the pain, use "as needed" and not "around the clock", and seek immediate medical attention if a child on codeine exhibits excessive sedation or abnormally noisy breathing.
Selection of patients for treatment with codeine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Physicians should individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management.
Individualization Of Dosage
As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the selection of the initial dose of codeine sulfate, attention should be given to the following:
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.
Continual re-evaluation of the patient receiving codeine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for noncancer-related pain, the continued need for the use of opioid analgesics should be re-assessed as appropriate.
During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.
Concurrent use of other opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol) concomitantly with codeine sulfate tablets may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma. Use codeine sulfate with caution and in reduced dosages in patients taking these agents.
Mixed Agonist/Antagonist Opioid Analgesics
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should NOT be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as codeine sulfate. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics including codeine sulfate, may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Use of MAO inhibitors or tricyclic antidepressants with codeine sulfate may increase the effect of either the antidepressant or codeine. MAOIs markedly potentiate the action of morphine sulfate, the major metabolite of codeine. Codeine should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
Patients taking cytochrome P-450 enzyme inducers or inhibitors may demonstrate an altered response to codeine, therefore analgesic activity should be monitored. Codeine sulfate is metabolized by the cytochrome P-450 3A4 and 2D6 isoenzymes. The concurrent use of drugs that preferentially induce codeine Ndemethylation (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 considered.
Codeine may be habit forming. Take codeine exactly as directed. Do not take more of it, take it more often, or take it in a different way than directed by your doctor. While taking codeine, discuss with your healthcare provider your pain treatment goals, length of treatment, and other ways to manage your pain. Tell your doctor if you or anyone in your family drinks or has ever drunk large amounts of alcohol, uses or has ever used street drugs, or has overused prescription medications, or if you have or have ever had depression or another mental illness. There is a greater risk that you will overuse codeine if you have or have ever had any of these conditions. Talk to your healthcare provider immediately and ask for guidance if you think that you have an opioid addiction or call the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-HELP.
Codeine may cause serious or life-threatening breathing problems, especially during the first 24 to 72 hours of your treatment and any time your dose is increased. Your doctor will monitor you carefully during your treatment. Tell your doctor if you have or have ever had slowed breathing or asthma. Your doctor will probably tell you not to take codeine. Also tell your doctor if you have or have ever had lung disease such as chronic obstructive pulmonary disease (COPD; a group of diseases that affect the lungs and airways), a head injury or any condition that increases the amount of pressure in your brain. The risk that you will develop breathing problems may be higher if you are an older adult or are weak or malnourished due to disease. If you experience any of the following symptoms, call your doctor immediately or get emergency medical treatment: slowed breathing, long pauses between breaths, or shortness of breath.
Included as part of the PRECAUTIONS section.
Death Related To Ultra-Rapid Metabolism Of Codeine To Morphine
Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 [CYP2D6] or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine.
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).
Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy.
When prescribing codeine, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.
Respiratory depression is the primary risk of codeine sulfate. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied byhypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Codeine produces dose-related respiratory depression.
Caution should be exercised when codeine sulfate is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilatory function is depressed. Opioid related respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Opioids, including codeine sulfate, should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of codeine sulfate may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-opioid analgesics should be considered, and codeine sulfate should be employed only under careful medical supervision at the lowest effective dose in such patients.
Misuse And Abuse of Opioids
Codeine sulfate is an opioid agonist of the morphine-type and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.
Codeine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing codeine sulfate in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Misuse and abuse of codeine sulfate poses a significant risk to the abuser that could result in overdose and death. Codeine may be abused by crushing, chewing, snorting or injecting the product.
Concerns about abuse and addiction should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interaction With Alcohol And Drugs Of Abuse
Codeine sulfate may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, because respiratory depression,hypotension, profound sedation, coma or death may result.
Head Injury And Increased Intracranial Pressure
Respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure resulting from vasodilation following CO2 retention may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids including codeine sulfate, produce adverse reactions which may obscure the clinical course of patients with head injuries.
Codeine sulfate may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. Codeine sulfate may produce orthostatic hypotension and syncope in ambulatory patients.
Codeine sulfate should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.
Codeine sulfate should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus because codeine sulfate diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.
Chronic use of opioids, including codeine sulfate, may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder. Codeine sulfate may cause or aggravate constipation.
Administration of codeine sulfate may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Use In Pancreatic/Biliary Tract Disease
Codeine sulfate should be used in caution in patients with biliary tract disease, including acute pancreatitis, as codeine sulfate may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.
Special Risk Patients
As with other opioids, codeine sulfate should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyrodism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.
Caution should be exercised in the administration of codeine sulfate to patients with CNS depression, acute alcoholism, and delirium tremens.
All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.