- Codeine Sulfate
- Death Related To Ultra-Rapid Metabolism Of Codeine To Morphine
- Respiratory Depression
- Misuse And Abuse of Opioids
- Interaction With Alcohol And Drugs Of Abuse
- Head Injury And Increased Intracranial Pressure
- Hypotensive Effect
- Gastrointestinal Effects
- Use In Pancreatic/Biliary Tract Disease
- Special Risk Patients
- Driving And Operating Machinery
- Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Reproduction And Developmental Toxicology
- Use In Specific Populations
- Labor And Delivery
- Nursing Mothers
- Pediatric Use
- Geriatric Use
- Renal Impairment
- Hepatic Impairment
- Does Tramadol Make You High?
- Why Tramadol Is Abused
- Recognizing a Codeine Overdose
- Signs and Symptoms
- Risk Factors
- What to Do If You Overdose on Codeine
- Preventing Codeine Overdose
- Codeine Symptoms and Warning Signs
- Codeine Withdrawal, Treatment and Next Steps
- Effects of codeine
- codeine (Rx)
- Black Box Warnings
- Opioid analgesic risk evaluation and mitigation strategy (REMS)
- Addiction, abuse, and misuse
- Life-threatening respiratory depression
- Accidental ingestion
- Neonatal opioid withdrawal syndrome
- Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children
- Interactions with drugs affecting cytochrome P450 isoenzymes
- Risks from concomitant use with benzodiazepines or other CNS depressants
- Black Box Warnings
- How to take codeine
- Precautions – before starting codeine
- Possible side effects
- Learn more
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 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 by hypoxia, 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.
Driving And Operating Machinery
Patients should be cautioned that codeine sulfate could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Patients should also be cautioned about the potential combined effects of codeine sulfate with other CNS depressants, including opioids, phenothiazines, sedative/hypnotics, and alcohol .
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years. Similiarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine (approximately 5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years.
Codeine was not mutatgenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.
Impairment Of fertility
No animal studies were conducted to evaluate the effect of codeine on male or female fertility.
Reproduction And Developmental Toxicology
Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits.
A study in hamsters administered 150 mg/kg bid of codeine (PO; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) reported the development of cranial malformations (i.e., meningoencephalocele) in several fetuses examined; as well as the observation of increases in the percentage of resorptions per litter examined. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, doses of 73-360 mg/kg level (PO; approximately 2-8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), reportedly produced cranioschisis in all of the fetuses examined.
In studies in rats, doses at the 120 mg/kg level (PO; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.
In pregnant mice, a single 100 mg/kg dose (SC; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg2 basis) reportedly resulted in delayed ossification in the offspring.
No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) of codeine during organogenesis.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Codeine has been shown to have embryolethal and fetotoxic effects (reduced fetal body weights and delayed or incomplete ossification) in the hamster, rat and mouse models at approximately 2-4 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison. Maternally toxic doses that were approximately 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of resorptions and incomplete ossification, including meningioencephalocele and cranioschisis. In contrast, codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison .
Neonatal codeine withdrawal has occurred in infants born to addicted and non-addicted mothers who had been taking codeine-containing medications in the days prior to delivery. Typical symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs occur shortly after birth and may require specific treatment.
Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.
Labor And Delivery
Opioid analgesics cross the placental barrier and may produce respiratory depression and psycho-physiologic effects in neonates. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Opioid analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required . A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.
Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine’s active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.
The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding .
The safety and effectiveness and the pharmacokinetics of codeine sulfate in pediatric patients below the age of 18 have not been established. FDA has not required pediatric studies in ages birth to one month because there is evidence strongly suggesting that codeine would be ineffective in this pediatric group since the metabolic pathways to metabolize codeine are not mature.
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the postoperative 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 or high morphine concentrations). These children 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 .
Codeine may cause confusion and over-sedation in the elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.
No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.
Does Tramadol Make You High?
Why Tramadol Is Abused
Tramadol’s “high” may be more mellow than other opioids, making it seem like a valid alternative to other opioid pain relievers with a potentially lower incidence of abuse. In 2014, however, the Drug Enforcement Administration (DEA) elevated tramadol above a “drug of concern” to a controlled substance, moving it into Schedule IV, citing similarities in its abuse potential to those of other scheduled opioid drugs. The Drug Abuse Warning Network (DAWN) reported that nonmedical use of tramadol was the cause of more than 20,000 emergency department visits in 2011, an increase of 250 percent from 2005. Tighter regulations on other opioid drugs may make tramadol a candidate for abuse, as it may be easier to obtain than drugs like OxyContin (oxycodone) or Vicodin (hydrocodone/acetaminophen).
Individuals who struggle with opioid addiction are more likely to abuse tramadol, as are those who suffer from chronic pain. Health professionals who are regularly exposed to it and have easy access to tramadol are also at higher risk, theDEApublishes.
Additionally, individuals who are being treated for opioid dependence, and taking opioid antagonist medications like naltrexone, may take tramadol as it seems to circumvent the opioid blockade and still produce a high, Psych Central reports. In this case, tramadol may serve as a substitute for other opioids that are blocked by the antagonist medication. Individuals may also take tramadol as an opioid substitute when trying to avoid withdrawal symptoms after “coming down” from opioids like heroin or more potent prescription opioids. Tramadol may temporarily ease drug cravings and withdrawal symptoms, making it an attractive drug of abuse to those who struggle with opioid dependence. Tramadol is also habit-forming and can lead to drug dependence and addiction with continued abuse, however.
Recognizing a Codeine Overdose
Table of Contents Authored By American Addiction Centers Editorial Staff Edited By Meredith Watkins, MA, MFT
A national crisis, opioid abuse includes a wide range of drugs—from heroin to any number of prescription medications. Nearly 4 million Americans older than 12—1.4% of the population—abuse prescription pain relievers, including codeine. Half a percent of adolescents between 12 and 17 have a pain reliever use disorder1. Of the 1,244,872 people who visited an emergency department in 2011 for non-pharmaceutical drug use, 1/3 were there because of opioids2.
Used for pain management, controlling diarrhea, or as a cough suppressant, codeine is a popularly abused opioid. Available as a combination pain reliever (with acetaminophen, ibuprofen, or other analgesics), codeine is also available as a syrup formulation. Depending on its potential for abuse and risk for dependency, codeine in its different doses and formulations is a Schedule II, III, or V drug under the Controlled Substances Act3.
As with other narcotic pain relievers, the number of people illicitly using codeine is increasing. Between 2012 and 2013, illicit users increased from 264,000 to 293,000 people 4. Prescription painkillers like codeine are a risk factor for heroin abuse.
Signs and Symptoms
Codeine induces a sense of euphoria and relaxation, while a codeine overdose occurs when you ingest enough of the drug to cause dangerous—even fatal—side effects. While a single misuse can be fatal, if you or someone you care for is struggling with a codeine addiction, be especially alert for the signs of an overdose. If overdose is suspected, promptly seek emergency medical assistance.
Some of these overdose effects may include 5:
- Mental status changes such as fatigue, drowsiness, and confusion.
- Sensations of dizziness and lightheadedness.
- Breathing problems ranging from slow and labored to not breathing at all.
- Cold and clammy skin.
- Fingernails and lips with a bluish tint.
- Stomach and intestinal spasms.
- Constricted pupils.
- Low blood pressure and weak pulse.
- Unresponsiveness and coma.
The most common cause of death from opiate overdose is respiratory failure, wherein the user simply stops breathing. In addition to loss of life and injury from trauma (falls, automobile accidents), non-fatal opiate overdose can damage the body in several ways, including6:
- Anoxic brain injury.
- Liver failure.
- Kidney failure.
- Pulmonary edema.
- Breakdown of skeletal muscles.
In addition to the risks from overdosing on codeine, dangers include combining associated medications with codeine. For example, when taken in excess, the Tylenol component of combination medicines such as Tylenol #3 and Tylenol #4 (both Tylenol with codeine) may lead to deadly liver failure from acetaminophen toxicity.
Treatment Advisors Are On Call 24/7 Who Answers? Thinking About Getting Rehab?
There are a number of factors that contribute to codeine overdose risks. First, the sheer number of opioids available has dramatically risen. Opiate prescriptions have increased from 76 million in 1991 to 207 million in 2013 7.
A major cause of opioid overdoses, including codeine overdose, is the simultaneous use of other substances—including other narcotics, benzodiazepines (like Xanax and Valium), cocaine (including crack), and alcohol.
Injecting narcotics in combination significantly increases overdose risk. For example, injecting heroin and cocaine increases the danger by 2.6 times 8.
Taking codeine routinely can lead to tolerance—requiring ever-increasing doses to achieve the same effect. Higher doses increase the risk of an overdose. Some people build a tolerance to high doses, abstain from the drug for a while, and suffer an overdose when they take the same amounts later. Others take whatever dose is available and overdose from simply ingesting too much or after a cumulative intake of narcotics and other substances (especially alcohol).
What to Do If You Overdose on Codeine
The risk of death or serious injury from a codeine overdose is simply too great to ignore. Because an overdose impairs your ability to recognize trouble, it’s never a good idea to abuse narcotics alone.
Once the signs and symptoms seem to confirm an overdose, take immediate action. Call 911 for emergency assistance and be prepared to provide the following information:
- The person’s age, weight, and condition.
- The name and dose of the medication.
- Whether the medicine is prescribed for the individual.
- How much medicine was taken and when.
While waiting for emergency assistance, take steps to ensure safety. For a codeine overdose, this generally means breathing support. To reduce the risk of aspiration, roll the person onto their side and clear their airway. If respiratory rate drops below 10 breaths per minute, emergency personnel may advise you to give rescue breaths. Immediately initiate CPR if there is no breathing at all 8.
Once at the emergency room, physicians will evaluate for the presence of other drugs and conduct a medical history to learn of any underlying health issues. You can expect diagnostic work-ups, including labs and imaging studies.
They will first address life-threatening conditions (especially breathing issues) and sometimes attempt to slow the absorption of any drug in the stomach by using activated charcoal. Naloxone, an opioid antidote, may be given to reverse life-threatening effects 8.
Once stabilized, your friend or family member may be transferred to a detox or treatment center. Some people discharge with a referral to or information about other treatment opportunities.
Preventing Codeine Overdose
Prevention is the best approach to addressing opioid abuse. The medical community is beginning to respond by introducing measures to limit the numbers of opioid prescriptions given. Along with first responders and other emergency medical personnel, increasing numbers of people with narcotics addictions are provided with naloxone kits6.
You can take several steps yourself, too. Never take any medication unless prescribed to you. This is especially important with narcotics since their use otherwise is illegal. Speak with your doctor about non-narcotic solutions to medical issues and avoid socializing with narcotics abusers.
If you take codeine in amounts more than prescribed, you may have an emerging addiction. Signs you are running into trouble include 9:
- Strong cravings for codeine.
- Needing higher doses to achieve the same effects.
- Experiencing withdrawal side effects when you stop taking codeine, such as restlessness and anxiety; muscle aches; nausea and vomiting; fever; and insomnia.
- Using codeine when it is unsafe to do so (like driving a car).
- Your drug use causes problems with relationships, at work, or at school.
- Being unable to quit or cut down on codeine use.
Experiencing even a single overdose strongly indicates the need for substance abuse treatment. Treatment usually begins following a detox period of a few days, which involves professionally managing the symptoms of withdrawal while addressing any associated medical issues10.
Following detox, different treatment options include outpatient or inpatient care. Both may involve some combination of medications, individual and group counseling, drug-avoidance training, and long-term recovery strategies.
Inpatient care provides a more immersive treatment setting in which recovery work will begin. For any form of inpatient or residential treatment, you must be willing to commit to a residential setting for a period of a few days to several weeks.
On the relatively intensive end of the outpatient treatment spectrum, partial-hospitalization programs prescribe medications and require a commitment of several hours daily, 5 days a week. Ideal for those with school or work obligations, most outpatient programs involve less time commitment than their inpatient treatment counterparts11.
- Substance Abuse and Mental Health Services Administration. (2016). Key Substance Use and Mental Health Indicators in the United States: Results from the 2015 National Survey on Drug Use and Health.
- Substance Abuse and Health Services Administration. (2015). The CBHSQ Report: Emergency Department Visits Involving Narcotics Pain Relievers.
- U.S. Drug Enforcement Administration. (2018). Controlled Substance Schedules.
- Substance Abuse and Mental Health Services Administration. (2014). Emergency Department Data.
- National Library of Medicine. (2015). Codeine Overdose.
- Yale Journal of Biology and Medicine. (2015). Reducing Fatal Opioid Overdoes: Prevention, Treatment, and Harm Reduction Strategies.
- National Institute on Drug Abuse. (2014). America’s Addiction to Opioids: Heroin and Prescription Drug Abuse.
- United Nations Office on Drugs and Crime. (2013). Opioid Overdose: Preventing and Reducing Opioid Overdose Mortality.
- American Psychiatric Association. (2015). Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, D.C.: American Psychiatric Association.
- Substance Abuse and Mental Health Services Administration. (2006). Detoxification and Substance Abuse Treatment.
- National Institute on Drug Abuse. (2014). Drugs, Brains and Behavior: The Science of Addiction: Treatment and Recovery.
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Codeine Symptoms and Warning Signs
Codeine Withdrawal, Treatment and Next Steps
Codeine causes symptoms of withdrawal similar to other opiates like morphine. These symptoms may be minor or severe depending on the extent of the addiction. Common symptoms of codeine withdrawal range from joint pain and achiness to depression.
Codeine withdrawal isn’t typically life-threatening, which is why some people choose to quit cold-turkey. However, the discomfort of withdrawal often leads to a relapse.
Without proper treatment, many people trying to give up codeine turn back to the drug in an attempt to ease their physical and emotional pain.
Regardless of how you first got hooked on codeine, you can get out of the drug’s snare. Abusing codeine over a long period of time will only make the drug’s effects worse as your tolerance to it builds—eventually, the high will wear off and you’ll need more of the drug just to maintain a normal balance. However, just as you became addicted to the drug, you can overcome it. Get in touch with someone who can help you today.
Effects of codeine
There is no safe level of drug use. Use of any drug always carries some risk – even medications can produce unwanted side effects. It’s important to be careful when taking any type of drug.
Codeine affects everyone differently, based on:
- the person’s size, weight and health
- whether the person is used to taking it
- whether other drugs are taken around the same time
- the amount taken.
The most common side effects of codeine are:
- confusion, difficulty concentrating
- euphoria, restlessness
- blurred vision
- dry mouth
- limbs feeling heavy or muscles feeling stiff
- mild allergic rash, itching and hives
- decreased heart rate, palpitations
- stomach-ache, nausea, vomiting, constipation
- difficulty urinating.1
These side effects may disappear with continued treatment, but if they persist, speak to a medical practitioner.
If the dose is too high, you might overdose. Call an ambulance straight away by dialling triple zero (000) if you experience any of these symptoms:
- inability to pass urine
- severe constipation and obstructed bowel
- cold clammy skin with a bluish tinge
- mental numbness
- very slow, shallow breathing
- hallucinations and sometimes seizures
- coma and death.1
Long-term effects of codeine
Regular use of codeine may eventually cause:
- reduced sex drive
- irregular periods
- tension and muscle twitches
- needing to use more to get the same effect
- dependence on codeine
- financial, work and social problems.1,2
Discuss the side effects of long-term use with a medical practitioner.
Using codeine with other drugs
The effects of taking codeine with other drugs, including alcohol, prescription medications and other over-the-counter medicines, are often unpredictable.1
Codeine taken with alcohol can cause mental clouding, reduced coordination and slow breathing.1
Giving up codeine after using it for a long time is challenging because the body has to get used to functioning without it. Please seek advice from a medical professional.
Withdrawal symptoms usually start within a few hours after the last dose and become strongest between 48 and 72 hours.3 These symptoms can include:
- cravings for codeine
- dilated pupils
- abdominal cramps, diarrhoea, nausea, vomiting
- lack of appetite
- runny nose and sneezing
- yawning and difficulty sleeping
- trembling, aching muscles and joints
- goosebumps, fever, chills, sweating
- restlessness, irritability, nervousness, depression.1,2
Black Box Warnings
Opioid analgesic risk evaluation and mitigation strategy (REMS)
- To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers
Healthcare providers are strongly encouraged to:
- Complete a REMS-compliant education program
- Counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products
- Emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist
- Consider other tools to improve patient, household, and community safety
Addiction, abuse, and misuse
- Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions
Life-threatening respiratory depression
- Serious, life-threatening, or fatal respiratory depression may occur
- Monitor for respiratory depression, especially during initiation or following a dose increase
- Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose
Neonatal opioid withdrawal syndrome
- Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
- If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
- Respiratory depression and death reported in children who received codeine following tonsillectomy and/or adenoidectomy that were also ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism
- Contraindicated in children
Interactions with drugs affecting cytochrome P450 isoenzymes
- Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors requires careful consideration of the effects on parent drug, codeine, and active metabolite, morphine
Risks from concomitant use with benzodiazepines or other CNS depressants
- Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
- Reserve concomitant prescribing of codeine sulfate tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
- Limit dosages and durations to minimum required
- Follow patients for signs and symptoms of respiratory depression and sedation
Hypersensitivity to codeine
Significant respiratory depression
Children younger than 12 years
Postoperative pain management in children (
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within last 14 days
Known or suspected gastrointestinal obstruction, including paralytic ileus
Codeine sulfate tablets contain codeine, a schedule II controlled substance; as an opioid, codeine sulfate tablets exposes users to risks of addiction, abuse, and misuse; addiction can occur at recommended dosages and if drug is misused or abused; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing codeine sulfate tablets, and monitor; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression); potential for these risks should not prevent proper management of pain in any given patient; patients at increased risk may be prescribed opioids such as codeine sulfate tablets, but use in such patients necessitates intensive counseling about risks and proper use of codeine sulfate along with intensive monitoring for signs of addiction, abuse, and misuse; prescribe the drug in smallest appropriate quantity and advise patient on proper disposal of unused drug
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper
Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock
In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma
Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms
Therapy may increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with history of seizure disorders for worsened seizure control during therapy
Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients
Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication
While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of codeine
Deaths have occurred in nursing infants exposed to high levels of morphine in breast milk because mothers were ultra-rapid metabolizers of codeine
Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; monitor closely
Monoamine oxidase inhibitors (MAOIs) may potentiate effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of taking MAOIs
Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible
Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function
Codeine pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension
Use caution in cardiac arrhythmias, drug abuse/dependence, emotional lability, gallbladder disease, head injury, hepatic impairment, hypothyroidism, increased ICP, prostatic hypertrophy, renal impairment, seizures with epilepsy, urethral stricture, urinary tract surgeryLife-threatening respiratory depression and death reported in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to active metabolite morphine; based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to respiratory depressant effect
When prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and signs of morphine overdose
At least one death reported in a nursing infant exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment with codeine sulfate oral solution
Risk of life-threatening side effects in nursing infants, especially if mother is an ultra-rapid metabolizer of codeine
- To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
- Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
- Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
- Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
- To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
Postoperative pain in children
- Prescribe an alternate analgesic for postoperative pain control in children undergoing tonsillectomy and/or adenoidectomy
- Deaths have occurred in children with obstructive sleep apnea who received codeine for postoperative pain following tonsillectomy and/or adenoidectomy
- Codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of morphine
Easy-to-read medicine information about codeine – what is it, how to take codeine safely and possible side effects.
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Codeine is commonly used in combination with other ingredients in pain relievers which you can buy without a prescription. Examples of pain relievers that contain codeine:
- codeine + paracetamol: Panadeine®, Panadeine Extra®, Panadeine Plus®
- codeine + ibuprofen: Nurofen Plus®, Panafen Plus®, Ibucode Plus®
Tell your doctor or pharmacist if you are already taking these.
Codeine is used for the relief of moderately severe pain such as after an injury, or operation. It is usually used when other milder painkillers such as paracetamol or non-steroidal anti-inflammatories (NSAIDs) don’t work well enough. Codeine belongs to a group of medicines called opioid painkillers. They act on your brain and nervous system to lessen the way you feel pain. Other pain relievers such as paracetamol and NSAIDs (ibuprofen, diclofenac, naproxen) may also be used with codeine. Read more about pain, pain-relief medication and opioid painkillers.
Codeine can also be used to treat dry cough and diarrhoea.
Use in children and adolescents
Medsafe, a unit of the Ministry of Health, New Zealand, has assessed the safety and effectiveness of codeine in children and adolescents. Codeine can cause serious breathing problems in children that could result in death.
- They have advised that codeine should not be used in children younger than 12 years.
- In adolescents 12 to 18 years, codeine should not be used for pain after surgery to remove tonsils or adenoids, for relief of cough, or in people who have breathing problems.
- The dose of codeine will be different for different people.
- Always take your codeine exactly as your doctor has told you. Depending on the reason you are taking it, your doctor may advise that you take regular doses or take codeine only when you need it for relief. Make sure you know which is right for you.
- The pharmacy label on your medicine will tell you how much codeine to take, how often to take it, and any special instructions.
Variations in response to codeine
Codeine is broken down in the liver to morphine, which is a strong pain reliever. People may respond differently to codeine depending on how their liver breaks down codeine.
- Some people are poor metabolisers, which means that they are unable to convert codeine to morphine, and don’t get adequate pain relief.
- On the other hand, some people break down codeine very rapidly (ultra-rapid metabolisers) and are at increased risk of developing side effects, even at low doses.
- Estimates suggest that up to 10% of the European population may be poor or ultra-rapid metabolisers. The prevalence in Maori and Pacific people is not known.
- If you are taking codeine for pain relief, and it doesn’t seem to be working, let your doctor know. Alternatively, if you are taking codeine and you get side effects such as nausea, vomiting, constipation, lack of appetite, drowsiness, extreme sleepiness, difficulty waking, confusion or shallow breathing, let your doctor know. Other options may be better for you.
How to take codeine
- You can take codeine with or without food.
- Stop taking codeine if your symptoms are relieved.
- Limit or avoid drinking alcohol while you are taking codeine. Combining codeine with alcohol can make you more sleepy, drowsy or dizzy.
- If you forget to take your dose, take it as soon as you remember. But, if it is nearly time for your next dose, just take the next dose at the right time. Do not take double the dose.
Precautions – before starting codeine
- Are you pregnant or breastfeeding?
- Do you have problems with your liver or your kidneys?
- Do you have problems with your prostate or any difficulties passing urine?
- Do you have any breathing problems, such as asthma or chronic obstructive pulmonary disease (COPD)?
- Have you had a recent head injury?
- Do you suffer from constipation – have been constipated for more than a week or have an inflammatory bowel problem?
- Have you ever been dependent on drugs or alcohol?
If so, it’s important that you tell your doctor or pharmacist before you start codeine. Sometimes a medicine isn’t suitable for a person with certain conditions, or it can only be used with extra care.
Possible side effects
Like all medicines, codeine can cause side effects, although not everyone gets them. Often side effects improve as your body gets used to the new medicine.
Addiction is an excessive craving. If you are addicted to codeine, it means you are not able to control your use of it. It is unusual for people who are prescribed codeine for short periods of time to become addicted to it. Some people are more likely to develop addiction than others – you may be at risk for addiction if you have mental health problems such as depression or a history of substance abuse, including alcohol and recreational drugs.
To reduce your risk of addiction, codeine should be used for the shortest possible time, at the lowest effective dose, with a plan in place to reduce and withdraw treatment.
Other side effects
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- Codeine may interact with a few medications and herbal supplements, so check with your doctor or pharmacist before starting codeine or before starting any new medicines.
- It may interact with medicines available without a prescription such as:
- cough suppressants (such as Benadryl Dry Forte®, Duro-Tuss®)
- sedating antihistamines (such as Phenergan®)
- Codeine New Zealand Formulary
- Opioid analgesics New Zealand Formulary
- Codeine – new restrictions on use in children and young adults Medsafe, 2018
- Helping patients cope with chronic non-malignant pain: it’s not about opioids BPAC, 2014
- Identifying and managing addiction to opioids BPAC, 2014