Codeine; Guaifenesin

What it is

A liquid combination of two drugs with different jobs: codeine phosphate, an opioid that suppresses cough, and guaifenesin, an expectorant that is thought to thin mucus. A typical product supplies codeine phosphate 10 mg and guaifenesin 100 mg per 5 mL. The products listed on DailyMed are marketed unapproved drugs carrying old-style over-the-counter Drug Facts labels rather than modern FDA-approved prescribing information; their labels give uses, a habit-forming warning and dosing down to age 6, and carry no boxed warning. Codeine itself is a Schedule II controlled substance when supplied as an approved single-ingredient product, and that product's label carries the full opioid boxed warning.

What the research says

Codeine has been the standard cough medicine for decades, and the trial evidence does not support it. Placebo-controlled trials in cough from upper respiratory infection and in chronic obstructive pulmonary disease found no significant difference from placebo in cough frequency or cough severity, and the 2026 systematic review that pooled antitussive trials could not even meta-analyse the codeine data because the studies were so inconsistent. The Cochrane review of over-the-counter cough medicines concluded there is no good evidence for or against them. Guaifenesin's record is also thin: of three placebo-controlled adult trials in Cochrane, one showed benefit and two did not. What codeine reliably does is sedate, constipate, cause physical dependence and, in people who convert it to morphine unusually fast, cause fatal respiratory depression.

Evidence grade: Not supported by the research.

How it works

Drug class: Opioid antitussive (codeine, a mu-opioid receptor agonist and prodrug of morphine) combined with an expectorant (guaifenesin)

Codeine is a weak opioid that binds the mu-opioid receptor itself only feebly; most of what it does comes from the liver converting about 5% to 10% of it into morphine via the enzyme CYP2D6. Morphine dampens the brainstem cough centre, which is the intended effect, and dampens the brainstem breathing centre, which is the dangerous one. Guaifenesin is an expectorant believed to add water to airway mucus and lower its viscosity so it clears more easily, although the review literature says the evidence for that mechanism is limited. (Source 1)

Boxed warning

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF CODEINE SULFATE TABLETS Addiction, Abuse, and Misuse Because the use of Codeine Sulfate Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 ), Dosage and Administration ( 2.1 )] .

(Source 2)

What it is used for

• The over-the-counter label claims relief of cough from a cold, but placebo-controlled trials do not show it. A 30 mg codeine syrup produced no significant difference from placebo in cough frequency or severity in the laboratory or at home, and Cochrane found no good evidence for or against over-the-counter cough medicines in acute cough. Evidence: not-supported. (Source 3)
• Three placebo-controlled adult trials of guaifenesin are in the Cochrane review: one showed significant benefit, two did not. A 2025 narrative review of 17 guaifenesin publications reports statistically significant improvement in sputum looseness versus placebo, while noting a high placebo response and some null studies. For stable chronic bronchitis a 2019 review found the published evidence for mechanism or efficacy limited. Evidence: limited. (Source 4)
• In chronic obstructive pulmonary disease, codeine 60 mg did not significantly change cough frequency or severity against placebo. One chronic-cough trial found codeine better than levodropropizine on severity scales but with more drowsiness, constipation and headache. The 2026 systematic review concluded the evidence for codeine remains limited and inconsistent and that P2X3 antagonists, not opioids, look most promising. Evidence: disputed. (Source 3)
• A Cochrane review of over-the-counter cough medicines added to antibiotics in pneumonia found four small studies and 224 participants in total, none of them usable for an antitussive, and concluded there is insufficient evidence to decide whether such medicines help. Evidence: not-supported. (Source 5)
• Codeine on its own is approved for mild to moderate pain where an opioid is appropriate and alternatives are inadequate; this is not what a codeine-guaifenesin cough liquid is sold for, and the label restricts opioid analgesics to patients in whom other options have failed. Evidence: limited. (Source 6)

Interactions

• Alcohol (label): Alcohol adds to codeine's sedation and breathing suppression; together they can cause profound sedation, respiratory depression, coma and death. This is in the boxed warning, not a minor caution. (Source 7)
• Benzodiazepines, gabapentin or pregabalin, muscle relaxants, antipsychotics and other sedatives (label): The same additive risk as alcohol. Observational studies cited in the label show that taking opioids and benzodiazepines together raises drug-related mortality compared with opioids alone. (Source 8)
• CYP2D6 inhibitors (for example quinidine, amiodarone, and several antidepressants) (label): These block the conversion of codeine to morphine, so codeine builds up and morphine falls: the cough or pain relief fades and someone physically dependent can go into withdrawal. Stopping the inhibitor flips it, morphine rises and breathing can be suppressed. (Source 9)
• St John's wort and other CYP3A4 inducers; CYP3A4 inhibitors such as grapefruit-sensitive pathways, macrolides, azole antifungals and protease inhibitors (label): The label names CYP3A4 inducers and inhibitors as a class rather than naming St John's wort or grapefruit, and the direction of the effect is complex: a CYP3A4 inhibitor pushes more codeine down the CYP2D6 route and raises morphine, which can suppress breathing, while an inducer lowers morphine and can cause withdrawal. We found no pharmacokinetic study of codeine with St John's wort or grapefruit juice, so for those two specifically the basis is theoretical, by class. (Source 10)
• Monoamine oxidase inhibitors (label): MAOIs can amplify the effects of morphine, codeine's active metabolite, including respiratory depression, coma and confusion; the label says codeine should not be used with an MAOI or within 14 days of stopping one. (Source 11)
• Food - a high-fat, high-calorie meal (pharmacokinetic study): Food does not meaningfully change how much codeine is absorbed or how fast. A high-fat high-calorie meal 30 minutes before a 60 mg dose made no significant difference. (Source 12)

Stopping it

• After more than a few days of regular use, stopping abruptly can precipitate opioid withdrawal; the label's position is to taper gradually rather than stop suddenly in anyone who may be physically dependent. (Source 13)
• Rapid reduction or abrupt discontinuation in someone physically dependent has been followed by serious withdrawal symptoms, uncontrolled pain and suicide, and by people seeking opioids elsewhere, including illicit opioids such as heroin. (Source 14)
• There is no single correct taper: the label states the schedule has to be built around the dose taken, the duration of treatment and the person, and agreed with them. (Source 15)
• Withdrawal can also be precipitated rather than gradual - by naloxone or nalmefene, or by a mixed agonist-antagonist or partial agonist such as pentazocine, butorphanol, nalbuphine or buprenorphine. (Source 16)
• Infants exposed through breast milk can withdraw too, when the mother's codeine is stopped or breastfeeding ends. (Source 17)

What goes wrong

Children who are CYP2D6 ultra-rapid metabolisers have died or nearly died from standard codeine doses, mostly after tonsillectomy or adenoidectomy. (Source 18)

• Case series, Very low certainty.
• Size: 4 reported cases (one previously published toddler plus 3 new fatal or life-threatening cases) from North America.
• Who: young children given codeine after adenotonsillectomy, several with obstructive sleep apnoea.
• How long: post-operative days.
• Result: 2 deaths with functional CYP2D6 gene duplications producing greater morphine from codeine; one severe respiratory depression in an extensive metaboliser. Case reports, so no rate.
• Funding: not stated in the abstract.

In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine.

Between roughly 1% and more than 10% of people, depending on ancestry, are CYP2D6 ultra-rapid metabolisers who reach dangerous morphine levels on labelled codeine doses. (Source 19)

• Official position, Moderate certainty.
• Size: not stated - prevalence estimates by population group.
• Who: general population, by ancestry group.
• How long: applies from the first dose.
• Result: Estimated at 1 to 10% for Whites, 3 to 4% for Blacks, 1 to 2% for East Asians, and possibly greater than 10% in Oceanian, Northern African, Middle Eastern, Ashkenazi Jewish and Puerto Rican groups.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups

Codeine's serious adverse reactions are respiratory depression, respiratory arrest, shock and cardiac arrest; the common ones are drowsiness, dizziness, nausea, vomiting, sweating and constipation. (Source 20)

• Official position, Certainty not rated.
• Size: not stated - clinical studies and postmarketing reports combined.
• Who: people taking codeine.
• How long: any.
• Result: No rates are given: the label states it is not always possible to reliably estimate frequency from voluntary reports, so there is no drug-versus-placebo comparison here.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.

Tolerance and physical dependence develop with continued codeine use, and physical dependence can appear after days to weeks. (Source 16)

• Official position, Moderate certainty.
• Size: not stated.
• Who: people on opioid therapy including codeine.
• How long: several days to weeks of continued use.
• Result: No rate given; the label states physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Breastfed infants have died or been severely sedated from morphine in breast milk when the mother took codeine, especially if she was an ultra-rapid metaboliser. (Source 21)

• Official position, Moderate certainty.
• Size: not stated - published studies and case reports.
• Who: breastfed infants of mothers taking codeine.
• How long: during maternal treatment.
• Result: No rate given; excessive sedation, respiratory depression and death reported.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk.

Codeine was the opioid most often found with a matching prescription in Norwegian overdose deaths, and most of those who died also had benzodiazepines. (Source 22)

• Cohort study, Moderate certainty.
• Size: 3,764 overdose deaths, 2005 to 2021, about 90% of Norwegian forensic autopsy cases linked to national registries.
• Who: people dying of overdose in Norway.
• How long: 17 years.
• Result: Codeine had the highest proportion of filled prescriptions before death at 67%, versus 27% for fentanyl; more than half of those with prescribed opioids also had benzodiazepines prescribed or in their blood.
• Funding: not stated in the abstract.

Fentanyl had the lowest proportion of filled prescriptions prior to death (27%), whereas codeine had the highest (67%).

Guaifenesin can form kidney stones, although this is very rare. (Source 23)

• Survey study, Low certainty.
• Size: 85,273 kidney stones analysed over 12 months in a US reference laboratory.
• Who: US adults and children whose stones were submitted for analysis.
• How long: December 2022 to November 2023.
• Result: Rare drug or metabolite stones made up 0.04% of submissions, and guaifenesin was among the drugs identified in them.
• Funding: not stated in the abstract.

Rare drug or metabolite stone submissions (0.04%) included xanthine, guaifenesin, triamterene, atazanavir, and N4-acetyl-sulfamethoxazole.

Taking codeine with alcohol, benzodiazepines or other central nervous system depressants can cause profound sedation, respiratory depression, coma and death. (Source 8)

• Official position, Moderate certainty.
• Size: not stated - supported by observational studies cited in the label.
• Who: people taking codeine with other sedating substances.
• How long: any concurrent use.
• Result: No rate given in the label; it reports observational studies showing concomitant opioid and benzodiazepine use increases drug-related mortality.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Codeine Sulfate Tablets with benzodiazepines and/or other CNS depressants, including alcohol

Over-the-counter codeine and guaifenesin labels still on DailyMed give doses for children aged 6 to under 12, which the approved codeine labelling now contraindicates. (Source 24)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: children aged 6 to under 12 given an over-the-counter codeine cough liquid.
• How long: every 4 hours, up to 6 doses in 24 hours.
• Result: The over-the-counter label directs 1 tsp (5 mL) every 4 hours for children 6 to under 12, while the approved codeine label states codeine is contraindicated for all children younger than 12 years of age.
• Funding: not applicable - two conflicting regulator-facing label positions, dated 2018 and 12/2025.

Children 6 to under 12 years of age: 1 tsp (5 mL) every 4 hours, or as directed by a doctor.

Life-threatening breathing suppression and death have occurred in children given codeine, mostly after tonsil or adenoid surgery, and many of these children were ultra-rapid codeine metabolizers. (Source 25)

• Official position, Moderate certainty.
• Size: not stated (post-marketing reports summarised in the label)
• Who: children, mostly after tonsillectomy and/or adenoidectomy.
• How long: not stated.
• Result: No rate given in the label; codeine is contraindicated in children under 12 years and after tonsillectomy/adenoidectomy under 18.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

Life-threatening respiratory depression and death have occurred in children who received codeine.

What the evidence supports

In chronic cough, codeine reduced cough severity more than levodropropizine, at the price of more opioid side effects. (Source 26)

• Systematic review, Low certainty.
• Size: one randomised trial within a review of 21 qualitative and 10 quantitative studies.
• Who: patients with chronic cough.
• How long: not stated in the review text.
• Result: Codeine significantly better on the visual analogue scale, Cough Severity Scale and Leicester Cough Questionnaire; drowsiness, constipation and headache more frequent on codeine without more discontinuations.
• Funding: independent - the review authors declared no commercial or financial relationships.

Codeine was significantly more effective than levodropropizine in reducing cough severity, as confirmed by changes in the VAS, Cough Severity Scale (CSS), and LCQ.

Guaifenesin improved sputum looseness against placebo in a 2025 narrative review of the controlled studies. (Source 27)

• Expert review, not systematic, Low certainty.
• Size: 17 guaifenesin publications identified from 36 initial studies.
• Who: adults with cough and mucus-related cold symptoms.
• How long: short-term cold studies.
• Result: Statistically significant improvements versus placebo in sputum looseness or adhesiveness; the review notes some studies showed no significant improvement and a relatively high placebo response.
• Funding: not stated in the abstract - a reviewer should check the published conflict-of-interest statement, as narrative reviews of nonprescription brands are often sponsor-written.

Data from studies of guaifenesin and dextromethorphan either used alone or combined with other active ingredients showed statistically significant improvements compared with placebo control in sputum looseness/adhesiveness and reductions in cough frequency/severity, respectively.

The regulator's position is that codeine on its own is approved for mild to moderate pain where an opioid is appropriate and other treatments are inadequate; this is a licensing decision, not trial evidence, and it is not the use of a codeine cough liquid. (Source 6)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: adults with mild to moderate pain.
• How long: not stated.
• Result: No effect size - an approved indication.
• Funding: not applicable - regulator-approved labelling, revised 12/2025.

Codeine Sulfate Tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

What the evidence does not support

Codeine 30 mg syrup was no better than placebo syrup for cough caused by an upper respiratory infection. (Source 28)

• Systematic review, Low certainty.
• Size: 91 participants in the cited trial (Eccles 1992), mean age 23 years, within a systematic review.
• Who: adults with cough associated with acute upper respiratory tract infection.
• How long: 3-hour laboratory assessment plus a 4-day home phase.
• Result: No significant differences in cough frequency or subjective cough severity between codeine and placebo, in the laboratory or at home.
• Funding: independent - the review authors declared no commercial or financial relationships.

no significant differences in cough frequency or subjective cough severity were observed between the codeine and placebo groups, either in the laboratory or during home monitoring

Two of three placebo-controlled adult trials of guaifenesin for acute cough showed no benefit. (Source 4)

• Systematic review, Low certainty.
• Size: 29 trials, 4,835 people in total (3,799 adults, 1,036 children); three adult guaifenesin trials.
• Who: children and adults with acute cough in community settings.
• How long: short-term.
• Result: One of three guaifenesin trials indicated significant benefit, the other two did not; pooling was judged inappropriate.
• Funding: independent (Cochrane review)

Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not.

Cochrane concluded there is no good evidence either way on whether over-the-counter cough medicines work for acute cough. (Source 29)

• Systematic review, Low certainty.
• Size: 29 placebo-controlled randomised trials, 4,835 people.
• Who: children and adults with acute cough in community settings.
• How long: short-term.
• Result: No pooled estimate; the review reports poor reporting, heterogeneity and small numbers in every drug category.
• Funding: independent (Cochrane review)

There is no good evidence for or against the effectiveness of OTC medicines in acute cough.

In children, antitussives were no more effective than placebo for cough. (Source 4)

• Systematic review, Low certainty.
• Size: 10 paediatric trials, 1,036 children, within a 29-trial review.
• Who: children with acute cough in community settings.
• How long: short-term.
• Result: Antitussives, antihistamines, antihistamine-decongestants and antitussive/bronchodilator combinations were all no more effective than placebo.
• Funding: independent (Cochrane review)

In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo.

There is not enough evidence to say whether over-the-counter cough medicines help cough in acute pneumonia. (Source 5)

• Systematic review, Low certainty.
• Size: 4 studies, 224 participants.
• Who: children, adolescents and adults with cough secondary to acute pneumonia.
• How long: up to 10 days.
• Result: No significant difference in 'not cured or not improved' for mucolytics (OR 0.85, 95% CI 0.40 to 1.80); the single antitussive study had no extractable pneumonia-specific data.
• Funding: independent (Cochrane review)

There is insufficient evidence to decide whether OTC medications for cough associated with acute pneumonia are beneficial.

The codeine data were too heterogeneous and inconsistent to pool, so no clear conclusion about its efficacy can be drawn. (Source 3)

• Meta-analysis, Low certainty.
• Size: 16,774 records screened; 21 studies in the qualitative synthesis, 10 in the meta-analysis.
• Who: adults and children with acute or chronic cough.
• How long: single-day laboratory sessions up to multi-week treatment.
• Result: No quantitative estimate was possible for codeine; the pooled class effect reported for P2X3 antagonists was SMD -0.50 (95% CI -0.67 to -0.34), P = 0.0001.
• Funding: independent - the authors declared no commercial or financial relationships.

It should be emphasized that this study did not present quantitative data for codeine, butamirate, dextromethorphan, and levodropropizine.

For stable chronic bronchitis, the published evidence for how guaifenesin works or whether it helps is limited, despite a long-standing over-the-counter monograph claim. (Source 30)

• Expert review, not systematic, Low certainty.
• Size: not stated - a comprehensive narrative review.
• Who: patients with stable chronic bronchitis and chronic mucus hypersecretion.
• How long: not applicable.
• Result: No pooled estimate; the review reports limited published evidence of either mechanism of action or clinical efficacy.
• Funding: not stated in the abstract.

there is limited published evidence of either mechanism of action or clinical efficacy in this disease state

The authors of a 2026 systematic review concluded that, despite long use, the evidence that codeine and other cough suppressants work remains limited, and the available data are scattered and inconsistent. (Source 31)

• Systematic review, Low certainty.
• Size: 16,774 records screened; 21 studies in the qualitative synthesis, 10 in the meta-analysis.
• Who: adults and children with acute or chronic cough.
• How long: single-day laboratory sessions up to multi-week treatment.
• Result: No effect estimate - this is the authors' overall conclusion.
• Funding: independent - the authors declared no commercial or financial relationships.

Our study confirms that despite the long history of use of codeine and other antitussives, both centrally (butamirate, dextromethorphan) and peripherally (levodropropizine), evidence for their effectiveness remains limited, and the available data are scattered and inconsistent.

A 2026 systematic review found that conventional cough suppressants, which include codeine, show inconsistent effectiveness. (Source 32)

• Systematic review, Low certainty.
• Size: systematic review and meta-analysis of randomised clinical trials.
• Who: adults and children with cough.
• How long: varied.
• Result: No effect estimate for codeine in the abstract; the class effect reported was for P2X3 antagonists.
• Funding: independent - the review authors declared no commercial or financial relationships.

Conventional and natural antitussives show inconsistent efficacy. P2X3 receptor antagonists appear most promising

Where the research disagrees

Whether guaifenesin works for cough and mucus symptoms

• Cochrane review of over-the-counter medications for acute cough, 2014, systematic review of placebo-controlled randomised trials: Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not. (Source 4)
• Narrative review in Postgraduate Medicine, 2025, narrative literature review with no stated pooling method or risk-of-bias assessment: The data reviewed in this article support the importance of guaifenesin and dextromethorphan in the armamentarium of effective nonprescription treatment options for cough and mucus-related cold symptoms. (Source 27)

How much

• Reference intake: Dosing is set by the prescriber. As a position, the over-the-counter Drug Facts label on a marketed codeine phosphate 10 mg / guaifenesin 100 mg per 5 mL liquid (SPL effective 2018) directs 2 tsp (10 mL) every 4 hours for adults and children 12 and over, not exceeding 6 doses in 24 hours. For codeine as a single-ingredient approved analgesic the label's position (revised 12/2025) is a starting range of 15 to 60 mg every 4 hours as needed. (Source 24)
• Upper limit: The approved codeine sulfate label states as a position (revised 12/2025) that adult doses above 60 mg give no further efficacy but more adverse reactions, and that the maximum 24-hour dose is 360 mg. The combination cough liquid's own label caps use at 6 doses in 24 hours. (Source 33)
• Studied: A placebo-controlled trial gave codeine 30 mg per 10 mL four times a day, a total of 120 mg a day, for cough from an upper respiratory tract infection (91 participants), and another gave codeine phosphate 60 mg as a single dose in chronic obstructive pulmonary disease (21 participants). (Source 3)
• Studied: Guaifenesin trials in the Cochrane review compared the expectorant with placebo in adults with acute cough; three such adult trials were identified. (Source 4)
• Studied: The codeine pharmacokinetic data in the approved label come from 15 mg of codeine sulfate every four hours for 5 days, which reached steady state within 48 hours. (Source 12)

A common belief, and what the research shows

The belief: Codeine cough syrup is a proven cough suppressant, and the guaifenesin in it is proven to break up mucus.

What the research shows: Neither claim survives the placebo-controlled trials. In cough from a viral infection, codeine 30 mg produced “no significant differences in cough frequency or subjective cough severity were observed between the codeine and placebo groups, either in the laboratory or during home monitoring”, and in chronic obstructive pulmonary disease codeine 60 mg did no better. Cochrane's verdict on the whole class is that “There is no good evidence for or against the effectiveness of OTC medicines in acute cough.” For guaifenesin, one of three adult placebo-controlled trials in Cochrane showed benefit and two did not.

Questions and answers

What is it?

It is a liquid medicine containing two drugs: codeine phosphate, an opioid cough suppressant, and guaifenesin, an expectorant meant to thin mucus. A common strength is codeine 10 mg with guaifenesin 100 mg per 5 mL. The label sells it as an antitussive and expectorant for cough from a cold or inhaled irritants. (Source 34)

What does it do in the body?

Codeine is a weak opioid in itself; most of its effect comes from the liver turning part of it into morphine, which quiets the brainstem cough centre and also the brainstem breathing centre. Guaifenesin is thought to add water to airway mucus and lower its viscosity so it clears more easily, though reviewers say the evidence for that mechanism is limited. (Source 1)

Is it good or bad for you?

Mostly bad value for an acute cough. Placebo-controlled trials have not shown codeine beats placebo for cough from a cold or in chronic lung disease, and Cochrane found no good evidence either way for over-the-counter cough medicines. Meanwhile codeine sedates, constipates, causes physical dependence within days to weeks, and in CYP2D6 ultra-rapid metabolisers - which can be more than one person in ten in some populations - standard doses have killed children and breastfed infants. Guaifenesin is far safer but its benefit is small and inconsistent. (Source 19)

How do you get more of it?

Codeine-containing cough liquids are prescription-only in the United States for anyone under 18 and are controlled substances; nothing in the literature supports seeking more of them. The trials that tested codeine for cough used 30 mg four times a day or a single 60 mg dose, and neither beat placebo, so a higher dose is not a route to more benefit - the approved label states adult doses above 60 mg add adverse reactions without adding efficacy. (Source 33)

If it is harmful, what reduces it?

For an overdose, an opioid reversal agent such as naloxone or nalmefene reverses the respiratory depression, and that is what the label directs. For ordinary discontinuation after regular use the answer is a gradual taper, not an abrupt stop, because abrupt stopping in a physically dependent person has led to serious withdrawal, uncontrolled pain and suicide. Codeine itself clears quickly - the plasma half-lives of codeine and its metabolites are about 3 hours. (Source 14)

Why might someone be low in it or missing it?

Nobody is naturally deficient in either drug. Reasons someone would not be taking it include the contraindications on the approved codeine label - all children under 12, and anyone under 18 after tonsillectomy or adenoidectomy - being a known CYP2D6 ultra-rapid metaboliser, breastfeeding, taking an MAOI, and the regulatory restriction of opioid cough products. Being a CYP2D6 poor metaboliser is a different problem: the drug is there but produces little morphine, so it does little. (Source 19)

Which whole foods contain it or feed it?

No food supplies either drug, and food does not change codeine absorption meaningfully: a high-fat, high-calorie meal 30 minutes before a 60 mg dose made no significant difference to the rate or extent of absorption. Alcohol is the dietary exposure that matters, and it matters a lot - it is named in the boxed warning alongside benzodiazepines as a cause of profound sedation, respiratory depression, coma and death. (Source 12)

What happens if you do not have it?

Nothing happens that would not happen anyway: the trials show cough from a cold runs its course about the same with or without codeine. Cochrane's conclusion is that there is no good evidence for or against these medicines, so going without is not a loss of proven benefit. The one real consequence of absence applies to someone already physically dependent, in whom stopping suddenly causes withdrawal. (Source 29)

How can you test for it?

There is no test for whether the cough syrup is working other than watching the cough. The test that matters for safety is CYP2D6 genotyping, which identifies ultra-rapid metabolisers who convert codeine to morphine too fast and poor metabolisers who get little effect; the genotypes concerned are gene duplications such as *1/*1xN or *1/*2xN. Codeine and morphine can also be measured in blood or urine, and codeine and its metabolites have plasma half-lives of about 3 hours, so detection windows are short. (Source 19)

References

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14. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (2.5 Safe Reduction or Discontinuation). 2025. Read the source
15. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (9.3 Dependence, tapering plan). 2025. Read the source
16. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (9.3 Dependence). 2025. Read the source
17. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (8.2 Lactation, Clinical Considerations). 2025. Read the source
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19. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (5.6 Ultra-Rapid Metabolism of Codeine). 2025. Read the source
20. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (6 Adverse Reactions). 2025. Read the source
21. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (8.2 Lactation). 2025. Read the source
22. European journal of clinical pharmacology. The role of prescribed opioids in Norwegian overdose deaths in 2005-2021.. 2025. PMID 40784976, DOI 10.1007/s00228-025-03897-5. Read the source
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24. DailyMed / marketed unapproved drug listing. Codeine Phosphate and Guaifenesin oral liquid - Drug Facts Directions (SPL effective time 2018-09-24). 2018. Read the source
25. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (Boxed warning, third part). 2025. Read the source
26. Frontiers in Pharmacology. Beyond codeine - the evidence landscape of conventional, natural, and emerging antitussive therapies: a systematic review and meta-analysis (Discussion: codeine versus levodropropizine). 2026. PMID 41847128, DOI 10.3389/fphar.2026.1756578. Read the source
27. Postgraduate medicine. Guaifenesin and dextromethorphan for management of cough and mucus-related cold symptoms in adults: a narrative literature review. (Methods, Results and Conclusion). 2025. PMID 41423743, DOI 10.1080/00325481.2025.2603034. Read the source
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31. Frontiers in Pharmacology. Beyond codeine - the evidence landscape of conventional, natural, and emerging antitussive therapies: a systematic review and meta-analysis (Conclusions). 2026. PMID 41847128, DOI 10.3389/fphar.2026.1756578. Read the source
32. Frontiers in pharmacology. Beyond codeine - the evidence landscape of conventional, natural, and emerging antitussive therapies: a systematic review and meta-analysis.. 2026. PMID 41847128, DOI 10.3389/fphar.2026.1756578. Read the source
33. DailyMed / Hikma Pharmaceuticals USA Inc.. Codeine sulfate tablets, for oral use, CII - FDA prescribing information, label revised 12/2025 (2.3 Initial Dosage). 2025. Read the source
34. DailyMed / marketed unapproved drug listing. Codeine Phosphate and Guaifenesin oral liquid - over-the-counter Drug Facts label (SPL effective time 2018-09-24). 2018. Read the source