Acetaminophen And Codeine and Tobacco: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Tobacco
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Smoking can change how your body handles this medicine. Cigarette smoke speeds up certain liver enzymes, so some medicines get broken down faster and may not work as well while you smoke. That's the general concern that was flagged here for the acetaminophen and codeine product.
One thing worth knowing: codeine is a "prodrug," meaning your body has to convert it into its active pain-relieving form. So the way smoking affects your pain relief can be a bit unpredictable. The good news is your care team can manage this by checking how well your pain is controlled and adjusting things as needed. Please talk with your pharmacist or doctor rather than changing anything on your own.
Mechanism: Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2, increasing metabolism of CYP1A2 substrates and reducing their exposure (AUC/Cmax). Evidence is established; onset unspecified and reflects chronic smoking status.
- Direction: Reduced substrate exposure and potentially reduced efficacy during active smoking.
- Caveat for this product: Acetaminophen and codeine are primarily metabolized via other pathways (glucuronidation/sulfation; codeine via CYP2D6 to morphine, a prodrug activation). CYP1A2 induction is not their dominant clearance route, so clinical impact may be modest.
- Management: Advise cessation; monitor analgesic/clinical efficacy, individualize dose, and reassess dosing if smoking status changes.
What happens
Reduced CYP1A2 substrates exposure
Interaction Deep Dive
The polycyclic aromatic hydrocarbons produced by cigarette smoking act to induce the metabolism of CYP1A2 substrates315, which in turn lowers exposure to those substrates. Pharmacokinetic differences may additionally arise from smoking, age, and gender 1. Because efficacy can be diminished, patients taking CYP1A2 substrates concurrently should be counseled to stop smoking 2. When CYP1A2 substrate treatment is necessary in individuals who smoke, watch for decreased efficacy 3 and, if warranted, raise the dose of the CYP1A2 substrate 4. Should the patient stop smoking, a reduction in the CYP1A2 substrate dose should be considered 5.
Why it happens (mechanism)
Induction of CYP1A2-mediated metabolism by tobacco smoke
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Here is how a care team typically handles this:
- They may encourage quitting smoking during treatment, since smoking can lower how well some medicines work.
- If you smoke and need this medicine, they may monitor how well it is working (for example, whether your pain is controlled) and adjust and individualize your dose if needed.
- If you stop smoking, tell your team, because your dose may need to be lowered.
What to do: Let your pharmacist or doctor know if you smoke or plan to quit, and report if the medicine seems less effective.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
11 reports — tap to read
a) A systematic review and meta-analysis covering 7 studies of OLANZapine-treated patients with schizophrenia or other psychiatric conditions found that the concentration/dose (C/D) ratio of OLANZapine was significantly lower among smokers (n=652) than among non-smokers (n=442); standard mean difference, -0.75 nanograms (ng)/mL (95% CI, -0.89 to -0.61 ng/mL) 6.
b) A systematic review and meta-analysis covering 4 studies of cloZAPine-treated patients with schizophrenia or other psychiatric conditions found that the concentration/dose (C/D) ratio of cloZAPine was significantly lower among smokers (n=120) than among non-smokers (n=76); standard mean difference, -1.11 nanograms (ng)/mL (95% CI, -1.53 to -0.7 ng/mL) 6.
c) Consumption of 7 to 12 cigarettes/day led to maximum enzyme induction and a significantly lower mean cloZAPine C/D ratio in smokers versus nonsmokers (2.8 vs 6 nanograms/mL/mg/day), with a comparable finding for the OLANZapine C/D ratio in a separate study (6.1 vs 12.8 nanograms/mL/mg/day). Smoking beyond 12 cigarettes/day yielded no additional induction and no further reduction in the C/D ratio of cloZAPine or OLANZapine 7.
d) Among patients given mirtazapine 30 mg/day for 4 weeks, smokers showed significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L) and a lower mirtazapine S(+)/R(-) ratio (0.28 vs 0.37) than nonsmokers. These smoking-related effects continued to be significant following multivariant analysis 4.
e) In patients on stable cloZAPine 100 mg/day, heavy smokers (30 or more cigarettes/day) exhibited a significantly higher mean plasma cloZAPine concentration coefficient of variation (CV) than smokers (30% vs 16%); nonetheless, no such difference appeared in patients on stable cloZAPine 300 or 600 mg/day in a study of patients with schizophrenia or schizoaffective disorder (N=47) 8.
f) In a study of patients on an average cloZAPine dose of 304 mg/day (N=18), plasma concentrations of cloZAPine and norcloZAPine (active metabolite) were significantly lower in smokers (median of 25 cigarettes or 4 pipes/day) than in nonsmokers. The cloZAPine plasma concentration was a significant 3.2-fold lower in smokers and norcloZAPine was 2.3-fold lower compared with the plasma concentration in nonsmokers 9.
g) Induction of CYP1A2 activity from cigarette smoking significantly lowered OLANZapine plasma concentrations and clinical effectiveness in smokers (10 to 40 cigarettes/day) relative to nonsmokers in a study of adults with thought disorder (N=17). After 15 days of OLANZapine 10 mg/day, the dose-corrected steady-state OLANZapine plasma concentration (C:D) ratio was roughly 5-fold lower in smokers than in nonsmokers (1.56 vs 7.9 nanograms/mL/mg). At the same time, Brief Psychiatric Rating Scale total scores were significantly higher for nonsmokers than for smokers (30.4% vs 12.5%) and showed a positive correlation with the steady-state plasma OLANZapine C:D ratio. Smoking prompted a significant 6-fold greater level of CYP1A2 activity in smokers than in nonsmokers, and the index correlated closely with the steady-state plasma OLANZapine C:D ratio 10.
h) Cigarette smoking appears to release polycyclic aromatic hydrocarbons that induce the metabolism of CYP1A2 substrates. In vivo blood clearance and urine metabolite data derived from caffeine demethylation have clearly shown the connection between CYP1A2 activity and cigarette smoking, which may carry clinical consequences when cigarette smoking coincides with therapy involving theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, or flecainide 3.
i) In a study of healthy volunteers (N=14), chronically-exposed passive smokers displayed a significantly higher mean theophylline clearance of 60.1 mL/kg/hr versus 40.9 mL/kg/hr for the nonsmokers 11. However, in a different study of volunteers (N=5), intense, short-term (5 days) passive smoking did not alter theophylline disposition 12. It was concluded that the brief duration of exposure to tobacco smoke accounted for the absence of an effect.
j) A retrospective study of patients with schizophrenia (N=50) showed that cigarette smokers (more than 1 pack/day) had significantly lower plasma concentrations of haloperidol (16.83 vs 28.8 nanograms/mL) and reduced haloperidol (active metabolite; 16.76 vs 34.23 nanograms/mL), as well as significantly increased haloperidol oral clearance (1.58 vs 1.1 L/min), compared with nonsmokers 13.
k) Giving oral imipramine 3.5 mg/kg to smokers (15 cigarettes/day) produced significantly lower mean plasma levels of combined imipramine and desmethylimipramine relative to nonsmokers (160 vs 290 nanograms/mL) 14.
Common questions
Can I take Acetaminophen And Codeine and Tobacco together?
Smoking speeds up certain liver enzymes and can lower how well some medicines work, so tell your pharmacist or doctor if you smoke or plan to quit and report any drop in pain relief. Do not change your dose on your own; your care team can adjust it. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Tobacco interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and Tobacco interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Here is how a care team typically handles this: They may encourage quitting smoking during treatment, since smoking can lower how well some medicines work. If you smoke and need this medicine, they may monitor how well it is working (for example, whether your pain is controlled) and adjust and individualize your d… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Tobacco need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (15)
- Product Information: ZYPREXA(R) oral tablets, olanzapine oral tablets. Lilly USA LLC (per FDA), Indianapolis, IN, 2019. DailyMed
- Product Information: POMALYST(R) oral capsules, pomalidomide oral capsules. Celgene Corporation (per manufacturer), Summit, NJ, 2021. DailyMed
- Zevin S & Benowitz NL: Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999; 36(6):425-438. PubMed
- Lind AB, Reis M, Bengtsson F, et al: Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour. Clin Pharmacokinet 2009; 48(1):63-70. PubMed
- Product Information: CLOZARIL(R) oral tablets, clozapine oral tablets. HLS Therapeutics USA Inc (per FDA), Rosemont, PA, 2021. DailyMed
- Tsuda Y, Saruwatari J, & Yasui-Furukori N: Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open 2014; 4(3):e004216-. PubMed
- Kennedy WK, Jann MW, & Kutscher EC: Clinically significant drug interactions with atypical antipsychotics. CNS Drugs 2013; 27(12):1021-1048. PubMed
- Diaz FJ, de Leon J, Josiassen RC, et al: Plasma clozapine concentration coefficients of variation in a long-term study. Schizophr Res 2005; 72(2-3):131-135. PubMed
- Ozdemir V, Kalow W, Posner P, et al: CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concentrationin patients with schizophrenia. J Clin Psychopharmacol 2001; 21(4):398-407.
- Carrillo JA, Herraiz AG, Ramos SI, et al: Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23(2):119-127. PubMed
- Matsunga SK, Plezia PM, Karol MD, et al: Effects of passive smoking on theophylline clearance. Clin Pharmacol Ther 1989; 46:399-407. PubMed
- Casto DT, Schnapf BM, & Clotz MA: Lack of effect of short-term passive smoking on the metabolic disposition of theophylline. Eur J Clin Pharmacol 1990; 39:399-402.
- Jann MW, Saklad SR, Ereshefsky L, et al: Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology (Berl) 1986; 90(4):468-470. PubMed
- Perel JM, Hurwic MJ, & Kanzler MB: Pharmacodynamics of imipramine in depressed patients. Psychopharmacol Bull 1975; 11:16-18.
- Jusko WJ: Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 1979; 9:221-236. PubMed
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