codeine, acetaminophen, butalbital and caffeine

Action and Spectrum

Actions and spectrum: 

• codeine: codeine is an opioid analgesic that acts by binding to opioid receptors in the brain, spinal cord, and other areas of the body. It helps to reduce pain perception and provide pain relief. 
• acetaminophen: acetaminophen is a non-opioid analgesic and antipyretic medication. It acts by inhibiting the production of prostaglandins responsible for pain and fever. acetaminophen provides pain relief and reduces fever. 
• butalbital: butalbital is a barbiturate that acts as a central nervous system depressant. It helps to relax muscles and relieve muscle tension associated with tension headaches. butalbital also has sedative properties and can help promote relaxation and sleep. 
• caffeine: It is acts as a stimulant that can help enhance the effects of other pain relievers. It constricts blood vessels in the brain, which can help alleviate headaches. caffeine also has mild analgesic properties and can improve alertness and reduce fatigue. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

codeine 

• Confusion, headache, malaise, restlessness, dizziness, lightheadedness, weakness 
• Anorexia, vomiting, nausea, xerostomia 
• Ureteral spasm, decreased urination 
• injection site burning, histamine release, blurred vision 
• Bradycardia, tachycardia, hypotension 
• Urticaria, Rash 
• increased LFT’s   
• Dyspnea 

>10% 

codeine 

• Constipation 
• Drowsiness

Frequency not defined 

butalbital 

• Abdominal pain, vomiting, nausea 
• Drowsiness, intoxicated feeling, sedation, dizziness, lightheadedness 
• Shortness of breath

acetaminophen 

• Urticaria, Pruritic maculopapular rash 
• Hepatotoxicity 
• laryngeal edema, Angioedema 
• Agranulocytosis, neutropenia, thrombocytopenia, leukopenia, pancytopenia, thrombocytopenic purpura 
• Anaphylactoid reaction

caffeine 

• Insomnia, nervousness, tinnitus, irritability restlessness, tremor 
• Diuresis 
• Tachycardia, palpitations 
• Diarrhea, vomiting, nausea 

Black Box Warning

Black Box Warning: 

There is no specific black box warning associated with the combination of codeine, acetaminophen, butalbital, and caffeine. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: The medication should not be used in individuals who have a known hypersensitivity or allergic reaction to any of its components, including codeine, acetaminophen, butalbital, or caffeine. 
• Respiratory Depression: codeine is contraindicated in individuals with severe respiratory insufficiency, acute asthma, or respiratory depression. 
• Porphyria: The combination should not be used in individuals with porphyria, a group of rare genetic disorders that affect the production of heme in the body. 
• MAOI Therapy: Monoamine oxidase inhibitors (MAOIs), which are a class of antidepressant medications, can interact with codeine and cause serious side effects. Therefore, the combination should not be used in individuals taking or within 14 days of discontinuing MAOI therapy.

Caution: 

• Respiratory Conditions: The medication contains codeine, which can cause respiratory depression. Caution should be exercised in individuals with respiratory conditions such as asthma, COPD, or other respiratory disorders. 
• Hepatic Impairment: The presence of acetaminophen in the medication warrants caution in individuals with mild to moderate hepatic impairment. Dosage adjustments or monitoring may be necessary in such cases. 
• Renal Impairment: Individuals with impaired renal function may require dosage adjustments or close monitoring when taking the medication due to the presence of acetaminophen. 
• CNS Depression: The combination of codeine, butalbital, and caffeine may cause central nervous system (CNS) depression, leading to drowsiness, sedation, and impaired cognitive and motor functions.  
• Drug Interactions: codeine, butalbital, and caffeine can interact with other medications, including sedatives, tranquilizers, other opioids, and MAOIs.  
• Substance Abuse and Dependence: Caution should be exercised in individuals with a history of substance abuse or addiction.

Comorbidities: 

• Liver Disease: The presence of acetaminophen in the medication may pose a risk to individuals with liver disease or impaired liver function. Caution should be exercised, and dosage adjustments may be necessary. 
• Kidney Disease: Individuals with kidney disease or impaired kidney function may require dosage adjustments or closer monitoring when using the medication due to the presence of acetaminophen. 
• History of Substance Abuse: codeine is an opioid, and it carries a risk of abuse, addiction, and dependence. Individuals with a history of substance abuse should be closely monitored when using this medication. 
• Hypertension: caffeine, one of the components of the medication, can potentially increase blood pressure. Individuals with hypertension or cardiovascular conditions should use the medication with caution and under the guidance of a healthcare professional. 
• Mental Health Conditions: The combination medication contains butalbital, a barbiturate, which can affect the central nervous system and may interact with certain mental health conditions. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk: Yes (acetaminophen); Yes (barbiturates); Yes (caffeine); Yes (codeine)  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

• codeine: codeine is an opioid analgesic that acts on opioid receptors in the central nervous system (CNS). It has analgesic (pain-relieving) effects and can also suppress coughing.  
• acetaminophen: acetaminophen, also known as paracetamol, is a non-opioid analgesic and antipyretic. It acts by inhibiting prostaglandin synthesis, which is involved in transmitting pain signals and regulating body temperature. acetaminophen is primarily metabolized in the liver and excreted in the urine. 
• butalbital: butalbital is a barbiturate that acts as a CNS depressant. It has sedative properties and can help relieve tension headaches. It enhances the inhibitory effects of GABA that helps regulate brain activity. 
• caffeine: It is a CNS stimulant that acts by blocking the adenosine action that promotes relaxation and sleep. caffeine can increase alertness and decrease drowsiness. It may also have a mild analgesic effect and can help enhance the effectiveness of other pain relievers.

Pharmacodynamics: 

• codeine: codeine acts on opioid receptors in the central nervous system, primarily the mu-opioid receptors. It exerts its analgesic effect by binding to these receptors and reducing the transmission of pain signals. codeine also has antitussive (cough suppressant) properties, which are mediated by its effects on the cough reflex in the brainstem. 
• acetaminophen: acetaminophen primarily acts as an inhibitor of cyclooxygenase (COX) enzymes, particularly COX-2, which are responsible for the synthesis of prostaglandins. By reducing the production of prostaglandins, acetaminophen exhibits analgesic and antipyretic (fever-reducing) effects. The exact mechanism of action has yet to be fully understood. 
• butalbital: butalbital is a barbiturate that acts as a depressant on the central nervous system. It enhances the inhibitory effects of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain. This leads to sedative and relaxant effects, helping to alleviate tension and reduce headaches. 
• caffeine: caffeine is a stimulant that primarily blocks the adenosine receptors in the brain. By blocking its action, caffeine increases neuronal activity and arousal, increasing alertness and reducing drowsiness. 

Pharmacokinetics: 

Absorption 

• codeine: codeine is well absorbed from the gastrointestinal tract after oral administration. 
• acetaminophen: acetaminophen is also well absorbed from the gastrointestinal tract. 
• butalbital: butalbital is rapidly and completely absorbed after oral administration. 
• caffeine: caffeine is rapidly and completely absorbed from the gastrointestinal tract. 

Distribution 

• codeine: codeine is widely distributed throughout the body and may cross blood-brain barrier, leading to its central nervous system effects. 
• acetaminophen: acetaminophen is distributed to most tissues in the body. 
• butalbital: butalbital is distributed throughout the body, including the central nervous system. 
• caffeine: caffeine is distributed to various tissues, including the brain. 

Metabolism 

• codeine: codeine is metabolized in the liver by the enzyme CYP2D6 into its active metabolite, morphine, which contributes to its analgesic effects. 
• acetaminophen: acetaminophen is primarily metabolized in the liver by conjugation with glucuronic acid and sulfate. 
• butalbital: butalbital is metabolized in the liver via oxidative reactions. 
• caffeine: caffeine gets metabolized in the liver by several enzymes, primarily CYP1A2, into three primary metabolites: paraxanthine, theobromine, and theophylline. 

Elimination and excretion 

• codeine: codeine and its metabolites are excreted primarily through the kidneys, with a small portion excreted in the feces. 
• acetaminophen: acetaminophen and its metabolites are primarily excreted in the urine. 
• butalbital: butalbital and its metabolites are excreted through the kidneys. 
• caffeine: caffeine and its metabolites are excreted primarily in the urine. 

Adminstartion

Administration: 

codeine/acetaminophen/butalbital/caffeine is typically administered orally in the form of tablets or capsules. The specific dosage and administration instructions may vary depending on the formulation and the prescribing healthcare professional’s recommendations. 

Typically, the medication is taken with water and may be taken with or without food. However, it is best to refer to the specific instructions provided with the medication or consult your healthcare provider for precise administration details. 

It is recommended to avoid exceeding dosage or frequency of administration, as this can have increased risk of adverse effects associated with the individual components of the medication. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: codeine, acetaminophen, butalbital and caffeine 

Pronounced: (KOH-deen- uh-see-tuh-MIN-uh-fen- byoo-TAL-bi-tal- ka-FEEN) 

Why do we use codeine, acetaminophen, butalbital and caffeine? 

codeine/acetaminophen/butalbital/caffeine is a combination medication that is primarily used for the management of tension headaches. The specific combination of ingredients provides various effects: 

• codeine is an opioid analgesic that helps relieve pain by acting on the CNS. 
• acetaminophen is a non-opioid analgesic and antipyretic that helps reduce pain and fever. 
• butalbital is a barbiturate that helps to relax muscle tension and reduce anxiety. 
• caffeine acts as a stimulant that can enhance the effects of pain medications and help alleviate headaches. 

Combining these ingredients is believed to synergistically relieve tension headaches, particularly those associated with muscle tension and stress.