CARISOPRODOL, ASPIRIN AND CODEINE PHOSPHATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Carisoprodol is a centrally acting skeletal muscle relaxant that produces muscle relaxation by blocking interneuronal activity in the descending reticular formation and spinal cord, likely acting as a prodrug to meprobamate, which enhances GABA activity at GABA-A receptors. Aspirin irreversibly acetylates cyclooxygenase (COX-1 and COX-2), inhibiting prostaglandin synthesis involved in pain, fever, and inflammation. Codeine phosphate is an opioid agonist with weak affinity for mu-opioid receptors; it is primarily metabolized to morphine via CYP2D6, which mediates its analgesic effects.
| Metabolism | Carisoprodol is hepatically metabolized via CYP2C19 to meprobamate (active). Aspirin is hydrolyzed to salicylic acid (active) by esterases in the GI tract, liver, and blood, then conjugated primarily with glycine (salicyluric acid) and glucuronic acid. Codeine is metabolized by CYP3A4 to norcodeine, CYP2D6 (major pathway) to morphine (active), and UGT2B7 to morphine-6-glucuronide and morphine-3-glucuronide. |
| Excretion | Carisoprodol: ~60% renal as metabolites, <1% unchanged. Aspirin: renal excretion of salicylate and metabolites (75% as salicyluric acid, 10% as glucuronides, 10% as free salicylate). Codeine: ~90% renal as conjugates, ~10% unchanged, ~10% as morphine and norcodeine. |
| Half-life | Carisoprodol: ~2 hours (range 1-3 h). Aspirin: ~2-3 hours for salicylate (low dose), up to 15-30 h at high doses or overdose (zero-order kinetics). Codeine: ~3-4 hours (range 2.5-4.5 h). Clinically, repeated doses may lead to accumulation of salicylate due to saturable metabolism. |
| Protein binding | Carisoprodol: ~60% bound to albumin. Aspirin: 80-90% bound to albumin (dose-dependent, decreases at high concentrations due to saturation). Codeine: ~25% bound to albumin. |
| Volume of Distribution | Carisoprodol: ~0.5 L/kg. Aspirin: ~0.15 L/kg (salicylate). Codeine: ~2.5 L/kg. Clinical meaning: Carisoprodol distributes widely, aspirin distributes primarily in plasma, codeine distributes well into tissues including CNS. |
| Bioavailability | Oral: Carisoprodol ~90%. Aspirin ~80-100% (rapidly hydrolyzed to salicylate, first-pass metabolism minimal). Codeine ~50% (extensive first-pass metabolism to morphine and other metabolites). |
| Onset of Action | Oral: Carisoprodol onset 30 min. Aspirin onset 30 min (analgesic). Codeine onset 30-60 min. |
| Duration of Action | Carisoprodol: 4-6 hours. Aspirin: 4-6 hours (analgesic), antiplatelet effect lasts 7-10 days. Codeine: 4-6 hours. Clinical note: Duration depends on dose and conversion to morphine (CYP2D6 phenotype). |
| Molecular Weight | Carisoprodol: 260.33 Da; Aspirin: 180.16 Da; Codeine phosphate: 397.36 Da (codeine base: 299.36 Da) |
1-2 tablets (carisoprodol 200 mg, aspirin 325 mg, codeine phosphate 16 mg) orally every 6 hours as needed for pain, maximum 6 tablets per day.
| Dosage form | TABLET |
| Renal impairment | Not recommended for use in patients with GFR < 30 mL/min or renal failure due to aspirin and codeine accumulation. For GFR 30-60 mL/min, use with caution and reduce dose by 50% or extend dosing interval. |
| Liver impairment | Contraindicated in Child-Pugh class C cirrhosis. For Child-Pugh class A or B: avoid or use with extreme caution; consider reducing codeine dose by 50% and monitor for hepatotoxicity from aspirin. |
| Pediatric use | Not recommended for children under 12 years of age due to risk of Reye's syndrome (aspirin) and respiratory depression (codeine). For children over 12 years: 1 tablet orally every 6 hours as needed, maximum 4 tablets/day. |
| Geriatric use | Avoid in elderly patients due to increased sensitivity to codeine (respiratory depression), aspirin GI bleeding risk, and carisoprodol sedation. If necessary, use lowest effective dose and monitor for falls and confusion. |
| 1st trimester | Avoid due to risk of teratogenicity (codeine, aspirin) and possible fetal harm. Aspirin associated with gastroschisis and cardiovascular defects; codeine may cause respiratory depression and withdrawal. |
| 2nd trimester | Caution: aspirin may affect maternal/neonatal hemostasis; codeine may cause fetal dependence. Use only if benefits outweigh risks. |
| 3rd trimester | Avoid: aspirin increases risk of premature closure of ductus arteriosus and oligohydramnios; codeine may cause neonatal respiratory depression and withdrawal; carisoprodol not well studied. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Placental transfer | All three components cross the placenta. Aspirin: significant transfer (protein binding limits but high doses saturate). Codeine: crosses readily (fetal concentrations ~80% maternal). Carisoprodol: crosses (meprobamate metabolite accumulates). |
■ FDA Black Box Warning
Addiction, abuse, and misuse; risk of opioid addiction, abuse, and misuse, which can lead to overdose and death. Life-threatening respiratory depression; accidental ingestion of even one dose, especially by children, can be fatal. Neonatal opioid withdrawal syndrome; prolonged use during pregnancy can result in withdrawal in the newborn. Concomitant use of CYP3A4 inhibitors or discontinuation of CYP3A4 inducers may increase codeine toxicity. Risks from concomitant use with benzodiazepines or other CNS depressants; may result in profound sedation, respiratory depression, coma, and death.
| Common Effects | cough |
| Serious Effects |
BreastfeedingThird trimester pregnancyKnown hypersensitivity to any componentCYP2D6 ultra-rapid metabolizer status (for codeine)Acute or severe hepatic impairmentAcute or severe renal impairmentPeptic ulcer disease or GI bleedingBleeding disordersSevere respiratory depressionPorphyriaConcomitant use of MAOIs or within 14 days
| Precautions | Risk of opioid addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant use with CNS depressants; severe hypotension; gastrointestinal obstruction; impaired mental or physical abilities; risk of serotonin syndrome with serotonergic drugs; severe hypoglycemia; adrenal insufficiency; carisoprodol withdrawal syndrome (including seizures); hypersensitivity/anaphylaxis; renal impairment (aspirin); risk of Reye's syndrome (aspirin use in children); bleeding risk (aspirin); hypersensitivity to NSAIDs; GI toxicity; pregnancy; lactation. |
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| Breastfeeding | Contraindicated: codeine is excreted into breast milk and may cause infant respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Aspirin may cause Reye's syndrome and platelet dysfunction. Carisoprodol is excreted and may cause sedation. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | First trimester: Aspirin (100-500 mg/day) associated with increased risk of gastroschisis; codeine is not a major human teratogen but risks cannot be excluded. Second/third trimester: Aspirin may cause premature closure of ductus arteriosus, oligohydramnios; codeine may cause neonatal respiratory depression and withdrawal. Carisoprodol: limited human data, animal studies show no clear teratogenicity. |
| Fetal Monitoring | Monitor fetal growth and amniotic fluid levels (aspirin effect on renal function). Assess ductus arteriosus patency in third trimester. Neonatal monitoring for respiratory depression, sedation, and withdrawal signs. Maternal renal/hepatic function and bleeding time if high-dose aspirin. |
| Fertility Effects | Aspirin may inhibit ovulation at high doses via prostaglandin synthesis inhibition; low-dose aspirin may improve implantation in some conditions. Codeine may reduce fertility via prolactin or GnRH suppression. Carisoprodol: no known effect on fertility. |
| Food/Dietary | Avoid alcohol; may enhance CNS depression. Avoid high doses of vitamin E or fish oil supplements that increase bleeding risk. Aspirin may cause GI irritation; take with food or milk. Avoid cranberry juice? (no clinically significant interaction). |
| Clinical Pearls | Carisoprodol is metabolized to meprobamate, a schedule IV controlled substance; monitor for abuse potential. Aspirin component increases bleeding risk; avoid in children with viral illness due to Reye's syndrome risk. Codeine is a prodrug requiring CYP2D6 activation; ultra-rapid metabolizers risk toxicity. Caution in elderly due to CNS depression and fall risk. |
| Patient Advice | This medication contains three drugs: a muscle relaxant, aspirin, and codeine (opioid). · Take with food or milk to reduce stomach upset. · Do not drive or operate machinery until you know how this medication affects you; it can cause dizziness and drowsiness. · Avoid alcohol and other sedatives; they can increase side effects. · Do not exceed prescribed dose; risk of dependence and withdrawal. · Stop use and seek medical help if you experience signs of bleeding (easy bruising, black stools) or allergic reaction (rash, difficulty breathing). · Do not give to children under 12 years, or children under 18 after tonsillectomy/adenoidectomy due to serious breathing problems. · If you are nursing, pregnant, or planning pregnancy, consult your doctor; codeine and aspirin can harm the baby. |