**2.3 Codeine**

IUPAC Name: (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13 hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol


Codeine, a 3-methylether derivative of morphine, is the third opioid alkaloid according to its density in the raw *Papaver somniferum L.* plant, was first isolated by Robiquet in 1833. Codeine and its metabolite, morphine, act by stimulating opioid receptors. The main effects are analgesia (lighter than morphine), central antitussive and antidiarrheal effects [83]. It can also do sedation, drowsiness, and respiratory depression. Codeine is used in the management of mild to moderate pain, in the treatment of cough, persistent diarrhea and restless leg syndrome. Codeine is taken orally and intramuscularly.

Absorption is rapidly in oral use and bioavailability is higher due to less first-pass metabolism (about 53%). Codeine is distributed to a variety of tissues, with priority being to the liver, spleen and kidney [84]. Codeine-6-glucuronide, morphine, and norcodeine is formed as a result of hepatic metabolism. Morphine is then metabolized to M3G and M6G, and contributes to analgesic effects of codeine. The half-life elimination is about 3 h and excretion is mostly done through urine and with less feces.

In adults 7–14 mg/kg, in children more than 5 mg/kg intake leads to death [85]. Codeine blood concentration within 20–50 μg/dL is toxically, if it is above 60 μg/dL is lethally [86].

Abnormal dreams, insomnia, depression, paresthesia, agitation, anxiety, ataxia, dizziness, disorientation, sedation, euphoria, fatigue, hallucination, headache, bradycardia, tachycardia, circulatory depression, flushing, pruritus, skin rash, urticaria, bronchospasm, dyspnea, respiratory depression, abdominal cramps, anorexia, constipation, diarrhea, nausea, urinary hesitancy, urinary retention, blurred vision, diplopia, miosis, nystagmus, laryngospasm, muscle rigidity, tremor, hypogonadism, etc. may occur due to codeine use.

Contraindications are hypersensitivity to codeine, pediatric patients <12 years of age, postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy, significant respiratory depression, acute or severe bronchial asthma in the absence of resuscitative equipment, GI obstruction.

*Effects on reproduction*: Prolonged codeine use can cause secondary hypogonadism, which can lead to infertility in both sexes [62].

*Effects on pregnancy*: It is known that, codeine crosses the placenta. The use in the first trimester can lead to respiratory tract malformation, pyloric stenosis, inguinal hernia, neural tube defects, cardiac and circulatory system defects, and cleft lip and palate [63, 87]. The use of codeine late in pregnancy may result in neonatal

withdrawal syndrome, characterized by tremor, jitteriness, diarrhea, and poor feding [88].

*Effects on lactation*: Both codeine and an active metabolite, morphine, can be detected in breast milk [89]. A milk: plasma ratio of codeine is unknown. Respiratory depression, sedation and withdrawal signs can be seen in infants of breastfeeding mothers receiving codeine [90].
