Codeine is a natural opiate analgesic, one of the alkaloids extracted from opium. Chemically, codeine is methyl-morphine. It has little or no analgesic efficacy of its own and relies for its effect on its transformation into morphine by N-demethylation.
Codeine has a strong tradition of use as an analgesic, and it is still commonly prescribed. However, the evidence base for codeine as a sole oral analgesic is extremely weak (this may reflect a lack of well-designed trials). There is good evidence that co-codamol 30/500 is a better analgesic than pure paracetamol (see Bandolier ).
Its most common presentation is as a phosphate salt (codeine phosphate), but it can come in other salts, e.g. codeine sulphate.
- not given intravenously due to risks of hypotension and seizures. If pain is severe enough to require parenteral analgesia, a more potent opioid would be more sensible.
- 30-60mg qds, up to 240mg a day.
Like any opioid, sufficiently large doses can result in toxicity. The main concern is respiratory depression and reduced consciousness leading to respiratory arrest.
Cautions and Interactions
- Breast feeding - While there is evidence for morphine crossing the maternal fetal barrier and abnormal metabolism being a rare cause of higher fetal levels most would regard licensed use and doses as safe.
- Drugs may inhibit the needed demethylation. Perhaps the most obvious example is levomepromazine in homozygous extensive metabolisers of CYP2D6 as this is often used in palliative care.
Some people find codeine strikingly ineffective. It is believed that codeine has little intrinsic analgesic effect and most or all of its analgesic effect is due to metabolites such as morphine, or codeine-6-glucuronide. Metabolism of codeine to morphine requires the 2D6 isoform of cytochrome p450. About 5-10% of caucasians lack the isoform required for metabolism accounting for the observation that some are relatively insensitive to the effect of codeine as they can not convert to morphine (see Pharmacogenetic polymorphisms). A further 5-10% metabolise codeine so rapidly into morphine ("extensive metabolisers") that they are very sensitive to codeine.
- ↑ a b Lötsch J, Skarke C, Schmidt H, Rohrbacher M, Hofmann U, Schwab M, Geisslinger G. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clinical pharmacology and therapeutics. 2006 Jan; 79(1):35-48.(Link to article – subscription may be required.)
- ↑ a b Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. British journal of clinical pharmacology. 1991 Apr; 31(4):381-90.
- ↑ a b Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. British journal of anaesthesia. 2002 Dec; 89(6):839-45.
- ↑ http://www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html
- ↑ Shanahan EC, Marshall AG, Garrett CP. Adverse reactions to intravenous codeine phosphate in children. A report of three cases. Anaesthesia. 1983;38:40-3.
- ↑ Parke TJ, Nandi PR, Bird KJ, Jewkes DA. Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations. Anaesthesia. 1992;47:852-4.
- ↑ Cox RG. Hypoxaemia and hypotension after intravenous codeine phosphate. Canadian journal of anaesthesia 1994;41:1211-3.
- ↑ Madadi P, Ross C, Hayden M, Carleton B, Gaedigk A, Leeder J, Koren G. Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case-Control Study. Clinical pharmacology and therapeutics. 2008 Aug 20.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Vevelstad M, Pettersen S, Tallaksen C, Brørs O. O-demethylation of codeine to morphine inhibited by low-dose levomepromazine. European journal of clinical pharmacology. 2009 Aug; 65(8):795-801.(Link to article – subscription may be required.)