Role of codeine in palliative care


  • Eric Prommer, MD


opioids, codeine, cough, cytochrome oxidase


Codeine is designated as one of the essential medicines of palliative care for symptoms such as pain and diarrhea. Essential drugs for palliative care are drugs that are effective for the treatment of common symptoms in palliative medicine, easily available, and are affordable. Codeine is recommended for the management of mild to moderate pain and is available as a combination product or as a stand-alone opioid. It is a prodrug and exhibits an affinity to μ-opioid receptors 200 times lower than morphine. Codeine is metabolized in the liver to inactive metabolites, which account for 90 percent of the transformed product, and morphine, which accounts for 10 percent of the transformed product and provides the main analgesic effect. The production of morphine is dependent on cytochrome oxidase 2D6 enzyme activity, which may not be fully active in some populations. The purpose of this review is to examine the efficacy of codeine for common symptoms encountered in palliative medicine, which has led to its designation as an essential medicine for palliative care.

Author Biography

Eric Prommer, MD

Director of Palliative Care, Mayo Clinic College of Medicine, Mayo Clinic Hospital, Scottsdale, Arizona; Assistant Professor, Division of Hematology/Oncology, Mayo Clinic College of Medicine, Mayo Clinic Hospital, Scottsdale, Arizona.


De Lima L, Krakauer EL, Lorenz K, et al.: Ensuring palliative medicine availability: The development of the IAHPC list of essential medicines for palliative care. J Pain Symptom Manage. 2007; 33(5): 521-526.

World Health Organization: Essential medicines: Definition and concept Available at Accessed December 6, 2006.

De Lima L, Sweeney C, Palmer JL, et al.: Potent analgesics are more expensive for patients in developing countries. J Pain Palliative Care Pharmacother. 2004; 18(1): 59-70.

Cherny NI: The problem of suffering and the principles of assessment in palliative medicine. In Hanks G, Cherny NI, Christakis NA, Fallon M, Kaasa S, Portenoy RK (eds): Oxford Textbook of Palliative Medicine. 4th ed. Oxford: Oxford University Press, 2010; Section 3: 43-58.

Trescot AM, Datta S, Lee M, et al.: Opioid pharmacology. Pain Physician. 2008; 11(2 Suppl): S133-S153.

Roy SD, Flynn GL: Solubility and related physicochemical properties of narcotic analgesics. Pharm Res. 1988; 5(9): 580-586.

Gourlay GK: Advances in opioid pharmacology. Support Care Cancer. 2005; 13(3): 153-159.

Coller JK, Christrup LL, Somogyi AA: Role of active metabolites in the use of opioids. Eur J Clin Pharmacol. 2009; 65(2): 121-139.

Ebert B, Andersen S, Krogsgaard-Larsen P: Ketobemidone, methadone and pethidine are non-competitive N-methyl-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett. 1995; 187(3): 165-168.

Lötsch J: Opioid metabolites. J Pain Symptom Manage. 2005; 29(5, Suppl 1): 10-24.

Srinivasan V, Wielbo D, Simpkins J, et al.: Analgesic and immunomodulatory effects of codeine and codeine 6-glucuronide. Pharm Res. 1996; 13(2): 296-300.

Mikus G, Weiss J: Influence of CYP2D6 genetics on opioid kinetics, metabolism and response. Curr Pharmacogenomics. 2005; 3(1): 43-52.

Projean D, Morin PE, Tu TM, et al.: Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica. 2003; 33(8): 841-854.

Talbott GA, Lynn AM, Levy FH, et al.: Respiratory arrest precipitated by codeine in a child with chronic renal failure. Clin Pediatr. 1997; 36(3): 171-173.

Dean M: Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004; 28(5): 497-504.

Schiff L, Schiff ER: Diseases of the Liver. Philadelphia, PA: Lippincott, 1993.

Moore A, Collins S, Carroll D, et al.: Paracetamol with and without codeine in acute pain: A quantitative systematic review. Pain. 1997; 70(2-3): 193-201.

Minotti V, Patoia L, Roila F, et al.: Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam, and acetylsalicylic acid (ASA) plus codeine in chronic cancer pain. Pain. 1989; 36(2): 177-183.

Dhaliwal HS, Sloan P, Arkinstall WW, et al.: Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain. J Pain Symptom Manage. 1995; 10(8): 612-623.

Rodriguez RF, Castillo JM, Castillo MP, et al.: Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: A double-blind comparative trial. Clin J Pain. 2008; 24(1): 1-4.

Pistevou-Gompaki K, Kouloulias VE, Varveris C, et al.: Radiotherapy plus either transdermal fentanyl or paracetamol and codeine for painful bone metastases: A randomised study of pain relief and quality of life. Curr Med Res Opin. 2004; 20(2): 159-163.

Chua TP, Harrington D, Ponikowski P, et al.: Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol. 1997; 29(1): 147-152.

Johnson MA, Woodcock AA, Geddes DM: Dihydrocodeine for breathlessness in “pink puffers”. Br Med J. 1983; 286(6366): 675-677.

Woodcock AA, Gross ER, Gellert A, et al.: Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med. 1981; 305(27): 1611-1616.

Baldi F, Bianco MA, Nardone G, et al.: Focus on acute diarrhoeal disease. World J Gastroenterol. 2009; 15(27): 3341-3348.

Nwachukwu CE, Okebe JU: Antimotility agents for chronic diarrhoea in people with HIV/AIDS. Cochrane Database Syst Rev. 2008; (4): CD005644.

Freestone C, Eccles R: Assessment of the antitussive efficacy of codeine in cough associated with common cold. J Pharm Pharmacol. 1997; 49(10): 1045-1049.

Luporini G, Barni S, Marchi E, et al.: Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer. Eur Respir J. 1998; 12(1): 97-101.

Smith J, Owen E, Earis J, et al.: Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006; 117(4): 831-835.

Band CJ, Band PR, Deschamps M, et al.: Human pharmacokinetic study of immediate-release (codeine phosphate) and sustained-release (codeine Contin) codeine. J Clin Pharmacol. 1994; 34(9): 938-943.

Desmeules J, Gascon MP, Dayer P, et al.: Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol. 1991; 41(1): 23-26.

Poulsen L, Brøsen K, Arendt-Nielsen L, et al.: Codeine and morphine in extensive and poor metabolizers of sparteine: Pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol. 1996; 51(3): 289-295.

Codd EE, Shank RP, Schupsky JJ, et al.: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: Structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995; 274(3): 1263-1270.

Beaver WT, Wallenstein SL, Rogers A, et al.: Analgesic studies of codeine and oxycodone in patients with cancer. I. Comparisons of oral with intramuscular codeine and of oral with intramuscular oxycodone. J Pharmacol Exp Ther. 1978; 207(1): 92-100.

Beaver WT, Wallenstein SL, Rogers A, et al.: Analgesic studies of codeine and oxycodone in patients with cancer. II. Comparisons of intramuscular oxycodone with intramuscular morphine and codeine. J Pharmacol Exp Ther. 1978; 207(1): 101-108.

Fallon M, Cherny NI, Hanks G, et al.: Opioid Therapy. In Oxford Textbook of Palliative Medicine. 4th ed. Oxford: Oxford University Press, 2010; Section 10: 661-698. 37. Sevelius H, McCoy JF, Colmore JP: Dose response to codeine in patients with chronic cough. Clin Pharmacol Ther. 1971; 12(3): 449-455.

Estfan B, LeGrand S: Management of cough in advanced cancer. J Support Oncol. 2004; 2(6): 523-527.

Woodcock AA, Johnson MA, Geddes DM: Breathlessness, alcohol and opiates. N Engl J Med. 1982; 306(22): 1363-1364.



How to Cite

Prommer, MD, E. “Role of Codeine in Palliative Care”. Journal of Opioid Management, vol. 7, no. 4, July 2011,



Review Articles