Journal of Pain & Palliative Care Pharmacotherapy. 2014;Early Online:1–4. Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2014.938888
COMMENTARY
To Prescribe Codeine or Not to Prescribe Codeine? J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Marc L. Fleming and Matthew A. Wanat A B STRA CT A recently published study in Pediatrics by Kaiser et al. (2014; Epub April 21, DOI: 10.1542/peds.2013-3171) reported that on average, over the past decade, children aged 3 to 17 were prescribed approximately 700,000 prescriptions for codeine-containing products each year in association with emergency department (ED) visits. Although, guidelines from the American Academy of Pediatrics issued warnings in 1997 and reaffirmed their concerns regarding the safety and effectiveness of codeine in 2006, it is still often prescribed for pain and cough associated with upper respiratory infection. With the impending rescheduling of hydrocodone combination products to Schedule II, physicians and mid-level prescribers may be compelled to prescribe codeine-containing products (e.g., with acetaminophen) due to reduced administrative burden and limits on Schedule II prescriptive authority for nurse practitioners and physician assistants in some states. This commentary expounds on the safety and effectiveness concerns of codeine, with a primary focus on patients in the ED setting. KEYWORDS codeine, emergency department, hydrocodone, pain management, Schedule, safety
Pain is a frequent chief complaint of patients seeking care in hospital and health system emergency departments.1,2 Following the US Food and Drug Administration’s decision3 to recommend rescheduling of hydrocodone combination products (e.g., Vicodin, Lortab, Norco) to Schedule II, one must ponder the potential scenarios that may follow regarding pain management. One such scenario could involve an increase in codeine combination (e.g., Tylenol #3) prescriptions for pain management, since administratively it would then be less burdensome for most prescribers.4 That is especially true in jurisdictions that prohibit mid-level practitioners, such as physician assistants, from prescribing Schedule II medications, and where it is deemed necessary to treat with an opioid.
The past decade has been characterized by a great increase in the number of opioid prescriptions related to emergency department (ED) visits.5 The percentage of patients for whom emergency physicians prescribed opioids such as hydrocodone, morphine, and oxycodone increased from 20.8% in 2001 to 31.0% in 2010.5 However, prescriptions for codeine experienced a decline in the past decade related to ED visits. Similarly, retrospective data analysis of the Automation of Reports and Consolidated Orders System (ARCOS) showed an increase in opioids for medical use from 2004 to 2011, whereas codeine use decreased by 20%.6 Interestingly, data from the federal Drug Abuse Warning Network (DAWN) shows that abuse of codeine increased 39% during this time, from 7716 episodes in 2004 to 9,927 in 2011.6 Based on these data, prescribers must carefully consider whether utilizing codeine in the treatment of ED patients will mitigate opioid abuse in a meaningful way. This commentary outlines some of the issues with codeine products following a recently published study, “National Patterns of Codeine Prescriptions for Children in the Emergency Department,” which highlighted continued use of codeine in pediatric patients despite concerns of safety and effectiveness in the ED setting.7 Due to the uncertainty of pharmacological action of codeine, in 2012 the World
Marc L. Fleming, PhD, MPH, RPh, is an assistant professor, Department of Pharmaceutical Health Outcomes & Policy, University of Houston College of Pharmacy, Houston, Texas, USA. Matthew Wanat, PharmD, BCPS, is a clinical assistant professor, Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA; and Clinical Pharmacy Specialist—Cardiology/Critical Care at the Michael E. DeBakey VA Medical Center, Houston, Texas, USA. Address correspondence to: Marc Fleming, PhD, Department of Pharmaceutical Health Outcomes & Policy, College of Pharmacy, University of Houston, Texas Medical Center Campus, 1441 Moursund Street, Room 437, Houston, TX 77030-3407, USA (E-mail: [email protected]).
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J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Health Organization (WHO) excluded codeine from its list of recommended medications for pain management, yet it is still readily prescribed in the United States. Some clinicians may view codeine with acetaminophen as a suitable substitute in the event that hydrocodone products become reclassified to Schedule II. Some issues that prescribers should consider regarding codeine will be subsequently addressed.
PHARMACOKINETICS AND SIDE EFFECTS Codeine is an oral mu-opioid receptor agonist used in the treatment of mild to moderate pain. Codeine has a very similar chemical structure to morphine; however, codeine has approximately 200 times less affinity for the mu-opioid receptor than morphine.8,9 Codeine is absorbed via the gastrointestinal tract and has an onset of action of 30 minutes, with peak effects seen within 60 to 90 minutes of ingestion. No changes in the effects of codeine have been reported when taken concurrently with food.8 Metabolism of codeine is complex and occurs via several different pathways, although the primary pathway determining efficacy of the medication is widely debated. Approximately 5–10% of codeine is metabolized via O-demethylation by the hepatic microsomal enzyme cytochrome P450 2D6 (CYP2D6) to morphine, which is then further metabolized to morphine-3-glucuronide and morphine6-glucuronide. Of these metabolites, morphine-6glucuronide possesses analgesic properties and is thought to provide the analgesic effects of codeine. About 10–15% of codeine is metabolized hepatically via CYP3A4 to an inactive metabolite norcodeine, and the remaining 70–80% is directly glucuronidated by UDP-glucuronosyltransferase 2B7 (UGT2B7) to codeine-6-glucoronide (C6G). It is unknown if C6G possesses any analgesic properties, but some prior literature has postulated C6G is the more likely metabolite to possess analgesic activity due to the very small conversion of codeine to morphine.10–12 The complex metabolism of codeine via several pathways and resulting metabolites formed make therapy with codeine unpredictable.13 Drug metabolism via the enzyme CYP2D6 is variable in patients, and changes based on their genetic profile, ethnicity, and polymorphisms. An estimated 8–23% of patients worldwide are classified as ultrarapid, intermediate, or poor metabolizers of CYP2D6, which can result in supratherapeutic or subtherapeutic effects from codeine.14 According to the Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and
Codeine Therapy: 2014 Update, ultrarapid metabolizers (1–2%) are not recommended to be prescribed codeine based on the potential for toxicity secondary to increased levels of the active metabolite of morphine. The incidence of ultrarapid metabolizers varies widely among different ethnicities, with an estimated prevalence rate of 0.5–1% in Chinese and Japanese patients, 1–10% in Caucasians, and 16–28% in North African, Ethiopian, and Arab patients. The guidelines also recommend avoiding codeine due to a lack of efficacy in poor metabolizers (5–10% of patients) and using with caution in intermediate metabolizers (2–11% of patients). This means up to 23% of patients may not be appropriate for therapy with codeine and presents a challenge when starting patients on codeine, because genetic testing for CYP2D6 is costly, not widely available, and may not be practical for a short course of pain therapy. The Food and Drug Administration (FDA) does not recommend routine genetic testing for CYP2D6 genotypes because patients with normal metabolism can still convert codeine to morphine at the same rate as ultrarapid metabolizers.15 Several studies have attempted to confirm whether CYP2D6 and the morphine metabolite are responsible for codeine’s analgesic activity.11,12 In a prospective study of 81 postoperative patients who received codeine, Poulsen and colleagues found undetectable levels of morphine in patients with both poor 2D6 metabolism and patients with normal 2D6 metabolism.12 Furthermore, patient pain levels were similar in patients with high levels of M6G and undetectable levels of M6G. More research is needed studying the effects of CYP2D6 and the other major metabolite of codeine, C6G. Although case reports and clinical studies have been published regarding the pharmacodynamics of codeine in children, it has remained a commonly prescribed pain medication throughout the years.7,16–18 However, in February 2013 the Food and Drug Administration (FDA) added a Boxed Warning to codeine for its use in pain management in children following tonsillectomy and/or adenoidectomy.15 Use of codeine is contraindicated in this patient population based on a comprehensive review of adverse events reported to the FDA. Thirteen cases were identified in the FDA database from 1969 to 2012 in which pediatric patients died as a result of codeine ingestion, with several of the children being classified as ultrarapid or extensive metabolizers. The FDA now recommends that codeine only be prescribed as an analgesic when the perceived benefits outweigh the risks, and at the lowest dose for the shortest duration necessary. Nursing mothers taking codeine should also closely monitor their infants for respiratory Journal of Pain & Palliative Care Pharmacotherapy
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Commentary
depression, or avoid codeine use if possible, because the drug and its metabolites are excreted in breast milk.14 Codeine shares a similar effect profile to other opioid receptor agonists, with a few variations. Although tolerance to codeine can occur within a few days, patients may experience side effects from codeine immediately in a dose-dependent fashion. Common side effects of codeine include nausea, constipation, diarrhea, respiratory depression, abdominal pain, myoclonus, urinary retention, sedation, confusion, and pruritus. Respiratory depression is dose dependent and can be potentiated in patients who are extensive CYP2D6 metabolizers, the elderly, children, and patients with airway obstruction such as obstructive sleep apnea or chronic obstructive pulmonary disease. Nausea is a common side effect of codeine and generally subsides over time. Codeine also exhibits a higher rate of constipation at equianalgesic doses compared with other opioid analgesics. Patients may also experience significant pruritus with codeine due to its conversion to morphine and subsequent histamine release.
CODEINE EFFECTIVENESS In June 2013, the Medicines and Healthcare Products Regulatory Agency (MHRA), which is the United Kingdom equivalent of the FDA, adopted guidelines that advise against prescribing codeine for any patient under the age of 12 years. However, some physicians still view codeine as being a safer drug than morphine,19 as evidenced by the 1.7 million prescriptions dispensed for pediatric patients (under age 17) from outpatient pharmacies in the United States for codeine-containing medications in 2011. These statistics indicate that a comfort level exists among physicians regarding the safety and effectiveness of codeine. Palangio et al. conducted a study comparing hydrocodone 7.5 mg plus ibuprofen 200 mg versus combination codeine 30 mg plus acetaminophen 300 mg (two tablets), which showed that two tablets of hydrocodone 7.5 mg plus ibuprofen 200 mg was more effective in pain management than two tablets of codeine 30 mg plus acetaminophen 300 mg.20 Furthermore, one tablet of hydrocodone 7.5 mg plus ibuprofen 200 mg was equally as effective as two tablets of codeine 30 mg plus acetaminophen 300 mg, and more patients in the codeine group discontinued treatment due to adverse events. In a randomized controlled trial (RCT) of pediatric ED patients aged 6 to 17 who presented with acute musculoskeletal pain, patients receiving ibuprofen reported significantly C
2014 Informa Healthcare USA, Inc.
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greater improvement in pain compared with those receiving codeine.21 Similarly, another double-blind RCT among pediatric patients with fracture pain reported that ibuprofen was shown to have similar effectiveness to acetaminophen with codeine across a median of four doses.22 However, more patients in the acetaminophen with codeine group reported a significant higher proportion of adverse events. A recently published prospective, double-blind RCT compared codeine 30 mg/acetaminophen 300 mg with hydrocodone 5 mg/acetaminophen 500 mg, in patients discharged from the ED.23 Pain was measured using a verbal numerical rating scale (NRS) from 0 to 10, with 0 representing no pain and 10, pain as bad as the patient could imagine. Patients were given a 3-day supply and contacted about their pain 2 hours after ingesting their most recent dose. The NRS pain intensity reports were lowered by half in each treatment group, with no significant difference between the two groups observed. The authors concluded that codeine plus acetaminophen may be a valid substitute for hydrocodone plus acetaminophen in ED patients upon discharge, in the event that the latter is reclassified to Schedule II. It should be noted that this study was conducted in adult patients, and no recommendations for treating pediatric ED patients were suggested. More importantly, the results of this study may not be generalizable because the study population was comprised almost exclusively of Hispanic and African American patients. Considering that up to 7% of Caucasians receive no benefit from codeine due to poor conversion of codeine to morphine, this lack of representation in this study may have led to a biased conclusion.24
CONCLUSION The FDA has made it very clear by issue of a Boxed Warning that codeine should be avoided in children following tonsillectomy and/or adenoidectomy. Furthermore, the MHRA guidelines recommend avoiding codeine in patients under the age of 12. Also, codeine should be avoided in breastfeeding mothers. Considering factors such as variable effectiveness of codeine based on pharmacogenomics and a poorly understood pharmacokinetics profile, it may be prudent to consider other options for pain management in the ED setting. Prescriber education and pharmacovigilance regarding codeine will become even more critical if hydrocodone products are rescheduled. If in fact rescheduling occurs, all health care providers and ED prescribers must be aware of issues related to codeine. Furthermore, the medical community should be cognizant of
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these concerns, thereby ensuring that codeine does not become an “easy substitute” for hydrocodone combination products when opioids are required for adequate pain management. Moving forward, more definitive studies are needed to assess the safety and effectiveness of other pain treatment options (e.g., tramadol) for patients seeking care in the ED setting.
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
[12]
[13]
[14]
[15]
REFERENCES [1] Pletcher MJ, Kertesz SG, Kohn MA, Gonzales R. Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008;299:70–78. [2] Cordell WH, Keene KK, Giles BK, Jones JB, Jones JH, Brizendine EJ. The high prevalence of pain in emergency medical care. Am J Emerg Med. 2002;20:165–169. [3] Traynor K. FDA advisers support rescheduling of hydrocodone products. Am J Health Syst Pharm. 2013;70:383–384. [4] American Academy of Pain Medicine. American Academy of Pain Medicine comments on rescheduling hydrocodone: patient and public health considerations. Available at: http://www.painmed.org/press/position-statements./ Published 2013. Accessed March 5, 2014. [5] Mazer-Amirshahi M, Mullins PM, Rasooly I, van den Anker J, Pines JM. Rising opioid prescribing in adult U.S. emergency department visits: 2001–2010. Acad Emerg Med. 2014;21:236–243. [6] Atluri S, Sudarshan G, Manchikanti L. Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011. Pain Physician. 2014;17:E119–E128. [7] Kaiser SV, Asteria-Penaloza R, Vittinghoff E, Rosenbluth G, Cabana MD, Bardach NS. National Patterns of codeine prescriptions for children in the emergency department. Pediatrics. 2014, Epub April 21, DOI: 10.1542/peds.2013-3171. R [8] Roxane Laboratories Inc. Codeine Sulfate [package insert]. Columbus, OH: Roxane Laboratories Inc. [9] Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59:385–390. [10] Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. Psychosomatics. 2003;44:515–520. [11] Persson K, Sjostrom S, Sigurdardottir I, Molnar V, Hammarlund-Udenaes M, Rane A. Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive
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[17]
[18]
[19] [20]
[21]
[22]
[23]
[24]
metabolisers and one poor metaboliser of dextromethorphan. Br J Clin Pharmacol. 1995;39:182–186. Poulsen L, Riishede L, Brosen K, Clemensen S, Sindrup SH. Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol. 1998;54:451–454. Racoosin JA, Roberson DW, Pacanowski MA, Nielsen DR. New evidence about an old drug—risk with codeine after adenotonsillectomy. N Engl J Med. 2013;368:2155–2157. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95:376–382. US Food and Drug Administration. FDA Drug Safety Communication: safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. Available at: http://www. fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf. Published 2013. Accessed May 20, 2014. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361:827–828. Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129:e1343–e1347. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant—an ultra-rapid metabolizer. Paediatr Anaesth. 2007;17:684–687. Wynn-Jones W, Casely E, Laycock H, Bantel C. Codeine: the ‘safe’ analgesic? Br J Anaesth. 2013;110:843–844. Palangio M, Damask MJ, Morris E, et al. Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain. Clin Ther. 2000;22:879–892. Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007;119:460–467. Drendel AL, Gorelick MH, Weisman SJ, Lyon R, Brousseau DC, Kim MK. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain. Ann Emerg Med. 2009;54:553–560. Chang AK, Bijur PE, Munjal KG, John Gallagher E. Randomized clinical trial of hydrocodone/acetaminophen versus codeine/acetaminophen in the treatment of acute extremity pain after emergency department discharge. Acad Emerg Med. 2014;21:227–235. Carter B, Hawcutt DB, Arnott J. The restrictions to the use of codeine and dilemmas about safe alternatives. J Child Health Care. 2013;17:335–337.
RECEIVED: 28 May 2014 ACCEPTED: 20 June 2014
Journal of Pain & Palliative Care Pharmacotherapy
COMMENTARY
To Prescribe Codeine or Not to Prescribe Codeine? J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Marc L. Fleming and Matthew A. Wanat A B STRA CT A recently published study in Pediatrics by Kaiser et al. (2014; Epub April 21, DOI: 10.1542/peds.2013-3171) reported that on average, over the past decade, children aged 3 to 17 were prescribed approximately 700,000 prescriptions for codeine-containing products each year in association with emergency department (ED) visits. Although, guidelines from the American Academy of Pediatrics issued warnings in 1997 and reaffirmed their concerns regarding the safety and effectiveness of codeine in 2006, it is still often prescribed for pain and cough associated with upper respiratory infection. With the impending rescheduling of hydrocodone combination products to Schedule II, physicians and mid-level prescribers may be compelled to prescribe codeine-containing products (e.g., with acetaminophen) due to reduced administrative burden and limits on Schedule II prescriptive authority for nurse practitioners and physician assistants in some states. This commentary expounds on the safety and effectiveness concerns of codeine, with a primary focus on patients in the ED setting. KEYWORDS codeine, emergency department, hydrocodone, pain management, Schedule, safety
Pain is a frequent chief complaint of patients seeking care in hospital and health system emergency departments.1,2 Following the US Food and Drug Administration’s decision3 to recommend rescheduling of hydrocodone combination products (e.g., Vicodin, Lortab, Norco) to Schedule II, one must ponder the potential scenarios that may follow regarding pain management. One such scenario could involve an increase in codeine combination (e.g., Tylenol #3) prescriptions for pain management, since administratively it would then be less burdensome for most prescribers.4 That is especially true in jurisdictions that prohibit mid-level practitioners, such as physician assistants, from prescribing Schedule II medications, and where it is deemed necessary to treat with an opioid.
The past decade has been characterized by a great increase in the number of opioid prescriptions related to emergency department (ED) visits.5 The percentage of patients for whom emergency physicians prescribed opioids such as hydrocodone, morphine, and oxycodone increased from 20.8% in 2001 to 31.0% in 2010.5 However, prescriptions for codeine experienced a decline in the past decade related to ED visits. Similarly, retrospective data analysis of the Automation of Reports and Consolidated Orders System (ARCOS) showed an increase in opioids for medical use from 2004 to 2011, whereas codeine use decreased by 20%.6 Interestingly, data from the federal Drug Abuse Warning Network (DAWN) shows that abuse of codeine increased 39% during this time, from 7716 episodes in 2004 to 9,927 in 2011.6 Based on these data, prescribers must carefully consider whether utilizing codeine in the treatment of ED patients will mitigate opioid abuse in a meaningful way. This commentary outlines some of the issues with codeine products following a recently published study, “National Patterns of Codeine Prescriptions for Children in the Emergency Department,” which highlighted continued use of codeine in pediatric patients despite concerns of safety and effectiveness in the ED setting.7 Due to the uncertainty of pharmacological action of codeine, in 2012 the World
Marc L. Fleming, PhD, MPH, RPh, is an assistant professor, Department of Pharmaceutical Health Outcomes & Policy, University of Houston College of Pharmacy, Houston, Texas, USA. Matthew Wanat, PharmD, BCPS, is a clinical assistant professor, Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA; and Clinical Pharmacy Specialist—Cardiology/Critical Care at the Michael E. DeBakey VA Medical Center, Houston, Texas, USA. Address correspondence to: Marc Fleming, PhD, Department of Pharmaceutical Health Outcomes & Policy, College of Pharmacy, University of Houston, Texas Medical Center Campus, 1441 Moursund Street, Room 437, Houston, TX 77030-3407, USA (E-mail: [email protected]).
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J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Health Organization (WHO) excluded codeine from its list of recommended medications for pain management, yet it is still readily prescribed in the United States. Some clinicians may view codeine with acetaminophen as a suitable substitute in the event that hydrocodone products become reclassified to Schedule II. Some issues that prescribers should consider regarding codeine will be subsequently addressed.
PHARMACOKINETICS AND SIDE EFFECTS Codeine is an oral mu-opioid receptor agonist used in the treatment of mild to moderate pain. Codeine has a very similar chemical structure to morphine; however, codeine has approximately 200 times less affinity for the mu-opioid receptor than morphine.8,9 Codeine is absorbed via the gastrointestinal tract and has an onset of action of 30 minutes, with peak effects seen within 60 to 90 minutes of ingestion. No changes in the effects of codeine have been reported when taken concurrently with food.8 Metabolism of codeine is complex and occurs via several different pathways, although the primary pathway determining efficacy of the medication is widely debated. Approximately 5–10% of codeine is metabolized via O-demethylation by the hepatic microsomal enzyme cytochrome P450 2D6 (CYP2D6) to morphine, which is then further metabolized to morphine-3-glucuronide and morphine6-glucuronide. Of these metabolites, morphine-6glucuronide possesses analgesic properties and is thought to provide the analgesic effects of codeine. About 10–15% of codeine is metabolized hepatically via CYP3A4 to an inactive metabolite norcodeine, and the remaining 70–80% is directly glucuronidated by UDP-glucuronosyltransferase 2B7 (UGT2B7) to codeine-6-glucoronide (C6G). It is unknown if C6G possesses any analgesic properties, but some prior literature has postulated C6G is the more likely metabolite to possess analgesic activity due to the very small conversion of codeine to morphine.10–12 The complex metabolism of codeine via several pathways and resulting metabolites formed make therapy with codeine unpredictable.13 Drug metabolism via the enzyme CYP2D6 is variable in patients, and changes based on their genetic profile, ethnicity, and polymorphisms. An estimated 8–23% of patients worldwide are classified as ultrarapid, intermediate, or poor metabolizers of CYP2D6, which can result in supratherapeutic or subtherapeutic effects from codeine.14 According to the Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and
Codeine Therapy: 2014 Update, ultrarapid metabolizers (1–2%) are not recommended to be prescribed codeine based on the potential for toxicity secondary to increased levels of the active metabolite of morphine. The incidence of ultrarapid metabolizers varies widely among different ethnicities, with an estimated prevalence rate of 0.5–1% in Chinese and Japanese patients, 1–10% in Caucasians, and 16–28% in North African, Ethiopian, and Arab patients. The guidelines also recommend avoiding codeine due to a lack of efficacy in poor metabolizers (5–10% of patients) and using with caution in intermediate metabolizers (2–11% of patients). This means up to 23% of patients may not be appropriate for therapy with codeine and presents a challenge when starting patients on codeine, because genetic testing for CYP2D6 is costly, not widely available, and may not be practical for a short course of pain therapy. The Food and Drug Administration (FDA) does not recommend routine genetic testing for CYP2D6 genotypes because patients with normal metabolism can still convert codeine to morphine at the same rate as ultrarapid metabolizers.15 Several studies have attempted to confirm whether CYP2D6 and the morphine metabolite are responsible for codeine’s analgesic activity.11,12 In a prospective study of 81 postoperative patients who received codeine, Poulsen and colleagues found undetectable levels of morphine in patients with both poor 2D6 metabolism and patients with normal 2D6 metabolism.12 Furthermore, patient pain levels were similar in patients with high levels of M6G and undetectable levels of M6G. More research is needed studying the effects of CYP2D6 and the other major metabolite of codeine, C6G. Although case reports and clinical studies have been published regarding the pharmacodynamics of codeine in children, it has remained a commonly prescribed pain medication throughout the years.7,16–18 However, in February 2013 the Food and Drug Administration (FDA) added a Boxed Warning to codeine for its use in pain management in children following tonsillectomy and/or adenoidectomy.15 Use of codeine is contraindicated in this patient population based on a comprehensive review of adverse events reported to the FDA. Thirteen cases were identified in the FDA database from 1969 to 2012 in which pediatric patients died as a result of codeine ingestion, with several of the children being classified as ultrarapid or extensive metabolizers. The FDA now recommends that codeine only be prescribed as an analgesic when the perceived benefits outweigh the risks, and at the lowest dose for the shortest duration necessary. Nursing mothers taking codeine should also closely monitor their infants for respiratory Journal of Pain & Palliative Care Pharmacotherapy
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Commentary
depression, or avoid codeine use if possible, because the drug and its metabolites are excreted in breast milk.14 Codeine shares a similar effect profile to other opioid receptor agonists, with a few variations. Although tolerance to codeine can occur within a few days, patients may experience side effects from codeine immediately in a dose-dependent fashion. Common side effects of codeine include nausea, constipation, diarrhea, respiratory depression, abdominal pain, myoclonus, urinary retention, sedation, confusion, and pruritus. Respiratory depression is dose dependent and can be potentiated in patients who are extensive CYP2D6 metabolizers, the elderly, children, and patients with airway obstruction such as obstructive sleep apnea or chronic obstructive pulmonary disease. Nausea is a common side effect of codeine and generally subsides over time. Codeine also exhibits a higher rate of constipation at equianalgesic doses compared with other opioid analgesics. Patients may also experience significant pruritus with codeine due to its conversion to morphine and subsequent histamine release.
CODEINE EFFECTIVENESS In June 2013, the Medicines and Healthcare Products Regulatory Agency (MHRA), which is the United Kingdom equivalent of the FDA, adopted guidelines that advise against prescribing codeine for any patient under the age of 12 years. However, some physicians still view codeine as being a safer drug than morphine,19 as evidenced by the 1.7 million prescriptions dispensed for pediatric patients (under age 17) from outpatient pharmacies in the United States for codeine-containing medications in 2011. These statistics indicate that a comfort level exists among physicians regarding the safety and effectiveness of codeine. Palangio et al. conducted a study comparing hydrocodone 7.5 mg plus ibuprofen 200 mg versus combination codeine 30 mg plus acetaminophen 300 mg (two tablets), which showed that two tablets of hydrocodone 7.5 mg plus ibuprofen 200 mg was more effective in pain management than two tablets of codeine 30 mg plus acetaminophen 300 mg.20 Furthermore, one tablet of hydrocodone 7.5 mg plus ibuprofen 200 mg was equally as effective as two tablets of codeine 30 mg plus acetaminophen 300 mg, and more patients in the codeine group discontinued treatment due to adverse events. In a randomized controlled trial (RCT) of pediatric ED patients aged 6 to 17 who presented with acute musculoskeletal pain, patients receiving ibuprofen reported significantly C
2014 Informa Healthcare USA, Inc.
3
greater improvement in pain compared with those receiving codeine.21 Similarly, another double-blind RCT among pediatric patients with fracture pain reported that ibuprofen was shown to have similar effectiveness to acetaminophen with codeine across a median of four doses.22 However, more patients in the acetaminophen with codeine group reported a significant higher proportion of adverse events. A recently published prospective, double-blind RCT compared codeine 30 mg/acetaminophen 300 mg with hydrocodone 5 mg/acetaminophen 500 mg, in patients discharged from the ED.23 Pain was measured using a verbal numerical rating scale (NRS) from 0 to 10, with 0 representing no pain and 10, pain as bad as the patient could imagine. Patients were given a 3-day supply and contacted about their pain 2 hours after ingesting their most recent dose. The NRS pain intensity reports were lowered by half in each treatment group, with no significant difference between the two groups observed. The authors concluded that codeine plus acetaminophen may be a valid substitute for hydrocodone plus acetaminophen in ED patients upon discharge, in the event that the latter is reclassified to Schedule II. It should be noted that this study was conducted in adult patients, and no recommendations for treating pediatric ED patients were suggested. More importantly, the results of this study may not be generalizable because the study population was comprised almost exclusively of Hispanic and African American patients. Considering that up to 7% of Caucasians receive no benefit from codeine due to poor conversion of codeine to morphine, this lack of representation in this study may have led to a biased conclusion.24
CONCLUSION The FDA has made it very clear by issue of a Boxed Warning that codeine should be avoided in children following tonsillectomy and/or adenoidectomy. Furthermore, the MHRA guidelines recommend avoiding codeine in patients under the age of 12. Also, codeine should be avoided in breastfeeding mothers. Considering factors such as variable effectiveness of codeine based on pharmacogenomics and a poorly understood pharmacokinetics profile, it may be prudent to consider other options for pain management in the ED setting. Prescriber education and pharmacovigilance regarding codeine will become even more critical if hydrocodone products are rescheduled. If in fact rescheduling occurs, all health care providers and ED prescribers must be aware of issues related to codeine. Furthermore, the medical community should be cognizant of
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these concerns, thereby ensuring that codeine does not become an “easy substitute” for hydrocodone combination products when opioids are required for adequate pain management. Moving forward, more definitive studies are needed to assess the safety and effectiveness of other pain treatment options (e.g., tramadol) for patients seeking care in the ED setting.
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Penn State Berks Campus on 08/11/14 For personal use only.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
[12]
[13]
[14]
[15]
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RECEIVED: 28 May 2014 ACCEPTED: 20 June 2014
Journal of Pain & Palliative Care Pharmacotherapy
