AN ALTERNATIVE TO CODEINE AND HYDROCODONE

Management of Persistent Cough

By Dr. Gideon Koren, MD FRCPC

This newsletter provides a scientic update on antitussive narcotic opioids, focusing on the differences in their metabolic pathways, in the context of statements by Health Canada, the US Food and Drug Administration and the European Medicines Agency about serious and sometimes fatal toxicity of codeine. The safety and effectiveness of normethadone, an alternative narcotic option for the management of persistent non-productive cough which follows a different metabolic route is discussed.

LEARNING OBJECTIVES:
1. 2. 3. 4. Recognize toxicity of codeine and the limitations of its use Identify patient groups especially at risk for codeine toxicity Review the efcacy and risks of hydrocodone Review the indication for antitussive narcotics as a treatment for persistent non-productive cough  that is nonresponsive to non-opioid therapies 5. Provide evidence that normethadone is a safe alternative because of its different metabolic pathway
Persistent cough can be very distressing to patients and can accompany a variety of health conditions, including respiratory infections of the upper and lower airways, chronic obstructive pulmonary disease, asthma, lung cancer, lung metastases, interstitial pulmonary processes, and gastroesophageal reflux. It may also occur as an adverse effect of some medications such as ACE inhibitors and NSAIDs. When left untreated, persistent cough can lead to dyspnea, nausea and vomiting, sleep impairment, chest and throat pain, and impaired communication.1,2 Opioids are time tested and effective centrally-acting antitussive medications. However, due to a risk of dependency with long-term use, opioids are recommended only if other (non-opioid) antitussives are not helpful to a patient. Common adverse events with opioid medications (nausea, drowsiness and constipation) are generally manageable and tend to decrease over time.1,2 In Canada, antitussive opioid options include products containing either codeine, hydrocodone or normethadone (Table 1). morphine (up to 50% higher than among extensive metabolizers) which in turn may lead to potentially fatal respiratory depression requiring intubation.6 Caution is also advised for any patient at risk for respiratory depression. In response to the 2008 Health Canada and FDA warning, labels of codeine-containing prescription and non-prescription medications have been updated to reflect these risks. In Canada, codeine is no longer recommended for children under 12 years of age. Health professionals and consumers are advised to seek alternatives to codeine for management of both cough and pain. The European Medicines Agency issued a similar warning and implemented a series of risk-minimization measures to address safety concerns related to codeine.

CODEINE IS METABOLIZED TO MORPHINE BY CYP2D6 ENZYME

Codeine is a prodrug which, once ingested, is converted by the liver to morphine (active drug) through the cytochrome P450 enzyme CYP2D6 (Figure 1). There is substantial genetic variability in the levels of CYP2D6 activity between individuals. Some people carry allelic variants of the CYP2D6 gene associated with high levels of the CYP2D6 enzyme. These people convert codeine into morphine more rapidly and completely than others. The prevalence in Asian populations has not been determined, however up to 7% of Caucasians and 9-30% of Afro-Americans are ultrarapid codeine metabolizers. The only method of determining whether a patient is an ultra-rapid metabolizer is by genetic testing.7 Notably, some

CODEINE CAUSES SERIOUS SIDE EFFECTS

Over the past few years, governmental health agencies around the world have issued warnings about the incidence of serious adverse effects and several deaths among children and adults who are ultra-rapid metabolizers of codeine or who are breastfed by mothers using codeine.3,4,5 The antitussive effect of codeine is due to a direct suppression of brainstem respiratory centers by morphine, the major codeine metabolite. In ultra-rapid metabolizers of codeine, regular doses of codeine can produce excessively high levels of

TABLE 1. Antitussive Opioid Medications

Enzymes in Metabolic Pathway Antitussive Opioid Medications Codeine products
N

Active Compound Codeine products Hydrocodone bitartrate Hydrocodone bitartrate Controlled-release hydrocodone resin complex and phenytoloxamine resin complex Normethadone HCl and p-hydroxyephedrine HCl

CYP2D6

CYP3A4 and CYP2B6

Main Metabolite Morphine Hydromorphone Hydromorphone Hydromorphone Inactive Metabolites

Hycodan

PMS-hydrocodone
N

Tussionex Cophylac

Dr. Koren, MD FRCPC, is pediatrician and expert in paediatric pharmacology, perinatal toxicology and renal handling of drugs. He is the founder and Director of the Motherisk Program at The Hospital for Sick Children in Toronto. Dr. Koren is Professor of Pediatrics, Pharmacology, Pharmacy and Medical Genetics at the University of Toronto, and Professor of Medicine, Pediatrics, and Physiology-Pharmacology at the Schulich School of Medicine of the University of Western Ontario. Dr. Koren has trained paediatricians from more than 40 countries and published over 1,400 peerreviewed articles in the areas of paediatric pharmacology and maternal-fetal toxicology. He is the rst Canadian scientist to receive the Sumner Yaffe Lifetime Achievement Award, which is given in recognition of signicant and sustained contributions toward the improvement of childrens health through the expansion of the eld of paediatric pharmacology and therapeutics.
Sponsored by an unrestricted educational grant from Valeo Pharma Inc.

FIGURE 1. Primary Metabolic Pathways

codeine CYP2D6 (methylmorphine) CYP2D6 morphine M6G M3G HM3G active metabolites active metabolite inactive metabolites

non-productive cough which does not serve a therapeutic function and interferes with the patients quality of life. Before prescribing an antitussive opioid medication, it is important to identify the underlying cause of cough and to provide appropriate therapy for the primary condition, as well as to ensure that modification of the cough does not increase the risk of physical or psychological complications. In Canada, non-codeine antitussive opioid medications include:
N Hycodan syrup and tablets (hydrocodone bitartrate) are indicated for controlling exhausting, non-productive cough. It is believed to act by directly depressing the cough center.9 NHycodan is not recommended for pregnant women, nursing mothers, patients with chronic constipation and anyone operating a vehicle or machinery. While the product monograph (last revised in 2007) states that in children benefit to risk ratio of NHycodan should be carefully considered, in light of the recent safety concerns with ultra-rapid 2D6 metabolizers, it is best to avoid hydrocodone in children because hydromorphone is more active than morphine. PMS-hydrocodone is a generic version of NHycodan available in Canada. N Tussionex suspension and tablets (hydrocodone and phenytoloxamine) are indicated for the treatment of exhausting or nonproductive cough, associated with a cold or with upper respiratory allergic condition that do not respond to non-narcotic antitussives. It is effective for approximately 8 to 12 hours. Hydrocodone is believed to inhibit coughing by interfering with the central modulation of afferent signals, and thus decreasing sensitivity of the cough centre to incoming stimuli, while phenyltoloxamine acts as a competitive inhibitor of histamine. It has been found that antihistamines may potentiate the antitussive effects of hydrocodone.10 N Cophylac (normethadone HCl and p-hydroxyephedrine HCl) is indicated for the treatment of cough associated with inflamed mucosa, which does not respond to products of lesser potency. NCophylac is also a centrally-acting opioid shown effective in patients with acute and chronic bronchitis, pneumonia, myocarditis heart failure, pleuropulmonary cancer, pulmonary tuberculosis and laryngeal tracheitis, among other conditions. Its a twice daily option with fewer safety concerns than codeine- and hydrocodone-containing medications, because it does not have an active metabolite. The dosage must be evaluated and adjusted relative to the childs age and weight. Benefit to risk ratio must be considered in patients with respiratory embarrassment, such as croup, and those prone to respiratory depression. NCophylac is not recommended for pregnant women or patients with chronic constipation.11

hydrocodone

hydromorphone CYP3A4 CYP2B6

normethadone
M6G = morphine-6-glucuronide M3G = morphine-3-glucuronide HM3G = hydromorphone-3-glucuronide

patients with the genotype of extensive (normal) 2D6 metabolism also display a phenotype of ultra rapid metabolism with a similar risk of CNS depression from morphine. In addition to conversion by CYP2D6 to morphine, codeine is also metabolized by an unknown mechanism to produce hydrocodone in quantities reaching up to 11% of the codeine concentration found in urinalysis. The clinical effect of the hydrocodone metabolite of codeine is currently unknown.7 Alternatively, some individuals are slow metabolizers of codeine due to a different genetic variation in the levels of the CYP2D6 enzyme. This includes an estimated 5-10% of Caucasians and up to 34% of AfroAmericans. The prevalence of slow codeine clearance is less than 1% in Asian populations. Effectiveness of codeine is also reduced by medications that inhibit CYP2D6, such as quinidine.7

HYDROCODONE-CONTAINING OPIOIDS ARE METABOLIZED TO HYDROMORPHONE BY CYP2D6 ENZYME AND POSE SIMILAR CONCERNS
Three hydrocodone-containing antitussive opioid options are currently available in Canada (Table 1). Similar to codeine, hydrocodone (a semisynthetic opioid) is also metabolized by the CYP2D6 enzyme but to the active metabolite hydromorphone rather than morphine (Figure 1).7 Hydromorphone is 5-10 times more potent than morphine.8 This represents a potential additional concern for ultra-rapid metabolizers because the same adverse reactions to hydromorphone that are observed with morphine may very well be presented. There is some evidence of excessive toxicity from hydrocodone in ultra-rapid metabolizers but more data is required to determine the extent.

CONCLUSION
Opioids are the gold standard for managing persistent, non-productive cough when other antitussive therapies are ineffective. The goal of cough suppression is to alleviate suffering and to prevent adverse effects due to exhausting cough. Before using opioids, the underlying cause of the cough must be evaluated and treated, as well the coughs potential therapeutic value should be considered. Until further research is conducted on the safety of codeine and hydrocodone, physicians should be aware of the potential for serious harm that these substances may induce in their patients. For patients who are candidates for codeine, normethadone should be considered. Normethadone is an antitussive opioid that provides rapid and effective relief of cough. It is suitable for all ages, including children under 12, because it does not undergo the same metabolic conversion as codeine and hydrocodone. No genetic variations have been reported in the normethadone metabolic pathway. Hence, NCophylac (normethadone-containing antitussive available in Canada) offers a safe alternative to codeine and hydrocodone based treatments.
N N N

NORMETHADONE IS METABOLIZED TO NON-ACTIVE METABOLITES BY DIFFERENT PATHWAYS CYP3A4 AND CYP2B6 ENZYMES
Normethadone, a synthetic opioid, is not metabolized by CYP2D6 and thus its pharmacological activity is unaffected by CYP2D6 levels (Figure 1). Normethadone is metabolized primarily by CYP3A4 and CYP2B6 enzymes which do not appear to have genetic variabilities similar to CYP2D6.7 Ultra-rapid metabolizers of normethadone have not been reported. Also, once metabolized, normethadone yields inactive metabolites. Hence, normethadone does not present similar safety concerns as codeine or hydrocodone and is not contraindicated for patients who are ultra-rapid metabolizers of codeine.

NON-CODEINE ANTITUSSIVE OPIOID MEDICATIONS

Opioid antitussives are effective for patients diagnosed with persistent,

COPHYLAC is a registered trade-mark of Valeo Pharma Inc. HYCODAN is a registered trade-mark of Bristol-Myers Squibb Pharma Company. TUSSIONEX is a registered trade-mark of Aventis Pharma Inc.

REFERENCES:
1. De Blasio et al. Cough 2011;7:7. 2.  Diagnosis and Management of Cough: ACCP Evidence-Based Clinical Practice Guidelines. Chest 2006;129. 3.  Health Canadas review recommends codeine only be used in patients aged 12 and over. healthycanadians.gc.ca. 4.  FDA safety announcement. 2-20-2013. Safety review update of codeine use in children.

5.  EU places restrictions on use of codeine in children. Medscape Medial News, June 28, 2013. 6. Gasche et al. NEJM 2004;351:282731. 7. Smith. Mayo Clin Proc 2009;84:613-24. 8. Felden et al. Br J Anaesth 2011;107:319-28. 9. NHycodan product monograph. 10. NTussionex product monograph. 11. NCophylac product monograph.