Pro–con debate: is codeine a drug that still has a useful role in pediatric practice?

Codeine is a drug that remains in world-wide clinical usage despite the availability of other opioids that are far better understood in terms of pharmacodynamics, pharmacokinetics, and side effects. Its continuing usage in clinical practice highlights a paradoxical inconsistency in the prescribing habits of codeine in the pediatric and pediatric anesthetic world. On one hand, codeine has been used extensively for many years as step-down drug from controlled opioids such as morphine, and as such continues to be regarded as ‘safe and effective’ by physicians and the general public. In most countries, it can be bought by the general public without a doctor’s prescription, which represents a tacit endorsement of its reliability. On the other hand, there is a body of evidence indicating highly variable unpredictable analgesia and side effects compared to other agents, with potential extremes of response varying from lack of effect to life-threatening complications. At the heart of the debate is the question of what are the active components of codeine and its metabolites. If codeine was being developed currently, a significant amount of new scientific clinical data would be required before it would become licensed. In trying to come to a balanced view, it is useful to try to look at both sides of the argument: from that of an experienced clinician who uses the drug regularly and from a clinical pharmacologist who can put the evidence from this stance into context. Codeine is commonly used to provide postoperative pain relief in children. It is listed by the World Health Organization (1) as the second step on the analgesic ladder for the treatment of cancer pain. It is added in if simple oral analgesics [Step 1 – paracetamol and nonsteroidal anti-inflammatory agents (NSAIDs)] have been inadequate, and before introducing potent opioids (Step 3). Its role in postoperative pain in children is very similar. It is given for postoperative analgesia after many common children’s operations as part of a multimodal approach, when paracetamol and NSAIDs are insufficient to control pain. In addition, with the extension of day-stay surgery and reduced in-patient stay, this opioid is particularly useful in providing analgesia as part of an analgesic cocktail following discharge home. Codeine is an effective analgesic for moderately severe pain available for easy oral administration both in hospital and at home. It is available in a formulation (syrup) which is easy to give by both nurses and parents and is easy to prescribe in that it is not regarded as a controlled substance. The effective dose has been established by long-term clinical usage and is easy to remember It should not be the drug of choice for acute severe pain (e.g: postcraniotomy) where morphine remains the drug of choice, but can be used effectively for moderate pain. Specific problems in a minority of patients (newborns) should not prohibit its use for the majority. No safer, fully investigated, more effective oral agents for moderate pain exist. Recent work suggests we are still struggling to provide effective pain relief for many children after surgery. A recent snap shot study of the level of pain experienced by hospitalized children in the Hospital for Sick Children, Toronto showed 64% of children had experienced moderate or severe pain in the 24 h before interview, with 23% in significant pain actually at the time of interview (2). There are no snap shot studies showing the typical levels of pain experienced by surgical children after discharge home. As pediatric anesthetists, we have a moral and ethical duty to provide effective pain relief for children after surgery, but in general, the available analgesic options have not changed significantly in the last decade. These include potent opioid analgesia such as morphine, weak opioids such as codeine, nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and local anesthetics. Both ketamine and clonidine have uses in specific situations endorsed by enthusiastic individuals, but they have failed to enter the mainstream of commonly used analgesic agents. With our limited armamentarium, it is crucially important that in our quest for scientific evidence-based purity, we do not discard a useful, safe, and effective agent when more current strategies are still struggling to provide reliable pain relief to our pediatric population. Codeine has been used for many years as an analgesic, but remains controversial. A recent study concluded that ‘The myth that codeine is a potent and efficacious analgesic must be exposed so that clinicians make more rational choices when managing and treating pain (3).’ Similarly, Williams and colleagues, in a review of codeine in paediatric medicine, concluded that ‘The popularity of codeine in children is not supported by convincing data of its efficacy or suitability, despite its apparent good safety record (4).’ If it is clearly so inappropriate to continue using agents that are ineffective, then why is codeine still being used? From the perspective of the practicing clinical anesthetist, there are three important questions to consider: Is codeine an effective analgesic? Is it safe? Are there better alternatives? In answering these questions, the underlying pharmacokinetics is relevant, but only in so far as it helps us to answer these questions. In the United Kingdom, no central records are kept of the number of prescriptions for codeine preparations issued by hospital pharmacies per year. However, discussions with colleagues across the United Kingdom suggest that codeine is still a commonly used analgesic and is felt to be a valuable agent. Nevertheless, clinical dogma is not enough and begs the question: ‘Is there a body of clinical evidence to support or refute its use?’ This is difficult with codeine as, along with many other established agents, there are no large randomized controlled trials of codeine in discreet, age-specific pediatric populations, and clinical situations. It is therefore necessary to consider adult studies to decide whether codeine is a useful and effective as an analgesic. While this is not ideal given the known differences in pharmacokinetics and pharmacodynamics that occur with maturation, the available data from other opioids would indicate that the major maturational changes in drug action occur within the first year of life (5, 6). Codeine is most commonly used in combination with paracetamol. A Cochrane Database review in 1998 compared the effectiveness of a range of single doses of paracetamol alone and in combination with codeine for moderate to severe pain (7). They calculated the number needed to treat (NNT) as a measure of analgesic efficacy. NNT was defined as the number of patients needed to receive a treatment for one patient to achieve at least 50% pain relief over 4–6 h compared to placebo. For postoperative pain, paracetamol 1000 mg had a NNT of 4.6 (95% confidence interval 3.8–5.4). The NNT for paracetamol 1000 mg plus codeine 60 mg was 1.9 (95% confidence interval 1.5–2.6). This figure was derived from data on only 127 patients in two trials and so is unreliable. The evidence was reassessed in 2001 by the Pain Research Unit of the University of Oxford using slightly broader but still stringent study inclusion criteria (8). They were able to identify six additional trials of paracetamol 1000 mg plus codeine 60 mg. With greater patient numbers, the number NNT for these therapeutic doses of paracetamol and codeine was 2.2 (confidence interval 1.7–2.9). The addition of codeine to paracetamol would appear to provide improved analgesia as a single dose in adults. These results may not reflect the true value of codeine as an analgesic. Codeine is not given as a single dose with a single dose of paracetamol but on a regular basis. A clinical study using extraction of the third molar tooth as a standardized pain experience showed pronounced improvement in pain relief with the second dose compared to the first dose of codeine 60 mg orally (9). For the experienced clinical anesthetist, the postoperative visit is as important as the preoperative assessment. It highlights the effectiveness of the initial part of the plan for postoperative analgesia and any associated morbidity. The outcome once discharged from hospital is unseen by anesthetists but falls to primary care. Wolf (10), in an editorial, on day case surgery almost a decade ago, highlighted the situation of initially good pain relief in hospital not continuing once discharged home. Any child or parent will testify that pain does not stop as the child leaves hospital. Tonsillectomy remains one of the commonest operations undertaken on children. It causes considerable pain lasting more than 7 days. The pattern is of intense or moderately intense pain for the first 3 days, followed by a gradual decline over the next 4 days (11). Pain assessment and management falls to parents or guardians. There are no published studies on pain relief in children at home with different analgesic regimes with or without codeine. Three years ago, the author (MT) was prepared to consider the view that codeine was not helpful as an analgesic and prospectively audited 60 tonsillectomies postoperatively. All were 23 h discharges and were advised to administer therapeutic doses of both paracetamol and ibuprofen on a regular basis for a week. They were asked to measure usual and worst levels of pain experienced on a daily basis using the Wong and Baker Faces scales and were telephoned days 3 and 5 postoperatively. Pain scores for worst pain experienced in previous 24 h were a median of 4 of 5 on Day 2 for both parent and child assessments remaining at 3 on Days 4 and 5. Fourteen of sixteen (23%) children had consulted their general practitioner by Day 5 because of waking in the night (commonly between 2 and 4 AM) with significant pain. Since then we have added codeine elixir to be given as required for breakthrough pain. Ongoing prospective audit is under way with only 1 of the first 29 (3%) children seeing general practitioners with inadequate pain relief by Day 5 postoperatively. This personal experience is confirmed by Ewah (12). She prospectively followed up 100 Day Case tonsillectomies for 3 days after operation. All received ibuprofen, paracetamol, and codeine regularly. None had visited general practitioners by Day 3 (personal communication), and low median pain scores were reported. Experience from two separate anesthetists auditing the effectiveness of their routine clinical practice attests to the effectiveness of codeine for pain relief at home following intermediate surgery. There are two reasons why this information does not exist in the scientific literature. First, there is no financial drive from the pharmaceutical industry to investigate this established and cheap agent. Second, the increasingly regulation around clinical investigations has reduced the ability of practicing clinical anesthetists from undertaking simple patient studies. Codeine, like all drugs, is not free of problems. It should not to be given intravenously as it may cause profound hypotension (possibly from histamine release) and grand mal convulsions. In addition, there are a number of specific patient groups where its use is associated with significant risk of complications. There is a recent, well-documented case of death of an infant (1 month old), who received combination medications including codeine as an anti-tussive and developed profound respiratory depression at home. The total codeine dose was 1.26 mg·kg−1 in a 6-h period (13). The use of codeine is also now not advisable in breastfeeding mothers. A case is reported of a breastfed baby dying from respiratory depression (14). Genotype analysis revealed that the mother to have a gene duplication (three functional CYP 2D6 alleles) and thus to be an ultra-rapid metabolizer (UM) of codeine to morphine. Analysis revealed high levels of morphine in expressed breast milk. As clinicians, we use codeine orally on a regular basis as part of a multimodal approach to pain management for a number of days at home. The children are over the age of 1 year and usually otherwise well. The earlier case reports are important but do not contraindicate our use of codeine for the majority. Despite its widespread clinical use, there has been only one recent case report of apnea in a child after oral codeine (15). It was attributed to the child being an UM of codeine to morphine. Subsequent correspondence casts very considerable doubt on the claims made in the case report. Therefore, use of codeine for many years and in many patients suggests a good safety record. If one accepts that codeine is an analgesic, then the arguments against its use include concerns relating to: Pharmacokinetics (genetic polymorphism). Adverse effects (side effects) The first is that the analgesic effect of codeine is because of its conversion to morphine by an enzyme showing substantial genetic polymorphism. The enzyme system involved is the cytochrome P450 2D6 enzyme system. Nine percent of UK patients are estimated to have low levels of the enzyme and are described as poor metabolizers (PM) (4). They form low levels of morphine and therefore would be expected to get little or no analgesia from morphine. A number of individuals show enzyme duplication and are described as UMs. They may produce abnormally high levels of morphine and are therefore at risk of profound respiratory depression. Clinically, we do not know the genotype of any individual postoperative child, and thus, we are at risk of under or overdosing the child. The case that codeine works by conversion to morphine appears to be unproven. Normally, very little of the total dose of codeine is actually metabolized by CYP 2D6 to morphine, the range being between 0.5% and 2–3%. Eighty percent of codeine is directly metabolized by the phase 2 uridine diphosphate glucuronosyl transferase (UGT) enzymes of the liver to form codeine-6-glucuronide (C6G). Veer et al. (16) have postulated that C6G is responsible for most of the analgesic action of codeine by activity at mu receptors. Interested readers are referred to Armstrong and Cozza (17) for a fuller discussion. Codeine has been regarded by some as having all the disadvantages of morphine without the advantages, meaning high levels of side effects without analgesia. Codeine certainly causes This is and is There is little evidence of high of other side effects. 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The of drugs is that they are usually by new agents that have improved therapeutic and risk would include agents local and and anesthetic and then do that despite its codeine continues to be so codeine continues to be used for a number of it appears to work when used in combination with other weak oral analgesics such as paracetamol. It is available in an oral formulation by on and no better has become is an opioid that has been used over in Codeine, like that has now almost from is morphine it is commonly used of because it is available as an oral and it is with paracetamol. It may be over the NSAIDs for postoperative despite data to safety and reduced postoperative and with of paracetamol and lack of of the pharmacokinetics have in reduced administration doses with reduced drug to the analgesic has some data showing the effectiveness of codeine to our available analgesic In addition, availability over the Both have that there are with being able to provide effective analgesia at home in children without using drugs such as morphine that can be associated with are the to codeine in providing reliable analgesia and what would from clinical This is an important would not be having this debate if we had all the codeine in pediatric it is important to why and we are using codeine at and then consider in that The of codeine for is to provide analgesia for moderately severe pain where we know the combination of paracetamol NSAIDs to be The only in of codeine in is in with NSAIDs is a and the of patients are home with this The of these drugs remains and on The is because some studies show no to paracetamol to is being used increasingly in our despite It should be that because a drug is not for pediatric use, this does not its clinical evidence is available to support the use of or other opioids agents in to have no first experience of the use of for the management of pain in children. The available is also very A recent review had to only that of in the of postoperative analgesics in children is It will only codeine in practice if we have good studies the clinical effectiveness and side effects of codeine in pediatric to the lack of pediatric studies postoperative analgesia after discharge from hospital. data suggest that the of from practice will have little is but the high of in children can be a data from postoperative pain suggest pain scores for compared to the of and was in given codeine data suggest in given codeine over this may not be a in children. The of is also the system responsible for codeine and individuals may be as or of of the and greater analgesic efficacy of are reported in metabolizers with reduced and morphine is an to codeine in hospital can be and use of hospital. using and are for but not for postoperative analgesia. such as or are also use, but have not or review to be used by most is available in only a opioids codeine and are in of the opioids from pain in at home in both and children. In some may be the only weak opioid used many drugs, the safety of codeine to be on years of so that no individual drug can be safe, the with therapeutic effects and side effects are this of clinical and despite the case reports by both should we that in some clinical such as pediatric where the drug has a record we should continue with this that there is very little in the pediatric to support that codeine in the a and effective analgesic in combination with other drugs for moderate postoperative pain. It is important that we do not continue what we have been but actually audit the effectiveness of our In it is important that we look at the pain and side effects experienced by our children following discharge from review our analgesic prescribing and for whether codeine is valuable or It is also important that we do not use codeine where other drugs are more It is not the treatment of choice for acute severe pain. would that oral not morphine also has a record and is an after pediatric Pain management is increasingly in the of a than individual codeine use by in other will It may be to have a approach to pediatric pain a hospital than management in one adult data and in 50% of patients after with compared with with morphine, and with codeine While codeine is associated with and than morphine remains the It is to that both have their both that codeine is to as a drug in pediatric for the there are and clinical arguments against codeine, the drug still has a central in and moderate pain years of to using of codeine with paracetamol and may pain management in children with to moderate pain. For more severe pain, there are good arguments to use oral morphine in to codeine. This is in a hospital where controlled drugs can be from a of the of safe, and effective opioid administration become more difficult because of drug may show for analgesia at home but an evidence against an active other agents have been to be more effective in a home with codeine is to in its current

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