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 general with pain relief by Day 5 postoperatively. This experience is by prospectively followed Day tonsillectomies for 3 days after All paracetamol, and codeine had general by Day 3 and median pain scores were from two anesthetists the effectiveness of their clinical practice to the effectiveness of codeine for pain relief at home following surgery. There are two why this does not in the scientific there is no from the to this established and agent. the clinical has reduced the of practicing clinical anesthetists from simple patient is not of It should not to be given as it may from and In addition, there are a number of specific patient where its use is associated with significant of complications. There is a case of of an who combination codeine as an and developed at home. 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