Introduction

In recent years, there has been a tendency amongst governmental regulatory bodies in different countries, including the Irish Medicines Board, toward de-regulation of prescription-only medicines to pharmacy status medicines in an effort to reduce state drug budgets. This practice has the added benefit of reducing the workload of GPs, of increasing patient self-medication, and, of extending the screening and patient education roles of community pharmacists. Accordingly, and especially in light of the current economic climate, this tendency is unlikely to revert. [1] Regulatory bodies have however faced criticism over this movement due to the safety concerns associated with the increased availability of potentially dangerous drug-substances. Codeine is an example of one such drug.

Codeine (3-methylmorphine) is an opioid analgesic thought to elicit its effect primarily via activation of OP2 (κ) and OP3 (μ) receptors within the spinal chord - mimicking the body's endogenously produced endorphins and inhibiting transmission to the CNS of nociceptive information. [2] [3] It is used clinically, and in the community, for the relief of pain (usually mild to moderate in nature) and as an antitussive agent, generally as a 2nd line treatment (in line with the WHO's pain relief ladder) where a 'weaker' analgesic has proved insufficient. Because of its structural similarity and its conversion in the body to morphine, it has been postulated that codeine produces similar side-effects in patients who use it repeatedly or in excess - most notably; tolerance and dependence. [4]

Image 1: Codeine differs from morphine only by the presence of a methyl group.

Because codeine dependence is suspected to be mainly linked to its conversion in the body to morphine (circa. 10% of any given dose) - it is believed that those individuals in whom the CYP2D6 microsomal isoenzyme is abundant will be more likely to experience withdrawal symptoms with repetitive/inappropriate use - conversely, those individuals who are deficient in the enzyme (circa. 10% of the population) may be much less likely to develop dependence. [5] It has indeed been shown that those individuals in whom this demethylation reaction does not occur are also resistant to the analgesia usually produced by codeine. [6]

The use of codeine in OTC products has however, been associated with tolerance and dependence when used inappropriately, which has left some to question whether these medicines should be available without prescription.

Discussion

Whether it's dispensed as a 'p status' or a prescription only medicine, the use of codeine is primarily indicated in order to treat mild to moderate pain, to allay unproductive cough or to alleviate laxity of the bowels. [4] Codeine is an opiate drug, very similar in structure to morphine, and as such, its use in healthcare is subject to considerable debate. Upon realisation that this opium derivative is available to patients without prescription in every pharmacy in the country, and at sub-therapeutic doses (<30mg) [7], it would seem understandable that its use is shrouded in controversy. Indeed, should codeine-containing medicines be available in Ireland without prescription?

In order to put forward the best response to the question posed in the title of this article, it is necessary to review the current best evidence base for the use of codeine-containing products; to compare the beneficence and the maleficence of the drug at OTC concentrations; and, to investigate how the sale of such products could be changed in order to ensure patient safety.

Problems with Research on Codeine

Unfortunately, the current data are not without limits. Simon Wills has argued that there are three primary problems associated with the available research on codeine use in OTC preparations:

Firstly, all healthcare professionals are well aware of the potential for abuse with opiates and consequently exhibit a personal bias in favour of accounts of opioid abuse.
Secondly, most of the available research data don't distinguish between individuals who abuse codeine and those who inadvertently misuse the drug.
Finally, only one of the OTC codeine-containing products available in Ireland actually contains codeine as its sole active ingredient (Codinex) - and the likelihood of any pharmacist dispensing this product without reluctance is quite unlikely. Generally, the opioid is present in conjunction with either ibuprofen or paracetamol - both of which are also capable of producing a form of dependence when used over an extended period of time. Notably, this dependence is also associated with withdrawal symptoms.

It's also important to point out that caffeine is present as an adjuvant in many of the available OTC codeine-containing products in order to counteract the sedative effects of the opiate. It has long since been documented that high doses of caffeine are also linked with similar withdrawal reactions when intake is suddenly stopped. [5]

Is OTC Codeine Addiction a Fallacy?

Wills goes on to say that codeine dependence is definitely possible if large enough quantities of the drug are taken consistently over a long duration of time. However, it is often more likely that dependence on combination products results from the effects of these other pharmacologically active compounds. Nonetheless it will usually be the stigmatised opium derivative that attracts the blame - despite the fact that its concentration is close to being negligible in most of these combination products. [5]

It has in fact been argued that the concentration of codeine in such preparations is simply too low to even justify its presence. Indeed, its use is only warranted because it is centrally-acting and there's a possibility of drug synergy (of which there have been reports). [8] When used as a single ingredient preparation at equivalent doses, codeine has been shown to possess poor analgesic properties. [8]

Wills goes on to say that the scope for codeine abuse with the available OTC products (excluding Codinex) is limited by other factors anyway.

The presence of paracetamol or ibuprofen in combination products reduces their potential for abuse due to the high risk of paracetamol overdose incurred on the user by exceeding the recommended dosage - something which is essential for addicts to do in order to achieve doses of codeine high enough for the desired psychotropic effect of the drug to become feasible. Rang et al have also discussed codeine use in the community, agreeing with Will's view by saying that it causes "little or no euphoria" and consequently is "rarely addictive". [6]

Some evidence to support this does exist. During the period between 1981 and 2005, the IMB has only received a total of eight ADR reports of dependence associated with the use of codeine-containing medicines, and all of these arose due to prolonged use and/or doses exceeding those recommended. [9]

A Different View on Codeine Dependence

MHRA Director of Vigilance and Risk Management of Medicines, Dr June Raine, has said that, taken in the correct manner and for the right purposes, codeine is a very effective and acceptably safe medicine. [10] However, Dr Raine also emphasised that "…these products can be addictive…" and that the MHRA were taking appropriate action to curb this problem in the UK. Here in Ireland, it seems that the IMB are of a similar opinion. At a recent briefing on the PSI draft guidelines, PSI Registrar and CEO, Dr Ambrose McLoughlin said that "…the safety concerns around the misuse of non-prescription medicinal products containing codeine are well established and this is an important medication safety issue." [11]

From the standpoint of those with firsthand experience, i.e. pharmacists; recent research conducted on OTC medicine misuse in Scotland has shown that codeine combination products are among the most commonly misused products by the general public with 55% of pharmacists acknowledging experience of misuse on either a frequent or on an occasional basis with these formulations. [12] The BMJ has also recently featured a letter reminding practitioners that OTC drugs can be highly addictive. Over a three month period, two doctors reported seeing three patients suffering from an addiction to Nurofen Plus®, all of whom had become tolerant to the codeine and exhibited side-effects relating to the ibuprofen. The two physicians also expressed discontent with the fact that "…there are no official statistics documenting the extent of dependence…" and they discuss the need for large-scale research on this topic to be conducted in the future. [13]

Dealing with Codeine Misusers

Before progressing any further, it's important to make a crucial distinction between the types of people who do misuse codeine-containing combination preparations (estimated to be as high as circa. 4% of the general public): [1]

• There are patients who are conscientiously disobeying the user instructions in order to try and achieve some sort of euphoria or 'high' from the codeine present in the preparations.
• There are patients who inadvertently become addicted to these products and who are aware of their dependence but continue to use them to satisfy their cravings.
• There are patients who are unknowingly misusing these products seemingly innocuously within the recommended limits both frequently and regularly - to treat drug-induced headache for example.

These distinctions are important because the action taken by an intervening pharmacist when dealing with the client will be different depending on the patient's circumstance. In a recent article for the Irish Pharmacy Journal, Dr Mark Ledwidge has discussed the difficulties faced by pharmacists when trying to intervene with patients. [1] He has said that those who unintentionally misuse these preparations generally do so as a result of misinformation and, although difficult to identify, are usually compliant once confronted and counselled on the potential dangers of misuse. If these patients are in denial of their problem, they can be much more problematic - similar to those who have unintentionally become addicted and who are aware of their problem, they tend to feel insulted or offended following confrontation by a pharmacist and can become quite aggressive.

The options open to pharmacists in such instances are quite limited because there is no formal referral pathway and refusal of supply may simply drive the client to another unexpectant pharmacy as a source of the desired product. A similar problem arises with those who try to abuse codeine for recreational purposes - although these are few in number seeing as the presence of other analgesics in the products makes paracetamol/aspirin overdose probable. [14] As well as this, research has concluded that individual pharmacists' efforts to deal with the problem of misuse are not likely to resolve abuse once it has been established. Dr Ledwidge has recommended that for treatment to be successful, a more co-ordinated communal approach needs to be adopted. Nonetheless, pharmacists should exercise their professional judgement and if they deem necessary, refuse the sale and confront the patient. [1]

Other Problems with Codeine

While it's probable that dependence from codeine-containing medicinal products are not actually due to the opiate - codeine use is not without other possible side-effects. Most importantly, codeine produces the same level of respiratory depression as morphine - although, even at high doses, this is not usually problematic in practice. [6] Constipation caused by a reduction in peristalsis and intestinal secretions is another good cause for concern with codeine use. It is usually circumvented in the community by concomitant use of another analgesic drug, allowing for administration of a lower dose of opiate. [3] However, constipation and respiratory depression may still present with patients inappropriately using codeine-containing products on a long-term basis. Patients may also be subject to chronic rebound headache syndrome, which in itself is problematic because it encourages continued use of the analgesic responsible for it. Depression with chronic codeine use has also been a subject of interest as of late, although much research remains to be done in this area. [5]

Guidance on Codeine use and Reason for Change

Mr Pat O'Mahony, CEO of the IMB, recently discussed the concerns that the regulatory organisation held with regard to the actual or potential abuse of codeine-containing products in pharmacies; "…We are currently having discussions with the PSI so that, fundamentally, the pharmacist would be involved in supplying those products directly to the patients. It wouldn't be done by an assistant but only by the pharmacist on the premises so that there would be a level of professional consultation and professional advice directly from the pharmacist with the patient," [11] Mr O'Mahony justified this move by highlighting a recent study in the UK which demonstrated that 40% of pharmacy assistants did not seek the pharmacist when a certain codeine-containing product was requested and that one in five assistants supplied the product without asking a single question. Mr O'Mahony went on to say that the IMB hoped to eradicate any similar activities occurring here in Ireland by ensuring direct pharmacist involvement in advising on and supplying such preparations - "genuine OTC pharmacy prescribing". On a final note, Mr O'Mahony also alluded to the future deregulation of currently prescription only medicines, saying that if one could be assured of professional involvement by a pharmacist in such situations, "…that would have a substantial bearing on our judgement as to what products could be released through that avenue".

Conclusion

There appears to be little reason for codeine to be used in compound analgesics despite the fact that its use is well established in clinical practice. Available research has failed to demonstrate superior pain relief associated with codeine-containing combination products over single API preparations, despite the fact that combination products are frequently used as a 2nd line treatment for this indication. Indeed, there appears to be little reason as to why its presence (at such low doses) in these products is even warranted, aside from the arguable possibility of an adjuvant effect. Alas, the experience of community pharmacists and the views of the general public indicate that these products do indeed offer more value by way of pain relief than other single-ingredient OTC analgesics and that they are indeed, a valuable resource to have available for the treatment of pain.

It has been argued that the adverse effects caused by codeine in combination medicinal products outweigh the potential for good that its presence may have. Despite these claims, there appears to be little evidence to substantiate such an argument and to the contrary, research suggests codeine-containing products, if used correctly, rarely cause physical dependence, let alone psychological dependence - the primary topics of controversy around their use. Again however, the experience of community pharmacists begs to differ, with the majority of practitioners acknowledging addiction or dependence to these products as a common phenomenon.

In conclusion, codeine-containing medicines should continue to be available without prescription here in Ireland, so long as patients are assured of receiving advice on the proper use of such medicines and of the potential harm which they can cause. A condition which will be guaranteed by the new guidelines lain out by the PSI.

Considering that more and more currently prescription only medicines are likely to be deregulated in Ireland in the coming years, it is of vital importance that pharmacists demonstrate the competence necessary to deal with issues such as those posed with codeine-containing products on the market at present. In fact, one could argue that preparations containing 30mg or more codeine could also be incorporated into pharmacist OTC prescribing in the future (as is the case in some other countries at present). Consumer safety shouldn't be compromised as long as patients are assured of a professional consultation and professional advice directly from the pharmacist dispensing the medicine - something which Mr Pat O'Mahony of the IMB alluded to being an important step for future developments in this area.

P.S.