What do you think of when I say the words “drug addict”? For many it evokes an image of someone living rough, intent on spending all their money or doing anything they can to secure their next dose. However, for me I think of the mother of one of my close friends, who, for years has teamed up with her daughter to buy over-the-counter codeine medications from 6 different local pharmacies in rotation – as to avoid suspicion and questioning from the pharmacists who, at any time, could deny them sale if addiction was thought to play a role in their purchase. Codeine is usually prescribed as it is an effective analgesic that tends to have less side effects than other opioid drugs, however, although codeine is unarguably less addictive than other opiates, such as morphine and heroin, it can still carry significant risks to health especially in terms of tolerance, dependence and addiction. In 2015, the UK consumed almost 16% of the worlds share of codeine, 4% higher than that of the United States. The Royal Pharmaceutical Society and the Faculty of Pain Medication at the Royal College of Anaesthetists have stated that they have concerns about the growing number of people using opioids such as codeine, and this comes at a critical time as over-the-counter and prescription painkiller addiction is on the rise.
What is Codeine?
Codeine is an opioid analgesic used to treat mild-severe pain and sometimes is used as a cough suppressant. Although effective, like every drug it has side effects, such as constipation, itchiness, slowed breathing, nausea, and in higher concentrations can cause pinpoint pupils, extreme sleepiness, an irregular heartbeat, coma and death. In the UK, codeine is a Class B controlled substance, or Class A drug when prepared for injection. Codeine is marketed as both a single-ingredient drug, only by prescription, and in combination preparations with paracetamol as co-codamol, a prescription medication, or with ibuprofen (such as over the counter as Nurofen Plus – my friend’s mum’s drug of choice). Thus, the possession of codeine without a prescription is legal as long as it is compounded with another ingredient and the dosage of the tabled does not exceed 100mg.
How does it work?
As an opioid, codeine is chemically and biologically similar to drugs such as morphine and heroin.
The structure of some opioids, including enkephalin. Source: http://askus.top/chemical-detox-for-opiates/opiates-madness-of-a-feral-gal.html
As such, they agonise opioid receptors in the nervous system. These receptors grouped into 3 main classes μ, κ, δ (mu, kappa, and delta) and are distributed in the pain centres of the central nervous system. They are usually stimulated by the body’s own neuropeptides, such as enkephalins, to facilitate and modulate the transmission and sensation of pain. Codeine acts as an agonist for the μ receptor, causing inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord and activation of descending inhibitory pain controls in the midbrain, dampening the sensation of pain as well as creating general sense of well-being (also called euphoria). As with any other opiate, uncontrolled use can lead to tolerance, physical dependence and addiction, even to the point where drug use becomes the defining behaviour in the life of the individual.
Codeine is a pro drug; In most humans 10% of a codeine dose is transformed to morphine through demethylation in the liver via CYP2D6. However, many studies show no major differences in terms of analgesic efficacy between those who are poor metabolisers and extensive metabolisers and therefore the extent to which the biotransformation of codeine to morphine affects analgesia is still largely unknown.
What’s the risk?
As an opiate, codeine runs a high risk of addiction that unfortunately can be difficult to detect and deal with. Many start out using codeine for genuine medical reasons and can easily be unaware or in denial that they are developing a substance dependence. Because of this, and that it is easily available over the counter, codeine is easy to abuse and over use.
Prolonged codeine use can lead to tolerance. Although numerous mechanisms for tolerance have been suggested, no concise theory reigns. It is thought, however, that tolerance is most likely due to opioid receptor desensitisation and molecular adaptations in neurons that reduce signal transduction from the receptor after acute activation. In essence this means you need more drug to have the same effect; clinically more than 10-fold dose escalations of opioid dose in chronic pain management are common. Abrupt cessation of codeine, especially following prolonged use, produces a highly unpleasant withdrawal syndrome mainly mediated by cellular adenylate cyclase signalling adaptations (see here for a good paper outlining this). Opioid withdrawal syndrome produces symptoms such as stomach cramps, elevated heart rate, sweating, irritability, headache and insomnia; it is because of this that many people find it difficult to stop taking codeine, as the presence of these unpleasant symptoms perpetuate and validate their belief that they need the pain killer in the first place. In fact, for many it is easier to ignore the possibilities of long term effects and continue to take codeine as they “feel fine”, rather than face these withdrawal symptoms. While this phase is associated with physical dependance, psychological addiction can also occur, which is characterised by a craving and major preoccupation for the drug. This psychological aspect is often linked with a desire to experience the euphoria associated with opioid use, however it is a much milder form in the case of codeine compared to morphine or heroin. This mental aspect often requires more support to get through, and can be a major barrier to breaking the cycle.
The risk of other health issues, as well as addiction, increases with long-term usage of codeine. Building up a tolerance leads to needing a higher dose in order to feel the same rush, and with this higher dose comes the main reported negative effects: namely pain upon discontinuation, mood swings, constipation, nightmares and insomnia; interestingly, one study showed that depressive symptoms increased significantly with codeine use of more than 6 months. In higher doses, continued use can cause serious respiratory depression and organ damage. Another serious problem with chronic codeine use is those effects mediated by other drugs in the formulation. For example, in the UK, paracetamol (acetaminophen) is often used in conjunction with codeine. Over long periods of time, paracetamol use produces an increased risk of gastrointestinal bleeding, an increase in systolic blood pressure, and most worryingly hepatotoxicity and hepatic necrosis due to a reactive toxic metabolite that is usually inactivated at normal doses.
In Summary
The increasing use of codeine is a worrying phenomena that deserves more attention. For most indications, there is little evidence codeine is more effective than alternative medicines, and crucially codeine is not intended to treat long term conditions. It’s easy to forget that codeine is an opioid, and as such carries a significant risk of addiction, tolerance, dependence, along with a whole host of negative side effects. One major key to combatting this problem is education – according to a recent cross section study of medical professionals, over half of prescribing professionals felt patients were unaware of the adverse effects and consequences of codeine combination medicines, and most felt that more communication with patients is needed to educate about the realities and responsibilities of codeine use.
For sensible codeine use, ensure you:
- Only take prescription strength codeine at the discretion of your doctor.
- Do not take over the counter codeine for more than 3 days.
- Keep an eye out for signs of addiction or dependence – being able to stop the cycle early is key!
If you feel you need support or guidance with addiction or dependency, please visit https://www.mind.org.uk/information-support/guides-to-support-and-services/addiction-and-dependency/#.W7DvGhNKjOQ for more information.
Written by Nancy
References
Buckley, J. (2018). It’s no surprise that prescription drug addiction in the UK is on the rise – I should know, they nearly killed me. The Independent.
Vitols, S. (2003). Paracetamol hepatotoxicity at therapeutic doses. Journal of Internal Medicine, 253(2), pp.95-98.
Allouche, S., Noble, F. and Marie, N. (2014). Opioid receptor desensitization: mechanisms and its link to tolerance. Frontiers in Pharmacology, 5(280).
Morgan, M. and Christie, M. (2011). Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. British Journal of Pharmacology, 164(4), pp.1322-1334.
Romach, M., Sproule, B., Sellers, E., Somer, G. and Busto, U. (1999). Long-Term Codeine Use Is Associated With Depressive Symptoms. Journal of Clinical Psychopharmacology, 19(4), pp.373-376.
McCrae, J., Morrison, E., MacIntyre, I., Dear, J. and Webb, D. (2018). Long-term adverse effects of paracetamol – a review. British Journal of Clinical Pharmacology, 84(10), pp.2218-2230.
Lautieri, A. (2018). The Effects of Codeine Use – DrugAbuse.com. [online] DrugAbuse.com. Available at: https://drugabuse.com/library/the-effects-of-codeine-use/#long-term-effects-of-codeine [Accessed 30 Sep. 2018].
Van Hout, MC. Bergin, M. Foley, M. Rich, E. Rapca, AI. Harris, R. Norman I. (2014) A Scoping Review of Codeine Use, Misuse and Dependence, final report. CODEMISUSED Project European Commission 7th Framework Programme, EU. Brussels
AddictionCenter (2018). Codeine Addiction and Abuse. [online] Addictioncenter.com. Available at: https://www.addictioncenter.com/opiates/codeine/ [Accessed 30 Sep. 2018].
Gardiner, S. (2006). Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice. Pharmacological Reviews, 58(3), pp.521-590.
Foley, M., Carney, T., Rich, E., Parry, C., Van Hout, M. and Deluca, P. (2016). Medical professionals’ perspectives on prescribed and over-the-counter medicines containing codeine: a cross-sectional study. BMJ Open, 6(7), p.e011725.
Kosten, T. and George, T. (2002). The Neurobiology of Opioid Dependence: Implications for Treatment. Science & Practice Perspectives, 1(1), pp.13-20.
Drewes, A., Jensen, R., Nielsen, L., Droney, J., Christrup, L., Arendt-Nielsen, L., Riley, J. and Dahan, A. (2012). Differences between opioids: pharmacological, experimental, clinical and economical perspectives. British Journal of Clinical Pharmacology, 75(1), pp.60-78.
Biomed Thread 