Associate Staff Member, Alcohol, Tobacco and Other Drug Research Unit, Medical Research Council, Cape Town, South Africa.

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2 Marie Claire Van Hout, PhD M.Sc International Programme in Addiction Studies (IPAS) M.Sc Health Promotion. School of Health Sciences, Waterford Institute of Technology, Ireland Coordinator, Substance Misuse Research Centre registered on the European Network of Centres for Pharmaco-epidemiology and Pharmaco-vigilance (European Medicines Agency). Associate Staff Member, Alcohol, Tobacco and Other Drug Research Unit, Medical Research Council, Cape Town, South Africa. Visiting Research Fellow, Centre for Public Health, Liverpool John Moore s University, Liverpool, United Kingdom Visiting Research Fellow, Glyndwr University, Wales, United Kingdom

3 Principal Investigator Dr Marie Claire Van Hout Marie Sklodowska Curie Actions-Industry-Academia Partnerships and Pathways (IAPP). Scored Highest in Life Sciences Division 96/100. Commenced 9/13 and funded for 36 months 2.04ml. 6 Partners, 27 Marie Curie Fellows. Expert Advisory Panel with representative experts from the European Medicines Agency, European Monitoring Centre for Drugs and Drug Addiction, Royal Pharmaceutical Society UK and Pharmaceutical Society of South Africa. Registered as EC funded study on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) register of the European Medicines Agency.

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6 CODEMISUSED aimed to explore the nature of codeine use, misuse and dependence in Ireland, United Kingdom and South Africa from perspectives of: National stakeholders Consumers Medical, pharmacy & addiction treatment professionals Addiction treatment patients Internet monitoring of online pharmacies and drug forum activity

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8 . Data will be used to inform: Manufacture and product formulation Monitoring and surveillance Consumer medicine information, packaging and warning labels Responsible prescribing Pharmacy dispensing, risk management and clinical audit Pharmacy screening and brief interventions Road and workplace safety interventions Internet supply and drug forum monitoring CPD training and E-Learning modules for health professionals Specific clinical and community pharmacy treatment protocols

9 Introduction Codeine, or 3-methylmorphine, is the most commonly consumed opiate worldwide, widely used for its analgesic, antidiarrhoeal and antitussive properties. The main pharmaceutical form is the tablet (60%) but codeine is also available as a capsule, effervescent tablet, syrup, suppository and solution Codeine products may also be marketed for subcutaneous or intramuscular injection. Intravenous use is not advised as it may cause hypotension and grand mal convulsions.

10 Regulatory Controls Uses and formulations of codeine vary across countries as do the laws that limit its supply. In most European countries non prescription products contain between 8 15mg of codeine per tablet, and are marketed as a single ingredient drug or in combination with non-steroidal antiinflammatory drugs such as ibuprofen (e.g. Nurofen Plus ), aspirin, paracetamol, caffeine and buclizine to enhance the synergistic effect of drug compounds. Preparations containing codeine of 30mg and above are typically classified as prescription only medicine.

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12 Medical guidelines for use Recommended dose is maximum 240mg per day in four divided doses with at least 4 hours intervals between doses. NOT more effective in providing pain relief if the single dose is increased above 60mg. Further dose increase will only cause increased adverse effects. Codeine s opiate effect and risk of development of tolerance within a short timeframe on regular or excessive use contributes to abuse potential..

13 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 7 th Framework Programme, EU. Brussels. Misuse of codeine containing preparations Codeine produces less euphoria than morphine but has considerable potential for misuse and dependence if not taken as directed. Misuse of opioid pharmaceuticals such as codeine is emerging as a global public health concern, amid calls for revised scheduling and increased pharmacovigilance. Global shift toward availability of non-prescription codeinecontaining products and promotion of patient selfmanagement. Misuse of over the counter codeine-containing products, particularly combination codeine analgesics, is on the increase in countries where available.

14 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 7 th Framework Programme, EU. Brussels. Misuse is defined as: The problematic consumption of codeine where risks and adverse consequences outweigh the benefits, and which includes use of codeine with or without prescription, outside of acceptable medical practice or guidelines, for recreational reasons, when self-medicating, with higher doses and for longer than advisable. Prevalence Difficulties in estimating the scale of misuse centre on codeine product availability in pharmacies and online, and the heterogeneous and hidden nature of misuse and dependent use.

15 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 7 th Framework Programme, EU. Brussels. Tolerance and dependence Codeine has an identified abuse potential which centres on its opiate effect and development of tolerance within a short timeframe on regular or excessive use. Risk of tolerance is increased through increasing the dose for therapeutic and non-medical or recreational purposes. Physical dependency and withdrawal symptoms mimic those of morphine and, whilst less severe, include cravings, preoccupation with obtaining and taking codeine, lack of control of consumption despite negative side effects, insomnia, restlessness, runny nose, stomach pains, diarrhoea and chills.

16 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 7 th Framework Programme, EU. Brussels. Adverse health consequences of misuse Prolonged use of codeine is strongly associated with depression and dysphoric mood states. Codeine can interact with other medications and substances such as alcohol, leading to respiratory depression and other central nervous system effects. Long term use of combination analgesic products containing ibuprofen and paracetamol can lead to gastric ulcers, gastrointestinal bleeding, hepatotoxicity, hypokalaemia, inflammatory bowel conditions, and profound hypokalaemia associated with a severe myopathy. Dependence occurs often in users with no history of substance use disorders and co-morbidity.

17 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 7 th Framework Programme, EU. Brussels. Other related consequences of misuse Impairment (driving and neurological damage). Injury risk ( trauma, fractures and lacerations in falls/accidents). Overdose. Injecting harms such as abscess, necrosis and BBV transmission.

18 Types of Misuse Use based on quantity of consumption. I. users that never exceed the maximum dose; i. users who sometimes consume slightly higher than the recommended dose; ii. users who consume significantly higher doses than recommended. Misuse Characteristics I. exceeding recommended doses and treatment duration; II. III. IV. 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 7 th Framework Programme, EU. Brussels. becoming dependent on codeine for medical reasons (ie. pain); using codeine to manage opiate withdrawals; using codeine for its euphoric effects; V. tampering with codeine preparations.

19 Who misuses Codeine? - Those who usually started to take codeine for therapeutic use but whose doses rapidly increase following experience of its euphoric effects; this group is aware of their dependence but continue to use it to stave off cravings and avoid withdrawal symptoms and often have limited insight into its dependent properties. - Those, many of whom have worsening pain, use it within recommended limits but use it frequently and regularly to manage their pain and may use it to stave off withdrawal associated headaches; this group is usually unaware of being codeine dependent. - Those who consciously misuse codeine for its euphoric effects. - Problematic heroin users and methadone maintenance patients who use codeine to manage withdrawal symptoms and when heroin and methadone are unavailable. Nielsen S, Cameron J, & Pahoki S. (2010). Over the Counter Codeine Dependence. Victoria, Australia: Turning Point Drug and Alcohol Centre.

20 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 7 th Framework Programme, EU. Brussels. Wide ranging profile of individuals who misuse codeine parental medication of children. youth drug users adolescents university students. pharmacy customers. drug treatment patients. psychiatric patients. older people.

21 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 7 th Framework Programme, EU. Brussels. The available evidence also suggests that many codeine dependent people regret their dependence and associated work and social problems and also reject a drug identity, seeing themselves different from other illicit drug users because of their continued work and social activity and; because they are reassured about its safety through its legal status and availability over the counter from community pharmacies.

22 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 7 th Framework Programme, EU. Brussels. Aberrant Behaviours Doctor hopping Pharmacy shopping Selling prescription codeine Forging prescriptions for codeine Obtaining prescriptions from non-medical sources Repeated episodes of lost and/or stolen prescriptions Aggressively demanding increased dosages of codeine Requesting specific products by name Repeated requests Tampering with codeine formulations

23 . Displacement Patterns between OTC and Prescribed Supply Source: Cooper, R (2013:4) 'I can't be an addict. I am.' Over-the-counter medicine abuse: a qualitative study BMJ Open, doi: /bmjopen

24 Van Hout, MC (2015). Nod and Wave: an Internet study of the codeine intoxication phenomenon. International Journal of Drug Policy. 26 (1), pp Codeine Intoxication: Online user information exchange Dulling of emotional and/or physical pain, opiate withdrawal management and for intoxication. Appeal centres on access via family medicine cabinets, prescribers and over the counter in pharmacies. Oral and rectal use, optimal codeine dose per session 250mg. Online indigenous harm reduction; learning to appreciate codeine s effect via moderated use in optimal settings, avoidance of tolerance by use of informed dosing schedules, cold water extraction of codeine, and using codeine as an alternative to stronger opioids. Dissociation, synaesthesia, and out of body experiences. Potentiating practices (i.e. grapefruit) and using over-the-counter medications (anti histamine, antacids) to improve intoxication experiences and reduce unpleasant side effects.

25 Van Hout, MC (2014). Kitchen Chemistry: A scoping review of the diversionary use of pharmaceuticals for non-medicinal use and home production of drug solutions. Drug Testing and Analysis. 6, 7-8, Types of Formulation Tampering and Home manufacture of drug solutions Cold Water Extraction Methods and Nurofen Plus splicing. Oral misuse of codeine cough syrups (i.e Purple Drank, Lemon Drop) Home-made solutions containing codeine cough mixture with alcohol, benzodiazepines, caffeine, kratom and soft drinks (Kratom Cocktails). Home-made solutions for injecting purposes using over the counter codeine products, with morphine (Braun, Home Bake) or by generation of desomorphine (Russian Magic)

26 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 7 th Framework Programme, EU. Brussels.. Treatment of Codeine Dependence Clinical profiles of codeine dependents vary but are over represented by females, those in middle to late age, poly substance users, alcohol users, opioid dependents and those with underlying psychiatric conditions. The literature in relation to treatment and management of codeine misuse lacks specificity to codeine protocols. Poor long term outcomes for codeine dependents at 12 month follow up.

27 Challenges for Policy and Practice: how to ensure the availability of codeine for therapeutic use but minimise the risk of misuse? Complexity of inter-relations between the different pharmacological, social, economic, legal and individual factors which shape patterns of use and misuse. Thin dividing line between therapeutic use and misuse of codeine. Focus of European drug agencies on the problem of heroin and substitution treatment for addiction with the result that codeine misuse is often hidden or overlooked. Unsystematic and poorly integrated drug monitoring systems which make it difficult to know the true extent of the codeine misuse problem and the profile of codeine users which hampers proactive drug policies. Potential use of unregulated internet retail sites to purchase codeine and access networks of codeine users..

28 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Manufacturing Stop manufacturing combination products containing codeine and retail single ingredient tamper proof products. Increase the safety of combination codeine products through including antidotes. For example, preparations containing paracetamol could be sold in combination with an antidote, (for example methionine) so that if the dose of paracetamol is increased to the point at which it is unsafe the liver is protected. Tamperproof preparations should be required and backed by legislation and drug companies provided with incentives to invest in these products.

29 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Manufacturing Bar code individual tablets in a blister pack to allow the providence of tablets to be traced. Manufacture smaller packs of codeine which would give only 3-days supply. Producing smaller packs of 18 tablets would have the additional effect of reducing the problem of accidental stockpiling of the drug, which increases dependence risk. In addition smaller packs would probably push up the purchase cost which may be a deterrent to purchase and so decrease overall consumption.

30 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Manufacturing Dependence producing colour coding tablets and/or a warning logo on all tablets and packets of codeine containing medications. Review the safety of available opioids to identify a single standard preparation that has the maximum safety, to be used in all combination preparations sold over the counter.

31 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Product Information and Public Education Strengthen health warnings on the outside of packs of tablets containing codeine For example This medicine contains codeine to more specific warnings such as Not to be taken by children, pregnant women or breastfeeding mothers. These messages could raise customers awareness of the potential for impairment, addiction and harm, and deter development of unintended misuse and habit forming use.

32 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Product Information and Public Education Increasing the visibility of the names of generic drugs which are included in the combination tablet. Public health campaigns that highlight that anyone can become addicted to codeine. Public health campaigns and national patient information campaigns could be adapted to address the different groups of codeine misusers who require targeted messages and interventions.

33 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Product Information and Public Education Development of a protocol to guide health professionals how to approach and advise members of the public to raise their awareness of the risks of codeine misuse and dependence.

34 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Responsible Prescribing.

35 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Responsible Prescribing Codeine should be a prescription only drug. All codeine formulations being recorded at point of sale together with the patient s name. Codeine and acute pain. Protocol on the Cochrane Library of Systematic Reviews by Moore and colleagues which plans an overview of Cochrane reviews to investigate the efficacy of pain medicines available over the counter in the UK for acute pain, that is, short-term pain of less than 12-weeks duration (aspirin, paracetamol, ibuprofen, diclofenac, naproxen, and other drugs alone, and in combinations with each other, with weak opioids like codeine, or with caffeine). This review should provide guidance for health professionals and the public on self-medication for acute pain, as well as responsible prescribing decisions. Development and testing of patient risk assessment tool or procedure for codeine misuse and dependence.

36 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Responsible Prescribing Codeine and chronic pain. Emerging evidence suggests that people who take opioids for more than a month derive little benefit because of the problem of tolerance which means that patients need to take increasingly high doses. Abuse risk of codeine to be clearly indicated at time of prescription in the prescribing manuals and on prescribing decision computer software. Use of opioid agreements. Discharge of patients from pain clinics and hospital with non-opioid containing medications. Handwritten prescription to avoid repeat prescriptions which can occur almost by default and faxed to a nominated community pharmacy. Prescriptions for codeine preparations should be for a maximum of one week Increased vigilance of doctors and other health professionals to health conditions and iatrogenic cause of psychiatric symptoms associated with codeine use.

37 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Monitoring and Surveillance Monitoring codeine sales and purchases through shared patient records and realtime monitoring. Purchases of over the counter and prescribed medications recorded on the patients own data card. Periodic audits of codeine prescription and dispensing.

38 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Dispensing, Screening and Brief Interventions in Community Pharmacies Dispensing Standards advise that non prescribed codeine products should be dispensed only when single ingredient medicinal products are ineffective, as 'second line' products for treatment of pain and used in accordance with marketing authorisations for short term use (no longer than three days). Health information posters in community pharmacies. Require customers to sign on receipt of codeine preparation to indicate they are aware of its dependence potential. Identify indicators of risk of codeine misuse and dependence in community pharmacy customers. Develop a brief self-screening measure to identify pharmacy customers who misuse codeine.

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40 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Dispensing, Screening and Brief Interventions in Community Pharmacies Develop and testing a brief intervention modelled on the Very Brief Advice on Smoking Intervention developed by the National Centre for Smoking Cessation and Training (NCSCT)

41 Incorporate codeine related enquiry within pharmacists medication use reviews Strengthen the contribution of community pharmacists to treatment of codeine misuse and dependence through: a) direct referral to primary and secondary care services; and b) delivery of structured treatment programmes Recommendations for Innovation: Safety in the Workplace and on the Road Compulsory urine testing in the workplace. Employee assistance programmes. Driving under the influence of codeine.

42 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Internet Supply of Codeine and Technological Support Regular audit of top ranked Google websites to check accuracy of health information on codeine use and misuse Health warnings as a pop-up feature of Internet shopping sites Investment in m-health

43 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Internet Supply of Codeine and Technological Support Online treatment programmes for codeine dependence Websites in South Africa such as (Turn to Help) and (Codeine Care Project) offer specific online and App based information and support for individuals experiencing misuse and dependence on codeine base products Websites in the UK such as (Over-Count) and Codeine Free Me offer useful support for individuals experiencing codeine dependence.

44 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Treatment Further investigation of psychosocial and psychological interventions for codeine dependence Development and testing of standardised criteria to rate codeine dependence and treatment pathways Further development and testing of mobile phone messaging to support adherence to treatment Specialist codeine treatment clinics.

45 Norman I & Van Hout MC. (2015) Mid term review report: work package 9 - innovation. CODEMISUSED Project European Commission 7th Framework Programme, EU: Brussels. Recommendations for Innovation: Learning Resources and Training for Health Professionals Supervised patient contact experience and multi disciplinary training to support care pathways Motivational interviewing training for all health professionals.

46 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 7 th Framework Programme, EU. Brussels. Recommendations for Research prevalence of misuse and dependence, therapeutic and non therapeutic pathways and trajectories to misuse and dependence, risk profiles and characteristics of users, poly pharming practices, adverse health and social consequences, treatment and interventions, and displacement between legitimate pharmacy supply and illicit sourcing.

47 Thanking you, the CODEMISUSED Team. Correspondence: Dr Marie Claire Van Hout - mcvanhout@wit.ie

48 Funding Acknowledgement The research leading to these results has received funding from the European Community's Seventh Framework Programme FP7/ under grant agreement no Thanking you, the CODEMISUSED Team. Correspondence: Dr Marie Claire Van Hout - mcvanhout@wit.ie