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3rd ANNUAL EDUCATION DAY Saturday November 3rd, :35 – 13:25

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1 3rd ANNUAL EDUCATION DAY Saturday November 3rd, 2012 12:35 – 13:25
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Not 4 Me Handouts provided, as there is always some tall person that decides to sit in the front! 3rd ANNUAL EDUCATION DAY Morgan Creek Golf Club, Surrey Saturday November 3rd, :35 – 13:25 T3 for the 3rd annual conference – I’d like to congratulate and thank the organizers for this remarkably coordinated tie-in! Seems like a natural, so I’m so glad to be here! This presentation provides insights why codeine, and codeine with acetaminophen products are poor choices for pain control, despite being the most popular Canadian prescription analgesic. Audience participation evoked to examine prescribing and current use of analgesics and choices they might now otherwise use. Codeine has been well noted in pain publications to not be metabolized by 5-10% of Caucasians. Yet, this information understates the difficulties utilizing codeine or acetaminophen plus codeine products for effective pain control. Participants develop a deep understanding of additional reasons for rejecting codeine as an effective analgesic. These reasons include hyper metabolizers of codeine, the lack of predictive capability to determine genetic hypo and hyper metabolizers of codeine, evidence based systematic reviews of codeine analgesic potency, drug interactions risks, safety risks and deaths that have occurred, abuse liability issues (codeine versus other opioids), street abuse, and why from a population wide basis, codeine falls short as an effective analgesic choice. UNIQUE PRESENTATION ** NOT TO BE MISSED ** BRUCE KENNEDY BSc.(Pharm.) M.B.A. Clinical Pharmacy Specialist – Palliative Care 1

2 T3 Composition Codeine 30 mg Caffeine 15 mg Acetaminophen 300 mg
Slide created by Bruce Kennedy, Palliative Care Pharmacist, T3 Composition Codeine 30 mg Caffeine 15 mg Acetaminophen 300 mg Brands: Tylenol No. 3 Generics: Novo-gesic C30, Acet 30 (PMS), Ratio-Lenoltec No 3 From Wikipedia: Caffeine citrate (Cafcit) is a citrate salt of caffeine, sometimes used in medical treatment, including short-term treatment of apnea of prematurity (lack of breathing in premature infants). Caffeine citrate functions in much the same capacity as does caffeine, but takes effect more quickly; its speed of dissociation is faster than that of caffeine. Like its sister compound, it can be used to dispel pain from a headache. However, caffeine citrate is typically only used to treat severe migraines. The drug is prepared simply by combining anhydrous caffeine with citric acid monohydrate and sodium citrate dihydrate. In method of action, the preparation is exactly identical to that of caffeine base as the citrate counter ion dissociates in water. Doses of caffeine citrate, due to the added weight of the citrate moiety, are understandably higher than with caffeine base, i.e., it takes a larger dose to get the same amount of caffeine. The ratio of therapeutic doses of caffeine base to its citrate salt is typically 1:2. It is therefore generally recommended that caffeine is prescribed in terms of caffeine base, and not caffeine citrate. Exdol 30 – 300 mg acetaminophen, 30 mg caffeine, 30 mg codeine – by Pendopharm (PMS)- no longer available – contacted PSM (Nadine in Medical Information) MD could write Rx for Tylenol #3 and patient receive Lenoltec #3 – does patient know if it has acetaminophen in it? Maybe not. I hope you will really enjoy this presentation today, and thank you to the conference organizers for accepting me to present it. I want to convince you not to use codeine, and to help me spread the word. Atasol 30 (often used in hospital) is similar, but slightly different; - has same codeine content 30 mg, - has extra acetaminophen content 325 mg, - has 30 mg caffeine citrate (but this provides same net caffeine of 15 mg as the others) 2 2

3 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Ibuprofen 400 mg when studied in 5456 patients had a NNT of 2.5 ! (in moderate to severe pain. Versus Placebo, pain relief over 4 to 6 hours NNT is Number Needed to Treat (for 1 in the group to get 50% pain relief) When codeine was studied in 1305 patients – only 196 or 15% received a 50% reduction in their pain !! (Oxford League Table – checked Oct 30, 2012) Terrible NNT Codeine 60 mg NNT = 16.7 Lower confidence level 11, higher 48 i.e. “at best 1 in 11, at worst 1 in 48” get 50% pain relief In 1305 pts studied only 15% have 50% pain reduction* Worst analgesic on Oxford chart* Some studies - no better than placebo** Acute Pain Systematic Reviews*** Addition of 60 mg codeine to acetaminophen added but 5 to 12% additional benefit reThe Oxford League Table of Analgesic Efficacy 1305 patients studied to get the NNT of 16 for codeine. There were 22 other comparitive analgesics on this chart. (4 of the 22 were combinations with acetaminophen) And the average NNT for the 22 other choices was ___ next worse on chart was 50 mg of tramadol with a NNT of 8.3 Numbers needed to treat are calculated for the proportion of patients with at least 50% pain relief over 4-6 hours compared with placebo in randomised, double-blind, single-dose studies in patients with moderate to severe pain. Drugs were oral, unless specified, and doses are milligrams. Later if possible, obtain JAGS ;521-3 Appraisal of codeine as an analgesic in older patients. Jochimsen PR, Noyes R Pain 1997 paper says that extra codeine 60 mg has a NNT of 9.1 meaning that for every pt given 600/650 mg acetaminophen plus 60 mg codeine, only ONE will achieve at least 50% pain relief who would not have if they received acetaminophen alone. So it’s possible that the addition of codeine may produce additional pain relief, but it’s much more likely that it won’t. Pain paper says placebo response is 3 – 48% in comparing the response of acetaminophen to placebo The NNT of 16 for codeine was with 1305 patients being studied West J Med :428 – Myth: codeine is a powerful and effective analgesic. Pooled 19 single-dose trials (BMJ 1996;313;313-25) showed that adding codeine as measured by the sum peak intensity difference was only 5% more, while was similar in regards to results in peak pain-intensity difference, total pain relief, and peak pain relief. And single dose studies – similar incidence of adverse effects, but greater in multidose studies. *Oxford League Table of Analgesic Efficacy 2007– Number Needed to Treat (NNT) ** J Clin Pharmacol 1984;24: An appraisal of codeine as an analgesic single-dose analysis, Br. J Anesthesia (6): Predicting postop analgesia outcomes: NNT league tables or procedure-specific evidence? ***Pain 1997 Paracetamol with and without codeine in acute pain: a quantitative systematic review, BMJ Analgesic efficacy and safety of paracetamol-codeine combination versus paracetamol alone:a systematic review 3 3

4 Codeine needs conversion to be an effective analgesic
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine needs conversion to be an effective analgesic Per this site, C-6G has have affinity to codeine mu opioid receptor, AND norcodeine also has a similar affinity to codeine – must be really, really low. Codeine is not an analgesic. What it transforms into IS an analgesic! Highly Polymorphic per Codeine and Morphine Pathway The CYP2D7 gene is generally considered a pseudogene; however a genetic variant resulting in a frame shift can cause active protein to be produced that is able to metabolize codeine to morphine Other point is that variations in CYP3A4 can have an affect mainly because if that route of metabolism is also shut down, say by a drug – codeine parent molecule builds up to cause toxicity. 53% of drugs via 3A4 per The importance of cytochrome P450 in palliative medicine Supp Care Cancer 2001 Variation in CYP3A4, or co administration of drugs that act at CYP3A4, can affect flux through the codeine pathway over 75 different variants of 2D The Oncologist 11: Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications of which 10 are the most important. 100 variants per Pharmacogenomics article sep 2008;9(9): Parvaz Madadi and Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use Per 1996 Drug Metabolism and Dispostion 24(7) Microsomal codeine n-demthylation: cosegregation with cytochrome P4503A4 activity the inhibition of 3A4 by drugs may produce greater 2D6 metabolism and greater morphine production. This conversion is going to be dependent on hepatic blood flow, so it will depend on the heart pumping ability Codeine is a pro-drug. Is pro short for problematic? Probably going to convert? Pro and Con “before it Converts? Wiki.answers.con says “pro” means forward “Occurring before” – derived from Greek “Prothrombin” profain, pro-found pro can also be in favour of. I’d definitely be in the con group for this pro-drug. Which would make me anti-pro-drug. Once the patient swallows codeine – a lot of complicated different individual things happen 4 4

5 Yet Same Occurrence of Adverse Effects
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Yet Same Occurrence of Adverse Effects 170 mg codeine doses 18 patients: 9 Poor Metabolizers (PM), Extensive Metabolizers (EM) No differences in adverse effects, but PM’s – only 0.17% morphine conversion (and no pain benefit) versus EM’s – 3.9% conversion into morphine 23 X difference ! 7-10% of Caucasians do not derive analgesic benefit from codeine – this quote came from Caraco et al 1996 –this was used as the reference for this info in 2008 Managing Pain book by Roman Jovey. The adverse effects studied in this pain study were: sedation, headache, dizziness, euphoria/dysphoria, relaxation, blurred vision, nausea, pruritus, flush, dry mouth. J Am Geriatr Soc Nov;26(11):521-3. Appraisal of codeine as an analgesic in older patients. Jochimsen PR, Noyes R Jr. Abstract In an investigation of a new oral analgesic agent, codeine was chosen as the reference drug because of its established reputation as an effective agent for the relief of pain. Thirty-five patients with cancer pain were studied. Their average age was 58 years, During a 5-day hospital stay they received, on each of three days, either codeine (120 mg or 60 mg) or placebo. At hourly intervals after ingestion the nurse observer collected data on pain intensity and the degree of pain relief, and the patients independently charted the hourly intensity. Statistical analysis failed to show any significant superiority of either dose of codeine over placebo. Moreover, codeine is known to have a constipating effect. Re-appraisal of the value of codeine as an analgesic agent in elderly patients seems justified. Pain :27-33 Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation 5 5

6 So then changes your 2D6 capability
Slide created by Bruce Kennedy, Palliative Care Pharmacist, When you age… So then changes your 2D6 capability CYP450 activity very low at birth CYP2D6 less than 1% activity in very young CYP2D6 still less than 25% when < 5 years old Australian prescriber concludes that “the wide variation in individual metabolism and the unpredictable influence on age on the effectiveness and safety of codeine means that it’s routine use in children is not recommended. It can be argued that he use of a small dose of morphine is preferable as it is more effective and predictable. Is there nothing that stays the same as you age? Also get the Pharmacogenomics article sep 2008;9(9): Parvaz Madadi and Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use – got it see minimum age recommendations Switzerland 10 years, Ireland 6 years, USA 3 Years, Canada 2 years, UK, France, Netherlands – 1 year, Germany 7 months. Comment from Tylenol with codeine elixir from eCPS accessed July 20, 2011 is just this: Safe dosage of the TYLENOL with Codeine Elixir has not been established in infants below the age of 2 years. Dextromethorphan 2008 Health Canada notice re not less than 6 years old for cough: 2008 Australian Prescriber June 31(3):63-5 Pediatric analgesia 6 6

7 Codeine pediatric use; impactful Canadian deaths
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine pediatric use; impactful Canadian deaths Newborn Breastfeeding case – Aug 2006 Mom took codeine 60 mg mg acetaminophen q12h x 2 days then 30 mg and 500 mg q12h x 14 more days Mom ultra rapid metabolizer, infant EM Two year old adenotonsillectomy – Aug 2009 Healthy 13 Kg, Hx snoring, sleep apnea Codeine mg q4-6h. Died 9 am Post-op Day 3 Ultrarapid metabolism-> morphine toxicity Four year old tonsillectomy - reported April 2012 Died at home after only 4 age-appropriate doses of 8 mg The 2012 article also describes one death of a 5 year old boy in the US, and a near miss in Canada NEJM 2 year old: Tonsils, Adenoids removed. Within 1 to 3 mg/Kg codeine/day recommended dose. Surgery was uncomplicated. Risk factors were that 1/3rd of cases of apnea do not resolve after this surgery, Autopsy showed bronchopneumonia which increased the hypoxic risk. Day 2 had fever and wheeziness. Australian prescriber concludes that “the wide variation in individual metabolism and the unpredictable influence on age on the effectiveness and safety of codeine means that it’s routine use in children is not recommended. It can be argued that he use of a small dose of morphine is preferable as it is more effective and predictable. Use of codeine in pediatrics has developmental AND genetic phenotype issues. Is there nothing that stays the same as you age? Also get the Pharmacogenomics article sep 2008;9(9): Parvaz Madadi and Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use Speaking of unpredictability. When will this reoccur? It’s unpredictable Dr von Dadelszen commented “ why use a constipating compound that relieves very little extra pain and is potentially dangerous for babies. It has tragic consequences in this country” The Annals of Pharmacotherapy 2003 Prediction of Milk/Plasma concentration ratio of drugs37: Ratio of codeine milk to plasma is 2.16 What kind of mind names a hospital “Sick Kids” ?? Dr Koren from Sick Kids in Toronto 17/72 newborns had signs of CNS depression – sedation, abnormal breathing Details(for Lancet 2006): April 2005 : Sx on Day 7-difficulty breastfeeding and lethargy starting, dead on Day 13 Postmortem no anatomical anomalies. Morphine level 70 ng/mL (versus typical zero to 2.2 mg/mL) She took codeine 60 mg and 1000 mg acetaminophen q12h x 2 days then 30 mg and 500 mg q12h x 14 more days Milk conc 87 ng/mL versus usual 1.9 – 20.5 ng/mL when on 60 mg codeine q6h CMAJ 2007: Thought to be the first record of a breastfed baby succumbing to toxicity through breast milk 3.88 Kg BW, male 90th percentile, unremarkable pregnancy and delivery. Says used Tylenol #3 but content of 500 mg acetaminophen (error?) Mom 3 functional 2D6 alleles, dad and baby 2 functional alleles. Peak morphine levels (first two days may have been 100 ng/mL versus expected around 2.2) Recommendations: Avoid codeine, use NSAIDs. Use codeine only 2-3 days only to prevent neonatal accumulation Genotype all postpartum women about to receive codeine. But notes that currently these tests are not available in most clinical facilities Follow monitor for opioid toxicity, test to morphine levels if ADR consistent, use naloxone prn Lancet 2008 Author’s reply; Four other premature infants exhibited apnea 4 to 6 days after 60 mg codeine administration to mothers – 1985 Develop Pharm And one other one they found. 2006 Lancet 368:704 Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother Canadian Family Physician Jan;53:33-5 Safety of codeine during breastfeeding 2009 NEJM 361:8 Aug 20 Codeine, ultrarapid-metabolism genotype and post operative death 2012 Pediatrics More codeine fatalities after tonsillectomy in North American children 129:e1-e5 7 7

8 Another pediatric case report
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Another pediatric case report 3 yr old admitted to ER with mom with cough/fever Taking long acting cough mixture with codeine, acetaminophen, ibuprofen, ivy extract x 6 days 2 & ½ hours later father finds twin brother dead in bed. (massive aspiration of gastric contents, diffuse cerebral edema) Misdosing 10 drops, not 0.5 mL using dosing spoon Each drop dose could vary from 12 to 23 mg codeine (instead of intended daily codeine dose of 10 mg) Both twins were ultrarapid metabolizers->morphine toxicity Surviving twin ventilated x 3 days, had severe hypotension I hate to use another pediatric case to emphasize the potential toxicity of codeine, but the impact show the significance of this problem, Formulation had 2 mg codeine per 82 mg of the formulation. Ten drops varied from to mg of the formulation and hence providing a variation between 12.3 to 23.4 mg of codeine. According to the company 10 drops weigh 500 mg of the formulation and contain 12.5 mg of codeine The German mixture contains 25 mg of codeine in 1 g of the commercial solution. It is in a cation exchange resin complex Surviving twin weighed 13.4 mg Twin that died weighed 14 kg “Killer cough” References for not using codeine according to these two papers include: American Academy of Pediatrics Committee on Drugs (1997) Use of codeine and dextromethorphan-containing cough remedies in children Pediatrics 99: and Chest :72S-74S Cough and the common cold: ACCP evidence based clinical practice guidelines Pratter MR December 18, 2008 – Health Canada said dextromethorphan should not be used in children under 6 years of age. Lead to the withdrawal of this codeine formulation in Germany It was a codeine retard by Heinrich Mack Nachf, Germany 2009 Eur J Pediatr 168: Drug dosing error – severe clinical course of codeine intoxictation in twins Int J Legal Med 123: Fatal and severe codeine intoxication in 3 year old twins – interpretation of drug and metabolite concentrations 8 8

9 Codeine’s routine use is not recommended in children
Slide created by Bruce Kennedy, Palliative Care Pharmacist, FH May 4, 2012(- was a rather weak response – and merely a “be aware” type of direction) Good Afternoon All, You have most likely heard of this matter through other means, however I wish to take this opportunity to alert you to the impact these recent reports may have on practice in Fraser Health. The main concern is that there may be Pre-Printed Orders (PPOs) which promote the use of codeine for children.  Until policy decisions are made regarding codeine use in children, there are several interim actions that can be taken to mitigate the risk:  Check pediatric/obstetric practice areas to identify and revise obstetric and post tonsillectomy PPO’s following guidelines in attached memo  Identify and revise other at-risk PPOs       The codeine risk among the general pediatric population is controversial however, the programs should review and determine the most appropriate course of action for the general pediatric population. C    Collaboration between Program and Pediatric Clinical Pharmacy Specialists (CPS) is paramount to ensure that areas which have at risk PPOs can be identified and revised. Please  share this information through your program clinicians to ensure that the PPO review and revisions occur as soon as possible. If you have any questions, please feel free to contact me. Thank you,  Janice  Janice Munroe BSc.Pharm. Fraser Health Medication Safety Coordinator Lower Mainland Pharmacy Services Codeine’s routine use is not recommended in children Removed from Toronto’s Hospital for Sick Children’s formulary UK commission for Human Medicines says not suitable to use OTC codeine medicines in children under 18 years of age Canadian physicians calling for halt to use; UBC Ob Gyn MD Dr Peter von Dadelszen wants T3 banned Globe & Mail Aug 22, 2008, Mar 31, 2009 CMAJ 2010 article – is it time to phase out codeine? Vancouver pediatrician Dr Noni MacDonald Dr Stuart MacLeod CMAJ section editor, Public Health Australian prescriber concludes that “the wide variation in individual metabolism and the unpredictable influence on age on the effectiveness and safety of codeine means that it’s routine use in children is not recommended. It can be argued that he use of a small dose of morphine is preferable as it is more effective and predictable. Is there nothing that stays the same as you age? Also get the Pharmacogenomics article sep 2008;9(9): Parvaz Madadi and Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use – got it see minimum age recommendations Switzerland 10 years, Ireland 6 years, USA 3 Years, Canada 2 years, UK, France, Netherlands – 1 year, Germany 7 months. Comment from Tylenol with codeine elixir from eCPS accessed July 20, 2011 is just this: Safe dosage of the TYLENOL with Codeine Elixir has not been established in infants below the age of 2 years. Dextromethorphan 2008 Health Canada notice re not less than 6 years old for cough: Accessed June 1, 2009 from: MD wants codeine banned at hospital Obstetricians weigh response after study exposes risks for breastfed babies LISA PRIEST From Friday's Globe and Mail, Tuesday, Mar. 31, :33PM EDT Canada's obstetricians say a study showing how a popular pain reliever can turn a mother's milk into a toxic brew for newborns has raised warning bells, with one doctor asking the country's busiest maternity hospital to yank the product off its shelves. "My suggestion is that all obstetric units across this country remove T3s [Tylenol 3] from their obstetric formulary," said perinatologist Peter von Dadelszen, associate professor of obstetrics and gynecology at the University of British Columbia. "... I've actually contacted the hospital leadership [at BC Women's Hospital] asking that it be yanked completely so we no longer have it available." Also yesterday, the Society of Obstetricians and Gynecologists of Canada said it will meet next week with the Canadian Pediatric Society to discuss the best and safest pain relief for nursing mothers - with an eye to having a guideline on the subject by 2009, said its executive vice-president, André Lalonde. "We don't want to panic people here. There's kind of a warning bell going out there, but we need a lot more studies to see it," Dr. Lalonde said in an interview from Ottawa. "The general advice is to take the smallest dose possible." The reactions follow a study by Gideon Koren, Parvaz Madadi and colleagues showing how nearly one-quarter of babies whose mothers took codeine while breastfeeding showed signs of central nervous system depression, such as sedation or abnormal breathing. Tariq Jamieson died in 2005 at 12 days old of a morphine overdose he got through his mother's breast milk. Rani Jamieson, an accountant in Toronto, had been prescribed codeine after she gave birth. She later learned that she carried multiple copies of a gene capable of converting the common pain reliever into strong concentrations of morphine. The Jamieson case was thought to be a rare pharmacological phenomenon; however, in the new study, 17 of 72 newborns showed symptoms of central nervous system depression, leading researchers to conclude it occurs more frequently. That has led Dr. Koren, director of the Motherisk Program at the Hospital for Sick Children in Toronto, to conclude that codeine as a treatment for mothers cannot be considered safe for all breastfed infants. Codeine is made by several drug companies, and is contained in Tylenol 3. The pain reliever, Dr. Koren estimates, is prescribed to as many as 120,000 Canadian women a year after childbirth. Shellie Suter, spokeswoman of Janssen-Ortho Inc., which markets the drug in Canada, said the company could not comment on the study as it has not had time to review it sufficiently. "The safety of patients who use our products is a priority for the company," Ms. Suter wrote in a prepared statement. "TYLENOL 3 (prescription Tylenol with codeine) is a safe and effective product when used according to the approved prescribing information." Canadian pharmacies dispensed more than 5.3 million prescriptions for the codeine-and-acetaminophen combination pills last year, according to IMS Health, a private health-information and consulting-services company. Prescriptions for the drug have fallen slightly, with 5.4 million prescriptions filled in 2006 and 5.6 million in 2005. No professional organization in Canada has guidelines on breastfeeding and codeine, but the American Academy of Pediatrics recommends it as compatible with nursing. That guideline was already being revisited before the Clinical Pharmacology & Therapeutics study was published on Wednesday. Now, experts are taking a closer look at it, said Ruth Lawrence, chairwoman of the section on breastfeeding for the American Academy of Pediatrics. "This recent revelation about codeine is of concern because codeine has always been pretty much treated rather casually," Dr. Lawrence said in a telephone interview from Rochester, N.Y. "... Probably the best advice to people is to be very cautious about using compounds that contain codeine." Ruth Wilson, who is president of the College of Family Physicians of Canada and still delivers babies, said she rarely prescribes codeine to mothers. "In my own practice if someone needs codeine, I think hard about it and make sure there is no other cause for that amount of pain," Dr. Wilson said. "In my own clinical experience, they [new mothers] can manage without it." Health Canada has said it is studying proposed labelling changes that better identify the potential risk to nursing children from codeine in breast milk. Codeine is rarely dispensed to mothers after childbirth in Europe, Britain or New Zealand, said Dr. von Dadelszen of BC Women's Hospital. He said other drugs can be used for pain relief. Two years ago, he and others lobbied to tighten access to codeine at his hospital so that a specific order has to be made to prescribe it. (It no longer comes through regular postpartum orders.) Yesterday, he pushed the issue further, asking hospital management to remove it for use after childbirth. "Why use a constipating compound that relieves very little extra pain and is potentially dangerous for babies," Dr. von Dadelszen asked. "It has had tragic consequences in this country.“ Posted AT 3:25 AM EDT on 22/08/08 From Friday's Globe and Mail 2010 Oct 4th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups 2010 Nov 23 Cdn Medical Assn Journal Has the time come to phase out codeine? p1825 9 9

10 Literature reports variable
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Ceiling effect T3: 3 ingredients, 3 ceiling’s each likely different depending on individual’s tolerance and pain Acetaminophen maximum 4 g/day (or less ~2.5 g-some patients) Codeine maximum Max dose: 240* to 800 mg/day Likely about 7 mg/kg Max single dose 60* to 120 mg Maximum dose unknown. But we don’t exactly know where the ceiling exists (poorly studied, literature inconclusive), and anyway will be individual These old references likely were not sure where the maximum dose was, because different people tolerated codeine differently But again, the maximum (either unknown/variable) is kind of irrelevant when we know that single dose effect is unpredictable, making the ceiling similarly variable between patients. Hey if the Maximum Codeine dose according to Martindale’s is 240 mg which is equi-equivalent to 24 mg of morphine. – if you were to Start a patient on morphine it would be around say 10 mg MS Contin bid or 20 mg per day, which is darn close to this 24 mg per day codeine maximum MAX DOSE/DAY Literature reports variable *Martindale 36th Ed 2009 10 10

11 WHO Ladder – Cancer Pain
Slide created by Bruce Kennedy, Palliative Care Pharmacist, WHO Ladder – Cancer Pain Pain persisting, or increasing Step 3 Opioid for severe pain +/- Step 1 choices Step 2 Opioid for moderate pain +/- Step 1 choices Step 1 Non-opioid +/- adjuvants Weak Opioids Address only a narrow portion of pain requirements. Need to by-pass them more often (weak’s work for 30%) versus 50% needing strong opioids “unnecessary” switch to another drug. Why create another potential problem and need for titration? Due to ceiling – you know it’s there Ladder released in 1986 WHO Cancer Pain Relief publication Generally considered a framework, rather than a rigid protocol. Pain management must be individualized. Meant to provide simple guidelines that were easy to follow. Major consequence of the ladder was the legitimizing of the use of strong opioids. The ladder generally applies to chronic pain of non-malignant origin as well A common misconception is that the prescriber must start at Step 1. It is acceptable to start at any point on the ladder, the goal is to tailor treatment to the severity of the pain. Reference for the % of patient in the mild, moderate, severe categories :2005 Palliative Medicine 19: Pain and pain treatments in European palliative care units. A cross sectional survey from the European association for palliative care Research Network – 3030 cancer patients, 143 palliative care centers in 21 European countries Could mention that Dr. Twycross is coming for 3 lectures during the first week of May, one of the 3 will a lecture to the public – topic Dying Well in the 21st century: unmet needs and the Worldwide Challenge. Plus one for professionals called: Evidence-based palliative care: realistic option or oxymoron The need for the 2nd step has been questioned, and when I put the question of codeine’s usefulness to Dr T he did agree that it’s not a particularly needed when other options are available. 11 11

12 What Dr Twycross is saying now
Slide created by Bruce Kennedy, Palliative Care Pharmacist, What Dr Twycross is saying now It is perhaps practical to skip Step 2 in countries where palliative care is well established Some pediatric PC services omitted Step 2 many years ago No absolute pharmacological need for starting with a weak opioid before progressing to a strong opioid Exception: Lack of access in some countries to strong opioids such as morphine Palliative Care Formulary Canadian Edition 2010 12

13 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine requires cautious and reduced dosing in both renal and hepatic impairment I’d say avoid completely in renal impairment, same for morphine – especially if dosing regularly Dosing adjustment in renal impairment: GFr mL/minute: Administer 75% of dose*,** GFr <10 mL/minute: Administer 50% of dose*,** Dosing adjustment in hepatic impairment: “Probably necessary”** Reduced hepatic blood flow or enzyme dysfunction - can significantly will affect conversion rate of codeine into morphine Accessed June 1, 2008 Micromedex Hepatic impairment comment: Dosage in Hepatic Insufficiency A)  Dosage reduction is probably indicated in patients with hepatic insufficiency. It is known that the duration of action of morphine is prolonged and requires dose adjustment (Schiff, 1969; Beckman, 1967). *2007 Drug Prescribing in Renal Failure 5th Ed Aronoff GR, Bennett WM, et al **http://www.merck.com/mmpe/lexicomp/codeine.html 13 13

14 Prodrug Conversion Conversion delays pain relief onset
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Prodrug Conversion C -> M Conversion delays pain relief onset Primary use of T#3 = p.r.n. dosing and is when onset of effect is important Drug Time to Onset PO Codeine 60 min +/- 30 min Morphine 30 – 90 min This assumes the conversion takes place. If it doesn’t how long does it take for this to be discovered, and an adjustment made, a different drug administered. Or potentially the patient gets 2 T#3 instead. – 8 hours of no pain relief The Pharmacological Basis of Therapeutics Clinical Pharmacology: The onset of action occurs within 10—30 minutes after intramuscular administration and 30—60 minutes after oral administration. Peak analgesic effects are achieved after 30—60 minutes following intramuscular administration and 60—90 minutes after oral administration and maintained for 4—6 hours. Peak antitussive activity is achieved within 1—2 hours of oral administration and can last for 4—6 hours. Micromedex: Onset and Duration A)  Onset 1)  Initial Response a)  Analgesia, all routes: 30 to 60 minutes (Gilman et al, 1990; Sevelius et al, 1965; Ruedy & O'Boyle, 1971). b)  Antitussive: 1 to 2 hours (Prod Info Brontex(R), 1997). 2)  Peak Response a)  Analgesia, Oral: 2 to 4 hours (Ruedy & Oboyle, 1971). B)  Duration 1)  Single Dose a)  Analgesia, all routes: 4 to 8 hours (Sevelius et al, 1971l Gilman et al, 1990). b)  Antitussive, all routes: 4 to 8 hours (Sevelius et al, 1971l Gilman et al, 1990).  2.2   Drug Concentration Levels A)  Therapeutic Drug Concentration 1)  Analgesia, 0.03 to 0.25 mcg/mL but does not correlate with brain concentration or relief of pain (Prod Info Fiorinal w/Codeine, 1997)(Schulz & Schmoldt, 1994). B)  Time to Peak Concentration 1)  Oral, 1 to 2 hours (Waife et al, 1975). 2)  Intramuscular, 30 minutes (AMA, 1980). 3)  Rectal, 30 minutes (McEwan et al, 2000). Goodman & Gillman’s The Pharmacological Basis of Therapeutics 2001 p 1946,1985 14 14

15 Drug Interactions - another problem
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Drug Interactions - another problem 2D6 drug inhibitors impact codeine’s conversion; delays pain relief reduces max blood level reduces pain relief increases toxicity risk CYP2D6 – involved in 11 to 25% of all drugs Many common drugs Less Drugs Less NEJM (27) p Codeine intoxication associated with ultrarapid CYP2D6 metabolism Chronic lymphocyctic leukemia 62 year old 3 day Hx fatigue, dyspnea, fever and a cough Only on valproic acid 1500 mg per day. 25 mg codeine started. Also ceftriaxone, clarithromycin, voriconazole On day 4 – bp way down – to ICU Glasgow scale was 6 (no eye opening, no verbal response, limb withdrawal after pain stimulation) Patient had 3 or 4 functional 2D6 alleles 11% was the Netherlands study 2007 The Annals of Pharmacotherapy Prevalence of patients using drugs metabolized by cytochrome P4502D6 in different populations: a cross-sectional study. Vol 41” One study with 15% of the population (Netherlands) had 11% PM, 4% UM, and 50% of psychiatric, 49% of pyschogeriatric, 46% of geriatric, used at least one drug metabolized by 2D6 NNG = Number needed to genotype to find one was 6.7 The 25% was from :The importance of cytochrome P450 in palliative medicine Supp Care Cancer 2001 Other drugs get in the way of codeine getting metabolized Over 75 different variants of 2D The Oncologist 11: Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications of which 10 are the most important. Highly Polymorphic per Codeine and Morphine Pathway Interactions 15 15

16 Codeine Drug Interactions
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine Drug Interactions Generic Drug Rank 2011* 2D6 Enzyme Impact on Codeine’s Pain Relieving Ability Citalopram 12 Substrate Venlafaxine 13 Inhibitor Trazodone 30 Risperidone 34 Amitriptyline 43 Celecoxib 49 Paroxetine 51 Substrate + Inhibitor Buproprion 55 Escitalopram 60 Ranitidine 69 Oxycodone 70 Sertraline 74 2011 STATs from: Could be a “useful” interaction – if you put patient on say fluoxetine – reduced codeine intake by 56% 2010 information obtained June 6, 2011 from: Notice the impact of all these commonly prescribed drugs on the already weak ability of codeine to relieve pain. Fatal intoxication with a SSRI, lorazepam and codeine case report The American Journal of Forensic Medicine and Pathology 28(4) year old. Ankle fracture – 30 mg and 60 mg codeine with acetaminophen Codeine was implicated by the pathologist in causing 2D6 reduced sertraline metabolism – toxic sertraline levels and a fatal serotonin syndrome Drug companies are trying to avoid the 2D6 enzyme when developing new drugs. *2012 Feb Pharmacy Practice Top Rx Drugs of 2011 Cytochrome Drug Interaction Table v 16 16

17 Other common drugs potentially interacting with codeine
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Other common drugs potentially interacting with codeine Inhibitors Amiodarone, cimetidine, chlorpheniramine, cocaine, diphenhydramine, duloxetine, fluoxetine, hydroxyzine, methotrimeprazine, methadone, metoclopramide Substrates Carvediolol, dextromethorphan, fluoxetine, fluvoxamine, haloperidol, lidocaine, metoclopramide, nortriptyline, ondansetron, propranolol, tamoxifen, tramadol Inducers Dexamethasone, rifampin And this is not a complete list. Consult pharmacist, or current drug interaction text 17 17

18 Life threatening codeine intoxication with drug interaction
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Life threatening codeine intoxication with drug interaction 62 yr old, lymphocyctic leukemia Dyspnea, fever, cough ER: ceftriaxone, clarithromycin, voriconazole, codeine 25 mg tid Day 4 unresponsive Ultra rapid metabolizer plus secondary codeine metabolism route inhibited by clarithromycin & voriconazole Morphine levels X higher than expected NEJM : Codeine intoxication associated with ultra rapid CYP 2D6 metabolism Erratum NEJM 2005;352:638 18 18

19 Codeine 2010 Morphine need was but 3.5 tons
Apparently 1 million grams in a metric ton Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine Is globally the most widely used narcotic Canada’s estimated 2012 need is 30 tons This is 5.7% of the world’s consumption For 0.49% of the world’s population Per capita we are #1 codeine consumers World Population: 7,077,969,692 Canada’s Population: 34,781,799 37th largest of 229 countries 0.49 % of world 2012 figures: World requirements 473,684,882 grams, Canada is 5 400,000 grams (2012 early) Canada’s is 26, 803,689 grams (September 2012 update) = 26,803,689 is 26,803 Kg and this (per converunits.com) is equal to 29.5 metric TONS World populations as of October 31, 2012 Canadians are the world’s largest consumers of codeine per capita, but we import all our opiates from France and Australia. Per website I googled 2004 was up by 3 tons ( %) from 2003 The statistic about codeine being the most widely used opiate globally came from page 81 of Actually for 2010 it went down to 26.2 tons per 2009 figures from Document from incp on work Populations stats taken on April 13, And 4 days later World population increased by 868,384 and Canada’s population increased by 3,010 Codeine should NOT be the most widely used narcotic worldwide. Morphine is the abundant opioid extracted from the poppy plant. Most of the codeine is from the conversion (think extra cost) to transform natural morphine back into codeine. Parts of the world don’t have very limited opioid access. 2010 Morphine need was but 3.5 tons The International Narcotics Control Board provides daily population figures 19 19

20 Canada’s Needed Opioids for 2012
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Canada’s Needed Opioids for 2012 Opioid Grams Codeine 26,803,689 Cannabis 16,384,044 Oxycodone 9,590,430 Morphine 6,500,000 Methadone 2,601,682 Hydromorphone 1,493,485 Meperidine 1,800,000 Fentanyl 155,1000 Hydrocodone 124,293 Sufentanil 298 Jokes: Cannabis needs for BC are likely less than the national average here in BC In fact don’t we export from here? Imagine the tax revenues if were legalized Accessed April Oct 2, 2012 update: Estimated Requirements of narcotic drugs

21 Round and Round Hydromorphone Morphine extracted Hydrocodone
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Round and Round Drug Range Usual Morphine 8 to 19% 15% Codeine 1.25 to 4.3 % Say 3% Thebaine Up to 5% Not stated Papaverine Zero to unknown Narceine Not medically used Narcotine Hydromorphone Morphine extracted Hydrocodone Codeine synthesized (Lab) Converts back to Morphine in body Codeine is usually synthesized from morphine, which is more abundant in nature. Per 94% of the global manufactured morphine goes into making codeine. Per Pharmacogenomics (9) Pharmacogentic insights into codeine analgesia: implications to pediatric codeine use. In the US 43.3 tons of codeine were used in the manufacture of other drugs – mainly to make Hydrocodone per page 82 90 – 95 % used per website accessed April And stated that 2009 was 95% morphine used to make codeine Accessed Nov 3 , 2012 from: My summary from the article: 6 main alkaloids. (but there are 20 other alkaloids that have little or no significance medically or economically at this time) About 5 times more morphine in a poppy plant than codeine! DrugRange Usual Morphine8 to 19%15%Codeine1.25 to 4.3 %Say 3%ThebaineUp to 5%Not statedPapaverineZero to unknownNot statedNarceineNot medically usedNarcotineNot medically used 95 % of global morphine is used to make codeine through a semi-synthetic manufacturing process Per 21 21

22 Frequency of CYP2D6 phenotypes in White Populations
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Genotyping “It might be good if physicians would know about the CYP2D6 genotype before administering codeine” Frequency of CYP2D6 phenotypes in White Populations Costs $$$, Unable to obtain as only available in research labs 7-10% of Caucasions do not derive analgesic benefit from codeine – this quote came from Caraco et al 1996 –this was used as the reference for this info in 2008 Managing Pain book by Roman Jovey page 147 – how simplified! 7-10% simplifies, range is 0- 27% is the reality. 27% comes from Pain and Chemical Dependency Book, highly polymorphic Note how there is an equal chance of being a poor metabolizer as being an ultrarapid metabolizer. About 7 – 10% for each. 29% Ethiopian UM, and 1.8 PM – per Oncologist Ultrarapid metabolizers: 1% Finland and Denmark, 10% in Greece, 29% Ethiopia per CMAJ 2007 Jan 53:33-5 Safety of codeine during breastfeeding Overall Western Europeans 5.45 Ultra-rapid metabolizers, range 1-10% depending on country of origin per 2009 Clin Pharma Ther 85 Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine The Pharmacogenomics Journal 2007;7: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D NEJM 351:27: Genes and the response to drugs 2010 Oct 4 Cdn Press Consider abandoning codeine until more safety research is done 22 22

23 Genetic Variations 144 variants of 2D6 exist*
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Genetic Variations 144 variants of 2D6 exist* Results in significant unpredictablity Unattainable to know patient’s CYP2D6 enzyme activity Drug effect, titration requires monitoring Ultrarapid metabolizers (UM’s) Have like dual convertor chambers (allele’s) 30 mg codeine in a UM has same effects as 45 mg in an EM (1.5 fold increase in morphine concentration) ~ 3% of many Caucasian populations Up to 30 to 45 x higher codeine metabolites conc than PM’s Good responders to codeine maybe UM’s! over 75 different variants of 2D The Oncologist 11: Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications of which 10 are the most important. Highly Polymorphic per Codeine and Morphine Pathway It “feels” to me that other unknown factors are responsible for why double the convertor chambers does not produce double the morphine metabolite. Whatever the reasons are, they are surely why a ceiling or maximum metabolism capacity for codeine exists. * The Pharmacogenomics Journal 2007;7: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 Pharmacogenomics 2008;9(9): Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use 23 23

24 Codeine (in Caucasians)
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Codeine (in Caucasians) Between all three of these groups it totals 46% of the Caucasian population should be selecting an alternative drug other than codeine ! Recommendation* % ** Poor Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone or be alert to symptoms of insufficient pain relief For cough: No 7.24 % Intermediate Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief 36.2 % Ultrarapid Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone) or be alert to adverse drug events (ADE’s) For cough: be extra alert to ADE’s due to increased morphine plasma concentration 2.6 % The impact on reliability for equi-analgesic conversion. Poor metabolizers – “just got constipated” Intermediate – no better than plain Tylenol Rapid – was nauseated! *2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines. **1997 American J Human Genetics 60:284-5

25 in Surrey?... Group % No PM % EM % UM % 51.6 203,815 1.5 - 10 0.8 - 10
Slide created by Bruce Kennedy, Palliative Care Pharmacist, in Surrey?... Group % No PM % EM % UM % Caucasian 51.6 203,815 South Asian 27.6 107,810 1.8 – 4.8 Chinese 5.1 20,210 <1.0 0.9 Filipino 4.2 16,555 Southeast Asian 2.4 9240 1.2 Korean 2.0 7665 Aboriginal 1.9 7630 Black 1.3 5015 4.9 Multiple Vis Minority 1.1 4395 Latin American 1.0 3785 2.2 – 6.6 1.7 Japanese 0.5 2090 0.5-1%* Arab 1805 16-28%* West Asian 0.2 1790 or From eCPS product monograph for t#3 (accessed july 20, 2011) Ultra-Rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6* 2×2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. Stats Canada 2006 Census Data 2006 The Oncologist 11; Interethnic differences in genetic polymorphisms in the U.S. population: clinical implications, *Tylenol #3 Prescribing Info July14, 2008 25

26 False Tolerance in Poor Metabolizers Toxicity with Opioid Switch
Slide created by Bruce Kennedy, Palliative Care Pharmacist, False Tolerance in Poor Metabolizers Toxicity with Opioid Switch Codeine 6 to 12 T3/day not working Patient not identified as poor metabolizer Patient presumed to be opioid-tolerant New opioid gets started too high – converted at “equianalgesic dose” – but codeine wasn’t getting converted before Gets converted at equianalgesic dose, but the codeine was not working before, so new opioid (e.g. morphine, fentanyl) gets started at far too large a dose How to manage the situation: Switch to plain acetaminophen regularly and add a prn opioid to start or another analgesic Or you give one T3 – no response, 2 T3’s – not really any better. (650 mg acetaminophen). Delays effective pain control. 26 26

27 Dosing, Use, Practicalities Overview
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Dosing, Use, Practicalities Overview T3 Massively (OVER) used Poor from a population based approach A combination product containing codeine makes poor sense to provide reliable pain relief, yet it’s the main Canadian prescription pain relief product T#3 (1971) released before we knew about; This 2D6 codeine enzyme non-conversion issue (1989) The WHO ladder (1986) Before T3 - using 292’s, meperidine (How good an idea was that???) See Yue QY, Svesson, JO, ALM C Sjoqvist F and Sawe J codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol :639-45 FDA concerned about the estimated 458 deaths annually from acetaminophen overdose, MOST of which is from combination Rx products like Vicodin, Percocet, Tylenol #3 7 of 38 of the expert panel votes considered elimination of these combo products the No1 priority to prevent acetaminophen overdoses. The only other (of the 9 options) to get more votes (9) was to reduce the maximum dose. Health Canada in January was considered acetaminophen labeling changes, and now when they were present at the June 2009 FDA expert panel meeting, may be digesting what further changes they may do. Interestingly, there are no single entity hydrocodone products in the US, only in combination! (but 240 combo’s) – FDA position paper 27 27

28 T3, T1 safety Does support of T3 use - support T1 abuse?
Slide created by Bruce Kennedy, Palliative Care Pharmacist, T3, T1 safety Codeine dependency A weak opioid - yet the wide availability of over- the-counter (OTC) codeine products is impactful Now many internet resources, methods to extract morphine from OTC and Rx codeine products; Youtube.com - Cold Water Extraction (CWE) videos performing Internet bulletinboards Heroinhelper.com 2 methods to extract from OTC acetaminophen/ASA products Opiophile.org Provide methods called “Homebake” in New Zealand and Australia Sophisticated methods using several chemicals including chloroform Does support of T3 use - support T1 abuse? 30 mL syringe, paper towel, funnel, water, small collection bottle, jar, tablet crusher, e.g. head of screwdriver – takes 2 min with practice Cold water, fridge, toilet paper, poly pipe, enamel cup, stove, cotton wool, 20 mL syringe You Tube: 4 ½ minutes screwdriver, 2 glasses, water, (2 mL per tablet) boil on stove, measuring cup, spoon, fridge, coffee filter, rubber band (one hour) No controlled trial of 8 mg codeine added to paracetamol has been reported. As per Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: a systematic review Anton J M de Craen, Giuseppe Di Giulio, Angela J E M Lampe-Schoenmaeckers, Alphons G H Kessels, Jos Kleijnen BMJ 1996;313: (Published 10 August 1996) And the Bandolier article seems to confirm this, that no T#1 studies were done. Bandolier Investigating over-the-counter oral analgesics With Ontario’s new “crackdown” proposed – what do you think will happen to the demand for T#1? in 8 months posted – 3,199 views (Tylenol #1 extraction) In one year for “CWE” – 11,819 views FDA in the US concerned about acetaminophen toxicity. 56,000 ER room visits, 26,000 hospitalizations, 458 deaths related to acetaminophen associated overdoses per year during the period. Acetaminophen was the leading cause of acute liver failure for the years 1998 to 2003 from 2009 FDA document Briefing on acetaminophen and liver injury options for reducing injury 28 28

29 Acetaminophen Combination Products Risk Toxicity
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Acetaminophen Combination Products Risk Toxicity Local SDM – Murrayville Square you will see 53 acetaminophen single ingredient products, of which only 8 were regular strength FDA (USA) very concerned as during 1990 to ,000 ER room visits, 26,000 hospitalizations, 458 deaths EACH YEAR related to acetaminophen associated overdoses From 1998 to 2003, acetaminophen was the leading cause of acute liver failure 48% of acetaminophen-related cases associated with accidental overdose Prescription combination products frequently used: Vicodin (acetaminophen and hydrocodone) is #1 Rx prescribed drug above all other prescription products in U.S., since 1997! In the US – the hydrocodone-acetaminophen combination has been the most frequently prescribed drug since 1997 Accessed Nov 1, 2012 New Label recommendations: Some US formulations Viocdin ES have 750 mg of acetaminophen per tablet. (and contains 7.5 mg hydrocodone bitartrate) In these photo’s above – taken at the Local SDM – Murrryville Square you will see 53 acetaminophen single ingredient products, of which only 8 were regular strength. I suspect that the number of acetaminophen combination OTC products containing acetaminophen would be stunning! Monitor this website for future updates about what FDA does with acetaminophen If there was a codeine combination product that did make sense it would be codeine with sennosides, Seni-cod Codi-sides Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology & Therapeutics Sep 3, 29

30 Acetaminophen Combination Products Risk Toxicity
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Acetaminophen Combination Products Risk Toxicity Reminder: Make the point about what a wimpy dose 325 mg acetaminophen is in hospital US acetaminophen product sales: 28 billion doses 11 billion Rx containing acetaminophen products (182 million Rx’s in 2005) 8 billion single dose acetaminophen e.g. Tylenol – 92% is 500 mg strength 9.7 billion combination OTC (e.g. Nyquil, Theraflu) FDA (2009)38 member expert panel voted and advised to Eliminate prescription acetaminophen products completely! (20 votes, 10/20 high priority) FDA (Feb 13/11) now recommend 325 mg per dosage limit in prescription products In the US – the hydrocodone-acetaminophen combination has been the most frequently prescribed drug since 1997 Some US formulations Viocdin ES have 750 mg of acetaminophen per tablet. (and contains 7.5 mg hydrocodone bitartrate) In these photo’s above – taken at the Local SDM – Murrryville Square you will see 53 acetaminophen single ingredient products, of which only 8 were regular strength. I suspect that the number of acetaminophen combination OTC products containing acetaminophen would be stunning! Monitor this website for future updates about what FDA does with acetaminophen If there was a codeine combination product that did make sense it would be codeine with sennosides, Seni-cod Codi-sides Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology & Therapeutics Sep 3, 30

31 Which product does not contain Acetaminophen? (471 do in Canada)
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Which product does not contain Acetaminophen? (471 do in Canada) 2009 = 435 2010 = 446 2012 = 471 Acetazone Actified Plus Arthritis pain extended relief Balminil Cough & Flu Benadryl Total Dayquil D Dristan ND caplets Hot Lemon relief Midol Night-Time Nyquil Sinus Liquicaps Pamprin Extra Strength Sinutab Theraflu Cold & Flu Triaminic cough & sore throat softchews If we can’t, how can/will patients? Was 435 products in as of April 13, 2010 now is now of Nov 2, 2012 FDA considering as one of their recommendations to eliminate OTC combination acetaminophen products But expert panel only 2/38 said a top priority In the US unintentional overdoses make up 54% of acetaminophen-related poison center calls (FDA position paper) In the US consumers purchased 28 billion doses of products containing acetaminophen (8 billion single dose acetaminophen eg Tylenol), 9.7 billion combination OTC (eg Nyquil, Theraflu) and 11 billion prescription containing acetaminophen products, and 182 miilion Rx’s in 2005 for combination Rx’s with acetaminophen From 1998 to 2003, acetaminophen was the leading cause of acute liver failure in the United States, with 48% of acetaminophen-related cases (131 of 275) associated with accidental overdose.* • A 2007 CDC population-based report estimates that, nationally, there are 1600 cases of ALF each year (all causes). Acetaminophen-related ALF was the most common etiology.** • Summarizing data from five different surveillance systems, there were an estimated 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths related to acetaminophen-associated overdoses per year during the period. *** 44% of consumers self-administer more than the recommended dose (OTC NSAIDs paper) mentioned in Clinical Therapeutics 2007 article;29 Suppl called Adverse drug interactions involving common prescription and OTC analgesic agents OTC 500-mg, single-ingredient tablets and capsules make up 92% of U.S. sales of single-ingredient acetaminophen.19 FDA Votes: 38 to 1 for single acetaminophen strength, for max 325 mg strength to reduce max to less than 4g/day, to ban combination Rx drugs containing acetaminophen 31 31

32 Caffeine “Why is it there?”
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Caffeine “Why is it there?” Regulatory fit/rules evasion- no duplicate Rx Helps headaches – 5,427,000* of them? Causes GI upset, effect on sleep Caffeine withdrawal could occur Adds unneeded drug-interaction-allergy risk, caffeine interacts with other drugs, smoking Little to no therapeutic role, esp. pain Remember the faster onset caffeine citrate in Atasol 30) – main hospital brand. The pain relief benefit of an extra 25 mg of acetaminophen minimal – only 8.3% more content. Caffeine’s effectiveness may be in the mood altering effect – per big 1993 review in Pharmacological Reviews by Saweynok and Yaksh 45(1) Also some evidence for dysmenorrhea Current Medical Research and Opinion (4): In the US – their primary opioid-acetaminophen combinations do not have the added caffeine. And codeine-acetaminophen sales in US was # 73 in 2006, far behind acetaminophen/hydrocodone at #1, and acetaminophen/oxycodone at # 28 There was 453 million prescriptions – and 1.25% of them were for acetaminophen, caffeine and codeine Huge growth in caffeinated beverages, but no growth in caffeinated pharmaceuticals. Do we need caffeine in the Rx on top of the average caffeine intake most people consume these days? Caffeine is metabolized by CYP 1A2. Caffeine has increased metabolism in smokers – 250% greater caffeine levels occurred after smoking cessation) per Riverview 2001 newsletter * Number of prescriptions in 2011 in Canada for acetaminophen, caffeine and codeine 32 32

33 Relieve Pain – Help patients
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Relieve Pain – Help patients So by now I’m hoping you’ve considered that the extra around 12% benefit that codeine adds to acetaminophen is worth it. But also that you realize that it’s not a reliable number (12%), and will vary between individuals. I hope that you avoid codeine use whenever possible, or ensure it is helping patients when it is used. If codeine and T3 are suboptimal What should we consider instead? 33 33

34 Study importation of codeine into Ethiopia!
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Morphine 200 X stronger affinity for mu receptor than codeine It’s the most significant active component of codeine Provides predictability. No worries about the PM’s Poor (0-19*%) *South African’s EM’s Extensive ( %) UM’s Ultra-rapid (0-29**%) **Ethiopian’s Why wait? Onset requires no 2D6 conversion Use a small dose – 2.5 mg PO to start Study importation of codeine into Ethiopia! NNT so much better – need to get it. 30 mg codeine in a UM about 3% of many Caucasian populations) would make the same effects as 45 mg EM (1.5 fold increase in morphine concentration) per The Pharmacogenomics Journal 2007;7: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6. Both clarithromycin and the azole preventing codeine metabolism via 3A4 into norcodeine. No Norcodeine detected in blood, and C-6G was 1/3rd that expected Can be a 45 times difference in 0-demethylated metabolites in persons with ultrarapid metabolism as it is in those with poor metabolism. Per NEJM (27): Codeine intoxication associated with ultrarapid CYP2D6 metabolism. Body content of morphine was 7.5 x greater than normal Affinity is 1/200th to 1/3000th that of morphine – per NEJM (27): Genes and the response to drugs and it quotes another article Life Science 1991 The Pharmacogenomics Journal 2007;7: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 34 34

35 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Hydromorphone Less histamine release risk than either codeine or morphine Codeine & morphine have a dose-related histamine releasing effect Meperidine<Codeine<Morphine<Oxycodone<Hydromorphone<Fentanyl Hydromorphone is a semi-synthetic opioid, as is oxycodone Codeine , like morphine has a dose-related histamine releasing effect Pharmacists Letter 2006 Opioid Intolerance Decision Algorithm Document # Martindale’s The Complete Drug Reference 36th Ed 2009 Codeine p 37 35 35

36 Oxycodone, Tramadol Options;
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Oxycodone, Tramadol Options; however are also metabolized by the same Cytochrome P450 2D6 enzyme Best to avoid when response to codeine suspected to be poor or excessive 2006 Progress in Neuro-Psychopharmacology & Biological Psychiatry 30: Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines 36 36

37 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Oxycodone Poor Metabolizer Insufficient data to allow calculation of dose adjustment. Select alternative drug – not tramadol or codeine – or be alert to symptoms of insufficient pain relief Intermediate Metabolizer Ultrarapid Metabolizer Insufficient data to allow calculation of dose adjustment. Select alternative drug – not tramadol or codeine – or be alert to adverse effects (e.g. nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) Small number of subjects studied – considering that we see widespread use of oxycodone, but still there is this unseen potential. 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines

38 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Tramadol Poor Metabolizer Select alternative drug – not oxycodone or codeine, be alert to symptoms of insufficient pain relief Intermediate Metabolizer Be alert to decreased efficacy. Consider alternative drug – not oxycodone or codeine – or be alert to symptoms of insufficient pain relief Ultrarapid Metabolizer Reduce dose by 30% and be alert for adverse effects (e.g. nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) or select alternative drug (e.g. acetaminophen, NSAID, morphine – not oxycodone or codeine. 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines

39 Intent is short-term, but on initiation use becomes long-term
Ontario seniors age 66 and older reviewed Low-risk short stay surgeries: cataract surgery, TURP, varicose vein stripping, laparoscopic cholecystectomy Pre - surgery 7 Days Post-surgical Discharge One Year after Surgery Opioid Use 391,139 pts 0%, - all were opioid-naive 27,636 pts 7.1 % 30,145 pts 7.7% Pre - surgery 7 Days Post-surgical Discharge One Year after Surgery NSAID Use 383,780 pts 0%, - all were NSAID-naïve 1169 pts 0.3 % 30,080 pts 7.8% Their conclusion: Short-term use of analgesics can lead to long-term use of those analgesics. Intention is short-term, but actual use may be long-term. 2012 Arch Intern Med(5): Long-term analgesic use after Low-Risk Surgery

40 Ibuprofen 400 mg when studied in 5456 patients had a NNT of 2.5 !
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Ibuprofen 400 mg when studied in 5456 patients had a NNT of 2.5 ! (in moderate to severe pain. Versus Placebo, pain relief over 4 to 6 hours NSAID’s Use short term, whenever possible Ibuprofen 400 mg NNT is 2.5 Could combine with acetaminophen NNT is 1.5 to 1.6 when combining Ibuprofen with acetaminophen 100 mg with 250 mg, 200 mg with 500 mg or 400 mg ibuprofen with 1000 mg acetaminophen But Bandolier comments that this common possible combination poorly studied Unfortunately! The NSAID GI risk alone results in greater overall morbidity than the risk of serious hepatotoxicity with acetaminophen (FDA position paper) Bandolier Investigating over-the-counter oral analgesics 40 40

41 Reverse Ladder Concept
What goes up, must come down? Consider Timeframes Monitoring for stepping down Presentation on preventing post-surgical pain Dr Negrarff Anesthesioloist and pain specialist at VGH did a presentation and review of chronic post-surgical pain that I attended two weeks ago – and you can download his presentation here: 2011 Anaesth Int Care 39; Acute pain management in opioid-tolerant patients: a growing challenge

42 Slide created by Bruce Kennedy, Palliative Care Pharmacist, bruce
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Acetaminophen Codeine’s lack of effect in PM’s gets “masked” in T3 Acetaminophen carries the pain relief load - so PM’s are not easily recognized clinically Is inexpensive No discharge prescription required No opioid abuse or addiction issues Safer with chronic use, when used within daily limits E.g. 4 g per day, less as indicated Physicians are reluctant to prescribe analgesics on triplicates. Is this a valid reason to prescribe T#3’s instead? Acetaminophen caution of course in liver dysfunction, alcohol use, concurrent drugs (e.g. warfarin), wt loss program or fasting. – See Cdn contemplated labeling changes. Some US formulations Viocdin ES had 750 mg of acetaminophen per tablet. ( and contains 7.5 mg hydrocodone bitartrate) In the US – the hydrocodone-acetaminophen combination has been the most frequently prescribed drug since 1997 – per FDA acetaminophen overdose and liver injury background paper. 42 42

43 Acetaminophen Benefit
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Acetaminophen Benefit Reminder: Make the point about what a wimpy dose 325 mg acetaminophen is in hospital NNT Figures = Number Needed to Treat (to achieve 50% pain relief in 1 patient) Codeine 60 mg 16.7 Codeine 60 mg plus Acetaminophen 300 mg 5.7 Acetaminophen 500 mg 3.5 600/650 mg 4.6 1000 mg 3.8 1500 mg 3.7 Acetaminophen 600/650 mg 4.2 Precautions: Single dose studies. Or single shot/punch at the pain. Acute pain. Oral route dosing only. Study size varied from 60 to 3248 people for the drugs I’m showing today Must emphasize the principle here – that some combinations do improve pain control, requiring higher doses Commercial product containing codeine 30 mg plus acetaminophen 500 mg does not exist. There is one study regarding the benefit of acetaminophen (30 patients) added to strong opioid It is J Clin Onc (16): Acetaminophen improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized double-blind placebo-controlled cross-over trial Stockler M, Vardy J, Warr D I don’t like codeine as an analgesic, due to variable effects, and what I see when I look at this table is that acetaminophen is the “heavier-duty” analgesic and it is likely carrying the load of the pain relief – in combination. By itself, acetaminophen’s effectiveness is diminished above 500 mg There are some variations in the table results that may seem unexpected, but I’m presenting for your awareness. 500 mg may be sufficient for pain. Could try up to 1000 mg per dose 1500 mg and 2000 mg acetaminophen doses have been tried in acute pain, without any further significant benefit. FDA feels that dropping the maximum dose from 1000 to 650 mg will have little loss of efficacy. Seems about right looking at this data. 92% of the sales of Rx combination products with acetaminophen in the US is the 500 mg strength – per FDA background statement. And 87% of the hydrocodone-acetaminophen products contain 500 mg or more of acetaminophen. FDA Votes: 38 to 1 for single acetaminophen strength, for max 325 mg strength to reduce max to less than 4g/day, to ban combination Rx drugs containing acetaminophen Oxford League Table of Analgesic Efficacy – Number Needed to Treat Acute pain, single dose studies, study size 138 to 2759 people 43 43

44 Codeine: any other Therapeutic Roles?
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine: any other Therapeutic Roles? Diarrhea: Loperamide (Imodium) far better Need 200 mg codeine PO for same effect as 4 mg of loperamide Needs conversion to morphine to work for diarrhea!* At doses effective for antidiarrheal effect – risks central (unwanted) adverse effects, such as sedation, analgesia Cough: Codeine no more effective than alternatives; morphine, methadone and likely dextromethorphan. (UK reg – not in children!) Medical Care of Dying Victoria Hospice Society Oxford Textbook of Palliative Medicine “There is no evidence that codeine is more constipating than any other opioid.- per Dr Janet Hardy page 57 in Codeine chapter Opioids in Cancer Pain 1st edition Goodman and Gillman 2008 said page 357 that codeine’s antitussive actions may involve distinct receptors that bind codeine itself. 1997 Clin Pharm Ther Effect of codeine in GI motility in relation to CYP2D6. (61), 2010 Oct 4th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups 44 44

45 Prescriptions In Canada
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Prescriptions In Canada 525 Million total of all prescriptions per year 27.5 Million of these (4.7%) are for analgesics 5.4 Million (20% of all analgesics) just for Acetaminophen/Caffeine/Codeine - makes it the 18th most commonly issued Rx in Canada # patient recipients British Columbia #1, Manitoba: #1, Ontario #2 Other provinces likely very similar Table 26b on page 53 (61 of the pdf) re #1 drug Call the Ontario ministry INFOline at (Toll-free in Ontario only) TTY Hours of operation : 8:30am - 5:00pm In 2005 BC PharmaCare showed 139,000 distinct beneficiaries and in 2006 it was 134,000 I think that 2009 is now 133,132 compares with lipitor at 188,670 for the 10,20 and 40 mg strengths CIHI report on Health care use in EOL in Western Cda had 129,052 users (distinct beneficiaries) in 2003 2011 Feb Pharmacy Practice Top Rx Drugs of 2011 PharmaCare Trends 2009/2010 45 45

46 Acetaminophen/Caffeine/ Codeine 30 mg % Change (Number of Rx's)
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Acetaminophen/Caffeine/ Codeine 30 mg Ranking in Canada % Change (Number of Rx's) 2011 18 -1.5% 2010 15 -1.6% 2009 - 0.1% 2008 14 +3% 2007 10 -9% 2006 8 -10% 2005 6 -2% 2004 5 2003 4 -1% 2002 -4% 2001 -3% 2000 2 +4% 1999 3 +6% 1998 n/a 1997 1 1996 figures are for combined brand Tylenol #3 and generics. 2007 and prior represents just figures for brand name Tylenol #3

47 Alternatives to T#3 To provide approximately the same pain relief (*);
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Alternatives to T#3 To provide approximately the same pain relief (*); 13 cents! 1-2 ¢ 2 ¢ 3 ¢ 9 ¢ 6-11 ¢ 9-18 ¢ mg of Acetaminophen 200 mg of Ibuprofen 500 mg Acetaminophen mg Ibuprofen ½ tablet of a generic Percocet 3.3 mg Oxycodone Morphine 2.5 to 5 mg tablet Hydromorphone 0.5 to 1 mg tablet Choices sequenced from least cost at the top, to the greatest cost These are prices from Meditech – accessed from Langley hospital inventory July 20th, 2011 bkennedy Cost Stock # T# T#3 C Pak Codeine 30 mg tab Percocet Percocet Cpak 325 aceta 325 aceta 100/BOTTLE 325 mg acet 1000's Not active 500 aceta 100/btle 500 mg ACET Not active ASA 325 mg Morphine 5 mg Morphine 5 mg cpak Oxycodone 5 mg Ibuprofen 200 mg 100/btl Ibuprofen 200 mg 100/btl Not active Ibuprofen 200 mg 100/btl No such # Hydromorphone 1 mg HM CPAK 1 mg Hydromorphone 2 mg HM CPAK 2 mg Meperidine 50 mg tabs Codeine Inj 30 mg/mL Codeine 5 mg/mL Syrup per 5mg/mL Oxycodone 10 mg Updated July 20, 2011 from LMH inventory prices * Maybe – Depends on several factors, assuming you are a normal (extensive) metabolilzer. Other factors, type, source of pain can also play a role This is a rough guide – assess patient, particularly prior to use of opioids 47

48 KEY LEARNING POINTS Codeine is a poor analgesic
Slide created by Bruce Kennedy, Palliative Care Pharmacist, KEY LEARNING POINTS Codeine is a poor analgesic Benefit, if occurs, is unpredictable Combined with acetaminophen increases outpatient risk of accidental overdose with other acetaminophen products Use the alternatives!

49 Not 4 Me Thank You ! Bruce Kennedy
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Not 4 Me Thank You ! Bruce Kennedy Clinical Pharmacy Specialist That’s the end of the lecture and I’m now prepared to take questions for anything I have the answer for. Ok so that’s a question I’m not able to answer and I’ve alerted security, as I expected that I may encounter hecklers today. You’re not a pharmacist by chance are you? But wait, since security may be slow to respond, I will take a stab. The nice part of aging, is how much easier it becomes to say “I don’t know” Link to another presentation I did with some other interesting pain aspects can be found here: 49 49

50 Still to DO Practice the 45 minute time frame
See about eliminating some slides Fix animation Check spelling Keep or eliminate the caffeine slide? Watch that 12 year old speech: Have you ever wondered….? Caffeine – safety… Caffeine content is unknown at Morgan Creek here – however see me, (or Dr Laugh) if you would like to volunteer for a study. Read, review that newer 2012 article (both of Dr Ross) Remove old stuff on the sides With me being a pharmacist, I’m feeling in awe of the faculty of esteemed presenters assembled today, as all he rest are Dr’s, including the comedian Dr Laugh!

51

52 Yet codeine pediatric use; impactful Canadian deaths
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Yet codeine pediatric use; impactful Canadian deaths 1) Newborn Breastfeeding case - Aug ’06 Mom took codeine 60 mg mg acetaminophen q12h x 2 days then 30 mg and 500 mg q12h x 14 more days Mom ultra rapid metabolizer, infant EM UBC Ob Gyn MD Dr Peter von Dadelszen- wants T3 banned Globe & Mail Aug 22, ’08, Mar 31, ’09 2) 2 year old adenotonsillectomy - Aug ’09 Healthy 13 Kg, Hx snoring, sleep apnea Codeine mg q4-6h. Died 9 am Post-op Day 3 Ultrarapid metabolism-> morphine toxicity NEJM 2 year old: Tonsils, Adenoids removed. Within 1 to 3 mg/Kg codeine/day recommended dose. Surgery was uncomplicated. Risk factors were that 1/3rd of cases of apnea do not resolve after this surgery, Autopsy showed bronchopneumonia which increased the hypoxic risk. Day 2 had fever and wheeziness. Australian prescriber concludes that “the wide variation in individual metabolism and the unpredictable influence on age on the effectiveness and safety of codeine means that it’s routine use in children is not recommended. It can be argued that he use of a small dose of morphine is preferable as it is more effective and predictable. Use of codeine in pediatrics has developmental AND genetic phenotype issues. Is there nothing that stays the same as you age? Also get the Pharmacogenomics article sep 2008;9(9): Parvaz Madadi and Gideon Koren Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use Speaking of unpredictability. When will this reoccur? It’s unpredictable Dr von Dadelszen commented “ why use a constipating compound that relieves very little extra pain and is potentially dangerous for babies. It has tragic consequences in this country” The Annals of Pharmacotherapy 2003 Prediction of Milk/Plasma concentration ratio of drugs37: Ratio of codeine milk to plasma is 2.16 What kind of mind names a hospital “Sick Kids” ?? Dr Koren from Sick Kids in Toronto 17/72 newborns had signs of CNS depression – sedation, abnormal breathing Details(for Lancet 2006): April 2005 : Sx on Day 7-difficulty breastfeeding and lethargy starting, dead on Day 13 Postmortem no anatomical anomalies. Morphine level 70 ng/mL (versus typical zero to 2.2 mg/mL) She took codeine 60 mg and 1000 mg acetaminophen q12h x 2 days then 30 mg and 500 mg q12h x 14 more days Milk conc 87 ng/mL versus usual 1.9 – 20.5 ng/mL when on 60 mg codeine q6h CMAJ 2007: Thought to be the first record of a breastfed baby succumbing to toxicity through breast milk 3.88 Kg BW, male 90th percentile, unremarkable pregnancy and delivery. Says used Tylenol #3 but content of 500 mg acetaminophen (error?) Mom 3 functional 2D6 alleles, dad and baby 2 functional alleles. Peak morphine levels (first two days may have been 100 ng/mL versus expected around 2.2) Recommendations: Avoid codeine, use NSAIDs. Use codeine only 2-3 days only to prevent neonatal accumulation Genotype all postpartum women about to receive codeine. But notes that currently these tests are not available in most clinical facilities Follow monitor for opioid toxicity, test to morphine levels if ADR consistent, use naloxone prn Lancet 2008 Author’s reply; Four other premature infants exhibited apnea 4 to 6 days after 60 mg codeine administration to mothers – 1985 Develop Pharm And one other one they found. 2006 Lancet 368:704 Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother Canadian Family Physician Jan;53:33-5 Safety of codeine during breastfeeding 2009 NEJM 361:8 Aug 20 Codeine, ultrarapid-metabolism genotype and post operative death 2010 CMAJ Oct 4 Has the time come to phase out codeine? Editorial 52 52

53 From: http://www. mhra. gov

54 WHO Ladder – Cancer Pain
Slide created by Bruce Kennedy, Palliative Care Pharmacist, WHO Ladder – Cancer Pain Pain persisting, or increasing Step 3 Opioid for severe pain +/- Step 1 choices Step 2 Opioid for moderate pain +/- Step 1 choices Step 1 Non-opioid +/- adjuvants Weak Opioids Address only a narrow portion of pain requirements. Need to by-pass them more often (weak’s work for 30%) versus 50% needing strong opioids “unnecessary” switch to another drug. Why create another potential problem and need for titration? Due to ceiling – you know it’s there Ladder released in 1986 WHO Cancer Pain Relief publication Generally considered a framework, rather than a rigid protocol. Pain management must be individualized. Meant to provide simple guidelines that were easy to follow. Major consequence of the ladder was the legitimizing of the use of strong opioids. The ladder generally applies to chronic pain of non-malignant origin as well A common misconception is that the prescriber must start at Step 1. It is acceptable to start at any point on the ladder, the goal is to tailor treatment to the severity of the pain. Reference for the % of patient in the mild, moderate, severe categories :2005 Palliative Medicine 19: Pain and pain treatments in European palliative care units. A cross sectional survey from the European association for palliative care Research Network – 3030 cancer patients, 143 palliative care centers in 21 European countries Could mention that Dr. Twycross is coming for 3 lectures during the first week of May, one of the 3 will a lecture to the public – topic Dying Well in the 21st century: unmet needs and the Worldwide Challenge. Plus one for professionals called: Evidence-based palliative care: realistic option or oxymoron The need for the 2nd step has been questioned, and when I put the question of codeine’s usefulness to Dr T he did agree that it’s not a particularly needed when other options are available. Moderate 20% Severe 50% Mild 30% 54 54

55 Codeine Drug Interactions
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine Drug Interactions Generic Drug Rank 2010* 2D6 Enzyme Impact on Codeine’s Pain Relieving Ability Venlafaxine 11 Substrate Citalopram 13 Inhibitor Risperidone 33 Trazodone 35 Amitriptyline 41 Paroxetine 46 Substrate + Inhibitor Celecoxib 49 Ranitidine 53 Buproprion 61 Oxycodone 62 Sertraline 73 Escitalopram 80 Could be a “useful” interaction – if you put patient on say fluoxetine – reduced codeine intake by 56% 2010 information obtained June 6, 2011 from: Notice the impact of all these commonly prescribed drugs on the already weak ability of codeine to relieve pain. Fatal intoxication with a SSRI, lorazepam and codeine case report The American Journal of Forensic Medicine and Pathology 28(4) year old. Ankle fracture – 30 mg and 60 mg codeine with acetaminophen Codeine was implicated by the pathologist in causing 2D6 reduced sertraline metabolism – toxic sertraline levels and a fatal serotonin syndrome Drug companies are trying to avoid the 2D6 enzyme when developing new drugs. *2011 Feb Pharmacy Practice Top Rx Drugs of 2010 Cytochrome Drug Interaction Table v 55 55

56 Codeine 2010 Morphine need was but 3.5 tons
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine Is globally the most widely used narcotic Canada imported 21.1 tons of codeine in 2004, that is 10.5% of world consumption Estimated Need (Tons):`09-29, ‘10-26, ‘11-27 Per capita we are #1 codeine consumers Canadians are the world’s largest consumers of codeine per capita, but we import all our opiates from France and Australia. Per website I googled 2004 was up by 3 tons ( %) from 2003 The statistic about codeine being the most widely used opiate globally came from page 81 of Actually for 2010 it went down to 26.2 tons per 2009 figures from Document from incp on work Populations stats taken on April 13, And 4 days later World population increased by 868,384 and Canada’s population increased by 3,010 Codeine should NOT be the most widely used narcotic worldwide. Morphine is the abundant opioid extracted from the poppy plant. Most of the codeine is from the conversion (think extra cost) to transform natural morphine back into codeine. Parts of the world don’t have very limited opioid access. World Population: 6,911,790,500 Canada’s Population: 34,043,879 37th largest of 234 countries 0.49 % of world 2010 Morphine need was but 3.5 tons The International Narcotics Control Board provides daily population figures 56 56

57 in Langley?... (district + city)
Slide created by Bruce Kennedy, Palliative Care Pharmacist, in Langley?... (district + city) Group % No PM % EM % UM % Caucasian 87.1 102187 Aboriginal 2.8 3300 Chinese 2.5 2895 <1.0 0.9 Korean 2.0 2380 South Asian 1.4 1695 1.8 – 4.8 Southeast Asian 1100 1.2 Filipino 0.8 940 Black 0.7 835 4.9 Japanese 0.6 660 0.5-1%* Latin American 650 2.2 – 6.6 1.7 Multiple + Vis Minority 0.3 355 West Asian 0.2 180 Arab 0.1 155 16-28%* For Community Profile search go to: Langley District Data Langley District populatin is 93,726 and Langley city population (again 2006) = 23,606 total is Less Aboriginal (850 city district) of Less all the others = caucasian or Stats Canada 2006 Census Data 2006 The Oncologist 11; Interethnic differences in genetic polymorphisms in the U.S. population: clinical implications, *Tylenol #3 Prescribing Info July14, 2008 57

58 Canada’s Needed Opioids for 2011
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Canada’s Needed Opioids for 2011 Opioid Grams Codeine 27,000,000 Cannabis 14,500,000 Oxycodone 7,000,000 Morphine 4,000,000 Methadone 2,500,000 Hydromorphone 1,500,000 Meperidine 1,300,000 Fentanyl 150,000 Hydrocodone 110,000 Sufentanil 240 Accessed April Estimated Requirements of narcotic drugs p. 48

59 Dosing, Use, Practicalities
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Dosing, Use, Practicalities Patient taking two codeine phosphate 30 mg tablets q6h and one breakthrough daily of 60 mg.* Pain is stable Sustained Release codeine (Codeine Contin) suggested for convenience What dose of Codeine Contin should patient take every 12 hours? No suppositories, limited availability of injection Only Harinder Takhar, pharmacy technician at RCH March 17, 2011 got this right. * = 240 mg plus 60 mg: Total 300 mg/day 59 59

60 Dosing, Use, Practicalities
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Dosing, Use, Practicalities Doses of Codeine Contin are expressed as codeine base. Codeine phosphate formulations contain approximately 75% codeine base. Patients currently receiving oral immediate release formulations of plain codeine phosphate may be transferred to Codeine Contin at an approximately 25% lower total daily codeine dosage 300 mg codeine phosphate per day Less 25% ( 75 mg) = 225 mg of codeine base Conversion is = 225 mg Codeine Contin Available as 50, 100, 150, 200 mg strengths Advise start on 100 mg Codeine Contin q12h Doses of Codeine Contin (codeine controlled release tablets) are expressed as codeine base. Codeine phosphate formulations contain approximately 75% codeine base. Patients currently receiving oral immediate release formulations of plain codeine phosphate may be transferred to Codeine Contin at an approximately 25% lower total daily codeine dosage, equally divided into two 12 hourly Codeine Contin doses. No suppositories, limited availability of injection 60 60

61 Dried Poppyseed Powder
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Recently – Doda Abuse Doda is Dried Poppyseed Powder Doda described as “poor man’s heroin” - contains morphine and codeine Surrey Newton MLA Harry Bains says is openly sold throughout Lower Mainland Sep 22, 2009 – 12 skids 2,700 Kg worth $5.4 million stopped at border Sep 23, 2009 – 26 skids with 4,500 Kg worth $ 9 million also stopped Nov 18, Doda manufacturer raided at a busy Surrey shopping mall seizing hundreds of pounds of doda – that is “tearing up the South Asian community” Aug 26, 2010 – Largest Poppy Plant Bust in Cdnn History in Chilliwack on 7 acres Seizure occurred on Wednesday, November 18th. It was the first large scale seizure in BC Doda Surrey RCMP became the first police agency in BC to seize a large quantity of “Doda”, also known as "poor man’s heroin". The increasing popularity and prevalence of "Doda" a drug derived from the opium poppy pod, and popular in the South Asian community has attracted the attention of Surrey RCMP who seized the large quantity of the product from a local business. Surrey RCMP have forwarded the seized product to a Health Canada Lab to confirm the presence of drugs that are prohibited under the Controlled Drugs and Substances Act, which makes it illegal to produce, possess or sell opium and its derivatives. Charges will be forwarded to Crown for approval after the lab results are known. Mixed with tea and commonly used by truckers and taxi drivers. Reported effects of doda are intense feelings of pleasure followed by calm drowsiness, red eyes, slurred speech, mood swings, constipation, loss of concentration, impotence and finally addiction, according to police. The drug is cheap and easily sold to minors. Seniors in the South Asian community told him the drug has been destroying many families in India and Pakistan, and they are concerned it’s increasingly taking hold in B.C. Opium contains about 40 different alkaloids. 61 61

62 T3 use in End-of-Life Care in BC
Slide created by Bruce Kennedy, Palliative Care Pharmacist, T3 use in End-of-Life Care in BC Number of Claimants ’03-’04 ≤ 180 days ≤ 720 days Furosemide 6,681 8,533 Morphine 4,665 5,356 Lorazepam 4,332 6,274 Codeine combo 3,940 7,654 Ramipril 3,598 5,234 Glyceryl trinitrate 3,342 5,164 Ciprofloxacin 3,239 7,199 Digoxin 3,008 3,994 Levothyroxine 2,998 - Warfarin 2,402 Cephalexin 3,932 Clarithromycin 3,924 Codeine in wide use for End-of-Life patients ! Location of death 38% acute hospital 27% long term care 15% hospital-palliative 17% home 3% other Codeine no interaction with Ramipril, Nitroglycerin, Ciprolfloxacin, Digoxin, Levothyroxine, Warfarin, Cephalexin, Clarithromycin in Miicromedex April 15, 2011 Page 28 of report

63 2006 CMAJ 175;11:1385 Changes in illicit opioid use across Canada
Slide created by Bruce Kennedy, Palliative Care Pharmacist, 125,000 injection drug users in Canada,most of whom use heroin and cocaine 25,000 methadone maintenance patients 679 participants in community outreach programs 7 Cdn cities. Data is of 585 participants (none were in methadone maintenance programs) Most were male, white, average age 35 years. 2 of 5 had received income from illicit sources in previous 30 days. One of their points, confirmed in the US was that street drug users are abusing a lot of drugs coming directly from the medical system, rather than illegal basement labs, I think one of the points I’m trying to make in this slide is that there are many abuseable choices. And the people who want to abuse, will find something to abuse, depending on the supply available in the city where they live. But our job is to treat pain. And if you look at the composite figures, Tylenol #3 and #4 at 29.6% is used more illicitly than is morphine at 22.4%. Also there is no evidence that morphine is more addictive than codeine, or that risk of addiction rises with higher opioid doses. Dr. N. Hagen Canadian Family Physician 1995 vol 41 p But the point regarding higher doses and addiction potential was disputed (no reference) by Dr Raju Hajela an addiction MD June 1995 page 969 2006 CMAJ 175;11:1385 Changes in illicit opioid use across Canada 63 63

64 Codeine Rotation – Certainly Uncertain
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Codeine Rotation – Certainly Uncertain Ratio’s poorly understood/remembered Orally codeine is reported to be 1/10th as potent as morphine – but this is only roughly Injectably codeine is 1/12th as potent as morphine – but again we know genetic variability will occur Why not just avoid an uncertain rotation conversion? We commonly in palliative care we often avoid oxycodone – due to inability in Canada to switch to the injectable form of oxycodone. Yet for the opioid codeine (available PO and INJ) – we don’t rotate to INJ – suggesting AGAIN that other PO/INJ opioids (e.g. morphine, hydromorphone, methadone) should be preferred. Maybe codeine is 1/13th as potent – per … Poorly researched- why is that when it is used so much??? Injectable Codeine is not used much – children issue. 64 64

65 Codeine Recommendation 4 B 3 A F 453 Subjects Poor Metabolizer
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Codeine 453 Subjects Recommendation Level of Evidence Clinical Relevance Poor Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone or be alert to symptoms of insufficient pain relief For cough: No 4 B Intermediate Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief 3 A Ultrarapid Metabolizer For analgesia: Select alternative drug (e.g. acetaminophen, NSAID, morphine – not tramadol or oxycodone) or be alert to adverse drug events (ADE’s) For cough: be extra alert to ADE’s due to increased morphine plasma concentration F 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines.

66 Dosing, Use, Practicalities Overview
Slide created by Bruce Kennedy, Palliative Care Pharmacist, Dosing, Use, Practicalities Overview Precise relative analgesic significance of metabolites uncertain Codeine converts into 1, 2 possibly 3 active ingredients (all acting on mu receptor), (competing too?) Morphine - Amount normally converted into morphine reported from 3.9 to 10% Codeine-6-Glucuronide Norcodeine Ensure with adverse drug assessments that people know that codeine metabolizes into morphine – ask about history of reaction to each drug *Codeine analgesia is due to codeine-6-glucuronide, not morphine Int J Clin Pract 2000 Jul-Aug 54(6) Vree TB et al Local conversion in the CNS of codeine to morphine via CYP2D6 may explain the analgesic effect of codeine despite low plasma concentrations of morphine.[2137] Sindrup SH, Brosen K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 1995;5:335—46. 66 66

67 Pro-drugs Why start with an inactive drug?
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Pro-drugs Why start with an inactive drug? Codeine is inactive to start with, and requires biotransformation into active (i.e. morphine) metabolite to relieve pain Start with an already active drug – to avoid dependency on enzyme biotransformation

68 Tramadol Tramadol is metabolized into 11 to 22 different metabolites
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Tramadol Tramadol is metabolized into 11 to 22 different metabolites The main metabolite – that is the active mu agonist is M1 – and is derived after metabolism via CYP2D6 Tramadol has been used as a probe drug for CYP2D6 metabolizer status Probe drug status per Ground S, Sablotski A Clinical Pharmacokinetics 2004:43: Clinical pharmacology of tramadol Per PCF UK 4th ed page 341 – tramadol is converted in the liver mainly via CYP2D6 to O-desmethyltramadol (M1) and this active metabolite is 6 times (in aminals) more potent than tramadol parent molecule. It causes more vomiting, dizziness and anorexia than codeine. Pharmacogenetics and opioids Ross JR, Quigley p in Opioids in Cancer Pain 2nd Edition Davis, MP, Glare P, Quigley C, Hardy, J 68 68

69 Tramadol Rate of pain treatment failure* Rate of nausea**
Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Tramadol Rate of pain treatment failure* 46.7% of poor metabolizer patients 21.6 % of extensive (i.e. most prevalent, ~ normal) metabolizers Rate of nausea** 50% in ultra rapid metabolizer patients 9% of extensive metabolizers Rate of overall adverse effects*** Greater for poor metabolizers Least for ultrarapid metabolizers i.e. PM > EM > UM *2003 Pain 105:231-8 Impact of CYP2D6 genotype on postoperative tramadol analgesia **2008 J Clin Psychopharmacology 28:78-83 Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol ***2007 Mol Diagn Ther 11: Impact of CYP2D6 genetic polymorphisms on tramadol pharmacokinetics and pharmacodynamics

70 NSAID’s + Acetaminophen
Slide created by Bruce Kennedy, Palliative Care Pharmacist, NSAID’s + Acetaminophen Use short term, whenever possible Could combine with acetaminophen 400 mg ibuprofen mg acetaminophen has NNT of 1.5 ! The NSAID GI risk alone results in greater overall morbidity than the risk of serious hepatotoxicity with acetaminophen (FDA position paper) Bandolier Investigating over-the-counter oral analgesics 70 70

71 NSAID’s + Acetaminophen
Slide created by Bruce Kennedy, Palliative Care Pharmacist, NSAID’s + Acetaminophen Use short term, whenever possible Could combine with acetaminophen 400 mg ibuprofen mg acetaminophen has NNT of 1.5 ! The NSAID GI risk alone results in greater overall morbidity than the risk of serious hepatotoxicity with acetaminophen (FDA position paper) Bandolier Investigating over-the-counter oral analgesics 71 71


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