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Not 4 Me Not 4 Me Slide created by Bruce Kennedy, Palliative Care Pharmacist, BRUCE KENNEDY BSc.(Pharm.) M.B.A. Clinical.

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Presentation on theme: "Not 4 Me Not 4 Me Slide created by Bruce Kennedy, Palliative Care Pharmacist, BRUCE KENNEDY BSc.(Pharm.) M.B.A. Clinical."— Presentation transcript:

1 Not 4 Me Not 4 Me Slide created by Bruce Kennedy, Palliative Care Pharmacist, BRUCE KENNEDY BSc.(Pharm.) M.B.A. Clinical Pharmacy Specialist – Palliative Care 3 rd ANNUAL EDUCATION DAY Morgan Creek Golf Club, Surrey Saturday November 3rd, :35 – 13:25 Handouts provided, as there is always some tall person that decides to sit in the front!

2 T3 Composition Codeine 30 mg Codeine 30 mg Caffeine 15 mg Caffeine 15 mg Acetaminophen 300 mg Acetaminophen 300 mg Brands: Tylenol No. 3 Brands: Tylenol No. 3 Generics: Novo-gesic C30, Acet 30 (PMS), Ratio-Lenoltec No 3 Generics: Novo-gesic C30, Acet 30 (PMS), Ratio-Lenoltec No 3 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) Slide created by Bruce Kennedy, Palliative Care Pharmacist,

3 Terrible NNT Codeine 60 mg NNT = 16.7 Codeine 60 mg NNT = 16.7 Lower confidence level 11, higher 48 Lower confidence level 11, higher 48 i.e. “at best 1 in 11, at worst 1 in 48” get 50% pain relief 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 * In 1305 pts studied only 15% have 50% pain reduction * Worst analgesic on Oxford chart * Worst analgesic on Oxford chart * Some studies - no better than placebo ** Some studies - no better than placebo ** Acute Pain Systematic Reviews *** Acute Pain Systematic Reviews *** Addition of 60 mg codeine to acetaminophen added but 5 to 12% additional benefit Addition of 60 mg codeine to acetaminophen added but 5 to 12% additional benefit *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 1996 Analgesic efficacy and safety of paracetamol-codeine combination versus paracetamol alone:a systematic review Slide created by Bruce Kennedy, Palliative Care Pharmacist, 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) 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

4 Codeine needs conversion to be an effective analgesic Slide created by Bruce Kennedy, Palliative Care Pharmacist,

5 Yet Same Occurrence of Adverse Effects 170 mg codeine doses 170 mg codeine doses 18 patients: 9 Poor Metabolizers (PM), 9 Extensive Metabolizers (EM) 18 patients: 9 Poor Metabolizers (PM), 9 Extensive Metabolizers (EM) No differences in adverse effects, but No differences in adverse effects, but PM’s – only 0.17% morphine conversion (and no pain benefit) versus PM’s – only 0.17% morphine conversion (and no pain benefit) versus EM’s – 3.9% conversion into morphine EM’s – 3.9% conversion into morphine 23 X difference ! 23 X difference ! Pain :27-33 Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation Slide created by Bruce Kennedy, Palliative Care Pharmacist,

6 When you age… CYP450 activity very low at birth CYP450 activity very low at birth o CYP2D6 less than 1% activity in very young o CYP2D6 still less than 25% when < 5 years old Slide created by Bruce Kennedy, Palliative Care Pharmacist, So then changes your 2D6 capability 2008 Australian Prescriber June 31(3):63-5 Pediatric analgesia

7 Codeine pediatric use; impactful Canadian deaths 1. 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 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 Mom ultra rapid metabolizer, infant EM 2. Two year old adenotonsillectomy – Aug 2009 Healthy 13 Kg, Hx snoring, sleep apnea Healthy 13 Kg, Hx snoring, sleep apnea Codeine mg q4-6h. Died 9 am Post-op Day 3 Codeine mg q4-6h. Died 9 am Post-op Day 3 Ultrarapid metabolism-> morphine toxicity Ultrarapid metabolism-> morphine toxicity 3. Four year old tonsillectomy - reported April 2012 Died at home after only 4 age-appropriate doses of 8 mg Died at home after only 4 age-appropriate doses of 8 mg Slide created by Bruce Kennedy, Palliative Care Pharmacist, 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 The 2012 article also describes one death of a 5 year old boy in the US, and a near miss in Canada

8 Another pediatric case report 3 yr old admitted to ER with mom with cough/fever 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 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) 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 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) 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 Both twins were ultrarapid metabolizers->morphine toxicity Surviving twin ventilated x 3 days, had severe hypotension Surviving twin ventilated x 3 days, had severe hypotension 2009 Eur J Pediatr 168: Drug dosing error – severe clinical course of codeine intoxictation in twins 2009 Int J Legal Med 123: Fatal and severe codeine intoxication in 3 year old twins – interpretation of drug and metabolite concentrations Slide created by Bruce Kennedy, Palliative Care Pharmacist,

9 Codeine’s routine use is not recommended in children Removed from Toronto’s Hospital for Sick Children’s formulary 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 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; Canadian physicians calling for halt to use; UBC Ob Gyn MD Dr Peter von Dadelszen wants T3 banned UBC Ob Gyn MD Dr Peter von Dadelszen wants T3 banned Globe & Mail Aug 22, 2008, Mar 31, 2009 Globe & Mail Aug 22, 2008, Mar 31, 2009 CMAJ 2010 article – is it time to phase out codeine? CMAJ 2010 article – is it time to phase out codeine? Vancouver pediatrician Dr Noni MacDonald Vancouver pediatrician Dr Noni MacDonald Dr Stuart MacLeod CMAJ section editor, Public Health Dr Stuart MacLeod CMAJ section editor, Public Health 2010 Oct 4 th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups Nov 23 Cdn Medical Assn Journal Has the time come to phase out codeine? p1825 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

10 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 Max dose: 240 * to 800 mg/day Likely about 7 mg/kg Likely about 7 mg/kg Max single dose 60 * to 120 mg Max single dose 60 * to 120 mg *Martindale 36th Ed 2009 MAX DOSE/DAY Literature reports variable Slide created by Bruce Kennedy, Palliative Care Pharmacist,

11 WHO Ladder – Cancer Pain Step 1 Non-opioid +/- adjuvants Step 2 Opioid for moderate pain +/- Step 1 choices Step 3 Opioid for severe pain +/- Step 1 choices Pain persisting, or increasing Slide created by Bruce Kennedy, Palliative Care Pharmacist,

12 What Dr Twycross is saying now Palliative Care Formulary Canadian Edition It is perhaps practical to skip Step 2 in countries where palliative care is well established 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 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 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 Exception: Lack of access in some countries to strong opioids such as morphine Slide created by Bruce Kennedy, Palliative Care Pharmacist,

13 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 I’d say avoid completely in renal impairment, same for morphine – especially if dosing regularly Dosing adjustment in renal impairment: Dosing adjustment in renal impairment: GFr mL/minute: Administer 75% of dose*,** GFr mL/minute: Administer 75% of dose*,** GFr <10 mL/minute: Administer 50% of dose*,** GFr <10 mL/minute: Administer 50% of dose*,** Dosing adjustment in hepatic impairment: “Probably necessary”** Dosing adjustment in hepatic impairment: “Probably necessary”** Reduced hepatic blood flow or enzyme dysfunction - can significantly will affect conversion rate of codeine into morphine Reduced hepatic blood flow or enzyme dysfunction - can significantly will affect conversion rate of codeine into morphine *2007 Drug Prescribing in Renal Failure 5 th Ed Aronoff GR, Bennett WM, et al **http://www.merck.com/mmpe/lexicomp/codeine.html Slide created by Bruce Kennedy, Palliative Care Pharmacist,

14 Prodrug Conversion Prodrug Conversion Conversion delays pain relief onset Conversion delays pain relief onset Primary use of T#3 = p.r.n. dosing and is when onset of effect is important 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 C -> M Goodman & Gillman’s The Pharmacological Basis of Therapeutics 2001 p 1946,1985 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

15 Drug Interactions - another problem 2D6 drug inhibitors impact codeine’s conversion; 2D6 drug inhibitors impact codeine’s conversion; delays pain relief delays pain relief reduces max blood level reduces max blood level reduces pain relief reduces pain relief increases toxicity risk increases toxicity risk CYP2D6 – involved in CYP2D6 – involved in 11 to 25% of all drugs 11 to 25% of all drugs Many common drugs Many common drugs Interactions Less Drugs Less Slide created by Bruce Kennedy, Palliative Care Pharmacist,

16 Codeine Drug Interactions *2012 Feb Pharmacy Practice Top Rx Drugs of 2011 Cytochrome Drug Interaction Table v GenericDrug Rank 2011 * 2D6 Enzyme Impact on Codeine’s Pain Relieving Ability Citalopram12Substrate Venlafaxine13Inhibitor Trazodone30Substrate Risperidone34Substrate Amitriptyline43Substrate Celecoxib49Inhibitor Paroxetine51 Substrate + Inhibitor Buproprion55Substrate Escitalopram60Inhibitor Ranitidine69Inhibitor Oxycodone70Inhibitor Sertraline74Inhibitor Slide created by Bruce Kennedy, Palliative Care Pharmacist,

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

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

19 Codeine Is globally the most widely used narcotic The International Narcotics Control Board provides daily population figures Canada’s estimated 2012 need is 30 tons Canada’s estimated 2012 need is 30 tons This is 5.7% of the world’s consumption This is 5.7% of the world’s consumption For 0.49% of the world’s population For 0.49% of the world’s population Per capita we are #1 codeine consumers 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist, 2010 Morphine need was but 3.5 tons Apparently 1 million grams in a metric ton

20 Canada’s Needed Opioids for 2012 OpioidGrams Codeine26,803,689 Cannabis16,384,044 Oxycodone9,590,430 Morphine6,500,000 Methadone2,601,682 Hydromorphone1,493,485 Meperidine1,800,000 Fentanyl155,1000 Hydrocodone124,293 Sufentanil298 Oct 2, 2012 update: Estimated Requirements of narcotic drugs Slide created by Bruce Kennedy, Palliative Care Pharmacist, 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

21 Round and Round Morphine extracted Codeine synthesized (Lab) Converts back to Morphine in body 95 % of global morphine is used to make codeine through a semi- synthetic manufacturing process Slide created by Bruce Kennedy, Palliative Care Pharmacist, Hydrocodone Hydromorphone Per drugs/2010/Narcotic_drugs_publication_2010.pdfhttp://www.incb.org/pdf/technical-reports/narcotic- drugs/2010/Narcotic_drugs_publication_2010.pdf DrugRangeUsual Morphine8 to 19%15% Codeine1.25 to 4.3 %Say 3% ThebaineUp to 5%Not stated PapaverineZero to unknownNot stated NarceineNot medically used NarcotineNot medically used

22 Genotyping Costs $$$, Costs $$$, Unable to obtain as only available in research labs Unable to obtain as only available in research labs 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 Frequency of CYP2D6 phenotypes in White Populations “It might be good if physicians would know about the CYP2D6 genotype before administering codeine” “It might be good if physicians would know about the CYP2D6 genotype before administering codeine” Slide created by Bruce Kennedy, Palliative Care Pharmacist,

23 Genetic Variations 144 variants of 2D6 exist * 144 variants of 2D6 exist * Results in significant unpredictablity Results in significant unpredictablity Unattainable to know patient’s CYP2D6 enzyme activity Unattainable to know patient’s CYP2D6 enzyme activity Drug effect, titration requires monitoring Drug effect, titration requires monitoring * * 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist, Ultrarapid metabolizers (UM’s) Ultrarapid metabolizers (UM’s) Have like dual convertor chambers (allele’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) 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 ~ 3% of many Caucasian populations Up to 30 to 45 x higher codeine metabolites conc than PM’s Up to 30 to 45 x higher codeine metabolites conc than PM’s Good responders to codeine maybe UM’s! Good responders to codeine maybe UM’s!

24 Codeine (in Caucasians) * 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines. ** 1997 American J Human Genetics 60:284-5 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 For cough: No 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 % Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated ! Between all three of these groups it totals 46% of the Caucasian population should be selecting an alternative drug other than codeine !

25 in Surrey?... Group%No PM % EM % UM % Caucasian , South Asian , – 4.8 Chinese5.120,210< Filipino4.216,555 Southeast Asian Korean Aboriginal Black Multiple Vis Minority Latin American – Japanese % * Arab % * West Asian 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

26 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

27 Dosing, Use, Practicalities Overview T3 Massively (OVER) used T3 Massively (OVER) used Poor from a population based approach 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 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; T#3 (1971) released before we knew about; This 2D6 codeine enzyme non-conversion issue (1989) This 2D6 codeine enzyme non-conversion issue (1989) The WHO ladder (1986) The WHO ladder (1986) Before T3 - using 292’s, meperidine (How good an idea was that???) Before T3 - using 292’s, meperidine (How good an idea was that???) Slide created by Bruce Kennedy, Palliative Care Pharmacist,

28 T3, T1 safety Codeine dependency Codeine dependency A weak opioid - yet the wide availability of over- the-counter (OTC) codeine products is impactful 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; Now many internet resources, methods to extract morphine from OTC and Rx codeine products; Youtube.com - Youtube.com - Cold Water Extraction (CWE) videos performing Cold Water Extraction (CWE) videos performing Internet bulletinboards Internet bulletinboards Heroinhelper.com Heroinhelper.com 2 methods to extract from OTC acetaminophen/ASA products 2 methods to extract from OTC acetaminophen/ASA products Opiophile.org Opiophile.org Provide methods called “Homebake” in New Zealand and Australia Provide methods called “Homebake” in New Zealand and Australia Sophisticated methods using several chemicals including chloroform Sophisticated methods using several chemicals including chloroform Does support of T3 use - support T1 abuse? Does support of T3 use - support T1 abuse? Slide created by Bruce Kennedy, Palliative Care Pharmacist,

29 Acetaminophen Combination Products Risk Toxicity FDA (USA) very concerned as during 1990 to ,000 ER room visits, 26,000 hospitalizations, 458 deaths EACH YEAR related to acetaminophen associated overdoses 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 From 1998 to 2003, acetaminophen was the leading cause of acute liver failure 48% of acetaminophen-related cases associated with accidental overdose 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! Prescription combination products frequently used: Vicodin (acetaminophen and hydrocodone) is #1 Rx prescribed drug above all other prescription products in U.S., since 1997! Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology & Therapeutics Sep 3, Slide created by Bruce Kennedy, Palliative Care Pharmacist, Local SDM – Murrayville Square you will see 53 acetaminophen single ingredient products, of which only 8 were regular strength

30 Acetaminophen Combination Products Risk Toxicity US acetaminophen product sales: 28 billion doses US acetaminophen product sales: 28 billion doses 11 billion Rx containing acetaminophen products (182 million Rx’s in 2005) 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 8 billion single dose acetaminophen e.g. Tylenol – 92% is 500 mg strength 9.7 billion combination OTC (e.g. Nyquil, Theraflu) 9.7 billion combination OTC (e.g. Nyquil, Theraflu) FDA (2009)38 member expert panel voted and advised to FDA (2009)38 member expert panel voted and advised to Eliminate prescription acetaminophen products completely! (20 votes, 10/20 high priority) 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 FDA (Feb 13/11) now recommend 325 mg per dosage limit in prescription products Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology & Therapeutics Sep 3, Slide created by Bruce Kennedy, Palliative Care Pharmacist, Reminder: Make the point about what a wimpy dose 325 mg acetaminophen is in hospital

31 Which product does not contain Acetaminophen? (471 do in Canada) Acetazone Acetazone Actified Plus Actified Plus Arthritis pain extended relief Arthritis pain extended relief Balminil Cough & Flu Balminil Cough & Flu Benadryl Total Benadryl Total Dayquil D Dayquil D Dristan ND caplets Dristan ND caplets Hot Lemon relief Hot Lemon relief Midol Night-Time Midol Night-Time Nyquil Sinus Liquicaps Nyquil Sinus Liquicaps Pamprin Extra Strength Pamprin Extra Strength Sinutab Sinutab Theraflu Cold & Flu Theraflu Cold & Flu Triaminic cough & sore throat softchews Triaminic cough & sore throat softchews Slide created by Bruce Kennedy, Palliative Care Pharmacist, 2009 = = = 471

32 Caffeine “Why is it there?” “Why is it there?” Regulatory fit/rules evasion- no duplicate Rx Regulatory fit/rules evasion- no duplicate Rx Helps headaches – 5,427,000 * of them? Helps headaches – 5,427,000 * of them? Causes GI upset, effect on sleep Causes GI upset, effect on sleep Caffeine withdrawal could occur Caffeine withdrawal could occur Adds unneeded drug-interaction-allergy risk, caffeine interacts with other drugs, smoking Adds unneeded drug-interaction-allergy risk, caffeine interacts with other drugs, smoking Little to no therapeutic role, esp. pain Little to no therapeutic role, esp. pain * * Number of prescriptions in 2011 in Canada for acetaminophen, caffeine and codeine Slide created by Bruce Kennedy, Palliative Care Pharmacist,

33 Relieve Pain – Help patients If codeine and T3 are suboptimal If codeine and T3 are suboptimal What should we consider instead? What should we consider instead? Slide created by Bruce Kennedy, Palliative Care Pharmacist,

34 Morphine 200 X stronger affinity for mu receptor than codeine 200 X stronger affinity for mu receptor than codeine It’s the most significant active component of codeine It’s the most significant active component of codeine Provides predictability. No worries about the Provides predictability. No worries about the PM’s Poor (0-19 * %) * South African’s PM’s Poor (0-19 * %) * South African’s EM’s Extensive ( %) EM’s Extensive ( %) UM’s Ultra-rapid (0-29 ** %) ** Ethiopian’s UM’s Ultra-rapid (0-29 ** %) ** Ethiopian’s Why wait? Onset requires no 2D6 conversion Why wait? Onset requires no 2D6 conversion Use a small dose – 2.5 mg PO to start Use a small dose – 2.5 mg PO to start The Pharmacogenomics Journal 2007;7: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 Slide created by Bruce Kennedy, Palliative Care Pharmacist, Study importation of codeine into Ethiopia!

35 Hydromorphone Less histamine release risk than either codeine or morphine Less histamine release risk than either codeine or morphine Codeine & morphine have a dose-related histamine releasing effect Codeine & morphine have 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 Meperidine

36 Oxycodone, Tramadol Options; Options; however are also metabolized by the same Cytochrome P450 2D6 enzyme however are also metabolized by the same Cytochrome P450 2D6 enzyme Best to avoid when response to codeine suspected to be poor or excessive 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

37 Oxycodone 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines 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 Insufficient data to allow calculation of dose adjustment. Select alternative drug – not tramadol or codeine – or be alert to symptoms of insufficient pain relief 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) Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

38 Tramadol 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines 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. Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

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 2012 Arch Intern Med(5): Long-term analgesic use after Low-Risk Surgery Pre - surgery 7 Days Post- surgical Discharge One Year after Surgery Opioid Use 391,139 pts 0%, - all were opioid-naive Opioid Use 27,636 pts 7.1 % Opioid Use 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 NSAID Use 1169 pts 0.3 % NSAID Use 30,080 pts 7.8%

40 NSAID’s Slide created by Bruce Kennedy, Palliative Care Pharmacist, Use short term, whenever possible Use short term, whenever possible Ibuprofen 400 mg NNT is 2.5 Ibuprofen 400 mg NNT is 2.5 Could combine with acetaminophen Could combine with acetaminophen NNT is 1.5 to 1.6 when combining NNT is 1.5 to 1.6 when combining Ibuprofen with acetaminophen Ibuprofen with acetaminophen 100 mg with 250 mg, 200 mg with 500 mg or 400 mg ibuprofen with 1000 mg 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 But Bandolier comments that this common possible combination poorly studied Unfortunately! Unfortunately! 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 dolier/booth/painpag/Acutrev/Ana lgesics/lftab.html Bandolier Investigating over-the-counter oral analgesics

41 Reverse Ladder Concept Consider Timeframes Monitoring for stepping down 2011 Anaesth Int Care 39; Acute pain management in opioid-tolerant patients: a growing challenge What goes up, must come down?

42 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 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 Is inexpensive No discharge prescription required No discharge prescription required No opioid abuse or addiction issues No opioid abuse or addiction issues Safer with chronic use, when used within daily limits Safer with chronic use, when used within daily limits E.g. 4 g per day, less as indicated E.g. 4 g per day, less as indicated Slide created by Bruce Kennedy, Palliative Care Pharmacist,

43 Acetaminophen Benefit Codeine 60 mg 16.7 Codeine 60 mg plus Acetaminophen 300 mg 5.7 Acetaminophen 500 mg /650 mg mg mg 3.7 Oxford League Table of Analgesic Efficacy – Number Needed to Treat Acute pain, single dose studies, study size 138 to 2759 people Slide created by Bruce Kennedy, Palliative Care Pharmacist, NNT Figures = Number Needed to Treat (to achieve 50% pain relief in 1 patient) Acetaminophen 600/650 mg 4.2 Reminder: Make the point about what a wimpy dose 325 mg acetaminophen is in hospital

44 Codeine: any other Therapeutic Roles? Diarrhea: Loperamide (Imodium) far better Diarrhea: Loperamide (Imodium) far better Need 200 mg codeine PO for same effect as 4 mg of loperamide Need 200 mg codeine PO for same effect as 4 mg of loperamide Needs conversion to morphine to work for diarrhea! * Needs conversion to morphine to work for diarrhea! * At doses effective for antidiarrheal effect – risks central (unwanted) adverse effects, such as sedation, analgesia 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!) Cough: Codeine no more effective than alternatives; morphine, methadone and likely dextromethorphan. (UK reg – not in children!) Slide created by Bruce Kennedy, Palliative Care Pharmacist, 1997 Clin Pharm Ther Effect of codeine in GI motility in relation to CYP2D6. (61), Oct 4 th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups

45 Prescriptions In Canada 525 Million total of all prescriptions per year 525 Million total of all prescriptions per year 27.5 Million of these (4.7%) are for analgesics 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 18 th most commonly issued Rx in Canada 5.4 Million (20% of all analgesics) just for Acetaminophen/Caffeine/Codeine - makes it the 18 th most commonly issued Rx in Canada # patient recipients # patient recipients British Columbia #1, Manitoba: #1, Ontario #2 British Columbia #1, Manitoba: #1, Ontario #2 Other provinces likely very similar Other provinces likely very similar 2011 Feb Pharmacy Practice Top Rx Drugs of 2011 PharmaCare Trends 2009/2010 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

46 Acetaminophen/Caffeine/ Codeine 30 mg Ranking in Canada % Change (Number of Rx's) % % % % % % % % % % % % % 19982n/a 19971n/a 19961n/a figures are for combined brand Tylenol #3 and generics and prior represents just figures for brand name Tylenol #3 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

47 Alternatives to T#3 To provide approximately the same pain relief (*); mg of Acetaminophen mg of Acetaminophen 200 mg of Ibuprofen 200 mg of Ibuprofen 500 mg Acetaminophen mg Ibuprofen 500 mg Acetaminophen mg Ibuprofen ½ tablet of a generic Percocet ½ tablet of a generic Percocet 3.3 mg Oxycodone 3.3 mg Oxycodone Morphine 2.5 to 5 mg tablet Morphine 2.5 to 5 mg tablet Hydromorphone 0.5 to 1 mg tablet Hydromorphone 0.5 to 1 mg tablet * 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist, 1-2 ¢ 1-2 ¢ 2 ¢ 2 ¢ 3 ¢ 3 ¢ 9 ¢ 9 ¢ 6-11 ¢ 6-11 ¢ 9-18 ¢ 9-18 ¢ 13 cents!

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

49 Not 4 Me Not 4 Me Bruce Kennedy Clinical Pharmacy Specialist Slide created by Bruce Kennedy, Palliative Care Pharmacist, Link to another presentation I did with some other interesting pain aspects can be found here: %20in%20Multiethnic%20%26%20Genetically%20Diverse%20BC.pdf %20in%20Multiethnic%20%26%20Genetically%20Diverse%20BC.pdf

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

51

52 Yet codeine pediatric use; impactful Canadian deaths 1) Newborn Breastfeeding case - Aug ’06 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 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 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 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 Healthy 13 Kg, Hx snoring, sleep apnea Codeine mg q4-6h. Died 9 am Post-op Day 3 Codeine mg q4-6h. Died 9 am Post-op Day 3 Ultrarapid metabolism-> morphine toxicity Ultrarapid metabolism-> morphine toxicity Slide created by Bruce Kennedy, Palliative Care Pharmacist, 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

53 From: p/documents/websiteresources/con pdf

54 WHO Ladder – Cancer Pain Step 1 Non-opioid +/- adjuvants Step 2 Opioid for moderate pain +/- Step 1 choices Step 3 Opioid for severe pain +/- Step 1 choices Severe 50% Pain persisting, or increasing Slide created by Bruce Kennedy, Palliative Care Pharmacist, Moderate 20% Mild 30%

55 Codeine Drug Interactions *2011 Feb Pharmacy Practice Top Rx Drugs of 2010 Cytochrome Drug Interaction Table v GenericDrug Rank 2010 * 2D6 Enzyme Impact on Codeine’s Pain Relieving Ability Venlafaxine11Substrate Citalopram13Inhibitor Risperidone33Substrate Trazodone35Substrate Amitriptyline41Substrate Paroxetine46 Substrate + Inhibitor Celecoxib49Inhibitor Ranitidine53Inhibitor Buproprion61Substrate Oxycodone62Inhibitor Sertraline73Inhibitor Escitalopram80Inhibitor Slide created by Bruce Kennedy, Palliative Care Pharmacist,

56 Codeine Is globally the most widely used narcotic The International Narcotics Control Board provides daily population figures Canada imported 21.1 tons of codeine in 2004, that is 10.5% of world consumption 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 Estimated Need (Tons):`09-29, ‘10-26, ‘11-27 Per capita we are #1 codeine consumers Per capita we are #1 codeine consumers World Population: 6,911,790,500  Canada’s Population: 34,043,879  37th largest of 234 countries  0.49 % of world Slide created by Bruce Kennedy, Palliative Care Pharmacist, 2010 Morphine need was but 3.5 tons

57 in Langley?... (district + city) Group%No PM % EM % UM % Caucasian Aboriginal Chinese < Korean South Asian – 4.8 Southeast Asian Filipino Black Japanese % * Latin American – Multiple + Vis Minority West Asian Arab % * 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

58 Canada’s Needed Opioids for 2011 OpioidGrams Codeine27,000,000 Cannabis14,500,000 Oxycodone7,000,000 Morphine4,000,000 Methadone2,500,000 Hydromorphone1,500,000 Meperidine1,300,000 Fentanyl150,000 Hydrocodone110,000 Sufentanil240 Estimated Requirements of narcotic drugs p. 48 Slide created by Bruce Kennedy, Palliative Care Pharmacist,

59 Dosing, Use, Practicalities Patient taking two codeine phosphate 30 mg tablets q6h and one breakthrough daily of 60 mg.* Pain is stable 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 Sustained Release codeine (Codeine Contin) suggested for convenience What dose of Codeine Contin should patient take every 12 hours? What dose of Codeine Contin should patient take every 12 hours? Slide created by Bruce Kennedy, Palliative Care Pharmacist, * = 240 mg plus 60 mg: Total 300 mg/day * = 240 mg plus 60 mg: Total 300 mg/day

60 300 mg codeine phosphate per day Less 25% ( 75 mg) = 225 mg of codeine base 300 mg codeine phosphate per day Less 25% ( 75 mg) = 225 mg of codeine base Conversion is = 225 mg Codeine Contin Conversion is = 225 mg Codeine Contin Available as 50, 100, 150, 200 mg strengths Available as 50, 100, 150, 200 mg strengths Advise start on 100 mg Codeine Contin q12h Advise start on 100 mg Codeine Contin q12h Slide created by Bruce Kennedy, Palliative Care Pharmacist, 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 Dosing, Use, Practicalities

61 Recently – Doda Abuse 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 Doda is Dried Poppyseed Powder Slide created by Bruce Kennedy, Palliative Care Pharmacist,

62 T3 use in End-of-Life Care in BC Codeine in wide use for End-of-Life patients ! Codeine in wide use for End-of-Life patients ! Slide created by Bruce Kennedy, Palliative Care Pharmacist, Number of Claimants ’03-’04 ≤ 180 days ≤ 720 days Furosemide6,6818,533 Morphine4,6655,356 Lorazepam4,3326,274 Codeine combo 3,9407,654 Ramipril3,5985,234 Glyceryl trinitrate 3,3425,164 Ciprofloxacin3,2397,199 Digoxin3,0083,994 Levothyroxine2,998- Warfarin2,402- Cephalexin-3,932 Clarithromycin-3,924 Pag e 28 of repo rt Location of death 38% acute hospital 27% long term care 15% hospital-palliative 17% home 3% other

63 2006 CMAJ 175;11:1385 Changes in illicit opioid use across Canada Slide created by Bruce Kennedy, Palliative Care Pharmacist,

64 Codeine Rotation – Certainly Uncertain Ratio’s poorly understood/remembered Ratio’s poorly understood/remembered Orally codeine is reported to be 1/10 th as potent as morphine – but this is only roughly Orally codeine is reported to be 1/10 th as potent as morphine – but this is only roughly Injectably codeine is 1/12 th as potent as morphine – but again we know genetic variability will occur Injectably codeine is 1/12 th as potent as morphine – but again we know genetic variability will occur Why not just avoid an uncertain rotation conversion? 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. 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. Slide created by Bruce Kennedy, Palliative Care Pharmacist,

65 Codeine 2011 Clinical Pharmacology & Therapeutics 89(5);May: Pharmacogenetics: from bench to byte- an update of guidelines 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 4B 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 For cough: No 3A 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 3F Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

66 Dosing, Use, Practicalities Overview Precise relative analgesic significance of metabolites uncertain Precise relative analgesic significance of metabolites uncertain Codeine converts into 1, 2 possibly 3 active ingredients (all acting on mu receptor), (competing too?) 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% Morphine - Amount normally converted into morphine reported from 3.9 to 10% Codeine-6-Glucuronide Codeine-6-Glucuronide Norcodeine Norcodeine Ensure with adverse drug assessments that people know that codeine metabolizes into morphine – ask about history of reaction to each drug Ensure with adverse drug assessments that people know that codeine metabolizes into morphine – ask about history of reaction to each drug Slide created by Bruce Kennedy, Palliative Care Pharmacist,

67 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

68 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 Pharmacogenetics and opioids Ross JR, Quigley p in Opioids in Cancer Pain 2 nd Edition Davis, MP, Glare P, Quigley C, Hardy, J Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

69 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 Slide created by Bruce Kennedy, Palliative Care Pharmacist, If you use this slide in your presentation, mentioning the source author graciously appreciated !

70 NSAID’s + Acetaminophen Slide created by Bruce Kennedy, Palliative Care Pharmacist, Bandolier Investigating over-the-counter oral analgesics Use short term, whenever possible Use short term, whenever possible Could combine with acetaminophen Could combine with acetaminophen 400 mg ibuprofen mg acetaminophen has NNT of 1.5 ! 400 mg ibuprofen mg acetaminophen has NNT of 1.5 !

71 NSAID’s + Acetaminophen Slide created by Bruce Kennedy, Palliative Care Pharmacist, Bandolier Investigating over-the-counter oral analgesics Use short term, whenever possible Use short term, whenever possible Could combine with acetaminophen Could combine with acetaminophen 400 mg ibuprofen mg acetaminophen has NNT of 1.5 ! 400 mg ibuprofen mg acetaminophen has NNT of 1.5 !


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