Not 4 Me
3rd ANNUAL EDUCATION DAY
Morgan Creek Golf Club, Surrey
Saturday November 3rd, 2012
12:35 – 13:25
BRUCE KENNEDY BSc.(Pharm.) M.B.A.
Clinical Pharmacy Specialist – Palliative Care
Bruce.Kennedy@fraserhealth.ca
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
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)
NNT is Number

Codeine 60 mgTerrible
NNT = 16.7 NNT

Lower confidence level 11, higher 48


Needed to Treat
(for 1 in the group to 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*
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


*Oxford League Table of Analgesic Efficacy 2007– Number Needed to Treat (NNT)
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/lftab.html
** J Clin Pharmacol 1984;24:96-102 An appraisal of codeine as an analgesic single-dose analysis,
Br. J Anesthesia 2002 94(6):710-14 Predicting postop analgesia outcomes: NNT league tables or procedurespecific 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
Codeine needs conversion
to be an effective analgesic
http://www.pharmgkb.org/images/pathway/codeineMorphine-pk.png
Yet Same Occurrence
of Adverse Effects






170 mg codeine doses
18 patients: 9 Poor Metabolizers
(PM),
9 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 !
Pain 1998 76:27-33 Same incidence of adverse drug events after codeine administration
irrespective of the genetically determined differences in morphine formation
When you age…
So then changes your
2D6 capability

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
2008 Australian Prescriber June 31(3):63-5 Pediatric analgesia
Codeine pediatric use;
impactful Canadian deaths
1. Newborn Breastfeeding case – Aug 2006


Mom took codeine 60 mg + 1000 mg acetaminophen q12h
x 2 days then 30 mg and 500 mg q12h x 14 more days
Mom ultra rapid metabolizer, infant EM
2. Two year old adenotonsillectomy – Aug 2009

Healthy 13 Kg, Hx snoring, sleep apnea

Codeine 10 - 12.5 mg q4-6h. Died 9 am Post-op Day 3

Ultrarapid metabolism-> morphine toxicity
3. Four year old tonsillectomy - reported April 2012

Died at home after only 4 age-appropriate doses of 8 mg
2006 Lancet 368:704 Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeineprescribed mother. 2007 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
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


2009 Eur J Pediatr 168:819-824 Drug dosing error – severe clinical course of codeine
intoxictation in twins
2009 Int J Legal Med 123:387-94 Fatal and severe codeine
intoxication in 3 year old twins – interpretation of drug and metabolite concentrations

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
2010 Oct 4th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups
http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con096756.pdf
2010 Nov 23 Cdn Medical Assn Journal Has the time come to phase out codeine? p1825
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/DAY
Likely about 7 mg/kg
Max single dose 60* to 120 mg
Literature
reports variable
*Martindale 36th Ed 2009
WHO Ladder –
Pain persisting,
or increasing
Step 2
Step 1
Non-opioid
+/- adjuvants
Opioid for
moderate pain
+/Step 1 choices
Cancer Pain
Step 3
Opioid for
severe pain
+/Step 1 choices
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 www.palliativebooks.com
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 10-50 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
*2007 Drug Prescribing in Renal Failure 5th Ed Aronoff GR, Bennett WM, et al
**http://www.merck.com/mmpe/lexicomp/codeine.html
C -> M
Drug
Codeine
Morphine
Prodrug Conversion
Time to
Onset
PO
60 min
+/- 30 min
30 – 90 min


Conversion delays
pain relief onset
Primary use of T#3
= p.r.n. dosing
and is when onset of
effect is important
Goodman & Gillman’s The Pharmacological Basis of Therapeutics 2001 p 1946,1985
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
Interactions
Codeine Drug Interactions
Generic
Drug
Citalopram
Venlafaxine
Trazodone
Risperidone
Amitriptyline
Celecoxib
Paroxetine
Buproprion
Escitalopram
Ranitidine
Oxycodone
Sertraline
Rank
2011*
2D6 Enzyme
12
13
30
34
43
49
51
55
60
69
70
74
Substrate
Inhibitor
Substrate
Substrate
Substrate
Inhibitor
Substrate + Inhibitor
Substrate
Inhibitor
Inhibitor
Inhibitor
Inhibitor
Impact on Codeine’s
Pain Relieving Ability
*2012 Feb Pharmacy Practice Top Rx Drugs of 2011
Cytochrome Drug Interaction Table v.5 2009 http://medicine.iupui.edu/clinpharm/ddis/
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
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 20 - 80 X higher than expected
NEJM 2004 351:2837-31 Codeine intoxication associated with ultra rapid CYP 2D6
metabolism Erratum NEJM 2005;352:638
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
The International Narcotics Control Board http://www.incb.org/incb/narcotic_drugs_reports.html
http://www.xist.org/earth/population1.aspx provides daily population figures
Canada’s Needed Opioids for 2012
Opioid
Codeine
Cannabis
Oxycodone
Morphine
Methadone
Hydromorphone
Meperidine
Fentanyl
Hydrocodone
Sufentanil
Grams
26,803,689
16,384,044
9,590,430
6,500,000
2,601,682
1,493,485
1,800,000
155,1000
124,293
298
Oct 2, 2012 update: Estimated Requirements of narcotic drugs
www.incb.org/incb/en/narcotic-drugs/estimates/nacotic-drugs-estimates.html
Round and Round
Hydromorphone
Morphine extracted
Hydrocodone
Codeine synthesized (Lab)
Converts back to Morphine in body
95 % of global morphine is used
to make codeine through a semisynthetic manufacturing process
Genotyping

Frequency of CYP2D6
phenotypes
in White Populations
“It might be good if
physicians would know
about the CYP2D6
genotype before
administering codeine”

Costs $$$,

Unable to obtain as only available in research labs
The Pharmacogenomics Journal 2007;7:257-65 Pharmacokinetics of codeine
and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6
2004 NEJM 351:27:2867-9 Genes and the response to drugs
2010 Oct 4 Cdn Press Consider abandoning codeine until more safety research
is done www.canadianhealthcarenetwork
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!
* www.cypalleles.ki.se
The Pharmacogenomics Journal 2007;7:257-65 Pharmacokinetics of codeine and its
metabolite morphine in ultra-rapid metabolizers due to CYP2D6
Pharmacogenomics 2008;9(9):1267-84 Gideon Koren Pharmacogenetic insights into
codeine analgesia: implications to pediatric codeine use
Codeine
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 %
Between all
three of
these
groups
it totals
Intermediate For analgesia: Select alternative drug
(e.g. acetaminophen, NSAID, morphine –
Metabolizer
36.2 %
46% of the
Caucasian
population
(in Caucasians)
Recommendation*
Poor
Metabolizer
%
**
not tramadol or oxycodone) or be alert to
symptoms of insufficient pain relief
For cough: No
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 %
should be
selecting an
alternative
drug
other than
codeine !
*2011 Clinical Pharmacology & Therapeutics 89(5);May:662-673 Pharmacogenetics: from
bench to byte- an update of guidelines. **1997 American J Human Genetics 60:284-5
in Surrey?...
Group
%
No
PM %
Caucasian
51.6
203,815
1.5 - 10
South Asian
27.6
107,810
1.8 – 4.8
Chinese
5.1
20,210
<1.0
Filipino
4.2
16,555
Southeast Asian
2.4
9240
Korean
2.0
7665
Aboriginal
1.9
7630
Black
1.3
5015
Multiple Vis Minority
1.1
4395
Latin American
1.0
Japanese
EM %
UM %
0.8 - 10
0.9
1.2
1.9-7.3
4.9
3785
2.2 – 6.6
1.7
0.5
2090
0.5-1%*
Arab
0.5
1805
16-28%*
West Asian
0.2
1790
Stats Canada 2006 Census Data
2006 The Oncologist 11;126-35 Interethnic differences in genetic polymorphisms in
the U.S. population: clinical implications, *Tylenol #3 Prescribing Info July14, 2008
False Tolerance
in Poor Metabolizers
Toxicity with Opioid Switch

Codeine 6 to 12 T3/day

Patient not identified as poor metabolizer

Patient presumed to be opioid-tolerant

not working
New opioid gets started too high –
converted at “equianalgesic dose” – but
codeine wasn’t getting converted before
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???)
T3, T1 safety


Codeine dependency
 A weak opioid - yet the wide availability of overthe-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

Heroinhelper.com
Internet bulletinboards


Opiophile.org



2 methods to extract from OTC acetaminophen/ASA products
Provide methods called “Homebake” in New Zealand and Australia
Sophisticated methods using several chemicals including chloroform
Does support of T3 use - support T1 abuse?
Acetaminophen Combination Products
Risk Toxicity


FDA (USA) very concerned as during 1990 to 1998 - 56,000
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!
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM170188.pdf
Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology &
Therapeutics Sep 3, 2010 289-291
Acetaminophen Combination Products
Risk Toxicity



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
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM170188.pdf
Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds Clinical Pharmacology &
Therapeutics Sep 3, 2010 289-291
http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm
Which product does not contain
Acetaminophen? (471 do in Canada)







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
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
* Number of prescriptions in 2011 in Canada for acetaminophen, caffeine and codeine
Relieve Pain – Help patients


If codeine and T3 are suboptimal
What should we consider instead?
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*%)

EM’s Extensive
(71- 100%)

UM’s Ultra-rapid
(0-29**%)
*South
African’s
**Ethiopian’s

Why wait? Onset requires no 2D6 conversion

Use a small dose – 2.5 mg PO to start
The Pharmacogenomics Journal 2007;7:257-65 Pharmacokinetics of codeine
and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6
Hydromorphone

Less histamine release risk than either
codeine or morphine
Meperidine<Codeine<Morphine<Oxycodone<Hydromorphone<Fentanyl

Codeine & morphine have a dose-related
histamine releasing effect
Pharmacists Letter 2006 Opioid Intolerance Decision Algorithm Document #220201
Martindale’s The Complete Drug Reference 36th Ed 2009 Codeine p 37
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 30:1356-58
Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer
2011 Clinical Pharmacology & Therapeutics 89(5);May:662-673
Pharmacogenetics: from bench to byte- an update of guidelines
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
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)
2011 Clinical Pharmacology & Therapeutics 89(5);May:662-673
Pharmacogenetics: from bench to byte- an update of guidelines
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:662-673
Pharmacogenetics: from bench to byte- an update of guidelines
Intent is short-term, but on initiation
use becomes long-term


1997-2008. Ontario seniors age 66 and older reviewed
Low-risk short stay surgeries: cataract surgery, TURP,
varicose vein stripping, laparoscopic cholecystectomy
Pre surgery
7 Days
Postsurgical
Discharge
One Year
after
Surgery
Pre surgery
7 Days
Postsurgical
Discharge
One Year
after
Surgery
Opioid Use
391,139 pts
Opioid Use
27,636 pts
Opioid Use
30,145 pts
NSAID Use
383,780 pts
NSAID Use
1169 pts
NSAID Use
30,080 pts
0%,
7.1 %
7.7%
0%,
0.3 %
7.8%
- all were
opioid-naive
- all were
NSAID-naïve
2012 Arch Intern Med(5):425-30. Long-term analgesic use after Low-Risk Surgery
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!
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/lftab.html
Bandolier Investigating over-the-counter oral analgesics
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/OTC%20analgesics1.html
Reverse Ladder Concept

Consider


Timeframes
Monitoring
for stepping down
2011 Anaesth Int Care 39;804-23. Acute pain management in opioid-tolerant patients: a growing challenge
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/493HJM.html
http://www.painbc.ca/content/pain-bc-conference-2012-evolution-pain-management
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
Acetaminophen Benefit
NNT Figures = Number Needed to Treat (to achieve 50% pain relief in 1 patient)
Codeine 60 mg
16.7
Acetaminophen
500 mg
600/650 mg
3.5
4.6
1000 mg
1500 mg
3.8
3.7
Codeine 60 mg plus
Acetaminophen 300 mg
5.7
Acetaminophen
4.2
600/650 mg
Oxford League Table of Analgesic Efficacy – Number Needed to Treat
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/acutrev/analgesics/lftab.html
Acute pain, single dose studies, study size 138 to 2759 people
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!)
1997 Clin Pharm Ther Effect of codeine in GI motility in relation to CYP2D6. (61), 459-66
2010 Oct 4th UK Medicines and Healthcare products Regulatory Agency OTC cough syrups
http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con096756.pdf
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
2011 Feb Pharmacy Practice Top Rx Drugs of 2011
PharmaCare Trends 2009/2010 http://www.health.gov.bc.ca/pharmacare/pdf/PCareTrends2009-10.pdf
Acetaminophen/Caffeine/
Codeine 30 mg
Ranking in
Canada
% Change
(Number of Rx's)
2011
18
-1.5%
2010
15
-1.6%
2009
15
- 0.1%
2008
14
+3%
2007
10
-9%
2006
8
-10%
2005
6
-2%
2004
5
+3%
2003
4
-1%
2002
5
-4%
2001
4
-3%
2000
2
+4%
1999
3
+6%
1998
2
n/a
1997
1
n/a
1996
1
n/a
2011- 2008 figures are for combined brand Tylenol #3 and generics.
2007 and prior represents just figures for brand name Tylenol #3
Alternatives to T#3
To provide approximately
the same pain relief (*);







13 cents!
1-2 ¢
 2 ¢
500 mg Acetaminophen + 200 mg Ibuprofen  3 ¢
½ tablet of a generic Percocet
 3 ¢
3.3 mg Oxycodone
 9 ¢
Morphine 2.5 to 5 mg tablet
 6-11 ¢
Hydromorphone 0.5 to 1 mg tablet  9-18 ¢
500 - 1000 mg of Acetaminophen
200 mg of Ibuprofen

* 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
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!
Not 4 Me
Bruce Kennedy
Clinical Pharmacy Specialist
Bruce.Kennedy@fraserhealth.ca
604-614-6328
Link to another presentation I did with some other
interesting pain aspects can be found here:
http://www.painbc.ca/sites/default/files/pdf_files/Prescribing%20Opioids
%20in%20Multiethnic%20%26%20Genetically%20Diverse%20BC.pdf
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
Yet codeine pediatric use;
impactful Canadian deaths
1) Newborn Breastfeeding case - Aug ’06



Mom took codeine 60 mg + 1000 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 Dadelszenwants 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 10 - 12.5 mg q4-6h. Died 9 am Post-op Day 3

Ultrarapid metabolism-> morphine toxicity
2006 Lancet 368:704 Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeineprescribed mother. 2007 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
From: http://www.mhra.gov.uk/home/groups/plp/documents/websiteresources/con096756.pdf
WHO Ladder –
Pain persisting,
or increasing
Step 2
Step 1
Opioid for
moderate pain
+/-
Cancer Pain
Step 3
Opioid for
severe pain
+/Step 1 choices
Non-opioid
+/- adjuvants
Step 1 choices
Mild
Moderate
Severe
30%
20%
50%
Codeine Drug Interactions
Generic
Drug
Venlafaxine
Citalopram
Risperidone
Trazodone
Amitriptyline
Paroxetine
Celecoxib
Ranitidine
Buproprion
Oxycodone
Sertraline
Escitalopram
Rank
2010*
2D6 Enzyme
11
13
33
35
41
46
49
53
61
62
73
80
Substrate
Inhibitor
Substrate
Substrate
Substrate
Substrate + Inhibitor
Inhibitor
Inhibitor
Substrate
Inhibitor
Inhibitor
Inhibitor
Impact on Codeine’s
Pain Relieving Ability
*2011 Feb Pharmacy Practice Top Rx Drugs of 2010
Cytochrome Drug Interaction Table v.5 2009 http://medicine.iupui.edu/clinpharm/ddis/
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
• World Population:
6,911,790,500
 Canada’s Population: 34,043,879
 37th largest of 234 countries
 0.49 % of world
The International Narcotics Control Board http://www.incb.org/incb/narcotic_drugs_reports.html
http://www.xist.org/earth/population1.aspx provides daily population figures
in Langley?...
Group
(district + city)
%
No
PM %
EM %
UM %
Caucasian
87.1
102187
1.5 - 10
0.8 - 10
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
0.9
1100
1.2
Filipino
0.8
940
Black
0.7
835
1.9-7.3
Japanese
0.6
660
0.5-1%*
Latin American
0.6
650
2.2 – 6.6
Multiple + Vis Minority
0.3
355
West Asian
0.2
180
Arab
0.1
155
4.9
1.7
16-28%*
Stats Canada 2006 Census Data
2006 The Oncologist 11;126-35 Interethnic differences in genetic polymorphisms in
the U.S. population: clinical implications, *Tylenol #3 Prescribing Info July14, 2008
Canada’s Needed Opioids for 2011
Opioid
Codeine
Cannabis
Oxycodone
Morphine
Methadone
Hydromorphone
Meperidine
Fentanyl
Hydrocodone
Sufentanil
Grams
27,000,000
14,500,000
7,000,000
4,000,000
2,500,000
1,500,000
1,300,000
150,000
110,000
240
http://www.incb.org/pdf/technical-reports/narcotic-drugs/2010/Narcotic_drugs_publication_2010.pdf
Estimated Requirements of narcotic drugs p. 48
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?
* = 240 mg plus 60 mg: Total 300 mg/day
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
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, 2009 - 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
T3 use in End-of-Life Care in BC
Number of Claimants ’03-’04

Codeine in
≤ 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
Location of death
Levothyroxine
2,998
-
Warfarin
2,402
-
Cephalexin
-
3,932
Clarithromycin
-
3,924
38% acute hospital
27% long term care
15% hospital-palliative
17% home
3% other
wide use for
End-of-Life
patients !
http://www.cihi.ca/cihiweb/dispPage.jsp?cw_page=AR_1729_E
2006 CMAJ 175;11:1385 Changes in illicit opioid use across Canada
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.
Codeine
453 Subjects
Poor
Metabolizer
Recommendation
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
Intermediate For analgesia: Select alternative drug
(e.g. acetaminophen, NSAID, morphine –
Metabolizer
not tramadol or oxycodone) or be alert to
symptoms of insufficient pain relief
For cough: No
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
Level of
Evidence
Clinical
Relevance
4
B
3
A
3
F
2011 Clinical Pharmacology & Therapeutics 89(5);May:662-673 Pharmacogenetics:
from bench to byte- an update of guidelines. www.Pharmgkb.org
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
http://www.pharmgkb.org/do/serve?objId=PA146123006&objCls=Pathway
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
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 287-299 in Opioids
in Cancer Pain 2nd Edition Davis, MP, Glare P, Quigley C, Hardy, J
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.
> EM
>ofUM
*2003
PainPM
105:231-8
Impact
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 11:171-81 Impact of CYP2D6 genetic polymorphisms on tramadol
pharmacokinetics and pharmacodynamics
NSAID’s
Acetaminophen
 Use short +
term,
whenever possible

Could combine with acetaminophen

400 mg ibuprofen + 1000 mg acetaminophen has NNT of 1.5 !
Bandolier Investigating over-the-counter oral analgesics
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/OTC%20analgesics1.html
NSAID’s + Acetaminophen


Use short term, whenever possible
Could combine with acetaminophen

400 mg ibuprofen + 1000 mg acetaminophen has NNT of 1.5 !
Bandolier Investigating over-the-counter oral analgesics
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/OTC%20analgesics1.html