Objectives:

1. Introduction
2. The role of pharmacist??
3. Implementing Therapy with Opioids
4. Summary
Introduction
75-95% of patients with advanced stages
will experience severe pain
“an unpleasant sensory &
emotional experience associated
with actual or potential tissue damage, or
described in terms of such damage”
-IASP
 unrelated
10%
Treatment
20%

Disease
70%

CAUSES
Basic principles
of pain
Management
The role of
pharmacist?????
Pain and
related symptom
management
Pharmacist’s Role

Ensure medication compliance in terms of counseling on expected

side effects and avoiding or treating associated side effects effectively

Patient should understand

Patient should UNDERSTAND

Risk associated with pain management Risk of not treating the pain
 Pharmacist Competencies

Interdiciplinary collaboration
 1
Pain
Pharmacotherapy

2
Interventional
Therapy
Pain Management
3
Compentencies for Toxicology
Pharmacists
4
Responsible opioid prescribing

5
Behavioral intervention

6
Addiction medicine

7
Inter-professional communication and collaboration

Herndon CM et al. J Pain Symptom Manage 2012; 43(5); 925-944

Pharmacy Services for Pain Management
• Medication history review and reconciliation
• Recommendations for initiation, modification, or
discontinuation of medication regimen
• Assessment of adherence to medications
• Pharmacokinetic and clinical monitoring of medication
• Patient education regarding self-administration and
monitoring of medications.
• Monitoring for therapeutic effects, drug interaction, ADE
• Identification of and monitoring for behaviors of medication
misuse, abuse, and/or addiction
• Facilitating communication between care team members
and pharmacies.
 Individualized Pharmaceutical-care
for Inpatients With Cancer Pain
• Change in medication adherence
• Change in pain score
• Change in quality of life
• Change in patients' knowledge of cancer pain and
analgesics
• Incidence of adverse events

Zhejiang cancer hospital, 2018

 Pain Management

Dosis Tepat???

Pasien Tn ABC, umur 51 tahun dengan Ca. Paru.

Diketahui VAS 7,
Nyeri terkontrol dengan Morphine 160 mg iv,
Dosis renjatan 10 mg iv bolus max 10 x/hari
Pasien direncanakan pulang dan diberikan terapi
hydromorfon untuk di rumah.
Dokter meresepkan hydromorfon 1x6 tab (16 mg).
IMPLEMENTING THERAPY
WITH OPIOIDS
 Opioids in cancer pain

When etiology of PAIN is related to

active cancer and its intensity is moderate
or severe, there is consensus that opioid
therapy is first line therapy
 OPIOIDS

TYPE OF OPIOIDS

CALCULATION PKPD OPIOIDS

TYPE OF OPIOIDS

qCodein
qFentanyl
qMorfin
qOxycodone
qHydromorfon
Codein

Weak opioid, one-tenth the potency of morphine

Metabolised to codeine-6-glucuronide (80%) à morphine

via CYP2D6 enzymes and excreted via the kidneys

Most of the analgesic effect comes from the metabolism into

morphine
• Slow metabolisers produce little or no morphine and thus
little analgesic effect
• Ultra rapid metabolisers produce greater than normal
amounts of morphine, which can lead to opioid toxicity
Codein

> Codeine Tablet 30 mg

> Coditam Tablet (Codein Onset of Action Duration of action
30 mg, Parasetamol 500 30-60 menit 4-6 jam
mg)

mild to moderate pain.

Inappropriate to switch from more constipation than other
codeine to another weak opioid if weak opioids. Laxatives should
pain is not well-controlled. be prescribed prophylactically
Morphine should be used instead
Fentanyl

Highly lipophilic, synthetic strong opioid that acts

predominantly on the µ-opioid receptor

It is already an active opioid and is metabolised by the

CYP3A4 enzyme into inactive metabolites norfentanyl and
hydroxyfentanyl, which are excreted through the kidneys
Fentanyl
• Available formulation
• Fentanyl 100 mcg/2ml
• Durogesic 12 mcg/hr
• Durogesic 25 mcg/hr
• Durogesic 50 mcg/hr

• Onset of Action
• Transdermal takes about 8-12 hours to have its maximal effect
and has a similar residual effect of 8-12 hours after it is removed,
it generallay lasts for 72 hours
• Injectable fentanyl can be given sc, onset 5-10 minutes, excreted
30-60 minutes, breakthrough doses can be given hourly if
necessary
Fentanyl
• When do we use fentanyl
• Cannot take orally (nausea and vomiting)
• Have difficulty with compliance to oral morphine
• Develop side effects or toxicity to morphine and there is a need
to opioid rotate
• Have severe constipation with morphine
• Renal impairment (CrCl < 30 ml/min) and liver impairment
(ALT/AST > 3x upper limit of normal)
• Are averse to morphine but agreeable to use another strong
opioid

• The side effects are similar to that of morphine : drowsiness and

sedation. However, it causes less constipation as it does not act on
gastrointestinal opioid receptors
Morphine

The commonest strong opioid used in managing cancer pain.

The prototype opioid agonist that acts mainly on µ-opioid
receptors but it also has effects on δ and κ-opioid receptors as
well

Metabolised via the CYP450 pathway in the liver to

morphine-6-glucuronide (M6G) and morphine-3-glucuronide
(M3G)

M6G is the active analgesic component while M3G is

responsible for undesirable neurotoxic side-effects like sedation,
confusion and addiction. They are both excreted by the kidneys
Morphine

• Available formulation
• Mo tablet 10 mg
• MST 10 mg, MST 15 mg, MST 30 mg
• Mo injectable 10 mg/ml given sc or iv

Mo tablet MST Mo SC Mo IV

Onset of 30 min 1-2 hr 15 min 5 min

action
Maximal effect - - 10-20 min 10-20 min

Duration of 4-6 hr 8-12 hr 4-6 hr 4-6 hr

action
Morphine

• The common side effects of morphine

• The common side-effects include constipation, nausea,
vomiting, sedation and confusion.
• ALL patients on morphine need to be on laxatives
• The other side-effects can be minimised by starting
morphine at lower doses. Even if they do occur, these
effects are usually transient and resolve within a few
days
• Morphine toxicity which manifests as myoclonic jerks,
pinpoint pupils and respiratory depression (Resp Rate
<8/min) is uncommon when used in correct doses and
titrated upwards carefully
Oxycodone
A synthetic opioid that interacts with both µ and κ receptors but is
similar to morphine in many aspects

Oxycodone is metabolised in the liver by CYP3A4, CYP2D6

enzymes to largely inactive metabolites like oxymorphone and
noroxycodone.
Oxycodone itself exerts its analgesic effects while its
metabolites have minimal analgesic effects. They are
subsequently excreted by the kidneys. Oxycodone, like
morphine, needs to be used with caution in liver and renal
impairment
Oxycodone is 1,5 to 2 times more potent than oral morphine and it
remains a paradox that oxycodone has high analgesic potency
despite a relatively low affinity for µ-receptors, compared to
morphine
Oxycodone

• Available formulation
• Oxyneo 10 mg, 15 mg, 20 mg tablet
• Oxynorm 10 mg, 20 mg injectable
• Parenteral Oxycodone (SC/IV) is half the dose of oral
oxycodone

Immediate Release* Sustained Release

Onset 30-60 min 30-60 min

Peak 60-90 min 1,5-3 hr

Duration 3-6 hr 8-12 hr

Oxycodone

• When do we use oxycodone

• Are averse to morphine but otherwise agreeable to the
use of strong opioids
• Have side-effects to morphine and need opioid rotation
• Should be used with caution in patients with kidneys
and liver impairment

• The side effects are similar to those of morphine

PKPD of OPIOIDS
Pharmacokinetics and Pharmacodynamics of Opiates
Pharmacokinetics and Pharmacodynamics of Opiates
 Break Through Pain (BTP)

Raghavendra, Mega., 2016. American Society of Regional Anasthesia and Pain Medicine: I
mplementing Therapy with Opioids in Cancer Patients, 2016
Basics of opioid Metabolism
• Production of both inactive and active metabolism
• Opioids differ in how they are metabolized
• People differ in how they metabolize opioids
• Extensive first-pass in liver
• – Phase 1 (modification reactions)
• CYP enzymes (3A4, 2D6)
• – Phase 2 (conjugation reactions)
• Glucuronidation
Metabolic Pathways
Clinical Implications
• Most opioids metabolized by CYP enzymes
• – Substantial drug interaction potential
• Cannot predict patient response
• – Need to individualize therapy
• – Opioid trials for tolerability/analgesic assessment
• Confounding medical conditions
• – Hepatic/renal impairment
• – Accumulation of active metabolites and increased
ADE’s
OPIOIDS CALCULATION
OPIOIDS CALCULATION

Step
Approach
 STEP 1

V A S ….....??

1 2 3 4 5 6 7 8 9 10
 STEP 2
Determine the daily usage

Initial Rescue
Dose/24 h Dose
Dose
 Individualized pain treatment
Taking at least:
60 mg oral morphine/day,
25 mcg transdermal fentabyl/jam,
30 mg oral oxycodone/day,
8 mg oral hydromorphone/day,
25 mg oral oxymorphone/day or
An equianalgesic dose of another
opioid for one week or longer

Opioid-tolerant patient Patient

&
Opioid naive
Opioid

Patient who do not meet the

above definition
Who not had opioid doses at
least as much as those listed
above for a week or more
Initiating shortacting opioids in
opioid-naïve patients
Initiating shortacting opioids in
opioid-tolerant patients
Titrating opioid Regimens with Around the clock and rescue
 Step 3.
Decide which opioid will be used and calculate new dose

Simplify analgesic regimen

for improved patient compliance, if feasible

Morphine 10 mg po, setiap 4 jam

Rescue dose : 10 mg prn, pasien mengalami renjatan 6 x

Total dosis harian = 60 mg + 60 mg = 120 mg

Konversi!!!
Conversion Examples

60

90

0.225

10
Konversi morphine ke fentanyl transdermal
Kasus:

Pasien mendapatkan 30 Morphine SR po setiap

12 jam.
Bagaimana konversi ke fentanyl transdermal

1. Hitung total dosis morphin po/24 jam

30 mg x 2 = 60 mg/hari

2. Gunakan rasio konversi,

200 mg/hari morphin po = 100 mcg/jam fentanyl transdermal;

60 mg/hari morphine po = 30 mcg/jam fentanyl transdermal

Sediaan : 12 mcg/jam ; 25 mcg/jam
 Consider opioid rotation if :

qPain is inadequately controlled, limited by adverse effects

qOut-of pocket costs
qLimitation based upen insurance formularies
qChange in a patient’s cognition
Step 4.
Reassess,Always Individualize!

Three option:

No Change Increase Decrease

More Art than science

Incomplete Cross Tolerance
• Tolerance
• continued exposure to a drug reduces its effectiveness.
• When switching opioid
• see increase in opioid sensitivity
• When converting from one opioid to another
• reduce the calculated dose by 25-50%
BARRIERS TO USING OPIOIDS FOR
CANCER PAIN
• incompetence of the medical staff to
assess pain
• patients’ reluctance to express the
intensity of their pain
• doctors’ and patients’ reluctance to use
opioids due to the fear of addiction
• the insufficient skill and knowledge of the
health care staff to use opioids for cancer
pain.
• the difficulty to obtain morphine due to
the excessively tight and complicated
regulation.
 • Failure to do appropriate assessment;
• Mild analgesics (e.g. mefenamic acid)
are used for severe cancer pain;
• Treatment for severe cancer pain is
started with mild analgesics;
• Slow onset of action opioids (e.g. slow
release morphine, fentanyl patch) are
used to alleviate breakthrough pain;
• Conversion to other opiods is done
COMMON before the daily requirement of
morphine is determined correctly;
• Failure to consider opioid rotation,
IN THE MANAGEMENT adjuvant therapy, biphosphonate, and
radiation for patients with persisting
OF CANCER PAIN cancer pain due to bone metastasis;
• Failure to anticipate opioidrelated side
effects;
• Opiod is given only when the patients
feel pain, not around the clock.
Educate the patients :
1. Safe use
2. Storage
3. Disposal opioids
 Pain Management

Dosis Tepat???

Pasien Tn ABC, umur 51 tahun dengan Ca. Paru.

Diketahui VAS 7,
Nyeri terkontrol dengan Morphine 160 mg iv,
Dosis renjatan 10 mg iv bolus max 10 x/hari
Pasien direncanakan pulang dan diberikan terapi
hydromorfon untuk di rumah.
Dokter meresepkan hydromorfon 1x6 tab (16 mg).
 Perhitungan dosis
MO drip 160 mg= MO po 480 mg

NCCN Indonesian advisory board

Hydromorphon = 480/30 = 16 Hydromorphon = 480/60 = 8

16 x 8 = 128 mg 8 x 8 =64 mg

Untuk tablet 16 mg, diperlukan 4 tablet

Untuk tablet 16 mg diperlukan 8 tablet
Untuk tablet 8 mg, diperlukan 8 tablet
Untuk tablet 8 mg diperlukan 16 tablet
 Pasien Tn. X, Nyeri hebat VAS 9

Nama Obat Dosis Cara

Pemberian
Fentanyl Transdermal 12,5 mcg/72 jam transdermal

Amitriptilin 1x1/2 tab po

ibuprofen 3x400 mg po

morphine prn iv

morphine prn po

Can You Find DRP?????

Summary
• The insufficient skill and knowledge of
the health care staff to use opioids for
cancer painàunmanage pain
• Pharmacist Should increase
competency in pain management
• Patient education by pharmacist is a
must
TERIMA KASIH