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Head of the Palliative Care Unit
of Latvian Oncology Center
at Riga Eastern University Clinical Hospital
Iš visu vaistu, kurious Visagalis davė
žmogui kančioms palengvinti, nė vienas nėra
toks universalus ir veiksmingas kaip opijus.
Tomas Sydenhamas (1624–1689)
Terminology: narcotics, opiates, opioids or opioid analgesics (weak & strong)
Turinys
1. Bazinis skausmas ir skausmo protrukiai.
2. Opioidiniu analgetiku ivedimas.
3. Titravimas.
4. Optimalaus opioidinio analgetiko paieška.
5. Rotacija ir ekvianalgezines dozes.
Salvadore Dali.
Project for Architecture, 1976
Pain Influence on Different Levels
Psysically
Social
relationships
Fatigue
Sleep disorder
Side effects
of analgesia
Early aggresive
pain control
Psychologically
Anxiety
Depression
Lack of vigilance
Persistant pain
Enhance
QoL
Mentally
Suffering
Lack of motivation
Pain behaviour
PAIN PERCEPTION:
Several individual dimensions
SENSORY
Somatic/visceral/
/neuropathic
EMOCIONAL
hopelessness,
anxiety,
defencelessness,
dislike,
anger...
COGNITIVE
attention,
self-control,
judgement,
awareness,
hope...
6
I. Bazinis skausmas ir skausmo protrukia:
Essential terminology
Definition of pain, 1986
(IASP – Tarptautine skausmo studiju asociacija):
Skausmas – nemalonus sensorinis ir emocinis potyris,
susijes sutikru ar menamu audiniu pažeidimu arba
nusakomas tais pačiais terminais kaip ir tikrasis pažeidimas
„ Pain is always subjective
„ ”Pain is what the patient says hurts”
(IASP, 1994, Robert Twycross, 2006)
„ Pain is a psychosomatic phenomenon...
(IASP – International Association for the Study of Pain,
Pain 2008, Syllabus, an Updated Review)
Background:
Baseline pain (BP)
defined as that pain reported by patients
as the average pain intensity
experienced for 12 hours or more
during a 24 hours period
(Hill CS et al, 1989)
INTENSITY
„ In own words describing pain –
mild, moderate, severe, excruciating
(can not define pain syndrome, affective
component)
„ VAS (visual analogue scale):
z
10 cm line, with 2 end-points –
no pain & worst possible pain
„ Numerical scales, between 1–10,
no pain Æ worst possible pain
„ Age-specific scales for children (faces)
“Veidukų”, skaitmeninė ir žodinė skausmo vertinimo skalės
(patvirtinta Lietuvos SAM 2004 m. isakymu Nr.V-608)
“Veidukų”
skalė
Skaitmeninė
skalė
Žodinė
skalė
Pirmas
“veidukas”
0
Nėra
skausmo
Antras
“veidukas”
1
2
Trečias
“veidukas”
3
Silpnas
skausmas
4
5
Vidutinis
skausmas
Ketvirtas
“veidukas”
6
7
Penktas
“veidukas”
8
Stiprus
skausmas
9
10
Nepakeliamas
skausmas
„ Acute pain:
z definite onset (hour, day...)
z definite subjective & objective physical symptoms
+ hyperactivity of the autonomic nervous system
„ Subdivided:
z subacute (comes on over several days, progressive pain)
z intermittent or episodic (in periods of time, on regular
or irregular basis)
DStrong acute pain Æ 9% into chronic pain
DMild acute pain Æ 3% into chronic pain
pain intensity
pain intensity
Acute and Chronic Pain:
Pain intensity
time
Acute pain
time
Chronic pain
Chronic Pain
(e.g. cancer, HIV/AIDS)
„ Less definite onset
„ Persists more than 3 months
„ Adaptation of the autonomic nervous system,
less objective signs than in acute pain
„ Changes in personality, lifestyle, mobility, function
„ Somatization of the chronic pain
Ð
Chronic Pain
„ Treat the cause
Ð
„ Treatment of pain complications, affecting lifestyle,
personality, social well-being
„ Careful assessment of the intensity of the pain
& psychoemotional distress
„ Anxiety is caused in 7–25% by chronic pain
„ Social fobia in 11%, specific fobia in 25%
ATC – around the clock (analgesia),
SR medication, prolonged, modified...
There is no difference, in principle, between
pain management in persons with AIDS
and those with advanced cancer,
according to the WHO
First Talk about Breakthrough Pain (BTcP)
(Portenoy RK & Hagen NA, 1990)
EssentialTerm inology:
„ Transient, transitory pain, pain flare, episodic pain,
end-of-dose (tail) pain, incident pain, BTcP(cancer)...
z
rescue medication, as needed, as required,
normal release, short acting, PRN (pro re nata)
„ BTcP in acute and chronic pain can occur...
How to Define Breakthrough Cancer Pain (BTcP)?
„ BTcP is a transient increase in pain intensity
over background pain
„ BTcP is a transitory exacerbation of pain
experienced by the patient who has relatively stable
or adequately controlled bacground pain as a result
of an opioid treatment regiment
(if strong, severe pain, cancer pain)
„ BTcP Æ transitory exacerbation of pain,
more severe,
greater cost of care...
Cancer BTP Features (I)
„ Prevalent at all stages of disease
„ More pronounced if advanced stage,
in poor performance status
„ If ATC analgesia is more complicated,
BTcP episodes are more expressed
„ Negative impact on Quality of Life (QoL):
patients not satisfied with analgesia
„ BTcP reduces function, mobility
„ Psychosocial impact – anxiety/depression
Cancer BTP Features (II)
„ Often BTcP episodes – poor prognostic factor
for the overall effectiveness of an opioid therapy?
„ Burden of patients, families, caregivers, health system
„ Higher direct costs
Æ e.g., prescription charges
„ Higher indirect costs Æ e.g., transportation
„ More emergency
„ More medical visits
„ More hospital admissions
„ Longer hospital stays
Breakthrough Pain (BTP) in Cancer
„ is directly related to
malignancy
z special cancer treatment
„ unrelated to cancer
z
and by characteris
„ nociceptive
„ neuropathic
„ mixed
38–74%
9–27%
16–52%
65–76%
11–35%
0–19%
Subtypes of BTP in Cancer
„ Incident pain 32–94%, precipitated by voluntary actions,
usually predictable, poor response to opioid therapy
„ Spontaneous pain 17–59%, absence of trigger,
pain unpredictable/predictable, e.g., cause dry cough
„ Tail or end-of-dose pain 2–29%, too low ATC dose,
intervals too long
„ Mixed
„ Non-cancer BTP 63–74%, neurology, heart failure...
Breakthrough Pain (BTP)
in Cancer
„
Fast onset, within 3–5
minutes, strong intensity
„
Predictable/unpredictable
„
Short lasting, 15 min–2 hrs,
in 64% of cases ≤30 min
„
Pain strong, severe
„
Pain may be often, even on
effective baseline therapy
„
Average 1–4 episodes a day
ATC
analgesia
Typical
BTP
episode
CHRONIC PAIN SYNDROME
II. Opiodiniu analgetiku ivedimas
„ Cancer pain diagnosis!
„ Pain intensity – mild, strong, severe?
„ Consider adjuvants (coanalgetics)
„ Use opioids according indications
„
„
„
„
(weak Æ severe pain)
Special cases – e.g. general oedema,
other access necessary. Other options?
Several opioids?
Motivate and document your choice
Use guidelines, steps!
„ NSAIDs
z
Pain Control
in Oncology, PC
z
z
z
z
z
z
z
z
z
Ac.Acetilsalicilicum
Paracetamol
Diklofenac
Indometacin
Piroxicam
Naproksen
Metamizol
Ibuprofen
Ketorolak
Lornoxikam
„ ADJUVANTS
(COANALGETICS)
z corticosteroids
z antidepressants
z anticonvulsants
z antispasmodics
z sedativs, hypnotics
z laxativs
z antiemetics
z bisphosphonates
z neuroleptics
„ WEAK OPIOIDS
z
z
z
P
A
I
N
z
z
Tramadol
Codein
Tilidin
Dihydrocodein
Dextropropoxiphen
„ STRONG OPIOIDS
z
z
z
z
z
z
z
z
z
Morphin(1%-1ml), tabs
Fentanyl (0,005%-2ml),
Fentanyl s/ling tabs
Promedol (2%-1ml)
Metadon
Oxycodon
Hydromorfon
Buprenorphin
Petidin
Heroin
WHO Pain Control Ladder, Steps
Pain
1 NSAIDs
adjuvants
Pain persists
or increases
2 Weak opioids
NSAIDs
adjuvants
Pain persists
or increases
3 Strong opioids
NSAIDs
adjuvants
„ Cancer-specific or disease-modifying treatments (also palliative setting):
– radiotherapy, chemotherapy, surgery, hormonal therapy
„ Local/regional methods (blocs, spinal, acupuncture, TENS (neuro)surgery etc.)
„ Additional therapies like physio-, psychotherapy, communication skills!
„ Solve and control other problems, suffering:
– physical, psychological, social, cultural, spiritual, existential
WHO Ladder (1986; 1996):
NSAIDs weak opioids strong opioids
„ If strong pain – NSAIDs small dosage of strong opioids?
Avoid the 2nd step?
„ Big dosage of weak opioids = Small dosage of strong opioids?
„ First line – Oxycodon, Fentanyl?
In Japan: strong pain – start with Oxycodon (2 randomized trials)
„ In many countries strict limits to prescribe opioids,
sequence – need guidelines!
Pain Control
PAIN
CO N TRO L
Visceral (deep)
+ Opioids
bowel obstruction, liver metastases,
retroperitoneal tumours
Soft tissue
Bone lesions
Nerve compression
Nerve destruction
NSAIDs + Opioids
NSAIDs + Opioids
NSAIDs + Steroids
+ Anti-depressants
Anti-convulsants
Nerve block
Muscle spasm
Muscle relaxants
+ Anti-depressants
Sedatives
Psychogenic disturbances
(depression, anxiety)
Combination of several opioids?
In family doctors practice – one or two
(tramadol, DHC, morphine, fentanyl)
WHO Ladder for Breakthrough Pain?
„ N SAID s(if mild PTP), e.g.
z
paracetamol, ketorolac, ibuprofen, diclofenac,
lornoxicam, metamizol... p/o, inj, supp
„ W eak opioids:
z
tramadol... caps, tabs, supp, drops, inj
„ Strong opioids:
z
if ATC is titrated with opioids, SR tabs or TDS, for BTcP
opioids are used (e.g., morphine – inj, tabs 10–20 mg),
fentanyl sublingual (desintegrating) tabs
III. Titravimas
„ Individual response
„ Individual opioids, dosage, esp., in opioid-naïve patients
„ Always start from the small dosage
„ Ready to cover side effects
„ Titration – with short acting or long acting drugs
„ Reach therapeutic effect, maintain it – plato (≥ 3 months)
„ Pain control is dynamic, observe patient closely 2–5 days
after start opioid titration
„ If not controlled any more – revise diagnosis, dosage, rotate
Reasons for Individual Variations
in Treatment Effectivity of Various Opioids
„ Polymorphism of µ-receptors
z
z
Different metabolism for the various opioids
Drug – Interactions
„
„
„
liver problems (hepatitis, metastases, insufficience)
renal problems (inflammation, obstruction of path)
opioid abuse (anamnesis) – like conventional opioid therapy,
with ATC and BTcP + narcology treatment
„ Variations in Opioid-Metabolism, e.g.,
z Oxycodone Æ CYP 2D6, Tramadol Æ 0-dismetiltramadol CYP206
or cytochrome P450 (weak metabolizers)
z UDP-Glucuronyl-Transferases Æ metabolize Morphine
Hepatic Metabolism of Morphine
(glucuronisation to hydrophil metabolites,
followed by renal elimination)
„ Competitive inhibition of the glucuronisation
via interference with
z
z
z
z
Phenothiazines, e.g., Lorazepam, Haloperidol
Gabapentin
Codeine
Cimetidine, Ranitidine
„ Stimulation of the hepatic metabolism:
z by EIAE (DPH, Carbamazepine)
z Barbiturates
„ NSAIDs slow the renal clearance of opioids
U.R. Kleeberg, HOPA Hamburg
Why? … because of individual…
patient characteristics and comorbidity influencing
„ absorption,
„ pharmacokinetics and pharmacodynamics,
„ pharmacogenomics
(e.g., differences male vs. female)
PetersH .-D .:
bestpractice onkologie
2007;2:44 -53
Morphine–receptors
are more sensitive in women,
for effective pain relief women need lower opioid doses,
and women suffer from more side effects
as compared to men.
Bundesgesundheitsblatt
2005;48:536 -540
36
Titration of the Dose
Æ
Pain Control
Overdosage Æ side effects
Pain level
No pain
Pain continues,
dosage insufficient
on e
i
t
a g
Titr dosa
of
Breakthrough Pain, Instant Pain:
with Short-acting Drugs (NSAIDs, Opioids)
Pain level
Breakthrough pain:
short-acting drugs
9.00
21.00
Prolonged or slow-release
medication
IV. Optimalus opioidiniu analgetiko paieška
„ ATC – according to the pain diagnosis and intensity.
SR or short acting opioids. Start with the lowest dosage
in chronic cancer pain because of individual response.
„ Elderly – smaller dosage. NB! Tramadol, Morphine!
Consider confusion, delirium, vomiting, obstipations...
„ End-of-life care, dying patient – opioids PRN,
as required or necessary.
TDS can be left or removed.
ATC – consider adjuvants. Cover all side effects.
„ BTcP – with short acting (i/v, i/m, p/o, s/l)
Therapeutic Drug Levels:
1) Titration of the appropriate opioid; 2) Therapeutic gap
Pain "Sinusoid Wave"
Toxicity
Therapeutic Effect
Pain
Bolus, opioids Opioids
Analgesia
Bolus
(Loading
Dose)
Start Continuous opioid
Infusion or Around
the Clock Regimen
Pain Management in ATC and BTcP Analgesia
„ Optimize ATC medication!
„ Moderate-to-severe cancer pain (not disease!) –
oral opioids, start with the first line if no other i!
„ Fixed schedule at ATC analgesia regimen
„ Use adjuvants (antidepressants, anticonvulsants,
corticosteroids, bisphosphonates, NSAIDs...)
„ Consider at ATC rescue medication for BTcP
„ Reduce side effects
Principles of Basic Management
of Breakthrough Pain
„ Recognize BTcP!
„ Assessment (e.g., verbal, numeric scales)
„ Location of pain
„ Anamnesis, examination
„ Aetiology, pathophysiology
„ Explanation through good communication!
Oral
Morphine
„
„
Morphine p.o. –
onset after 30–40 min.
BTcP is reduced before
medication starts to act
Long BTcP – up to 4 hrs
in rare cases
(BTcP for 2 hrs in 2%)
„
Opioid overdosage
between BTcP
„
Risk of side effects
Baseline
analgesia
Morphine
orally
CHRONIC PAIN SYNDROME
Typical BTP episode in cancer
Oral treatment with morphine
Ideal Rescue Medication
„ Rapid onset of action
„ Short duration
„ Minimal side effects
„ Easy to use for patients
„ Available
„ Inexpensive
Sublingual
Fentanyl
„
Rapid onset,
max in 12–15 minutes
z in 10 minutes –
a considerable
pain control
„
Bioavailability
50–70%
„
Short action time –
about an hour
ATC
analgesia
CHRONIC PAIN SYNDROME
Typical BTP episode in cancer
Administration of Fentanyl s/l
VAS
cP
T
B
10
IR
ine
h
rp
o
M
yl
n
ta
n
Fe
g
n
i
l
/
S
Individual dosing
Pain limit by effective
basic opioid medication
Analgesic gap
t
0
30'
60'
90'
120'
150'
Fentanyl Trials Consider...
„ BTcP in s/l analgesia dose is not proportionate
to the baseline opioid dosage (5–15% or from
4-hourly dosage) as in i/v, parenteral usage
„ Titration of BTcP medication is needed!
Start with low dose,
titrate it until effective dose!
Novel Lipophilic Drugs are in Development,
esp., FENTANYL– Transmucosal Opioid Delivery
„ O ral
z
z
z
OTFC or oral transmucosal fentanyl citrate,
impregnated lozenge, start in minutes
FBT or fentanyl buccal tab, using effervescence – pH shift
Mucoadhesive patches
„ N asal– rapid onset, small volume
„ Bronchial– nebulizers, inhaled aerosolized opioids,
free and liposome encapsulated fentanyl
„ Rectal– if no oral, bleeding, generalized oedema
Modification
of the Pathological Process
„ Antineoplastictherapies
z improve ATC and BTP with opioids, e.g.,
„
chemotherapy, radiotherapy, hormonal
and biological therapies, surgery, e.g.,
– bowel obstruction, fixation of bones,
mobilize joints (BTP expressed!)...
„ Considertoxiceffects
Invasive BTcP Measures
(Short-Term Therapy)
„ After surgery
or
„ if pharmacological means are not effective:
z
z
z
z
i/v access (opioids)
neural blocks
trigger-point injections
neuraxial analgesia:
epidural
„ intrathecal with opioids,
local anaesthetics
„
Lifestyle Changes
„ Uncontrolloed chronic pain and BTcP
can cause disability
„ Loss of social activities
„ Increases dependance on medication
and health professionals
...and tasksto ease problem s...
„ To limit some activities
„ Use specific aids for activities
„ Exercises, activate patient! Relaxation...
For Opioid Guidelines
„ Opioids – reimbursed drugs! (reference 100%, 75%, 50%...)
„ 1st, 2nd line opioids, indications
„ Costs, economical arguments
„ Essential drug list in pain control (EDL)!
Including NSAIDS, weak and strong opioids, adjuvants
„ Necessary for algologists, family doctors, other specialists
„ Should be revised
Opioid analgesics
Cost per one unit:
„ Sevredol(Morphine sulphate)
z
z
tab. 10 mg = Ls 0,34
tab. 20 mg = Ls 0,39
„ M orphine (hydrochloride)
z
amp. 10 mg = Ls 0,33
„ D oltard (Morphine sulphate)
z
z
tab. 30 mg = Ls 0,19
tab. 60 mg = Ls 0,26
„ Vendal(Morphine hydrochloride)
z
z
tab. 30 mg = Ls 0,19
tab. 60 mg = Ls 0,26
List of the Reimbursed Drugs
(starting Guidelines and List of Essential Drugs)
Reimbursed 100% in Ls
25 mcg/h 5 TDS
21,27 Ls
1 TDS
4,25 Ls = 72 hrs
50 mcg/h 5 TDS
35,69 Ls
1 TDS
7,13 Ls
100 mcg/h 5 TDS
62,40 Ls
1 TDS
12,48 Ls
Conversion into Equianalgesic Doses
„ Fentanyl 25 mcg/h = Morphine 60 mg p/o (in 24 hrs)
= Tramadol 300 mg (x 3 or 72 hrs)
„ Fentanyl 50 mcg/h = Morphine 120 mg p/o
„ Fentanyl 100 mcg/h = Morphine 240 mg p/o
Textbook of Pain. Fourth Edition.
PD Wall, R Melzack.
Compendium, 2005
Costs in 72 hrs
Morphine p/o
Morphine
in ampoules
60 mg/d x 3
fentanyl 25 mcg/h
(20) 30 mg x 3 = 90 mg
(Ls 2,47 +
syringes,
gauzes, high
spirit, service)
Sevredol 20 mg Æ 60 mg x 3 = 180 mg
Doltard, Vendal
(Ls 4,25)
60 mg x 3 = 180 mg
(Ls 3,51)
(Ls 2,34)
V. Rotacija ir ekvianalgezines dozes
„ Alergy to opioids is very seldom!
„ Cause for rotation:
z
z
z
receptors not responsive
enzyme systems disregulated
severe side effects (at the beginning, 3–7 days)
„ Before rotation ensure the drug has the optimal dosage,
correct intervals, adjuvants (esp., in neuropathic pain)
„ Next rotation drug decrease for 30%, then titrate up
„ Baseline (ATC) drug titrate + cover pain with
short-acting opioid, used for BTcP
Morphine Analgesic Equivalents
„ Morphine p/o : codeine p/o
1 : 10
„ Morphine p/o : dihydrocodeine p/o
1:6
„ Morphine p/o : tramadol p/o
1:5
„ Morphine p/o : tramadol s/c
1 : 10
„ Morphine p/o : fentanyl i/v
100 : 1
„ Morphine p/o : morphine s/c
2:1
„ Morphine p/o : morphine i/v, i/m
3:1
„ Morphine p/o : fentanyl TDS ...
Æ Ð
Titration of Equianalgesic Dosage of TDS
Morphine mg/24 hrs
<135
135–224
225–314
315–404
405–494
495–584
585–674
675–764
765–854
855–944
945–1034
TDS μg/h
25
50
75
100
125
150
175
200
225
250
275
Ekvivalentinės opioidų paros dozės
Vaistas
Vartojimo forma
Paros dozė
Fentanilis (μg/val.)
(Durogesic)
Transderminė
terapinė sistema
Morfinas (mg)
per os
30
60
90
120
150
180
210
240
Morfinas (mg)
i r., i/v
10
20
30
40
50
60
70
80
Tramadolis (mg)
i r., i/v
100
200
300
400
25
50
75
100
Pastabos: empiriškai 100 μg fentanilio atitinka 2–4 mg/val. morfino; metadonas neturi aiškiai
apibrežtos ekvivalentinės dozės, todėl titruojamas individualiai.
Jane Baubliene.
Skausmo samprata ir gydymas.
Vilnius, 2006