OPIOID ANALGESICS
(ANALGESICS – ANODYNES)
Department of Pharmacology MU
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Pain
◼ Definition:
„subjective unpleasant sensory or
emotional experience accompanied
by real or potential damage of
tissues, with motoric and vegetative
responses “
A) by duration
B) according to pathophysiology
Pain – types and classification
A) According to length of experience
1) acute: sign of and disease, danger or damage to
organism...
2) chronic: more than 3 months / unusually long for a
given disease or disorder
Pain – types and classification
A) According to length of experience
1) acute: physiological sensory perception,
- tissue damage,
- mobilizes defensive forces of the organism in
order to remove the inducing cause of the pain
2) chronic: pathological,
pain may persists even after the removal of the
causes → difficult to determine whether the pain
arose as a result of persistent pathological activity
in the nerve endings in the periphery, or is the
source of the CNS
Pain – types and classification
B) According to pathophysiology
1) nociceptive – irritation of nociceptors
Therapy: „analgesic ladder“ according WHO
(see below; not used for aggressive procedure in
the treatment for cancer or breakthrough pain)
2) neurological and neuropathic pain
Therapy: antidepressants and anticonvulsants
(in combination with opioids or some muscule
relaxants; neuroprotective vitamins – thiamine;
antimigraine drugs from the group of the so-called
triptans; antipsychotics = neuroleptics)
Pain – types and classification
B) According to pathophysiology
3) psychogenic pain
somatization, hypochondric and
somatoform disorder
Therapy: psychopharmac drugs
(antidepressants – TCA, SSRI, anxiolytics,
antipsychotics)
Pain – types and classification
◼neuralgia
sharp, paroxysmal pain, affects peripheral or
cranial nerves (often the trigeminus, facialis)
→ after traumatological damage,
compression, viral infects (herpetic),
metabolic (DM)
◼pain in the chronic compression of
peripheral nerves and nerve roots
hernia of the intervertebral discs,
compression of the nerve in the spinal cord
→ pain + paresthesia, pain acquires a hot
character
Special types of pain
◼ischemic pain
due to disorders of blood circulation in the
myocardium, smooth or skeletal muscle
◼migraine
migraine is characterized by attacks of
pulsating, mostly unilateral headache lasting
typically 4-72 hours with nausea, possible
vomiting, photofobia and phonofobia,
suffering from 12% of the adult population
Special types of pain
◼phantom pain
surgically or traumatically removed parts of the human
body, most commonly the lower limb or other parts
of the body (ablation of the breast, as well as after
the removal of the visceral organs - the colon);
apply pathophysiological influences peripheral, central
and psychogenic;
◼breakthrough pain
sudden, transient, mostly short-term worsening of
pain in patients who have well-controlled baseline
pain;
usually in patients treated with opioids for cancer
diagnosis; typically in progression of cancer
Special types of pain
◼ delivery pain
- belongs to the strongest pain reliever, nevertheless,
that before the birth are rising thresholds for somatic
and visceral pain
- the tissue is developed by excessive pressure, they
are strongly being pushed and lacerations occur
- tissues are under influence of bradykinin, H+, K+,
histamine and serotonin
- induction of stress → ↑ cortisol, epinephrine,
norepinephrine, dopamine → somatic and
psychological reactions
Special types of pain
ONCOLOGICAL PAIN
SOMATIC
MANIFESTATIONS
sharp or dull pain
Inflammatory response
colic pain
neuralgia
EMOTIONAL
MANIFESTATIONS
anxiety
depression
SOCIO-ECONOMIC IMPACT
personality changes
care of the security of the family
the breakdown of the family
loss of friends
EXISTENTIAL CONCERNS
concerns about the course
of the disease
general uncertainty
the fear of death
VAS: Visual analogue scale
Diagnostics of Pain
NO PAIN THE WORST PAIN
YOU CAN IMAGINE
Process of pain perception
algognostic component
algothymic component
Pain – causes and mechanism
Mediators of pain
(act on the nociceptors = pain receptors)
„algogenic substances“
bradykinin + ↑PGE (mediators of
inflammation), increase sensitivity of nociceptors
histamine
acetylcholine
substance P (pain)
tissue damage production of prostaglandines and other
substances effects on the free nerve endings
transduction of signal up to the brain neurons PAIN
Endogenous pain suppressing (analgesic)
substances:
endorphins
enkephalins
dynorphins
binding to α2 and NMDA receptors
Pain – causes and mechanism
Pain transduction – 3 neuron`s tract
tractus spinothalamicus
(spinothalamic tract)
vs. tractus spinoreticulothalamicus
(spinoreticulothalamic tract)
MAIN PAIN PATHWAYS
the tracks leading from the spinal cord (spinal ganglia) to
specific areas of the brain (finally to the cerebral cortex)
information about pain is received and processed
Pain transduction – 3 neuron`s tract
→ spinothalamic tract – 3 neuron`s phylogenetically
younger pathway
– sharp, well localized pain
→ spinoretikulothalamic tract – phylogenetically older
polysynaptic system, impulses are transmitted to the
higher centres through short axonal pathways
– dull, poorly localized pain
◼ vegetative response: blood pressure change,
tachypnea, mydriasis, diaphoresis, increased muscle
tone,...
Analgesics – anodynes (opioids)
Non-opioid analgesics (analgesics – antipyretics NSAIDs)
Local anaesthetics
General anaesthetics
Adjuvant therapy (antidepressants, neuroleptics antipsychotics,
antiepileptics - anticonvulsants, antimigrenics,
central/peripheral myorelaxants, corticoids, bisphosphonates,
caffeine…)
Pharmacological modulation of
pain
analgesics – anodynes (opioids)
Analgesics – suppress perception of pain (increase the pain
threshold) selectively without influencing perception of other
stimuli
non-opioid analgesics
act on spinal and supraspinal level,
cause effects on somatic and visceral
pain, strong effects on consciousness,
act substantially more strongly than
non-opioid analgesics
mostly peripheral effects (some have
central effects!), effects on
inflammation, weaker effects in
general, no effects on visceral pain,
no addiction
Pharmacological modulation of
pain
Analgesics - anodynes
Opiates
substances similar structurally to morphine with analgesic
effect (natural origin, currently produced synthetically)
Opioids
+ synthetic, semisynthetic and endogenous opioid peptides +
exogenous opioid analgesics
blocking transmission of pain signals between cells of the
CNS (in the spinal cord, brain), as well as endogenous
opioids:
endorphins, enkephalins, dynorphins
→ binding to opioid receptors (agonists)
Opioid receptors - μ κ δ (σ)
• G-protein coupled
•the interaction of the opioid with receptor → G- protein
inhibition → reduction of neurotransmitter release +
inhibition of neuronal activity
•adenylylcyclase inhibition, facilitation of K+ channels
opening postsynaptically, inhibition of Ca2+ channels
opening presynaptically
◼
◼ κ
◼ δ
◼(σ)
◼ μ – supraspinal analgesia, euphoria, sedation, miosis,
breath depression, addiction, GIT effects
◼ κ – spinal + peripheral analgesia, sedation, dysphoria, miosis,
GIT effects, (somatic addiction)
◼ δ – spinal analgesia, breath depression, inhibition of GIT
motility
◼ [σ – dysphoric effect, psychotomimetic effect
(hallucinations, perception disturbances), anxiety]
Opioid receptors - μ κ δ (σ)
Opioid receptors - μ κ δ (σ)
FOR ANALGESIC EFFECT IS CRUCIAL ESPECIALLY
ACTIVATION OF RECEPTORS:
μ – supraspinal analgesia
κ – spinal + peripheral analgesia
Pharmacological influence on
opioid receptors
Atypical opioids
agonists
(strongly effective,
moderate/weakly effective)
partial agonists – dualists
mixed agonists - antagonists
antagonists
Pharmacological effects
of analgesics - anodynes
CENTRAL: analgesic
suppression of respiratory center
sedation (+-)
suppression of anxiety
euphoria/dysphoria
antitussive effect
nausea and vomiting
 tendency to convulsions/cramps
miosis
secretion of ADH,
 GnRH, corticotropine, FSH, LH, ACTH, cortisol,
testosterone)
TOLERANCE !!!
(to all effects of opioids except constipation and miosis!)
ADDICTION !!!
Pharmacological effects
of analgesics - anodynes
PERIPHERAL: • decrease intestinal motility, slowdown
propulsion of GIT content
• increase muscle tone of GIT and urinary
bladder
• increase sphincter tone of gall bladder and
urinary bladder
• constriction of pyloric sphincter, delayed
gastric emptying
• vasodilation, orthostatic hypotension
• histaminoliberation
• inhibition of ciliated epithelium
Pharmacological effects
of analgesics - anodynes
PERIPHERAL: • urological tract – increase tone of renal pelvis,
ureter, m. detrusor and sphincter of
bladder…urine retention, especially in postoperative
conditions
• uterus - ↓ tone and motility, may prolong labor
Pharmacological effects
of analgesics - anodynes
ABSORPTION
DISTRIBUTION
parenteral
oral („first pass effect“ !!!)
perrectal
transdermal
sublingual
transmucous (nasal)
parenchymatous organs
muscles
adipose tissue (lipophilic drugs ➙ e.g. fentanyl)
pass well across BBB ➙ brain (fentanyl,
heroin,..)
Can cross placental barrier !!!
Pharmacokinetics
of analgesics - anodynes
BIOTRANSFORMATION
EXCRETION
primarily in liver
polar metabolites
• inactive metabolites
• active metabolites (codeine, tramadol,
morphine…)
• kidneys - urine
• liver - bile
Pharmacokinetics
of analgesics - anodynes
Opioid agonists
morphine
• 10 % of opium content, together with codeine,
thebaine
+ other phenanthrene alkaloids
• isolated in 1803 (Sertürner)
• high affinity to receptors – selective µ agonism
morphine
➢ see above effects
➢ application routes:
➢ orally (also p.o. with sustained release)
➢ parenterally (i.v., i.m., s.c., epidural,… )
➢ perrectally
Indications: chronic cancer pain, pain after surgery,
injuries, (pain during acute myocardial infarction →
today, given preference to other opioids)
Opioid agonists
Other strong opioid analgesics
methadone
• less sedation and euphoria than in morphine
• ↑ bioavailibility after oral administration, ↑t ½
• acts on opioid + NMDA receptors
• Use: addiction treatment (heroin) ➙ 2 benefits
➙ change from injection application to oral administration
➙ ↑t ½ decreases plasmatic fluctuation of methadone ➙ less
withdrawal symptoms
Other strong opioid analgesics
heroin (= diacetylmorphine)
• not used in clinical medicine (in Czech Republic)
(but in Great Britain can be therapeutically used!)
• causes severe addiction; abused!
• heroin belongs to the most health and personality
devastating substance!!!
fentanyl, sufentanil, remifentanil,…
• pass well across HEB (↑ concentrations in CNS)
• strong, short analgesia (fentanyl 100 x more
potent
than morphine, sufentanil 1000 x more potent than
morphine)
• strong respiratory depression!, ↓ emetogenic
potency, CAVE ➙ can cause muscle rigidity
• risk of serotonin syndrome in combination with
5-HTergic drugs
Other strong opioid analgesics
fentanyl, sufentanil, remifentanil,…
• Indications, use:
• in anaesthesiology ➙ neuroleptanalgesia
(= neuroleptic (AP) + opioid)
➙ analgosedation (e.g. opioid +
BZD)
• therapy of strong pain – acute myocardial infarction,
cancer pain,…
• fentanyl in TTS (↑ duration of action – can be used in
chronic cancer pain), transmucous (can be
used in breakthrough pain)
Other strong opioid analgesics
piritramid
• less respiratory depression than morphine
• less emetogenic potency
• usually well tolerated parenteral administration
• Use: therapy of acute strong pain, e.g. after surgery (PCA),
acute myocardial infarction, pain after injuries,…
Others: oxycodone, hydromorfone (not registered in Czech
Rep.), oxymorphone (not registered in Czech Rep.)
CAVE: all strong opioids are prescribed to forms with blue
band („opiate forms“), very strict accounted and subjected
to the rules for handling with narcotics and
psychotropic drugs and their precursors!!!
Other strong opioid analgesics
Other strong opioid analgesics
pethidine (=meperidine)
• ↓suppression of respiratory center than morphine
• ↓analgesic potency than morphine (5-10 x weaker)
• metabolite norpethidine is proconvulsive and
causes hallucinations
• administration orally and parenterally
Indications: cancer pain, pain after injuries, pain during
acute myocardial infarction, pain after surgery,
premedication before general anaesthesia…today
not often used (high risk of abuse, hallucinations!)
codeine
• 10 % mtb. to morphine
• antitussive effect in subanalg. doses
• analgesic effect in combinations (paracetamol, ASA)
analgesic potency: codeine 50mg ~ ASA 1g
• risk of addiction than strong opioids
• CAVE ↑ risk of addiction of combined (compositive)
analgesics
• causes obstipation
• not used in children!!!
Opioid agonists (moderate and
weak potent)
dihydrocodeine
• suitable in pains combined with cough (this co-incidency is not
necessary for dihydrocodeine indication)
• in Czech Rep. dihydrocodeine in sustained release drug form
(effect 12 h) ➙ indication for chronic moderate and strong
pain
Side effects: obstipation, ↑liver tests, histaminoliberation
Opioid agonists (moderate and weak
potent)
CAVE: codeine and dihydrocodeine are prescribed to
normal forms - without blue band!
Partial agonists + mixed agonists -
antagonists
• lower affinity to μ receptors, high affinity to κ rec.,
• respectively κ-agonists - μ-antagonists or partial μ
receptor
agonists (buprenorphine)
• less potential for addiction, but exists!
• lower analgesic effect than full agonists
• less side effects than full agonists
buprenorphine
• partial μ rcp. agonist
• ↓tolerance in comparism with other opioids
• ↓abuse potential, obstipation and other GIT effects
•↑ „first pass effect“ ! Do not administer orally!!!
• Use: 1) strong chronic pain (TTS!)
2)substitution therapy of opioid (heroin) addiction ➙ combined with
opioid antagonist naloxone in one drug form (sublingual) ➙ in injection
application naloxone antagonizes effects of buprenorphine (in sublingual
administration naloxone does not act!)
Partial agonists + mixed agonists -
antagonists
Partial agonists + mixed agonists – antagonists –
other representatives
• mixed agonists – antagonists
• usually μ-antagonists and κ-agonists (event. also δ-
agonists)
• possibility of σ-receptor activation → psychotomimetic and
hallucinogenic effects)
• analgesic effects are weaker than full agonists
• today minimal use
• pentazocin, butorfanol – in Czech Rep. not registered
nalbuphine
• for short-term therapy of moderate and strong pain
• unsuitable for long-term therapy
• parenteral administration (i.v., i.m., s.c.)
• causes respiratory depression comparable to morphine, but
suppression of respiratory center has drug ceiling effect
• Use: perioperative pain, suppression of pain in
obstetrics (BE AWARE: in newborns risk of breathing
depression, bradycardia, cyanosis and hypotension →
newborn`s monitoring necessary!)
Partial agonists + mixed agonists – antagonists –
other representatives
Atypical opioids
tramadol
low affinity to μ receptors + norepinephrine and serotonin
reuptake inhibition (= atypical mechanism of action, similar
to some antidepressants from SSRI group; effect of
tramadol can not be fully antagonized by opioid
antagonists)
• approximately 1/6 – 1/10 of morphine analgesic potency
• very suitable combination with paracetamol
• less side effects (minimal respiratory depression)
• risk of serotonin syndrome
• in Czech Rep. very often prescribed analgesic,
prescription to normal forms without blue band; more drug
forms
• RISK OF ADDICTION!!!
Use: therapy of moderate and strong pain
(acute and chronic)
tapentadol
• dual mechanism of action
- μ agonist + NRI (+ σ agonist)
NEW GROUP – MOR-NRI (μ receptor agonism – noradrenaline reuptake
inhibitor)
• more effective than tramadol, analgesia comparable with oxycodone, but less
adverse effects
• suitable for the treatment of acute (but also chronic pain – e.g.
vertebrogenic; also effective in diabetic neuropathy - neuropathic pain!!!)
• relatively few adverse effects (compared to classical strong opioids, e.g.
oxycodone)
• p.o. administration (also tbl. with sustained release)
Atypical opioids
CAVE: tapentadol is prescribed to forms with blue band
(„opiate forms“), very strict accounted and subjected to
the rules for handling with narcotics and psychotropic
drugs and their precursors!!!
Antagonists of opioid receptors
naloxone, naltrexone
Indications: treatment of opioid intoxication, treatment
of respiratory depression induced by
opioids, addiction diagnostics (withdrawal
symptoms)
TRIAD: coma, respiratory depression, miosis
Antagonist / partial agonist
nalmefen
antagonist , δ, partial Ƙ agonist
„controlled drinking“
Opioid-induced side effects
◼ respiratory depression (suppression of breathing)
◼ nausea and vomiting
◼ sedation, inhibition of cognitive functions
◼ constipation (solution = oxycodone + naloxone)
◼ ADDICTION
◼ be carefull in pro-convulsive states! (e.g. epilepsy –
proconvulsive action – decrease of the threshold
for seizures)
◼  intracranial pressure
Intoxication by opioid agonists
nausea, „flush“, tinnitus
apathy, sedation, sleep, miosis
superficial breathing
cyanotic, cold skin, tachycardia
asphyxia
TRIAD: coma, respiratory depression, miosis
Treatment:
naloxone i.v.
ventilation, vital functions,
parenteral liquids in unconsciousness
Withdrawal symptoms
„craving“ („drogenhunger“), „craving“ for the another dose
(psychic addiction arises easiest to heroin, oncology
patients treated with opioids ➙ < 1% of patients)
unrest, depression
anxiety, weakness, nervousness, mydriasis
lacrimation, ↑ nose secretion, frisson (goosebumps),
↑ perspiration, pain, stenocardia
occur approximately after 3-4 weeks of opioid administration
Rules of pain therapy management
◼ Choice and course of analgetic therapy depends on intensity
and character of pain described by the patient – individual
dosing – titration may take weeks in CHP
◼ Acute pain – course - from up going down – start with strong
medication (opioid), parenteral administration, fast onset (eg.
pain in AIM, renal or biliar colic)
◼ In chronic pain – course – from down going up – non-invasive
preparations (p.o., TTS), slower release according to a time
plan
◼ In some types of fluctuating chronic pain it may be necessary
to give patient rescue medication in case of breakthrough pain
◼ Combination of non-opioid and opioid analgesics has
additive effect
◼ Benefits of analgesic therapy should exceed its side
effects.
◼ AE must be prevented rather than treated when they
appear – eg. antiemetics, diet, laxatives
◼ There is not a maximal dose of opioid – (in case of full
agonists and cancer pain)
◼ Rotation of opioids
Rules of pain therapy management
Rotation of opioids
◼ Switch in case of AE
◼ Sometimes even in equianalgesic dose
increase of effect
General rules of pain
pharmacotherapy management
◼WHO's pain relief ladder
 Step 1 (VAS 0-4)
◼non-opioid analgesics ± adjuvant treatment
 Step 2 (VAS 4-7)
◼pain persists, intensifies, no change in the
objective finding
◼weak/moderate opioid analgesics ± non-opioid
analgesics ± adjuvant treatment
 Step 3 (VAS 7-10)
◼pain persists, intensifies, there is no indication
for another treatment
◼strong opioid analgesics ± non-opioid
analgesics ± adjuvant treatment ±
weak/moderate opioid analgesics
Other indications of opioids
◼ antitussive effect
◼ can be induced by codeine and dextromethorphan in dry nonproductive
cough
◼ constipative effect
◼ can be induced by loperamide and diphenoxylate in functional
diarrhea
◼ p r e m e d i c a t i o n before anaesthesia and surgery under
general anaesthesia
◼ leads to calm the patient and based on the synergism of drugs
reduces the total dose of narcotics (thereby increasing the safety
of anaesthesia)
◼ particularly fentanyl and its derivatives are used
◼ combination of opioid analgesic with neuroleptic (fentanyl +
droperidol) within neuroleptanalgesia
◼ r e p l a c e m e n t (substitution) therapy of addiction to heroin
or other opioids – methadone, buprenorphine