Download Opioid analgesics

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
OPIOID
ANALGESICS
Assoc. Prof. Ivan Lambev
E-mail: [email protected]
Pain is the most common symptom for which patients
see a doctor. Different types of drugs are used for
treatment of pain. In general, they include:
1. Drugs, relieving pain due to multiple
causes (analgesics)
 narcotic analgesics (morphine, fentanyl, etc):
act chiefly in the CNS
 non-narcotic analgesics (paracetamol, metamizole):
act chiefly peripherally
2. Drugs relieving pain due to a single
cause or specific pain syndrome only
They are not classified as analgesics:
e.g. naratriptan (migraine),
carbamazepine (neuralgias),
glyceryl trinitrate (angina pectoris),
adrenal steroids (inflammatory pain),
butylscopolamine (spasm of visceral smooth
muscles), baclofen (spasm of striated muscles), etc.
3. Adjuvant drugs (anxiolytics, neuroleptics,
antidepressants) may modify the perception of pain
and remove the concomitants of pain such as anxiety,
fear, depression. Placebo gives relief in 3%.
4. Anaesthetics (general and local) are used
during surgical operations, some diagnostic,
and other painful procedures.
Nociception is a consequence of tissue injury
(trauma, inflammation). It causes the release of
chemical mediators (ACh, PGE, NA, 5-HT,
glutamate, bradykinin, endogenous opioids,
adenosine). They have neuronal or non-neuronal
origin. These mediators activate nociceptors.
Nociceptors are pain-receptors. Nociceptors
transmit information by thin myelin (A-delta)
and non-myelin (C) fibers to the spinal cord and brain.
Pain perception has a complex mechanism.
It is a result of nociceptive impulses reaching
the brain (thalamus, cortex), plus impulses
from other peripheral receptors, e.g. heat and
mechanoceptors, whose threshold of response
is reduced by the same chemical mediators.
These are processed in the brain whence
modulated inhibitory impulses pass down
to regulate the continuing afferent input.
But pain can occur without nociception
(e.g. some neuralgias). Pain is a psychological state,
though most types of pain have a physical cause.
MAIN TYPES OF PAIN
Acute pain (defined as < 3 months duration) transmitted
principally by fast conducting myelin A-delta fibers. It has
major nociceptive input (physical trauma, pleurisy,
myocardial infarction, perforated peptic ulcer).
The narcotic (opioid) and sometimes non-narcotic
analgesics are used for treatment of acute pain.
Chronic pain (defined as > 3 months duration) is
transmitted principally by slow conducting non-myelinated
C fibers. It is better regarded as a syndrome
rather than a symptom. It is depressing
to the patient who sees no prospect for relieving
the suffering. Analgesics alone are often insufficient
and adjuvant drugs (antidepressants or neuroleptics)
as well as non-drug therapy (including psychotherapy)
have increasing importance.
Neuropathic pain follows damage of the nervous system.
Acute pain without nociceptive (afferent) input (e.g. some
neuralgias) is less susceptible to analgesics. The suitable
drugs are some antidepressants and carbamazepine.
Transient pain is provoked by activation of nociceptors
in the skin and other tissues in the absence of tissue
damage. It protects humans from physical damage
coming from the environment or excessive stressing of
the tissue. It is a part of normal life and does
not need treatment.
HISTORY
Opium is the dried juice of the seed head of poppy. It was used
in prehistorical times (e.g. in Egypt, Ebers’Papyrus – XVI
BC) as an analgesic, tranquillizer, antitussive drug, and for
treating diarrhoea. The principal active ingredient in crude
opium – morphine, was isolated in 1806 from Frederic
Sertűrner, who tested pure drug on himself and three
young men. He observed that morphine caused cerebral
depression and relieved toothache. Gay Lussac named this
drug, which was the first discovered alkaloid,
after Morpheus (the son of Somnus) – morphine.
Papaver somniferum L.
..
F. SERTURNER
(1783–1841)
Morphine
•Opium
- morphine (1806)
- codeine
- papaverine
Afghanistan
Pakistan
Thailand
Poppy
Prof. Gay Lussac
(1778–1850)
Morpheus
and Iris
Opium contains two groups of alkaloids:
• with phenantrene structure
(morphine, codeine, thebaine)
• with isochinoline structure (papaverine, noscapine).
Morphine and codeine are narcotic analgesics;
papaverine is a vasodilator; noscapine is an antitussive
agent which is suspected of genotoxicity.
Opium contains ≈10% morphine.
Mechanism of action
of opioid analgesics
Effects are mediated via opioid receptors
m (mu): mediate analgesia
at the supraspinal level
d (delta): analgesia in the periphery
k (kappa): analgesia at the spinal level
ORL1 (opioid receptor like 1): dependence
There are
endogenous analgesic substances
with peptide structure and
morphine-like action.
They are called endogenous peptides
and were discovered during the
investigation of the mechanism
of analgesic action of morphine.
Endogenous opioid peptides are:
a) enkephalins activate μ and δ-receptors;
b) endorphins activate μ, κ and δ-receptors;
c) dynorphins activate μ, κ and δ-receptors.
d) nociceptin – ORL1 (tolerance)
Opioid peptides act in CNS as:
- neurotransmitters
- modulators of response (usually inhibitory)
The main effects of morphine are:
on the CNS
Depression, leading to analgesia,
respiratory depression (decrease in sensitivity
of the respiratory centre to PCO2), depression
of cough reflex, sleep)
Excitation, leading to vomiting, miosis (pupil
constriction), convulsions (very rare)
Changes of mood – euphoria
(sense of well-being) or dysphoria.
Tolerance and dependence
(psychological and physical)
Smooth muscle stimulation
Gastrointestinal muscle spasm
(with constipation) and biliary tract spasm
Bronchospasm
Retentio urinae
Cardiovascular system
Dilation of resistance and capacitance
vessels
Other effects
Sweating, histamine release, pruritus,
piloerection, antidiuretic effect
Urine from
patients
intoxicated
with opioids
1 ml/i.p.
Phenomenon
of Straub
Tolerance and dependence
Tolerance – it is increasing of the dose of a
drug required to produce the same effect.
It occurs rapidly with opioids (with
morphine 12–24 hours, e.g. the hot plate
test – in mice, after 3 days the dose of
morphine required for analgesia
increases 5-fold).
Important in drug addiction – may need to
increase dose 50-fold.
Tolerance is not shown equally on all effects.
Tolerance extends to:
analgesia
euphoria
respiratory depression
To much lesser extent on:
constipation
pupil constriction
This is why constipation can be such a big
problem with opioids.
Why does tolerance occur?
There are several potential reasons:
- Increased metabolism of the drug
- Decreased receptor affinity
DEPENDENCE
Takes two forms : physical
psychological
Physical dependence – problems include
withdrawal syndrome (addiction):
- Irritability
- Weight loss
- Shakes
- Sweating
- Piloerection “cold turkey”
- Effects last off in 8–10 days
Psychological dependence
Problems are:
- Desire for the drug
- Want to experience the “rush” – positive
- Don’t want the withdrawal – negative
- Some opioids, e.g. codeine & pentazocine,
are much less likely to cause dependence
Principal uses of morphine and other opioids
•Relief of moderate to severe acute pain
(or chronic pain often in terminal illness)
•Brief relief of anxiety in serious and frightening
diseases accompanied by pain (e.g. traumas
but without commotio)
•Relief of dyspnoe in acute left ventricular failure,
and in terminal cases
•Premedication in surgery
•Treating of dry cough (usually codeine,
dextromethorphan).
Alcaloids
•Strong analgesics:
Morphine Hydrochloride
- 1% 1 ml (= 10 mg) i.m. with 1 mg Atropine
- Morphine Sulfate
1 tab./12 h p.o. in humans
•Antitussive and
week analgesic:
- Codeine
10–20 mg/dose
Semisynthetic derivative (opioid analogs)
Morphine derivatives
•Ethylmorphine, Heroin
Codeine derivatives
•Dextromethorphan (antitusive agent)
•Dihydrocodeine
(Dicodin®): 1 tab./12 h
•Hydrocodone (Vicodin®)
•Oxycodone: p.o.
Thebaine derivatives
•Buprenorphine, Etorphine
ETORPHINE
(strong μ/κ/δ-agonist) with remarkable
very high potency, more than 1000–3000 times
that of morphine. It is a semisynthetic derivative
of thebaine.
It is used im combination with
Acepromazine (phenothiazine derivative)
to immobilize large wild animals for trapping
and research purposes, since the required
dose, even for an elephant, is small enough
to be incorporated into a dart or pellet.
Targin® (oxycodone & naloxone)
Suboxone® (buprenorphine & naloxone)
Targin® (oxycodone & naloxone)
Suboxone® (buprenorphine & naloxone)
HEROIN
(diamorphine – BAN, diacetylmorphine)
Similar action to morphine
More active than morphine
More lipid soluble – crosses BBB faster to give
greater rush
Shorter duration of action than morphine
Synthetic derivatives
PHENYLPIPERIDINES
pethidine, fentanyl
METHADONES
methadone, dextropropoxyphene
BENZOMORPHANS
pentazocine
TRAMADOL
PETHIDINE
(Meperidine – USAN; Lydol® – Sopharma)
Sol. 5% 2 ml (= 100 mg/2 ml) s.c./i.m.
Almost identical to morphine
Tends to cause restlessness
rather than sedation
Antimuscarinic effects: dry mouth
blurred vision
Less antitussive
Shorter duration of action (4-6 h) –
preferred in labour
TRAMADOL
Tramadol provides moderate pain relief. Because of its dual
actions as a µ-agonist and monoamine transport inhibitor,
it produces less respiratory depression for a given analgesic
effect. Tramadol is a weak agonist at µ-receptors. Its
major metabolites are more potent agonists at µ-receptors.
Tramadol also inhibits monoamine transporters
(principally NA and 5-HT) which is thought to produce
analgesia synergistically
with µ-agonism.
FENTANYL
>80 times more potent than
morphine in analgesia
Actions similar to morphine
Main use is in anaesthesia, used in
conjunction with droperidol, a
neuroleptic, producing
neuroleptanalgesia
Durogesic® (Fentanyl):
TTS/72 h
Durogesic
Durogesic
TTS
NEUROLEPTANALGESIA
•Fentanyl 100 mcg +
•Droperidol 5 mg i.m.
Similar to Fentanyl:
•Alfentanil (NB: without “y”)
•Sufentanil (NB: without “y”)
METHADONE
Similar actions to morphine
Longer duration of action
(t1/2 37 h)
Less problems with withdrawal
Can be used to wean heroin and morphine
addicts off the drug
DEXTROPROPOXYPHENE (t1/2 5 h) is structurally similar
to methadone and differs in that it is less analgesic and
less dependence producing. Its weak μ/κ/δ-agonist
analgesics usefulness approximates to that of codeine,
but its duration of action is longer.
Pentazocine –
κ/δ-agonist/weak μ-antagonist
Low efficacy for mild and moderate pain
codeine, dihydrocodeine, dextropropoxiphene,
oxycodone, pentazocine, tramadol
High efficacy for severe pain
alfentanil, buprenorphine, heroin,
fentanyl, methadone, morphine,
pethidine, sufentanil
Analgesics in
chronic tumour pain
according to WHO
1st step (weak pain): Paracetamol (Acetaminophen)
or NSAIDs
2nd step (moderate pain): weak opioids (e.g.
Codeine, Dihydrocodeine, Oxycodone,
Propoxiphen, Tramadol) ± Paracetamol or NSAIDs
3th step (sivere pain): strong opioids (e.g. Fentanyl
– Durogesic® TTS, Morphine or Pethidine) ±
Paracetamol or NSAIDs
Yellow
Reception
Form
for
Prescribing
of
Opioid Analgesics.
Durability: 7 days
The recipe is stored
in licensed pharmacies
10 years!
OPIOID COMPETITIVE ANTAGONISTS
Naloxone (μ, κ and δ-antagonist)
Naltrexone (μ, κ and δ-antagonist)
Nalorphine (Allylnormorphine) –
μ-antagonist/κ-agonist)
Opioid agonists which does not cross BBB
• Loperamide (Imodium®) and Racecadotril (Hidrasec®)
These drugs stimulate mu- and delta-receptors, present
in the small and large intestines. Activation of mu-receptors
decreases peristaltic movements. Activation of deltareceptors contributes to their antisecretory effects.
Although all opioids such as morphine and codeine have
antidiarrhoeal effects, their CNS effects and dependence
liability limit their usefulness. Loperamide directly stimulates
mu- and delta-receptors. Racecadotril blocks enzyme
encephalinase and increases local concentration of
enkephalins in intestinal mucosa which then stimulate
mu- and delta-receptors. This drug can be used orally from
children under 5 years old (including babies), but
Loperamide is contraindicated in children < 5 years old.
mu- and delta-receptors. Racecadotril blocks enzyme
encephalinase and increases local concentration of
enkephalins in intestinal mucosa which then stimulate
mu- and delta-receptors. This drug can be used orally from
children under 5 years old (including babies), but
Loperamide is contraindicated in children < 5 years old.