Transcript 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 (anxyolitics, 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
myelin C fibers. It is better regarded as a
syndrome rather than 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
skin and other tissues in absence of tissue damage.
It protects humans from physical damage coming from
environment or excessive stressing of tissue. It is a part
of normal life and does not need treatment.
HISTORY
Opium is the dried juice of seed head of poppy. It was used
in prehistorical times (e.g. in Egypt, Ebers’papirus – XVI
b .n. c) as analgesic, tranquillizer, antitussive drug and for
treating of 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
Opium contains two groups of alkaloids:
• with phenantrene structure
(morphine, codeine, thebaine)
• with isochinoline structure (papaverine, noscapine).
Morphine and codeine are narcotic analgesic;
papaverine is a vasodilator; noscapine is antitussive
agent which is suspected of genotoxicity.
Opium contains ≈10% morphine.
Some terminology
OPIOID: produces morphine-like effects.
OPIATE: has a morphine-like structure.
Opioid is the preferred modern term.
Opioids can be divided into two groups:
- Morphine analogues – with structure similar to
morphine
- Synthetics – with structure unrelated to morphine
N
CH
3
CH
3
N CH3
O
HO
O
OH
morphine
CH
methadone
Mechanism of actions
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
morphinolike action.
They are called endogenous peptides
and was discovered during the
investigation of 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,
piloeraction, antidiuretic effect
Phenomenon of Straub
Tolerance and dependence
Tolerance it is increasing dose of drug
required to produce the same effect.
It occurs rapidly with opioids (with
morphine 12–24 hours, e.g. hot plate test
– in mice, after 3 days 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
resp. depression
To much less 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
- Piloeraction “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
Morphine and its analogues
Morphine Hydrochloride
1% 1 ml (= 10 mg) i.m.
Morphine Sulphate (Sulfate):
1 tab./12 h p.o. (depot-effect)
Codeine: 10–20 mg/dose
Dihydrocodeine:
1 tab./12 h p.o. (depot-effect)
Oxycodone: p.o.
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
THEBAINES
buprenorphine, etorphine
PETHIDINE
(Meperidine – USAN; Lydol® – Sopharma)
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
FENTANYL
>80 times more potent than morphine
in analgesia
Main use is in anaesthesia, used in conjunction
with droperidol to produce neuroleptanalgesia
Effentora® – buccal tablets from 100 to 800
mcg, used in cancer BTP (breakthrough pain)
Durogesic®: TTS/72 h
Durogesic TTS
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. It is 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
ETORPHINE (strong μ/κ/δ-agonist) with remarkable
very high potency, more than 1000 times that a morphine.
It is used to immobilize wild animals for trapping and
research purposes, since require dose, even for
an elephant, is small enough to be incorporated
into a dart or pellet.
Low efficacy for mild and moderate pain
codeine, dihydrocodeine, dextropropoxiphene,
oxycodone, pentazocine
High efficacy for severe pain
alfentanil, buprenorphine, heroin,
fentanyl, methadone, morphine,
pethidine, sufentanil, tramadol
Tramadol – partial μ-agonist,
inhibitor of NA and 5-HT reuptake.
Analgesics in chronic
tumour pain
according to WHO
1st step: weak pain – Paracetamol
2nd step: mild pain – Paracetamol + NSAIDs
3rd step: moderate pain – Paracetamol or NSAIDs
+ weak opioid (e.g. Codeine or Dihydrocodeine)
4th step: strong pain – Paracetamol or NSAIDs
+ strong opioid (e.g. Fentanyl – Durogesic TTS,
Morphine or Pethidine)
OPIOID COMPETITIVE ANTAGONISTS
Naloxone (μ, κ and δ-antagonist)
Naltrexone (μ, κ and δ-antagonist)
Nalorphine (Allylnormorphine) μ-antagonist/κ-agonist)