Transcript stu narcotic analg..

OPIOID ANALGESICS
Dr. Hazar 2011
NEURAL MECHANISMS OF PAIN
• Pain is a subjective experience, hard to
define exactly, even though we all know what
we mean by it. Typically, it is a direct
response to an untoward event associated
with tissue damage, such as injury,
inflammation or cancer, but severe pain can
arise independently of any obvious
predisposing cause (e.g. trigeminal
neuralgia), or persist long after the
precipitating injury has healed (e.g. phantom
limb pain).
• It can also occur as a consequence of brain or nerve
injury (e.g. following a stroke or herpes infection).
Painful conditions of the latter kind, not directly
linked to tissue injury, are very common and a major
cause of disability and distress, and in general they
respond less well to conventional analgesic drugs
than do conditions where the immediate cause is
clear. In these cases, we need to think of pain in
terms of disordered neural function, comparable
with schizophrenia or epilepsy, rather than simply as
a 'normal' response to tissue injury.
• Therefore it is useful to distinguish two
components, either or both of which may be
involved in pathological pain states:
• the peripheral nociceptive afferent neuron,
which is activated by noxious stimuli
• the central mechanisms by which the
afferent input generates a pain sensation
Mechanisms of pain and
nociception
• Nociception is the mechanism whereby
noxious peripheral stimuli are transmitted to
the central nervous system. Pain is a
subjective experience not always associated
with nociception.
• Polymodal nociceptors (PMNs) are the main
type of peripheral sensory neuron that
responds to noxious stimuli. The majority are
non-myelinated C fibres whose endings
respond to thermal, mechanical and
chemical stimuli.
• Chemical stimuli acting on PMNs to cause pain
include bradykinin, protons, ATP and vanilloids (e.g.
capsaicin ). PMNs are sensitised by prostaglandins,
which explains the analgesic effect of aspirin-like
drugs, particularly in the presence of inflammation.
• The vanilloid receptor TRPV1 (transient receptor
potential vanilloid receptor 1) responds to noxious
heat as well as capsaicin-like agonists. The lipid
mediator anandamide is an agonist at vanilloid
receptors, as well as being an endogenous
cannabinoid receptor agonist.
• Nociceptive fibres terminate in the superficial layers
of the dorsal horn, forming synaptic connections
with transmission neurons running to the thalamus.
• PMN neurons release glutamate (fast transmitter)
and various peptides (especially substance P) that
act as slow transmitters. Peptides are also released
peripherally and contribute to neurogenic
inflammation.
• Neuropathic pain, associated with damage to
neurons of the nociceptive pathway rather than an
excessive peripheral stimulus, is frequently a
component of chronic pain states and may respond
poorly to opioid analgesics
Modulation of pain transmission
• Transmission in the dorsal horn is subject to
various modulatory influences, constituting
the 'gate control' mechanism.
• Descending pathways from the midbrain and
brain stem exert a strong inhibitory effect on
dorsal horn transmission. Electrical
stimulation of the midbrain periaqueductal
grey area causes analgesia through this
mechanism.
• The descending inhibition is mediated mainly
by enkephalins, 5-hydroxytryptamine,
noradrenaline and adenosine . Opioids cause
analgesia partly by activating these
descending pathways, partly by inhibiting
transmission in the dorsal horn, and partly
by inhibiting excitation of sensory nerve
terminals in the periphery.
• Repetitive C-fibre activity facilitates
transmission through the dorsal horn ('windup') by mechanisms involving activation of
NMDA and substance P receptors
Opioid analgesics
• Opioid drugs include:
– phenanthrene derivatives structurally related to
morphine
– synthetic compounds with a variety of dissimilar
structures but similar pharmacological effects.
• Important morphine-like agonists include
diamorphine and codeine; other structurally
related compounds are partial agonists (e.g.
nalorphine and levallorphan) or antagonists
(e.g. naloxone).
• The main groups of synthetic
analogues are the piperidines (e.g.
pethidine and fentanyl), the methadonelike drugs, the benzomorphans (e.g.
pentazocine) and the thebaine
derivatives (e.g. buprenorphine ).
• Opioid analgesics may be given orally,
by injection, or intrathecally to produce
analgesia.
Opioid receptors
• μ-Receptors are thought to be responsible for most of the
analgesic effects of opioids, and for some major unwanted
effects (e.g. respiratory depression, euphoria, sedation and
dependence). Most of the analgesic opioids are μ-receptor
agonists.
• δ-Receptors are probably more important in the periphery but
may also contribute to analgesia.
• κ-Receptors contribute to analgesia at the spinal level and may
elicit sedation and dysphoria, but produce relatively few
unwanted effects and do not contribute to dependence. Some
analgesics are relatively κ-selective.
• σ-Receptors are not true opioid receptors but are the site of
action of certain psychotomimetic drugs, with which some
opioids interact.
• All opioid receptors are linked through Gproteins to inhibition of adenylate cyclase.
They also facilitate opening of potassium
channels (causing hyperpolarisation) and
inhibit opening of calcium channels
(inhibiting transmitter release). These
membrane effects are not linked to the
decrease in cAMP formation.
• Functional heterodimers, formed by
combination of different types of opioid
receptor, may occur and give rise to further
pharmacological diversity.
Actions of morphine
• The main pharmacological effects are:
–
–
–
–
–
–
analgesia
euphoria and sedation
respiratory depression and suppression of cough
nausea and vomiting
pupillary constriction
reduced gastrointestinal motility, causing
constipation
– histamine release, causing bronchoconstriction
and hypotension.
• The most troublesome unwanted effects are
constipation and respiratory depression.
• Morphine may be given by injection (intravenous or
intramuscular) or by mouth, often as slow-release
tablets.
• Acute overdosage with morphine produces coma
and respiratory depression.
• Morphine is metabolised to morphine-6-glucuronide,
which is more potent as an analgesic.
• Morphine and morphine-6-glucuronide are the active
metabolites of diamorphine and codeine.
Tolerance and dependence
• Tolerance develops rapidly, accompanied by
physical withdrawal syndrome.
• The mechanism of tolerance may involve
adaptive up-regulation of adenylyl cyclase. It
is not pharmacokinetic in origin, and
receptor down-regulation is not a major
factor.
• Dependence is satisfied by μ-receptor
agonists, and the withdrawal syndrome is
precipitated by μ-receptor antagonists.
• Dependence comprises two components: (i) physical
dependence, associated with the withdrawal
syndrome and lasting for a few days; and (ii)
psychological dependence, associated with craving
and lasting for months or years. Psychological
dependence rarely occurs in patients being given
opioids as analgesics.
• Weak, long-acting μ-receptor agonists such as
methadone may be used to relieve withdrawal
symptoms.
• Certain opioid analgesics, such as codeine,
pentazocine, buprenorphine and tramadol, are much
less likely to cause physical or psychological
dependence.
Opioid antagonists
• Pure antagonists include naloxone (short
acting) and naltrexone (long acting). They
block μ, δ and κ-receptors more or less
equally. Selective antagonists are available
as experimental tools.
• Other drugs, such as nalorphine and
pentazocine, produce a mixture of agonist
and antagonist effects.
• Naloxone does not affect pain threshold
normally but blocks stress-induced
analgesia and can exacerbate clinical pain.
• Naloxone rapidly reverses opioid-induced
analgesia and respiratory depression, and is
used mainly to treat opioid overdose or to
improve breathing in newborn babies
affected by opioids given to the mother.
• Naloxone precipitates withdrawal symptoms
in morphine-dependent patients or animals.
Pentazocine may also do this.
Other analgesic drugs
• Paracetamol resembles non-steroidal
anti-inflammatory drugs and is effective
as an analgesic, but it lacks antiinflammatory activity. It may act by
inhibiting cyclo-oxygenase (COX)-3, a
splice variant of COX-1, but probably
has other effects as well. In overdose, it
causes hepatotoxicity.
• Various antidepressants (e.g.
amitriptyline), as well as antiepileptic
drugs (e.g. carbamazepine , gabapentin
), are used mainly to treat neuropathic
pain.
• Other drugs occasionally used include
the NMDA receptor antagonist
ketamine and the local anaesthetic
drug lignocaine (lidocaine
History of Opioids
• Opium is extracted from poppy seeds
(Paper somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
History cont’d
• Used medicinally and recreationally from
early Greek and Roman times
• Opium and laudanum (opium combined
with alcohol) were used to treat almost all
known diseases
• Morphine was isolated from opium in the
early 1800’s and since then has been the
most effective treatment for severe pain
History and Background
• Invention of the hypodermic needle in
1856 produced drug abusers who self
administered opioids by injection
• Controlling the widespread use of opioids
has been unsuccessful because of the
euphoria, tolerance and physiological
dependence that opioids produce
Terminology
• “opium” is a Greek word meaning “juice,”
or the exudate from the poppy
• “opiate” is a drug extracted from the
exudate of the poppy
• “opioid” is a natural or synthetic drug that
binds to opioid receptors producing
agonist effects
Natural opioids occur in 2 places:
• 1) In the juice of the opium poppy
(morphine and codeine)
• 2) As endogenous endorphins
• All other opioids are prepared from either
morphine (semisynthetic opioids such as
heroin) or they are synthesized from
precursor compounds (synthetic opioids
such as fentanyl)
Pharmacological Effects
• Sedation and anxiolysis
–
–
–
–
Drowsiness and lethargy
Apathy
Cognitive impairment
Sense of tranquility
• Depression of respiration
– Main cause of death from opioid overdose
– Combination of opioids and alcohol is especially dangerous
• Cough suppression
– Opioids suppress the “cough center” in the brain
• Pupillary constriction
– pupillary constriction in the presence of analgesics is
characteristic of opioid use
Pharmacological effects cont’d.
• Nausea and vomiting
– Stimulation of receptors in an area of the medulla called the
chemoreceptor trigger zone causes nausea and vomiting
– Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
– Opioids relieve diarrhea as a result of their direct actions on the
intestines
• Other effects
– Opioids can release histamines causing itching or more severe
allergic reactions including bronchoconstriction
– Opioids can affect white blood cell function and immune function
Mechanism of action
• Activation of peripheral nociceptive fibers causes
release of substance P and other pain-signaling
neurotransmitters from nerve terminals in the
dorsal horn of the spinal cord
• Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by
exogenous opioid agonists by acting
presynaptically to inhibit substance P release,
causing analgesia
Primary Effect of Opioid Receptor Activation
• Reduction or inhibition of neurotransmission, due largely
to opioid-induced presynaptic inhibition of
neurotransmitter release
• Involves changes in transmembrane ion conductance
– Increase potassium conductance (hyperpolarization)
– Inactivation of calcium channels
Three Opioid Receptors
• Mu
• Kappa
• Delta
Delta Receptor
• It is unclear what delta’s responsible for.
• Delta agonists show poor analgesia and
little addictive potential
• May regulate mu receptor activity
Mu-Receptor: Two Types
• Mu-1
– Located outside spinal
cord
– Responsible for
central interpretation
of pain
• Mu-2
– Located throughout
CNS
– Responsible for
respiratory depression,
spinal analgesia,
physical dependence,
and euphoria
Kappa Receptor
• Only modest analgesia
• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects
Mu and Kappa Receptor Activation
Response
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence
Mu-1
Mu-2
Kappa
Mu and Kappa Receptors
DRUGS
MU
KAPPA
Agonist
Agonist
AgonistAntagonist
Antagonist
Agonist
Pure
Antagonists
Antagonist
Antagonist
Pure Agonists
Terminology
• Pure Agonist: has affinity for binding plus efficacy
• Pure Antagonist: has affinity for binding but no efficacy;
blocks action of endogenous and exogenous ligands
• Mixed Agonist-Antagonist: produces an agonist effect at
one receptor and an antagonist effect at another
• Partial Agonist: has affinity for binding but low efficacy
AGONISTS
*Morphine
*Heroin
*Hydromorphone
*Fentanyl
*Codeine
*
General Pharmacokinetics
• LATENCY TO ONSET
•
*oral (15-30 minutes)
•
*intranasal (2-3 minutes)
•
*intravenous (15 – 30 seconds)
•
*pulmonary-inhalation (6-12 seconds)
• DURATION OF ACTION – anywhere between 4 and 72
hours depending on the substance in question.
• Metabolism – hepatic via phase 1 and phase 2
biotransformations to form a diverse array of metabolites
( ex., morphine to morphine-6-glucuronide).
Morphine
• PHARMACOKINETICS
• Routes of administration (preferred)
*Oral- latency to onset –(15 – 60 minutes )
•
* also sniffed, swallowed and injected.
•
* duration of action – ( 3 – 6 hours)
•
* First-pass metabolism results in poor
•
availability from oral dosing.
•
* 30% is plasma protein bound
• EFFECTS AND MEDICAL USES
•
*symptomatic relief of moderate to severe pain
•
*relief of certain types of labored breathing
•
*suppression of severe cough (rarely)
•
*suppression of severe diarrhea
•
*AGONIST for mu, kappa, and delta receptors.
Hydromorphone
• PHARMACOKINETICS
•
*Routes of administration (Preferred)
•
*Oral -latency to onset (15 – 30 minutes)
•
*Intravenous-Duration of Action (3-4
hours)
•
*Peak effect (30-60 minutes)
• PROPERTIES AND EFFECTS
•
* potent analgesic like morphine but is 710 times as potent in this capacity.
•
*used frequently in surgical settings for
moderate to severe pain. (cancer, bone
trauma, burns, renal colic.)
Fentanyl
• Pharmacokinetics
• Routes of Administration
* Oral, and transdermal & possibly I.V
*Highly lipophilic
*latency to onset (7-15 min. oral; 12-17 hrs
transdermal
*duration of action ( 1-2 hours oral; 72 transdermal)
*80 – 85% plasma protein bound
*90 % metabolized in the liver to inactive metabolites
Other properties
* 80 times the analgesic potency of morphine
and 10 times the analgesic potency of
hydromorphone.
*high efficacy for mu 1 receptors.
*most effective opiate analgesic
Antagonists
• Naloxone
• Naltrexone
Naltrexone
• PHARMACOKINETICS
•
*latency to onset (oral tablet 15-30 min.)
•
*duration of action 24-72 hours
•
*peak effect (6-12 hours)
• STRUCTURAL DISTINCTION
•
*Differs from naloxone insofar as the
•
allyl group on the nitrogen atom is supplanted
•
by a cyclopromethyl group.
• EFFECTS
•
*Reverses the psychotomimetic effects of opiate
•
agonists.
•
* Reverses hypotension and cardiovascular
instability
•
secondary to endogeneous endorphins (potent
vasodilators)
Tolerance and Dependence
Tolerance
• Tolerance is a diminished responsiveness to
the drug’s action that is seen with many
compounds
• Tolerance can be demonstrated by a
decreased effect from a constant dose of
drug or by an increase in the minimum drug
dose required to produce a given level of
effect
• Physiological tolerance involves changes in
the binding of a drug to receptors or changes
in receptor transductional processes related
to the drug of action
Tolerance continued
• Molecular basis of tolerance involves glutaminergic
mechanisms (glutamate-excitatory amino acid
neurotransmitter)
• 1997, Gies and colleagues stated that activation of
glutamate NMDA receptors correlates with
resistance to opioids and the development of
tolerance
• Mu-receptor mRNA levels are regulated by activation
of these receptors
• NMDA receptor blocker ketamine prevented the
development of this late-onset and long-lasting
enhancement in pain sensitivity after the initial
analgesia effect dissipated
Tolerance continued
• Thus, glutaminergic NMDA receptors MAY regulate
mu-receptor mRNA, accounting for the development
of tolerance to the continuous presence of opioid
• Cross-tolerance is the condition where tolerance for
one drug produces tolerance for another drug –
person who is tolerant to morphine will also be
tolerant to the analgesic effect of fentanyl, heroin,
and other opioids
• * note that a subject may be physically dependent on
heroin can also be administered another opioid such
as methadone to prevent withdrawl reactions
• Methadone has advantages of being more orally
effective and of lasting longer than morphine or
Tolerance continued
• Methadone maintenance programs allow
heroin users the opportunity to maintain a
certain level of functioning without the
withdrawl reactions
• Although most opioid effects show
tolerance, locomotor stimulation shows
sensitization with repeated opioid
administration
• Toxic effects of opioids are primarily from
their respiratory depressant action and this
effect shows tolerance with repeated opioid
use
• Opioids might be considered “safer” in that a
Dependence
• Physiological dependence occurs when
the drug is necessary for normal
physiological functioning – this is
demonstrated by the withdrawl
reactions
• Withdrawl reactions are usually the
opposite of the physiological effects
produced by the drug
• Psychological factors involved in
drug dependence
Biochemical mechanism postulated to explain morphine tolerance and
dependence. Morphine inhibits adenylyl cyclase, thus reducing cAMP formation
(green line). A secondary rise in adenylyl cyclase expression occurs (red line), so
that cAMP production recovers in the presence of morphine (i.e. tolerance
develops). On cessation of morphine treatment, excessive cAMP production
occurs, causing withdrawal symptoms, until the high level of adenylyl cyclase
expression returns to normal. Later work has shown that other elements in the
cAMP signalling pathway, in addition to adenylyl cyclase itself, are similarly
affected by chronic drug exposure, in vivo as well as in vitro.
Cellular and physiological mechanisms involved in
drug dependence showing the relationship between
the immediate and delayed effects of drug-taking and
drug withdrawal. DA, dopamine.
Drug dependence
• Dependence is defined as a compulsive craving that develops
as a result of repeated administration of the drug.
• Dependence occurs with a wide range of psychotropic drugs,
acting by many different mechanisms.
• The common feature of dependence-producing drugs is that
they have a positive reinforcing action ('reward') associated
with activation of the mesolimbic dopaminergic pathway.
• Dependence is often associated with (i) tolerance to the drug,
which can arise by various biochemical mechanisms; (ii) a
physical abstinence syndrome, which varies in type and
intensity for different classes of drug; (iii) psychological
dependence (craving), which may be associated with the
tolerance-producing biochemical changes.
• Psychological dependence, which usually outlasts the physical
withdrawal syndrome, is the major factor leading to relapse
among treated addicts.
• Although genetic factors contribute to drug-seeking behaviour,
no specific genes have yet been identified
Clinical use of drugs in
substance dependence‫؟؟؟‬
•
•
•
Tobacco dependence:
– short-term nicotine is the drug of choice as adjunct to behavioural therapy in smokers
committed to giving up
– bupropion is also effective but lowers seizure threshold, so is contraindicated in
people with risk factors for seizures.
Alcohol dependence:
– long-acting benzodiazepines (e.g. chlordiazepoxide) can be used to reduce withdrawal
symptoms and the risk of seizures; they should be tapered over 1-2 weeks and then
discontinued because of their abuse potential
– disulfiram is used as an adjunct to behavioural therapy in suitably motivated
alcoholics after detoxification; it is contraindicated for patients in whom a hypotensive
acetaldehyde-induced reaction (p. 632) would be dangerous (e.g. those with coronary
or cerebral vascular disease)
– acamprosate can help to maintain abstinence; it is started as soon as abstinence has
been achieved and maintained if relapse occurs, and it is continued for 1 year.
Opioid dependence:
– opioid agonists or partial agonists (e.g., respectively, methadone and buprenorphine )
administered orally or sublingually may be substituted for injectable narcotics, many
of whose harmful effects are attributable to the route of administration
– naltrexone, a long-acting opioid antagonist, is used as an adjunct to help prevent
relapse in detoxified addicts (opioid-free for at least 1 week)
– lofexidine, an α2 agonist (cf. clonidine; Ch. 11) is used short term (usually up to 10
days) to ameliorate symptoms of opioid withdrawal, and is then tapered over a further
2-4 days
Pharmacology of nicotine
• At a cellular level, nicotine acts on nicotinic acetylcholine
receptors (nAChRs), mainly of the α4β2 subtype, to cause
neuronal excitation. Its central effects are blocked by receptor
antagonists such as mecamylamine.
• At the behavioural level, nicotine produces a mixture of
inhibitory and excitatory effects.
• Nicotine shows reinforcing properties, associated with
increased activity in the mesolimbic dopaminergic pathway,
and self-administration can be elicited in animal studies.
• Electroencephalography changes show an arousal response,
and subjects report increased alertness accompanied by a
reduction of anxiety and tension.
• Learning, particularly under stress, is facilitated by nicotine .
• Peripheral effects of nicotine are due mainly to ganglionic
stimulation: tachycardia, increased blood pressure and
reduced gastrointestinal motility. Tolerance develops rapidly to
these effects.
• Nicotine is metabolised, mainly in the liver,
within 1-2 hours. The inactive metabolite,
cotinine, has a long plasma half-life and can
be used as a measure of smoking habits.
• Nicotine gives rise to tolerance, physical
dependence and psychological dependence
(craving), and is highly addictive. Attempts at
long-term cessation succeed in only about
20% of cases.
• Nicotine replacement therapy (chewing gum
or skin patch preparations) improves the
chances of giving up smoking but only when
combined with active counsel
Harmful effects of smoking
• Smoking accounts for about 10% of deaths
worldwide, mainly due to:
– cancer, especially lung cancer, of which about
90% of cases are smoking-related; carcinogenic
tars are responsible
– ischaemic heart disease; both nicotine and
carbon monoxide may be responsible
– chronic bronchitis; tars are mainly responsible.
• Smoking in pregnancy reduces birth weight and
retards childhood development. It also increases
abortion rate and perinatal mortality. Nicotine and
possibly carbon monoxide are responsible.
• The incidence of Parkinson's disease is lower in
smokers than in non-smokers
Cannabis
• Main active constituent is Δ9-tetrahydrocannabinol
(THC), although pharmacologically active
metabolites may be important.
• Actions on central nervous system (CNS) include
both depressant and psychotomimetic effects.
• Subjectively, subjects experience euphoria and a
feeling of relaxation, with sharpened sensory
awareness.
• Objective tests show impairment of learning,
memory and motor performance.
• THC also shows analgesic and antiemetic activity, as
well as causing catalepsy and hypothermia in animal
tests.
• Peripheral actions include vasodilatation, reduction
of intraocular pressure, and bronchodilatation.
• Cannabinoid receptors belong to the G-proteincoupled receptor family, linked to inhibition of
adenylyl cyclase and effects on calcium and
potassium channel function, causing inhibition of
synaptic transmission. The brain receptor (CB1)
differs from the peripheral receptor (CB2), which is
expressed mainly in cells of the immune system.
Selective agonists and antagonists have been
developed.
• Anandamide, an arachidonic acid derivative, is an
endogenous ligand for the CNS cannabinoid
receptor; its function has not yet been ascertained.
• Cannabinoids are less liable than opiates, nicotine
or alcohol to cause dependence but may have longterm psychological effects.
• Nabilone , a THC analogue, has been developed for
its antiemetic property.
• Although cannabinoids are not available for clinical
use, trials are in progress for symptomatic treatment
of multiple sclerosis and AIDS.
Withdrawl Reactions
Acute Action
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Analgesia
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Reduced sex drive
Flushed and warm skin
Withdrawl Sign
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•
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Pain and irritability
Hyperventilation
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Diarrhea
Pupillary dilation
Hyperthermia
Lacrimation, runny nose
Spontaneous ejaculation
Chilliness and “gooseflesh”
Dependence continued
• Acute withdrawl can be easily precipitated in drug
dependent individuals by injecting an opioid
antagonist such as naloxone or naltrexone – rapid
opioid detoxification or rapid anesthesia aided
detoxification
• The objective is to enable the patient to tolerate high
doses of an opioid antagonist and undergo complete
detox in a matter of hours while unconscious
• After awakening, the person is maintained on orally
administered naltrexone to reduce opioid craving