Dr
Morphine, the prototype agonist is a naturalMorphine, the prototype agonist is a natural
alkaloid derived from
alkaloid derived from P. somniferumP. somniferum
Semisynthetic and synthetic agents are alsoSemisynthetic and synthetic agents are also
available available available available
These drugs are used where strong analgesicThese drugs are used where strong analgesic
action is required action is required
The termThe term opioidopioid refers broadly to allrefers broadly to all
compounds related to opium compounds related to opium
Classification
Classification
Strong agonists:Strong agonists: morphine, heroin, pethidine (meperidine),morphine, heroin, pethidine (meperidine),
methadone, fentanyl, sufentanil, remifentanil, alfentanil, methadone, fentanyl, sufentanil, remifentanil, alfentanil, oxymorphone, hydromorphone, levorphanol
oxymorphone, hydromorphone, levorphanol
Moderate/low agonists:Moderate/low agonists: codeine, oxycodone, hydrocodone,codeine, oxycodone, hydrocodone,
propoxyphene, diphenoxylate, difenoxin, loperamide propoxyphene, diphenoxylate, difenoxin, loperamide
Mixed agonistsMixed agonists--antagonists:antagonists: nalbuphine, buprenorphine,nalbuphine, buprenorphine,
Mixed agonistsMixed agonists--antagonists:antagonists: nalbuphine, buprenorphine,nalbuphine, buprenorphine,
butorphanol, pentazocine butorphanol, pentazocine
Others:Others: tramadol, tapentadoltramadol, tapentadol
Antitussives:Antitussives: noscapine, dextromethorphan, codeine,noscapine, dextromethorphan, codeine,
levopropoxyphene levopropoxyphene
Antagonists:Antagonists: naloxone, naltrexone, nalmefene, alvimopan,naloxone, naltrexone, nalmefene, alvimopan,
methylnaltrexone bromide methylnaltrexone bromide
Endogenous opioid peptides
Endogenous opioid peptides
Peptides with opioid like pharmacologicalPeptides with opioid like pharmacological
properties properties
Three families have been describedThree families have been described
-- endorphinsendorphins -- endorphinsendorphins
-- enkephalins (leu and metenkephalins (leu and met--enkephalin)enkephalin) -- dynorphinsdynorphins
Endogenous peptidesEndogenous peptides endomorphinendomorphin--1 & 21 & 2
also share properties of opioid peptides also share properties of opioid peptides e.g. analgesia and high affinity to
e.g. analgesia and high affinity to μμ receptors
Present at CNS sites involved in painPresent at CNS sites involved in pain
modulation modulation
Released during pain or anticipation ofReleased during pain or anticipation of
pain pain pain pain
Mechanism of action of opioids
Mechanism of action of opioids
Act through activating opioid receptorsAct through activating opioid receptors
Opioid receptors are involved inOpioid receptors are involved in
transmission and modulation of pain transmission and modulation of pain
Some effects are mediated partly throughSome effects are mediated partly through
Some effects are mediated partly throughSome effects are mediated partly through
action on peripheral receptors action on peripheral receptors
Opioid receptors
Opioid receptors
Three major classes (Three major classes (μμ, , δδ, & , & κκ))
Various subtypes also existVarious subtypes also exist
All are GAll are G--protein coupled receptorsprotein coupled receptors
Receptors are located in brain, spinal cord Receptors are located in brain, spinal cord
Receptors are located in brain, spinal cordReceptors are located in brain, spinal cord
(dorsal horn) and peripheral tissues (dorsal horn) and peripheral tissues
(primary afferents relaying pain sensation) (primary afferents relaying pain sensation)
Receptor
Subtype Functions EndogenousOpioid Peptide Affinity
(mu) Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed
gastrointestinal transit; modulation of
Endorphins
> enkephalins > dynorphins
Opioid Receptor Subtypes, their functions, and their endogenous peptide affinities
gastrointestinal transit; modulation of hormone and neurotransmitter release
dynorphins
(delta) Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release
Enkephalins > endorphins and dynorphins (kappa) Supraspinal and spinal analgesia;
psychotomimetic effects; slowed gastrointestinal transit
Dynorphins > > endorphins and enkephalins
Cellular action of opioid : Inhibition of cyclic adenosine monophosphate (cAMP)
formation leads to opening of potassium channels and closing of calcium channels. Potassium efflux causes membrane hyperpolarization. The closing of calcium
channels inhibits the release of neurotransmitters from nociceptive nerve terminals (glutamate, substance P, Ach, NE, serotonin etc.)
Opioids cause analgesia partly by activatingOpioids cause analgesia partly by activating
inhibitory descending pathways, partly by inhibitory descending pathways, partly by
inhibiting transmission in the dorsal horn, and inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve partly by inhibiting excitation of sensory nerve terminals in the periphery
terminals in the periphery terminals in the periphery terminals in the periphery
Repetitive CRepetitive C--fibre activity facilitates transmissionfibre activity facilitates transmission
through the dorsal horn ('wind
through the dorsal horn ('wind--up') byup') by
mechanisms involving activation of NMDA and mechanisms involving activation of NMDA and substance P receptors
Summary of modulatory mechanisms in the nociceptive pathway. HT,
5-hydroxytryptamine; BK, bradykinin; CGRP, calcitonin gene-related peptide; NA,
noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; SP, substance P.
Supraspinal control system: Opioids excite neurons in the periaqueductal grey matter (PAG) and in the nucleus reticularis paragigantocellularis (NRPG), which in turn project to nucleus raphe magnus (NRM). From the NRM, 5-hydroxytryptamine (5-HT)- and enkephalin-containing neurons run to the
substantia gelatinosa of the dorsal horn, and exert an inhibitory influence on transmission. Opioids
also act directly on the dorsal horn, as well as on the peripheral terminals of nociceptive afferent
neurons. The locus coeruleus (LC) sends noradrenergic neurons to the dorsal horn, which also inhibit transmission.
Schematic diagram of the gate control system. This system regulates the passage of impulses from the peripheral afferent fibres
to the thalamus via transmission neurons originating in the dorsal horn. Neurons in the substantia gelatinosa (SG) of the dorsal horn act to inhibit the transmission pathway. Inhibitory interneurons are activated by descending inhibitory neurons or by non-nociceptive afferent input. They are inhibited by nociceptive C-fibre input, so the persistent C-fibre activity facilitates excitation of the transmission cells by either nociceptive or non-nociceptive inputs. This autofacilitation causes successive bursts of activity in the nociceptive
Pharmacological effects: Morphine
Pharmacological effects: Morphine
Analgesia:Analgesia: strong analgesic (spinal &
supraspinal action); analgesia increases with dose; reduce both aspect of pain experience (sensory & affective);
experience (sensory & affective);
selectively suppress pain without affecting other sensations or producing
proportionate generalized CNS depression; intrathecal injection cause regional
Analgesia is primarily through action on Analgesia is primarily through action on μμ receptor; morphine does act at
receptor; morphine does act at δδ and and κκ receptor sites but to what extent this
receptor sites but to what extent this
contributes to analgesic action is unclear contributes to analgesic action is unclear contributes to analgesic action is unclear contributes to analgesic action is unclear Morphine action at
Morphine action at μμ receptor may evoke receptor may evoke release of endogenous opioids that
release of endogenous opioids that additionally act at
Euphoria:Euphoria: IV morphine inIV morphine in patients & drugpatients & drug users produce pleasant floating sensation users produce pleasant floating sensation ((↓anxiety and stress); ↓anxiety and stress);
Dysphoria (restlessness and malaise) may Dysphoria (restlessness and malaise) may Dysphoria (restlessness and malaise) may Dysphoria (restlessness and malaise) may also occur;
also occur;
Euphoric effects are due to DA release in Euphoric effects are due to DA release in nucleus accumbance
Sedation:Sedation: drowsiness, clouding ofdrowsiness, clouding of
mentation but little or no amnesia; mentation but little or no amnesia; induces
induces sleepsleep more frequently in elderlymore frequently in elderly (easily arousable); disrupts both REM and (easily arousable); disrupts both REM and (easily arousable); disrupts both REM and (easily arousable); disrupts both REM and NREM sleep
NREM sleep
combination with other CNS depressants combination with other CNS depressants may induce very deep sleep
Respiratory depression:Respiratory depression: by inhibitingby inhibiting
brainstem respiratory mechanism; brainstem respiratory mechanism; rate and TV both reduced (
rate and TV both reduced (↑↑ in alveolarin alveolar Pco
Pco );); Pco
Pco22););
depression is
depression is dose relateddose related and isand is
influenced by degree of sensory input influenced by degree of sensory input occurring at that time
occurring at that time Problematic in
Tolerance & physical dependence:Tolerance & physical dependence:
mechanism is unclear, may be due to, mechanism is unclear, may be due to, -- upregulation of cAMP systemupregulation of cAMP system
-- receptor recyclingreceptor recycling
-- receptor recyclingreceptor recycling
-- receptor uncouplingreceptor uncoupling (dysfunction of(dysfunction of structural interaction b/w
structural interaction b/w μμ receptors, G receptors, G proteins, 2
proteins, 2ndnd messenger and their targetmessenger and their target ion channels)
ion channels)
Cough suppression:Cough suppression: cough reflex iscough reflex is
depressed, more sensitive to depressant depressed, more sensitive to depressant action of morphine than respiratory
action of morphine than respiratory depression
depression depression depression
Miosis:Miosis: due to III cranial nervedue to III cranial nerve
stimulation; central action; valuable in stimulation; central action; valuable in diagnosis of overdose
Truncal rigidity:Truncal rigidity: increase in tone ofincrease in tone of
large truncal muscles usually apparent large truncal muscles usually apparent with high doses of highly lipid soluble with high doses of highly lipid soluble agents (fentanyl, alfentanil etc.) if
agents (fentanyl, alfentanil etc.) if agents (fentanyl, alfentanil etc.) if agents (fentanyl, alfentanil etc.) if administered IV rapidly;
administered IV rapidly;
It is due to supraspinal effect; It is due to supraspinal effect;
May reduce thoracic compliance; May reduce thoracic compliance; may necessitate use of NMBs
Nausea & vomiting:Nausea & vomiting: through activationthrough activation
of CTZ (also vestibular component of CTZ (also vestibular component involved)
involved)
Temperature:Temperature: Opioids alter theOpioids alter the
Temperature:Temperature: Opioids alter theOpioids alter the
equilibrium point of the hypothalamic equilibrium point of the hypothalamic heat
heat--regulatory mechanisms such thatregulatory mechanisms such that body temperature usually falls slightly; body temperature usually falls slightly; However, chronic high dosage may
However, chronic high dosage may increase body temperature
CVS:CVS: bradycardia (pethidine causebradycardia (pethidine cause
tachycardia on i.v. inj); may cause tachycardia on i.v. inj); may cause hypotension (due to vasodilatation hypotension (due to vasodilatation secondary to histamine release, VMC secondary to histamine release, VMC depression) if CVS is stressed
depression) if CVS is stressed depression) if CVS is stressed depression) if CVS is stressed Cerebral vasodilatation if Pco
Cerebral vasodilatation if Pco22 is increasedis increased →
→ ↑↑ ICTICT
There is a shift of blood from pulmonary to systemic circuit due to greater
GIT:GIT: cause constipation through action incause constipation through action in
CNS and on ENS (increased tone and CNS and on ENS (increased tone and decreased propulsive movements), decreased propulsive movements), ↓↓
secretion, increased water absorption: no secretion, increased water absorption: no secretion, increased water absorption: no secretion, increased water absorption: no tolerance
tolerance
Biliary tract:Biliary tract: contract biliary smoothcontract biliary smooth
muscles (colic), constrict sphincter of Oddi muscles (colic), constrict sphincter of Oddi (elevated plasma amylase and lipase)
Uterus:Uterus: slightly prolong labor due toslightly prolong labor due to
reduce uterine tone (central & peripheral reduce uterine tone (central & peripheral action)
action)
Bronchi:Bronchi: constriction due to histamineconstriction due to histamine
Bronchi:Bronchi: constriction due to histamineconstriction due to histamine
release
release –– dangerous in asthmaticsdangerous in asthmatics
Neuroendocrine:Neuroendocrine: stimulate release ofstimulate release of
ADH, GH, prolactin but inhibit release of ADH, GH, prolactin but inhibit release of LH
Renal effects:Renal effects: function are depressedfunction are depressed
due to decrease renal plasma flow;
due to decrease renal plasma flow; ↑↑eses ureteral and bladder tone
ureteral and bladder tone;; ↑↑ tone oftone of sphincter
sphincter -- Urinary retentionUrinary retention
Pruritus:Pruritus: at therapeutic dose produceat therapeutic dose produce
flushing, warming and itching of the skin flushing, warming and itching of the skin (CNS effect plus histamine release)
(CNS effect plus histamine release) –– More common with parenteral
More common with parenteral
administration; spinal/epidural injection administration; spinal/epidural injection cause intense pruritus of lips and torso cause intense pruritus of lips and torso
Immune system:Immune system: modulate immunemodulate immune
response through action on lymphocytes response through action on lymphocytes proliferation, Antibody production and
proliferation, Antibody production and chemotaxis
chemotaxis chemotaxis chemotaxis
Pharmacokinetics: opioids
Pharmacokinetics: opioids
Oral dose of the opioid (eg, morphine)
much higher than the parenteral dose (because of the first-pass effect)
Considerable interpatient variability exists: Considerable interpatient variability exists:
prediction of an effective oral dose difficult
Codeine and oxycodone are effective
orally
All opioids bind to plasma proteins with
Distribute and localize in highest
concentrations in tissues that are highly perfused (brain, lungs, liver, kidneys, and spleen)
spleen)
Skeletal muscles serves as the reservoir May accumulate in fatty tissue after
frequent high-dose or continuous infusion of highly lipophilic opioids eg, fentanyl
The opioids are converted in large part toThe opioids are converted in large part to
polar metabolites (mostly glucuronides) polar metabolites (mostly glucuronides)
Morphine, is conjugated to M3GMorphine, is conjugated to M3G
(neuroexcitatory) & M6G (only 10%) (neuroexcitatory) & M6G (only 10%) (neuroexcitatory) & M6G (only 10%) (neuroexcitatory) & M6G (only 10%)
Accumulation of these metabolites mayAccumulation of these metabolites may
occur in patients with renal failure occur in patients with renal failure
Hydromorphone 3 Glucuronide (H3G), alsoHydromorphone 3 Glucuronide (H3G), also
has CNS excitatory properties has CNS excitatory properties
Esters (eg, heroin, remifentanil) areEsters (eg, heroin, remifentanil) are
rapidly hydrolyzed by esterases rapidly hydrolyzed by esterases
Hepatic oxidative metabolism is theHepatic oxidative metabolism is the
primary route of degradation for primary route of degradation for primary route of degradation for primary route of degradation for
meperidine, fentanyl, alfentanil, sufentanil meperidine, fentanyl, alfentanil, sufentanil
Accumulation of a demethylatedAccumulation of a demethylated
metabolite of meperidine (i.e. metabolite of meperidine (i.e.
normeperidine) may occur in patients with normeperidine) may occur in patients with decreased renal function or during
decreased renal function or during decreased renal function or during decreased renal function or during overdose
overdose –– causes excitement (seizures,causes excitement (seizures, tremors, hyperreflexia etc.)
tremors, hyperreflexia etc.)
Also nonAlso non--selective MAOIs interfere withselective MAOIs interfere with
hydrolysis but not with demethylation of hydrolysis but not with demethylation of
pethidine: norpethidine excess
Codeine, oxycodone, and hydrocodoneCodeine, oxycodone, and hydrocodone
undergo metabolism in the liver by P450 undergo metabolism in the liver by P450 isozyme CYP2D6
isozyme CYP2D6
Genetic polymorphism of CYP2D6 mayGenetic polymorphism of CYP2D6 may
Genetic polymorphism of CYP2D6 mayGenetic polymorphism of CYP2D6 may
cause variation in analgesic response to cause variation in analgesic response to codeine
codeine
Polar metabolites, are excreted mainly inPolar metabolites, are excreted mainly in
the urine with small amounts of the urine with small amounts of unchanged drug sometimes
Adverse Effects
Adverse Effects
Sedation; restlessness, lethargy,Sedation; restlessness, lethargy,
hyperactivity (
hyperactivity (dysphoric reactiondysphoric reaction))
Respiratory depressionRespiratory depression –– infants &infants &
elderly are more susceptible, may cause elderly are more susceptible, may cause elderly are more susceptible, may cause elderly are more susceptible, may cause apnea in newborn if given to mother
apnea in newborn if given to mother
during labor; dangerous in patient with during labor; dangerous in patient with respiratory insufficiency
respiratory insufficiency -- acute respiratoryacute respiratory failure
Nausea & vomitingNausea & vomiting
ConstipationConstipation –– does not diminish withdoes not diminish with
continued use continued use
Increased ICTIncreased ICT
Increased ICTIncreased ICT
Postural hypotensionPostural hypotension –– exaggeratedexaggerated
response if person is hypovolemic response if person is hypovolemic
Urinary retentionUrinary retention –– elderly individualselderly individuals
are more susceptible are more susceptible
AllergyAllergy –– itching, urticaria more frequent withitching, urticaria more frequent with
parenteral and spinal administration parenteral and spinal administration
Tolerance:Tolerance: begin with 1begin with 1stst dose; develops moredose; develops more
readily if large doses given at short intervals; readily if large doses given at short intervals; readily if large doses given at short intervals; readily if large doses given at short intervals; tolerance may be as great as 35 fold;
tolerance may be as great as 35 fold;
develops to analgesic, sedating, respiratory develops to analgesic, sedating, respiratory
depressant, antidiuretic, emetic & hypotensive depressant, antidiuretic, emetic & hypotensive effects but not to the
effects but not to the miotic, constipatingmiotic, constipating &&
convulsant
Develops due to PK and PD factors Develops due to PK and PD factors
Tolerance dissipates within days to months after Tolerance dissipates within days to months after discontinuation;
discontinuation;
Rate (appearance & disappearance) & degree Rate (appearance & disappearance) & degree Rate (appearance & disappearance) & degree Rate (appearance & disappearance) & degree depend on drug and individual;
depend on drug and individual;
Tolerance also develops to mixed agonist Tolerance also develops to mixed agonist--antagonist but to a lesser extent;
antagonist but to a lesser extent;
No tolerance develops to antagonistic actions of No tolerance develops to antagonistic actions of mixed or pure antagonistic agents
Cross tolerance among
Cross tolerance among μμ agonists is often agonists is often partial or incomplete
partial or incomplete -- basis forbasis for “opioid“opioid rotation”
rotation” (improved analgesia at a(improved analgesia at a
reduced overall equivalent dosage of a reduced overall equivalent dosage of a reduced overall equivalent dosage of a reduced overall equivalent dosage of a different opioid)
different opioid)
NMDA antagonist (ketamine) & NMDA antagonist (ketamine) & δδ antagonist with
antagonist with μμ receptor agonist action receptor agonist action may prevent tolerance
Physical dependencePhysical dependence –– withdrawalwithdrawal
syndrome on discontinuation of drug syndrome on discontinuation of drug
s/s rhinorrhea, lacrimation, chills, diarrhea s/s rhinorrhea, lacrimation, chills, diarrhea gooseflesh, hyperventilation, mydriasis,
gooseflesh, hyperventilation, mydriasis, gooseflesh, hyperventilation, mydriasis, gooseflesh, hyperventilation, mydriasis, vomiting, anxiety, and hostility etc.
vomiting, anxiety, and hostility etc. Number
Number andand intensityintensity of the s/s dependof the s/s depend on the degree of physical dependence
The time of
The time of onset, intensity,onset, intensity, andand duration
duration of abstinence syndrome varyof abstinence syndrome vary based on the drug previously used
based on the drug previously used Morphine / heroin
Morphine / heroin, Onset, Onset –– 6 to 10 hrs,6 to 10 hrs, Morphine / heroin
Morphine / heroin, Onset, Onset –– 6 to 10 hrs,6 to 10 hrs, Peak
Peak -- 36 to 48 hrs, Duration36 to 48 hrs, Duration -- 5 days5 days Meperidine
Meperidine -- syndrome subsides in 24 hsyndrome subsides in 24 h Methadone
Methadone several days to reach theseveral days to reach the peak and it may last as long as 2 weeks peak and it may last as long as 2 weeks
Antagonist precipitated withdrawal Antagonist precipitated withdrawal --Within 3 minutes after injection of the
Within 3 minutes after injection of the antagonist, peaking in 10
antagonist, peaking in 10––20 min and20 min and largely subsides after 1 hour
largely subsides after 1 hour largely subsides after 1 hour largely subsides after 1 hour In the case of agents with
In the case of agents with mixed effectsmixed effects,, syndrome appears to be somewhat
syndrome appears to be somewhat
different from that produced by morphine different from that produced by morphine and other agonists
Psychologic dependencePsychologic dependence –– euphoria,euphoria,
indifference to stimuli, sedation & indifference to stimuli, sedation &
abdominal effects akin to orgasm on iv abdominal effects akin to orgasm on iv administration
administration administration administration
Abuse liability is high b’coz of these Abuse liability is high b’coz of these factors and it is further reinforced by factors and it is further reinforced by development of physical dependence development of physical dependence
Patients with Addison’s disease and thosePatients with Addison’s disease and those
with myxedema may have prolonged and with myxedema may have prolonged and exaggerated responses to opioids
Acute morphine poisoning
Acute morphine poisoning
In nonusers adults 50 mg i.m. may cause
serious toxicity
Lethal dose is about about 250 mg S/S: Stupor or coma, shallow and S/S: Stupor or coma, shallow and
occasional breathing, cyanosis, pinpoint pupil (dilated in pethidine poisoning), fall in BP, convulsions, pulmonary edema,
Establish airway and ventilate the patient,Establish airway and ventilate the patient,
maintain BP; gastric lavage with KMnO maintain BP; gastric lavage with KMnO44;; Naloxone:
Naloxone: 0.40.4--0.8 mg i.v. repeat every0.8 mg i.v. repeat every 22--3 min till respiration picks up and3 min till respiration picks up and
22--3 min till respiration picks up and3 min till respiration picks up and subsequently every 1
subsequently every 1--4 hr based on4 hr based on response to therapy
response to therapy
Care should be taken to avoid Care should be taken to avoid precipitating withdrawal in
precipitating withdrawal in dependentdependent patients (extremely sensitive to
patients (extremely sensitive to antagonists)
The safest approach is to dilute the The safest approach is to dilute the standard naloxone dose (0.4 mg) and standard naloxone dose (0.4 mg) and slowly administer it intravenously,
slowly administer it intravenously, monitoring arousal and respiratory monitoring arousal and respiratory monitoring arousal and respiratory monitoring arousal and respiratory function
function
For reversing opioid poisoning in children, For reversing opioid poisoning in children, the initial dose of naloxone is 0.01 mg/kg the initial dose of naloxone is 0.01 mg/kg
The DOA of the available antagonists isThe DOA of the available antagonists is
shorter than that of many opioids shorter than that of many opioids
(patients can slip back into coma) e.g. (patients can slip back into coma) e.g. methadone
methadone
In such cases, continuous infusion ofIn such cases, continuous infusion of
naloxone should be considered naloxone should be considered
Toxicity owing to overdose of pentazocineToxicity owing to overdose of pentazocine
and other opioids with mixed actions may and other opioids with mixed actions may require higher doses of naloxone
Cautions during therapy
Cautions during therapy
Avoid combining full agonist with partial agonistAvoid combining full agonist with partial agonist
(eg. Pentazocine with morphine) (eg. Pentazocine with morphine)
Don’t use in patient with head injuriesDon’t use in patient with head injuries
In patients with impaired respiratory functionIn patients with impaired respiratory function --
In patients with impaired respiratory functionIn patients with impaired respiratory function
--may lead to acute respiratory failure may lead to acute respiratory failure
Use in Patients with Impaired Hepatic or RenalUse in Patients with Impaired Hepatic or Renal
Function
Function -- dosage should be reduceddosage should be reduced
Patients with adrenal insufficiency andPatients with adrenal insufficiency and
hypothyroidism may have prolonged and hypothyroidism may have prolonged and exaggerated responses to opioids
Drug interactions
Drug interactions
Depressant effects of some opioids may beDepressant effects of some opioids may be
exaggerated and prolonged by phenothiazines, exaggerated and prolonged by phenothiazines, MAOIs and TCAs
MAOIs and TCAs -- mechanisms not clearmechanisms not clear
Some phenothiazines reduce the opioid requiredSome phenothiazines reduce the opioid requiredSome phenothiazines reduce the opioid requiredSome phenothiazines reduce the opioid required
to produce a given level of analgesia to produce a given level of analgesia
Depending on the specific agent, theDepending on the specific agent, the
respiratory
respiratory--depressant effects also seem to bedepressant effects also seem to be enhanced, the degree of sedation is increased, enhanced, the degree of sedation is increased, and the hypotension accentuated
Some phenothiazine may be antianalgesicSome phenothiazine may be antianalgesic
AmphetamineAmphetamine increase the analgesic andincrease the analgesic and
euphoriant effects and decrease sedation euphoriant effects and decrease sedation
Some (Some (e.g.,e.g., hydroxyzinehydroxyzine) enhance the analgesic) enhance the analgesic
Some (Some (e.g.,e.g., hydroxyzinehydroxyzine) enhance the analgesic) enhance the analgesic
effects of low doses of opioids effects of low doses of opioids
TCAs may enhance morphineTCAs may enhance morphine--induced analgesiainduced analgesia
SedativeSedative--hypnotics increase CNS depressionhypnotics increase CNS depression
particularly respiratory depression particularly respiratory depression
Clinical uses
Clinical uses
AnalgesiaAnalgesia –– used in cancer pain,used in cancer pain,
postoperative pain, during labor, severe postoperative pain, during labor, severe colics etc.
colics etc.
Severe, constant pain is better controlled Severe, constant pain is better controlled Severe, constant pain is better controlled Severe, constant pain is better controlled than sharp intermittent pain
than sharp intermittent pain
ROA: oral, rectal, parenteral, transdermal, ROA: oral, rectal, parenteral, transdermal, buccal transmucosal, intranasal etc.
Acute pulmonary edema:Acute pulmonary edema: i.v. morphinei.v. morphine
produces rapid relief from dyspnea in LVF produces rapid relief from dyspnea in LVF -- reduce anxiety (reduce anxiety (↓↓perception of shortnessperception of shortness
of breath,
of breath, ↓ sympathetic stimulation↓ sympathetic stimulation)) of breath,
of breath, ↓ sympathetic stimulation↓ sympathetic stimulation)) -- reduce cardiac pre & afterloadreduce cardiac pre & afterload
-- shift blood from pulmonary to systemicshift blood from pulmonary to systemic circuit
circuit
* If respiratory depression is a problem, * If respiratory depression is a problem,
furosemide is a preferred option furosemide is a preferred option
Diarrhea:Diarrhea: may control diarrhea of any causemay control diarrhea of any cause
synthetic agents with more selective GI action synthetic agents with more selective GI action and with few or no CNS effects are used. e.g. and with few or no CNS effects are used. e.g. loperamide, diphenoxylate
loperamide, diphenoxylate loperamide, diphenoxylate loperamide, diphenoxylate
Cough:Cough: lower than analgesic doses arelower than analgesic doses are
required, synthetic agents with no analgesic and required, synthetic agents with no analgesic and addictive action are preferred
addictive action are preferred
eg. Dextromethorphan, noscapine, codeine etc. eg. Dextromethorphan, noscapine, codeine etc.
Anaesthesia:Anaesthesia:
-- As preanaestheic medicationAs preanaestheic medication
-- As adjunct to other anaestheic agentsAs adjunct to other anaestheic agents
In high doses (eg. Fentanyl) as primary In high doses (eg. Fentanyl) as primary
-- In high doses (eg. Fentanyl) as primaryIn high doses (eg. Fentanyl) as primary
component of anaesthetic regimen component of anaesthetic regimen
Commonly used in CV and other types of Commonly used in CV and other types of
high risk surgery where primary aim is to high risk surgery where primary aim is to minimize CV depression
Shivering:Shivering: all opioid reduce shiveringall opioid reduce shivering
(postanaesthetic or infusion related) but (postanaesthetic or infusion related) but pethidine has most marked effect
pethidine has most marked effect block shivering through action on a block shivering through action on a subtype of
CODEINE
CODEINE
PotencyPotency –– 1/101/10thth of the morphineof the morphine
Approximately 60% as effective orally asApproximately 60% as effective orally as
parenterally as an analgesic and as a parenterally as an analgesic and as a respiratory depressant
respiratory depressant respiratory depressant respiratory depressant
Low affinity for opioid receptorsLow affinity for opioid receptors
--analgesic effect is due to its conversion to analgesic effect is due to its conversion to morphine (via CYP2D6)
morphine (via CYP2D6)
Antitussive actions may involve distinctAntitussive actions may involve distinct
receptors that bind codeine itself receptors that bind codeine itself
TRAMADOL
TRAMADOL
WeakWeak μμ agonist (affinity 1/6000 of morphine)agonist (affinity 1/6000 of morphine)
Inhibits NE & 5HT uptake (analgesia partly)Inhibits NE & 5HT uptake (analgesia partly)
As effective as morphine in mildAs effective as morphine in mild--toto--moderatemoderate
As effective as morphine in mildAs effective as morphine in mild--toto--moderatemoderate
pain (less effective in severe or chronic pain) pain (less effective in severe or chronic pain)
As effective as meperidine in labor pain and mayAs effective as meperidine in labor pain and may
cause less neonatal respiratory depression cause less neonatal respiratory depression
An active metabolite (2An active metabolite (2--4 times as potent) may4 times as potent) may
account for part of the analgesic effect account for part of the analgesic effect
Supplied as a racemic mixtureSupplied as a racemic mixture
RD < morphine; constipation < codeineRD < morphine; constipation < codeine
Can cause seizuresCan cause seizures
Analgesia is not entirely reversible by naloxoneAnalgesia is not entirely reversible by naloxone
Analgesia is not entirely reversible by naloxoneAnalgesia is not entirely reversible by naloxone
RD can be reversed (but naloxone increases the riskRD can be reversed (but naloxone increases the risk
of seizure) of seizure)
Avoid in patients with a history of addictionAvoid in patients with a history of addiction
Avoid with MAOIs/ drugs lowering seizure thresholdAvoid with MAOIs/ drugs lowering seizure threshold
MEPERIDINE (PETHIDINE)
MEPERIDINE (PETHIDINE)
A potentA potent μμ receptor agonist with LAreceptor agonist with LA propertyproperty
Constipation & urinary retention is less commonConstipation & urinary retention is less common
Analgesic potency; 1/8Analgesic potency; 1/8--1/10 of morphine1/10 of morphine
1/31/3rdrd as effective when given orallyas effective when given orally
1/31/3rdrd as effective when given orallyas effective when given orally
No longer recommended for chronic painNo longer recommended for chronic pain
Not to be used for >48 h; or in doses greaterNot to be used for >48 h; or in doses greater
than 600 mg/day than 600 mg/day
Produces less neonatal respiratory depressionProduces less neonatal respiratory depression
than morphine/methadone
Can block neuronal uptake of 5HTCan block neuronal uptake of 5HT
Should not be used with MAOIs (or atShould not be used with MAOIs (or at
least for 14d after discontinuation of least for 14d after discontinuation of MAOIs)
MAOIs) –– can causecan cause MAOIs)
MAOIs) –– can causecan cause
-- serotonin syndrome (if patient is onserotonin syndrome (if patient is on MAOIs)
MAOIs)
-- or features of acute pethidine overdoseor features of acute pethidine overdose (if patient is on pethidine)
FENTANYL
FENTANYL
Synthetic, MOR agonistSynthetic, MOR agonist
100 times more potent than morphine100 times more potent than morphine
Do not release histamineDo not release histamine
Commonly used in anaesthesia (rapid Commonly used in anaesthesia (rapid
Commonly used in anaesthesia (rapidCommonly used in anaesthesia (rapid
peak analgesia and rapid termination of peak analgesia and rapid termination of action after small bolus dosing; MAC
action after small bolus dosing; MAC
sparing effect; minimal CVS depression) sparing effect; minimal CVS depression)
Agonist/antagonists
Agonist/antagonists
Developed with the hope that they wouldDeveloped with the hope that they would
have less addictive potential and less RD have less addictive potential and less RD than morphine and related drugs
than morphine and related drugs
A "ceiling effect," limiting the amount ofA "ceiling effect," limiting the amount of
A "ceiling effect," limiting the amount ofA "ceiling effect," limiting the amount of
analgesia attainable, often is seen analgesia attainable, often is seen
PentazocinePentazocine andand nalorphine,nalorphine, can producecan produce
severe psychotomimetic effects severe psychotomimetic effects
Nalbuphine & butorphanolNalbuphine & butorphanol –– MORMOR
antagonist but KOR agonist antagonist but KOR agonist
PentazocinePentazocine –– weak MOR antagonist orweak MOR antagonist or
partial MOR agonist + KOR agonist partial MOR agonist + KOR agonist partial MOR agonist + KOR agonist partial MOR agonist + KOR agonist
BuprenorphineBuprenorphine –– partial MOR agonistpartial MOR agonist
(dissociates very slowly) + KOR antagonist (dissociates very slowly) + KOR antagonist
Pentazocine
Pentazocine
CNS effects similar to morphine (ceiling forCNS effects similar to morphine (ceiling for
RD effect) RD effect)
Higher doses can produce dysphoric andHigher doses can produce dysphoric and
psychotomimetic effects psychotomimetic effects
At high dosesAt high doses -- ↑ ↑ HR & BP due toHR & BP due to
At high dosesAt high doses -- ↑ ↑ HR & BP due toHR & BP due to
activation of supraspinal receptors activation of supraspinal receptors (reversed by naloxone)
(reversed by naloxone) -- avoid in IHDavoid in IHD
DoesDoes’’nt reverse morphine induced RD butnt reverse morphine induced RD but
can ppt withdrawal in morphine addicts can ppt withdrawal in morphine addicts
Nalbuphine
Nalbuphine
Similar to pentazocine but less likely toSimilar to pentazocine but less likely to
cause dysphoria and relatively safe in cause dysphoria and relatively safe in patients with stable IHD
patients with stable IHD
Show ceiling effect for analgesia & RDShow ceiling effect for analgesia & RD
Show ceiling effect for analgesia & RDShow ceiling effect for analgesia & RD
Can produce withdrawal in morphineCan produce withdrawal in morphine
dependent dependent
Abuse potential in nonusers is similar toAbuse potential in nonusers is similar to
pentazocine pentazocine
Butorphanol
Butorphanol
Best suited for relief of acute painBest suited for relief of acute pain
Cardiac effects are similar to pentazocineCardiac effects are similar to pentazocine
Available also as nasal formulationAvailable also as nasal formulation ––
useful for acute pain relief including useful for acute pain relief including useful for acute pain relief including useful for acute pain relief including migraine pain
migraine pain
Buprenorphine
Buprenorphine
2020--50 times more potent than morphine50 times more potent than morphine
but is a partial MOR agonist (limited IA) but is a partial MOR agonist (limited IA)
Analgesia longer and RD is slower and lastAnalgesia longer and RD is slower and last
longer than morphine longer than morphine longer than morphine longer than morphine
May produce withdrawal in dependentMay produce withdrawal in dependent
RD is not a problem (ceiling ??)RD is not a problem (ceiling ??)
Prior naloxone administration prevent RD,Prior naloxone administration prevent RD,
but RD not reversed once it has developed but RD not reversed once it has developed
Available as sublingual formulation alsoAvailable as sublingual formulation also
Can produce physical dependenceCan produce physical dependence
Injectable preparations are used asInjectable preparations are used as
analgesic analgesic analgesic analgesic
Oral formulation (alone or FDC withOral formulation (alone or FDC with
naloxone)
naloxone) –– is used for treatment of opioidis used for treatment of opioid dependence but has limited role in t/t of
dependence but has limited role in t/t of addicts who require high maintenance addicts who require high maintenance
dose of opioids (as it is a partial agonist) dose of opioids (as it is a partial agonist)
Antitussives
Antitussives
Among the most effective drug for coughAmong the most effective drug for cough
suppression suppression
Act at doses below those required toAct at doses below those required to
produce analgesia produce analgesia produce analgesia produce analgesia
Different opioid receptors may be involvedDifferent opioid receptors may be involved
MOA ??? both central & peripheral effectsMOA ??? both central & peripheral effects
e.g. dextromethorphan, noscapine,e.g. dextromethorphan, noscapine,
levopropoxyphene, codeine etc. levopropoxyphene, codeine etc.
Antidiarrheal
Antidiarrheal
Diphenoxylate: Diphenoxylate:
-- A meperidine congenerA meperidine congener
-- At therapeutic dosesAt therapeutic doses -- little or nolittle or no
morphine like effects morphine like effects morphine like effects morphine like effects
-- At high dosesAt high doses –– typical opioid effectstypical opioid effects -- Available only in combination withAvailable only in combination with
atropine sulfate atropine sulfate
Loperamide: Loperamide:
-- Slow motility by action on Sm muscles of GITSlow motility by action on Sm muscles of GIT -- May also reduce GI secretionMay also reduce GI secretion
Poorly absorbed from GIT, poor penetration Poorly absorbed from GIT, poor penetration
-- Poorly absorbed from GIT, poor penetrationPoorly absorbed from GIT, poor penetration
in CNS (efflux by P
in CNS (efflux by P--glycoprotein)glycoprotein)
-- Verapamil, quinidine enhance its CNS effectsVerapamil, quinidine enhance its CNS effects -- Even large doses do not produce pleasurableEven large doses do not produce pleasurable
effects of opioids effects of opioids
OPIOID ANTAGONOSTS
OPIOID ANTAGONOSTS
Bind competitively to opioid receptorsBind competitively to opioid receptors
Little or no intrinsic activityLittle or no intrinsic activity
Few effects in absence of agonist (exogenous)Few effects in absence of agonist (exogenous)
Visible effects in certain situations ie. Shock,Visible effects in certain situations ie. Shock,
Visible effects in certain situations ie. Shock,Visible effects in certain situations ie. Shock,
endogenous opioid system activated endogenous opioid system activated
No withdrawal syndrome on discontinuationNo withdrawal syndrome on discontinuation
No known abuse potentialNo known abuse potential
Naloxone
Naloxone
More selective forMore selective for μμ receptorsreceptors
Not given orallyNot given orally –– very high FPE in liververy high FPE in liver
Prevent/reverse effects of an agonistPrevent/reverse effects of an agonist
Respiration improves in minutes, reverseRespiration improves in minutes, reverse
Respiration improves in minutes, reverseRespiration improves in minutes, reverse
sedation, improves BP if depressed sedation, improves BP if depressed
Reverse psychotomimetic & dysphoricReverse psychotomimetic & dysphoric
effects of pentazocine (high dose needed) effects of pentazocine (high dose needed)
DOA depends on dose (1DOA depends on dose (1--4 h)4 h)
Uses:
Uses: opioid overdose; low dose (0.04 mg) to treatopioid overdose; low dose (0.04 mg) to treat ADRs associated with iv/epidural opioids, prevent ADRs associated with iv/epidural opioids, prevent RD in neonates
RD in neonates
Naltrexone:Naltrexone: active by oral route; longer actingactive by oral route; longer acting
(~24h); more potent than naloxone; may produce (~24h); more potent than naloxone; may produce (~24h); more potent than naloxone; may produce (~24h); more potent than naloxone; may produce hepatotoxicity
hepatotoxicity
Uses:
Uses: -- treatment of alcohol dependencetreatment of alcohol dependence
-- prevention of relapse to opioid dependence,prevention of relapse to opioid dependence, following opioid detoxification
following opioid detoxification
-- available also as ER injectable suspensionavailable also as ER injectable suspension (i.m.) given every 4 weeks (380 mg)
Methylnaltrexone bromide:Methylnaltrexone bromide: blockblock
peripheral
peripheral μμ receptors in gut, poor CNS receptors in gut, poor CNS penetration;
penetration; Use: opioid
Use: opioid--induced constipation ininduced constipation in Use: opioid
Use: opioid--induced constipation ininduced constipation in patients with advanced illness, when patients with advanced illness, when
response to laxative therapy inadequate response to laxative therapy inadequate Dose 8
Dose 8--12mg s.c every other day12mg s.c every other day
Alvimopan:Alvimopan: accelerate the time to GIaccelerate the time to GI
recovery following partial bowel resection recovery following partial bowel resection surgery (for hospital use only)
surgery (for hospital use only) Peripherally acting μ
Peripherally acting μ--opioid receptoropioid receptor Peripherally acting μ
Peripherally acting μ--opioid receptoropioid receptor antagonist
antagonist
Nalmefene:Nalmefene: relatively pure MORrelatively pure MOR
antagonist; more potent; longer acting; antagonist; more potent; longer acting; used i.v.
