OPIOIDS (Analgesic Agents)

Resident: B.Ankhzaya (MNUMS)

Content

1. History
2. Classification
• Endogenous opioid
• Exogenous opioid
3. Opioid Mechanism of Action
4. Drugs
 HISTORY

• Opium is among the oldest drugs in the world. (Fossilized opium poppies
have been found in Neanderthal excavation sites dating back to 30,000
bce).
• German pharmacist and chemist Friedrich Sertürner isolated a stable
alkaloid crystal from the opium sap and named it “morphine” after the
Greek god of dreams, Morpheus
• American Civil War
• The synthesis of heroin in 1874
• In 1937, meperidine (pethidine) became the first synthetic opioid
synthesized based on the central structure of morphine. Since then, many
synthetic and semisynthetic opioids have been produced, including the
clinically important opioid antagonists naloxone and naltrexone.
MECHANISM OF OPIOID ANALGESIA
 THE ENDOGENOUS OPIOID SYSTEM

1. Endogenous opioid peptides

• Endorphins (B-endorphin- MOR)
• Enkephalins (met and leu-enkephalin-KOR)
• Dynorphins ( Dynorphin A - DOR)

2. Opioid receptors (µ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-

opioid receptor (DOR), and orphanin FQ/nociception (NOP) receptor)
At least three MOR subtypes have been described:
• µ1 is predominantly involved in opioid analgesia,
• µ2 is involved in opioid-induced respiratory depression
• µ3 is involved in opioid-induced immune suppression.
 CLASSIFICATION OF EXOGENOUS OPIOIDS

Synthesis
Natural (known as opiates) morphine
Semisynthetic (derived from the morphine codeine, heroin, hydromorphone,
molecule) oxycodone, oxymorphone
Synthetic meperidine, alfentanil, fentanyl,
sufentanil, remifentanil

Potency (all may potentially produce serious side effects, including sedation,
respiratory depression, hypotension, or bradycardia)
Weak codeine, dextropropoxyphene, tramadol,
hydrocodone
Medium: morphine, methadone, oxycodone,
hydromorphone
Strong: fentanyl, sufentanil, alfentanil,
remifentanil
Effect at Opioid Receptor
Full agonists: morphine, methadone
Partial agonists: buprenorphine at MOR
Antagonists: naloxone, naltrexone
Onset and Offset of Action
Rapid: remifentanil, alfentanil

Slow: morphine, buprenorphine

PHARMACOKINETICS
 MORPHINE

• Tabulet-5,10,15, 30, 50, 60,100,

200 mg
• Solution-5, 20,25,50mg/ml
• Oral solution -10mg/5ml (100ml)
• Suppositories- 5mg

• IV ,IM, Orally, Subcutaneously,

rectaly , epidurally and
intrathecally
 Dose

IM 0,05-0,2 mg/kg peak plasma levels usually reached after

20–60 min and duration of action is 3-4
hours
IV 0,03-0,15 mg/kg usually 1-2mg boluses, The onset of action
is slightly more rapid with following IV
administration.
Single epidural dose 5–15 mg the effects of which persist for 48 h.

Intrathecally 0.1 and 0.5 mg provide 12–18 hours of analgesia

 Pharmacokinetics

• Morphine is extensively metabolized by the gut wall and the liver to

morphine-3-glucuronide (M3G) (70%), morphine-6 glucuronide (M6G)
(10%) and to sulphate conjugates. M6G is 10-20 times more potent than
morphine and is normally excreted in urine.

• It accumulates in renal failure and accounts for increased sensitivity to

morphine.

• Neonates are more sensitive than adults to morphine due to reduced hepatic
conjugating capacity.

• In the elderly, owing to reduced volume of distribution, peak plasma level of

morphine is higher compared to younger patient.
 Effect of Organ systems

CNS good sedative and anxiolytic properties,

euphoria, dysphoria and hallucination
RS respiratory depression and cough
suppression.
CVS It has minimal effect on cardiovascular
system and may produce bradycardia and
hypotension
GIS Nausea and vomiting are common side-
effects. Constipation , less movement of
GIT
EYE Meiosis is common
Others Histamine release may lead to rash,
itching and bronchospasm (in susceptible
patients)
Tolerance and dependence may develop.
 PAPAVERETUM

• Mixture of hydrochloride salts of

opium alkaloids: morphine
hydrochloride, codeine hydrochloride
and papaverine hydrochloride

• 15,4 mg Papaveretum contains 13,16

mg morphin hydrochloride, 1,04 mg
codeine hydrochhloride, 1,2 mg
papaverine hydrochloride
• Subcutaneously, IM, IV

CNS Severe headache (high doses)

In comparison with morphine, it provides
greater degree of sedation for a given
level of analgesia
GIS fewer gastrointestinal side-effects..
 CODEINE

• Orally and IM
• The dose for an adult is 30-60mg
by either route and can be
repeated at 6 hour intervals, if
required.
• Varying doses of codeine (8-
30mg) are commonly
incorporated with NSAIDs in
compounds employed in the
treatment of mild to moderate
pain.
• Codeine is also used in antitussive
and antidiarrhoeal preparations.
 Effect of organ system

CNS • little euphoria

• minimal pain relief.
• It may cause disorientation and
excitement
GIS • Constipation is common side effect.
RS • less likely to cause respiratory
depression than morphine.
 DIAMORPHINE (heroin)

• 5 , 30 mg powder
• It is 1.5-2.0 times more potent
than morphine.
• It is a pro-drug and is converted to
the active components of
acetylmorphine and morphine by
esterases in the liver, plasma and
central nervous system.
 Dose
• Diamorphine can also be given by
the same routes as morphine in
approximately half the dose. Due to
its higher lipid solubility, it is less
likely than morphine to cause
delayed respiratory depression when
used epidurally or intrathecally.
• It can be administered as
hydrochloride salt by IM or SC
infusion in a smaller volume of
solution than an equivalent dose of
morphine. This is an important
consideration for patients with
terminal malignant disease who may
require large doses of opioid for
pain relief
Pharmacokinetics
• Diamorphine is 200 times more lipid
soluble than morphine and, therefore,
passes more rapidly across the blood-
brain barrier into the CNS where it is
converted to morphine.
• Therefore, it has more analgesic
potency and a more rapid onset of
action than morphine.
• Because of the extensive first pass
metabolism, it has low bioavailability.
Effects
• It shares common opioid effects with
morphine. It is associated with an
increased euphoria
• May cause less nausea and vomiting
than morphine.
 PETHIDINE (meperidine)

• Tabulettas-50 or 100 mg
• Solution -10mg/ml or 50mg/ml ,
100mg/ml
Doses: (acute pain)
• IM: 50-100mg
• IV: 25-100mg
• SC: 50-100 mg
• Orally: 50-150 mg
The doses can be repeated every 4
hours.
 Pharmacokinetics

• Pethidine is 30 times more lipid soluble than morphine.

• Oral bioavailability is 50%.
• It is metabolized in the liver by ester hydrolysis to
norpethidine and pethidinic acid that are excreted in the urine
and therefore accumulate in renal failure.
• Pethidinic acid is an inactive compound.
• At higher concentration, norpethidine can produce
hallucination and convulsions.
• Pethidine is often used for labour analgesia. It readily crosses
the placenta, and a significant amount reaches to the foetus
over several hours.
 Effect of Organ system

CNS Serious side effects like hypotension or

hypertension, hyperpyrexia, convulsion and
coma may occur.

CVS Tachycardia, However as is the case with

morphine, a significant decrease in BP may
occur when pethidine is administered to elderly
or hypovolaemic patients.

GIS Dry mouth , It may produce less biliary tract

spasm than morphine.

EYE Meiosis is less

 FENTANYL

• It is a synthetic
phenylpyperidine derivative
and is 100 times more potent
than morphine.
• Fentanyl is available as a
colourless solution for
injection
• 2,5,20,50 ml (50mcg of 1ml )
 Dose

IV Intraoperative IV 2–50 mcg/kg (rapid onset 1-3 min and

anesthesia a short duration of action 30 minutes)

Postoperative IV 0.5–1.5 mcg/kg

analgesia

Spinal analgesia Local anaesthetics 10-25mcg

Epidural analgesia 25-100mcg

transdermal patch chronic pain conditions and as a lollipop to premedicate children

 Pharmacokinetics

• Fentanyl is 500 times more lipid soluble than morphine, consequently it is

rapidly and extensively distributed in the body (volume of distribution
4l.kg-1).
• At small doses (1-2mcg.kg-1), plasma and CNS concentrations may
decrease quickly to below an effective level during the rapid distribution
phase.
• However, following prolonged administration or with high doses, its
duration of action is significantly prolonged. In these circumstances, the
distribution phase is complete while the plasma concentration is still high.
• Fentanyl, alfentanil, sufentanil, and remifentanil are lipophilic opioids that
rapidly cross the blood–brain barrier.
• Fentanyl, alfentanil, and sufentanil are metabolized by the liver catalyzed
by the cytochrome P450 enzyme system. The major metabolite of fentanyl
is the inactive compound norfentanyl

• Recovery from the effect of the drug then depends on its slow elimination
from the body (terminal half life 3.5 hours).

• Fentanyl is predominantly metabolized in the liver to norfentanyl which is

inactive. The metabolite is excreted in the urine over a few days

• Serum concentrations of fentanyl reach a plateau within 14–24 h of

application (with peak levels occurring after a longer delay in elderly than
in younger patients) and remain constant for up to 72 h.
 Effect of organ system

• Many properties of fentanyl are similar to morphine.

• Higher doses are used to obtund sympathetic response to laryngoscopy and
intubation.
• Large doses (50- 100 microgram/kg) have been used for cardiac surgery to obtund
metabolic stress response. At such high doses, sedation is profound and
unconsciousness may occur. In addition, muscular rigidity of the chest wall may
affect ventilation.

CNS • In small doses it has little sedative

effect.

RS • It produces respiratory depression in a

dose-dependent manner.
 ALFENTANIL

• Alfentanil is a synthetic
phenylpiperidine derivative
structurally related to fentanyl; it
has 10-20% of its potency.
• It may be administered
intravenously as either a bolus or
continuous infusion.
Effects
Most effects of alfentanil are similar
to fentanyl but with quicker onset and
shorter duration of action.
 Dose

IV Intraoperative 8–100 mcg/kg

anesthesia
Loading dose

Maintenance 0.5–3 mcg/kg/min used in the intensive

infusion IV care unit for sedation
in patients on
mechanical
ventilation.
Bolus doses 10mcg.kg useful for short term
analgesia and
attenuation of the
cardiovascular
response to
intubation
 Pharmacokinetics

• Although it has much lower lipid solubility than fentanyl, the

lower pKa of alfentanil (6.5 versus 8.4 for fentanyl) means that
more alfentanil is present in the unionized form compared to
fentanyl (89% compared to 9%). Consequently, its onset of
action is more rapid.
• Because of its lower lipid solubility, less alfentanil is
distributed to muscles and fat. Hence, its volume of
distribution is relatively small and more of the dose remains in
blood from which it can be cleared by the liver.
 REMIFENTANIL

• It is a synthetic phenylpiperidine
derivative of fentanyl with similar
potency but is ultra short-acting
• which is 100–200 times more
potent than morphine

• It is available as white crystalline

powder in glass vial containing 1,
2 or 5mg remifentanil
hydrochloride.
 Dose

IV Intraoperative anesthesia 1.0 mcg/kg

Loading dose

Maintenance infusion IV 0.5–20 mcg/kg/min

Postoperative 0.05–0.3 mcg/kg/min

analgesia/sedation
 Pharmacokinetics

• Remifentanil is rapidly broken down by non-specific plasma

and tissue esterases resulting in a short elimination half life (3-
10 minutes).
• It is context insensitive, in that the half life, clearance and
distribution are independent of duration and strength of
infusion.
• Remifentanil contrasts with the other piperidines in that it is
not metabolized in the liver (contains a methyl ester side chain
that is metabolized by within the erythrocyte and by tissue
nonspecific esterases)
 Effects

• Certain properties of remifentanil like rapid onset, rapid offset,

organ independent metabolism and lack of accumulation make
it suitable for use during various surgical procedures.
However, it should be used cautiously at higher rates of
infusion as serious side effects for example bradycardia,
hypotension, apnoea and muscle rigidity may occur.
• REMIFENTANIL FOR OBSTETRIC LABOR PAIN(bolus doses
of 20 to 40 µg with a 3-minute lockout period may provide
analgesia when an epidural is not available
 TRAMADOL

• Tramadol is phenylpiperidine
analogue of codeine. It is weak
agonist at all opioid receptors with
20-fold preference for MOP
receptors. It inhibits neuronal
reuptake of norepinephrine.
• It potentiates release of serotonin
and causes descending inhibition
of nociception.
• Oral and parenteral dosage
requirements are similar, 50-
100mg 4 hourly.
Pharmacokinetics
Absorption Tramadol has high oral bioavailability
of 70% which can increase o 100%
with repeated doses due to reduction
in first pass effect. It is 20% bound to
plasma proteins.
Distribution Its volume of distribution is 4l.kg-1

Metabolism It is metabolized in the liver by

demethylation into a number of
metabolites - only one of them (O-
desmethyltramadol) has analgesic
activity.
Excretion Its elimination half-life is 4-6 hours.
PARTIAL OPIOID AGONIST

Mixed • Pentazocine
agonist- • Nalbuphine
antagonist • Meptazinol

• Buprenorphine
Agonist
 PENTAZOCINE

• 3%-1ml ampoules
• KOR,DOR –agonist ,MOR-
antagonist
• HR, BP increases
• Nausea, vomiting,
hallucination are more
common than morphine
 OPIOID-INDUCED RESPIRATORY DEPRESSION

PATIENTS AT HIGHER RISK FOR OPIOID RELATED RESPIRATORY

DEPRESSION
Obese
Central or peripheral hypopneic and apneic periods during sleep

Neuromuscular disorders

Premature neonates

Chronic opioid users

Elderly patients
 GENDER DIFFERENCES

• Women have a greater analgesic effect from PCA than men

• This is best explained by a difference in morphine potency with greater
potency in women coupled to a slower onset and offset of the drug in
women. As a consequence, morphine takes longer to induce adequate
analgesia in women; a speedier effect is observed in men.
• Because of the lower potency in men, they require multiple additional
morphine administrations; women require fewer additional doses.
• Similar to analgesia, there are gender-related differences in opioid-induced
respiratory depression and nausea and vomiting, with greater effects
observed in women than men.
 OPIOID ANTAGONIST (NALOXONE)

• Naloxone is a pure opioid agonist and

will reverse opioid effects at MOP,
KOP and DOP receptors,
• The usual dose is 200-400mcg
intravenously, titrated to effect.
• Smaller doses (0.5-1.0mcg.kg-1) may
be titrated to reverse undesirable
effects of opioids, for example itching
associated with the intrathecal or
epidural administration of opioids,
without significantly affecting the
level of analgesia.
• The duration of effective antagonism
is limited to around 30 minutes and
therefore longer acting agonists will
outlast this effect and further bolus
doses or an infusion (5-10mcg.kg-1.h-
1) will be required to maintain
reversal.
 NALTREXONE

• Naltrexone has similar mechanism

of action, but has few
pharmacokinetic advantages
compared to naloxone. It has a
longer half-life and is effective
orally for up to 24 hours. It has
been used to treat opioid addiction
and compulsive eating with
morbid obesity.
WEBLINKS:

1. file:///D:/My%20lessons/Anasthesiology%20Residency%201st/Resident%
20Ankhzaya's%20files/Books%20of%20Anesthesiology/Morgan%205th
%20Edition.pdf
2. http://www.e-safe-
anaesthesia.org/e_library/03/Opioid_pharmacology_Update_2008.pdf
3. file:///D:/My%20lessons/Anasthesiology%20Residency%201st/Resident%
20Ankhzaya's%20files/Books%20of%20Anesthesiology/Barash's%20Han
dbook%20of%20Clinical%20Anesthesia%207th%20Edition.pdf