OPIOIDS

PAIN AND ANALGESICS

• Pain: ”an
unpleasant sensory and
emotional experience with
actual or potential tissue
damage or described in terms of
such damage” (International
Association for the Study of
Pain, 1979)

• Analgesia: absence of pain,

without loss of consciousness
 PAIN AND ANALGESICS:
IMPORTANT TERMS
 ANALGESICS = drugs which selectively relieve pain, by acting in the CNS
or in the peripheral pain mechanisms, without significantly altering
consciousness (opioids and NSAIDs)

 OPIOIDS = drugs which bind to the opioid receptors in the CNS and
produce morphine-like effects, blocked by opioid antagonists. They may be
natural, synthetic and semisynthetic

 OPIATES = natural alkaloids derived from the resin of the opium poppy or
semisynthetic substances directly derived from these alkaloids

 NARCOTICS = drugs derived from opium or opium like compounds, with

potent analgesic effect associated with sedative effect (significant
alteration of mood and behavior; induction of sleep) and the potential for
dependence and tolerance following repeated administration
 PAIN AND ANALGESICS:
IMPORTANT CONSIDERATIONS

Not all pains are the same

Not all patients have the same pain sensitivity

Not all patients have the same pain relief from opioids

Not all patients have the same side effects of opioids

Not all opioids are the same

PAIN CLASSIFICATION

Duration: Pathology:
Acute pain Malignant
Chronic pain Non-malignant

Pathophysiology:
Tissue:
Inflammatory
Nerve
Viscera Neuropathic
Joints Idiopathic Topography
Bone Extremity
Skin Thoracic
Spinal
Localization: Head
Superficial
Deep
 PAIN CLASSIFICATION
 BY SOURCE

VASCULAR: from vascular or perivascular tissues

NEUROPATHIC: from injury to peripheral nerve fibers or damage to CNS

SUPERFICIAL: from skin or mucous membranes

 BY ETIOLOGY

NOCICEPTIVE: results from activation of sensory receptors (nociceptors) by

chemical, thermal or mechanical stimuli [functional, physiologic or ‘normal’ pain
High sensitivity to NSAIDs and OPIOIDS. Reduced over time.

NEUROPATHIC: results from damage to peripheral nerves or CNS tissues or

from altered processing of pain in CNS. Does not respond to NSAIDs and
OPIOIDS treatment; long lasting pain.
 THE GATE CONTROL THEORY OF PAIN

MOST COMMON AND WELL DESCRIBED THEORY, USES THE ANALOGY OF

A GATE TO DESCRIBE HOW AN IMPULSE FROM DAMAGED TISSUE IS
SENSED IN THE BRAIN:

Release of: Stimulation of pain-receptive

Tissue •Bradykinin nerve endings, or
injury •Histamine NOCICEPTORS,
•Prostaglandins starting the pain process
•Potassium
•ATP
•Lactic acid Aδ FIBERS C FIBERS
 THE GATE CONTROL THEORY OF PAIN

Aδ FIBERS C FIBERS Aβ FIBERS

•Myelin sheath • No myelin sheath •Large-diameter fibers

•Large and thick fibers • Small fiber size •Non-nociceptive

(do not transmit pain
•Conduct fast • Conduct slowly stimuli)

•Sharp and well-localized • Dull and non-localized •Inhibit the effects of

acute pain long-term chronic pain firing by Aδ and C fibers

TYPES OF PAIN IS RELATED TO PROPORTION OF Aβ TO Aδ and C

FIBERS IN THE DAMAGED AREA
 THE GATE CONTROL THEORY OF PAIN
Aδ and C fibers enter the spinal cord of the DORSAL HORN

THE DORSAL HORN IS THE LOCATION OF THE ‘GATE’:

Regulates the flow of sensory impulses to the brain

Closing the gate stops impulses transmission to the CNS  NO PAIN PERCEPTION

ACTIVATION OF LARGE NON- ACTIVATION OF SMALL NOCICEPTOR

NOCICEPTOR Aβ FIBERS CLOSES THE C FIBERS OPENS THE GATE,
GATE, INHIBITING IMPULSE ALLOWING IMPULSE TRANSMISSION
TRANSMISSION TO THE BRAIN AND TO THE BRAIN AND GIVING
PERCEPTION OF PAIN PERCEPTION OF PAIN

Cells that control the gate have an action potential threshold: impulses must
overcome this threshold to be sent to the brain

If other stimuli besides pain are transmitted, the gate through which pain stimuli must
travel is temporarily blocked  THE BRAIN IS UNABLE TO RECEIVE PAIN STIMULI
WHEN INTERPRETING OTHER STIMULI
PAIN TRANSMISSION: THE GATE THEORY

Aβ fibers
OPEN GATE:
C fiber blocks inhibitory action of
Inhibitory


Projection
interneuron neuron interneuron and pain stimulus
.
projection to the brain can occur
C fibers

Aβ fibers CLOSED GATE:

Aβ fiber stimulates inhibitory
Inhibitory
interneuron
Projection
neuron
interneuron which in turn blocks
pain stimulus projection to the brain
C fibers

PAIN TRANSMISSION DEPENDS ON THE RELATIVE

RATES OF FIRING OF C AND Aβ FIBERS
 PAIN PATHWAY
FOUR PROCESS:

TRANSDUCTION: noxious stimuli

are translated into electrical activity at
sensory nerves endings (Aδ and C
fibers)

TRANSMISSION: propagation of
impulses

MODULATION: modification of this

propagation

PERCEPTION: elaboration of these

stimuli in the brain, adding an affective
and motivational aspect

EACH OF THESE PROCESSES IS A POTENTIAL

TARGET FOR ANALGESIC THERAPY
 PAIN PATHWAY 1.: TISSUE DAMAGE
TRANSDUCTION
 Mechanical damage
1. Tissue injury  Extreme temperature
 Chemical irritation

2. Release of chemical mediators and enzymes that

alter the activity and sensitivity of sensory neurons
(Prostaglandins, Leukotrienes, Bradykinin, Histamine)

3. Result
– Increase in nociceptor activity
– Hyperalgesia
– Neurogenic inflammation
 PAIN PATHWAY 2.: TRANSMISSION
THE ASCENDING PATHWAY

Start from terminals of primary afferent sensory neurons:

– Aδ: first pain felt; fast conducting; localized pain;
neurotransmitter: glutamate
– C: slow conducting; second pain; dull, deep and throbbing pain;
neurotransmitter: substance P
Higher threshold compared to Ad, reduced by noxious stimuli
 PAIN PATHWAY 2.: TRANSMISSION
ASCENDING AND DESCENDING PATHWAY
 PAIN PATHWAY 3.: MODULATION
DESCENDING INHIBITORY PATHWAY

EXERTS AN INHIBITORY EFFECT ON PAIN TRANSMISSION

NERVE FIBERS FROM THE BRAIN INNERVATE THE GATE

THE BRAIN EXERTS SOME CONTROL OVER THE GATE:

- Evaluate, identify, localize the pain

- Control the gate before it is open

Involved neurotransmitters are

NE and 5-HT
 PAIN PATHWAYS

ASCENDING NOCICEPTIVE PAIN PATHWAY

Injury  activation of primary afferent nociceptor
information to the dorsal horn of spinal cord
 activation of second order neurons.
Axons of SON form an ascending tract
brainstem and several areas of the thalamus
higher neurons that project to to various cortical
regions.

DESCENDING IHIBITORY/ANTINOCICEPTIVE
PATHWAY
Frontal cortical areas, hypothalamus, amygdala
 midbrain periacqueductal grey
 control of pain transmission in the dorsal horn.
 PAIN PATHWAY 4.: PERCEPTION
Physical and emotional process, involving psycological and cultural aspects, like
memory and learning

From the dorsal horn, pain stimuli travel upward to the THALAMUS
The dorsomedial nucleus of the thalamus projects to the BRAIN

CONSCIOUS PERCEPTION of pain takes place in the thalamus

SUBJECTIVE INTERPRETATION of pain is the role of the cerebral cortex
(Emotional response: fear, anxiety and panic)
PHARMACOLOGICAL TREATMENT OF PAIN
PHARMACOLOGICAL TREATMENT OF PAIN
 THE WORLD HEALTH ORGANIZATION LADDER FOR
CHRONIC CANCER PAIN MANAGEMENT

Freedom from cancer pain

Opioids for moderate to severe pain

(MORPHINE, METHADONE, FENTANYL) 3. SEVERE
± non-opioid; ± adjuvants

Pain persisting or increasing

Opioid for mild to moderate pain
(CODEINE, TRAMADOL)
2. MODERATE
± non-opioid, ± adjuvants

Pain persisting or increasing

Non-opioid (NSAIDs: ASA, PARACETAMOL) 1. MILD

± adjuvants

[ADJUVANT ANALGESIC = medication that is not primarily designed to control pain but can be used for
this purpose. They may also be called coanalgesics; usually are antidepressants and anticonvulsants]
THE WORLD HEALTH ORGANIZATION LADDER FOR
CHRONIC CANCER PAIN MANAGEMENT

INVASIVE INTERVENTIONS

OPIOIDS SWITCHING/
5%
ADMINISTRATION ROUTE CHANGE

10-20%
3. SEVERE

2. MODERATE
75-85%
1. MILD
 OPIOIDS: HISTORY

OPIUM=dark brown
resinous material obtained
from poppy (Papaver
somniferum) capsules

• Oldest drugs known to mankind: Sumer 4000 BC

• Used for asthma, bad eyesight, diarrhoea and as euphoriants

• 1806: isolated the crystalline pure substance from opium poppy (Papaver
somniferum) and named morphine (Morpheus - Greek god of dreams)

• 1950: Arnold Beckett proposed that morphine-like compounds act by

binding to specific receptors in the brain, the endogenous opiod peptides
receptors
 OPIOID ANALGESICS

PAIN RELIEVERS THAT CONTAIN OPIUM, DERIVED FROM

THE OPIUM POPPY, OR CHEMICALLY RELATED TO OPIUM

MAIN THERAPEUTIC USE:

TO ALLEVIATE MODERATE TO

SEVERE PAIN

Cough center suppression

Treatment of diarrhea
 OPIOID ANALGESICS

A drug that activates some or all opioid

Opioid agonist
receptor subtypes and does not block any
A drug that blocks some or all opioid
Opioid antagonist
receptor subtypes
A drug that activates some opioid receptor
Mixed agonist-antagonist subtypes and blocks other opioid receptor
subtypes
 OPIOID ANALGESICS
MECHANISM OF ACTION:
bind to opioid receptors, resulting in pain impulse transmission and perception inhibition

OPIOID RECEPTORS CLASSIFICATION:

LOCATION CLINICAL EFFECTS

µ (‘mu’ or MOP) brain, spinal cord, mesenteric
[2 SUBTYPES] plexus, peripheral neurons,
inflammed tissues, immune cells,
respiratory and GI tract
Supraspinal analgesia, mood alteration
(euphoria/sedation), miosis,
respiratory depression,
nausea, vomiting, reduced GI motility
tolerance and physical dependence

δ (‘delta’ or DOP) brain, mesenteric plexus Spinal analgesia, affective behaviour,

[2 SUBTYPES]
decreased colonic transit time, release
of growth hormones, proconvulsant,
cardiovascular depression
κ (‘kappa’ or KOP) brain, spinal cord, mesenteric Spinal analgesia, sedation, dysphoria,
[3 SUBTYPES] plexus, miosis, decreased colonic transit time,
respiratory depression
 OPIOID RECEPTORS IN DORSAL HORN:
OPIOID ANALGESICS AGONIST MECHANISM OF ACTION

 Activation of µ,κ, and δ

receptors on presinaptic end of AFFERENT NOCICEPTIVE FIBER
an afferent nociceptive fiber
reduces accitatory
neurotransmitter release to
postsynaptic projection neuron

 Activation of µ receptor on
postinaptic neuron in the
dorsal horn induces IPSP and
no trasmission to neurons that (Glutamate, etc.)
projet to the cortical region µ,d,κ receptors

µ receptors
DORSAL HORN
NO PAIN PERCEPTION
 MECHANISM OF ACTION OF µU-OPIOID RECEPTOR
AGONISTS IN THE SPINAL CORD

Opioid receptors are coupled with inhibitory G-proteins and their

activation has a number of molecular effects, including:
closing of voltage sensitive calcium channels
 stimulation of potassium efflux leading to hyperpolarization

reduction in neuronal cell excitability that in turn results in

reduced transmission of nociceptive impulses.

 Pure opioid agonists (morphine, diamorphine, pethidine and

fentanyl) bind to opioid receptors avidly and demonstrate high
intrinsic activity at the cellular level

 Partial opioid agonists (buprenorphine, pentazocine), bind to

opioid receptors but produce a sub-maximal effect compared
to pure agonists

• Opioid antagonists (naloxone, naltrexone), have receptor

affinity but no intrinsic activity.
 MECHANISM OF ACTION OF OPIOID
RECEPTOR ANTAGONISTS AND AGONISTS
Named using the first letter of the first ligand that was found to bind to them:
Morphine was the first chemical shown to bind to "mu" receptors (M rendered as the
corresponding Greek letter μ)
Ketocyclazocine was first shown to attach itself to "κ" (kappa) receptors
The "δ" (delta) receptor was named after the mouse vas deferens tissue in which it
was first characterized
Consist of an extracellular N-terminus, 7 trans-membrane helices, 3 extracellular
loops, 3 intracellular loops, and an intracellular C-terminus.

Agonist binding  conformational change

 active conformation, driven by intermolecular
rearrangement between the trans-membrane helices

Antagonist drug binds to the opioid receptors with

higher affinity than agonists  BUT no conformational
change which rearranges the trans-membrane helices
 NO receptor activation
 OPIOID RECEPTORS
CNS distribution is not uniform: they are at areas concerned with pain

•cerebral cortex
•pontine nuclei
•amygdala
•olfactory bulbs
•thalamus
•hypothalamus
•midbrain: periaqueductal gray
•spinal cord: substantia gelatinosa

•peripheral sensory neurons

 ENDOGENOUS OPIOID PEPTIDES

ENDOGENOUS NEUROTRANSMITTERS THAT BIND TO OPIOID

RECEPTORS AND INHIBIT TRANSMISSION AND RECOGNITION OF
PAIN, BY CLOSING GATE  MORPHINE LIKE ACTIVITY, TO FIGHT
PAIN

THREE DISTINCT FAMILIES OF PEPTIDES HAVE BEEN IDENTIFIED: THE

ENKEPHALINS, THE ENDORPHINS, AND THE DYNORPHINS

EACH FAMILY DERIVED FROM A DISTINCT PRECURSOR POLYPEPTIDE:

 PROENKEPHALIN (PROENKEPHALIN A)  ENKEPHALINS
 PROOPIOMELANOCORTIN (POMC)  ENDORPHINS
 PRODYNORPHIN (OR PROENKEPHALIN B)  DYNORPHINS
 ENDOGENOUS OPIOID PEPTIDES

ENKEPHALINS
Bind to δ-opioid receptors and are involved in nociception

ENDORPHINS
Are produced by hypothalamus and pituitary gland, involved in
analgesia and well-being (during exercise, crying, spicy food
consuption); bind to µ-receptors

DYNORPHINS
Bind to k-receptors, implicated in analgesia, appetite regulation,
control of the circadian rhythm
 ENDOGENOUS OPIOID PEPTIDES
ENKEPHALINS

 5 amino acids long neuromodulators (pentapeptides)

 Discovered 1975, two main forms have been found:

 Met-enkephalin (methionine at 5' position): Tyr-Gly-Gly-Phe-Met
 Leu-enkephalin (leucine at 5' position): Tyr-Gly-Gly-Phe-Leu

 Proenkephalin gene codes for a peptide 276 amino acid long

 Cleavage of proenkephalin A gives 4 copies of [Met]-enkephalin and 1 copy

of [Leu]-enkephalin (also produced, in 3 copies for cleavage, from
prodynorphin, or proenkephalin B)
 ENDOGENOUS OPIOID PEPTIDES
ENDORPHINS

 30 amino acid long peptides, acting as neurohormones:

 α-endorphins
 β-endorphins
 γ-endorphins
 Last 5 amino acids are the same sequence as enkephalins
 γ-endorphins are cleaved from proopiomelonocortin (POMC)
 POMC is processed into melanocyte-stimulating hormone
(γ-MSH), adrenocorticotropin (ACTH) and lipotropin (β-LPH)
 Within the 91-amino-acid sequence of β-LPH are found
β-endorphin and β-MSH
 Conservation between species, with little difference in humans
 ENDOGENOUS OPIOID PEPTIDES

DIFFERENCES BETWEEN NEUROTRANSMITTERS, NEUROMODULATORS

AND NEUROHORMONES

NEUROTRANSMITTER = molecule stored in vesicles and released in response to

an increase in intracellular Ca2+, allowing electrical signals to be transmitted to the
postsynaptic neuron or effector target cells.

NEUROHORMONE = messenger that is released by neurons into the haemolymph

and which may therefore exert its effects on distant peripheral targets

NEUROMODULATOR = messenger released from a neuron in the central nervous

system, or in the periphery, that affects groups of neurons, or effector cells, that have
the appropriate receptors. It often acts through second messengers and can produce
long-lasting effects. The release may be local so that only nearby neurons or effectors
are influenced, or may be more widespread (in this case the distinction with a
neurohormone can become very blurred)
 CLASSIFICATION OF OPIOIDS
MORPHINE 9-14%
• NATURAL: PHENANTHRENE CODEINE 0,5-2%
THEBAINE 0,2-1%

• SEMISYNTHETIC:
– heroin (diacetylmorphine)
– oxycodone
– oxymorphone
– hydromorphone

• SYNTHETIC:
– pethidine (meperidine)
– methadone
– tramadol
– benzomorphans
– fentanyl, alfentanil, sufentanil, remifentanil
SUMMARY OF OPIOID ANALGESIC AND ANTAGONISTS

OPIOID ANALGESICS AND ANTAGONISTS

Strong agonists Mixed agonist-antagonists

and partial agonists
Alfentanil Buprenorphine
Fentanyl Butorphanol
Heroin Nalbuphine
Meperidine Pentazocine
Methadone
Morphine
Oxycodone Antagonists
Remifentanil
Sufentanil Nalmefene
Naloxone
Naltrexone
Moderate/low agonists
Other analgesics
Codeine
Propoxyphene Tramadol

(according to Lippincott´s Pharmacology, 4th ed., 2009)

 OPIOIDS CHEMISTRY
BENZOMORPHANS

Phenanthrene
 MORPHINE

CHEMISTRY A
E B
D
• Pentacyclic alkaloid (five rings structure) C

• Three major rings (a, b, c)

• Oxygen bridge at 4,5 position
• Phenolic groups (-OH) at position 3 and 6
• Modifications at those positions change pharmacokinetics
and potency of drug
• Nitrogen at 17 position (N17-Methyl group): changing it by
adding an alkyl group converts morphine to naloxone (i.e.
from an agonist to an antagonist)
 MORPHINE PHARMACOKINETICS
ABSORPTION
Can be taken orally, sublingually, rectally, subcutaneously, intranasally, intravenously,
intramuscularly
Readily absorbed from GI tract, nasal mucosa, lung
Accumulates in kidney, liver and spleen; enters brain slowly
CNS is primary site of action (analgesia/sedation)
Readily crosses placental barrier ( dependence in fetus)

METABOLISM/EXCRETION
metabolic transformation in liver:
conjugation with glucuronic acid:
M3G (no analgesic effect)
M6G (half as potent as morphine)
excreted by kidney
half life: 2/3 hours
lose 90% in first day
 MORPHINE ADMINISTRATION

•Not given orally, due to poor oral biavailability

(extensive first-pass metabolism)
•Significantly variable first pass effect from person to
person and interspecies variable effect
•Acts promptly and its main effects involve the CNS:
 analgesia
 sedation
 euphoria
 mood change
 mental cloudiness
 THERAPEUTIC USES OF MORPHINE

 Relief of pain
 Terminal illness
 Preoperative medication
 Postoperative medication
 Acute pulmonary edema
 Diarrhea
 Cough
 MORPHINE EFFECTS

ANALGESIA: CHANGES OUR REACTION AND OUR

PERCEPTION OF PAIN
• Severe cancer pain is more tolerated
• Relieves all types of pain, but most effective against continuous
dull pain
• Sharp and stabbing pain also relieved
• If given to a pain free individual, first experience is dysphoric
(opposite to euphoric)

• SEDATION, but no loss of consciousness

EUPHORIA: sense of well being, reason why is abused

Morphine, like other prescription opiates, can quickly lead to abuse and
dependency, even when the user begins taking it for legitimate medical reasons
 EFFECTS OF MORPHINE ON RESPIRATION

Primary and continuous, dose-related respiratory-depression

(increase in dose  further respiratory depression)
– decreased rate
– decreased volume
– decreased tidal exchange

 Due to µ opioid receptors activation

 CNS becomes less responsive to CO2 (depression of the excitability

of brainstem chemosensory neurons) thereby causing a depression
of the ventilatory response to increased CO2 levels

 Irregular breathing pattern, with periods of apnea

 MORPHINE EFFECT ON PUPIL SIZE

Excessive constriction of the pupil (still responsive to bright light) due

to enhanced parasympathetic stimulation  miosis
µ and k effect
Stimulation of the Edinger-Westphal nucleus of the oculomotor nerve
Important diagnostically: other causes of respiratory depression cause
dilation of the pupil
 MORPHINE EFFECTS ON THE
GASTROINTESTINAL SYSTEM

Increase in tone in stomach, small intestine and large intestine and

decrease in mobility  constipation
Mediated primarily by μ-opioid receptors in the bowel
Delay of passage of food, so more reabsorption of water
Decreased HCl secretion
Tolerance does not affect this effect

Nausea and vomiting

stimulation of chemoreceptor trigger zone (CTZ), a part of the
vomiting center, where opioid receptors are present
 MORPHINE CARDIOVASCULAR EFFECTS

May induce bradycardia

Induced vasodilation, thus a decrease in blood pressure and

orthostatic hypotension, due to:
release of histamine
depression of vasomotor center
direct action decreasing tone of blood vessels
 MORPHINE EFFECTS ON SMOOTH MUSCLES

• Biliary tract
– Marked increase in the pressure, due to contraction of Sphincter of Oddi

• Urinary bladder
– Increase in tone of detrusor muscle
– Urinary retention

• Bronchial muscle
– Bronchoconstriction
– Contraindicated in asthmatics, particularly before surgery

• Uterus
– Can prolong labor
 MORPHINE NEUROENDOCRINE EFFECTS

Inhibit the release of gonadotropin-releasing hormone

(GnRH) and corticotropin-releasing factor (CRF)

 Decreased circulating concentration of luteinizing hormone

(LH), follicle-stimulating hormone (FSH), ACTH, and β-endorphin

 As a result of the decreased concentrations of these pituitary

hormones, the concentrations of testosterone and cortisol in
plasma decline; secretion of thyrotropin is relatively unaffected
OPIOIDS EFFECTS ON THE IMMUNE SYSTEM

µ receptors are expressed on immune cells

REDUCED
 antibodies production
 NK cells activity
 cytokines expression
 phagocytic activity
 TOXICITY OF MORPHINE
Morphine is ADDICTIVE and prone to ABUSE
High doses (overdose situation) of morphine cause excitatory spinal
reflexes
High doses of many OPIOID cause convulsions, due to stimulation at
DOP
If the dose is reduced after long-term use, opioid withdrawal symptoms
may occur (generally the opposite of therapeutic symptoms)

Acute overdose
•respiratory depression
•pinpoint pupils (miosis)
•coma

Treatment
1. establish adequate ventilation
2. give OPIOID antagonist (naloxone)
 TOLERANCE TO MORPHINE
Opioids change the chemistry of the brain (i.e.: increase in µ opioid
receptors production) and lead to drug dependence and tolerance :
over time the dose needs to be increased to achieve the same effect

Rapid development of tolerance to the analgesic effect

Slow development of tolerance to many other opioid effects:
– Nausea
– Sedation
– Respiratory depression
– Cardiovascular effects
– Euphoria

 Tolerance does not affect:

– Miosis
– Constipation
 DRUG INTERACTIONS WITH OPIOIDS
Many drugs have the potential to interact negatively with opioid
medications:

Anti-seizure medications
Certain antibiotics (clarithromycin)
Certain antifungals
Certain antiretroviral drugs used for HIV infection
Drugs used to treat psychiatric disorders
Muscle relaxers
Sedative, such as diazepam (Valium)
Alcohol

In general:
Opioids metabolized by CYP450 system (codeine, oxycodone, hydrocodone, fentanyl,
tramadol, and methadone) are associated with numerous drug interactions that can
result in either a reduction or excess in opioid effects
Opioids that are not metabolized by that system (morphine, oxymorphone, and
hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic
drug interactions
 DRUG INTERACTIONS WITH OPIOIDS
In general, the coadministration of OPIOIDS with CNS depressants
often produces an additive depression (potentiation)

OPIOID and PHENOTHIAZINES (antipsycotics)

• additive CNS depression
• enhancement of the actions of OPIOID (respiratory depression)
• greater incidence of orthostatic hypotension

OPIOID and TRICYCLIC ANTIDEPRESSANTS/MAO INHIBITORS

• increased hypotension
• severe and immediate reactions that include excitation, rigidity and severe respiratory
depression

MORPHINE and AMPHETAMINE

•enhanced analgesic effect
 CODEINE

 Methyl group on 3’ position (-OH group in morphine)

 One tenth the analgesic properties of morphine;
greater effects in combined formulations with
paracetamol and NSAIDs
 Given orally, absorbed readily from GI tract, in a more regular and
predictable way than morphine
 Metabolized to morphine by CYP450 enzyme (CYP2D6), which then
undergoes glucuronidation; methyl group protects from glucuronidation
and reduces first pass metabolism
 Therapeutic use: antitussive drug for cough (not under 12 years of age)
 Onset of action 30’, maximum effect at 2 hours, lasts for 4-6 hours
 Tolerance and physical dependence is protracted from morphine
 OXYCODONE

 Semisynthetic opioid obtained from thebaine

 Used for treatment of moderate to severe pain, usually taken by mouth

(1.5 times the effect of the equivalent amount of morphine) available in
immediate release and controlled release formulations

 Combination products are available with paracetamol or aspirin; abuse-

deterrent formulations are available in combination with naloxone

 Acts by activating the μ-opioid receptor; onset of pain relief typically

begins within 15 minutes and lasts for up to 6 hours; half life 4,5 hours

 Metabolism occurs in the liver mainly via the cytochrome P450 system.
Around 10% of a dose is excreted unchanged in the urine; metabolites
are subsequently conjugated with glucuronic acid and excreted in the
urine
 HYDROCODONE

 Synthesized from codeine

 Used orally for relief of moderate-to-severe pain and as a cough

suppressant

 It is approximately equipotent to oxycodone, with an onset of action

of 10–30 min and duration of 4–6 h.
 OXYMORPHONE

 Semisynthetic alkaloid produced from thebaine

 Potent MOR agonist with an onset of analgesia after parenteral

dosing of about 5–10 min and a duration of action of 3–4 h

 Extensively metabolized in liver and excreted as the 3- and 6-

glucuronides
 HEROIN (DIACETYLMORPHINE)
 At 3’ and 6’ positions, acetyl groups instead of hydroxyl groups
 The most lipophilic of all opioids (morphine is the least lipophilic)
 From 3 to 4 times the analgesic potency of morphine;
most commonly used as a recreational drug for its euphoric effects
 Usually injected IV  rapidly crosses the blood brain barrier and in
the brain it is deacetylated to 6-MAM and morphine
 When taken orally, undergoes extensive first pass metabolism
(deacetylation) making it a prodrug  systemic delivery of morphine
 Withdrawal begin within 6–24 hours of discontinuation;
symptoms similar to morphine but more intense
• mydriasis
• diarrhea
• vasoconstriction
• dysphoria
• anxiety
• depression
 HYDROMORPHONE
 Semi-synthetic opioid, with ketone at 6’ hydroxyl position of morphine

 5 times more potent than morphine (strong agonist, more lipophilic)

 Commonly used IV; poor oral, intranasal and rectal bioavailability (not lipophilic, poorly
absorbed through membranes)
 Onset of action: less than 5 minutes; 30’ after oral ingestion

 More sedation than morphine so less euphoric feeling ( not abused)

 Side effects same as morphine and heroin

 Less constipating effect

 Tolerance and physical dependence are more intense than
morphine, because of its high potency, but vary among
individuals
 FENTANYL
 Synthetic drug, used as pain mediation, anesthesia
and recreational drug
 80 to 100 times more potent than morphine, as a µ
receptor agonist
 Strong potency relative to morphine, largely due to its high lipophilicity (
more easily penetrate the CNS)
 Rapidly and shortly acting drug: onset of action is 5 minutes, duration is 30-45
min
 Usually taken intravenously
 Same side effects of other opioids; however, despite more potent, tends to
induce less nausea and histamine-mediated itching than morphine
 Highly abused (in 2019 more than 90000 cases of fentanyl overdose in USA)
 PHETIDINE (MEPERIDINE)
 Synthetic opioid produced in 1940's, indicated for the treatment of
moderate to severe pain
 Taken orally, intramuscularly, subcutaneously or intravenously
 Same CNS actions and potency as morphine: sedation, analgesia,
respiratory depression; equal risk of addiction of morphine
 Unlike morphine:
• more respiratory depression
• more bronchoconstriction activity
• less constipation
• no antitussive activity

 Drug most abused by health care professionals due to its availability

 Withdrawal similar to morphine
 DIPHENOXYLATE

 Meperidine type drug, which can be OTC drug now

 Therapeutic use: to treat diarrhea (acts by slowing
intestinal contractions), but not in children
 Used in combination with atropine to prevent drug
abuse and overdose
 Very little analgesic properties at therapeutic dose

 No antitussive effect
 At high doses it has analgesic problems: respiratory depression and
euphoria, vomiting, nausea
 METHADONE

 Pharmacological activity similar to morphine (synthetic µ

opioid receptors agonist) and same potency
 Long duration of activity: effects last for 8 to 36 hours
(mean half life: 22 hours)
 Usually taken by mouth (absorbed well orally); rarely given by IV or IM
injection
 Same side effects and overdose symptoms of other opioids; withdrawal
symptoms more protracted than those from opioids with shorter half-
lives
 Powerful pain reliever, also used for opioid maintenance therapy in
opioid dependence (detoxification to manage opioid withdrawal
symptoms)
 TRAMADOL
 Synthetic analogue of codeine,
used to treat moderate (same potency of morphine)
to severe pain (less effective than morphine)
 Taken by mouth in an immediate-release formulation or by injection

( onset of action in 1 hour; peak in 2 to 4 hours; lasts about 6 hours)

May be sold in combination with paracetamol or as longer-acting

formulations
µ opioid receptors agonist and serotonin-norepinephrine reuptake
inhibitor (SNRI, like antidepressant medications serotonin syndrome and
seizures)
Racemic mixture: the positive enantiomer inhibits serotonin reuptake, the
negative one inhibits noradrenalin reuptake; both are µ opioid receptors
agonists
 TAPENTADOL:
INNOVATIVE ANALGESIC DRUG

Centrally acting opioid analgesic with a dual mechanism of

action:
 agonist of MOR
 norepinephrine reuptake inhibitor (NRI)

 Analgesic potency 2-3 times lower than that of morphine, comparable

to that of oxycodone
 Analgesia occurs within 32 minutes of oral administration and lasts for
4-6 hours
 Not a pro-drug: does not rely on metabolism to produce its therapeutic
effects; no known active metabolites
 Used to treat moderate to severe pain (both nociceptive and
neuropathic), spec. for both acute and chronic musculoskeletal pain
 TAPENTADOL:
INNOVATIVE ANALGESIC DRUG

Lower incidence of adverse effects in comparison to

equivalent doses of morphine:

Lower incidence of gastrointestinal side effects,

including vomiting and costipation

No cardiovascular side effects

Delayed development of tolerance in chronic pain

management
 TAPENTADOL VS TRAMADOL

TAPENTADOL TRAMADOL

• Single molecule •Racemic mixture

• No metabolic activation •Pro-drug
• No active metabolites •MOR agonist after metabolic
• Synergic MOR agonist and NRI activation (CYP2D6)
activity •NE and 5-HT reuptake inhibitor

MOR NRI 5-HT-RI

NRI
agonist

MOR
agonist
 OPIOID ANTAGONISTS:
NALOXONE
 No agonist/analgesic activity
 Competitive antagonist at µ and k
receptors
 Displaces morphine and other OPIOID
from receptor site and quickly reverses
all their actions
 It will precipitate withdrawal in person
on heroin, this effect is immediate (3-5
minutes) and it only lasts for 30-45
minutes (must be reinjected often)
 Increased blood pressure
 Metabolized same as morphine,
through glucuronic acid and excreted
through kidney
 OPIOID ANTAGONISTS:
NALTREXONE
 Same effect of naloxone
 Taken as oral tablets or by IM injection, onset of action in 30 minutes
 Long duration of activity: single dose blocks heroin effects for 24 hours
 Should not be started until 7-10 days of abstinence from opioids (risk of acute
opioid withdrawal) Some physicians use a naloxone challenge to determine
whether an individual has any opioids remaining: dose of naloxone and
monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be
started
 Also used for treatment of alcoholism (mechanism of action not fully understood)
 OVERALL MANAGEMENT OF PAIN
 MILD PAIN
Non-opioid analgesics: Paracetamol
NSAIDs: Aspirin, Ibuprofen

 MODERATE PAIN
1. Low efficacy opioid: Dihydrocodeine
2. Low efficacy opioid + NSAIDs: Dihydrocodeine +
Ibuprofen
3. Moderate efficacy opioid + NSAIDs: Tramadol + Ibuprofen

 SEVERE PAIN
1. High efficacy opioids: Morphine
2. High efficacy opioids + NSAIDs: Morphine + Ibuprofen

 OVERWHELMING PAIN
High efficacy opioid + anxiolytic Morphine + Diazepam
and/or major tranquilliser : Morphine + Chlorpromazine