 Pain is an unpleasant sensation that can be acute or

chronic and involves complex neurochemical processes

in the peripheral and central nervous system
 Pain is subjective, and the physician must rely on the
patients’ perception and description of their pain
 For mild to moderate pain NSAIDs like ibuprofen are
used
 Neurogenic pain responds best to anticonvulsants (e.g
pregabalin), tricyclic antidepressants (amitriptyline), or
SNRI (duloxetine)
 For severe or chronic pain opioids are the drug of
choice
 Opioids are natural or synthetic compounds that
produce morphine like effects
 “Opiate” is the term used for drugs obtained from
opium poppy such as morphine and codeine
 Opioids are used to relieve intense pain, like post-
surgery pain or pain caused by diseases like cancer
 Opioids with euphoric effects have abuse potential
 Mechanism of action:
◦ Bind to μ opioid receptors relieving pain
◦ Mimic the action of endogenous peptide neurotransmitters
(endorphins, enkephalins, and dynorphins)
 Three major receptor families μ (mu), κ (kappa), and δ
(delta)
 G protein–coupled receptor family and inhibit adenylyl
cyclase
 Also associated with ion channels, increasing postsynaptic
K+ efflux (hyperpolarization) or reducing presynaptic Ca2+
influx, thus slowing neuronal firing and transmitter release
 The analgesic properties of the opioids are mediated by the
μ receptors
 κ receptors in the dorsal horn also contribute (e.g
butorphanol and nalbuphine owe their analgesic effect to κ-
receptor activation)
 Enkephalins interact more selectively with the δ receptors in
the periphery
 Strong agonists (High affinity for μ receptors)
◦ Morphine
◦ Hydromorphone
◦ Oxymorphone
◦ Heroin
◦ Fentanyl
◦ Hydrocodone
◦ Methadone
◦ Oxycodone
◦ Meperidine
 Moderate/low agonists
◦ Codeine

 Mixed agonist-antagonists and partial agonists

◦ Pentazocine
◦ Butorphanol
◦ Buprenorphine
◦ Nalbuphine

 Antagonists
◦ Naloxone
◦ Naltrexone

 Other analgesics
◦ Tramadol
◦ Tapentadol
Morphine:
 The major analgesic drug contained in crude opium
 Has high affinity for μ receptors
 Mechanism of action:
◦ μ-Receptor agonist
◦ Opioids cause hyperpolarization of nerve cells, inhibition of
nerve firing, and presynaptic inhibition of transmitter release
◦ Morphine acts at κ receptors in the dorsal horn of the spinal
cord, and decreases the release of substance P, which
modulates pain perception in the spinal cord
◦ Morphine inhibits the release of many excitatory transmitters
from nerve terminals carrying nociceptive (painful) stimuli
 Actions:
◦ Analgesia (relief of pain without loss of consciousness)
◦ Euphoria: powerful sense of contentment and well being
◦ Respiratory depression by reduction of the sensitivity of
respiratory center neurons to carbon dioxide
(main cause of death in overdose)
 Tolerance to this effect develops quickly with repeated
dosing, which allows the safe use of morphine for the
treatment of pain
◦ Depression of cough reflex (antitussive effects)
◦ Miosis (Pinpoint pupil; important for diagnosis of
morphine abuse)
 Actions
◦ Emesis: due to triggering of chemoreceptor zone
◦ GI effects: constipation
◦ Cardiovascular: at large doses hypotension and
bradycardia may occur
◦ Histamine release: Morphine releases histamine from mast
cells, causing urticaria, sweating, and vasodilation, can
cause bronchoconstriction
◦ Hormonal actions: Morphine increases growth hormone
release and enhances prolactin secretion, and ADH
 Therapeutic uses:
◦ Analgesia
◦ Treatment of acute pulmonary edema: IV morphine
relieves dyspnea by its vasodilatory effect
 Administered IM, SC, IV

(significant first pass effect)

 In case of chronic neoplastic pain, morphine can be
administered as extended release tablets or pumps that
allow the patient to control pain through self
administration
 Not used for analgesia during labor

 Infants born of addicted mothers show physical

dependence and exhibit withdrawal symptoms if
opioids are not administered
 Adverse effects
◦ Respiratory depression
◦ Hypotension
◦ Vomiting
◦ Tolerance and physical dependence: Repeated morphine use
causes tolerance to respiratory depressant, analgesic and
euphoric effects
 Detoxification of morphine-dependent individuals is
accomplished through the oral administration of
methadone, buprenorphine or clonidine
 Morphine should be used cautiously in patients with
bronchial asthma, liver failure, or impaired renal
function
 A synthetic opioid used for acute pain
 Mechanism of action: Meperidine binds to opioid
receptors, particularly μ receptors providing
analgesia
 Adverse effects
◦ Respiratory depression
◦ Repeated administration can cause anxiety,
tremors, muscle twitches, and rarely convulsions,
due to the accumulation of the neurotoxic
metabolite normeperidin
 μ-Receptor agonist
 NMDA receptor antagonist, useful in treatment of
neurogenic pain
 Causes less euphoria and less dependence than
morphine
 Uses:
◦ Analgesia
◦ Controlling withdrawal symptoms of dependent abusers
of morphine and heroin
 μ-Receptor agonist
 Has 100-fold the analgesic potency of morphine
 Used in anesthesia
 Administered IV, epidurally or intrathecally
 Epidural fentanyl is used to induce anesthesia and
for analgesia post-operatively and during labor
 Can cause hypoventilation
 Sufentanil, alfentanil, and remifentanil are related
to fentanyl
 Synthetic derivative of morphine
 3 times more potent than morphine
 Causes more euphoria than morphine
 No medical use
 Oxycodone
◦ Orally active and is sometimes formulated with aspirin or
acetaminophen
◦ Used to treat moderate to severe pain Oxymorphone
 Oxymorphone
◦ Narcotic analgesic
 Hydromorphone
◦ Oral hydromorphone is 8-10 times more potent than oral morphine as
an analgesic and is used most often to treat severe pain
 Hydrocodone
◦ Analgesic potency of oral hydrocodone is approximately that of
morphine
◦ Hydrocodone is often combined with acetaminophen or ibuprofen to
treat moderate-to-severe pain
 Moderate/low agonist
 Good antitussive activity at doses that do not cause
analgesia
 Metabolized to morphine in the body by CYP2D6
causing analgesic effects (30% that of morphine)
 Causes euphoria
 Lower abuse potential than morphine at commonly
used doses
 Mixed agonist-antagonists: Drugs that stimulate
one receptor but block another

 The effects of these drugs depend on previous

exposure to opioids
◦ In individuals who have not recently received opioids
(naïve patients), mixed agonist-antagonists show
agonist activity and are used to relieve pain
◦ In patient with opioid dependence, the agonist-
antagonist drugs may show primarily blocking effects
and produce withdrawal symptoms
 Acts as an agonist on κ receptors and a weak antagonist at
μ and δ receptors
 Pentazocine promotes analgesia by activating receptors in
the spinal cord, and it is used to relieve moderate pain
 Produces less euphoria than morphine
 Causes respiratory depression at higher doses
 High doses increase blood pressure and can cause
hallucinations, nightmares, dysphoria, tachycardia, and
dizziness
 In angina, pentazocine increases the mean aortic pressure
and pulmonary arterial pressure increasing the work of the
heart
 Does not antagonize the respiratory depression of
morphine
 Tolerance and dependence develop on repeated use
 Partial μ receptor agonist
 Acts like morphine in naive patients
 Can precipitate withdrawal in morphine users
 Used in opiate detoxification, has less severe and
shorter duration of withdrawal symptoms compared to
methadone
 Has a long duration of action because of its tight
binding to the μ receptor
 Adverse effects
◦ Respiratory depression that cannot easily be reversed by
naloxone
◦ Nausea
◦ Dizziness
Tramadol
 Centrally acting analgesic that binds to μ-opioid receptor
 Weakly inhibits reuptake of norepinephrine and serotonin
 Used to manage moderate to moderately severe pain
 Less respiratory depression than morphine
 Anaphylactoid reactions have been reported
 Toxicity through drug-drug interactions with medications, such
as SSRIs and TCAs or in overdose leads to CNS excitation and
seizures
 Tramadol should be avoided in patients taking MAOIs

Tapentadol
 Centrally acting analgesic that binds the μ-opioid receptor and is
also a norepinephrine reuptake inhibitor
 Used to manage moderate to severe pain
 Bind with high affinity to opioid
receptors but fail to activate the
receptor-mediated response
 Administration of opioid antagonists
produces no profound effects in
normal individuals
 In patients dependent on opioids,
antagonists rapidly reverse the
effect of agonists, such as morphine
or any full μ-agonist causing
symptom of opiate withdrawal
 Used to reverse the coma and respiratory depression of
opioid overdose
 Rapidly displaces all receptor-bound opioid molecules
reversing their effects
 Within 30 seconds of IV injection of naloxone the
respiratory depression and coma characteristic of high
doses of morphine are reversed causing the patient to
be revived and alert
 Naloxone is a competitive antagonist at μ, κ, and δ,
receptors
 Short half life (30-80 min)
 Can cause withdrawal symptoms in opioid abusers
 Similar effects to naloxone with a longer
duration of action

 A single oral dose can block Heroin effects for

up to 48 hours

 Can cause hepatotoxicity