ANALGESICS

(OPIOID ANALGESICS)

Algesia (Pain)
Is an illdefined, unpleasant sensation,
usually evoked by an external or internal
noxious stimulus.

Analgesic
An analgesic is any member of the diverse group of drugs used to
relieve pain (achieve analgesia). The word analgesic derives from
Greek an- ("without") and -algia ("pain"). Analgesic drugs act in
various ways on the peripheral and central nervous systems; they
include paracetamol (acetaminophen), the non-steroidal antiinflammatory drugs (NSAIDs) such as the salicylates, narcotic
drugs such as morphine, synthetic drugs with narcotic properties
such as tramadol, and various others.
Analgesics are divided into two groups
A. Opioid / Narcotic / Morphine like analgesics
B. Nonopioid / Non-narcotic / Aspirine like / anti pyretic or
antiinflammatory analgesics

OPIOID ANALGESICS
Opium The dark brown, resinous material obtained from
poppy (papaver somniferum) capsule is called Opium. It
contains two types of alkaloids.
Phenanthrene derivatives
Morphine (10% in opium)
Codeine (0.5% in opium)
Thebaine (0.2% in opium), (Nonanalgesic)
Benzoisoquinoline derivatives
Papaverine (1%)
Noscapine (6%) Nonanalgesic
(Narcotine)

OVERVIEW
Opioids have been the mainstay of pain treatment for thousands of years, and they
remain so today. Opioids such as heroin and morphine exert their effects by
mimicking naturally occurring substances, called endogenous opioid peptides
or endorphins. Much now is known about the basic biology of the endogenous
opioid system and its molecular and biochemical complexity, widespread
anatomy, and diversity. The diverse functions of this system include the best
known sensory role, prominent in inhibiting responses to painful stimuli; a
modulatory role in gastrointestinal, endocrine, and autonomic functions; an
emotional role, evident in the powerful rewarding and addicting properties of
opioids; and a cognitive role in the modulation of learning and memory. The
endogenous opioid system is complex and subtle, with a great diversity in
endogenous ligands (more than a dozen) yet with only four major receptor
types. This chapter presents key facts about the biochemical and functional
nature of the opioid system that then are used to understand the actions of
clinically used opioid drugs and strategies for pain treatment.

Terminology
The term opioid refers broadly to all compounds related to opium.
The word opium is derived from opos, the Greek word for
"juice," the drug being derived from the juice of the opium poppy,
Papaver somniferum. Opiates are drugs derived from opium, and
they include the natural products morphine, codeine, and
thebaine, and many semisynthetic derivatives. Endogenous
opioid peptides are the naturally occurring ligands for opioid
receptors. The term endorphin is used synonymously with
endogenous opioid peptides but also refers to a specific
endogenous opioid, b-endorphin. The term narcotic was derived
from the Greek word for "stupor." At one time, the term referred
to any drug that induced sleep, but then it became associated with
opioids. It often is used in a legal context to refer to a variety of
substances with abuse or addictive potential.

II Opioid Agonists
A. Opium alkaloids and derivatives
B. Synthetic compounds

III. Antagonists
IV. Mixed agonist-antagonists
V. Partial agonists

Desirable properties of
morphine as an analgesic
Effective over a wide range of
doses
Effect on mood
Sedation

Undesirable properties of
morphine as an analgesic
Sedation*
Mental Clouding
Dysphoria
Constipation*
Dizziness
Nausea and vomiting
Respiratory
depression*
Cough reflex
depression*

Circulatory depression
Pinpoint pupils
Pruritis and rash
Biliary tract spasms
Ureter and vesical
spasms
Urinary retention
Behavioral dependence
Physical dependence

Tolerance
Associative or behavioral tolerance
Nonassociative or pharmacologic
tolerance
Cross-tolerance
Intrinsic efficacy may affect
development of tolerance and crosstolerance

Codeine
About 1/10th the potency of
morphine
lower efficacy than morphine
about 10% converted to morphine
by CYP450 2D6
7-10% of patients do not possess
this enzyme

Mixtures containing Codeine

Acetaminophen or NSAIDs
Logic: Additive or synergistic
analgesia without concomitant
increase in adverse effects.

Hydromorphone
(Dilaudid)
About 8-10X potency of
morphine
Slightly shorter duration than
morphine
available as suppository

Oxymorphone
(Numorphan)
Same as hydromorphone

Hydrocodone and
Dihydrocodeine
Same as oxycodone

Oxycodone
About 10X potency of codeine
Also metabolized by CYP4502D6
Controlled release formulation
(OxyContin)

Heroin
Crosses blood-brain barrier more
rapidly than morphine
2-4 X greater potency than
morphine
Converted to morphine

Synthetic compounds
Meperidine
Fentanyl, Sufentanyl, Alfentanyl
Remifentanyl
Methadone
L--acetyl-methadol: LAAM
Propoxyphene

Meperidine
About 1/8th potency of morphine
shorter duration
fewer smooth muscle spasms than
morphine
No meiosis
biotransformed to a toxic metabolite
that builds up and can cause seizures.

Fentanyl

80 - 100 x potency of morphine

fast onset, short duration
used i.v. for anesthesia
available as patch
available as oral slow release
device.

Methadone
Potency similar to morphine for i.v.
administration, but 4 x more potent
orally
long plasma half-life
used in treatment of narcotic
dependence
Duration of action increases with
repeated use

Propoxyphene
Potency compared to codeine
Potency compared to placebo
Produces cardiotoxicity and
pulmonary edema
Active metabolite produces
convulsions

Tramadol
Opioid receptor agonist (mu and
delta)
NE and 5-HT reuptake blocker
(antidepressant)
-2 adrenoceptor agonist
These two actions are synergistic
for analgesia

LAAM
Extremely long plasma half-life
(>72 hr)
Suppresses opiate withdrawal for
4-5 days

Opioid Antagonists
Naloxone
Naltrexone
Nalmefene

Signs of Overdose

Stuporous or in coma
Respiratory rate extremely low
pinpoint pupils
low body temperature
flacid skeletal muscles, jaw relaxed

Naloxone
Short half-life
not effective orally

Naltrexone

Long half-life
effective orally or injected
available in oral form only
used for treatment of
dependence

Nalmefene
Intermediate duration (4-6 hr)
orally active
no hepatotoxicity with long term
use

Mixed agonist-antagonists

Nalorphine and cyclazocine

Pentazocine: Talwin NX
Butorphanol
Nalbuphine

Nalorphine and Cyclazocine

Kappa3 receptor agonists

Mu receptor antagonists
produce psychotomimetic effects
produce dysphoria

Pentazocine
Kappa and delta agonist
Ts and blues
Talwin NX

Butorphanol

Kappa receptor agonist

Mu receptor antagonist
Available as nasal spray
5 X more potent in women than
men

Nalbuphine
Kappa receptor agonist
Mu receptor antagonist
Little dysphoria compared to
nalorphine
Less abuse potential than
morphine

Partial agonist:
Buprenorphine
Partial agonist at mu receptors
Partial agonist at kappa3 receptors
Antagonist at kappa1 receptors
Lower efficacy analgesic than
morphine

Salvinorin A
Active ingredient in Salvia Divinorum
Very selective kappa opioid agonist
Hallucinogen

Dependence and Withdrawal

Dependence varies from mild craving to
compulsion to take the drug
Degree depends upon dose and
frequency
Withdrawal signs opposite in direction
to the drug effects.
Will last about 72 hrs for morphine or
heroin
Not life threatening

Other factors that influence

the effectiveness of opioid
treatment
Progression of tissue-damaging
disease
Sensitization of CNS neurons
Collateral transmission

Reference
Laurence L. Brunton, (2006). GOODMAN & GILMAN'S THE
PHARMACOLOGICAL BASIS OF THERAPEUTICS - 11th Ed.
McGraw-Hill MEDICAL PUBLISHING DIVISION.

Thank you