Opioids

Dr. Yuri Clement,

Pharmacology Unit, FMS
 Gary: Case of chronic pain

Gary, a 42-year-old man with a 1-year history of total hip replacement,

presents to your clinic for the first-time and complains of chronic hip pain. He
walks with a limp and uses a cane. His vitals are normal, BMI 31.

He has 2-year history of depression, treated with sertraline. Denies current or

past alcohol, tobacco, or drug use.

His orthopedist initially managed his pain with oxycodone, but switched to
ibuprofen (800mg tid). Recent extensive reevaluation for hip pain was – ve.

http://www.drugabuse.gov/nidamed-medical-health-
professionals/centersexcellence/substance-use-disorder-patient-case-studies
 Gary: Case of chronic pain
He requested that his orthopedist prescribe something stronger like “oxys”,
as ibuprofen was ineffective. He was referred to his primary care physician to
discuss pain management.

He has a large, well-healed scar over the left lateral thigh and hip area with
no tenderness or warmth over the hip. He has full range of motion. He
doesn’t want to return to his orthopedist, because “he doesn’t believe that I’m
still in pain.”
Overview
Basic concepts
Opioid receptors and distribution
Morphine (prototype)
• CNS and peripheral effects
• Indications and contraindications
Opioid agonists
Tolerance and physical dependence
Partial agonists and mixed agonist-antagonists
Other analgesics
Opioid antagonists
Opioid Use and Abuse
 “Are you
experiencing any
other unusual
symptoms
besides dizziness
and Chess pain?”
What is pain?
Pain is an unpleasant sensory or
emotional experience associated with
actual or potential tissue damage, or
described in terms of such damage"
World Health Organization, 2014

“… for millions of people across the globe, excruciating pain

is an escapable reality of life.” Taylor, J Law Med Ethics 2007
The multi—dimensional concept of “total pain”
Epidemiology of Pain
• Acute, chronic and intermittent, or combination.

• Main causes: cancer, osteo- and rheumatoid arthritis, postoperative, injuries,

spinal problems.

• 10% newly diagnosed with cancer pain annually

• In US in 2012, ~260million prescriptions for opioid medication.

• About 20% of patients with non-cancer pain or pain-related diagnoses

receive opioid prescription
 Opioid Receptor Activity
Opioid Receptor subtype
(endogenous opiopeptide affinity) Mediates

Supraspinal and spinal analgesia,

µ respiratory depression, euphoria,
(Endorphins>enkaphalins>dynorphins) sedation, addiction, constipation,
miosis.
Associated with morphine-like
analgesia and euphoria.

 Supraspinal and spinal analgesia,

diuresis, miosis, sedation, respiratory
(Enkaphalins>endorphins & depression, constipation, dysphoria,
dynorphins) psychomimetic effects.

 Supraspinal and spinal analgesia.

(Dynorphins ??>endorphins &

enkaphalin)
Opioid receptor distribution
Ascending pain transmission:
Dorsal horn of spinal cord, brain
stem, thalamus, cortex

Descending inhibitory
pathways:
Periaqueductal gray matter of
midbrain, nucleus raphe magnus
and nucleus locus coeruleus of
brainstem (mediate respiration,
cough, nausea and vomiting,
blood pressure maintenance,
pupillary diameter, stomach
secretion)

Spinal action of opioids provides regional analgesic effect void of respiratory

depression, nausea and vomiting and sedation.
 Mechanism of Action

NET EFFECT:

↓neurotransmitter
release

• Glutamate
• Substance P
• Acetylcholine
• Norepinephrine
• Serotonin
Papaver somniferum: Opium
'flower of joy.'

Egyptian, Greek and Roman historical

records show its medicinal use for over
6000 years.

Widely used in Asia minor, China, India,

Iran, Turkey, southeastern for centuries.

Crude opium contains ~25 different

alkaloids. Main alkaloids are:
Morphine (~10%),
Codeine (0.8-2.5%),
Thebaine (0.5-2%),
Papaverine (0.5-2.5%),
Noscapine (4-8%),
Meconic Acid (3-5%).
MORPHINE

Named after Morpheus

the Greek God of dreams
 Morphine

First plant alkaloid isolated. In 1803 by 20-year-old

German pharmacist Friedrich Wilhelm Adam Sertürner.

Prototype opioid; most semisynthetic and synthetic analogs share

chemical structure and pharmacological properties.

Usually given parenterally, oral absorption slow and erratic with significant
1st pass metabolism.

Onset: 5-15minutes; duration of action: 4 hours in drug naïve individuals.

One metabolite is a very potent analgesic.

Distributed to all tissues, small percentage enters brain; crosses placenta

and in addict mothers physical dependence in newborn.
CNS Effects (Morphine I)
Analgesia:
Reduces both sensory and emotional components of pain. Dependent
on subjective factors such as temperament and setting. Relieves
visceral, somatic and cutaneous pain, and more effective against dull
constant pain than sharp, severe, intermittent pain.

Euphoria:
Sensation of pleasant floating and detachment, freedom of anxiety and
distress, even with a single dose. Dysphoria in few patients.
(Analgesia depends on the ability to induce euphoria)

Sedation:
Drowsiness; little or no amnesia. More so in elderly, but easily
aroused. Disrupts normal sleep patterns.
 CNS Effects (Morphine II)
Respiratory depression:
Dose-related inhibition of brainstem respiratory mechanisms with
↓pCO2 sensitivity.

(Most common cause of death in opioid overdose).

Cough suppression:
Depression of cough centre. Codeine is opioid of choice with greater
antitussive activity than morphine, and less respiratory depression
and dependence. (Effect not correlated to analgesia and respiratory
depression.)

Miosis:
Minimal tolerance; indicator of opioid overdose.
 GI Effects
• Constipation:
High density of µ receptors in GI tract, also
centrally mediated. ↑tone, ↓ motility.
Merperidine has lesser effect than other
opioids. Minimal tolerance to this effect.

Useful in treatment of diarrhea

• Nausea and vomiting:

Stimulation of brainstem chemoreceptor
trigger zone.
 Peripheral effects
• No major effects on HR or BP. Large doses cause
bradycardia and hypotension. (Meperidine may cause
tachycardia.)

• Diminished renal function, antidiuretic effect

• Pruritus: Utricaria, sweating and itching. By both central

action and peripheral histamine release.
*Caution in asthmatics

• Hormonal effects:
• ↓LH, testosterone; ↑prolactin, ↑ ADH (↑ urinary retention,
BPH), somatotropin.
 Indications
Analgesia
• Greater effect for severe constant dull pain vs sharp, intermittent
pain
• Little evidence to support long-term use (>6 months) of sustained-
release opioids

Acute pulmonary edema/MI

• Decreased anxiety, reduced preload and afterload

Adjunctive anaesthesia
• As premedicant (sedative, anxiolytic and analgesic),
intraoperatively as adjunctive or primary component of
anaesthetic regimen.
• As regional anaesthesia, with local anaesthetics

Post-operative shivering
• Meperidine
 Contraindications
Head injuries
• ↑pCO2 causes vasodilation and increase intracranial pressure

Pregnancy
• Fetus may become physically dependent in utero. Withdrawal
syndrome on delivery
• Neonates should not be given morphine due to low metabolic capacity

Impaired pulmonary function

• Asthma, emphysema and cor pulmonale.

Impaired hepatic and renal function

• Prolonged and exaggerated effect due to accumulation

Endocrine disease
• Prolonged and exaggerated effects in Addison’s disease and
hypothyroidism
Drug interactions

MAO Inhibitors
• High incidence of hyperpyrexic coma, and hypertension

CNS Depressants (Sedative/Hypnotics)

• Potentiate all opioid-depressant effects of CNS, particularly
respiratory depression.

Antipsychotics/Tricyclic Antidepressants
• Increased sedation, variable effects on respiratory depression.
Opioid Agonists
Natural, semi-synthetic and synthetic compounds that
produce morphine-like effects; most are controlled.

Act primarily at µ-opioid receptors. May also cause the

release of endogenous opioid peptides that act at  and 
receptors.

Correlation between  and  receptor interactions and opioid

analgesic effect uncertain.

Peripheral receptors (in immune cells and GI tract)

 Opioid
Agonists
Class Drug Approximate Duration
potency of Points to note
(compared with analgesia
morphine) (hrs)
Phenanthrenes Morphine* 1 4-5 Drug of choice in PE and MI

Hydromorphone† 7 – 10 (oral) 4-5 Faster onset than im and sc morphine.

Oxymorphone† 7 – 10 (parenteral) Preferred over morphine in renal dysfunction,

3 (oral) less active metabolites

Oxycodone† 2 3-6 In combination with paracetamol. Hepatic

metabolism to oxymorphone. Dose-dependent
analgesia. Should not be used in children.
CYP3A4 interactions.
Codeine* 0.15 - 0.3 4-6 Mild to moderate pain. In combination with
paracetamol for mild to moderate pain. Prodrug
metabolized to morphine. Antitussive activity.
Limit use in children.
Dihydrocodeine† 0.15 – 0.3 4-6

Hydrocodone† 0.5 - 1 4-6 Moderate to severe pain, in combination with

paracetamol. Hepatic metabolism to
hydromorphone
 Opioid Agonists
Class Drug Approximate Duration of
potency analgesia Points to note
(compared with (hrs)
morphine)

Phenylheptylamines Methadone 1 4-8 Better oral bioavailability than morphine.

Less sedation, euphoria.
Also blocks NMDA receptors and
monoaminergic reuptake transporters.
Useful in neuropathic and cancer pain.
Phenylpiperidines Fentanyl 100 Peak effect: 3-5 mins Given iv, epidurally, intrathecally for
analgesia and sedation. Combined with
local anaesthesia for epidural analgesia.
No active metabolites, option for renal
dysfunction
Sufentanyl 500 - 700 Peak effect: mins For analgesia and sedation during surgical
procedures requiring anaesthesia.
Afentanyl Peak effect: 90secs

Remifentanil Peak effect: 90 secs

Meperidine 2 – 3 hrs (iv) Not first line, for short-term management

of acute pain. In renal insufficiency and
high doses, accumulation of metabolite
may cause seizures. Do not use in elderly,
renal or hepatic dysfunction, chronic pain
syndromes, respiratory diseases. Caution
with concomitant SSRIs or MAOs.
Morphinans Levorphanol 5 4-5 Less constipating.
 Pharmacokinetics
Most well absorbed parenterally (im, sc).

Extensive 1st pass metabolism affects bioavailability. Codeine and

oxycodone have reduced 1st pass metabolism (suitable for oral
administration)

Morphine metabolized to polar glucuronides (with opioid activity) and

excreted by kidneys. In renal failure, active metabolites (morphine 3-G and
6-G) may have CNS adverse effects.

Codeine metabolized to morphine; in ultra-rapid metabolizers, higher

conversion to morphine could cause respiratory depression and even death.
Formulations
 Methadone
Initially used for controlled opioid detoxification with less severe
and violent symptoms. Substitution, then slowly weaned.

N-methyl-D-aspartate (NMDA) receptor blocking action may be

involved in relief of neuropathic and cancer pain.

Although analgesic effect last for 4 - 8hrs, long t1/2 (12-40 hrs)
allows long time for steady state to be attained (35 hrs to 2
weeks).

With repeated dosing drug accumulation occurs, with attendant

toxicity.

Can produce physical dependence.

 Gary: Case of chronic pain
One month later: Gary is currently taking oxycodone 5 mg q6h,
(120/month), as prescribed. He rates his pain as “15” out of 10
all the time and describes no improvement in function.

He is transitioned to sustained-relief morphine, and he signed a

controlled substance agreement.

After a stable period of several months, he surprises you by

presenting without an appointment and requesting an early refill.
Tolerance
Gradual loss of effectiveness. Large doses needed for same
effect, develops within 2-3 weeks at therapeutic doses.

In addition to diminishing analgesic effect, tolerance develops

to sedative, respiratory depressant, antidiuretic, hypotensive
and emetic effects.

Faster with chronic high dose use, and within hours for ultra-
potent opioids. Could be as high as 35-fold!

No tolerance to miotic, convulsant or constipating

actions.

60mg morphine produces respiratory arrest in opioid naïve subject;

2000mg has no marked respiratory depression in maximally tolerant addict.
 Tolerance
Cross-tolerance: when tolerance to one potent opioid leads to
tolerance to all other opioids.

Cross-tolerance could be partial or incomplete which allows

“opioid rotation”. Sometimes with significantly improved
analgesia at reduced overall equivalent dose.

Counteracted by giving sustained-release doses at fixed-

intervals.

Ketamine (NMDA-receptor antagonist) sometimes used as

adjunctive analgesia to prevent and reverse tolerance

The risk of tolerance, and possibly addiction, should not be used as a barrier to providing
adequate pain control with the best possible care and quality of life.
WHO Cancer pain ladder: http://www.who.int/cancer/palliative/painladder/en/
Dependence
Due to tolerance and characteristic withdrawal or abstinence
syndrome on discontinuation with exaggerated rebound effect.
Partial agonists & mixed
agonist-antagonists
In opioid naïve individuals, agonist effect predominant; in opioid
dependent individuals antagonist effect precipitates withdrawal syndrome.

Buprenorphine
• Avid binding to µ receptors, long duration of action.
Antagonist at  and  receptors.
• Causes little sedation, respiratory depression, hypotension.

• Preferred over methadone in opioid detoxification (shorter

and less severe withdrawal syndrome).
• Once-weekly transdermal patches available, and in
combination with naloxone to prevent abuse.
Partial agonists & mixed
agonist-antagonists
Pentazocine
• Limited role for chronic moderate pain

• Less euphoria than morphine

• High doses ↑BP, cause hallucinations, nightmares,

dysphoria, tachycardia and dizziness.

• Precipitate withdrawal in morphine abusers.

• Tolerance and dependence may develop with repeated use

Partial agonists & mixed
agonist-antagonists
Nalbuphine

• Strong  agonist, partial µ antagonist.

• No effect on heart, does not ↑BP.
• Ceiling effect for respiratory depression.

Butorphanol
• Nasal formulation for severe headaches.
• ↑BP
 Other analgesics
Tramadol
• MAIN EFFECTS: Blockade of 5-HT reuptake, also inhibition of NE
transport function.
• Weak affinity for µ receptors. Analgesic effect independent of µ receptor
interaction
• Useful as adjunctive analgesia with pure opioid agonists in chronic
neuropathic and cancer pain.
• Adverse Effects: Seizures (contraindicated in epilepsy), nausea and
dizziness. Increased risk of serotonin syndrome [mild; shivering and
diarrhea to severe; muscle rigidity, fever and seizures] esp. with SSRIs
use.
• Minimal effect on respiration or CVS.

Tapentadol
• MAIN EFFECTS: mainly inhibits NE reuptake, moderate µ activity
• For moderate to severe pain, as effective as oxycodone, but with less
respiratory depression and GI effects.
• Risk of seizures and serotonin syndrome
Summary of clinical effects:
Full agonists, Partial agonists and mixed agonist-antagonists

Drug Analgesia Antitussive Constipation Respiratory Abuse

Depression Liability
Morphine +++ ++ +++ +++ +++
Meperidine ++/+++ -  +++ ++
Methadone +++ ++ ++ +++ ++
Levorphanol +++ ++ ++ +++ +++
Oxycodone ++ ++ ++ ++ +++
Codeine + ++ ++ + 
Nalbuphine ++/+++ -  ++/+++ 
Butorphanol ++/+++ -  ++/+++ 
Pentazocine ++/+++ -  ++/+++ +
Antagonists
Morphine derivatives with high affinity for µ-opioid receptors

No analgesic effects.

Displaces all receptor-bound opioid.

Dramatic reversal of opioid effects within minutes, almost

instantaneously precipitates withdrawal syndrome.

Normalizes respiration, level of consciousness, pupil size,

bowel activity and awareness of pain.

No tolerance or withdrawal syndrome with cessation

 Antagonists
Drug Indications Points to note
Naloxone •Partial Post-Operative Opioid Reversal Short t1/2. Patients should be
closely monitored as severe
respiratory depression may
•Acute Opioid Overdose disappear with a single dose,
only to relapse into coma
shortly thereafter.
Naltrexone •Opioid maintenance Long t1/2. Duration of action
24hrs. Only use is to aid
maintenance of non-opiate in
•Chronic alcoholism former addicts. Concurrent
opiate use will be without
effect. Should not be
•Smoking cessation (combined with
administered to a patient
bupropion) failing a naloxone challenge
to confirm opiate-free state
•Combined with morphine for post-
operative pain control in controlled-release
formulation
 Opioid Use and Abuse

In US, between 1999 and 2014 there were >165,000 deaths due to opioid
overdose and the rate is steadily increasing
Websites
CDC guidelines for prescribing opioids for chronic pain – US, 2016

https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm

Safe and Effective Opioid Prescribing for Chronic Pain

http://www.opioidprescribing.com/overview

European Pain Federation position paper on appropriate opioid use in chronic

pain management

http://onlinelibrary.wiley.com/doi/10.1002/ejp.970/pdf