The document discusses opioid analgesics and their mechanisms of action. It notes that the body has an endogenous analgesic system centered in the brainstem that is stimulated by opioids. Opioids work by binding to mu, delta, and kappa receptors in the brain and spinal cord, inhibiting pain signal transmission. Several opioid analgesics are described, including morphine, codeine, heroin, fentanyl, and methadone. Tolerance, side effects, metabolism, and antagonists are also discussed. The future of opioid analgesics is seen to involve further study of the kappa receptor and endogenous opioid peptides to develop safer drugs.

1. OPIOID ANALGESICS
Ravish Yadav

2. Opioid Analgesics
The body has its own analgesic system that has evolved to kick-in when
an animal is injured
This in-built analgesia provides short-term relief from pain that enables
an animal to escape from predators or extract themselves from a
dangerous situation without being crippled with pain
Opioid analgesics utilise this system to provide controlled pain-relief
This system is stimulated by other stimuli beside pain, including
exercise and stress

3. Brain stem
Spinal cord
Thalamus
Cortex
Peripheral stimulus
Descending
modulation
pathway
Reticular
formation in
brain stem
Target area for
opioid analgesia

4. Neuromodulation of nociceptive pathways
The body possesses its own analgesic system which is centred in the
periaqueductal grey matter of the brain
Efferent neurons from this area synapse in the reticular formation of
the brain stem and then to the first order afferent neurons in the spinal
cord
Here they release neurotransmitters which block the synaptic
transmission of the afferent fibres and so attenuate the experience of
pain
This area is a key target for analgesic drugs including opioids and
(probably) paracetamol

5. Neuromodulation of nociceptive pathways
Inhibitory neurotransmitters include GABA, norepinephrine and a
family of endogenous opioid peptides
The endogenous opioid peptides vary in influence with location and
include…
Brain – b-endorphin, dynorphin and enkephalins
Spinal cord
• interneurons - esp. dynorphin
• descending pathways – esp. enkephalins

6. Neuromodulation of nociceptive pathways
Endogenous opioid peptides bind to several sub-types of opioid
receptor…
• m (mu)
• d (delta)
• k (kappa)
Opioid drugs can bind to these receptors as agonists and produce
similar effects to the endogenous opioid peptides
Most analgesic effects associated with m receptors

7. Neuromodulation of nociceptive pathways
Most analgesic effects associated with m receptors
The following opioid analgesics are specific for m receptors…
• morphine
• codeine
• methadone
• buprenorphine
• Fentanyl
d and k receptors also contribute to analgesia
Nalbuphine and pentazocine also have specificity for d and k receptors

8. Mechanism of Neuromodulation
The binding of endogenous or exogenous opioids to opioid receptors
promotes the opening of K+ channels and inhibits the opening of Ca2+
channels
Opening K+ channels hyperpolarises membranes and reduces neuronal
activity
Closing Ca2+ channels inhibits synaptic activity by reducing the release
of neurotransmitters

9. Synapses between afferent nociceptive neurons and secondary ascending neurons
relay pain signals to the brain. The entry of Ca2+ into the pre-synaptic primary neuron
and the release of K+ from the post-synaptic secondary neuron are processes involved
in signal transmission across the synapse.
Primary
afferent
nociceptor
terminal
Secondary
ascending
neuron
Ca2+ Ca2+
K+
K+
Neurotransmitter
glutamate
m opioid
receptor
m opioid
receptor

10. Mechanism of Neuromodulation
Opioids bind to m receptors associated with these channels
This firstly enhances the opening of K+ channels and secondly inhibits
the opening of Ca2+ channels
This hyperpolarises the membrane and inhibits the release of
neurotransmitters respectively
Both of these events inhibit the transmission of nociceptive signals to
ascending pathways to the brain

11. Secondary
ascending
neuron
Primary
afferent
nociceptor
terminal
Ca2+ Ca2+
K+ K+
Neurotransmitter
glutamate
m opioid
receptor
m opioid
receptor
Opioid
Opioid
Opioids binding to ion channel associated m receptors inhibit the influx of calcium ions into the
pre-synaptic terminal and increase the outflow of potassium ions from the post-synaptic
membrane. This has the effect of reducing the release of the neurotransmitter glutamate and
hyperpolarising the post-synaptic membrane. Synaptic transmission is inhibited.

13. Physiological action of opioids
The effects of opioids on neurological pathways is complex…
1. attenuation of nociceptive synapses in the dorsal horn
2. attenuation of nociceptive stimulation in periphery
3. stimulation of descending pathways that inhibit
nociceptive synapses

14. Opioids – side effects
Most opioid side effects associated with m receptors
• respiratory depression (reduces sensitivity of
respiratory centres in brain stem to CO2)
• euphoria (and dysphoria via k receptors)
• sedation
• dependence
• reduction in GI motility
• bronchoconstriction (histamine release stimulated)
Different opioid drugs interact with different subspecies of receptor
producing different actions and side effects

15. Opioids - tolerance
Tolerance can develop rapidly with opioid use, requiring an increase in
dose for effective analgesia.
Tolerance may be observed in side-effects too…
Tolerance may be observed in the mechanism that results in
respiratory depression but constipation is worsened by large doses.

16. Pharmacokinetics
Morphine is erratically absorbed but oral administration may be
acceptable for chronic pain
Codeine is well absorbed orally but subject to considerable first-pass
metabolism in the liver
The half life of most morphine analogues is around 3-6 hours

17. Opioid antagonists
Opioid antagonists such as naloxone (short acting) and naltrexone
(long-term), block m receptors and reverse the action of opioids
However, antagonists can make clinical pain worse

18. Morphine
•Morphine is the golden standard among
opioid analgesics to which the structure
and strengths of all other drugs are
compared
•It is the primary ingredient in opium and
was isolated in 1806
•Morphine has strong binding affinity for
the mu and delta opioid receptors and
some weak affinity for the kappa
receptor

19. Morphine
• Morphine is administered in subcutaneous,
intravenous or epidural injections or orally in the
form of a solution (however this form is far less
potent).
• Morphine acts extremely fast and crosses the
blood brain barrier quickly but is not as fast acting
lipid-soluble opioids such as codeine or heroin.

20. Morphine Metabolism
•Once morphine is administered about one third of it
become bound to proteins in the plasma
•The major pathway for the metabolism of morphine
is conjugation with glucuronic acid
•Two metabolites are formed from this conjugation
which cross the blood brain barrier. Morphine-6-
glucuronide seems to be the metabolite responsible
for the associated interactions of morphine with the
opioid receptors.

21. Morphine
• PHARMACOKINETICS
• Routes of administration (preferred)
*Oral
latency to onset –(15 – 60 minutes )
• * it is also sniffed, swallowed and injected.
• * duration of action – ( 3 – 6 hours)
• * First-pass metabolism results in poor
• availability from oral dosing.
• * 30% is plasma protein bound
• EFFECTS AND MEDICAL USES
• *symptomatic relief of moderate to severe pain
• *relief of certain types of labored breathing
• *suppression of severe cough (rarely)
• *suppression of severe diarrhea
• *AGONIST for mu, kappa, and delta receptors.

22. Side Effects of Morphine
• Side effects of morphine include a depression of cough due to
respiratory depression, nausea caused by increased vestibular
sensitivity, and decreased gastric motility and some constipation.
• Morphine use is also thought to be associated with some cases of
renal failure as well as acute pancreatitis.

23. Codeine
• Codeine is also an alkaloid that is
found in opium but to a far
lesser extent than morphine.
• It differs structurally from
morphine in that its phenol
group is methylated. It is often
referred to as methyl-morphine.

24. Codeine
•Oxycodone and methadone are analogs of codeine
•Codeine itself has low binding affinity to all of the
opioid receptors. Its analgesia producing effects
come from its conversion to morphine.
•When codeine is administered about ten percent is
converted to morphine by O-demethylation that
occurs in the liver by an enzyme called cytochrome
p450.
•Because of this Codeine is far less potent than
morphine

25. Codeine
•Codeine is usually administered
orally and it is much more
effective orally than morphine
(about 60%)
•Because of the side effect of
respiratory depression and
depressed cough, codeine is
often found in cough medicines

26. Abuse of Codeine
• The use of Codeine as a recreational drug for its euphoric effects is
spreading greatly.
• This abuse is mostly isolated to Texas
• Recreational users refer to codeine as “lean” and will mix the drug
with alcohol or other drugs.

27. Heroin
•Heroin is diacetylmorphine
produced from the acetylation of
morphine.
•Heroin was first synthesized in
1874.
•Although Heroin is illegal, it is still
legally prescribed, mostly in
terminal patients, as diamorphine.

28. Heroin
• Heroin is mostly found in a white crystalline form diacetylmorphine
hydrochloride.
• It is administered through intravenous injections but can also be
administered orally or vaporized.
• It binds most strongly to the mu receptor and is also active in the form
of morphine as its acetyl groups are removed.
• It produces euphoric effects similar to morphine, however, it is
thought that these effects are greater and more addicting because of
its extremely rapid effect.
• Its fast action is a result of being extremely lipid-soluble because of its
acetyl groups and therefore it immediately crosses the blood brain
barrier.

29. Heroin
• The use of Heroin causes the body to
produce far less of its natural opioid
peptides, the endorphins. This creates
a dependence on heroin.
• When a heroin user stops using the
drug the withdrawal symptoms are
severe.
• Withdrawal symptoms include anxiety,
depression, cramps, vomiting,
diarrhea, restless leg syndrome (hence
kicking the habit), and a severe sense
of pain caused by nothing.
• Many addicts in withdrawal
experience “itchy blood” which can
drive the addict to scratch cuts and
bruises into his body.

30. Methadone
• Methadone is often used to treat heroin addiction
because it is a longer lasting opioid.
• It has a half life of 24 to 48 hours compared to 2 to
4 hours found with morphine and codeine.
• It is an analog of codeine and it was first
synthesized in 1937.

31. Other Opioid Analgesics
•Many other opioid analgesics
exists and are currently being
developed that our based from
the common opiate structure
•These drugs have differences in
their substituents that changes
their effects and methods of
action at their receptors

32. Other Opioid Analgesics
•Fentanyl is about 1000
times stronger than
morphine.
•Carfentanil is about
10,000 more times more
potent than morphine
(It is used as a
tranquilizer for large
animals)

33. Opioid Antagonists
•Opioid Antagonists are used to treat opioid
overdose cases.
•Most are derived from Thebaine (an alkaloid of
Opium)
•The have strong binding affinity for the mu
receptors
•They work by competitive inhibition at the binding
site (It binds but does not change the receptor
while at the same time blocking the agonist).

34. Opioid Antagonists
• Naloxone is an example of a
opioid antagonist.
• It is administered intravenously.
• It can rapidly produce the
withdrawal symptoms associated
with opioid addiction.
• Naltrexone is another example of
an opioid antagonist. It is more
potent than Naloxone and is used
in the treatment of alcohol
addiction but its mechanism in
this treatment is unknown.

35. Fentanyl
• Pharmacokinetics
• Routes of Administration
* Oral, and transdermal (possibly intravenous)
*Highly lipophilic
*latency to onset (7-15 minutes oral; 12-17 hours
transdermal
*duration of action ( 1-2 hours oral; 72 transdermal)
*80 – 85% plasma protein bound
*90 % metabolized in the liver to inactive metabolites
Other properties
* 80 times the analgesic potency of morphine
and 10 times the analgesic potency of
hydromorphone.
*high efficacy for mu 1 receptors.
*most effective opiate analgesic

36. Future of Opioid Analgesics
• The future of Opioid Analgesics seems to be linked to the study of the
Kappa Receptor. The kappa receptor induces analgesia without the
dangerous and unwanted side effects that the mu and delta receptors
are associated with. However there are not any selectively strong
agonists to this receptor as of now.

37. Future of Opioid Analgesics
• Another area of research important to the future of opioid analgesics
is the study of the endogenous opioid peptides.
• Because these peptides are endogenous, on metabolic degradation
(unlike opiates) they break down to amino acids. Hence, the
metabolites are nontoxic and to not cause kidney and liver damage .”
• Also, because they are made from amino acid residues, “a large
number of analogs can be synthesized from a few basic building blocks
and simple modifications may be attempted to develop analogs with a
desired biological effect .”
• The further study of the endogenous opioid peptides seems to be
integral to development of new safer drugs.