Opioids and opiates act on mu, kappa, and delta opioid receptors throughout the body and brain. Mu receptors are responsible for analgesia, respiratory depression, and euphoria, making overdose dangerous. Chronic use can increase tolerance and risk of overdose. While prescription opioids started the current crisis, many users transition to highly dangerous illegal opioids like fentanyl and fentanyl analogs. Naloxone is used to treat overdoses but very potent synthetic opioids require high doses or continuous infusion.

1. Opiates and Opioids,
Opioid Receptors & Mechanisms of Action
A. Ramasha M. Galappatthy
W. P. Rivindu H. Wickramanayake
Group no. 04a
6th Year 2nd Semester – 2020 October
Tbilisi State Medical University, Georgia

2. ● Conventionally, the term opiates refer to natural compounds usually obtained
from the poppy flower base.
● Opioids are synthesized by chemical processes.
● Opiates and opioids are among the most commonly abused substances throughout
the world.
● Addiction to opioids and opiates has become a significant health problem in the
developed world since the 2000s.
● About 21 to 29 percent of patients prescribed opioids for chronic pain misuse
them, and about 8 and 12 percent develop an opioid use disorder.
● It is estimated 4 to 6 percent who misuse prescription opioids transition to heroin.
● Opioid overdoses accounted for more than 42,000 deaths in 2016, more than any
previous year on record. About 40% of opioid overdose deaths involved a
prescription opioid.
Introduction

3. ● Opioids are derived synthetically from generally unrelated compounds.
● Opiates are derived from the liquid of the opium poppy either by direct refinement or by
relatively minor chemical modifications.
● Both opioids and opiates act on three major classes of opioid receptors: mu, kappa, delta,
and several minor classes of opioid receptors like nociceptin, and zeta.
● Simplifying significantly, the mu receptors are thought to provide analgesia, respiratory
suppression, bradycardia, physical dependence, gastrointestinal dysmotility, & euphoria.
● The kappa agonism can yield hallucinations, miosis, and dysphoria.
● The delta receptor likely has pain control and mood modulation effects, but some have
suggested that mu agonism is necessary for the delta receptor to function strongly for
analgesia.
● The nociceptin receptor modulates brain dopamine levels and has clinical effects like
analgesia and anxiolysis.
● The zeta receptor, also known as the opioid growth factor receptor, can modulate certain
types of cell proliferation, such as skin growths, and is not thought to have many functions
in the modulation of pain or emotion.
Continued;

4. ● Effects of chronic cocaine on kappa opioid receptors.
● In cocaine naïve animals, after dopamine release activates D1-containing medium spiny neurons, dynorphin is released resulting in
activation of KORs which further leads to inhibition of dopamine release. Such a feedback maintains homeostatic balance.
● After noncontingent intermittent cocaine exposure while there is no change in KOR function, DAT function is upregulated. After
noncontingent chronic cocaine exposure, however, there is an upregulation of KOR function and downregulation in DAT function.
● Thus, once dopamine is released and it activates D1-containing medium spiny neurons dynorphin is released, but it is hypothesized
that this dynorphin release is greater.
● Furthermore, studies have shown that KOR function is upregulated following chronic ethanol exposure.
● Thus, when KOR is activated by dynorphin, there is an enhanced effect of KORs on the inhibition of dopamine release resulting in
low dopamine in the extracellular space.
● DAT = dopamine transporter; KOR = kappa opioid receptor.

5. ● Impact of heteromerization on mu opioid receptor signaling and trafficking.
● Heteromerization can take place in the endoplasmic reticulum.
● Association with another opioid receptor positively modulates mu opioid receptor G protein-dependent
signaling whereas association with a non-opioid receptor negatively regulates it.
● Heteromerization also favors the recruitment the β-arrrestin dependent pathway upon internalization in the
endosomal compartments.

7. ● Causes of opioid overdose can include:
• Complications of substance abuse
• Unintentional overdose
• Intentional overdose
• Therapeutic drug error
● Risk of opioid overdose increases in the following:
• Those that take escalating doses
• Return to use after cessation
• Those with severe medical and psychiatric conditions such as depression, HIV, and
lung/liver disease
• Those that combine opioids and sedative medications
• Male gender
• Younger age (20 to 40 years)
• White non-Hispanic race
● More than 1.5 million emergency department visits are related to opioid analgesics.
● Opioids are a common cause of death due to overdose.
Etiology

8. ● The 2014 United Nations Office on Drug and
Crime estimates that at least 0.4% of the
population or close to 20 million people regularly
use heroin or opium.
● The highest level of usage are in South West Asia
(1.21%), followed by Southeastern and Eastern
Europe (0.83%) and Transcaucasia and Central
Asia (0.81%).
● In Europe, the major cause of opiate deaths has
been associated with the illicit use of fentanyl and
its analogs.
● In countries where there is a heroin shortage,
fentanyl and related products have replaced
heroin as the illicit drug of use.
● Opiates:
• Buprenorphine
• Fentanyl
• Hydromorphone
• Methadone
• Morphine
• Oxycodone
● Use of codeine
decreased by 20%.
Epidemiology

9. ● Opioids work via the endogenous opioid system by acting as a potent agonist
to the mu receptor.
● This results in a complex cascade of intracellular signals resulting in dopamine
release, blockade of pain signals, and a resulting sensation of euphoria.
● Opioid receptors are located in the brain, spinal cord, and gut.
● In overdose, there is an excessive effect on the portion of the brain regulating
respiratory rate, resulting in respiratory depression and eventually death.
● The typical symptoms seen in overdose are pinpoint pupils, respiratory
depression, and a decreased level of consciousness. This is known as the
“opioid overdose triad”.
● Opioids may be agonists, partial agonists, or agonist-antagonists of opioid
receptors.
● The currently available opiates lower the perception of pain and in some case
decrease the pain stimulus.
Pathophysiology

10. ● There are several types of opiate receptors in the CNS & the PNS.
● When receptors are stimulated, it results in suppression of sensation of pain.
● However, not all opiate receptors have same analgesic potency when stimulated.
● Opioids reduce pain perception by inhibition of synaptic neurotransmission and
binding of opioid receptors in the central and peripheral nervous systems.
● Main opioid receptors that mediate effects of opioids are mu, kappa, & delta.
● Mu receptors mediate analgesia, euphoria, sedation, respiratory depression,
gastrointestinal dysmotility, and physical dependence.
● Mu receptors cause a medullary diminished response to hypercarbia and also
a decrease in the respiratory response to hypoxia, resulting in a decreased
stimulus to breathe and development of apnea.
● Kappa receptors mediate analgesia, diuresis, miosis, and dysphoria.
● Delta receptors mediate analgesia, inhibition of dopamine release, and
cough suppression.
Continued;

11. ● The role of the sigma and delta opiate receptors has not been as well studied.
● However, when the sigma receptors are stimulated the individual will develop
hallucinations, dysphoria, and psychosis, whereas the delta receptors will
produce analgesia, euphoria, and seizures.
● Sigma receptors are no longer considered opioid because naloxone does not
antagonize them.
● Tolerance occurs rapidly with opioids.
● With overdose, patients often succumb to respiratory failure.
● Tolerance to loss of the hypercarbic drive takes longer to develop than other
euphoric effects, but opioid-tolerant patients do not develop complete
tolerance to loss of hypoxic stimulus.
● This leaves them susceptible to death from overdose.
Continued;

12. ● Opiates can be administered intravenously (IV), topically, inhaled,
intramuscularly (IM), and orally.
● Following intravenous administration, the peak effects of the opiate are reached
within 5 to 10 minutes but may take up to 90 minutes when administered orally.
● Following nasal insufflation, drugs Like heroin and butorphanol can reach peak
levels within 10 to 15 minutes and about 30 to 45 minutes following
intramuscular injection.
● Fentanyl which is the only available topical analgesic agent often takes 2 to 4
hours to reach peak levels.
● When administered orally, the majority of opiate absorption occurs in the small
intestine.
● When large doses of opiates are consumed, this can lead to gastric aperistalsis
and a delay in gastric emptying and absorption of the drug.
● Once in the body, opiates are broken down by the liver to inactive compounds
that are excreted primarily by the kidneys.
Toxicokinetics

13. ● Opiates like buprenorphine and fentanyl are highly lipid soluble and tend to redistribute into
the fatty tissues and thus, have a prolonged half-life.
● Since all opiates are broken down by the liver, they tend to have a long half-life when
consumed in the presence of liver dysfunction (for example, cirrhosis).
● In these patients, opiate toxicity can occur rapidly even with small doses as the drug remains in
the body for a long time.
● The hepatic microsomal CYP2D6 enzyme is responsible for breaking down codeine into the
active metabolite, morphine.
● Some individuals carry more than 2 copies of the enzyme, and these ultrarapid metabolizers
breakdown codeine into morphine rapidly; thus, individuals who take even normal doses of
codeine may develop morphine toxicity.
● The same mechanism of ultrarapid breakdown explains why tramadol can cause opiate toxicity.
● Once broken down in the liver, the opiate metabolites are excreted in the urine.
● Individuals with renal dysfunction may develop adverse effects from the accumulated active
metabolites like normeperidine.
● Several other studies show that long-acting opiates used for non-cancer pain can increase the
risk of adverse cardiac events compared to tricyclics or anticonvulsants.
Continued;

14. ● Available in oral, IM, and IV formulations, sublingual and inhaler formulas
on the market.
● Butorphanol is available in an intranasal form and fentanyl is available both
as a topical and as an inhaler.
● The transdermal delivery of opiates like fentanyl has been widely accepted in
healthcare settings for analgesic relief.
● This route of administration is favored because the drug levels take 4 to 6
hours to peak and there is a long elimination half-life, thus making the drug
suitable for use in patients with chronic continuous pain.
● In addition, because of the relatively prolonged slow onset of action, this
route of administration is rarely known to precipitate toxicity.
● However, the topical formulation of fentanyl can contribute toward the
toxicity of parenteral or oral opiates.
Formulas of Opiates and Delivery

15. ● Dextromethorphan was once widely available in many over the counter cough
preparations, but because of diversion, it is no longer available in over the
counter products.
- Dextromethorphan may have been an over the counter preparation,
but at high doses, it is known to cause sedation and even respiratory depression.
- Further, the use of dextromethorphan by patients who have been
prescribed monoamine oxidase inhibitors can lead to the life-threatening
serotonin syndrome that can lead to adverse cardiac events.
● Tramadol (Ultram), although classified as a non-opiate analgesic, has a dual
mode of action by acting on non-opiate and opiate receptors.
- Tramadol has a comparatively long duration of action of 5 to 6
hours.
- If it is known that a patient has overdosed on tramadol, naloxone is
recommended, and most people require repeated doses or a continuous IV infusion.
Continued;

16. ● Several types of synthetic fentanyl derivatives on the street like alpha-Methylfentanyl, which
are extremely potent.
● In fact, several deaths have been reported in drug abusers with the needle still in the arm.
● One other synthetic derivative, 3-Methylfentanyl, is several thousand times more potent than
morphine and when people overdose on it, extremely high doses of intravenous naloxone
infusions are required.
● Deaths from these fentanyl derivatives often occur in clusters as the sellers go from street to
street, leading to multiple deaths along the way.
● Pentazocine is classified as a partial agonist-antagonist and is used to treat moderate to severe pain.
- It acts by stimulating the K-opiate receptors (KOR) and inhibiting the Mu-opiate receptors (MOR).
- The drug shares many of the same features of other opiates in terms of adverse effects.
- The one unique feature about pentazocine is that it also is known to cause nightmares, hallucination,
and delusions.
- The drug is also subject to a high ceiling effect, meaning once a certain dose is reached, no further
pain relief can be obtained.
- Although the pharmacological effects of pentazocine can be reversed by naloxone, extremely high
doses of naloxone (10 to 115 ng) are required.
Continued;

17. ● Propoxyphene is an opiate analgesic and was once prescribed to manage mild pain and cough.
- Naloxone can reverse the toxicity of propoxyphene but not the cardiac arrhythmias.
- The cardiac arrhythmias are due to the quinidine-like effects of propoxyphene and are unresponsive to
naloxone.
- Propoxyphene is known to cause sinus bradycardia, ear block or ventricular arrhythmia. The
treatment is to immediately administer sodium bicarbonate.
● Diphenoxylate/Atropine: This combination product is often used to treat diarrhea.
- The diphenoxylate acts like an antidiarrheal agent, and the atropine is an anticholinergic that is added
to deter deliberate overdose.
- Atropine has no antidiarrheal activity. When high doses are ingested, one may note mainly
anticholinergic side effects, respiratory depression, and constipation.
- Because of the long half-life of diphenoxylate, the adverse effects can be worrying.
- The majority of cases of diphenoxylate/atropine overdose are seen in children.
- If the child is seen in the emergency room within a few hours after ingestion, gastric decontamination
with activated charcoal may be attempted. |
- All children need to be observed for a minimum of 6 hours to ensure that they do not develop
arrhythmias.
Continued;

18. ● Body packers: Over the past 2 decades, the transport of illicit drugs in the body has
become very common.
- These individuals place drugs inside plastic bags or condoms and ingest them.
- Often the number of packages ingested vary from 1 to 3 dozen and even though well
wrapped, sometimes the packages do break open and systemic toxicity results.
- Others may develop complications like bowel obstruction or intestinal perforation.
- In some cases, when the individual is pursued by police, he or she may stuff the drugs
into the anus, vagina, or ingest them.
- These individuals are likely to suffer from adverse effects because the drugs are often not
properly packaged.
- After ingestion, systemic symptoms appear rapidly, and these individuals often require
aggressive medical therapy to prevent death, and in some cases, surgery is required to
relieve a bowel obstruction.
- Even after surgery, if the drugs have been absorbed into the systemic circulation, the risk
of death is often high.
Continued;

19. References
 https://www.ncbi.nlm.nih.gov/books/NBK470415/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851054/
 https://www.ncbi.nlm.nih.gov/books/NBK431077/
 https://www.ncbi.nlm.nih.gov/books/NBK459161/
 https://www.ncbi.nlm.nih.gov/books/NBK526012/
 Wang S. Historical Review: Opiate Addiction and Opioid Receptors. Cell
Transplant. 2019 Mar;28(3):233-238. [PMC free article] [PubMed]
 https://www.researchgate.net/figure/Effects-of-chronic-cocaine-on-kappa-opioid-
receptors-In-cocaine-naive-animals-after_fig3_319646539
 https://www.frontiersin.org/articles/10.3389/fphar.2018.01240/full
 https://www.researchgate.net/figure/Schematic-illustration-of-mechanisms-involved-in-
opioid-receptor-desensitization-by_fig1_270661788
 https://europepmc.org/article/pmc/1661636