1 Opiods

Review Material: Opioids

I. Overview:

- Pain management is a challenging aspect of clinical medicine.

- Pain is an unpleasant sensation resulting from neurochemical processes in the peripheral and central nervous
systems.

- Pain is subjective and relies on the patient's perception and description.

- Different types of pain require specific treatment approaches.

- Mild to moderate arthritic pain can be relieved using nonopioid analgesics like NSAIDs.

- Neuropathic pain responds well to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine

- Opioids can be considered for severe acute pain or chronic malignant/nonmalignant pain.

- Opioids are natural, semisynthetic, or synthetic compounds with morphine-like effects.

- They bind to specific opioid receptors in the CNS, mimicking endogenous neurotransmitters.

- Opioids are primarily used to relieve intense pain from surgery, injury, or chronic diseases.

- However, their availability has led to abuse, necessitating the use of opioid antagonists in cases of overdose.

II. Opioid Receptors:

- Opioid effects are mediated by three main receptor families: mu (MOR), kappa (KOR), and delta (DOR).

- Each receptor family has different drug binding specificities.

- The analgesic properties of opioids are primarily mediated by mu receptors, which modulate responses to
thermal, mechanical, and chemical nociception.

- K receptors in the dorsal horn also contribute to analgesia by modulating responses to chemical and thermal
nociception.

- Enkephalins interact selectively with delta receptors in the periphery.

- All opioid receptors belong to the G protein-coupled receptor family and inhibit adenylyl cyclase.

- They are associated with ion channels, leading to hyperpolarization or reduced neuronal firing and transmitter
release in the spinal dorsal horn.

(Note: The review material provided here summarizes the content related to opioids and opioid receptors. It may
be useful for studying the basic concepts and principles associated with opioids in pain management.)

Review Material: Opioid Agonists

III. Opioid Agonists:

A. Morphine:

- Morphine is a strong mu receptor agonist and the prototypical opioid.

- Codeine is a weak mu opioid agonist compared to morphine.

- Available opioids differ in receptor affinity, pharmacokinetic profiles, routes of administration, and adverse
effect profiles.

- Morphine is used as a reference point to compare other opioids for selecting appropriate pain management
strategies.

1. Mechanism of action:

- Morphine interacts with opioid receptors in neuronal cells of the CNS, smooth muscles of the gastrointestinal
(GI) tract, and urinary bladder.

- Morphine has some affinity for kappa (k) and delta (δ) receptors, but it is somewhat selective for the mu
receptor.

- Morphine inhibits the release of excitatory transmitters involved in transmitting painful stimuli.

- Therapeutic uses of morphine include analgesia and other applications.

2. Actions:

a. Analgesia: Morphine raises the pain threshold at the spinal cord level and alters the brain's perception of pain.

b. Euphoria: Morphine produces a sense of contentment and well-being, possibly by disinhibiting dopamine-
containing neurons.

c. Respiration: Morphine causes respiratory depression by reducing the responsiveness of respiratory center
neurons to carbon dioxide. Respiratory depression is a common cause of death in opioid overdoses.

d. Depression of cough reflex: Morphine and codeine have antitussive properties.

e. Miosis: Morphine stimulates mu and kappa receptors, leading to pinpoint pupils.

f. Emesis: Morphine stimulates the chemoreceptor trigger zone, causing vomiting.

g. GI tract: Morphine relieves diarrhea, decreases intestinal motility, and increases anal sphincter tone. It also
causes constipation and increases biliary tract pressure.

h. Cardiovascular: Morphine has minimal effects on blood pressure and heart rate at lower doses, but higher
doses can cause hypotension and bradycardia. It is contraindicated in individuals with head trauma or severe
brain injury.

i. Histamine release: Morphine releases histamine, leading to urticaria, sweating, and vasodilation. Caution
should be exercised in patients with asthma.

j. Hormonal actions: Prolonged use of morphine can cause opioid-induced androgen deficiency, resulting in
decreased sex hormone production.

k. Labor: Morphine may transiently prolong the second stage of labor.

3. Pharmacokinetics:

- Morphine has a linear pharmacokinetic profile.

- Oral absorption is slow and erratic, but extended-release oral preparations provide more consistent plasma
levels.

- Subcutaneous and intravenous (IV) injections produce the most reliable response.

- Morphine rapidly distributes to all body tissues, including the fetus, and should not be used for labor analgesia.

- Metabolism occurs in the liver, resulting in active metabolites (morphine-S-glucuronide [M6G] and morphine-3-
glucuronide [M3G]), which are renally excreted.
3 Opiods

- Morphine's duration of action is 4 to 5 hours when administered systemically to opioid-naive individuals but
longer with epidural administration.

4. Adverse effects:

- Adverse effects are common across the opioid class.

- Severe respiratory depression is a significant risk with mu agonists and can lead to overdose and death.

- Opioid-induced constipation (OIC) is a common adverse effect.

- Other adverse effects include sedation, nausea, vomiting, urinary retention, dizziness, confusion, and physical
dependence.

- Morphine should be used cautiously in patients with liver disease and renal dysfunction.

5. Tolerance and physical dependence:

- Repeated use leads to tolerance for respiratory depression, analgesia, euphoria, emesis, and sedation.

- Tolerance does not usually develop for miosis or constipation.

- Physical and psychological dependence can occur with morphine and other opioids.

- Withdrawal symptoms may be severe but rarely cause death.

6. Drug interactions:

- Morphine can interact with other medications, especially CNS depressants like phenothiazines, MAO inhibitors
(MAOis), and benzodiazepines.

- Simultaneous prescribing of opioids and benzodiazepines is strongly discouraged due to the enhanced
depressant effects.

- A black box warning alerts prescribers about the dangerous combination of opioids and benzodiazepines.

Review Material: Opioid Agonists (Continued)

B. Codeine:

- Codeine is a naturally occurring opioid and a weak analgesic compared to morphine.

- Its analgesic actions result from conversion to morphine by the CYP2D6 enzyme.

- CYP2D6 activity varies among individuals, and ultrarapid metabolizers may experience higher levels of
morphine, leading to potential overdose and toxicity.

- Codeine is commonly used in combination with acetaminophen for pain management.

- It exhibits good antitussive activity at doses that do not cause analgesia.

- Dextromethorphan is a synthetic cough suppressant preferred over codeine in situations requiring cough
suppression due to its lower abuse potential and lack of analgesic action.

C. Oxycodone and Oxymorphone:

- Oxycodone and oxymorphone are orally active, semisynthetic analogs of morphine and codeine, respectively.

- Oxymorphone is approximately ten times more potent than morphine parenterally but drops to about three
times the potency when administered orally.
4 Opiods

- Oxycodone is approximately two times more potent than morphine and is available in immediate-release and
extended-release formulations.

- Oxycodone is mainly metabolized by the CYP2D6 and CYP3A4 enzymes.

D. Hydromorphone and Hydrocodone:

- Hydromorphone and hydrocodone are orally active, semisynthetic analogs of morphine and codeine,
respectively.

- Oral hydromorphone is about 4 to 7 times more potent than oral morphine.

- Hydromorphone is preferred over morphine in patients with renal dysfunction.

- Hydrocodone is a weaker analgesic than hydromorphone but comparable to morphine. It is often combined
with acetaminophen or ibuprofen for pain management.

- Hydrocodone is metabolized in the liver, including conversion to hydromorphone via CYP2D6.

E. Fentanyl:

- Fentanyl is a synthetic opioid related to meperidine.

- It is highly potent, approximately 100 times more potent than morphine.

- Fentanyl is used for anesthesia and acute pain management.

- It has a rapid onset and short duration of action, making it suitable for IV, epidural, or intrathecal
administration.

- Various formulations are available, including transmucosal, nasal, and transdermal patches.

- The transdermal patch is used for chronic severe pain but is contraindicated in opioid-naive patients and
acute/postoperative pain.

- Fentanyl is metabolized by CYP3A4, and inhibitors of this enzyme can potentiate its effects.

F. Sufentanil, Alfentanil, Remifentanil, and Carfentanil:

- Sufentanil, alfentanil, remifentanil, and carfentanil are synthetic opioid agonists related to fentanyl.

- Sufentanil and carfentanil are even more potent than fentanyl, while the others are less potent and shorter-
acting.

- They are mainly used for analgesia and sedation during surgical procedures.

- Carfentanil, although not used in clinical practice, is of toxicological interest due to its potency and association
with opioid-related deaths.

Review Material: Opioid Agonists (Continued)

G. Methadone:

- Methadone is a synthetic opioid with variable equianalgesic potency compared to morphine.

- It is a mu agonist, NMDA receptor antagonist, and norepinephrine/serotonin reuptake inhibitor.

- Methadone is used for nociceptive and neuropathic pain, opioid withdrawal, and maintenance therapy.

- Its withdrawal syndrome is milder but more protracted compared to other opioids.

- Methadone induces less euphoria and has a longer duration of action than morphine.
5 Opiods

- It is well absorbed after oral administration and has a constipating effect.

- Methadone has a long half-life ranging from 12 to 40 hours, with a duration of analgesia of 4 to 8 hours.

- Steady-state attainment can vary, and dosage adjustments should occur every 5 to 7 days.

- Methadone metabolism involves multiple CYP450 isoenzymes, leading to potential drug interactions.

- It can produce physical dependence and prolong the QTc interval, requiring ECG monitoring.

H. Meperidine:

- Meperidine is a lower-potency synthetic opioid structurally unrelated to morphine.

- It is primarily a kappa agonist with some mu agonist activity.

- Meperidine is highly lipophilic and has anticholinergic effects, increasing the risk of delirium compared to other
opioids.

- It has an active metabolite called normeperidine, which can be neurotoxic, especially in patients with renal
insufficiency.

- Meperidine should only be used for short-term pain management (≤48 hours) due to its short duration of
action and potential toxicity.

- It is contraindicated in elderly patients, those with renal/hepatic insufficiency, preexisting respiratory

- Serotonin syndrome can occur when meperidine is used concomitantly with selective serotonin reuptake
inhibitors (SSRIs).

Review Material: Partial Agonists and Mixed Agonist-Antagonists

IV. Partial Agonists and Mixed Agonist-Antagonists:

- Partial agonists have less intrinsic activity than full agonists and show a ceiling to their pharmacologic effects.

- Mixed agonist-antagonist drugs stimulate one receptor while blocking another.

- The effects of these drugs depend on previous exposure to opioids, and in opioid-naive individuals, they act as
agonists for pain relief.

- In the presence of a full agonist, mixed agonist-antagonists can precipitate opioid withdrawal symptoms.

A. Buprenorphine:

- Buprenorphine is a potent partial agonist at the mu (μ) receptor and an antagonist at the kappa (K) receptors.

- It has a longer duration of action and high affinity for opioid receptors compared to morphine.

- Buprenorphine can displace full mu agonists, leading to withdrawal symptoms in opioid-dependent patients.

- Due to its partial agonist activity, buprenorphine provides a "ceiling effect," causing less euphoria and lower
abuse potential than full agonists.

- It has a lower risk of respiratory depression, except when combined with CNS depressants.

- Buprenorphine is available in various formulations and is approved for moderate to severe pain and
medication-assisted treatment of opioid addiction.

- Adverse effects include respiratory depression that is not easily reversed by naloxone, decreased/increased
blood pressure, nausea, dizziness, and QTc interval prolongation.
6 Opiods

B. Pentazocine:

- Pentazocine acts as an agonist on kappa receptors and a weak antagonist or partial agonist at mu receptors.

- It can be administered orally or parenterally.

- Pentazocine produces less euphoria than morphine but can cause respiratory depression, increased blood
pressure, tachycardia, and hallucinations at higher doses.

- It does not antagonize the respiratory depression of morphine but can precipitate withdrawal effects in
morphine users.

- Caution should be exercised when using pentazocine in patients with angina or coronary artery disease due to
its potential to increase blood pressure.

C. Nalbuphine and Butorphanol:

- Nalbuphine and butorphanol are mixed opioid agonist-antagonists.

- They have a limited role in the treatment of chronic pain.

- Butorphanol is available in a nasal spray for severe headaches but has been associated with abuse.

- Both nalbuphine and butorphanol are available in injectable formulations.

- These medications have a lower propensity for psychotomimetic effects compared to pentazocine.

- Nalbuphine does not affect the heart or increase blood pressure.

- A benefit of all three medications is that they exhibit a ceiling effect for respiratory depression.

Review Material: Other Analgesics and Antagonists

V. Other Analgesics:

A. Tapentadol:

- Tapentadol is a centrally acting analgesic that acts as an agonist at the mu opioid receptor and inhibits
norepinephrine reuptake.

- It is used to manage moderate to severe acute and chronic pain, including neuropathic pain associated with
diabetic peripheral neuropathy.

- Tapentadol is mainly metabolized to inactive metabolites via glucuronidation and does not significantly interact
with the CYP450 enzyme system.

- Dosing adjustment is not necessary in mild to moderate renal impairment.

- Tapentadol should be avoided in patients who have received MAO inhibitors within the past 14 days.

- It is available in immediate-release and extended-release formulations.

B. Tramadol:

- Tramadol is a centrally acting analgesic that binds to the mu opioid receptor and weakly inhibits
norepinephrine and serotonin reuptake.

- It undergoes extensive metabolism via CYP2D6, resulting in an active metabolite with higher mu receptor
affinity.
7 Opiods

- Tramadol is used to manage moderate to severe pain and has less respiratory depressant activity compared to
morphine.

- Naloxone can only partially reverse tramadol toxicity and may increase the risk of seizures.

- Tramadol has been associated with misuse and abuse and should be used with caution in patients with a
history of seizures.

- Overdose or drug interactions with SSRIs, MAO inhibitors, and tricyclic antidepressants can lead to CNS
excitation and seizures.

- Anaphylactoid reactions have been reported.

VI. Antagonists:

- Opioid antagonists bind with high affinity to opioid receptors but do not activate receptor-mediated responses.

- They produce no profound effects in individuals not taking opioids.

- In opioid-dependent patients, antagonists rapidly reverse the effects of agonists (e.g., morphine) and
precipitate opioid withdrawal symptoms.

- Opioid withdrawal symptoms may include various signs and symptoms as summarized in Figure 14.12.

Origin of Opiods:

Natural:

Morphine

Codeine

Semi synthethic:

Buprenorphine

Hydromorphone

Hydrocodone

Oxycodone

Oxymorphone

Synthethic:

Fentanyl

Meperidine

Methadone

Tapentadol

Tramadol
8 Opiods

Penantrenes+ Action on Opioid Receptors:

- Morphine: Agonist

- Codeine: Agonist

- Oxycodone: Agonist

- Oxymorphone: Agonist

- Hydromorphone: Agonist

- Hydrocodone: Agonist

- Levorphanol: Agonist

- Buprenorphine: Partial agonist/antagonist

- Nalbuphine: Partial agonist/antagonist

- Butorphanol: Partial agonist/antagonist

- Naloxone: Antagonist

Benzmorphan + Action on Opioid Receptors:

- Pentazocine: Mixed agonist/antagonist

Phenylpiperidines + Action on Opioid Receptors:

- Fentanyl: Agonist

- Alfentanil: Agonist

- Remifentanil: Agonist

- Sufentanil: Agonist

- Meperidine: Agonist

Diphenylheptane:

- Methadone: Agonist

Phenylpropylamines:
9 Opiods

- Tramadol: Agonist

- Tapentadol: Agonist

Mechanism of action of mu opioid receptor agonists in the spinal cord:

- Activation of the opioid receptor decreases Ca2+ influx in response to incoming action potential.

- This decrease in Ca2+ influx leads to a decrease in the release of excitatory neurotransmitters, such as
glutamate.

- Activation of the opioid receptor also increases K+ efflux from the postsynaptic neuron.

- The increased K+ efflux reduces the response of the postsynaptic neuron to excitatory neurotransmitters.

Review of Opioids:

1. Morphine:

- Routes: PO (IR and ER), PR, IM, IV, SC, LA, SL, EA

- Comments:

- Metabolite M3G has no analgesic action but can be neuroexcitatory.

- Metabolite M6G is two to four times more potent than the parent drug and can cause oversedation and
respiratory depression.

- Abuse-deterrent formulations available.

- Active metabolites are renally eliminated and can accumulate in renal impairment.

2. Methadone:

- Routes: PO, IV, IM, SC

- Comments:

- No active metabolites.

- Racemic mixture.

- Metabolized by many CYP450 isoenzymes, posing a high risk of drug interactions.

- Substrate of P-glycoprotein.

- Long and variable half-life, increasing the risk of overdose.

- Very lipophilic and redistributes to fat stores.

- Duration of analgesia is shorter than elimination half-life, leading to the potential for accumulation with
repeated dosing.

- Can prolong QTc interval and cause torsades de pointes.

- Conversion to and from methadone and other opioids should be done with great care due to varying
equipotent dosing.

3. Fentanyl:

- Routes: IV, EA, IA, TD, OTFC, SL, buccal, nasal

- Comments:

- No active metabolites; suitable for patients with renal dysfunction but should be used with caution.

- Metabolized by CYP3A4.

- Approximately 100 times more potent than morphine.

- Less histamine release, sedation, and constipation compared to morphine.

4. Oxycodone:

- Routes: PO (IR and CR)

- Comments:

- Metabolized by CYP2D6 and CYP3A4.

- Black box warning for CYP3A4 drug interactions.

- Less histamine release and nausea compared to morphine.

- Abuse-deterrent formulation available.

5. Oxymorphone:

- Routes: PO (IR and ER), IV

- Comments:

- Immediate-release formulation has a longer duration of action and elimination half-life (8 hours) compared to
other immediate-release opioids.

- Oral bioavailability increases with food and should be administered 1 to 2 hours after eating.

- Bioavailability increased with coadministration of alcohol.

6. Hydromorphone:

- Routes: PO (IR and ER), PR, IV, SC, EA, IA

- Comments:

- Metabolized via glucuronidation to H6G and H3G, which are renally eliminated and can cause CNS side effects
in patients with renal insufficiency.

- Abuse-deterrent formulation available.

7. Hydrocodone:

- Routes: PO (IR and ER)

- Comments:

- Active metabolite is hydromorphone.

- Metabolized by CYP2D6 and CYP3A4.

- Abuse-deterrent formulations available.

8. Tapentadol:

- Routes: PO (IR and ER)

- Comments:

- Centrally acting analgesic with μ agonist activity and inhibition of norepinephrine reuptake.

- Efficacy in treating nociceptive and neuropathic pain.

- Metabolized predominantly by glucuronidation with no CYP450 interactions.

- Seizures and serotonin syndrome can occur in predisposed patients.

9. Tramadol:

- Routes: PO (IR and ER), Topical

- Comments:

Metabolized by Phase 1 and 2 enzymes (CYP2D6, CYP2B6, and CYP3A4) with potential drug interactions.

- Serotonin syndrome can occur due to drug interactions.

- Clinically used for pain treatment in children under 12 years old.

- Contraindicated in children aged 12-18 years who are obese, have severe lung disease, or have sleep apnea.

- Not recommended for breastfeeding mothers due to adverse reactions in infants.

- Dosing adjustments required in renal impairment.

- Review dosing recommendations in severe hepatic impairment.

10. Codeine:

- Routes: PO, SC

- Comments:

- Prodrug metabolized by CYP2D6 to the active drug morphine.

- Rapid metabolizers of CYP2D6 can experience toxicity.

- Inhibitors of CYP2D6 prevent conversion of codeine to morphine, thereby impeding pain control.

- Not recommended in patients with renal dysfunction.

- Use only for mild or moderate pain.

- Clinically used in the treatment of pain or cough in children under 12 years old.

- Contraindicated in children aged 12-18 years after tonsillectomy or adenoidectomy.

- Not recommended in children aged 12-18 years who are obese, have severe lung disease, or have sleep
apnea.

- Not recommended in breastfeeding mothers due to adverse reactions in infants.

11. Meperidine:

- Routes: PO, IV, SC, EA, IA

- Comments:

- Not recommended as a first-line opioid choice.

- Active metabolite normeperidine accumulates with renal dysfunction, leading to toxicity.

- Naloxone does not antagonize the effects of normeperidine and could worsen seizure activity.

- Not recommended in elderly patients, patients with renal dysfunction, or for chronic pain management.

12. Buprenorphine:

- Routes: SL, TD, IM, IV, Buccal (transmucosal), Implant

- Comments:

- Long duration of action; very lipophilic.

- Incompletely reversible by naloxone (transmucosal).

- Metabolized by CYP3A4, caution required for drug interactions with strong CYP3A4 inhibitors or inducers.

- Implant formulation available.

- Can prolong QTc interval.

- Transdermal patch is applied every 7 days.

- Abuse-deterrent formulations available.

Selected Clinical Uses of Opioids:

1. Analgesia:

- Morphine is the prototype opioid agonist.

- Opioids are used for pain management in trauma, cancer, and other types of severe pain.

2. Treatment of Diarrhea:

- Opioids decrease the motility and increase the tone of intestinal circular smooth muscle.

- Agents commonly used for this purpose include diphenoxylate and loperamide.

3. Relief of Cough:

- While morphine can suppress the cough reflex, codeine and dextromethorphan are more commonly used for
cough relief.

4. Treatment of Acute Pulmonary Edema:

- Intravenous morphine can dramatically relieve dyspnea caused by pulmonary edema associated with left
ventricular failure.

- This effect may be due to the vasodilatory effect of morphine, which decreases cardiac preload and afterload,
as well as anxiety experienced by the patient.

5. Anesthesia:

- Opioids are used as preanesthetic medications, for systemic and spinal anesthesia, and for postoperative
analgesia.

A Comparison of Opioid Agonist Efficacy:

Low Efficacy:

- Codeine
13 Opiods

Moderate Efficacy:

- Buprenorphine

- Nalbuphine

- Pentazocine

High Efficacy:

- Alfentanil

- Fentanyl

- Hydrocodone

- Methadone

- Morphine

- Oxycodone

- Remifentanil

- Sufentanil

Clinical Symptoms Associated with Opioid-Induced Androgen Deficiency (OPIAD):

- Sexual dysfunction

- Fatigue

- Hot flashes

- Depression

- Weight gain

- Decrease in muscle mass

- Osteoporosis

- Possible infertility

Adverse Effects Commonly Observed in Individuals Treated with Opioids:

- Hypotension

- Dysphoria (anxiety, depression, unease)

- Sedation

- Constipation

- Urinary retention

- Nausea

- Potential for addiction

- Respiratory depression

Buprenorphine is used in opiate detoxification because it has less severe and shorter duration of withdrawal
symptoms compared to methadone.
14 Opiods

Opiate Withdrawal Syndrome:

Stage I (up to 8 hours):

- Anxiety

- Drug craving

Stage II:

- Anxiety

- Insomnia

- Gastrointestinal disturbance

- Rhinorrhea

- Mydriasis

- Diaphoresis

Stage III:

- Tachycardia

- Nausea

- Vomiting

- Hypertension

- Diarrhea

- Fever

- Chills

- Tremors

- Seizure

- Muscle spasms

Strong Agonists:

- Alfentanil

- Fentanyl

- Heroin

- Hydrocodone

- Hydromorphone

- Levorphanol

- Meperidine

- Methadone
15 Opiods

- Morphine

- Oxycodone

- Oxymorphone

- Remifentanil

- Sufentanil

Moderate/Low Agonists:

- Codeine

Mixed Agonist-Antagonist and Partial Agonist:

- Buprenorphine

- Butorphanol

- Nalbuphine

- Pentazocine

Antagonists:

- Naloxone

- Naltrexone

Other Analgesics:

- Tapentadol

- Tramadol