Module 3 Section 6 (Management of Pain)

Question 1

In general, drugs that treat pain are divided into two categories. What are they?

Answer 1

• Opioid analgesics, such as morphine

- Non-opioid analgesics, such as ibuprofen

Question 2

What are opioid analgesics? Provide an example.

Answer 2

Substances that are derived from opium and act on the opioid receptors in the brain to relieve pain. For example, morphine.

Question 3

What are non-opioid analgesics? Provide an example.

Answer 3

Substances that act independently of the opioid receptors to relieve pain. For example, ibuprofen.

Question 4

What forms do non-opioid analgesics come in?

Answer 4

Some are available as over-the-counter drugs, such as acetylsalicylic acid (i.e. aspirin) and acetaminophen (i.e. Tylenol), while others require a prescription.

Question 5

True or false: non-opioid analgesics alleviate pain, with low potential for drug abuse and dependence.

Answer 5

True

Question 6

How do non-opioid analgesic drugs work?

Answer 6

All non-opioid analgesic drugs function by inhibiting the enzymes cyclooxygenase (COX)-1 and/or COX-2, thereby reducing the amount of prostaglandins.

Question 7

What are prostaglandins?

Answer 7

Prostaglandins are endogenous substances that sensitize the nerve endings to mediators of pain, reducing fever, and inhibiting the propagation of inflammation.

Question 8

What are non-steroidal anti-inflammatory drugs (NSAIDs)?

Answer 8

They are the largest group of non-opioid analgesic drugs.

Question 9

What do NSAIDs do?

Answer 9

NSAIDs inhibit prostaglandin synthesis. Most NSAIDs are well absorbed, highly metabolized by CYP450 enzymes in the liver, and excreted via the kidneys.

These drugs have analgesic (reduces pain), antipyretic (reduces fever), and anti-inflammatory (reduces inflammation) effects.

NSAIDs are particularly useful for the management of pain that is associated with inflammation.

Question 10

What are the most commonly used NSAID dugs?

Answer 10

The most commonly used drugs in this class are acetylsalicylic acid, ibuprofen (i.e. advil), and naproxen.

Question 11

What are the adverse effects of NSAIDs? (7)

Answer 11

• Gastrointestinal: abdominal pain, nausea, vomiting, and ulcers (rare)
• Hepatic: liver function abnormalities, liver failure (rare)
• Renal: renal insufficiency, renal failure
• Pulmonary: individuals with asthma are at a higher risk for experiencing an allergic reaction to NSAIDs
• Cardiovascular: fluid retention, edema, hypertension
• CNS: headaches, tinnitus, dizziness
• Skin: rashes

Question 12

What are some non-selective NSAIDs?

Answer 12

• Acetylsalicylic acid (ASA)
• Ibuprofen
• Naproxen
• Diclofenac

Question 13

What is Acetylsalicylic acid (ASA) used for?

Answer 13

ASA can be used for mild to moderate pain and for fever. An additional use for ASA is in the prevention of strokes and myocardial infarcts, as low dose ASA has been shown to reduce the risk of these serious diseases by inhibiting platelet aggregation and hence clot formation.

Question 14

What are some adverse effects for ASA?

Answer 14

It’s associated with the development of Reyes syndrome (a rare but serious illness affecting the central nervous system.

It causes brain and liver damage and can be fatal) when given to children with fevers.

Therefore, acetaminophen is the drug of choice in children with fever.

Question 15

True or false: A 200 mg dose of ibuprofen is more effective than a 325 mg dose of ASA in a number of conditions.

Answer 15

True

It’s more effective in conditions such as dental pain and menstrual pain.

Question 16

How does Ibuprofen work? What is Ibuprofen used for?

Answer 16

The mechanism of action of ibuprofen is reversible inhibition of COX-1 and COX-2 enzymes. However, testing using human blood indicates that ibuprofen is somewhat more effective in inhibiting COX-1.

It’s probably one of the most efficacious over-the-counter agents on the market. Clinically, ibuprofen can be used to close patent ductus arteriosus (a congenital heart defect) in preterm infants and for post-surgical dental pain.

Question 17

How does Naproxen work? What is it used for?

Answer 17

Naproxen reversibly inhibits both COX-1 and COX-2.

It may well emerge as the most effective over-the-counter anti-inflammatory agent available. Clinically, naproxen is useful for rheumatologic indications, such as rheumatoid arthritis. Naproxen is also available as an ophthalmic solution and a topical preparation.

Question 18

How does diclofenac work? What is Ibuprofen used for?

Answer 18

Diclofenac is a relatively non-selective inhibitor of COX-1 and COX-2.

Clinically, it is used as an ophthalmic preparation for prevention of postoperative ophthalmic inflammation and as a topical gel for solar keratosis (i.e. a skin condition caused by damage from the sun).

Additionally, diclofenac can be used as a rectal suppository for preemptive analgesia and postoperative nausea.

Question 19

Compare and contrast classical and newer NSAIDs.

Answer 19

Since classical NSAIDs inhibit both COX-1 and COX-2 enzymes, they inhibit the production of both protective and inflammatory prostaglandins.

However, inhibition of the production of just the inflammatory prostaglandins would be ideal, as inhibiting protective prostaglandins predominantly only contributes to the adverse effects of the drugs. As such, newer NSAIDs have been developed that selectively inhibit COX-2.
- COX-2 selective inhibitors have analgesic, antipyretic, and anti-inflammatory properties similar to the non-selective COX inhibitors, however the gastrointestinal adverse effects are decreased by about half.

Question 20

What are some examples of selective NSAIDs?

Answer 20

• Celecoxib

- Meloxicam

Question 21

What are some examples of selective NSAIDs?

Answer 21

• Celecoxib: this NSAID is approximately 10 to 20 times more selective for COX-2 than for COX-1. It’s prescribed to relieve pain and inflammation caused by arthritic conditions such as osteoeoarthritis and rheumatoid arthritis. It can also be used to treat post-surgical pain
• Meloxicam: this drug also preferentially inhibits COX-2, however not to the same extent as that of celecoxib. It can also be used to relieve pain and inflammation caused by arthritic conditions.

Question 22

What is the main problem surrounding the other selective NSAIDs?

Answer 22

Other COX-2 selective inhibitors have been developed (e.g. rofecoxib), however, clinical data suggested that patients taking these drugs had an increased incidence of cardiovascular thrombotic events, such as heart attack or stroke, resulting in their withdrawal from the market.

Question 23

True or false: Acetaminophen is not an NSAID.

Answer 23

True

It functions as an analgesic and an antipyretic, but not as an anti-inflammatory.

Question 24

True or false: acetaminophen (Tylenol) is the most widely used over-the-counter analgesic, comprising more than 50% of the market.

Answer 24

True

Question 25

What is the mechanism of action for acetaminophen?

Answer 25

Inhibition of prostaglandin formation (COX I and COX II) is responsible for the analgesic and antipyretic effects. However, acetaminophen does not have any anti-inflammatory or anti-platelet action.

Question 26

What are the therapeutic uses of acetaminophen?

Answer 26

Acetaminophen is very well tolerated at therapeutic doses, and it is the drug of choice in cases where ASA causes GI irritation and in febrile conditions in children and young adults (acetaminophen is not associated with Reyes syndrome). It is also safe to take during pregnancy.

Question 27

Why does acetaminophen impact the liver negatively?

Answer 27

Acetaminophen overdose can lead to fatal liver injury.
- In cases of overdose, the individual usually consumes at least 5 to 10 grams (20 tablets) or more of acetaminophen.

There is some evidence that liver injury can occur with large therapeutic doses of acetaminophen if taken for a long time. Alcoholics and individuals with liver disease are more susceptible to the liver toxicity.

Question 28

True or false: cirrhosis makes the liver more susceptible to liver toxicity due to acetaminophen overdose.

Answer 28

True

As a result, acetaminophen must be used with caution in these patients.

Question 29

Hepatotoxicity (liver toxicity) can result from acetaminophen overdose, which is related to the metabolism and depletion of glutathione. Explain how this occurs.

Answer 29

1) Acetaminophen can undergo either glucuronidation or sulfation (phase II reactions) to produce non-toxic metabolites.
2) Although, about 5% of acetaminophen will undergo hydroxylation (phase I reaction) and structural rearrangement to produce a toxic intermediate, known as NAPQI.
3) NAPQI can be effectively detoxified by glutathione (GSH) conjugation (phase II reaction), although due to the body’s limited amount of glutathione, acetaminophen overdose can deplete glutathione stores, leading to toxicity.

Question 30

How are acetaminophen overdoses treated?

Answer 30

Treatment for acetaminophen overdose is to give the antidote N-acetylcysteine with supportive measures. N-acetylcysteine is a source of glutathione, which results in a decrease in the amount of NAPQ1 (i.e. the liver damaging compound) available for tissue damage, and hence a decrease in liver damage. N-acetylcysteine is most effective if it is administered within 8 hours of acetaminophen exposure.

Question 31

What are opioid analgesics? What are they used for? What are some examples?

Answer 31

Drugs obtained from Papaver somniferum (i.e. the opium poppy) have been used to alleviate pain for millennia.

Opium contains at least 20 different chemical compounds, of which morphine and codeine are analgesic drugs.

Morphine and codeine comprise about 10% and 0.5% of the crude exudate, respectively.

Morphine is one of the most useful drugs known to pharmacologists, unfortunately, it is renowned for causing dependence and addiction.

Question 32

What is the difference between opiates and opioids?

Answer 32

Opiate: Any drug derived from opium.
- Ex:

Opioid: Any natural or synthetic substance that exerts actions on the body similar to those induced by morphine and that are antagonized by the drug naloxone. Opioids include:

• Opiates (e.g. morphine)
• Substances structurally related to morphine (e.g. heroin)
• Synthetic drugs with structures different from that of morphine (e.g. methadone)
• Endogenous brain peptides that exert analgesic actions (i.e. endorphins).

Question 33

Where are opioid receptors located?

Answer 33

Opioid receptors are located in the peripheral and central nervous systems.

However, these receptors are also located in other tissues, such as the gastrointestinal tract, which causes constipation.

Question 34

What occurs when opioid receptors are activated?

Answer 34

Opioid receptors are G-protein coupled receptors, activating second messenger systems to cause an effect.

Question 35

What are the 3 types of opioid receptors? What occurs when they’re activated?

Answer 35

1) MOP (Mu (μ) opioid receptors)
- These receptors are present in all structures of the brain and spinal cord.
- When activated, these receptors primarily mediate analgesia, but they are also responsible for morphine-mediated depression of respiration in the brain stem.
- MOP receptors are also involved in the compulsive abuse behaviour demonstrated by opiate users. The endogenous ligands forMOP receptors are beta-endorphin and endorphin 1 and 2.

2) KOP (Kappa (k) opioid receptors)
- These receptors are involved in analgesia, dysphoria, and miosis (i.e. pin-point pupils).
- The mixed opioid agonists/antagonists (for example pentazocine), act predominantly on these receptors.
- The endogenous ligands for KOP receptors are the dynorphins, although the endorphins have some activity at these receptors

3) DOP (Delta (δ)opioid receptors)
- These receptors are involved in analgesia at the level of the spinal cord and brain.
- They may also modulate the emotional response to opioids.
- The endogenous ligands for DOP receptors are the enkephalins.

Question 36

Explain the mechanisms of action of opioids. How do opioids act to influence pain?

Answer 36

Morphine and other opioids will block pain pathways in the spinal cord and in the brain. This effect is exerted through activation of primarily MOP receptors.

1) Reduced presynaptic release of chemical transmitters that are mobilized by pain impulse.
2) Blockade of postsynaptic effect of those transmitters.
3) Activation of descending inhibitory pathways to block pain input.
4) Reduced emotional reaction to pain by acting on the limbic area of the brain.

Question 37

Match the term with the definition:

• Respiratory depression
• Miosis
• Analgesia
• Heart rate and thermoregulation
• Suppression of the cough centre
• Decreased gastrointestinal motility
• Endocrine effects
• Sedation

___: Opioids, including morphine and heroin, produce analgesia and indifference to pain, reducing the intensity of pain and the perception or reaction to the pain. There is no ceiling to the intensity of pain which can be relieved. Respiratory depression is the limiting factor.

___: All opioids produce sedation, at least those that are analgesics.

___: Relief or prevention of cough occurs through suppression of the cough centre in the medulla.

___: Opioids supress the respiratory center in the brain stem. In particular, the response to respiratory drive by carbon dioxide is blunted. Depression of respiration is the single most important side effect of the opioids and is usually the cause of death in overdose.

___: All opioids cause constipation.

___: Opioids reduce the release of the hormone that is responsible for regulating the release of sex hormones from the hypothalamus. This results in a reduction in the production of testosterone, estrogens, and progesterone. The overall result is a drop in libido in men and menstrual irregularities in women.

___: Constriction of the pupils of the eyes. All opioids which gain access to the central nervous system will cause pin-point pupils. This is a sign of the opioid user.

___: With high doses, the heart rate is irregular, body temperature is low, and the skin is cold and clamm

Answer 37

Analgesia: Opioids, including morphine and heroin, produce analgesia and indifference to pain, reducing the intensity of pain and the perception or reaction to the pain. There is no ceiling to the intensity of pain which can be relieved. Respiratory depression is the limiting factor.

Sedation: All opioids produce sedation, at least those that are analgesics.

Suppression of the cough centre: Relief or prevention of cough occurs through suppression of the cough centre in the medulla.

Respiratory depression: Opioids supress the respiratory center in the brain stem. In particular, the response to respiratory drive by carbon dioxide is blunted. Depression of respiration is the single most important side effect of the opioids and is usually the cause of death in overdose.

Decreased gastrointestinal motility: All opioids cause constipation.

Endocrine effects: Opioids reduce the release of the hormone that is responsible for regulating the release of sex hormones from the hypothalamus. This results in a reduction in the production of testosterone, estrogens, and progesterone. The overall result is a drop in libido in men and menstrual irregularities in women.

Miosis: Constriction of the pupils of the eyes. All opioids which gain access to the central nervous system will cause pin-point pupils. This is a sign of the opioid user.

Heart rate and thermoregulation: With high doses, the heart rate is irregular, body temperature is low, and the skin is cold and clam

Question 38

What are the long-term effects of using opioids?

Answer 38

Adverse effects of long-term use include mood instability, pupillary constriction (impairs night vision), constipation, reduced libido, menstrual irregularity, and respiratory impairment

Question 39

Why do you think opioids are some of the most commonly abused substances?

Answer 39

Opioids, such as morphine, heroin, and fentanyl, are very efficient at eliminating the sensation of pain, reducing the intensity of pain, creating an indifference to pain, as well as decreasing the reaction to pain. There is no limit to the intensity of pain which can be relieved.

Those who have suffered severe and painful injuries and have been prescribed an opioid for the pain may start abusing the drug if they take more than the recommended dose, or take it for longer than intended. Many people who are addicted to opioids also have at least one psychological comorbidity.

Question 40

What are the therapeutic uses of opioid drugs?

Answer 40

• Relief of severe pain (e.g. post-surgical pain and pain experience by some terminally ill patients). Analgesia is the major use for the opiates.
• Treatment of diarrhea. Diphenoxylate (Lomotil) is an over-the-counter opioid which is not an analgesic, does not produce dependence, but is useful in controlling diarrhea.
• Suppression of cough. All opioids are effective cough suppressants, however, better alternatives with lower dependence liability are available.
• Opioid dependence (Methadone only).

Question 41

True or false: tolerance, dependence, and addiction develops to all opioid analgesics.

Answer 41

True

While tolerance develops to most pharmacological effects of the opioids, it does not develop to constriction of the pupils or constipation.

Question 42

Does cross- tolerance occur between opioid analgesics?

Answer 42

Cross-tolerance between all opioid analgesics occurs, providing they act on the same receptor.

Therefore, individuals who have tolerance to heroin will also have tolerance to methadone, as both drugs bind to opioid receptors.

Question 43

Is neonatal drug dependence to opioids possible?

Answer 43

A mother dependent on opioid analgesics during pregnancy faces an increased risk of premature delivery and a low birth weight infant.

At birth, the infant undergoes an abrupt termination of drug supply, resulting in a withdrawal reaction (irritability, sleep disturbances, poor feeding, and occasionally seizures). The withdrawal may last weeks to months.

Question 44

How are opioid overdoses treated?

Answer 44

Overdose of all opioid drugs can produce profound respiratory depression, which is the cause of death.

Treatment consists of opioid antagonists, such as naloxone, and support of respiration and other vital functions.

Question 45

How is opioid dependence treated in Canada?

Answer 45

In Canada, methadone is the drug of choice used to treat opioid dependence. The advantages of methadone are that:

• it is effective orally, removing the risks associated with intravenous use.
• It is readily available, so the addict does not need to resort to crime to fulfill their need.
• it is a long acting opioid, meaning that the euphoria experienced is not as intense, decreasing overall abuse potential.

The overall result is that health risks to the addict are less. Once on methadone therapy, the doses of methadone can be slowly decreased until the individual is no longer dependent on the drug (i.e. methadone cessation programs), or the dose of methadone can remain constant (i.e. methadone maintenance programs).

Question 46

Which one of the statements regarding non-steroidal anti-inflammatory drugs is correct?

a) They reduce only pain and fever.
b) They inhibit the production of prostaglandins.
c) They only inhibit the COX-1 enzyme.
d) They are not available as over-the-counter medications.

Answer 46

b) They inhibit the production of prostaglandins.

Question 47

Which one of the statements regarding morphine is correct?

a) It causes mydriasis (dilation of pupil).
b) It causes respiratory depression.
c) It binds to muscarinic receptors.
d) It does not cause dependence

Answer 47

b) It causes respiratory depression.