Opioids

Question 1

FUNCTIONAL EFFECTS ASSOCIATED WITH OPIOID RECEPTORS

Answer 1

• Supraspinal analgesia: μ,κ,δ
• Spinal analgesia: μ,κ,δ
• Respiratory depression: μ
• Reduced GI motility: μ,δ
• Psychotomimesis: κ
• Sedation: μ,κ

Question 2

NEURAL MECHANISMS OF ANALGESIA

Answer 2

• inhibit ascending pain transmission.
• Activate descending pain-inhibitory circuits.
• Spinal: Opioids inhibit ascending pain transmission.
• Supraspinal: Pain-inhibitory descending neurons send processes to the spinal cord and inhibit pain transmission neurons.
  
  • The descending pain-inhibitory neurons are inhibited by GABA.
  • Opioids inhibit GABAergic neurons.

Question 3

RECEPTOR DISTRIBUTION AND NEURAL MECHANISMS OF ANALGESIA

Answer 3

• Usually opioids are given systemically.
• Therefore they act concurrently at both spinal and supraspinal sites.
• Interaction at these sites tends to increase their overall analgesic efficacy.

Peripheral Analgesia

• There are opioid μ receptors on the peripheral terminals of sensory neurons.
• Peripheral administration of opioids,e.g., into the knees of patients undergoing arthroscopic knee surgery, has shown clinical benefit.

Question 4

Meperidine

Answer 4

• Mu-opioid agonist

Question 5

Pentazocine

Answer 5

• partial mu-agonist or antagonist
• partial kappa-agonist

Question 6

Butorphanol

Answer 6

• partial mu-agonist or antagonist
• kappa-agonist

Question 7

Nalbuphine

Answer 7

• mu antagonist
• kappa agonist

Question 8

Buprenorphine

Answer 8

• partial mu agonist
• kappa antagonist

Question 9

PERIPHERAL EFFECTS

Answer 9

Partial list

• Biliary tract: Opioids contract biliary smooth muscle, which may result in biliary colic.
• Genitourinary tract: Renal function is depressed due to decreased renal plasma flow.
• Uterus: May prolong labour. Mechanism unclear.
• Pruritus: Flushing, warming of the skin, sweating and itching.

Question 10

METABOLISM OF OPIOIDS

Answer 10

• 10% of morphine is metabolized to morphine-6- glucuronide (M6G).
• M6G is an active metabolite with analgesic potency 4-6 times that of its parent compound.
• M3G and M6G are polar metabolites with limited ability to cross the blood-brain barrier.
• Probably do not contribute significantly to the CNS effects of morphine.
• However,the effects of these metabolites should be considered in patients with renal impairment.
• Esters such as heroin and remifentanil are rapidly hydrolyzed by tissue esterases.
• Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and to morphine, which is then conjugated with glucuronic acid.
• Accumulation of a metabolite of meperidine, normeperidine, may occur in patients with decreased renal function.
• In **high concentrations, normeperidine may cause seizures. **
• Fentanyl is metabolized by CYP3A4 in the liver.
• Fentanyl has no active metabolites; fastest in onset

Question 11

EXCRETION OF OPIOIDS

Answer 11

• Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine.
• Small amounts of unchanged drug may also be found in the urine.
• Glucuronide conjugates are also found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.

Question 12

USES OF THE OPIOID ANALGESICS

Answer 12

Partial list

• Acute Pulmonary Edema: Proposed mechanisms include reduced anxiety, and reduced cardiac preload and afterload.
• Diarrhea: Loperamide and diphenoxylate are the most commonly used drugs to control diarrhea.

Question 13

CONTRAINDICATIONS AND CAUTIONS

Answer 13

PATIENTS WITH HEAD INJURIES

• CO2 retention caused by respiratory depression results in cerebral vasodilation.
• In patients with elevated ICP, this may lead to lethal alterations in brain function.

PATIENTS WITH ENDOCRINE DISEASE: Patients with adrenal insufficiency or hypothyroidism may have prolonged and exaggerated responses to opioids.

Question 14

DRUG INTERACTIONS

Answer 14

Partial list

Antipsychotics

• Increase sedation.
• Variable effects on respiratory depression.
• Accentuation of CV effects (antimuscarinic and α-blocking actions).

MAO inhibitors

• concurrent use of meperidine and an MAOI has resulted in excess 5HT & has resulted in a potentially life-threatening reaction in several patients.
• Similar interactions have been seen when tramadol was taken with MAOIs.

Question 15

HYDROMORPHONE AND OXYMORPHONE

Answer 15

• Strong agonists useful in treating severe pain.
• Rapidly hydrolyzed to 6-MAM, which, is then hydrolyzed to morphine.
• Both heroin and 6-MAM are more liposoluble than morphine and enter the brain more readily.
• Morphine and 6-MAM are responsible for the pharmacological actions of heroin.

Question 16

MEPERIDINE

Answer 16

• Strong μ receptor agonist.
• No longer recommended for treatment of chronic pain due to concerns over metabolite toxicity.
• meperidine short T1/2 but metabolite has long T1/2
• Large doses of meperidine repeated at short intervals produce tremors, muscle twitches, dilated pupils, hyperactive reflexes and convulsions.
• These symptoms are due to the accumulation of the metabolite normeperidine, which has a half- life of 15-20 hours compared with 3 hours for meperidine. -> not suitable for routine dosing

DRUG INTERACTIONS

• The most prominent is an excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death.
• Due to the ability of meperidine to block reuptake of serotonin.
• Meperidine should not be used in patients taking other serotonergic agents such as MAO inhibitors.

Question 17

FENTANYL

Answer 17

• STRONG μ agonist.
• Rapid onset and short duration of action (15-30 minutes).
• The fentanyl subgroup also includes sufentanil, alfentanil, and remifentanil.
• Fentanyl is 100 times more potent than morphine, and sufentanil is 1000 times more potent than morphine.
• Alfentanil is seldom used.

Question 18

METHADONE

Answer 18

• Approximately equal in potency to morphine.
• Induces less euphoria and has a longer duration of action.
• Methadone is a μ receptor agonist, an NMDA receptor antagonist, and a serotonin and norepinephrine reuptake inhibitor.
• These multiple mechanisms of action make methadone an interesting choice for chronic pain.

Adverse

• QT prolongation, torsades de pointes and death have been reported with methadone.
• A related compound, levomethadyl acetate, which has an even longer half-life than methadone, has been approved by the FDA for use in detoxification clinics.

Question 19

DEXTROPROPOXYPHENE

Answer 19

• MILD TO MODERATE μ agonist
• Weaker analgesic than codeine.
• Often used in combination with acetaminophen.
• Propoxyphene has an increased risk of seizures and cardiac conduction abnormalities and should be avoided in the elderly.

Question 20

TRAMADOL

Answer 20

• Weak μ agonist and norepinephrine and serotonin reuptake inhibitor.
• Useful in neuropathic pain. ex. diabetic neuropathy
• Tramadol is associated with an increased risk of seizures in patients with a seizure disorder and those taking medications that lower seizure threshold.
• Use of tramadol with other serotonergic drugs should be avoided because it may precipitate a serotonin syndrome.

Question 21

PENTAZOCINE, BUTORPHANOL, NALBUPHINE & BUPRENORPHINE

Answer 21

• MIXED AGONIST-ANTAGONISTS:
• The mixed opioid agonist–antagonists are potent analgesics in opioid-naive patients.
• They precipitate withdrawal in patients who are physically dependent on opioids.
• Useful in mild to moderate pain.
• They were developed to reduce the addiction potential of the opioids.
• Pentazocine is a κ agonist and a μ antagonist or partial agonist.
• Butorphanol is a κ agonist and a μ antagonist or partial agonist.
• Nalbuphine is a κ agonist and a μ antagonist.
• Buprenorphine is a partial μ agonist and a κ antagonist.
• Buprenorphine is approved for the management of opioid addiction.
• Mixed agonist-antagonists are not recommended as routine analgesics, because they have ceiling effect.

Adverse

• Also, pentazocine, butorphanol and nalbuphine may cause psychotomimetic effects.
• Psychotomimetic effects are uncommon with buprenorphine.

Question 22

DIPHENOXYLATE

Answer 22

• ANTIMOTILITY AGENTS
• Widely used in the treatment of diarrhea.
• They act by several different mechanisms, mediated principally through either μ or δ receptors on enteric nerves, epithelial cells, and muscle.
• At the usual doses, diphenoxylate and loperamide lack analgesic effects