Module 34

Question 1

How effective are opiates for the treatment of chronic pain?

Answer 1

• Opiates are not effective for chronic pain and can even increase sensitivity to pain. Therefore, withdrawal can be a challenge.

Question 2

One would not expect that a glucuronide conjugate could readily cross the blood-brain barrier. How do the physical properties of morphine-6-glucuronide compare with what would be expected for a glucuronide? How does the binding of the 6-glucuronide to the opiate receptor compare with that of morphine. What is the evidence that the 6-glucuonide contributes to the analgesic effects of morphine

Answer 2

• Glucuronides are very polar and would not be expected to penetrate the CNS very well; however, the morphine-6-glucuronide takes on a conformation in which there is internal hydrogen bonding and less interaction with water. This makes the morphine-6-glucuronide much less polar than most glucuronides.
  
  • Glucuronides tend not to have high affinities for receptors because of their interaction with water; however, morphine-6-glucuronide binds to the opiate receptor with an affinity about 100 times that of morphine. Yet, most of the analgesic effects of morphine come from the parent drug rather than the glucuronide metabolite.
  • Despite this the morphine-6-glucuronide has been developed as a drug that is used after surgery and has somewhat different properties than morphine. It also means that patients with impaired renal function may have an enhanced response to morphine since the glucuronide is cleared by the kidneys.

Question 3

What is the active agent when codeine is used as an analgesic, and why have many hospitals removed it from their formularies?

Answer 3

• Of course the answer is that codeine must be o-demethylated to morphine, which is the active agent. Because this metabolic pathway is mediated by the polymorphic enzyme, CYP2D6, the efficacy of codeine is not reliable. Therefore, many hospitals have removed it from their formularies.

Question 4

What is the most common mechanism of opioid “allergy”? How would you deal with this issue?

Answer 4

• Although patients can be truly allergic to opiates (i.e. an IgE-mediated reaction), it appears to be rare. The most common mechanism for the symptoms associated that are often called allergic reactions appears to be that these agents can cause direct degranulation of mast cells leading to the release of histamine and other mediators.
  
  • In most cases this just causes itching, but in a few cases it can be a life-threating reaction similar to a true allergy.
    Skin testing is not very useful because there are many false positives. Dose appears to be important, and in some cases patients will not react to more potent opiates in which the effective dose is lower, but caution is required.

Question 5

How might an opiate increase acute belly pain of unknown origin?

Answer 5

• Opiates cause contraction of the sphincter of Oddi, which controls the flow of bile and pancreatic secretions into the intestine.
  
  • If the abdominal pain is due to cholecystitis or pancreatitis, this constriction can cause obstruction and increase the pain. Demerol is said to cause less contraction of the sphincter than morphine, but the data are not definitive.