Miscellaneous Articles

Opioids – Weak Acid or Weak Base

Compiled by Michael Storm CRNA, MNA, CCRN (2013)

Morgan/Mikhail 4th ed.p.955 states: “Albumin, which tends to bind acidic drugs (e.g. barbiturates, benzodiazepines, opioid agonists), typically decreases with age.” One of our course participants called this to question. The following is what other textbooks have to say.

Miller 7th ed.p.791

Miller is very specific and states: “Opioids are weak bases.”

Stoelting/Hillier 4th ed.p.93-94

Stoelting/Hillier is less blunt, but we can deduct the same answer from them.
Reasons for poor penetration of morphine into the CNS include
a) relatively poor lipid solubility
b) high degree of ionization at physiologic pH

p.93 (chart):
pK for morphine 7.9; percent nonionized (pH 7.4) 23%

Let’s look at how weak acids and bases will dissociate when placed in acidic and alkalotic environments.

  • Weak acid + acidic environment = non-ionized is increased
  • Weak base + alkalotic environment = non-ionized is increased
  • Weak acid + alkalotic environment = ionized is increased
  • Weak base + acidic environment = ionized is increased

To summarize:

  • acid + acid and base + base = non-ionized
  • acid + base and base + acid = ionized

Let’s try to look at the pH line and place a weak acid with a pK of 7.9:

As seen from this situation a weak acid with a pK of 7.9 placed in a relative acidic environment, such as the human body (pH = 7.4) will exists in mostly a non-ionized form.

Take a new pH line and place a weak base with a pK of 7.9:

We now see that a weak base placed in a relative acidic environment (again human pH = 7.4) is mostly in the ionized form.

Now when reexamining the above two statements from Stoelting/Hillier it should be obvious that morphine (pK 7.9), which is the classic opioid agonist, is a weak base.

Barash 6th ed.p.469

Barash has the same numbers for pK and ionization as used in Stoelting/Hillier above (chart p.469) and in describing the pharmacokinetics for an opioid it, among other things, states: “An opioid with a pKa much lower than 7.4 will have a much greater nonionized fraction in plasma than one with a pKa close to or greater than physiologic pH.”

Using the same concepts as above under Stoelting/Hillier we can deduct that a weak base with a pK of less than physiologic pH (7.4) would have a large non-ionized fraction (a weak acid with a pK less than 7.4 would have a larger ionized fraction).

So, what Barash in essence is stating is that an opioid is a weak base.


I will state the consensus is clear opioids are weak bases. I’m not sure what Morgan/Mikhail is referring to in their Geriatric chapter, but we will conclude: