Visual representation:

=== 🔄 A Simple Analogy===

IR opioids = Drinking juice straight from a glass 🥤 — quick in, then slowly processed (comaparatively)

MR opioids = Drinking through a thin straw 🧃 — the body’s ready to process, but has to wait for it to arrive.

===🔍 Clinical Implications===

Don’t assume a long half-life = slow clearance — it could just be slow absorption.

Be cautious as kinetics may differ depending on formulation (IR v MR).

The time to reach steady state is delayed,

Often taking 2–3 days with modified-release opioids.

But because it's entering more slowly, the absorption becomes the rate limiting step — not elimination (see graph below)

This is flip-flop kinetics → where the usual roles are reversed

Here, the terminal half-life seen on the graph reflects absorption, not elimination. That’s why:

=== Modified-Release (MR) Opioids: Flip-Flop Kinetics ===

Now, consider sustained-release morphine or oxycodone.

The MR formulation slows the rate of absorption dramatically

Once the drug enters the bloodstream, it's now cleared comparatively quicker to the rate of absorption

As a result:

Steady state is reached in 4–5 elimination half-lives

Which may be as little as a day or less for some IR opioids

The terminal elimination phase of the plasma concentration-time graph reflects elimination

This is standard pharmacokinetics — absorption is fast, so elimination becomes the rate-limiting step (see graph below)

===Immediate-Release (IR)
Opioids: Standard Kinetics===

When you give a patient IR morphine the drug is absorbed quickly from the gut

The body eliminates it comparatively slower than the time taken for absorption

Thanks to that open imidazole ring at low pH, it can be made into a stable injectable solution.

Most other benzos (diazepam, lorazepam) are poorly water soluble and need organic solvents like propylene glycol → which cause venous irritation. Midazolam avoids that.

In acidic environments (like in the injection solution), the ring is protonated → water-soluble → stable for IV prep.

At physiological pH, the ring closes → lipophilic → rapid CNS penetration → quick onset of action.

Edited by palliative medicine physician Dr Jonathan Pickard, and consultant pharmacist Mr Jonathan Hindmarsh, 54 expert authors provide “diagnostic skills and clinical reasoning that helps temper knowledge and understanding with pragmatism and practicality in the face of life-limiting illness.”