In theory once 80 to 100% of opioid receptors are saturated, effective analgesia should take place unless there is an element of opioid resistance.

We all know that opioid analgesics  act through receptor mechanisms. Recent biochemical advances have identified a number of receptors at various sites along the pain pathways. Stimulation of nociceptors causes follow-on stimulation of axons. Stimulation of axons causes the cell body to produce a mu receptor which is essentially the target for opioids.

When mu receptors do not migrate to the required region and painful stimulation still occurs, subtle changes occur in the nerve cell membrane. Subsequent opening of protein channels allow a different receptor, an N-methyl-d-aspartate (NMDA) receptor to be expressed. The NMDA receptor does not respond to opioids but instead causes continued stimulation of the pain pathway when exposed to substances such as glutamate. Once NMDA receptors are expressed, the NMDA receptor feed back to the cell nucleus and codes for production of further NMDA receptors. The result is a gradual exponential rise in numbers of NMDA receptors with consequent wind up of the pain pathway. Once wound up the the system becomes relatively resistant to morphine since morphine fails to block the NMDA receptor. This explains one of the mechanism of neuropathic pain and also explain opioid resistant pain. This neurophysiology is one of the most compelling reasons for early and aggressive pain management. There is indication for palliative care to be involved early. Some scientists believe that early aggressive pain management results in ultimately less analgesia being required in the terminal phase because the wind up phenomenon is prevented from developing.