Article Text

Resistance to respiratory depression in ‘opioid induced hyper-algesia’: a hidden clinical danger
  1. Marie Joseph
  1. St Raphael’s Hospice, Sutton SM3 9DX, UK
  1. Correspondence to Dr Marie Joseph, St Raphael’s Hospice, Sutton SM3 9DX, UK; mariejoseph{at}


‘Opioid induced hyper-algesia’ is a paradoxical phenomenon known to occur with high-dose opioid therapy when attempting to control severe pain. The high opioid load leads to exacerbation of existing ‘central sensitization’ process in the spinal cord dorsal horn and parts of the brain. This situation usually occurs in the clinical context of uncontrolled complex pain with a predominant neuropathic pain component. There is resistance to the analgesic effect of the opioid which worsens with increasing doses. It was not commonly known that in this situation there is often a resistance to the respiratory depression effect of the opioid too caused by similar mechanisms. The patient therefore may not show any clinical features of opioid toxicity despite the high opioid dose. However, subsequently if any analgesic adjustment is made in particular with co-analgesic adjuvants or attempts at using small added dose of combined opioid therapy, reversal of both analgesic resistance as well as resistance to respiratory depression occurs unless the existing high opioid dose is significantly reduced. This reversal can result in serious and life-threatening respiratory depression. We report two cases in which this totally unexpected serious phenomenon took place.

Therefore, the lessons learnt helped to significantly reduce the high opioid dose when attempting to use co-analgesic adjuvants in an attempt to control severe complex pain.

  • 'opioid induced hyper-algesia'
  • 'central sensitization'
  • uncontrolled complex pain
  • resistance to respiratory depression
  • co-analgesic adjuvants
  • combined opioid therapy

Statistics from


  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.