Studies in opioid induced respiratory depression

  • Rakulan Santhakumar

Student thesis: Master's ThesisMaster of Science (MSc)

Abstract

The main cause of fatality from opioid overdose is opioid induced respiratory depression (OIRD), with much of the street heroin being cut with fentanyl. Heroin habits often follow drug abstinence-relapse cycles. Currently, overdose is reverse by antagonising the μ-opioid receptor with naloxone. This may lead to opioid withdrawal syndrome, which can induce aggression, a problem to first responders and clinicians. Clinically, balancing analgesia and respiratory depression can present itself to be difficult. AMPA receptor mediators show promise in reversing respiratory depression without affecting analgesia.

Heroin and fentanyl dose-dependently depressed respiration in male CD1 mice with heroin doing so through depressing respiratory rate and fentanyl through depressing respiratory rate and tidal volume. The idea that 6-MAM over morphine is the active metabolite of heroin is relatively new. In this study, 6-MAM induced OIRD. It has been previously shown that heroin fentanyl mixtures act synergistically in decreasing oxygen saturation within the brain. A heroinfentanyl mixture failed to show additivity or synergy in causing respiratory depression as a ceiling effect in response likely occurred. Investigating alternative OIRD reversing agents and the role of the AMPA receptor during opioid induced respiratory depression. Ketamine has been shown to reverse opioid induced respiratory depression to some of the fentanyls but has yet been shown to reverse heroin induced respiratory depression (HIRD). Ketamine (10, 30mg/kg i.p.) and the metabolite, 2R,6R-hydroxynorketmaine (10, 30mg/kg i.p.) failed to reverse HIRD. Tianeptine 30mg/kg i.p. induced OIRD equipotent to heroin 10mg/kg i.p. and showed to induce analgesia (measured in tail flick latency). The decrease in potency could be attributed to AMPA receptor potentiation. Respiratory depression and analgesia showed reversal by naloxone (0.3 mg/kg i.p.), indicating μ-opioid receptor agonism. Many users claim that they perceive an enhanced rate of tolerance to euphoria following periods of abstinence. After heroin pre-treatment using osmotic mini-pumps an enhanced rate of tolerance development to respiratory depression after a 6-day abstinence period is indicated. However, robust tolerance was not seen with the current protocol. When mice were pre-treated with methadone, this enhanced rate was not present. Indicating a PKC mediated mechanism as heroin metabolites are said to induce desensitisation of the μ-opioid receptor.

This thesis reports a variety of emerging novel fields within the field of opioid induced respiratory depression and provides an insight into a possible future direction of opioid induced respiratory depression mediating agents and the process of understanding the real-world use of heroin and incorporating behaviours into experimental design.
Date of Award23 Mar 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorGraeme Henderson (Supervisor) & Eamonn P Kelly (Supervisor)

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