Opioids are available widely, both those prescribed and those illicitly obtained. Opioid toxicity can be rapidly fatal and is a leading cause of accidental death worldwide.
Naloxone is an effective antidote, that can reverse the life-threatening effects of opioids rapidly.

Many opioids are available. They vary considerably by potency and duration of action. Some also have non-opioid effects. Their effects are dose dependant, but tolerance occurs with regular use, making prediction of effects based on dose difficult.

Commonly available opioids include codeine, buprenorphine, dihydrocodeine, fentanyl and its analogues, heroin, methadone, morphine, oxycodone, tramadol and tapentadol.

Opioids can come as a co-formulation with other medications such as paracetamol, ibuprofen and naloxone. Naloxone is added to prevent constipation (e.g. Targin) or to deter intravenous injection (Suboxone), taken orally it is poorly absorbed and does not affect toxicity, but if injected (i.e. dissolving Suboxone wafers) it can lead to opioid withdrawal (which can be followed by opioid toxicity as the naloxone wears off).

Opioids give their effects by binding to opioid receptors located in the brain, spinal cord and gut. Most available opioids are receptor agonist but buprenorphine acts as a partial agonist.
The main opioid receptors that mediate the effects are the mu, kappa and delta.

• Mu receptors: These mediate the most important clinical and toxicological effects including analgesia, sedation, and respiratory depression. They cause diminished response to hypercapnia in the medulla.
• Kappa receptors: miosis, analgesia.
• Delta receptors: analgesia, inhibition of dopamine release, cough suppression.

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The classical triad of opioid toxicity is sedation, respiratory depression and miosis.

• Sedation: Ranges from mild drowsiness to coma.
• Respiratory depression: This is the most important feature of toxicity as it can rapidly lead to death. It is seen as reduced minute volume, reduced respiratory rate and/or hypoxia.
• Ophthalmological effects: Miosis is common but is not always present and not specific to opioid intoxication. Concern for opioid toxicity should not be dismissed because miosis is not present.
• Other effects: QT- prolongation (methadone), serotonin toxicity (multiple agents including tramadol/tapentadol), constipation.

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The most important feature of opioid toxicity that needs addressing is respiratory depression. Patients should have their respiratory status closely monitored: continuous pulse oximetry, respiratory rate monitoring, pCO2.
Avoid supplemental oxygen unless there is another reason for this (e.g. aspiration pneumonia) as providing oxygen will mask developing respiratory depression- instead provide antidotal therapy with naloxone if hypoxia develops.

Antidote- Naloxone:

Naloxone is readily available and reverses the sedation and respiratory depression caused by opioids. It can be given by various routes – intravenous, intramuscular, intra-nasal. In those that are opioid dependant naloxone can induce an unpleasant withdrawal state.
Provide naloxone if there is evidence of respiratory depression i.e. hypoxia or evidence of hypoventilation (low RR or high pCO2). Use:

• Naloxone 100mcg (Child: 0.01mcg/kg) intravenously, every 2-3 minutes until respiratory depression resolved
• Naloxone 800-1600mcg intramuscularly

For most short acting/immediate release opioids once the toxicity has been reversed, further doses are not required. However, in those with longer acting ingestions, recurrent toxicity can occur if the effects of naloxone abate before the causative agent has cleared.
If the patient requires repeated boluses of naloxone due to recurrent respiratory depression, then a naloxone infusion may be required. Use:

• Naloxone 4mg in sodium chloride 0.9% 100ml by intravenous infusion. Start the infusion at an hourly rate of approximately 2/3 of the total effective bolus dose. Then titrate to clinical effect.

Note: Due to its half-life, reaching a new steady state will take several hours, if increasing the infusion rate, then first give a bolus dose of naloxone to achieve the desired clinical end points, then increase the infusion rate.

Before discharging a patient, who has received naloxone, adequate time must be given for the naloxone effects to have abated so that patient does not redevelop toxicity post-discharge. Appropriate observations times are:

• 2 hours after a single bolus dose of intravenous naloxone
• 4 hours after a single bolus of intramuscular or intranasal naloxone
• 4 hours after a naloxone infusion has been ceased

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