Link to [[2.1.1.3 Opioid Teaching Resources]]
Link to [[Problems for Discussion- 2- Opioids.|Problems for Discussion]]
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[[toc]]
=Opioids=

==DRUGS INCLUDED IN THIS CATEGORY==

* Morphine
* Codeine
* Heroin
* Pethidine (meperidine)
* Diphenoxylate
* Fentanyl
* Methadone
* Oxycodone
* Pentazocine
* (Dextro)propoxyphene

==**OVERVIEW**==

Opioids present with a syndrome which includes miosis, coma, respiratory depression and vomiting. A rapid response to naloxone is usual if hypoxic brain damage or other events have not been superimposed. The treatment is primarily supportive, although naloxone may also be used in certain circumstances. In recreational overdoses (i.e. dependent patients), a [[3.5.2 Opioid Withdrawal |withdrawal reaction]] to naloxone is common.

==**MECHANISM OF TOXICITY EFFECTS**==

Opioids are opioid receptor agonists. Stimulation of these receptors in the central nervous systems leads to analgesia, vomiting and profound sedation in a dose dependent manner. These effects are potentiated by other sedative drugs (e.g. [[2.1.11.5.1 Acute Management of Alcohol Problems|alcohol]], [[Benzodiazepines|benzodiazepines]]) and the majority of fatal overdoses involve other substances. [[Non-cardiogenic Pulmonary Oedema|Non-cardiogenic pulmonary oedema]] occurs in a substantial number of opioid overdoses, however the mechanism behind this is unknown. Dextropropoxyphene and its metabolite norpropoxyphene have 'antiarrhythmic' (and consequently proarrhythmic) activity. This may lead to [[Cardiotoxic drugs|arrhythmias]] and negative inotropic effects. Pethidine and pentazocine have serotonergic effects in addition to their opioid effects and, usually in combination with other drugs, may cause the [[3.2.1.3.1 Serotonergic Toxidrome|serotonin syndrome]]

==**KINETICS IN OVERDOSE**==

The opioids are a diverse group of substances. The most important kinetic difference between them is their half-life in overdose which
varies from hours to days.

===Absorption===
Opioids are generally rapidly absorbed, with peak concentrations within two hours of oral ingestion, one hour of IM administration and minutes of IV injection. First pass metabolism is noted with some of these drugs (codeine, morphine, propoxyphene) however these drugs also have active metabolites. Oral controlled release formulations of morphine and oxycodone and topical preparations of fentanyl are also available and are frequently used in palliative care. Absorption from these preparations will continue for up to 12 hours.

===Distribution===
These drugs have volumes of distribution of 1-5 L/kg and cross well into the central nervous system.

===Metabolism - Elimination===
These drugs are primarily hepatically metabolised. The half-life of most of these drugs is between 1 and 5 hours. However methadone (about 24hours) and propoxyphene (12 to 24 hours) are exceptions.

==CLINICAL EFFECTS==

===Central nervous system===
CNS depression is the major clinical manifestation. Increasing doses lead to increasing degrees of sedation with initial analgesia and
sedation, followed by loss of response to verbal stimuli, loss of response to tactile stimuli, loss of control over normal respiration and
failure of temperature and blood pressure regulation.

===Cardiac===
Dextropropoxyphene may lead to cardiac effects and ECG changes. The ECG changes seen in propoxyphene overdose are similar to those seen in [[2.1.11.9.2.1 Tricyclic Antidepressants|tricyclic antidepressant poisoning]] <TCAs.htm> with QRS and QT prolongation, varying degrees of heart block and tachyarrhythmias.

===Pulmonary===
Aspiration and non-cardiogenic pulmonary oedema <Pulmonary%20oedema.htm> are common complications.

===Other===
Pentazocine and pethidine may contribute to the development of a [[3.2.1.3.1 Serotonergic Toxidrome|serotonergic syndrome]] <Serotonin%20toxicity.htm>.

==INVESTIGATIONS==

===Imaging===
A chest X-ray should be obtained in severe opioid overdose as aspiration and non-cardiogenic pulmonary oedema <Pulmonary%20oedema.htm> are common complications.

===ECG===
An ECG should be done in overdoses involving propoxyphene.

===Blood concentrations===
Drug concentrations are not helpful in the management of overdose.

===Urine drug screen===
Patients with recreational overdoses should have a urine drug screen for drugs of abuse to identify other substances that may have been taken or abused.

===Other investigations===
Patients with suicidal ingestions who present with an opioid syndrome should have [[2.1.1.1 Acetaminophen|paracetamol]], salicylate and electrolytes done to detect coingestion of [[2.1.1.1 Acetaminophen|paracetamol]] and/or [[2.1.1.4 Salicylates|aspirin]] , as combination tablets are a frequent source of codeine or propoxyphene.


==DIFFERENTIAL DIAGNOSIS==

The differential diagnosis for a patient presenting with a typical opioid syndrome is any other sedating drug. The presence of [[Pupil Size and Reaction|miosis]] is not limited to opioid drug overdose but occurs in [[Benzodiazepines|benzodiazepine]] , chloral hydrate, [[Barbiturates|barbiturate]], [[2.1.11.9.3 Antipsychotics|phenothiazine]] , alcohol and [[2.2.7.4.5 Organophosphates|organophosphate]] overdose. A failure to respond to naloxone indicates ingestion (or coingestion) of one of these other drugs is more
likely.

==DIFFERENCES IN TOXICITY==

Prolonged toxicity is seen with methadone and propoxyphene overdose due to their long half lives and this may necessitate treatment for several days. Propoxyphene may cause direct cardiac effects. Drugs such as codeine, which are prodrugs, have much less toxicity in overdose as they need to be converted to more active metabolites. Drugs administered by the intravenous route in recreational overdoses may involve various adulterants which occasionally will be of clinical importance.

Adulterants found in street drugs include such diverse substances as
* Ketamine
* [[Quinine]]
* Talc
* Glucose powder
* Strychnine
* Caffeine
* Other illicit drugs, e.g. amphetamines, [[Barbiturates|barbiturates]]

Unexplained symptoms in patients with recreational overdose should prompt a search for these substances and should include an ECG to detect cardiotoxic drugs.

==TREATMENT==

===Supportive===
Patients should be closely observed for the development of respiratory depression. If necessary, naloxone can be given to counteract the sedating effect of opioids. Intubation and ventilation will occasionally be required for patients who have developed respiratory complications of their overdose.

===GI Decontamination===
[[3.2.2.2.3 Activated charcoal| Activated charcoal]] <Charcoal.htm> may be given to patients who have oral ingestions of opioid drugs within 1-2 hours. Controlled release preparations should be treated with [[3.2.2.2.3 Activated charcoal|activated charcoal]] <Charcoal.htm> and [[3.2.2.2.4 Whole bowel irrigation (lavage)|whole bowel irrigation]]. <WBI.htm>

===Antidotes===

===**//Naloxone//**===
**Mechanism**
Naloxone is a receptor antagonist with a short half life. The duration of action of a single dose is usually less than 1-2 hours. As this is shorter than the duration of action of most opioids, repeat doses are often required to maintain consciousness.

**Dose**
Naloxone is given 0.4 mg IV or IM repeated up to a total dose of 2 mg.
Failure to respond to 2 mg means further doses are unlikely to be helpful. Use the minimum dose necessary to raise the patient's level of consciousness to a point where respiratory depression is avoided and the patient may be woken.
Too large a dose of naloxone may not only precipitate opioid withdrawal, but may lead to the patient absconding
from the hospital department. As the naloxone wears off over the next hour the patient may then collapse in the gutter outside the hospital
(see Coroner/Medical Examiner).

**Monitoring and infusions**
Patients should be observed carefully for relapse for at least 2-3 hours. If a patient does redevelop marked sedation after their first naloxone dose, an infusion of naloxone may be required (commencing with a dose that is half to two thirds of the dose required initially to wake
them given per hour). pCO_2 estimation is the most accurate way to assess respiratory depression due to opioids and should be regularly
estimated in patients on infusions.

Controlled release morphine and oxycodone, methadone and propoxyphene overdoses may require a continuous infusion for as long as several days.

**Adverse effects**
Adverse effects from naloxone are limited to the occasional precipitation of a withdrawal syndrome in patients with chronic dependence.

===**Treatment of specific complications**===
**Propoxyphene induced arrhythmias**
Patients ingesting propoxyphene with abnormal ECGs (increased PR, QRS & QT durations) should be monitored until the ECG returns to normal. Treatment of tachy- and bradyarrhythmias should be similar to that used in [[2.1.11.9.2.1 Tricyclic Antidepressants|TCA poisoning]] with [[Alkalinisation|alkalinisation]] as the first line therapy.

==LATE COMPLICATIONS- FOLLOW UP==

Patients with recreational overdoses should be referred to drug and alcohol services. If the patient is not sedated and has not received
naloxone within the previous three hours, the patient may be discharged. Patients with propoxyphene overdoses should have ECG monitoring until their ECG returns to normal. Long term sequelae are only likely if there has been a period of hypoxia with subsequent hypoxic brain injury.

[[file:Medical monitoring of Opioids prescribed for Chronic.doc]]

==REFERENCES==

Meredith TJ, Jacobsen D, Haines JA, Berger J-C (eds). Naloxone, flumazenil and dantrolene as antidotes. IPCS/CEC evaluation of antidotes series Vol 1. Cambridge University Press 1993
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7945608&dopt=Abstract| Chamberlain JM, Klein BL. ]]A comprehensive review of naloxone for the emergency physician. American Journal of Emergency Medicine 1994;12:650-660.
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7629986&dopt=Abstract| Hoffman RS, Goldfrank LR.]] The poisoned patient with altered consciousness. Controversies in the use of a 'coma cocktail'. JAMA 1995;274:562-569.