More on opioids and glutamate

[Guest guest]

Don't the apparent focus of the article on questions about drug

addicts derail you - there are nuggets here of direct relevance for

us, even for those of you for whom pain is not a primary symptom.

Nelly, I will want to discuss this whole glutamate thing with you,

dear. We may need to have a version of our Pub Med toilet paper with

nothing but glutamate references - maybe a special " Glutamate

Madness Edition " of our TP.

Dr. Hodologica, you are being paged.

Abstract: [paragraph breaks added]

Addiction. 1999 Jul;94(7):961-72.

Comment in:

Addiction. 1999 Jul;94(7):973-4.

Mechanisms of fatal opioid overdose.

White JM, Irvine RJ.

Department of Clinical and Experimental Pharmacology, University of

Adelaide, Australia.

There has been increasing recognition of the problem of fatal opioid

overdose. This review examines the pharmacological basis of

respiratory depression following opioid administration. Respiration

is controlled principally through medullary respiratory centres with

peripheral input from chemoreceptors and other sources. Opioids

produce inhibition at the chemoreceptors via mu opioid receptors and

in the medulla via mu and delta receptors.

While there are a number of neurotransmitters mediating the control

of respiration, glutamate and GABA are the major excitatory and

inhibitory neurotransmitters, respectively. This explains the

potential for interaction of opioids with benzodiazepines and

alcohol: both benzodiazepines and alcohol facilitate the inhibitory

effect of GABA at the GABAA receptor, while alcohol also decreases

the excitatory effect of glutamate at NMDA receptors.

Heroin and methadone are the major opioids implicated in fatal

overdose. Heroin has three metabolites with opioid activity.

Variation in the formation of these metabolites due to genetic

factors and the use of other drugs could explain differential

sensitivity to overdose.

Metabolites of methadone contribute little to its action. However,

variation in rate of metabolism due to genetic factors and other

drugs used can modify methadone concentration and hence overdose

risk. The degree of tolerance also determines risk. Tolerance to

respiratory depression is less than complete, and may be slower than

tolerance to euphoric and other effects. One consequence of this may

be a relatively high risk of overdose among experienced opioid

users.

While agonist administration modifies receptor function, changes

(usually in the opposite direction) also result from use of

antagonists. The potential for supersensitivity to opioids following

a period of administration of antagonists such as naltrexone

warrants further investigation. While our understanding of the

pharmacological basis of opioid-related respiratory depression has

advanced, better understanding of the role of heroin metabolites,

the metabolism of methadone, drug interactions and tolerance would

all be of considerable value in knowing how best to respond to this

problem.

Publication Types:

Review

Review, Tutorial

PMID: 10707430 [PubMed - indexed for MEDLINE]