Propofol and analgesia

[Versatil]

Is there any analgesic activity related with propofol?

I am thinking that the way it penetrates lipid membrane it could in someway.

I am also searching some works on the channels modulations by propofol. If anyone could help me in that...

A detailed link on the dynamics and kinetics of propofol could also help me by the way, if anyone has one. Because Golan has a just a brief review of propofol and Katzung lacks of details.

Thank you.

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[Paseo Del Norte]

If I am not mistaken, analgesia is a component of anaesthesia?



http://www.drugs.com/mmx/propofol.html

http://druginfo.nlm.nih.gov/drugpor...en.jsp&TXTSUPERLISTID=0002078548&QV1=PROPOFOL

 

[Versatil]

If I am not mistaken, analgesia is a component of anaesthesia?



http://www.drugs.com/mmx/propofol.html

http://druginfo.nlm.nih.gov/drugpor...en.jsp&TXTSUPERLISTID=0002078548&QV1=PROPOFOL

I would say yes and no.

If you are in pain and I give you propofol, the pain will remain, but does it change your perception of pain? That could be interesting and that's what I am trying to find.
If anyone could help me on that.

The lipid membrane penetration could be an interesting path.

 

[lushmd]

If I am not mistaken, analgesia is a component of anaesthesia?

The four basic aspects of general anesthesia are amnesia, analgesia, reversible loss of consciousness, and muscle relaxation. However, this is not to say that all agents/medications capable of inducing general anesthesia have all of these qualities. Although there is some (scant) research to the contrary, propofol is not thought to contribute to analgesia (and for that matter, is not as good an amnestic agent as volatile anesthetics).

 

[IlDestriero]

If I am not mistaken, analgesia is a component of anaesthesia?
http://www.drugs.com/mmx/propofol.html
http://druginfo.nlm.nih.gov/drugpor...en.jsp&TXTSUPERLISTID=0002078548&QV1=PROPOFOL

You are correct that analgesia is a component of anesthesia, but that does not mean that anesthetic drugs, like propofol, have any analgesic properites other than producing unconsciousness, or antinociception, where you may or may not perceive pain. Propofol has no analgesic effect, in contrast to drugs like ketamine or opiates. Another example would be local anesthetics in a block or spinal. They block nerve conduction and inhibit your ability to perceive stimulation distal to the block, antinociception. They're not really analgesics.
Here's a link to the components of anesthesia to help in your understanding.
http://www.clinicalwindow.net/cw_issue_07_article3.htm

 

[Paseo Del Norte]

You are correct that analgesia is a component of anesthesia, but that does not mean that anesthetic drugs, like propofol, have any analgesic properites other than producing unconsciousness, or antinociception, where you may or may not perceive pain. Propofol has no analgesic effect, in contrast to drugs like ketamine or opiates. Another example would be local anesthetics in a block or spinal. They block nerve conduction and inhibit your ability to perceive stimulation distal to the block, antinociception. They're not really analgesics.
Here's a link to the components of anesthesia to help in your understanding.
http://www.clinicalwindow.net/cw_issue_07_article3.htm

Thanks for the link.

 

[Licoricestick]

You are correct that analgesia is a component of anesthesia, but that does not mean that anesthetic drugs, like propofol, have any analgesic properites other than producing unconsciousness, or antinociception, where you may or may not perceive pain. Propofol has no analgesic effect, in contrast to drugs like ketamine or opiates. Another example would be local anesthetics in a block or spinal. They block nerve conduction and inhibit your ability to perceive stimulation distal to the block, antinociception. They're not really analgesics.
Here's a link to the components of anesthesia to help in your understanding.
http://www.clinicalwindow.net/cw_issue_07_article3.htm

and in addition, the definition of pain (according to the IASP) is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or perceived in terms of such damage" therefore, by definition unconscious, anaesthetised patients do not experience pain. Of course, that doesn't mean that their nervous system doesn't change in response to the nociceptive stimulus (ie the wind up phenomenon) but that is a different thing to actually experiencing pain.

 

[rsgillmd]

and in addition, the definition of pain (according to the IASP) is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or perceived in terms of such damage" therefore, by definition unconscious, anaesthetised patients do not experience pain. Of course, that doesn't mean that their nervous system doesn't change in response to the nociceptive stimulus (ie the wind up phenomenon) but that is a different thing to actually experiencing pain.

I guess it would depend on your definition of experiencing. I would argue because the nervous system is responding to the nociceptive stimulus, they are "experiencing" pain -- just not on a conscious level.

 

[Intensivist]

by definition, they experience nociception, but no pain (those on general anaesthtics) but, besides ketamine, there's no general anesthetic with analgesic properties

 

[Versatil]

by definition, they experience nociception, but no pain (those on general anaesthtics) but, besides ketamine, there's no general anesthetic with analgesic properties

What about N2O, nitrogen, xenon and halogenated ethers??

Except dextrometorphan, the NMDA antagonists are good anesthetics with analgesia.

 

[Intensivist]

n2o to cause sufficient analgesia must reduce your FiO2 below safe level, therefore not that strong, while other volatile agents aren't used due to many reasons...

regarding NMDA antagonists, besides ketamine, no other has been aproved to be used in anesthesia

 

[Licoricestick]

n2o to cause sufficient analgesia must reduce your FiO2 below safe level, therefore not that strong, while other volatile agents aren't used due to many reasons...

Just cause agents aren't commonly used doesn't mean they don't have a place. Methoxyflurane is still in use as an analgesic by Australian paramedics (look up penthrane inhaler), and I doubt we're the only country using it for this purpose (we're not a big enough market to get the drug companies to continue to manufacture drugs just for us).

Xenon is still used, despite being limited by cost.

As for N2O I'm perplexed by your comment! Have you ever actually used it? Nitrous is a terrible anaesthetic (MAC 105% age 30), but a VERY good analgesic agent. Current uses include - painful stimuli on the ward (eg dressing changes), especially in paediatric patients and labour analgesia; adjunct to general anaesthesia (yes it is being used less frequently, but that has nothing to do with it's analgesic properties or the reduced FiO2 required to utilise it); aid to painful procedures prior to anaesthesia induction (eg IV cannulation in the really needle phobic patient without EMLA cream on); adjunct to sedation (eg dental - wisdom teeth often done under LA + N2O +/- oral BZD - works great). Previous uses include as the sole agent for anaesthesia for dental extractions, the sole analgesic component in neurolept anaesthesia (ie droperidol + N2O).

As reduction in FiO2 to an unsafe level before you get effect....What the?? Good analgesic effect can be easily achieved with 50-70% N2O. Last time I checked 30% or more inspired oxygen was not unsafe.

And as for NMDA receptor antagonists and anaesthesia - tramadol and less commonly methadone are used as part of anaesthesia.

 

[Intensivist]

sorry, wasn't clear enough about N2O, but now you have cleared it

anyways, what l meant to say is that bad anesthetic, but ok analgesic, eventhough not that potent, or am l mistaking... We never rely on it for deeper analgesia, for let say hip/shoulder replacement, but l remembered once having a pt with open femur fracture having no pain by only inhaling N2O so it makes me wonder...
Anaesthetists (MDs) here use it very often in GA, for maintenance in comb with Sevo...

Once again, sorry for posting unadvisedly!

 

[Versatil]

n2o to cause sufficient analgesia must reduce your FiO2 below safe level, therefore not that strong, while other volatile agents aren't used due to many reasons...

regarding NMDA antagonists, besides ketamine, no other has been aproved to be used in anesthesia

N2O should always be taken with O2, and it's always the case. Otherwise, the practice is very dangerous.

N2O and ketamine are known to induce and produce anesthesia, even though we'd rather use specific hypnotics for induction for several reasons. If we look in the past, N2O was one of the first choices for anesthesia.

Are you an anesthesiologist or an intensivist (or both)?

And as for NMDA receptor antagonists and anaesthesia - tramadol and less commonly methadone are used as part of anaesthesia.

Tramadol and methadone are NMDA antagonists???
Are you talking about the interaction with some opioid dextro-isomers more specifically?

 

[IlDestriero]

Tramadol and methadone are NMDA antagonists???
Are you talking about the interaction with some opioid dextro-isomers more specifically?

Tramadol and methadone bind to the NMDA receptor and act as antagonists.
Here's a list of some other drugs that are NMDA antagonists: (from the source of all knowledge)

• Amantadine[15]
• Dextromethorphan
• Dextrorphan
• Ethanol
• Ketamine
• Ketobemidone
• Memantine
• Methadone
• Nitrous oxide
• Phencyclidine
• Rilutek (Riluzole) (used in ALS)[16]
• Tramadol
• Xenon

 

[Versatil]

I didn't know .

Interesting, never heard of that.

Thanks!

 

[dhb]

by definition, they experience nociception, but no pain (those on general anaesthtics) but, besides ketamine, there's no general anesthetic with analgesic properties

Since Ketamine dissociates sensory input from perception shouldn't it be classified as antinociceptive rather than analgesic??

 

[caspian]

Since Ketamine dissociates sensory input from perception shouldn't it be classified as antinociceptive rather than analgesic??

Ketamine primarily acts as an NMDA antagonist, but if I'm not mistaken it does exhibit partial agonism at the mu opiate receptor providing true analgesic effects.

 

[cooter7524]

Tramadol and methadone bind to the NMDA receptor and act as antagonists.
Here's a list of some other drugs that are NMDA antagonists: (from the source of all knowledge)

• Amantadine[15]
• Dextromethorphan
• Dextrorphan
• Ethanol
• Ketamine
• Ketobemidone
• Memantine
• Methadone
• Nitrous oxide
• Phencyclidine
• Rilutek (Riluzole) (used in ALS)[16]
• Tramadol
• Xenon

Supposively isoflurane fits this category as well.

 

[Licoricestick]

Since Ketamine dissociates sensory input from perception shouldn't it be classified as antinociceptive rather than analgesic??

Would you still describe it as dissociative even in low doses - like 4mg/hr?

 

[Intensivist]

neither yet, hopefully one day both

 

[Versatil]

Would you still describe it as dissociative even in low doses - like 4mg/hr?

At 4mg/hr, ketamine is highly dissociative IMO.

Ketamine primarily acts as an NMDA antagonist, but if I'm not mistaken it does exhibit partial agonism at the mu opiate receptor providing true analgesic effects.

ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors(mu2) and sigma receptors.

mu2 receptor binding

 

[proman]

At 4mg/hr, ketamine is highly dissociative IMO.

How many patients have you cared for on ketamine drips? 4mg/hr is a small dose. Over the weekend I had 2 patients in the PACU on ketamine, one at 7.5mg/hr the other at 15. Both were completely lucid and fully interactive with reality, mine and their's.

 

[caspian]

ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors(mu2) and sigma receptors.

mu2 receptor binding

The plot thickens:

It seems Ketamine is an agonist at mu, kappa, and delta receptors.
Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells.

Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG.

http://www.ncbi.nlm.nih.gov/pubmed/9915326


The authors did not specify whether they used recombinant mu1 or mu2, but in a different paper by the same lab they stated that while ketamine interacted with mu2, it only activates it at supraclinical doses.

Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells.

Hirota K, Sikand KS, Lambert DG.
University Department of Anaesthesia, Leicester Royal Infirmary, Leicester LE1 5WW, UK.


They claimed it was this unique property that afforded Ketamine analgesic effects without respiratory depression seen with traditional opiate agonists.

To those in clinical practice, have you found this to be true? Have you ever observed respiratory depression in patients on Ketamine monotherapy?

 

[caspian]

Is there any analgesic activity related with propofol?

I am thinking that the way it penetrates lipid membrane it could in someway.

I am also searching some works on the channels modulations by propofol. If anyone could help me in that...

A detailed link on the dynamics and kinetics of propofol could also help me by the way, if anyone has one. Because Golan has a just a brief review of propofol and Katzung lacks of details.

Thank you.

I'm going to stick my neck out and give you what I understand to be the pharmacodynamics of propofol. PLEASE if anybody has any information that refutes this let me know!

Propofol's exact mechanism of action is still being fleshed out, but the overall consensus is that it's main anesthetic effect is by way of it's potentiation of inhibitory GABA-A-receptive neurons in the CNS.

Specifically, it is not so much propofol's lipid profile that determines it's action, but rather it's affinity for the post-synaptic beta-3 subunit of the GABA-A-receptor on neocortical neurons. Upon binding, propofol increases the duration of each inhibitory action potential (similar to barbituates, but at a unique binding site).

Even more interesting is the fact that propofol has presynaptic effects regulating GABA release.
In vitro, propofol causes a slowly developing, depolarizing tonic increase in Cl- concentrations that effectively increases the firing rate of glutaminergic neurons. These excitatory neurons ultimately project to GABAergic neurons perhaps leading to an increase in GABA release.


Neeeeeat



Links Links Links:
Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery.

http://www.ncbi.nlm.nih.gov/pubmed/10637364

General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.

http://www.ncbi.nlm.nih.gov/pubmed/11259561

Distinct actions of etomidate and propofol at beta3-containing gamma-aminobutyric acid type A receptors.

http://www.ncbi.nlm.nih.gov/pubmed/19555700

Propofol facilitates glutamatergic transmission to neurons of the ventrolateral preoptic nucleus.

http://www.ncbi.nlm.nih.gov/pubmed/19934872

Presynaptic actions of propofol enhance inhibitory synaptic transmission in isolated solitary tract nucleus neurons.

http://www.ncbi.nlm.nih.gov/pubmed/19559683

Hope this helps.

 

[Licoricestick]

How many patients have you cared for on ketamine drips? 4mg/hr is a small dose. Over the weekend I had 2 patients in the PACU on ketamine, one at 7.5mg/hr the other at 15. Both were completely lucid and fully interactive with reality, mine and their's.

I have and do use ketamine in quite a lot of patients, fairly standard addition for analgesia poorly responsive to opioids, high opioid use, or where pain and oversedation are an issue in the acute pain services I have worked in. On of the major australian acute pain people (Pam Macintyre) advocates what we have used at these hospitals: 2-4mg/hr in >70yr olds and 4-8mg/hr in <70yr olds. Bolus doses for rescue analgesia in recovery/on ward of 4mg.

I know it seems like a small dose, but it does have good analgesic and opioid sparing properties at those doses, and patients report far less disturbing dreams etc, and are generally happy to try ketamine again. Those that have accidentally had higher (but still subanaesthetic) boluses often refuse point blank to have it again cause they had such a bad experience before.

Clearly it does not induce a dissociative state in low doses, and I would argue that, although its full MoA as an analgesic is not know, it does act in the spinal cord, where we know it prevents wind up. Thus my original question to dhb.

 

[proman]

I have and do use ketamine in quite a lot of patients, fairly standard addition for analgesia poorly responsive to opioids, high opioid use, or where pain and oversedation are an issue in the acute pain services I have worked in. On of the major australian acute pain people (Pam Macintyre) advocates what we have used at these hospitals: 2-4mg/hr in >70yr olds and 4-8mg/hr in <70yr olds. Bolus doses for rescue analgesia in recovery/on ward of 4mg.

I know it seems like a small dose, but it does have good analgesic and opioid sparing properties at those doses, and patients report far less disturbing dreams etc, and are generally happy to try ketamine again. Those that have accidentally had higher (but still subanaesthetic) boluses often refuse point blank to have it again cause they had such a bad experience before.

Clearly it does not induce a dissociative state in low doses, and I would argue that, although its full MoA as an analgesic is not know, it does act in the spinal cord, where we know it prevents wind up. Thus my original question to dhb.

My question re: clinical experience was direct at the person I quoted, not you. Ketamine's an interesting drug. We commonly think of nociception and antinociception, both endogenous pathways. There are some drugs, like thiopental, that inhibit anti-nociception and are though to be nociceptive, when in reality I think it's just removal of inhibition that we see. I've had 30% nitrous and that's damn disassociative.

 

[Licoricestick]

My question re: clinical experience was direct at the person I quoted, not you.

I did get that, but on the reread

Ketamine's an interesting drug. We commonly think of nociception and antinociception, both endogenous pathways. There are some drugs, like thiopental, that inhibit anti-nociception and are though to be nociceptive, when in reality I think it's just removal of inhibition that we see. I've had 30% nitrous and that's damn disassociative.

Very true, and there is just so much about the physiological processes of pain and its modulation (pharmacological and other) that we just don't understand yet.

 

[Versatil]

How many patients have you cared for on ketamine drips? 4mg/hr is a small dose. Over the weekend I had 2 patients in the PACU on ketamine, one at 7.5mg/hr the other at 15. Both were completely lucid and fully interactive with reality, mine and their's.

Sorry, i've been mistaken, I thought we were talking of 4mg/kg, which is extremely dissociative btw.

The plot thickens:

It seems Ketamine is an agonist at mu, kappa, and delta receptors.
Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells.

Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG.

http://www.ncbi.nlm.nih.gov/pubmed/9915326


The authors did not specify whether they used recombinant mu1 or mu2, but in a different paper by the same lab they stated that while ketamine interacted with mu2, it only activates it at supraclinical doses.

They claimed it was this unique property that afforded Ketamine analgesic effects without respiratory depression seen with traditional opiate agonists.

To those in clinical practice, have you found this to be true? Have you ever observed respiratory depression in patients on Ketamine monotherapy?

Do we have any other investigation on receptor stereoselectivity since 1999?

As for the respiratory depression, yes, it's dose-related.

 

[Versatil]

http://www.anesthesia-analgesia.org/content/104/6/1563.full

 

[dhb]

Btw , N2O is used a lot in Belgium/France (rest of europe) for painfull procedures in kids: lacs , ivs, spinal taps etc... in my experience it's actually a quite good analgesic even at 50%.

 

[epidural man]

by definition, they experience nociception, but no pain (those on general anaesthtics) but, besides ketamine, there's no general anesthetic with analgesic properties

Not true.

Dexmetetomidine can be run at large enough doses for general anesthesia. It also has analgesic properties.

 

[rsgillmd]

Not true.

Dexmetetomidine can be run at large enough doses for general anesthesia. It also has analgesic properties.

??? You are making me want to go back to the books. Does Dex have actual analgesic properties, or is it simply opioid sparing properties? Put another way, for a given painful stimulus with no other analgesics on board, will it produce analgesia if given after the fact? I'm not sure. My use with it is limited. Haven't used it since CA-2 year, so I've forgotten some of the mechanistic details.

 

[Idiopathic]

??? You are making me want to go back to the books. Does Dex have actual analgesic properties, or is it simply opioid sparing properties? Put another way, for a given painful stimulus with no other analgesics on board, will it produce analgesia if given after the fact? I'm not sure. My use with it is limited. Haven't used it since CA-2 year, so I've forgotten some of the mechanistic details.

Yes, even though your question is fairly obtuse. When given at the end of a procedure, more comfortable and less morphine in PACU, in short.

 

[sevoflurane]

I use it every day:

http://www.anesth-analg.com/content/98/1/153.full

http://www.anesthesia-analgesia.org/content/111/2/490.abstract