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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by ed_uk on March 25, 2005, at 15:38:45
I'm posting a study which may be of interest, I have a few things to say first.....
Effexor = venlafaxine
Benadryl = diphenhydramineTo summarise the study, Benadryl can inhibit the metabolism of Effexor, reducing its clearance.
Since Effexor is metabolised to O-desmethylvenlafaxine, an active metabolite, the clinical significance of this finding is not clear.
Since Effexor has been implicated in causing arrhythmias, it is possible that combining a high dose of Effexor with Benadryl might cause cardiovascular side effects.
It is possible that Benadryl attenuates Effexor withdrawal symptoms by reducing its clearance. It might be advisable to avoid combining high doses of Effexor with Benadryl.
Nefopam, a derivative of diphenhydramine (Benadryl) is thought to be a weak serotonin reuptake inhibitor. I've been wondering whether Benadryl is also a serotonin reuptake inhibitor- this may partly explain its apparant efficacy in relieving Effexor withdrawal symptoms.
Benadryl is sedative and anti-emetic, these properties may be helpful in treating insomnia and nausea respectively, symptoms which may occur during Effexor withdrawal.
The study.....
J Clin Psychopharmacol. 2001 Apr;21(2):175-84.
Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O'Hara G, LeBlanc J, Turgeon J.
Quebec Heart Institute, Laval Hospital, Canada.
CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.
Ed.
Posted by SLS on March 25, 2005, at 17:15:11
In reply to Drug Interaction between Benadryl and Effexor....., posted by ed_uk on March 25, 2005, at 15:38:45
This is good stuff, Ed. It could explain much. The one thing that I find interesting, though, is that people find diphenhydramine useful weeks and months after discontinuation. This could perhaps be explained if it indeed inhibits the reuptake of 5-HT. Can you find anything that I can take a look at regarding this? Nefopam is a derivative and not a metabolite?
Thank you berry much.
- Scott
> I'm posting a study which may be of interest, I have a few things to say first.....
>
> Effexor = venlafaxine
> Benadryl = diphenhydramine
>
> To summarise the study, Benadryl can inhibit the metabolism of Effexor, reducing its clearance.
>
> Since Effexor is metabolised to O-desmethylvenlafaxine, an active metabolite, the clinical significance of this finding is not clear.
>
> Since Effexor has been implicated in causing arrhythmias, it is possible that combining a high dose of Effexor with Benadryl might cause cardiovascular side effects.
>
> It is possible that Benadryl attenuates Effexor withdrawal symptoms by reducing its clearance. It might be advisable to avoid combining high doses of Effexor with Benadryl.
>
> Nefopam, a derivative of diphenhydramine (Benadryl) is thought to be a weak serotonin reuptake inhibitor. I've been wondering whether Benadryl is also a serotonin reuptake inhibitor- this may partly explain its apparant efficacy in relieving Effexor withdrawal symptoms.
>
> Benadryl is sedative and anti-emetic, these properties may be helpful in treating insomnia and nausea respectively, symptoms which may occur during Effexor withdrawal.
>
> The study.....
>
> J Clin Psychopharmacol. 2001 Apr;21(2):175-84.
>
> Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.
>
> Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O'Hara G, LeBlanc J, Turgeon J.
>
> Quebec Heart Institute, Laval Hospital, Canada.
>
> CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.
>
> Ed.
Posted by ed_uk on March 25, 2005, at 18:21:26
In reply to Re: Drug Interaction between Benadryl and Effexor..... » ed_uk, posted by SLS on March 25, 2005, at 17:15:11
Hi Scott!
>Nefopam is a derivative and not a metabolite?
Yes, it's a derivative, it's used as an analgesic in the UK. The brand name is Acupan.
From PubMed..........
'The drug (nefopam) is an analogue of orphenadrine, consisting of a cyclization of the diphenhydramine molecule.'
To compare structures:
You can see that diphenhydramine's side chain has been turned into a ring to produce nefopam.
Orphenadrine, the anticholinergic, is structurally very similar to diphenhydramine.....
http://www.psychotropics.dk/usr_view_molecule.asp?ID=2292&backurl=Alphaindex%2Fview%5Falpha%2Easp%3FStartchar%3DO&backurlname=Alphabetical+index&historyline=&Catalogtype=A'These data suggest that nefopam is effective as an inhibitor of norepinephrine and serotonin uptake at doses previously shown to be analgesic in mice, consistent with uptake inhibition being a postulated mechanism important in its analgesic effect. Nonetheless, nefopam is a relatively weak inhibitor of monoamine uptake with a short duration of action in mice.'
'The effect of (+/-), (+) and (-)-nefopam on the uptake of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in synaptosomal preparations from rat forebrain, hippocampus and striatum has been investigated. All three forms of nefopam inhibited the amine uptake in the investigated structures, the order of potency being (+) greater than (+/-) greater than (-). (+)-Nefopam was 7-30 times more potent than (-)-nefopam. The same order of potency has also been found for the antinociceptive effect of these three forms, however, the differences were smaller. Inhibition of 5-HT and noradrenaline uptake may not be the sole mechanism underlying the analgesic effect of nefopam.'
...............................................................................................................................................
Nefopam is hypothesised to act as an analgesic due to its properties as a monoamine reuptake inhibitor. Diphenhydramine and orphenadrine also appear to possess analgesic activity, perhaps diphenhydramine is also a reuptake inhibitor??
'We report three patients with advanced cancer pain refractory to adjuvants and oral, intravenous, and epidural opioids, who achieved sustained pain relief after the repeated administration of diphenhydramine. Diphenhydramine may be useful in the treatment of neuropathic and nociceptive pain that has failed to respond to treatment with opioids and adjuvant analgesics. We suggest a starting dose of 25 mg of oral or parenteral diphenhydramine every 6 to 8 hours, with titration to effect.'
'The analgesic effect of morphine in rats, as reflected in elevated thresholds for tail shock induced vocalizations, was markedly potentiated by the antihistamine, diphenhydramine.'
Diphenhydramine also acts as a local anesthetic when injected locally........ 'Diphenhydramine is an adequate alternative of local anesthetics in patients with history of hypersensitivity to local anesthetics.'
Diphenhydramine's antihistamine property may also account for its analgesic effects.....
'Histamine activates pain-transmitting nerve fibres, releases pain-related neuropeptides, and is painful when injected into the skin. Histamine agonists mimic these effects, suggesting that histamine plays a role in mediating the signal transduction of tissue damage or other painful stimulus. Certain 'antihistamines' (histamine H1 receptor antagonists) and other antihistaminics are 'analgesic' in preclinical or clinical models. Potential sites of action of these agents include the brain and spinal cord and a specific histamine receptor subtype might be involved (three subtypes have been identified). However, *it is possible that other mechanisms account for the analgesic effect*.'
Not all sedative antihistamines are analgesic though.... certain antihistamines may possess other properties which produce analgesia................
'In clinical studies, diphenhydramine, hydroxyzine, orphenadrine and pyrilamine have been shown to produce analgesia as simple entities but chlorpheniramine has not.'
Perhaps diphenhydramine produces analgesia via effects on monoamine uptake??
What do you know- I just found this.........
From 1980.......
At low concentrations 'two other H1 antihistamines, promethazine and diphenhydramine...............had no effect on 5HT or DA uptake. Diphenhydramine had a small inhibitory effect on NE uptake.'
Perhaps diphenhydramine's effect on NE uptake is sufficient to relieve withdrawal symptoms in some patients.
I wonder whether diphenhydramine has any significant effects on serotonin uptake at higher concentrations??????? Perhaps it has an effect similar to nefopam at high doses.
I have noticed that when I d/ced citalopram and lofepramine (NE upatake) at the same time, the withdrawal symptoms were worse than when d/cing citalopram alone. Perhaps venlafaxine's withdrawal symptoms are especially bad because of its effects on NE as well as serotonin.
Regards,
Ed.PS. Diphenhydramine's antihistamine effect may relieve insomnia.
It's anticholinergic properties may relieve GI distress and diarrhea.
It's antiemetic properties may relieve nausea.
Since anticholinergics affect dreaming, perhaps its anticholinergic properties reduce nightmares.
Posted by SLS on March 25, 2005, at 19:09:10
In reply to Re: Drug Interaction between Benadryl and Effexor..... » SLS, posted by ed_uk on March 25, 2005, at 18:21:26
Hi Ed.
That's a little bit too much reading for me to do right now. However, I just want to remark that histamine itself is a neurotransmitter that tends to be excitatory in the brain. Blocking the H1 receptors might account for some of the effects diphenhydramine has on nociception. I really have no idea.
I can't thank you enough for producing such useful posts. They never go to waste.
- Scott
Posted by SLS on March 25, 2005, at 19:14:40
In reply to Re: Drug Interaction between Benadryl and Effexor..... » SLS, posted by ed_uk on March 25, 2005, at 18:21:26
Hi Ed.
Someone recently contributed what seem like a great idea for discontinuing Effexor and Paxil. He suggested a crossover to Prozac and add a small amount of desipramine from which to taper. Pretty cool.
- Scott
Posted by ed_uk on March 26, 2005, at 9:48:52
In reply to Re: Drug Interaction between Benadryl and Effexor..... » ed_uk, posted by SLS on March 25, 2005, at 19:09:10
Hi Scott!
>I can't thank you enough for producing such useful posts.
:-)
Regards,
Ed.
Posted by ed_uk on March 28, 2005, at 17:05:57
In reply to Re: Drug Interaction between Benadryl and Effexor..... » SLS, posted by ed_uk on March 26, 2005, at 9:48:52
Posted by Dr. Bob on March 31, 2005, at 0:22:17
In reply to OMG, my posts have disappeared!!!!!! (nm), posted by ed_uk on March 28, 2005, at 17:05:57
> OMG, my posts have disappeared!!!!!!
Sorry, but when I delete posts, for example:
http://www.dr-bob.org/babble/wdrawl/20050323/msgs/476621.html
then I delete responses to them, too.
Bob
Posted by ed_uk on March 31, 2005, at 13:43:39
In reply to Re: OMG, my posts have disappeared!!!!!!, posted by Dr. Bob on March 31, 2005, at 0:22:17
Hi,
>I delete responses..........
Never mind!
Regards,
Ed.
Posted by xxNightOwl28 on April 17, 2005, at 6:57:54
In reply to Re: OMG, my posts have disappeared!!!!!! » Dr. Bob, posted by ed_uk on March 31, 2005, at 13:43:39
I am quite confused by all the terminology, but I take Effexor 150mgxr on for 3 yrs now, and occasionally 4 or 5 times per month I take Benydrl or Tylenol PM and sometimes NyQuil, When I do I get some slight but noticable kind of withdrawl symptoms even though I am not reducing my Effexor dose. My main concern is do you think it is harmful to me to do this?? My doc isn't helping.
This is the end of the thread.
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