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.'
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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.
poster:ed_uk
thread:475495
URL: http://www.dr-bob.org/babble/wdrawl/20050323/msgs/475591.html