Nefopam (Acupan)

[haribo1]

Hi,
My hip pain has increased. The GP offered me fentanyl patches but I really don't want to take an opiate of that potency for any length of time so I asked for nefopam. Now, I can find little about the way this stuff works. I know the exact method of action is not totally understood but it IS centrally active but what the hell does it bind to? Here is an image:

It's supposed to be similar (a little stronger) than tramadol in efficiacy. Anyone have any ideas on how the damned stuff works?

 

[Ham-milton]

Well, it's a 5HT, NE and DA reuptake inhibitor. That's not surprising considering the similarities to diphenhydramine (the founding father of SSRIs, actually). The analgesic effects are probably due to that.

But then again, there's this:

In order to specify the nature of interactions between the analgesic compound nefopam and the glutamatergic system, we examined the effects of nefopam on binding of specific ligands on the three main subtypes ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain membrane preparations. Functionally, we investigated the effects of nefopam against the seizures induced by agonists of these excitatory glutamate receptors in mice. Since the synaptic release of glutamate mainly depends upon the activation of membrane voltage-sensitive sodium channels (VSSCs), the nature of interactions between nefopam and these ionic channels was studied by evaluating the effects of nefopam on binding of 3H-batrachotoxinin, a specific ligand of the VSSCs in rat brain membrane preparations. The functional counterpart of the binding of nefopam on VSSCs was evaluated by its effects on the 22Na uptake-stimulated by veratridine on human neuroblastoma cells and in the maximal electroshock test in mice. Nefopam showed no affinity for the subtypes of ionotropic glutamate receptors up to 100 microM. On the other hand, nefopam was effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam displaced 3H-batrachotoxinin and inhibited the uptake of 22Na in the micromolar range and it protected mice against electroshock induced seizures. Nefopam may block the VSSCs activity: consequently, at the presynaptic level, this effect led to a reduction of glutamate release and at the postsynaptic level, it led to a decrease of the neuronal excitability following activation of the glutamate receptors.

but then again there's this:

Authors
M. T. Fernández-Sánchez1, R. Díaz-Trelles1, A. Groppetti3, B. Manfredi3, A. T. Brini3, G. Biella, M. L. Sotgiu5, A. Novelli

1Department of Biochemistry and Molecular Biology, University of Oviedo, Oviedo, Spain
2Department of Psychology, University of Oviedo, Oviedo, Spain
3Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy
4Department of Science and Biomedical Technologies, University of Milan, Milan, Italy
5Institute of Neuroscience and Bioimaging, CNR, Segrate, Italy
Abstract

Summary. Nefopam hyghochloride is a potent analgesic compound commercialized in most Western Europe for 20 years, which possesses a profile distinct from that of opioids or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanisms remain unclear. While, nefopam structure resembles that of orphenadrine, an uncompetitive NMDA receptor antagonist, here we report that differently from orphenadrine, nefopam (100 7M) failed to protect cultured cerebellar neurons from excitotoxicity following direct exposure of neurons to glutamate. Moreover, nefopam failed to displace MK-801 binding to hippocampal membranes. Nefopam effectively prevented NMDA receptor-mediated early appearance (30 min) of toxicity signs induced by the voltage sensitive sodium channel (VSSC) activator veratridine. The later phase (24 h) of neurotoxicity by veratridine occurring independently from NMDA receptor activation, was also prevented by nefopam. Nefopam effect was not mimicked by the GABA receptor agonist muscimol.

And finally, after having circled the globe, we're back to this:

Title: Analgesia by nefopam: does it act through serotonin?
Author: Marazziti, D : Rotondo, A : Ambrogi, F : Cassano, G B
Citation: Drugs-Exp-Clin-Res. 1991; 17(5): 259-61
Abstract: In an attempt to clarify the possible mode of action of nefopam, a new analgesic compound, the authors tested its effects on imipramine (IMI) binding to platelet membranes. The results showed that nefopam exerted a concentration-dependent inhibition of IMI binding, with a potency comparable to that of tricyclic antidepressants. This finding suggests a possible intervention of serotonergic mechanisms in nefopam-related analgesia.

 

[haribo1]

Thanks for that, now I can do some PROPER research. I take 60mg x3 daily and the level of relief approaches morphine (but no side-effects so far). Wonder if the drug can be modified to make the NE & DA reuptake inhibition more... fun.

 

[Riemann Zeta]

It certainly looks like a DAT inhibitor (and I guess most DAT inhibitors are also NET inhibitors). And I guess it is also a voltage gated sodium channel modulator, like various anticonvulsants that are also used for neuropathic pain and bipolar disorder. Why is this compound not available worldwide? It's a non-opioid analgesic, that should be enough to ensure government approval.

 

[Ham-milton]

It does? The 'N' is too close to the benzene to have the PEA structure embedded.

It looks like a benzo to me (only superficially, of course)!

 

[hugo24]

I had this once but just didn't like because of sideeffects,besides that the effects on pain were minimal (a whiplash-syndrom).Maybe it is better suited as AD?

But I really like the structure!

 

[Bondmaker]

it looks to me...

like it overlaps with the methadone structure? I agree, it's a dead ringer for diphenhydramine, but when you lock-up many molecules and reduce their degrees of freedom, they often show unique behavior, not expected. Do you know if it has opioid binding?

 

[Riemann Zeta]

Indeed, it is almost identical to diphenhydramine, but without the aliphatic chain flexibility. The reason that I mentioned that it looked like a neurotransmitter transporter inhibitor is the presence of a diphenylmethoxy moiety and a tertiary nitrogen. Remember that diphenhydramine does have some activity at monoamine transporters (mainly SERT and DAT--a lot of the modern SSRIs were derived from the diphenhydramine structure), but its affinity for these transporters is extremely low when compared to its affinity for the histamine H1 receptor and the muscarinic M1 receptor.

 

[Ham-milton]

oh, I see. I didn't notice the similarity to diphenhydramine. It doesn't have any appreciable affinity to mu receptors.

 

[Smyth]

Nice find. It sorta reminds me of what tametraline looks like. Although you wont find a structure for this online, its related to sertraline and is basically the compound in which the chlorine atoms are absent. This was the parent compound from which sertraline was discovered if I could find a review that outlines this then that'd be interesting to read. Tametraline fucntions as a NARI.

At first I thought "Nefopam (Acupan)" was a weird opioid due to the fact that it carries a tertiary amine, but it appears that it is a MARI (MA = monoamine; CA = catecholamine).

Like somebody else said, it does look sorta vaguely like benzodiazepine even though it isnt really anything like it.

Im assuming you have a good relationship with a pain doc since one if my reasons for abandoning my psychiatrist is that he was such a lamer that I couldn;t even get a script for bupropion let alone ritalin. These folks get paid in excess of £100,000 annually and they are a bunch of lamers. I'm sure they wont mind me boycotting them but they seemed very frustrated when I decided to call it quits. Still, that's what happened after they removed the incentive for me to play their idiot mind games.

 

[Limpet_Chicken]

I was put on nefopam while I was inside, for a combination of a long running knee problem and a neck injury, because they wouldn't continue the DHC script I was using for it on the out, I found it really unpleasant stuff, I'm not sure what the per-tablet dosage was, but it made me tachycardic pretty quickly, after about two or three days of taking 1 tab BD, subjectively it made me feel pretty wierded out too.

Not much of an impact on the pain either, if any.

 

[fool of light]

Hello guys.

Recently my girl had a surgery and as a post-surgery pain managment was offered 1g paracetamol or 2ml/20mg nefopam intravenously. Not knowing what nefopam was however knowing paracetamol on its own is shit and she's in terrible pain I advised her to take nefopam. She got 20mg-2ml. Did nothing to her,poor girl..anyway.

However reading a bit more about nefopam really interested me and it didn't take me more than 2days to get it from some local pharmacy (one of many reasons I love Asia) in its hydrochloride form 30mg a cap. Interesting is that it's 0 size cap ("0"cap weighs roughly 100mg on its own) packed with white powder weighing more than 0.6g..will have to contact the manufacture and ask what other rubbish is inside...

Today was the day..have read everything I could on the internet starting with wiki finishing with some scientific comparative articles about nefopam and other analgesics (20mg equals roughly 12mg of morphine)..haven't found a single decent report of a recreational use of this thing at all..just bunch of some posts coming from people in terrible pain using it purely as a pain relief and the rest was just speculations based on it's triple reuptake inhibition and a possibility of having similar effect to tramadol hcl possibly enhanced in effect about some dopamine inhibition. Just to be clear here I love tramadol (125-150mg sweet spot) which I've in modesty been working with for more than a year by now. Some extra dopamine would hurt my experience I thought..Sooo..

As I mentioned my girl was given ridiculous dose 20mg intravenous..didn't help her at all..now I see that most of pain people posting their nefopam pain results taking 60-90mg 3x a day...ok, so having experience with doll(tramadol) and codeine lets try 90mg single dose almost empty stomach and clear head..

* t+0.5h feeling that sth's definitely coming..a bit like 150mg of t-doll t+3h..
* t+1h feeling pretty pleasantly heavy..however not as pleasant and natural I feel on doll..my appetite was totally gone,lying in beanbag felt like the best I could do and also not as mildly talkative like on doll..
* t+1.5h not really having fun focusing on anything (however my head is still pretty clear not messed up like on benzos), only thing making me feel right is going to bed, off to bed I went..feeling more stable,enjoying melting and slowly drifting away to dream-realms... - felt quit close to doll t+5to6h with some good smokes but less enjoyable
* t+4h waking up feeling pretty much ok, slightly light but clearheaded overall pretty rested.
* t+5 feeling nefopam's gone...for the rest of the night with some minor sleep breaks Im taking care of my crying newborn babies with no sign of any negative emotional or physiological after taste but can't feel any positive uplifting afterglow like even t+10h on doll..
* t+12h getting ready to work feeling pretty good even though not much sleep at night.

Sooo...
What to say..I guess that most of you got a picture..so far I consider 90mg single dose being better solution for many issues people take benzos for...let me try a milder dose in a day or two thinking if 70-80mg single dose and I ll get back to you soon..

Take care till then..

 

[Hammilton]

I'm confused, in my initial response I compared it to diphenhydramine, and then a few posts later I say that I didn't notice the similarity to diphenhydramine? I dunno what was going on my brain back then, It's a good thing I got it together (get it, got it together, went from being Ham-milton to Hammilton? okay it's a weak pun)

 

[SeenSoFar]

On the wikipedia page it says this has affinity for 5-HT_2A... I am assuming this is antagonist activity? I don't have journal access at present, so if anyone could clarify things vis-a-vis it's affinity and efficacy at 5-HT_2A, that would be awesome. If it is indeed an agonist, it would make a lot of sense as to why it is not available in the United States. The FDA has been retardedly reluctant in approving 5-HT_2A agonists, even if they have no psychedelic/recreational potential. Hell, they slapped a Schedule IV on lorcaserin, the first FDA-approved 5-HT_2A agonist, and by all accounts it isn't really psychedelic or even any fun...

 

[endotropic]

On the wikipedia page it says this has affinity for 5-HT_2A... I am assuming this is antagonist activity? I don't have journal access at present, so if anyone could clarify things vis-a-vis it's affinity and efficacy at 5-HT_2A, that would be awesome. If it is indeed an agonist, it would make a lot of sense as to why it is not available in the United States. The FDA has been retardedly reluctant in approving 5-HT_2A agonists, even if they have no psychedelic/recreational potential. Hell, they slapped a Schedule IV on lorcaserin, the first FDA-approved 5-HT_2A agonist, and by all accounts it isn't really psychedelic or even any fun...

That information on the wikipedia page comes from a 2012 article that only looked at drug/receptor binding with no mention of efficacy. It's possible that another paper has tested efficacy since then, but I haven't seen anything.

In this report though, they tested nefopram's analgesic efficacy in rats, and found that 5-HT2C antagonists reduced nefopram's effects, while 5-HT2A antagonists did nothing. That suggests nefopram is a 5-HT2A antagonist/5-HT2C agonist, although that's far from conclusive evidence.

Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception.

 

[anonyFen]

Hey, so I got some of this stuff the other day on an online pharmacy, it requires a prescription, but its a prescription they can give you after you answer some questions to their team so their due diligence is satisfied.
seems like a pretty reasonable way to do it, i had a hell of a time trying to get hold of something when i hurt my back, and they gave me tramadol which actually totally fucked me up, i ended up on subutex trying to get off it (30x100mg caps) and basically i felt like amy winehouse and it properly put me off anything opiate or opioid. codien and dihydrocodine give me hives, i guess because they strain the liver as prodrugs so basically it seems like i have developed an allergy to morphine derivatives i guess cos the liver or kidneys get strained and the body begins to develop a rejection response, i swear even the subutex was giving me a rash. so anyway, this stuff seems great! they just arrived today and i had one earlier, instead of a spliff as im trying to give up smoking so i dont look sleepy all the time. chewed the tablet and it made my mouth totally numb, something i associate with coke cut with benzocaine. immidiately felt a kind of woozyness i associate with antihistamines like diphenhydramine, and walking around in the hour after taking it i kind of felt a bit sluggish, though that could have been from smoking a cigarette, but i kind of really dont like the way antihistamines make you drowsy. alot of the seretonin and dopamine antagonists are like this, where all except quitiapine (esp mirtrazapine which is basically paralyzing and so totally unsuitable as a sleep aid for which it was prescribed. unless you like lying there not being able to sleep or move in a weird kind of fever state) are just too strong as antihistamines. this stuff isnt quite as bad, and apart from being a bit docile and lazy it seems like i could tolerate it in a social setting, where being in pain is a real disruption. pain relief definitely seems to be the main affect appart from this slight woozyness, but in agreement with another report on here, i felt a weird kind of comfy heavyness in my body when i lay down after getting back from walking around. i could have drifted off but i had made coffee, which actually seems to have made me less lethargic. maybe in combo with a stimulant it would override the histamine effect, which otherwise could be basically offputting. in terms of recreational abuse, its way less delirium inducing than tramadol, which is kind of drunkening - so id really put its only noticable effects down to CNS relaxation. veery good if your like a stoner that likes to curl up and watch a film, actually something that i cant get from cannabis in recent years. from the research i guess this kind of indicates the glutamate action could mean its more like an NMDA disasociative, with maybe a slight-slight ketamine like euphoria, but more like it in that its just kind of floaty and relaxed. i was excited about its dopamine reuptake, and happy that it was not as tightly binding to the seretonin transporter, since i dont like to mess with my serotonin system as im prone to depression. as a tripple reuptake inhibitor it seems kind of like cocaine, though way less strong, and unfortunately in this regard quite short acting. i think the dopamine system adjusts very quickly, im an ex crack smoker, so i bet my body has immense defences against dopamine transport blockers, so that effect (slightly like really clean very mild coke) was very short lived, compared to the long halflife of the secondary metabolite which i guess will probably more closely resemble to long tail effects of diphenhydramine, though it was nothing like that stuff, which makes you nod off and causes you to pass out with dramatic efficacy. there was no kind of direct sleep induction similar to dyphenhydramine, which i guess follows from its reduced binding to the H1,2 receptors which modern drugs really try to avoid. interesting structure activity relation from the steric hinderance in the explanation of this mechanism, though more likely a resonant electrical effect rather than anything to do with conformational enumeration, or so called molecular "flexibility", which seems a very tenuous premise on which to base structure activity relations. also despite the large nitrogenous ring, it does not bare any resemblance experientially to a benzo, except maybe in the sudden onset being slightly exhilarating, but i guess thats the same with any drug that is rapidly absorbed and peaks to precipitate disinhibition of the adrenal cortex, though of course this could be explained as a NET ligand.