Two Possible Adjuncts to Central Pain Treatment by Clark Renwick Herniman:

This original article details more on N-type calcium channels and pain. We are very grateful to the author for providing this material.

Two Possible Adjuncts to Central Pain Treatment:
A Review of Nefiracetam and Aniracetam
Clark Renwick Herniman


Aniracetam and nefiracetam are analogues of the drug piracetam (Gualtieri, et. al., 2002.). These drugs were originally developed to treat Alzheimer’s disease although their action on N-type calcium channels may make them effective as analgesics as well (McGivern and McDonough, 2005). Aniracetam, 1-(p-anisoyl)-2-pyrrolidinone, is the older of the two drugs. Its cognitive effects were first reported in 1979 and it was introduced into clinical use in 1993 (Gouliaev and Senning, 1994). It is an approved drug in both Italy and Switzerland, however the FDA has not approved it for use in the United States (Ibid.). Currently there are a number of Internet based businesses selling it as a nutritional supplement.

Nefiracetam, N-(2,6-dimethylphenyl)-2-(2-oxo- 1-pyrrolidinyl) acetamide, is a newer compound that may be even more promising in the treatment of central pain than aniracetam. It was developed as by Daiichi pharmaceuticals, and is an approved medication in China, although it was withdrawn from US stage III clinical trials for lack of efficacy (Current Opinions in Investigational Drugs, 2002). Although it is not conclusively shown to be effective as an Alzheimer’s disease medication, studies have shown that it could possibly be useful as an analgesic (Rashid, M.H. and Ueda H., 2002).


The pharmacology of aniracetam is complex and the mechanism by which it exerts its cognition enhancing effects is still unknown. It has a slight affinity for muscarinic receptors and modulatory effects on acetylcholine and glutamate receptors (Gualtieri, et. al., op. cit.). In an effort to pinpoint the source of aniracetams neurotransmitter modulating effect, studies were done to test the effects of aniracetam on various ion channels. These studies found that aniracetam effectively blocks the N-type calcium current (Rabasseda, Mealy, and Presti, 1994).

Aniracetam has been shown to be a relatively non-toxic compound. Its LD50 is 4.5 g/kg orally in rats and 5.0 g/kg orally in mice while its ED50 in rodents is 10-100 mg/kg (Gouliaev and Senning, op. cit.). No toxic or teratogenic effects were found in the animal studies done with aniracetam (Ibid.).

In humans, side effects are rare and can include insomnia and anxiety. The average dose that is found to be effective in most human trials was 750-1500 mg (Dean and Morganthaler, 1994). Some trials show that multiple doses are required throughout the day (Ibid.). This may be because aniracetam is metabolized into the less active anisoyl-GABA (Gualtieri, et. al., 2002.).

While there are many studies on aniracetams cognitive effects, few studies have been done to test its analgesic efficacy. One study found that aniracetam reversed thermal hyperalgesia observed in nerve-injured mice (Rashid and Ueda, 2002). The analgesia produced by aniracetam was not antagonized by naloxone, proving that the analgesic mechanism of aniracetam is not due to a direct effect on the opioid receptors (Ibid.).


The pharmacology of nefiracetam is similar to that or aniracetam, although it has a number of additional effects (Gualtieri, et. al., op. cit.). It has been shown to bind to alpha4beta2 nicotinic acetylcholine receptors and the glycine-binding site on NMDA receptors (Narahashi, 2004). It also activates choline acetyltransferase (ChAT), which catalyzes the synthesis of acetylcholine from choline and acetyl-CoA (Current Opinions in Investigational Drugs, 2002). Like aniracetam, it has been show to modulate N-type calcium channels (Gualtieri, et. al., op. cit.).

Because nefiracetam is a newer drug, its safety is not as established as aniracetams. Some studies have shown toxic effects in dogs at doses of 300mg/kg (Current Opinions in Investigational Drugs, 2002). It is also a more potent drug and the average human dose is 450-900 mg. per day (Ibid).

Nefiracetam was found to be more effective than aniracetam in reversing thermal hyperalgesia in mice (Rashid and Ueda, 2002). Nefiracetam may also have the added effect of being able to reduce opioid tolerance (Itoh, 1998). Nefiracetam does not have any direct effect on opioid receptors, nor does it have any addictive properties. Rather than effecting opioid receptors directly, it is nefiracetam reduces opioid tolerance by increasing cAMP levels (Ibid.).

Further thoughts

Although non-specific calcium channel blockers have been used extensively in the treatment of central pain, they possess many adverse side effects that have limited their effectiveness. Recent research has identified specific types of calcium ion channels (McGivern and McDonough, op. cit.). One of these channels, the N-type calcium ion channel, is specific to neurons (Ibid). It is thought that drugs that specifically block this channel would have fewer side effects than other calcium channel blockers (Ibid). Research suggests that aniracetam and nefiracetam may be more selective for these channels than other calcium channel blockers (Gualtieri, et. al., op. cit.).

Rashid and Ueda tested the analgesic efficacy of nefiracetam, aniracetam, and other similar compounds (Rashid and Ueda, op. cit.). Aniracetam and nefiracetam were the only compounds that were shown to be effective (Ibid.). One of the things that aniracetam and nefiracetam have in common is that they affect N-type calcium channels. None of the other compounds that were tested are known to affect N-type calcium channels. Further studies that test the relationship between the calcium channel modulating effect of these compounds and their analgesic capability would be interesting to see.

Regardless of their mechanism of action, these drugs seem to warrant further study. Although they have been shown to effectively treat hyperalgesia it not currently known if they will effectively alleviate allodynia as well (Hyperalgesia vs. Allodynia, 2004). If these medications were found to be effective in treating hyperalgesia, allodynia, and opioid tolerance, they could help ease the suffering of many people in chronic pain.

Works Cited
1. Current Opinions in Investigational Drugs, Vol. 3 No. 5, pg. 788-794, May 2002
2. Dean, W. and Morganthaler, J., Smart Drugs and Nutrients, 1994
3. Gualtieri, et. al., Design and Study of Piracetam-like Nootropics, Controversial Members of the Problematic Class of Cognition-Enhancing Drugs, 2002
4. Gouliaev, A.H. and Senning, A., Piracetam and other structurally related nootropics, 1994
5. Hyperalgesia vs. Allodynia, 2004
6. Itoh, A. Et. al., A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine, 1998
7. McGivern, J. and McDonough, S., Calcium Channels and Pain,
8. Narahashi, T., et. al., Mechanisms of action of cognitive enhancers on neuroreceptors, 2004
9. Rabasseda, X.; Mealy, N.; Presti, G., Drugs of Today, 1994
10. Rashid, M.H. and Ueda H., Nonopioid and neuropathy-specific analgesic action of the nootropic drug nefiracetam in mice, 2002