A unique combination between selected vitamins B and palmitoylethanolamide

Low dose vitamins B and palmitoylethanolamide (PEA) can form a strong synergy resulting in significant painkilling effects, without any serious side effects. These are results from recent studies and clinical experience. See picture, based on the important works of Kopruszinski et al (2015).


Schermafbeelding 2015-12-05 om 13.52.56

Clinical experience with PEA and PEA in combination with a number of selected low dose vitamins B

In the clinic for neuropathic pain (www.neuropathy.nl) we have worked for some time now with a new treatment combination between the natural painkiller palmitoylethanolamide and a number of selected and low dosed vitamin B’s.

We have seen that a number of patients who found relief of their complaints (mostly chronic pain due neuropathy) on PeaPure (400 mg PEA capsules) improved even further after they started being treated with PeaPlex (3 times daily 400 mg PEA and 133 mg vitamin B complex capsules). Furthermore, doubling the dose after 1 months sometimes could even further boost the analgesic effects.

Boosting of analgesic effects of PEA by selected low dose vitamins B

Recently this boost effect of vitamins B added to other analgesic compounds such as PEA has been reviewed and demonstrated by Kopruszinski et al (2015) in their seminal paper: ‘Vitamin B complex attenuated heat hyperalgesia following infraorbital nerve constriction in rats and reduced capsaicin in vivo and in vitro effects “

We will review some on the proof that vitamins B added to an other analgesic compound can enhance its effect, as well as the rationale of combining various vitamins of the B group with one another and with PEA. We will also review the findings of Kopruszinski et al (2015). These findings are key for understanding how low doses of selected vitamins B can bring synergy between each other and together with PEA.

One important element related to the clinical use is the safety of this combination. In our hands we did not detect any side effects, and the efficacy of the combination seemed stronger than all compounds taking independently of one another.

PEA: unique natural effect on pain and inflammation and the base for synergism

Palmitoylethanolamide has proven itself as a standalone natural compound alleviating pain and reducing chronic inflammation. There is a compelling number of articles supporting these effects of PEA, and a recent Numbers to Treat analysis and Numbers to Harm demonstrated PEA is in a remarkable safe and effective natural painkiller (Keppel Hesselink, Kopsky, 2015). PEA has also been administered together with other painkillers. PEA enhances those painkilling effects and reduces the need for increasing doses of these painkillers. This enhancement effect is related to the unique natural mechanism of action of PEA.

Vitamins B: natural effects and unique painkilling synergies

The water-soluble vitamin of the B-complex groep, thiamine, pyridoxine and cyanocobalamin (i.e. B1, B6 and B12) are the key vitamins of the B group. These vitamins have been documented to reduce pain and neuropathies already since the last century. (Jurna and Reeh, 1992).
Pain can be reduced in patients suffering from pain due to diabetic neuropathy pain via vitamins from the B-complex group. Moreover, these vitamins are known to potentiate the painkilling effect of other analgesics (Abbas and Swai, 1997; Medina-Santillán et al., 2004; Simeonov et al., 1997; Talaei et al., 2009). This painkilling effect of vitamins B is also documented in patients suffering from other peripheral neuropathies.(Eckert and Schejbal, 1992; Kluzer and Lampo, 1972; Levin and Moseĭkin, 2009).
The same holds true in a great number of different experimental studies were painkilling effects could be documented. (Caram- Salas et al., 2004; Caram-Salas et al., 2006; Jolivalt et al., 2009; Mixcoatl-Zecuatl et al., 2008; Song et al., 2009; Wang et al., 2005; Yu et al., 2014).

Synergy between various vitamins B and between vitamins B and painkillers: rationale for a new combination (PeaPlex)

Even in models for severe, very difficult to treat painsyndromes, such as in trigeminal neuropathic pain Kopruszinski at all found that repeated treatment with B1, B6 and B12 vitamins, could prevent an increasing pain syndrome and these vitamins could enhance the painkilling effects of a special analgesic compound used in this severe pain disorder, carbamazepine (Kopruszinski et al., 2012). They emphasized the importance of such synergy. The same authors also found a remarkable and important fact, which can be seen as the rationale for the new combination between vitamins B and palmitoylethanolamide (as in PeaPlex): The painkilling effects of the combination of various vitamins from the B complex group was significantly greater than the painkilling effects of each individual vitamin! Moreover, a different research group found that repeated treatment with the combination of vitamins B caused long-lasting alleviation pain in certain experimental pain models. (Wang et al., 2005).

B vitamins used in combination with each other presented antipain effects even after a single administration and more stable effects can be induced after prolonged administration of combinations of these vitamins B.
Low dose vitamins B can further enhance painkilling effects of other painkillers. While low dose vitamins B pacify overactive neurons, PEA especially pacifies overactive glia, the neuron-feeding cells in our brain and nervous system.

Recently, in 2015, this adjuvant painkilling effect of vitamins B added to other painkillers has been outlined in the treatment of a severe painsyndrome, trigeminal pain. (Kopruszinski et al, 2015)
In this study it was found that:

The antihyperalgesic effect of the low-dose combination presented a synergistic effect with a single dose of carbamazepine (an analgesic against trigeminal pains) either in the acute or repeated treatment regimen. Acute treatment with the vitamin B complex enhanced carbamazepine ability to block hyperalgesia (pain), which was observed at a dose of carbamazepine ineffective without vitamins B.

Further conclusions were:

Our findings also corroborate previous reports that repeated administration of a vitamin B complex is commonly more efficacious than single administration, as well as produces long-term inhibition of hyperalgesia associated with neuropathic pain (Jolivalt et al., 2009; Wang et al., 2005)

The final conclusion was:
In conclusion, these findings reinforce the idea that B vitamins can synergize with analgesics to provide greater pain relief in neuropathic pain conditions, and suggest that B vitamins may desensitize TRPV1 ion channels to alleviate pain.

All the above studies demonstrate:

  1. vitamins from the B group can act as analgesics and thus are natural painkillers
  2. the dose of active painkilling vitamins B is low
  3. repeated low dose of vitamins B can create an add-on painkilling effect
  4. various selected vitamins from the B group can increase each other’s neuroprotective and painkilling properties
  5. various selected vitamins B can enhance the painkilling properties of classical painkillers.

References on synergisms between vitamins B and analgesics

Abbas, Z.G., Swai, A.B., 1997. Evaluation of the efficacy of thiamine and pyridoxine in the treatment of symptomatic diabetic peripheral neuropathy. East Afr. Med. J. 74 (12), 803-808.
Bartoszyk, G.D., Wild, A., 1989. B-vitamins potentiate the antinociceptive effect of diclofenac in carrageenin-induced hyperalgesia in the rat tail pressure test. Neurosci. Lett. 101 (1), 95-100.
Caram-Salas, N.L., Medina-Santillan, R., Reyes-Garcia, G., Granados-Soto, V., 2004. Antinociceptive synergy between dexamethasone and B vitamins complex in a neuropathic pain model in rat. Proc. West Pharmacol. Soc. 47, 88-91.
Caram-Salas, N.L., Medina-Santillan, R., Reyes-Garcia, G., Granados-Soto, V., 2006. Thiamine and cyanocobalamin relieve neuropathic pain in rats: synergy with dexamethasone. Pharmacology 77 (2), 53-62.
Eckert, M., Schejbal, P., 1992. Therapy of neuropathies with a vitamin B combination. Symptomatic treatment of painful diseases of the peripheral nervous system with a combination preparation of thiamine, pyridoxine and cyanocobalamin. Fortschr. Med. 110 (29), 544-548.
França, D.S., Souza, A.L., Almeida, K.R., Dolabella, S.S., Martinelli, C., Coelho, M.M., 2001. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur. J. Pharmacol. 421 (3), 157-164.
Fu, G.Q., Carstens, E., Stelzer, B., Zimmermann, M., 1998. B vitamins suppress spinal dorsal horn nociceptive neurons in the cat. Neurosci. Lett. 95 (1-3), 3192-3197.
Hung, K.L., Wang, C.C., Huang, C.Y., Wang, S.J., 2009. Cyanocobalamin, vitamin B12, depresses glutamate release through inhibition of voltage-dependent Ca2+ influx in rat cerebrocortical nerve terminals (synaptosomes). Eur. J. Pharmacol. 602 (2-3), 230-237.
Jurna, I., Reeh, P.W., 1992. How useful is the combination of B vitamins and analgesic agents? Schmerz. 6 (3), 224-226.
Kluzer, G., Lampo, B., 1972. Importance of the association of Nivaline and vitamins of the B group in the treatment of neuropathies. Minerva Med. 63 (29), 1686-1697.
Kopruszinski, CM, Renata C. Reis, Elisangela Bressan, Peter W. Reeh and Juliana G. Chichorro, Vitamin B complex attenuated heat hyperalgesia following infraorbital nerve constriction in rats and reduced capsaicin in vivo and in vitro effects, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2015.05.063
Kopruszinski, C.M., Reis, R.C., Chichorro, J.G., 2012. B vitamins relieve neuropathic pain behaviours induced by infraorbital nerve constriction in rats. Life Sci. 91 (23-24), 1187-1195.
Levin, O.S., Moseikin, I.A., 2009. Vitamin B complex (milgamma) in the treatment of vertebrogenic lumbosacral radiculopathy. Zh. Nevrol.
Psikhiatr. Im. S. S. Korsakova 109 (10), 30-35.
Medina-Santillan, R., Morales-Franco, G., Espinoza-Raya, J., Granados-
Soto, V., Reyes-Garcia, G., 2004. Tratment of diabetic neuropathic pain with gabapentine alone or combined with B vitamins complex. Proc. West Pharmacol. Soc. 47, 109-112.
Mixcoatl-Zecuatl, T., Quiñónez-Bastidas, G.N., Caram-Salas, N.L., Ambriz-Tututi, M., Araiza-Saldaña, C.I., Rocha-González, H.I., Medina-Santillan, R., Reyes-Garcia, G., Granados-Sotto, V., 2008. Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats. Methods Find. Exp. Clin. Pharmacol. 30 (6), 431-441.
Reyes-Garcia, G., Caram-Salas, N.L., Medina-Santillan, R., Granados-Soto, V., 2004. Oral administration of B vitamins increase the antiallodynic effect of gabapentin in the rat. Proc. West Pharmacol. Soc. 47, 76-79.
Simeonov, S., Pavlova, M., Mitkov, M., Mincheva, L., Troev, D., 1997. Therapeutic efficacy of “Milgamma” in patients with painful diabetic neuropathy. Folia Med. 39 (4), 5-10.
Song, X.S., Huang, Z.J., Song, X.J., 2009. Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology 110 (2), 387-400.
Talaei, A., Siavash, M., Majidi, H., Chehrei, A., 2009. Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int. J. Food Sci. Nutr. 60, Suppl 5, 71-76.
Wang, Z.B., Gan, Q., Rupert, R.L., Zeng, Y.M., Song, X.J., 2005. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain 114 (1-2), 266-277.

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