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Primum non nocere: supplements as analgesics, a neglected area.

Jan M. Keppel Hesselink, MD, PhD

Professor of molecular pharmacology

Our analgesic armamentarium is rooted in pharmaceuticals. Drugs initially protected by a patent, new chemical entities (NCE), molecules which never existed on earth till medical chemists started synthesizing these NCE’s. Within the realm of these analgesics there are just a handful variations: non-steroidal anti-inflammatory drugs, NSAID’S (ibuprofen), opioids (tramadol, oxycontin), antidepressants (amitriptyline, venlafaxin), anti-epileptics (gabapentine, pregabalin), paracetamol/acetaminophen and a waste basked of various old co-analgesics such as baclofen. Cannabinoids are for the courageous pain physicians only, although there are many safety reasons to prefer Cannabinoids over opiates.

Our treatment approach is very much dictated by efficacy based on RCT’s, and the meta-analysis based on these trials, as well on the Numbers Needed to Treat (NNT), an efficacy defined parameter. How different would our approach be if we selected our approach not based on efficacy plots but on the ‘Likelihood to be helped or harmed (LHH)’ a number which is based both on the Numbers Needed to Treat (NNT) as well as on the Numbers Needed to Harm (NNH). Without going into the science of calculus, just as a simple physician, I would propose to redefine for the purposes of argumentation, the ‘Likelihood to be helped or harmed’ as the simple quotient of NNH/NNT. The highest quotient would be preferable, in line with one of the medical axiomata: Primum non nocere, the Latin phrase that means “first, do no harm.”

Let us first take amitriptyline. Based on literature amitriptyline has a NNT of 4.6 and a NNH of 4.1. The ratio would be 4.1/4.6 makes 0,89. (Moore et al, 2012) For Serotonin noradrenaline reuptake inhibitors the NNT is 5.1, and the NNH 16; the ratio would be 3,1. (Finnerup et al, 2007)

Let us now take a supplement with proven efficacy and safety, for instance palmitoylethanolamide (PEA). A natural compound we often use in our clinic for neuropathic pain, either as a stand alone therapy, or as part of a multimodal approach. This endogenous lipid has been explored for its analgesic properties since 35 years and based on a clinical trial in 636 sciatic patients  (Guida et al, 2010) we presented the NNT for 600 mg PEA/day as 1.5 at the SIAARTI, and with only very few side effects (NNH 216) the ratio for PEA would be 144. (Keppel Hesselink, 2011) If we consider alpha-lipoic acid (ALP), a compound in Germany registered as drug for neuropathic diabetic pain, the NNT for 600 mg ALP/day is 2,7 and the number of adverse events were not significantly different than placebo, let us define the NNH as the same number as PEA, to be strict, 216. (Tang et al, 2007) The ratio would be 80.

Palmitoylethanolamide, alpha-lipoic acid and molecules from the class of dietary supplements are not generally seen as analgesics. There are much more compounds in this forgotten or neglected class, for instance curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that has been refered to as very inexpensive, orally bioavailable and highly safe in humans. The compound is able to block TNF-α action and production in in vitro models, in animal models and in humans. Curcumin is much cheaper compared to the man made infliximab’s ($15 000-20 000 per person per year) and Aggarwal et al boldly state: “With health-care costs and safety being major issues today, this golden spice (Curcuma) may help provide the solution.” Aggarwal et al (2013)

Natural compounds, even with higher NNT, needed to be considered more often for our patients suffering from pain. We should not focus only on pharmaceuticals and their efficacy, but also on analgesic supplements and safety.

More info in PEA under this link


Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol. 2013 Aug;169(8):1672-92. doi: 10.1111/bph.12131.

Finnerup NB, Otto M, Jensen TS, Sindrup SH. An evidence-based algorithm for the treatment of neuropathic pain. MedGenMed. 2007 May 15;9(2):36.

Guida G, de Martino M, de Fabiani A, et al. La palmitoiletanolamida en el dolor neuropatico cronico por lumbociatalgia de tipo compresivo: estudio clinico multicentrico. Palmitoylethanolamide treatment of sciatic pain: results form a multicenter studyDolor. 2010;25:35–42.

Keppel Hesselink JM. Palmitoylethanolamide in sciatic pain-result fron a RCT in sciatic pain-NNT, presented at SIAARTI (Società Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva), 2011: https://www.youtube.com/watch?v=9VhmK886pCg

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012 Dec 12;12:CD008242. doi: 10.1002/14651858.CD008242.pub2.

Tang J, Wingerchuk DM, Crum BA, Rubin DI, Demaerschalk BM. Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy. Neurologist. 2007 May;13(3):164-7.