Between 1912 and 1960, the meaning of the word autacoid was quite different from the current meaning; the word referred to hormone stimulation. Autacoid in its present meaning was used from the 1960s and the first autacoids identified were histamine, serotonin and bradykinin. Bradykinin at that time (1963) was defined as a so-called tissue-hormone, in the sense that there is no specialized gland to secrete it [2]. Serotonin was defined in 1970 per exlusionam as: “Serotonin belongs to the group of autacoids, i.e. substances of intense pharmacological activity that are normally present in the body and that cannot be classed with hormones or neurohumors.” [3, p. 848] Clearly at that time not all requirements for the classification of a compound as an autacoid were transparent. For hormones, neurotransmitters and autacoids, operational definitions had to emerge step by step. In order to define whether a certain substance can be defined as a hormone, a neurotransmitter or an autacoid, a number of criteria need to be fulfilled (see Table 1). Some autacoids can also be classified in another context as neurotransmitters, for instance NO, ATP, and a number of endocannabinoids such as 2-Arachidonoylglycerol (2-AG); certain neurotransmitters can also act as hormones, such as the catecholamines. Most autacoids play an important role in chronic pain states.

The identification of lipid autacoids gave rise to a number of patents and stimulated research in the field of chronic inflammation. However, the use of the term “autacoid” has been in decline since 1992. During that year more than 8000 publications could be identified in PubMed, dropping to around 4000 in 2015 (Fig. 1).

The first glimpse of the potential value of autacoid medicine was identified in 1964 focusing on neuroprotection. It was stated: “the value of physiological compounds, added in excess of their normal concentrations, to forestall the first irreversible changes in the cells” [4]. The authors were quite visionary and published the first paper in literature suggesting to explore physiological acting compounds as drugs for cell and tissue protection.

In 1981, Melmom and co-workers pointed out that autacoids should be regarded as moderators of a number of immune functions, and that concentrations of autacoids in tissues during inflammation were sufficient to allow them to modify the functions of a number of cells which control and express both humoral- and cell-mediated immunity [5]. These autacoids were subsequently characterized by them as feedback modifiers connecting the early and late phases of the immune response. They identified the first building block of Autacoid Medicine, when they stated: “We should probably begin devising a strategy for using these “self-medications” as alternatives to drugs that are less selective in their actions.” (pp. 100–101).

They also pointed out the fact that autacoids can influence the immune process at different stages, and that they can influence different subpopulations of cells at concentrations which probably exist endogenously during physiologic and pathologic events, indicates that they can and should be seriously considered not only as ordinary modulators of the inflammatory and immune processes, but also as potential drugs that can ameliorate these pathologic conditions (p. 104).

In 1986, the eminent neuroscientist Professor Erminio Costa (1924–2009) stipulated this principle in an unpublished keynote lecture he delivered in Washington [6]. He emphasized Pharma should learn from nature how to design a pharmacology of modulation. Costa thus pointed out how nature itself can become our tutor in developing new therapeutic inroads, in so far as we can trigger and activate endogenous repair and defense mechanisms of the body by administrating the endogenous molecules related to these pathways. These statements are consistent with the vision of Melmom et al. [5].

Professor Bruni from the Department of Pharmacology, University of Padova and working for the Italian company Fidia, emphasized that due to the potency and efficacy, autacoids stimulated drug discovery. He was also probably the first author to point out the role of plasma membrane in the production of lipid autacoids [7] (Fig. 2).

An important family of lipid autacoids was identified by the Nobel laureate Rita Levi-Montalcini, who first described palmitoylethanolamide (PEA) in 1993 and tested a number of derivatives as anti-inflammatory and anti-pain compounds in a series of preclinical models. For these compounds she introduced ALIAmides, as an acronym for ALIA: Autacoid Local Inflammatory Antagonism. A few years later in 1996, the term was refined by Levi-Montalcini in a broader way [8]. She also included the (neuro-) repair function of autacoids, and ALIA was presented as the abbreviation of Autacoid Local Injury Antagonism. In a paper on the protective effects of PEA in central neuron death, she explained: “Palmitoylethanolamide, in reality, appears to exert a more broad local autacoid anti-injury function, thus the acronym autacoid local injury antagonism for ALIA.” Here we see that it was actually Levi-Montalcini anticipated the neuroprotective function of these lipid autacoids.

There are many different families of autacoids and we suggest six classes, as depicted in Table 2.

The lipid autacoids vary from small signaling lipids to high-molecular-weight glycerophospholipids, with many structural isomers making the profiling of the lipidomic landscape a difficult task. Serhan and his colleagues identified new families of lipids, the lipoxins in the 1980s and the resolvins in resolving inflammatory exudates, (resolution–phase interaction products) in 2002 [9]. The lipid autacoids from the family of “specialized pro-resolving mediators” (SPMs) such as resolvins, protectins, and maresins, are all synthesized via oxidation of omega-3 essential fatty acids precursors. Lipoxin, derived from arachidonic acid, is considered an SPMs also. All the compounds and derivatives from the class SPMs counteract inflammation in tissues triggered by pro-inflammatory prostaglandins and leukotrienes. This holds also true for the lipid autacoids belonging to the N-acylethanolamides such as palmitoylethanolamide, which inhibits such pro-inflammatory signals via the activation of the peroxisome proliferator-activated receptors (PPARs).

After 1992 a number of patents were filed on lipid autacoids, which created a proprietary platform but also seemed to obstruct developmental progress in this field. We will review these patents and patent strategies and discuss some of their shortcomings from the perspective of the pain clinician and their patients.

The essence of a patent is to protect an innovative and new idea for the inventor, and the innovation described in a patent is meant to be developed into an application which will serve mankind (IP—Intellectual Property). Patents in the therapeutic field should, therefore, lead to therapies. If patents do not lead to such therapies, there are flaws in the process leading from idea to application. We need to analyze this process in more detail because in autacoid medicine such flaws seem to exist and impair development.

First patents on recognized lipid autacoids were the patents filed by a small Italian company, LifeGroup Spa, a company run in the 1990s by the previous CEO of Fidia, Dr. F. Della Valle. It was in Fidia where much of the lipid autacoid R&D started, as outlined above via the work of Professor Bruni. Della Valle was also a key player in the field (and intimately connected to Erminio Costa and Rita Levi-Montalcini) who organized an intense network of research activity between the academia and his pharmaceutical industry. This served as an example of how to create positive synergies [10, 11]. In the patents from LifeGroup we find results from the research of Levi-Montalcini on PEA and derivatives in mast cell models. At that time PEA was referred to by LifeGroup under the development code LG2110/1 and the priority date of the first patent was 31 December 1991 [12]. The patent described a number of N-acyl-derivatives of hydroxyamines “suitable for the therapeutic treatment of pathologies characterized by degranulation of mast cells caused by a neurogenic and/or immunogenic hyperstimulation”. The one figure in the patent depicted the effects of the oral treatment of PEA as LG2110/1) in a dose of 10 mg/kg BW in an experimental allergic encephalomyelitis (encephalitis) model. This dose had clear positive effects on the neurological outcome. In this patent the synthesis of many N-acyl-derivatives of hydroxyamines were described and a number tested positively in animal models for various inflammatory indications, such as arthritis. Apart from PEA, which has been a known registered drug for the treatment of respiratory viral indications (brand name Palmidrol) since the 1970s, none of the derivatives were ever further developed by LifeGroup or any other pharmaceutical company for any other indication [13]. The patent, therefore, functioned as a road block for other organizations to explore the anti-inflammatory effects and the clinical value of this entire family of compounds. In 1996, LifeGroup Spa’s burn rate was such that further steps to develop PEA and related compound became impossible. The expectation was that PEA would be registered for neuropathic pain (sciatic pain) and possibly for multiple sclerosis within a short timeframe, but these expectations were not met in real life as the Italian authorities took too much time reviewing the application, resulting in the premature end of the company. The lesson learned from this case is perhaps that an extensive Intellectual Proprietary Platform around a family of lipid autacoids needs an aggressive license-out policy in order to disseminate the principle broadly. This did not happen, but happily efforts lead to the market entry of PEA many years later (around 2007), although none of the possibly more promising derivatives were ever developed. For some years patent protection for these compounds stopped, and there is no longer an incentive for any industry to test those PEA derivatives. The same strategic problem has happened with the patent portfolio based on Serhan’s work around resolvins and lipoxins.

Charles N. Serhan and his hospital filed a great number patents to protect many inventions related to a number of lipid autacoid families such as the lipoxins, resolvins, maresins, protectins, docosatrienes, and their analogues [14]. The first patent on lipoxin A and B was filed in 1984 (priority date May 4, 1984) [15]. Many more patents in this field have been filed since by Serhan et al. starting at the end of the last century [16–21]. However, since May 1, 2017, over 1600 publications on lipoxins can be found in PubMed, but only one clinical pilot trial in atopic eczema can be identified.

In one of the first patents from Serhan in 1994, a number of putative indications are summarized for new lipoxin derivatives as having superior pharmacokinetic properties compared to lipoxin A and B: “Compounds having the active site of natural lipoxins, but a longer tissue half-life are disclosed. These small molecules are useful for treating vasoconstrictive, inflammatory, myeloid suppressive, cardiovascular, and gastrointestinal diseases” [22]. Lipoxins at that time were already known as antagonists to leukotrienes, important mediators of inflammation. The patent claims compounds with the same bioactivities as natural lipoxins, but characterized by a longer in vivo half-life time due to a new metabolic transformation region in the molecule of either lipoxin A4 or B4, resistant to in vivo metabolism. Moreover, the long series of derivatives claimed in the patent (many hundreds of molecules) were synthesized to be more lipophilic than the natural lipoxins in order to enhance their uptake via biological membranes. A number of claims (10–20) in this patent were related to these lipoxin derivatives to be used as drugs in the treatment of inflammation or an inflammatory response in rheumatoid arthritis or induced by physical trauma and radiation exposure. In addition, a great number of potential indications were summarized, some related to pain states: anaphylactic reactions, allergic reactions, shock, inflammation, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn’s disease, endotoxin shock, traumatic shock, hemorrhagic shock, bowel ischemic shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, brain injury, systemic lupus erythematosus, glomerular kidney disease and myeloid suppressive disorders. Not long afterwards, lipoxins were demonstrated to have impressive effects as TNF-alpha inhibitors, and thus the potential field of neuropathic pain opened [23].

None of the derivatives of the lead compound lipoxin A4 have been taken up in clinical development since 1994 [24]. In 2015 in a review on lipoxins we found the statement: “Since lipoxins … have clinical relevance, we discuss their important role in clinical research to treat a wide range of diseases like inflammatory disorders, renal fibrosis, cerebral ischemia, and cancer” [25]. Although much research has been conducted in this field, this has led to 1599 preclinical publications and only one reported clinical pilot trial. It seems that the many lipoxin-related patents filed since 1984, summarized above, did not substantiate into even one clinical available drug.

For patents, it seems that a sunset clause is missing: this would be a statutory provision providing that a particular patent will expire on a particular date, unless it is reauthorized by the legislature based on clear and explicate activities related to its research and development. This would at least stimulate the patent holders to translate the patent findings into hands on development activities, or to license a patent in an earlier phase to third parties.

The relevance of lipid autacoids for the treatment of chronic disorders is vast, and especially since many lipid autacoids possess clear pro-resolving and anti-inflammatory activities the putative indications are many. We point out just a few and for the sake of argumentation we select for each class the same indications.

Lipid autacoids have been explored in a great number of in vitro and in vivo test models related to the disorders of the central and peripheral nervous system. In this section we will discuss the analgesic efficacy of RvE1 and PEA in models for peripheral neuropathic pain. However, RvE1 and its derivatives are not yet available for the clinician and PEA in various formulations has been available in Europe since 2007 as a nutraceutical so prescriptions are not required.