Fundamentals of and Critical Issues in Lipid Autacoid Medicine: A Review
Fundamentals of and Critical Issues in Lipid Autacoid Medicine: A Review
Jan M. Keppel Hesselink 0
0 J. M. Keppel Hesselink (&) Institute for Neuropathic Pain, Bosch en Duin , Utrecht , The Netherlands
The identification of a number of families of lipid signal molecules since the 1990s created new therapeutic possibilities for a great number of disorders characterized by chronic inflammation and pain. These lipid autacoids have been explored in a great variety of animal models related to inflammation, pain, (neuro-)protection, and repair. Based on the data from these models, as well as on a number of proof of principle studies in the clinic in indications such as neuropathic pain, a new chapter in medicine is about to begin. We would like to introduce the term ''Autacoid Pain Medicine'' for this chapter. There are, however, a number of methodological and strategic issues to overcome in this field. One of the roadblocks is related to patent strategies around families of these molecules. As this is not always recognized we will present a number of examples.
ALIAmides; Analgesia; Autacoids; Endocannabinoids; Lipoxins; Pain; Palmitoylethanonolamide; Phospholipids; Protectins; Resolvins; Treatment
Autacoid medicine is based on a therapeutic
intervention in a disease process based on the
administration of an autacoid or an autacoid
derivative. Autacoids are locally produced
modulating factors, influencing the function of
nearby cells and/or tissues, which are produced
on demand and which subsequently are
metabolized in the same cells and/or tissues .
The word autacoid stems from the Greek
autos (self) and akos (medicinal agent or drug).
Sometimes we can find the older terms
‘‘secretagogues’’ or ‘‘tissue hormones’’ for such
signaling molecules. Autacoid medicine makes use of
the innate mechanisms of defense and repair,
which are modulated following administration
of an autacoid. In order for such administration
to be successful, the autacoid needs to reach the
target tissues and build up sufficient
concentrations at the site of action, and the choice for
a delivery vehicle is an important factor for
success. Autacoids used for the treatment of
eczema, psoriasis and cornea disorders (such as
stromal and Fuchs dystrophy) can reach the
target tissues relatively simply via topical
formulations. Autacoids for treating chronic
inflammations of the kidney, liver, heart and
brain are creating some new pharmaceutical
development challenges. Treatment via
autacoids however offer a number of advantages
over the treatment using New Chemical Entities
(NCEs). As autacoids are endogenous molecules,
metabolic pathways are intrinsic to the tissue.
This implies no production and accumulation
of toxic metabolites, and a quick resolving of
non-active autacoids via innate metabolic
processes, with less chance for irreversible or
troublesome side effects and no long-term safety
issues or idiosyncratic reactions. In this paper
selected lipid compounds will be discussed, as
in the field of lipid autacoids where most
experience has been gathered.
This article is based on previously conducted
studies and does not involve any new studies of
human or animal subjects performed by any of
THE HISTORY OF AUTACOIDS AND THE RISE OF AUTACOID MEDICINE
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 . 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
Table 1 Basic characteristics of hormone, neurotransmitter and autacoid
A gland or tissue
A gland or tissue
Membrane or nuclear receptors
Degradation in the blood or endocytosis of the
Peptides/proteins steroids amines
Fig. 1 Profile of PubMed search of the term ‘ autacoid’. The first publications appeared in 1934, peaked around
1990–1992, and since 1993 there has been a steady decline
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’’
. 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
humoraland cell-mediated immunity . 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.
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
In 1986, the eminent neuroscientist
Professor Erminio Costa (1924–2009) stipulated this
principle in an unpublished keynote lecture he
delivered in Washington . 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. .
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
Fig. 2 Professor Bruni correctly stated in 1988 that one of
the major metabolic route for many lipid autacoids is via
the plasma membrane Adapted from Autocoids from
membrane phospholipids, Bruni A. 1988, Pharmacological
membrane in the production of lipid autacoids
 (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 . 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.
CLASSES OF AUTACOIDS
There are many different families of autacoids
and we suggest six classes, as depicted in
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 . 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
Table 2 Classes of autacoids
Neuropeptides, endothelin, vasoactive
intestinal peptide, gastrin
Growth factors, interleukins, cytokines,
leptin, matrix metalloproteases, galanin,
N-acetylglucosamine, heparin, adenosine
endocannabinoids, resolvins, protectins,
belonging to the N-acylethanolamides such as
palmitoylethanolamide, which inhibits such
pro-inflammatory signals via the activation of
the peroxisome proliferator-activated receptors
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.
PATENTS ON LIPID AUTACOIDS AND THEIR DERIVATIVES: PITFALLS OF IP PROTECTION FOR DEVELOPMENT
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
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 . 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 . 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 . The first patent on lipoxin A and B
was filed in 1984 (priority date May 4, 1984)
. 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’’ .
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 .
None of the derivatives of the lead
compound lipoxin A4 have been taken up in clinical
development since 1994 . 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’’ . 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.
PUTATIVE INDICATIONS OF LIPID
AUTACOIDS RELATED TO CHRONIC
INFLAMMATION AND PAIN
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.
Alzheimer’s disease , depression , sepsis
, asthma , reperfusion injury [30, 31],
glaucoma and retinitis , obesitas ,
auto-immune inflammatory demyelination
disorders , arthritis , osteoarthritis ,
infections , sciatic  and neuropathic pain
Alzheimer’s disease , depression , sepsis
, asthma , reperfusion injury ,
glaucoma and retinitis , obesitas ,
auto-immune inflammatory demyelination disorders
, arthritis , osteoarthritis , infections
, sciatic  and neuropathic pain .
In most indications explored the
N-acylethanolamide palmitoylethanolamide has been
tested. This is related to the fact that PEA has been
available in a number of European countries
since 2007 as a nutraceutical.
Palmitoylethanolamide: Alzheimer’s disease
, depression , sepsis , asthma ,
reperfusion injury , glaucoma and retinitis
, obesitas , auto-immune inflammatory
demyelination disorders , arthritis ,
osteoarthritis , infections , sciatic 
and neuropathic pain .
In the list above it is clear that there is a
major overlap and representatives from each
class of lipids are evaluated positively in the
respective models for these disorders. In most of
these disorders the animal models have
generated supportive data, and in some cases positive
clinical trials can be seen as proof of principle.
Such clinical trials support the use of certain
lipid autacoids such as PEA in neuropathic pain.
Of course, we need to mention that positive
clinical studies also support or suggest the use of
Cannabis in the same list of disorders, including
as a key treatment of various pain states.
Mechanisms of actions of Cannabis,
endocannabinoids and lipid signaling molecules
belonging to the autacoids clearly overlap.
LIPID AUTACOIDS AS NEUROPROTECTANTS AND ANALGESICS IN MODELS OF NEUROPATHIC PAIN
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.
Resolvins for the treatment of neuropathic pain
have been claimed in a patent of 2009 . In this
patent a number of resolvins (hundreds, as well as
salts and esters) were described, active in the
nanogram dose range, producing
anti-hyperalgesic effects in models for inflammatory and
neuropathic pain. Many of these findings were
presented in a paper in 2010 . RvE1 was
reported to reduce pain in mice models for central
and peripheral pain after (intrathecal)
administration of very a low dose: 0.3 and 1.0 and 10 ng,
and was more effective compared to 10 lg of the
COX-2 inhibitor NS-398 . A stable metabolic
analogue 19-(p-fluorophenoxy)-RvE1 (19-pf-RvE1)
had a comparable, but longer effect after
intrathecal administration: 6 h. Peripheral
administered RvE1 also led to reduced intraplantar
capsaicin-induced acute pain. However, all
administration of the resolvin and its analogues
was parenteral and led to relatively short-lived
effects. The experiments led the authors to
state that resolvins and their metabolically
stable analogs may represent a new family of
analgesics useful in treating
inflammation-associated pain states such as arthritic and post-operative
pain. This position was also taken in the review in
Nature Medicine in 2010, where the
above-mentioned findings were discussed and where again it
was pointed out that these results seem to be very
promising for the development of a drug to be used
in humans . This argument was based on only
one element of the compounds tested, the
nanomolar and picomolar potency, which was
regarded as a desirable characteristic for any
candidate drug. The challenge, the authors concluded,
would be to develop resolvins into a clinically
RvE1 is presented as a new therapeutic target
for the treatment of inflammatory pain as it
strongly inhibits TRPV1 activity associated with
peripheral inflammation . In addition, there
are central mechanisms of action, on glia level.
Such findings support researchers to express the
belief, given the potent analgesic efficacy and
safety profiles of endogenous lipid mediators
that resolvins, their metabolically stable
analogues and small molecule agonists that target
the resolvin’s signaling pathways, may offer new
therapeutic tools for the management of
neuropathic pain . Also, pathomechanistic studies
spinal (intrathecal) pretreatment of RvE1
(100 ng) in a chronic constriction injury of the
sciatic nerve (CCI) could reduce the mechanical
allodynia 24 h after administration .
With over 600 PubMed indexed papers on
palmitoylethanolamide (PEA), this lipid
autacoid is by far the best explored in preclinical, as
well as in clinical studies.
All studies are in line with its analgesic and
anti-inflammatory actions in a dose range of
10–30 mg/kg body weight. Doses up to 100 mg/kg
body weight have been administered to humans
without any evidence of adverse effects. Given its
very benign safety profile, the compound is also
fit for elderly and multi-morbid patients . For
the clinical data on PEA, we refer to the many
review articles written since 2012. PEA seems safe
and effective in a range of neuropathic pain
syndromes, from painful diabetic neuropathy to pain
in chronic idiopathic axonal neuropathy [72–75].
In nerve compression syndromes, such as sciatic
pain and carpal tunnel syndrome, a series of
placebo controlled studies support the safe and
effective use of PEA in these indications. Analysis
of data from an RCT in over 600 sciatic pain
patients demonstrated a NNT for PEA of 1.5 .
Its neuroprotective profile has been evaluated in
the ophthalmological clinic where the
compound proved to possess retinoprotective
The author has worked with PEA in his clinic
for neuropathic pain since 2010 and has treated
many thousands of patients, mainly those with
axonal neuropathies such as diabetic
neuropathy and chronic idiopathic axonal neuropathy
(CIAP) and sciatic pain . Based on his
experience and results of recent RCTs, he
recommends a dose of 1200 mg daily in neuropathic
pain, for at least 2 months. This time frame
seems to help the autacoid to reset the system.
He also found that partial responders sometimes
became full responders after doubling this dose.
He has used a number of formulations of PEA,
and he and other Dutch colleagues found only
patented formulations containing microPEA
formulations to be effective and safe. Patients
have indicated that use of cheap ‘‘me-toos’’ lead
to suboptimal efficacy, most probably due to the
absence of an optimal formulation. There are
only three micro-PEA formulations based on
patent protected know-how of formulations of
PEA with adequate bioavailability: PEA-um
(ultramicronized), PEA-m (micronized), and
PEA-opt (optimized). For a crystalline lipid as
PEA, formulations containing micro-PEA seem
key for the clinical success. Studies supporting
the safety and efficacy of other PEA formulations
to date are absent.
Lipid autacoids and their derivatives move
tissue towards balance in the case of overactive
inflammation, and this is one of the key
elements in neuropathic pain. The various classes
of lipid autacoids such as the lipoxins,
protectins, resolvins, N-acylethanolamides, and
endocannabinoids have been extensively tested
positively in animal models for a great variety of
disorders, all characterized by
(neuro-)inflammation, including in pain models. PEA is the
most advanced compound, as this molecule has
been extensively tested since the 1970s and is
available as a nutraceutical without the
necessity of a prescription. This is a both a strength
and a weakness; for patients the compound is
easily accessible, for pain physicians the
compound is outside of their (pharma-)scope.
Research in this field of Autacoid Medicine
has been hampered by the many patents filed in
the 1990s, and the absence of serious drug
development in this field because the majority
of research was driven by academia. Many
compounds are mentioned in these patents,
compounds with great promise, which have
never been tested nor licensed out by the
inventors. Formulation development in this
field is also rare, and as most compounds have a
short half-life time, such work is mandatory for
Lipid autacoids hold great hope for pain
medicine especially since its side-effect profiles
will be benign, and as the metabolic routes are
endogenous no surprises are to be expected
related to their metabolites. Now that a great
number of patents have expired, new
possibilities for formulation of used patents may re-open
the path to serious Research and Development.
No funding or sponsorship was received for
this study or the publication of this article. The
named author meets the International
Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this manuscript, takes
responsibility for the integrity of the work as a
whole, and has given final approval for the
version to be published.
M. Keppel Hesselink has
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by any of the
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
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