Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20

Current understanding of the mixed pain concept:

a brief narrative review

Rainer Freynhagen, Harold Arevalo Parada, Carlos Alberto Calderon-Ospina,

Juythel Chen, Dessy Rakhmawati Emril, Freddy J. Fernández-Villacorta,
Hector Franco, Kok-Yuen Ho, Argelia Lara-Solares, Carina Ching-Fan Li,
Alberto Mimenza Alvarado, Sasikaan Nimmaanrat, Maria Dolma Santos &
Daniel Ciampi de Andrade

To cite this article: Rainer Freynhagen, Harold Arevalo Parada, Carlos Alberto Calderon-Ospina,
Juythel Chen, Dessy Rakhmawati Emril, Freddy J. Fernández-Villacorta, Hector Franco, Kok-Yuen
Ho, Argelia Lara-Solares, Carina Ching-Fan Li, Alberto Mimenza Alvarado, Sasikaan Nimmaanrat,
Maria Dolma Santos & Daniel Ciampi de Andrade (2019) Current understanding of the mixed pain
concept: a brief narrative review, Current Medical Research and Opinion, 35:6, 1011-1018, DOI:
10.1080/03007995.2018.1552042

To link to this article: https://doi.org/10.1080/03007995.2018.1552042

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CURRENT MEDICAL RESEARCH AND OPINION
2019, VOL. 35, NO. 6, 1011–1018
https://doi.org/10.1080/03007995.2018.1552042
Article ST-0479.R1/1552042
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REVIEW

Current understanding of the mixed pain concept: a brief narrative review

Rainer Freynhagena,b, Harold Arevalo Paradac, Carlos Alberto Calderon-Ospinad,e, Juythel Chenf, Dessy
Rakhmawati Emrilg, Freddy J. Fern
andez-Villacortah, Hector Francoi, Kok-Yuen Hoj, Argelia Lara-Solaresk, Carina
Ching-Fan Lil, Alberto Mimenza Alvaradom, Sasikaan Nimmaanratn, Maria Dolma Santoso,p and Daniel Ciampi
de Andradeq
a
Department of Anaesthesiology, Critical Care Medicine, Pain Therapy and Palliative Care, Benedictus Hospital Tutzing, Tutzing, Germany;
b
Department of Anaesthesiology, Klinikum Rechts der Isar, Technische Universit€at Mu€nchen, Munich, Germany; cSports medicine private
practice, Bogota, Colombia; dPharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad
del Rosario, Bogota, Colombia; eCenter For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine
and Health Sciences, Universidad del Rosario, Bogota, Colombia; fPain Clinic, Hospital Santo Tomas, Panama City, Panama; gNeurology
Department, Medical Faculty of Syiah Kuala University/Dr Zainoel Abidin Hospital (RSUZA), Banda Aceh, Indonesia; hDepartment of
Orthopaedics, Universidad Nacional de Trujillo, Trujillo, Peru; iClinica Neurologia y Neurofisiologica Integral, Guatemala City, Guatemala;
j
Pain Management Service, Raffles Hospital, Singapore; kDepartment of Pain and Palliative Care, Instituto Nacional de Ciencias M
edicas y
Nutrici
on Salvador Zubir
an, Mexico City, Mexico; lHong Kong Pain Medicine Centre, Central, Hong Kong; mDepartment of Geriatrics,
Instituto Nacional de Ciencias M
edicas y Nutrici
on Salvador Zubir
an, Mexico City, Mexico; nDepartment of Anesthesiology, Faculty of
Medicine, Prince of Songkla University, Hat Yai, Thailand; oDepartment of Anesthesiology, Asian Hospital and Medical Center, Muntinlupa
City, Philippines; pDepartment of Anesthesiology, The Medical City, Pasig City, Philippines; qPain Center, Department of Neurology, Hospital
das Clinicas FMUSP, S~ao Paulo, Brazil

ABSTRACT ARTICLE HISTORY

Despite having been referenced in the literature for over a decade, the term “mixed pain” has never Received 23 July 2018
been formally defined. The strict binary classification of pain as being either purely neuropathic or Revised 13 November 2018
nociceptive once left a good proportion of patients unclassified; even the recent adoption of Accepted 20 November 2018
“nociplastic pain” in the IASP Terminology leaves out patients who present clinically with a substantial
KEYWORDS
overlap of nociceptive and neuropathic symptoms. For these patients, the term “mixed pain” is Mixed pain; chronic pain;
increasingly recognized and accepted by clinicians. Thus, an independent group of international multi- classification; pain
disciplinary clinicians convened a series of informal discussions to consolidate knowledge and articu- assessment;
late all that is known (or, more accurately, thought to be known) and all that is not known about pain management
mixed pain. To inform the group’s discussions, a Medline search for the Medical Subject Heading
“mixed pain” was performed via PubMed. The search strategy encompassed clinical trial articles and
reviews from January 1990 to the present. Clinically relevant articles were selected and reviewed. This
paper summarizes the group’s consensus on several key aspects of the mixed pain concept, to serve
as a foundation for future attempts at generating a mechanistic and/or clinical definition of mixed
pain. A definition would have important implications for the development of recommendations or
guidelines for diagnosis and treatment of mixed pain.

Introduction The discrete pathophysiological classification of pain as

Clinical discussions on “mixed pain” have been ongoing for
over a decade yet it remains a poorly defined condition, rep-
resenting an unmet need in clinical practice. Uniform pain
terminology to communicate information about our patients
and their pain is important to distinguish one case of chronic
pain from another and, therefore, defining basic pain terms
and classifying pain syndromes have consistently been the
focus of several committees and task forces of the
International Association for the Study of Pain (IASP).
However, even after the most recent definitions of the
IASP’s Task Force on Taxonomy, pain terminology still
lacks precision.
being either purely neuropathic or purely nociceptive has
often been challenged as both inaccurate and over-simplis-
tic1–3. This criticism led to changes in pain taxonomy and the
development of more universally accepted definitions of
types of pain though the term “mixed pain” was (and contin-
ues to be) neglected.
The IASP’s 1994 definition of neuropathic pain as “pain
initiated or caused by a primary lesion or dysfunction in the
nervous system” generated heated debate, specifically sur-
rounding the term “dysfunction” which was generally viewed
to be too broad and imprecise. The IASP Special Interest
Group on Neuropathic Pain (NeuPSIG) subsequently

CONTACT Rainer Freynhagen rainer.freynhagen@artemed.de Department of Anaesthesiology, Critical Care Medicine, Pain Medicine and Palliative Care,
Pain Center Lake Starnberg, Benedictus Hospital Tutzing GmbH & Co. KG, Academic Teaching Hospital Technische Universit€at M€
unchen, Bahnhofstrasse 5, 82327
Tutzing, Germany
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
www.cmrojournal.com
1012 R. FREYNHAGEN ET AL.
endorsed a new definition of neuropathic pain in 2008, as
“pain arising as a direct consequence of a lesion or disease
affecting the somatosensory system”4, which was later
adopted by the IASP council with an annotation that
“neuropathic pain is a clinical description (and not a diagno-
sis), which requires a demonstrable lesion or a disease that
satisfies established neurological diagnostic criteria”5. This
much more robust definition has remained unchallenged
ever since.
In turn, nociceptive pain – thought to be by far the most
common human pain type – is defined by the IASP as “pain
that arises from actual or threatened damage to non-neural
tissue and is due to activation of nociceptors” (pain associ-
ated with active inflammation falls under this category). The
note accompanying this term in the IASP Terminology states
that “this term is designed to contrast with neuro-
pathic pain”5.
This original taxonomy was problematic, positing a frame-
work of pain neurobiology in which there is either pain
experienced with a normally functioning somatosensory ner-
vous system (i.e. nociceptive pain) or pain experienced when
the somatosensory nervous system exhibits any kind of
abnormal function (i.e. neuropathic pain). Put another way,
these definitions positioned nociceptive pain as the only
alternative to neuropathic pain, and vice versa. This strict
binary classification of pain left a sizeable proportion of
patients unclassified, specifically: (1) patients who present
clinically with a substantial overlap of nociceptive and neuro-
pathic symptoms; and (2) patients who do not exhibit signs
or symptoms of any actual or threatened tissue damage, nor
evidence of a lesion or disease of the somatosensory system.
For the latter patient group, which includes patients with
fibromyalgia, complex regional pain syndrome type 1, or
“functional” visceral pain disorders (such as irritable bowel
syndrome and bladder pain syndrome), a 2016 topical review
by Kosek and colleagues proposed utilizing a third mechanis-
tic descriptor to describe the chronic pain state2. The
authors’ candidate adjectives for this third descriptor
included (1) “nociplastic”, to reflect changes in function of
nociceptive pathways; (2) “algopathic”, to describe a patho-
logical perception or sensation of pain not generated by
injury; and (3) “nocipathic”, to denote a pathological state of
nociception. Reactions to the proposal within the medical
pain community were largely positive6, though a few critics
contended that a further mechanistic pain descriptor was
not necessary7,8. Nonetheless, in November 2017, the IASP
Council adopted the proposal for a third mechanistic descrip-
tor of pain6, electing to include the term “nociplastic pain” in
the IASP Terminology5. The Task Force on Taxonomy defined
nociplastic pain as “pain that arises from altered nociception
despite no clear evidence of actual or threatened tissue dam-
age causing the activation of peripheral nociceptors or evi-
dence for disease or lesion of the somatosensory system
causing the pain”. Thus, if one were to count pain of psycho-
logical origin in this framework – a patient’s report of which
should be accepted as pain, as highlighted in the note
accompanying the IASP definition of pain5 – a clinician has
at least four different classes of pain to consider.
For patients who present clinically with a substantial overlap
of nociceptive and neuropathic symptoms in the same body
area, the term “mixed pain” is increasingly recognized and
accepted by pain clinicians, and the term is used in the scien-
tific literature to describe such specific patient scenarios.
Notably, however, mixed pain has never been formally defined
– the term “mixed pain” does not appear in the IASP
Taxonomy, and it is still missing in textbooks, educational pro-
grams, and guidelines of medical associations and health
authorities. This lack of a formal definition – coupled with the
vagueness and imprecision inherent in the term – has resulted
in “mixed pain” being inadequately used in an extensive array
of contexts, including as a description for, among others: pain
due to a primary injury and its secondary effects9; pain that
transitions from nociceptive pain to neuropathic pain9; pain
that yields ambiguous scores on neuropathic pain scoring
tools, such as painDETECT10; pain experienced by a non-homo-
geneous group of study patients11; pain with combined ele-
ments of somatic, visceral and neuropathic pain12; pain
generated from combined central and peripheral pain mecha-
nisms post-stroke13; or simply pain occurring at multiple sites14.
One might think that attempting a definition at this point
in time is premature given the fact that the mechanisms by
which mixed pain is generated are presently still unclear
and, moreover, the elaboration and development of clinical
criteria to identify patients with nociplastic pain has only just
begun15. Within the pain research field there are those who
argue that there is no foundation for a definition of mixed
pain, suggesting that the development of one would be a
“pseudo-intellectual exercise”. However, given the increasing
clinical evidence and patient need, it would be an over-sim-
plification to oppose a concept while arguing that the reason
the term “mixed pain” does not appear in the IASP
Taxonomy or textbooks and guidelines most likely is due to
lack of need. In our view, it is crucial to clarify and define a
pain term which is increasingly used worldwide.
Furthermore, it is only logical to take the first steps in the
direction of an initial definition of “mixed pain”, as such a
definition would have important implications:
1. It would promote a better understanding and awareness
of mixed pain among healthcare professionals, which
would improve identification and diagnosis of patients;
2. It would allow the categorization of some patients with
chronic pain conditions currently classified as “pain of
unknown origin”;
3. It would establish the basis for the development of new
therapeutic strategies and agents which target poten-
tially distinct mixed-pain mechanisms;
4. It would form the basis for the development of new
mixed-pain screening and diagnostic tools for both
research and clinical use; and
5. It would be the impetus for development of recommen-
dations or guidelines for the management of
mixed pain.
Granting that an attempt at a definition is controversial,
what is entirely appropriate and, in fact, imperative at this

stage is to consolidate current knowledge and articulate all
that is known (or, more accurately, thought to be known)
and all that is not known about mixed pain. This can serve
as a first foundation for future attempts at generating a
more widely accepted mechanistic and/or clinical definition
of mixed pain.
Methods
On the initiative of the first author, an international group of
pain clinicians from multiple specialities – pain medicine spe-
cialists, anaesthesiologists, neurologists, orthopaedic sur-
geons, rheumatologists and general internists from Brazil,
Colombia, Germany, Guatemala, Hong Kong, Indonesia,
Mexico, Panama, Peru, the Philippines, Singapore and
Thailand – participated in a series of informal discussions on
mixed pain, carried out online and on the sidelines of three
regional medical conferences in Asia and Latin America in
2017. The formation of the group resulted from personal
contacts, was arbitrary, and was not endorsed by any scien-
tific or medical society. However, members of the group are
all highly experienced practicing pain clinicians who see
patients with mixed pain on a regular basis; most are
involved in pain research and are abreast of current develop-
ments, and are leaders of their respective national
pain societies.
Members were asked to reflect on and respond to a set
of questions on mixed pain developed by the first author,
answers to which were then discussed and debated upon
face to face by the larger groups. The discussions yielded a
short, bulleted list of general statements representing the
group’s consensus on several key aspects of the mixed pain
concept. This paper elaborates on these discussion points.
To inform the group’s discussions, a Medline search for
the Medical Subject Heading (MeSH) “mixed pain” was per-
formed via PubMed. The search strategy encompassed clin-
ical trial articles and reviews from January 1990 to the
present. Clinically relevant articles were selected and
reviewed, with the pertinent highlights of these articles pre-
sented below.
Results
What is known (or thought to be known) about
mixed pain
1. The literature on mixed pain goes back at least
two decades
The concept of somatic pain conditions exhibiting a combin-
ation of nociceptive and neuropathic components has been
reported in the literature for almost 20 years and recently
with increasing frequency10,16,17. The term “mixed pain” –
used in reference to a pathophysiological category of pain –
was first employed by Grond and colleagues in 1999. Having
conducted a survey of 593 cancer patients treated by a pain
service, they reported that 181 patients had both nociceptive
pain and neuropathic pain – these patients they categorized
as having “mixed pain”18.
CURRENT MEDICAL RESEARCH AND OPINION 1013
Subsequently, in a paper arguing that understanding of a
patient’s pathophysiological process, initiation of appropriate
treatment and enhancement of patient outcomes can only
be achieved with improvements in pain classification, Ross
observed that “[current] classification schemes do not recog-
nize that patients with pain often have mixed pain syn-
dromes and do not fall neatly into these schemes”3.
The discussion of mixed pain as a pathophysiological con-
cept in literature truly emerged in 2004, when a German
group extensively discussed “the mixed pain concept as a
new rationale” in the German Medical Association’s official
science journal19, then presented it at a symposium organ-
ized by the German Pain Society, the German chapter of the
IASP. A parallel publication by the same working group then
linked the mixed pain concept explicitly to a specific pain
condition, namely chronic sciatica20; here they offered the
description of “mixed pain” in recognition of the different
pain-generating mechanisms underlying typical sciatic pain,
and discussed the challenges to providing effect-
ive treatment.
Two consecutive publications in 2005 expanded clinical
understanding of the condition. The first focused on the
pathophysiology of mixed pain, arguing that a mixture of
nociceptive and neuropathic pain-generating mechanisms in
certain patients with chronic pain challenges the notion of a
strict demarcation between these mechanisms1. The second
publication focused on the implications of mixed pain patho-
physiology on therapy, highlighting the necessity of a treat-
ment approach that combines therapies targeting both
nociceptive and neuropathic pain components21.
Several years later, Freynhagen and Baron provided a
comprehensive review of the mixed pain concept as linked
to chronic back pain22, elaborating on key ideas in mixed-
pain pathophysiology, diagnosis and management that were
first outlined in their 2004 paper.
Interest in mixed pain as a clinical and research topic has
risen exponentially in recent years. A search of “mixed pain”
as a MeSH term on Medline yielded 563 publications span-
ning preclinical studies, clinical trials and systematic reviews
in the decade since the term first emerged (i.e. 1999–2010);
in contrast, the number of publications to emerge subse-
quently (i.e. 2011 to the present) was 1779. Besides studies
in low back pain, recent publications have described mixed
pain in different novel contexts.
2. Several chronic pain states are considered in the litera-
ture to be mixed pain
A number of commonly encountered pain states have been
described in the literature as “mixed pain”. Notably, what
these conditions share is a common characterization of mani-
festing clinically with a substantial overlap of the different
known pain types in any way (nociceptive, neuropathic, noci-
plastic; Figure 1).
Cancer pain. It seems widely accepted that cancer pain is
often of mixed aetiology23,24. Results of a systematic review
of 22 studies reporting on 13,683 patients with active cancer
reporting pain, and in which a clinical assessment of pain
had been made, showed that the prevalence of neuropathic
1014 R. FREYNHAGEN ET AL.

Potential mixed pain states

Sciatica, Low back pain, Neck pain, Cancer pain, Osteoathritis pain, Chronic postsurgical pain,
Musculoskeletal disorders, Chronic Temporomandibular disorders, Lumbar spinal stenosis, Pain in Fabry Disease,
Chronic joint pain, Painful ankylosing spondylitis, Leprosy, Burning mouth syndrome, …

Headaches Fibromyalgia
Vulvodynia Irritable bowel
Interstitial cystitis Chronic fatigue
… …

Ankylosing spondylitis
Unspecific back pain
Rheumatoid arthritis …
Sickle-cell disease Sciatica
Myofascial pain Post-stroke
Osteoarthritis Spinal cord injury
Visceral pain Multiple sclerosis
Tendonitis Trigeminal neuralgia
Bursitis Postherpetic neuralgia
Gout Small-fiber neuropathies
… Painful polyneuropathies

Figure 1. The three different types of pain defined by the IASP give rise to overlap which can be acknowledged as “mixed pain” (Freynhagen#). Conditions
described as “mixed pain” in the literature share a common characterization of manifesting clinically with a substantial overlap of the different known pain types.

pain ranged from a conservative estimate of 19.1% to a lib-
eral estimate of 39.1%, when patients with mixed pain
were included25.
Low back pain. Low back pain, ranked among the top 10
diseases and injuries in terms of highest number of disabil-
ity-adjusted life years worldwide26, is often classified as
mixed pain, associated with both neuropathic and nocicep-
tive pain components17,20,22. A systematic review of low back
pain trials highlighted that 20–55% of patients with chronic
low back pain had a greater than 90% likelihood of having a
neuropathic pain component, while in another 28% of
patients, a neuropathic pain component was suspected17.
Osteoarthritis pain. Osteoarthritis pain, always the proto-
type of nociceptive pain, is now increasingly considered a
result of the co-occurrence of nociceptive and neuropathic
pain mechanisms at both local and central levels27. In a 2014
review, Thakur and colleagues made the case for recognizing
patients with osteoarthritis having pain with neuropathic fea-
tures as comprising a distinct subgroup, with a different
osteoarthritic aetiology, and a sensitivity to pharmacological
agents that contrasts with other patients with the condi-
tion28. The proportion of such patients is not inconsequen-
tial: in a study involving patients with knee osteoarthritis
who were asked to describe the quality and severity of their
pain, 34% used both neuropathic and nociceptive pain
descriptors, suggesting “that [osteoarthritis] can be associ-
ated with a mixture of pain mechanisms”29. Results of the
most recent systematic review and meta-analysis of patients
with knee or hip osteoarthritis – culling data from nine
studies involving a total of more than 2000 patients –
showed an overall prevalence of neuropathic pain compo-
nents of 23%30.
Postsurgical pain. Mixed pain is also hypothesized to be
associated with postsurgical pain. A 2006 paper estimated
that 10–50% of patients who underwent routine surgery
developed acute postsurgical pain that eventually became
chronic31. While iatrogenic neuropathic pain is regarded as a
major cause of chronic postsurgical pain, ongoing nocicep-
tion is recognized as a contributing factor in certain patients.
A more recent French multicentre prospective cohort study
looked at neuropathic aspects of persistent postsurgical pain
occurring within 6 months after nine types of elective surgi-
cal procedures. From 2397 patients, the cumulative risk of
neuropathic postsurgical persistent pain was estimated at
20.6% for the whole cohort; the risk ranged from 3.2% for
laparoscopic herniorrhaphy to 37.1% for breast can-
cer surgery32.
Pain in primary care versus the orthopaedic setting. A
recently published Spanish cross-sectional study of 5024
patients in primary care and orthopaedic settings reported
that pain of mixed pathophysiology was the most common
pain condition (59.3%), followed by nociceptive and neuro-
pathic pain (31.8% and 8.9%, respectively)16. Mixed pain
was more frequent in primary care settings (61.2%) than in
orthopaedic settings (57.3%); it was found to be particularly
associated with spine-related complaints (80% of cases),
though it was also detected in other, non-spine-
related conditions.

3. Mixed pain is phenotypically heterogeneous
In a survey of 1083 patients with axial low back pain, investi-
gators identified five distinct subgroups of patients showing
a characteristic “sensory profile”, or a typical constellation
and combination of pain symptoms; notably, patients of
some subgroups exhibited distinct neuropathic characteris-
tics, while patients in other groups showed nociceptive fea-
tures33. Further, participants of a qualitative, focus-group
study involving representative types of patients suffering
from osteoarthritis described a wide variety of painful sensa-
tions which differed in terms of intensity (e.g. “pain as an
electrical shock”), duration (from ongoing “background pain”
to sharp, instantaneous pains brought on by “bad move-
ment”), depth (muscle-deep vs bone-deep), and associated
symptoms (most often anxiety related to the sensation of
intense pain)34. Finally, among patients who had undergone
joint replacement and reporting persistent postsurgical pain,
pain symptoms ranged from mild to “severe–extreme”
(occurring in 15% of study patients post-total knee replace-
ment), with the persistent pain most commonly described as
“aching”, “tender”, and “tiring”35.
The authors hypothesized that this complexity of presen-
tations is rooted in the chronological presentation of noci-
ceptive versus neuropathic versus nociplastic
symptomatology: nociceptive, neuropathic and nociplastic
pain components in any combination may occur simultan-
eously or concurrently in a patient with a mixed pain condi-
tion36, denoting, ostensibly, that these components are
operating at the same time or during the same time course;
or one pain component (and, presumably, one mechanism)
may be more clinically predominant at a given time, driven
or blocked by different molecular mechanisms leading to a
decrease or increase in the excitability of spinal cord neu-
rons37. Then again, it may well be that mixed pain is sub-
served by an entirely independent pathophysiological
mechanism (or mechanisms), distinct from nociceptive,
neuropathic or nociplastic mechanisms and, as yet, uncharac-
terized (see What is not known about mixed pain below).
4. The presence of mixed pain has negative implications
for quality of life
An early study of 8000 patients with low back pain reported
that 37% had predominantly neuropathic pain components
and that these patients suffered longer and more severely,
and were more susceptible to depression, panic/anxiety dis-
orders and sleep disorders than patients in the rest of the
study cohort38. A prospective multicentre study of 1519
patients reported that neuropathic pain and mixed pain
were associated with impaired physical and mental QoL, pro-
ducing a substantial level of disability in these patients;
mixed pain was specifically associated with lower physical
and mental QoL than neuropathic pain alone39. A study of
80 patients with treated leprosy found that 12 of 14 patients
reporting either neuropathic pain or mixed pain had high
scores on the General Health Questionnaire (GHQ-12), indica-
tive of possible depression40.
CURRENT MEDICAL RESEARCH AND OPINION 1015
In accordance with the published literature16,38,40,41, all
members of the group generally perceived patients with
mixed pain as having more comorbidities, such as depres-
sion, anxiety and sleep disorders, that collectively contribute
to psychosocial problems, and as having more complex clin-
ical presentations that negatively impact on response to
treatment. It was also agreed that these patients are more
difficult to treat.
What is not known about mixed pain
1. We do not know the mechanism(s) of mixed-
pain generation
Whether mixed pain is the manifestation of neuropathic
and nociceptive mechanisms operating simultaneously or
concurrently, or the result of an entirely independent patho-
physiological mechanism – distinct from nociceptive, noci-
plastic and neuropathic pain – is currently unknown. In other
words, is mixed pain simply the addition of two or more
components or does the mixture of different types of mecha-
nisms result in the emergence of a true, qualitatively differ-
ent clinical entity? And is mixed pain more frequent when
pain occurs in large areas of the body (which might, how-
ever, be simply a probability issue, linking larger pain areas
with higher odds of the presence of a concurrent
pain mechanism)?
Assessing the results of their cross-sectional study of 5024
Spanish patients suffering from pain in primary care and
orthopaedic settings, Ibor and colleagues proposed that
“[the consideration of mixed pain as] an independent cat-
egory in the pathophysiological classification of pain is
justified”, given that patients with mixed pain “showed a
greater clinical complexity” than patients with either nocicep-
tive or neuropathic pain – these patients exhibited more
comorbidities; were associated with more adverse psycho-
social factors; responded less effectively to treatment; and
experienced a lower health-related quality of life16. However,
they offered no clear evidence or hypothesis of a bona fide
unique mechanism – distinct from neuropathic and nocicep-
tive pain-generating mechanisms – underpinning mixed pain
as an independent pain type.
Notably, an exhaustive review of the pertinent literature
yielded no animal or human studies establishing that such a
distinct, independent mechanism is operative in patients suf-
fering from mixed pain. The most detailed characterization of
chronic lumbar radicular pain – so far the prototypical
mixed-pain state – describes it as the end-result of several
neuropathic and nociceptive pain-generating mechanisms,
including lesions of nociceptive sprouts within the degener-
ated lumbar disc; mechanical compression of the nerve root;
and action of inflammatory mediations originating from the
degenerative disc even without mechanical compression22.
2. We do not know how to screen for and diagnose mixed
pain definitively
The updated grading system for neuropathic pain empha-
sized the importance of identifying pain associated with
1016 R. FREYNHAGEN ET AL.
sensory abnormalities, in conjunction with performance of
diagnostic tests, to confirm a lesion or disease of the som-
atosensory system42. However, this grading system was never
designed to identify mixed pain syndromes; therefore, its
ability to identify a neuropathic component in situations
such as low back pain, osteoarthritis pain, persistent postsur-
gical pain or cancer pain remains uncertain and raises doubts
about its suitability as a gold standard.
Also, there are currently no validated screening tools spe-
cific for the detection of mixed pain, or of the nociceptive
pain component alone. However, there are existing validated
tools for neuropathic pain screening or assessment that can
be deployed to detect the presence of this component43.
These tools include the self-reported Leeds Assessment of
Neuropathic Symptoms and Signs (s-LANSS) tool44, Douleur
Neuropathique en 4 Questions (DN4)45 and painDETECT38, as
elaborated in the NeuPSIG guidelines on assessment of
neuropathic pain46. Notably, a recent systematic review eval-
uating the performance of screening tools for neuropathic
components in cancer pain found that it is clinically more
challenging to distinguish predominantly neuropathic pain
from predominantly nociceptive pain within a mixed pain
context, particularly for clinicians with little or no training in
pain assessment24. Consequently, the reviewers assessed the
performance of currently available screening tools and identi-
fied concordance between the clinician diagnosis and screen-
ing tool outcomes for LANSS, DN4 and painDETECT, leading
them to conclude that these screening tools are practical for
identifying potential cases of neuropathic cancer pain24.
It is important to note that the pain part of a neuropathic
problem has to be established using other pieces of the
diagnostic armamentarium in addition. Additional diagnostic
assessments, including quantitative sensory testing47, corneal
confocal microscopy48 and skin biopsy49, may be helpful for
the clinician to diagnose the presence of a neuropathic pain
component in rare but challenging cases (e.g. small-fibre
neuropathy). Detection of elevated inflammatory markers,
such as pro-inflammatory cytokines and C-reactive protein
(CRP), may be used to identify the presence of inflammation,
which would support a possible nociceptive pain compo-
nent50. However, no diagnostic gold standard is available.
The authors concluded that, as there is no available vali-
dated tool to screen for the nociceptive pain component at
present, the diagnosis of mixed pain is made based on clin-
ical judgement following detailed history-taking and thor-
ough physical examination, rather than by formal
confirmation following explicit screening or diagnos-
tic criteria.
3. We do not know how to provide definitive treatment
for mixed pain
The phenotypical complexity of mixed pain makes assess-
ment and diagnosis of the mixed-pain patient considerably
challenging for the clinician, and treatment even more so –
no clear guidelines specific to mixed pain are currently avail-
able and, thus, the best guidance on treatment decision-
making can be derived only from treatment recommenda-
tions for neuropathic pain36.
Table 1. Mixed pain: practice pearls.

Currently, the diagnosis of mixed pain is made based on clinical judge-
ment following detailed history-taking and thorough physical examination,
rather than by formal confirmation following explicit screening or diagnos-
tic criteria (which are, as yet, not available).

When encountering a patient who presents with an overlap of nocicep-
tive and neuropathic symptoms, consider mixed pain as a working diagno-
sis.

For a patient with a working diagnosis of mixed pain, consider early
treatment with a combination of agents targeting nociceptive and neuro-
pathic mechanisms.

For a patient with a working diagnosis of mixed pain, perform a thor-
ough evaluation for comorbidities (e.g. disturbed sleep, depression, anxiety)
and manage accordingly.
Discussion
Given the foregoing considerations, the authors provide a
few practice pearls for clinicians who encounter a patient
with presumptive mixed pain (Table 1).
One criticism that has been levelled at Kosek et al. regard-
ing their conceptualization of “nociplastic pain” is that the
term is “nothing more than a rather trivial clinical observa-
tion … [that] serves [no] defined clinical or scientific
purpose”8. It is not unlikely that such a criticism will also be
levelled at this present effort to consolidate current know-
ledge on mixed pain, or any future effort to articulate a
mechanistic definition of mixed pain.
In response, the authors align themselves with the pos-
ition staked by Kosek and colleagues, who pointed out that
any novel pain descriptor is aimed at filling a gap in our lexi-
con of pain terminology for patients presenting with chronic
pain51. As “nociplastic pain” was conceptualized to fill the
lexicon gap between the two current concepts available to
describe the biomedical or somatic dimension of the pain
experience (i.e. nociceptive and neuropathic), so too will a
future definition of mixed pain fulfil the role of a mechanistic
descriptor for the pain presenting as various combinations of
nociceptive, neuropathic or nociplastic components.
Furthermore, even as such an advancement of the current
conceptual framework beyond nociceptive/neuropathic/noci-
plastic is crucial in and of itself, it assumes greater import-
ance in the context of our patients with chronic pain, who
still are often told that their pain is not real or “all in their
head”. A future definition of mixed pain will allow affected
patients to validate their own experience of chronic pain,
facilitating doctor–patient communication and positively
impacting on treatment outcomes. Moreover, it should spur
a more widespread recognition that chronic pain is a disease
in its own right – a concept that is familiar to pain clinicians
and researchers but has still not sufficiently spread through-
out the medical community and the lay public52.
Importantly, the authors hope that this foundational work
on mixed pain, together with the recent conceptualization of
nociplastic pain, will serve as an impetus for future research,
particularly in the detection, quantification and definition of
peripheral and central sensitization, and of alterations in
nociception. This current lack of tools and techniques to
gauge nervous system sensitization in both clinical practice
and the laboratory setting prevents the full characterization
of pain-generating mechanisms in patients with nociplastic

Table 2. Important questions for future research.

How are “peripheral sensitization” and “central sensitization” detected
and quantified?

What are the underlying mechanisms of mixed pain?
 Is mixed pain the manifestation of neuropathic and nociceptive
mechanisms operating simultaneously or concurrently?
 Or is it the result of an entirely independent pathophysiological
mechanism – distinct from nociceptive, nociplastic and neuropathic pain?

Is mixed pain more frequent when pain occurs in large areas of the
body?

Is an independent category of “mixed pain” in the pathophysiological
classification of pain justified?

Which (chronic) pain states can be classified as mixed pain?

Why do patients with mixed pain exhibit more comorbidities?

Why is mixed pain specifically associated with lower physical and
mental quality of life?

What screening and/or diagnostic tools can be utilized to identify
mixed pain?

What therapeutic strategies/agents can be used to target potentially
distinct mixed-pain mechanisms?
pain, as well as in those presenting with two or more pain
components15. What the authors believe to be the most
important questions for future research into mixed pain are
summarized in Table 2.
Conclusions
To the authors’ knowledge, this paper represents a first pub-
lished consolidation of knowledge on the mixed pain con-
cept which can serve as a foundation for future attempts at
generating a mechanistic and/or clinical definition of mixed
pain. Based on the preceding considerations, the group
formed consensus around the following starting point:
“Mixed pain is a complex overlap of the different known pain
types (nociceptive, neuropathic, nociplastic) in any combination,
acting simultaneously and/or concurrently to cause pain in the
same body area. Either mechanism may be more clinically
predominant at any point of time. Mixed pain can be acute
or chronic.”
It is foreseeable that this advancement of the current con-
ceptual framework of the neurobiological basis of chronic
pain beyond nociceptive, neuropathic and nociplastic pain
will gain increasing acceptance even as it is debated and dis-
cussed, given that a clear definition of mixed pain will have
profound implications – this may, indeed, form the founda-
tion of forthcoming clinical diagnostic criteria and treat-
ment strategies.
Transparency
Declaration of funding
The expert consensus meetings, and medical writing and editing serv-
ices, were sponsored by Merck Consumer Health.
Author contributions: All authors were involved in the conception and
design of the manuscript. R.F. was responsible for drafting of the paper;
all authors participated in revising it critically for intellectual content;
and all authors gave the final approval of the version to be published.
All authors agree to be accountable for all aspects of the work.
CURRENT MEDICAL RESEARCH AND OPINION 1017
Declaration of financial/other relationships
R.F. reports personal fees from Astellas, Gr€ unenthal, Lilly, Pfizer, Merck,
Develco, Mitsubishi Tanabe Pharma and Galapagos, outside the submit-
ted work. C.A.C.O. reports that he is a consultant for Merck. J.C. reports
personal fees from Pfizer and Merck. K.Y.H. has received honoraria from
Halyard Healthcare, Pfizer, Menarini and Merck, outside the submitted
work. A.L.S. discloses that she is a consultant or speaker for Pfizer, Merck
Sharp & Dohme, Teva, Merck and Gr€ unenthal. M.D.S. reports that she is
a member of a Merck clinical advisory board. The remaining authors
have no conflicts of interest to declare.
CMRO peer reviewers on this manuscript have no relevant financial
or other relationships to disclose.
Acknowledgements
The authors would like to thank Dr Jose Miguel (Awi) Curameng of
MIMS (Hong Kong) Limited for providing medical writing and editing
support for this manuscript.
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