Maturitas 117 (2018) 17–21

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Pain management of chronic wounds: Diabetic ulcers and beyond T

a b,c d e
Stavroula A. Paschou , Maria Stamou , Hubert Vuagnat , Nicholas Tentolouris ,
⁎
Edward Judef,g,
a
Division of Endocrinology and Diabetes, “Aghia Sophia” Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
b
Harvard Reproductive Sciences Center, Massachusetts General Hospital, Boston, MA, USA
c
Mount Auburn Hospital, Harvard Medical School Teaching Hospital, Cambridge, MA, USA
d
Woundhealing Centre, Medical Directorate, Geneva University Hospitals, Geneva, Switzerland
e
Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Greece
f
Diabetes Centre, Tameside Hospital NHS Foundation Trust, Ashton-under-Lyne, UK
g
Manchester University and Manchester Metropolitan University, Manchester, M13 9PL, UK

A R T I C LE I N FO A B S T R A C T

Keywords: Patients who suffer from ulcers often experience pain of sufficient severity to reduce their quality of life. The aim
Wound of this review article is to collect, analyze and qualitatively resynthesize information regarding the definition and
Ulcer prevalence of ulcer pain, the pathophysiology of such pain, its assessment, and the optimal systemic and topical
Pain treatments. Early identification and prompt treatment are key to pain management. Further management should
Dressing
focus on appropriate dressing as much as on pain medication. The goal is to provide maximum relief with
Diabetes
minimum side-effects.

1. Introduction medical treatment.

Pain is defined as an unpleasant sensory and emotional experience
associated with actual or potential tissue damage. Pain perception is
generally subjective and an observer cannot really judge the level of
pain reported by an individual. In this context, the use of one of the
many validated tools developed can help in measuring the individual’s
pain. Patients suffering from ulcers very often experience pain and for
some this is lived as their main problem, disrupting their quality of life
[1,2]. The aim of this review is to present the reader with updated
information regarding the definition of ulcer pain, to discuss the pa-
thophysiology of such pain and to provide an individualized guide for
the optimal diagnostic and treatment approach.
2. Methods
In order to identify relevant publications for this review, a search
with combinations of terms “pain”, “wound”, “ulcers”, “diabetic foot”
in English language was conducted in PubMed until June 2018. Special
attention was paid to guidelines or original papers focusing on the
management of patients with ulcers. This review collected, analyzed
and qualitatively resynthesized information regarding: (1) the defini-
tion and prevalence of ulcer pain, (2) the pathophysiology of such pain,
(3) the appropriate diagnostic assessment and (4) the appropriate
3. Results and discussion
3.1. Definition and prevalence
Wound pain is defined as an unpleasant sensation deriving from
ongoing inflammatory or other tissue damage. Pain manifestations can
vary and are broadly divided into the following categories: (i) The
background pain that is a continuous or intermittent pain that is felt
even at rest, (ii) the incident pain that occurs during day-to-day ac-
tivities such as mobilisation, (iii) the procedural pain that results from
routine procedures such as dressing change or wound cleansing, and
finally (iv) the operative pain that is associated with significant wound
intervention, such as debridement or biopsy [1]. The severity of pain
experienced by an individual is usually related to the type and extent of
the physical trigger, which can be affected by psychosocial factors, such
as age, gender, culture, education, mental status, anxiety, depression
and also different environmental factors such as timing of procedure,
setting and resources, all which can increase the pain sensation of the
patient.
The patients’ pain can either be nociceptive, which usually is an
appropriate physiological response to a painful stimulus, occurring
during acute or chronic inflammation, secondary to tissue damage and

⁎
Corresponding author at: Diabetes Centre, Tameside Hospital NHS Foundation Trust, Ashton-under-Lyne OL6 9RW, UK.
E-mail address: edward.jude@tgh.nhs.uk (E. Jude).

https://doi.org/10.1016/j.maturitas.2018.08.013
Received 23 April 2018; Received in revised form 2 August 2018; Accepted 30 August 2018
0378-5122/ © 2018 Elsevier B.V. All rights reserved.

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S.A. Paschou et al.
is usually time limited, or neuropathic that is an “inappropriate” re-
sponse caused by primary lesions or dysfunction in the nervous system.
The latter is frequently linked to nerve damage and is perceived as al-
tered or unpleasant sensations [1,2].
Diabetic neuropathy and diabetic foot ulcers are truly debilitating
conditions for patients and contribute to 50% of all chronic wounds in
industrialized countries with a prevalence of 5–7% (1–1.4 million
people in Europe) and incidence of 2–3% (with 400–600,000 new cases
per year in Europe) [2,3]. Apart from the major debilitating con-
sequences in patients’ health and everyday life, the financial burden of
managing such ulcers can also be devastating. The chronic nature of
such ulcers generates medical cost of 7,700–25,000 Euros per patient
with global annual health cost reaching 10 billion Euros [4]. Apart from
diabetic foot ulcers, 30% of chronic wounds consist of venous leg ulcers
with an annual incidence of 1–1.5%, requiring 4% of the total health
care budget in UK [5]. Pressure ulcers, contributing to 20% of all
chronic wounds, have a prevalence of more than 0.5 million people in
the UK, with the majority of these patients requiring hospitalization,
and 1 out of 5 in hospital patients will develop a pressure ulcer. The
cost for managing pressure ulcers can reach up to £4,300-6,400 per
patient in the UK [3,4]. Although other causes of ulcer exist, these 3
main ones, by their number and the morbidity they bear are largely on
top of our preoccupations. Their incidence is directly or indirectly
linked to aging, with special characteristics for each category. Risk and
therefore incidence for venous leg ulcers is more tightly linked to the
evolution of venous deficiency, mobility, and obesity, resulting in fluid
overload. Risk for pressure ulcers is affected by a decrease in mobility
and being ‘bed-bound’, and/or sensitivity which happens more in the
elderly. Diabetic foot ulcers are more commonly seen in patients with
impaired sensation and are linked to aging both by the later onset of
type 2 diabetes and to the years needed to develop peripheral neuro-
pathy. Thus, it is clear that the medical diagnoses, prevention, timely
treatment of such conditions are crucial not only for better management
of the patients, but also for decreasing the related health care cost
[3–5].
3.2. Pathophysiology
Pathophysiology is highly different in various ulcers. Neuropathy is
an important risk factor for the development of diabetic foot ulcers,
while peripheral vascular disease and poor glycemic control increase
the risk for delayed healing. Patients, who suffer from peripheral neu-
ropathy can experience diminished perception of pain and temperature.
This can delay the recognition of an injury to their feet compared to
other patients. Poor perfusion in diabetic patients’ lower extremities
can also delay the process of healing and make the inflammation in-
crease rapidly. Additional factors such as dry skin (and fissuring), often
due to autonomic neuropathy but also aging, can also facilitate the
entry of microorganisms to the deeper skin structures, increasing the
risk of infection. Diabetic foot infections are associated with substantial
morbidity and mortality [6]. In addition, secondary trauma can prevent
wound healing and increase the risk for secondary infections. Poor
glycemic control can also impair the host immune response, making
wound healing and recovery from the infection a more difficult task [7].
Diabetic neuropathy and pain related to the diabetic foot ulcer itself are
distinct entities. In case of a diabetic foot ulcer, there usually is lack of
wound sensation and pain experienced by the patient, which by no way
means that all diabetic foot ulcers are painless. Also and interestingly,
ischemic pain in diabetic patients can be often confused for neuropathic
pain. Classically, ischemic aching is aggravated by elevation, while
shooting pains are associated with neuropathic pain.
When such wounds get infected, it is most likely due to poly-
microbial organisms [6,8–10]. Diabetic foot infections can either be
superficial (such as cellulitis), usually secondary to aerobic gram posi-
tive cocci (including Staphylococcus aureus, Streptococcus agalactiae,
Streptococcus pyogenes, and coagulase-negative staphylococci) or
18
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Maturitas 117 (2018) 17–21
deep, which may involve multiple organisms such as enterococci, En-
terobacteriaceae, Pseudomonas aeruginosa, and anaerobes. Anaerobic
infections should also be considered if the patient demonstrates any of
the following signs: necrosis, malodorous drainage, or gangrene with
signs of systemic involvement [11–15]. Increased pain is now being
recognized as an early marker for infection. Infected ulcers are painful
due to wound breakdown and nerves damage [16].
Venous leg ulcers (VLU) occur on a terrain of chronic venous in-
sufficiency (CVI) which is linked to the leg muscular pump dysfunction
leading to venous hypertension. During calf muscles contraction, val-
vulae normally prevents blood reflux from the deep venous system to
the superficial one. Out of the many causes of CVI, two main one arise:
primary varicose diseases and late effects of deep venous thrombosis.
This reflux will lead to an increase of pressure in the skin, which will
trigger processes that, although not entirely identified, will end up in
skin breakdown [5,17].
Pressure-induced ulcers (PU), similarly to diabetic foot ulcers, can
derive from multiple injuries, triggered by a complex process that re-
quires the application of external pressure to an area of the skin usually
facing a bony prominence [18]. However, not all patients who undergo
such external pressure will develop PU. The factors that predispose
some patients to develop PU are multifactorial: (i) The characteristics of
the pressure: pressure applied to the skin in excess decreases the de-
livery of oxygen and nutrients to tissues, resulting in tissue hypoxia,
microthrombosis, accumulation of metabolic waste products, and free
radical generation. The higher the pressure, the faster and more de-
vastating is the formation of the ulcer. Of course, the longer the pres-
sure is applied, the worse the lesion will be [19,20]. (ii) The tissue
susceptibility and the nature of the underlying structures: muscle tissue
can be very susceptible to pressure, followed by subcutaneous fat and
then dermis. A high-stage pressure injury usually commences as a deep
tissue injury that may then progress to the surface. There is little evi-
dence to suggest that high-stage pressure injuries develop as a gradual
progression from stage 1 through stage 4 [21,22]. (iii) Body position
and supporting material: immobility is one of the major risk factors for
pressure ulceration and air-mattresses have proven to provide some
support and relief in chronically immobilized patients. Pressure over
bony surfaces can be high and body position can play a role. For ex-
ample, sitting position generates higher pressures compared to lying
position and finally (iv) compression and reperfusion injury: reduced
skin perfusion can be associated with pressure induced ulcers. Even
though hypoxia can play a major role in the development of ulcers, it is
the compression induced ischemia compared to any other type of
ischemia that is responsible for worsening of PU [23,24].
3.3. Diagnostic assessment
The diagnosis of chronic wounds, which can be either diabetic, VLU
or PU is mainly clinical [25]. The diagnosis of infection of these ulcers
is more certain in presence of cumulated classical features of in-
flammation, such as erythema, warmth, tenderness, swelling, indura-
tion and purulent secretions [26]. However, signs specific to secondary
wounds, such as increased pain, serous exudate, delayed healing, dis-
coloration of granulation tissue, friable granulation tissue, pocketing at
the base of the wound, foul odor and wound breakdown have been
proved to be better indicators of chronic wound infection than the
above-mentioned classic signs [16,27]. The presence of microbial
growth alone in wound cultures is not sufficient to make a diagnosis of
infection [28]. Pain is particularly common in patients having ischemic
and neuroischemic ulcers, as well as infected ulcers, where the in-
flammatory response, stimulated by the infecting microorganisms,
causes the release of inflammatory mediators and stimulates the pro-
duction of enzymes and free radicals, which can cause tissue damage.
Pain may result from direct stimulation of peripheral pain receptors by
the mediators, from tissue damage, and from the swelling that occurs as
part of the inflammatory response. The inflammation and cell damage
S.A. Paschou et al.
may also lead to an increase in overall pain.
The pain sensation threshold can be lowered by the increase of the
pain receptors sensitivity. Thus, infection management can be very
important for the pain control. The skin surrounding the wound can
become sensitive and painful and, for some patients, the lightest touch
or simply air moving across the wound can be intensely painful [27,28].
The big challenge comes with diabetic foot ulcers, where there usually
is a lack of wound sensation and pain experienced by the patient. Thus,
it is not uncommon for a diabetic patient to report that they only no-
ticed their wound when they found blood or pus on their sock. This is
why daily plantar foot checks (if required using a mirror for the in-
spection) are now part of diabetic foot ulcer educational re-
commendations. As mentioned before, in diabetic patients pain can be
of other origins, mainly ischemic or neuropathic; both should not be
confused. Ischemic aching is aggravated by elevation, while the
shooting, tingling, burning pains are more associated with neuropathic
pain. Finally, even though management must start at the primary care
setting, it is important to know when to refer to the specialist for further
assessment.
3.4. Pain management
Pain that patients with chronic wounds experience can be sig-
nificantly debilitating [29]. It can be influenced by several factors such
as emotional distress, expectance of pain and anxiety. As wound pain is
multifactorial, different options for pain management must be con-
sidered: Local pharmacologic and non-pharmacologic treatment in-
cluding autolytic debridement, dressing application and local anaes-
thetics, psychosocial therapy (i.e. encouraging patients to organize
their day by socialisation, exercise and relaxation) and systemic treat-
ment are the usual modes of management and will be further developed
in the article [30–32].
3.4.1. Topical treatment and dressing techniques
It is important to realize that patients with increased sensitivity who
feel pain at the slightest touch, are likely to find the additional pain
from a dressing-related procedure excruciating [33]. Dressing adhesives
may contribute to pain and trauma, with repeated application and re-
moval of adhesives mechanically stripping the stratum corneum from
the underlying epidermal and/or dermal cells but also stimulating
mechanically the underlying inflammatory tissues and damaging the
granulation tissues. Thus, dressings that minimise trauma and pain on
application/removal should be chosen to avoid wound damage and
patient stress. In a study by Price et al, 14.7% of patients experienced
dressing-related pain ‘most of the time’ and 17.2% of patients experi-
enced dressing-related pain ‘all of the time’ [30]. Therefore, significant
number of patients experience pain during dressing change and this
must be addressed before undertaking this procedure.
In a randomised, crossover study conducted by Woo et al., a cohort
consisting of 32 patients was examined. The aim of the study was to
compare the patient pain experience between two different adhesive
foam coated dressings in the management of chronic wounds. The au-
thors concluded that a soft silicone foam coated dressing minimised
pain levels at dressing removal and minimised periwound maceration
when compared with a regular adhesive hydrocellular polyurethane
foam dressing [33]. White and colleagues in 2008 also concluded that
dressings with soft silicone adhesive technology benefit the patient by
minimising pain during dressing wear, at dressing removal and fol-
lowing dressing change when compared with advanced dressings with
traditional adhesives [34].
The intrinsic properties of soft silicone are such that these dressings
may be removed without causing trauma to the wound or to the sur-
rounding skin. There are different types of soft silicone dressings in-
cluding atraumatic wound contact layers, absorbent dressings for
exuding wounds and a dressing for the treatment of hypertrophic scars
and keloids. Meuleneire et al., reported that pain severity was
19
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Maturitas 117 (2018) 17–21
significantly higher at baseline than at the first and final visits
(p < 0.0001) with the use of a soft silicone dressings containing silver.
Also, pain severity scores at dressing removal was significantly higher
at baseline than at the first and final visits (p < 0.0001) [35].
Hollinworth & Collier concluded that 81% of respondents in a
survey reported that patients experienced most pain when dressing
products were removed. Selection of atraumatic dressings was the most
common strategy used to prevent pain and trauma [36]. However, re-
spondents demonstrated confusion about the availability and properties
of wound dressings aimed at minimising pain and trauma. In-
appropriate use of less expensive but more traumatic dressings may
result in reducing the wound healing process and lead to additional
financial costs [36]. Another study noted that dressing removal (51%)
and wound cleansing (41%) were the phases of the wound care inter-
ventions most likely to cause pain [37]. Dressing adherence to the
wound and periwound area and inadequate wound moisture balance
can cause pain [38]. There are a variety of silicone dressings available
including polymers: silicon + O2, inert (not absorbed, non-allergenic),
non-absorbent, minimally adhesive etc. However, there is still in-
sufficient knowledge for the use of low-adherent or non-adherent
wound dressings products among care givers [24–30].
Dressings with topical analgesics may also sometimes benefit by
resulting in less pain at dressing change. In a study by Romanelli et al, a
total of 185 patients were assessed using ibuprofen foam dressings (IFD)
(n = 98) and were compared to local best practice (n = 87). The pri-
mary endpoint of the study was pain relief over 7 days assessed daily
using a 5-point verbal rating scale (no relief, slight relief, moderate
relief, lots of relief, and complete relief) and showed significant re-
duction in all scales with IFD (p < 0.0001) [33]. Although hard evi-
dence of effectiveness is lacking, some groups built up experience with
the use of topical morphine directly on the wounds [39,40]. This needs
further investigation especially in patients who experience severe pain
at dressing change and between dressings.
In patients with diabetes, it is important to remember that there is a
misconception that they do not feel pain [41] and, as such, patients at
risk of diabetic foot ulceration may be treated inappropriately. Identi-
fication of a patient’s pain status is essential when treating patients with
diabetic foot ulcers. Increased pain sensations or loss of sensory feeling
may result from nerve damage in diabetic patients. Atraumatic dressing
should be used to minimise pain and trauma during wear and at dres-
sing removal [34].
To sum up, when it comes to choosing the appropriate dressing it is
important to remember the classical properties of a good wound dres-
sing as summed up in Table 1. Considering that removal is among the
most painful moment, dressing should be removed with a large quantity
of saline or water (under a shower if required). Enough time should be
allowed for removal. Medical adhesive remover can be used. Some can
leave a residue that impairs adherence of replacement dressing, thus
afterwards, the skin must be rinsed before a new dressing applied. A
skin barrier (spray, cream or wipe) can also prove to be valuable. Hy-
drocolloid strips can be used to protect the wound border [42,43].
3.4.2. Systemic pain management
Apart from the various dressing techniques that are used to treat
chronic ulcers, pain medications are also widely used [30]. Those in-
clude both non-opioid and opioids analgesics. The non-opioid analge-
sics include paracetamol, acetaminophen, non-selective nonsteroidal
anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, these
acting more on nociceptive pain. One must be cautious in the use of
these medication in regard to, renal insufficiency, peptidic ulcer for
NSAIDs or liver insufficiency with paracetamol, acetaminophen, An-
ticonvulsants (gabapentin or pregabalin) and sometimes anti-
depressants (tricyclics and serotonin and norepinephrine reuptake in-
hibitors) acting on the neuropathic component of pain. Of course,
analgesics and antidepressants are not indicated as first line manage-
ment of pain associated with the infection of the wound. Given the
S.A. Paschou et al.
Table 1
Dressing related properties in wound pain management and wound healing.
Dressing properties
Maintain high humidity at the dressing wound interface
Manage excess exudate
Allow for gaseous exchange
Provide thermal insulation
Prevent infection
Be free from particulate and toxic components
Avoid wound trauma during therapy and on removal
Allow monitoring of the wound with minimum interference
Be comfortable,
Cost-effective
If having an antimicrobial activity, it must be sustained, long lasting and
be delivered over the entire wound bed surface
prevalence of chronic pain that accompanies wounds and its often
disabling effects, it is not surprising that opioid analgesics are com-
monly prescribed for chronic pain related to different conditions such
as chronic wounds [25,35].
Practically, always take into account the needed time for the sub-
stance given to be effective. In general 45–60 minutes will be sufficient
for most usual oral drugs.
Opioids act via the mu-opioid receptors in human brain with high
concentrations in the thalamus, amygdala, brain stem and the spinal
cord. It is less known, but interestingly, opioid receptors are also ex-
pressed in the wound and they can contribute both to pain control but
also to wound healing [44]. Mu-opioid receptors in peripheral term-
inals modulate the perception of pain, and receptors in the small in-
testine regulate gut motility. This can explain the most common side
effect of opioid analgesics, which is constipation. The effect of opioids
in the mu-opioid receptors in other brain regions such as the brain stem
can also explain the effect of opioids on the respiratory drive or nausea
induction. The central action of opioids accounts for the pain relief
effect and the perception of pleasure and well-being. Opioid addiction
has always been of a concern, which was recently strengthened by the
so called opioid crisis [45]. This still has to be properly analyzed, but
we do know that risk factors for opioid addiction are: the high dosing of
the medication, the long duration of treatment (> 3 months), the usage
of extended release medications, the combination with benzodiaze-
pines, as well as patient related factors such as the age (> 65 years or
adolescence), renal or hepatic impairment, depression, history of
overdose or substance use disorder including alcohol [46]. Other
pharmacologic techniques such as nitrogen monoxide-oxygen mixture,
have proven to be useful, but are not available in every setting [47].
Non pharmacologic techniques can also be used, such as hypnosis, re-
laxation. Although further research is needed they certainly can add up
to standard pharmacological approaches [48].
4. Conclusions
In conclusion, the pain elicited by chronic ulcers can be a debili-
tating medical issue for the patients, providers and generally for the
health care system. It is important to keep in mind that wound related
pain is more common than we think and the cost related to the wound
pain is more than we can imagine. Chronic pain secondary to ulcers can
affect patients’ quality of life and wound healing. Observing pain and
managing it appropriately can lead to better outcomes for patients.
Targeting wound specific issues and systemic treatment may be
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Maturitas 117 (2018) 17–21
Impact on wound healing
Wound healing is a complex biological process, as so it needs to occur in similar middle as human
body fluids
Excessive exudate may cause secondary lesion to periwound skin. If containing enzymes it will
damage granulation tissues. In an infected wound, it may retain bacterial toxins
Such as oxygen, carbon dioxide and water vapour
Wound healing is a complex biological process, as so it needs to be conducted as close as body
temperature as possible
By being a barrier both to external germs but also to the spread of germs from the wound
Cytotoxicity to human cells and components would reduce wound healing efficiency. The material
must also be nonsensitising and nonallergenic
In a wound, tissues are fragile and irate; the dressing is also a mechanical protection. The dressing
must not stick into the wounds and adhere to firmly on the periwound skin in order not to damage
the wound
As some wound evolutions are not as positive as we would like, it is important to be able to react
quickly without having to remove the dressing
In order to be efficient the dressing must be worn for days, it is important that it does not interfere
with the patients every day life
For a similar result, the dressing’s cost must be balanced with global nursing time reduction
By far not all wounds require antimicrobial dressing, but if used, they should be locally efficient
necessary to alleviate wound related pain. Early identification and
prompt treatment of such ulcers is the first very important step for the
management of pain that they can provoke. Further management
should focus on the appropriate dressing as well as on the systemic pain
medication, always in the concept of providing the maximum relief
with the minimum side effects for our patient’s wellbeing. Close follow
up of the patients is required by primary health providers and specialist
for the right management of such a complicated medical issue.
Contributors
Stavroula A. Paschou conceived and designed the review, and per-
formed the literature search and wrote the manuscript.
Maria Stamou performed the literature search and wrote the
manuscript.
Hubert Vuagnat critically revised the article for important in-
tellectual content and contributed to the discussion.
Nicholas Tentolouris critically revised the article for important in-
tellectual content and contributed to the discussion.
Edward Jude conceived and designed the review, critically revised
the article for important intellectual content and contributed to the
discussion.
All authors read and approved the final manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Funding
No funding was received for this study/for the preparation of this
review.
Provenance and peer review
This article has undergone peer review.
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