Manuka honey in wound management: greater than the sum of its parts?

Abstract

Few involved in wound care will have escaped the considerable interest which has been generated by the resurgence in honey. Equally, there will be many clinicians around the globe who are wondering why all the fuss, as they will have been using honey all along. However, even with the advent of ‘medical-grade’ honey, combined with considerable research into the numerous potential modes of action, there remains a lingering scepticism regarding the value of honey as a justified, modern intervention in wound care.
The purpose of this brief review is to summarise the ongoing chemical, biochemical and microbiological research and to correlate it with clinical outcomes. The purpose being to present the enquiring clinician with an evidence summary with which clinical choices may be made. While much of the early research was into generic honeys, one particular source, manuka, appears especially effective, and as such this has been the focus of recent studies.

Full text

education
JOURNAL OF WOUND CARE VOL 25, NO 9, SEPTEMBER 2016 539
Few involved in wound care will have escaped the considerable interest which has been generated by the
resurgence in honey. Equally, there will be many clinicians around the globe who are wondering why all the
fuss, as they will have been using honey all along. However, even with the advent of ‘medical-grade’ honey,
combined with considerable research into the numerous potential modes of action, there remains a lingering
scepticism regarding the value of honey as a justied, modern intervention in wound care.
The purpose of this brief review is to summarise the ongoing chemical, biochemical and microbiological
research and to correlate it with clinical outcomes. The purpose being to present the enquiring clinician with
an evidence summary with which clinical choices may be made. While much of the early research was into
generic honeys, one particular source, manuka, appears especially effective, and as such this has been the focus
of recent studies.
Declaration of interest: RJW was commission by MA Healthcare and Advancis Medical to write this article.
Honey has been used to treat wounds for
millennia.1,2 Indeed, until the modern
age of evidence-based medicine, honey
was so highly regarded as a treatment for
wounds that it was accepted as a rst-line
intervention. It is, however, the scientic and clinical
focus on honey which has come about in the past 30
years that has led to the classication of medical-
grade honey and the commercial availability of highly
regulated products.
Biological research into honey
The literature includes reports on numerous honeys,
from different oral sources, for in vitro antimicrobial
activity in particular. Due to the pioneering work of
the late Peter Molan3 in New Zealand over the past 25
years, it has emerged that of the range of honeys
tested, those from one source, manuka, has
particularly high antimicrobial activity.4 Subsequently
many other reports have supported and claried this
activity this is summarised in a review by Carter et
al.5 It is owing to a series of seminal articles by Molan6
and colleagues7,8 in 1999 that the modern approach
to honey in wound can be traced. Until that time
there had been debate as to the clinical effects of
honey being largely osmotic.9 Molan, based upon the
considerable evidence available, identied a number
of distinct actions of honey (primarily manuka) on
the wound, namely:
● Antimicrobial
● Anti-inammatory
honey ● wound care ● anti-inflammatory ● antimicrobial ● debridement ● manuka
● Debridement
● Exudate control.
In addition Molan6 has listed the numerous
advantages of honey based upon the available evidence:
● Provides a protective barrier to prevent
cross-infection
● Creates an antibacterial moist healing environment
● Rapidly clears infecting bacteria including
antibiotic-resistant strains
● Has a debriding effect
● Rapidly removes malodour
● Hastens healing through stimulation of tissue
regeneration
● Prevents scarring and hypertrophication
● Minimises the need for skin grafting
● Is non-adherent and therefore minimises trauma
and pain during dressing changes
● Anti-inammatory action reduces oedema
● Has no adverse effect on wound tissues.
● Reduced costs of dressing materials and anti-
bacterial agents
● More rapid healing
● Less need for surgical debridement
● Less need for skin grafting.
Given that this list is substantiated by numerous
publications at the time of publication, and that
numerous additional studies have been added since, it
is evident that honey offers considerable advantages.
Manuka honey in wound management:
greater than the sum of its parts?
R. White,1 PhD, Professor of Tissue Viability, Director DDRC Wound Care Plymouth
E-mail: richard@medicalwriter.co.uk
© 2016 MA Healthcare ltd
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by Richard White on October 1, 2016.
Use for licensed purposes only. No other uses without permission. All rights reserved.

education
JOURNAL OF WOUND CARE VOL 25, NO 9, SEPTEMBER 2016
540
Manuka honey
When considering which oral source honey to
research and develop for commercial purposes, a
number of important considerations must be made.
Accepted that clinical and scientic evidence are
essential, it is vital that the honey be available from a
sustained, consistent source such that the specications
and quality assurance consistent with a regulated
medical product be maintained.10,11 It is important that
all clinicians using honey, or any other medical device,
be aware of the requirements demanded by current
regulations. It is in this respect that manuka honey is
the current ‘standard’ in wound care and thus the focus
of this review.
Antimicrobial action
To some degree all honeys have an antimicrobial action
as an evolutionary adaptation to prevent spoilage. In
many honeys this is based on peroxidise activity.
However, this has been attributed to the content of
methyl glyoxal (MGO) in manuka honey.12,13 The
activity of manuka honey is not inhibited by catalase
whereas peroxide activity is.14 The evidence for all
antimicrobial activity in vitro is extensive and well
established. In vivo, in the wound itself, manuka has
been shown to be clinically effective in reducing
bioburden.15–18 Additionally, manuka has been shown
to be effective against organisms, which are known to
be involved in malodour as well as those, in biolm
colonies.19–23 The action of the honey on various
organisms, including antibiotic resistant species15,24,25
has been evaluated in vitro14 and the extensive list of
susceptible organisms published.5 The mechanisms for
this action, including a synergy, have also been
reported.13,26 This aspect of manuka action has recently
been examined using 83clinical isolates of six genera
of wound pathogens.3,27 The study involved
measurement of both minimum inhibitory
concentrations (MICs) and minimum bactericidal
concentrations (MBCs) and electron microscopy for
evidence of cell lysis. The authors concluded that
‘the ndings provide optimism that topical manuka
honey might have a role to play in limiting multidrug
resistant Gram-negative bacteria’.
Indeed, the action of antibiotics against wound
pathogens has been shown to be enhanced by the
presence of sub-lethal manuka).28 The question whether
or not resistance might become a problem has been
addressed and dismissed at present.29
Clinical impact of manuka honey
Healing of chronic wounds
‘Chronicity’ has been attributed to an uncontrolled
inammation in the wound tissues and to pathogenic
organisms. In order to redress the balance, some form
of anti-inammatory, or immunomodulatory action30
is indicated in conjunction with an antimicrobial. The
immunomodulatory effect is stimulation or inhibition
of the release of cytokines TNFa, Il-1β and Il-6, from
monocytes and macrophages depending on the
condition of the wound. The combination of the anti-
inammatory, immunomodulatory and antimicrobial
actions of manuka honey has proven effective in the
kick-start of delayed healing wounds. The effective use
of manuka honey in a range of chronic wounds has
been reported in a number of reviews.31–35 The clinical
research in this area is growing, recent studies have
shown that in diabetic foot ulcers manuka honey
‘represents an effective treatment for NDFU [neuropathic
diabetic foot ulcers] leading to a signicant reduction in
the time of healing and rapid disinfection of ulcers’.36
Needless to say, further randomised controlled trials
are required to provide substantive evidence. In the
meantime there is substantial ‘weak’ evidence and
sufcient support from expert clinicians to indicate the
value of manuka honey in chronic wound management.
Debridement
This action has been reported over the past 20 years
and is hypothesised to be owing to a stimulation of
plasmin activity in the wound, so denaturing the
brin which attaches slough to the wound bed. This
theory is based upon the known effects of plasminogen
activator inhibitor.14 This mechanism is consistent
with autolysis, where the creation of a moist wound
environment at the appropriate pH leads to the
removal of slough.
Anti-inammatory action
By concentrating on the known inflammatory
mediators active in wounds,37–39 researchers have
discovered that manuka honey is effective in reducing
inammation,40,41 oedema,6,42 and exudate levels via
antimicrobial and anti-inammatory actions. The
clinical manifestations of these actions also include
pain reduction, reported in many clinical studies.43,44
In addition to overt anti-inammatory action, manuka
honey has been shown to exert an immunomodulatory
effect, for example the stimulation of TNFa, IL-1β and
TGFa a by monocytes.30,45,46
Exudate interaction
It is now known that honey is a biologic wound
dressing,14 which has been claimed by Molan and
Rhodes to have:
'multiple bioactivities that work in concert to expedite the
healing process. The physical properties of honey also
expedite the healing process: its acidity increases the
release of oxygen from haemoglobin thereby making the
wound environment less favourable for the activity of
destructive proteases, and the high osmolarity of honey
draws uid out of the wound bed to create an outow of
lymph as occurs with negative pressure wound therapy'.
© 2016 MA Healthcare ltd
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by Richard White on October 1, 2016.
Use for licensed purposes only. No other uses without permission. All rights reserved.

education
JOURNAL OF WOUND CARE VOL 25, NO 9, SEPTEMBER 2016
542
In some respects the chemical process of pH lowering
attributed to manuka and other honeys is responsible
for inuencing the dissociation of oxygen from
haemoglobin as Molan has stated. The reduction of the
pH to an acid milieu also reduces the activity of MMPs:
these have an alkalines pH optimum.
The secondary dressing effects
Needless to say, the activity of honey in the wound is
dependent to a large degree to its duration in situ. This
can be prolonged by having an impregnated dressing,
or by use of an appropriate secondary dressing, the
choice of which will vary according to the degree of
exudate, location and projected wear time. Thus before
selecting a honey-based wound treatment, it is essential
that these considerations be acknowledged and the
appropriate product or combination be used.
Characterisation of manuka honey
Pure manuka honey is produced by introduced
European honey bees (Apis mellifera) from the manuka
or tea tree (Leptospermum scoparium) which grows in
New Zealand and southeastern Australia. Qualitative
tests have been developed for the identication of
honey which is claimed to be pure manuka. For
example, MGO can be assayed to give a broad
indication of identity of floral source.47 More
specically, lepteridine can be isolated, characterised
and quantied.48 In his review of 2015, Molan points
to the bee-derived protein apalbumin-1 (also known
as MRJP-1) and its glycated form, make good
candidates to develop a purity assay for manuka
honey.24,49 The quality and purity has been
questioned,50 it is thus necessary that medical
products claiming to be ‘manuka’ be veried and
certicated following valid assays. It is only then that
clinicians can be assured that the products they are
using will perform consistently, and be t for purpose.
Systematic reviews
Clinical studies on honey in wound management have
been subject to systematic reviews in recent years. The
conclusions in the most recent51 state that: 'It is
difcult to draw overall conclusions regarding the
effects of honey as a topical treatment for wounds due
to the heterogeneous nature of the patient populations
and comparators studied and the mostly low-quality of
the evidence. The quality of the evidence was mainly
downgraded for risk of bias and imprecision. Honey
appears to heal partial-thickness burns more quickly
than conventional treatment and infected
postoperative wounds more quickly than antiseptics
and gauze. Beyond these comparisons any evidence
for differences in the effects of honey and comparators
is of low or very low quality and does not form a
robust basis for decision making'. However, these are
the subject of considerable dispute, many of which
are documented at the end of the report. As the
reviews have included studies on all qualifying
studies, and that the use of medical-grade honey has
not been a prerequisite for selection, analyses and
conclusions are based on generic honey. Given that
we are now in the age of regulated, quality assured
product which has been standardised, it is
inappropriate (and not scientic) to include other
honeys in such an analysis. These have not been
standardised to any degree, are not at all quality-
assured and not commercially available.
Discussion
Given that no single intervention provides a panacea
for wound care, medical-grade manuka honey goes a
considerable way towards that status. Equally, as no
one dressing or topical application is suited to all
wounds and all patients, honey must also be regarded
as an option, to be targeted to the appropriate wound
and patient. Given that systematic reviews have
‘diluted’ the manuka effect by the inclusion of other,
non-specic or generic honeys, the clinical outcomes
achieved in many indications are impressive. This is
also complemented by the proven effects on multi-
resistant bacteria, a feature which, in the
post-antibiotic age, becomes priceless. For a natural
product, used for millennia and now developed into
a regulated medical device, honey has shown its real
value. Given that research is still uncovering new
aspects of the biological performance, it is
extraordinary how subtly evolution has led to such an
ex–quisite material. More that the sum of its parts,
certainly, but what more remains to be discovered?
Conclusion
Honey is a valuable option in wound management.
More specifically pure manuka honey, with its
considerable evidence base, is pre-eminent among
honeys for multifunctional activity in wound
management. For something which has been long used
to treat ‘purulent’ wounds, research has shown the
further capacity to reduce inflammation, affect
debridement, and promote healing. JWC
References
1 Majno, G. The healing hand.
Harvard University Press,
Cambridge, MA, USA, 1975.
2 Blair, S. An historical
introduction to the medicinal use
of honey. In: Cooper, R.A., Molan,
P., White, R.J. (eds.) Honey in
modern wound management.
HealthComm UK, Aberdeen, 2009.
3 Cooper, R.A. Honey for wound
care in the 21st century. J Wound
Care 2016; 25: 9, 544–552.
4 Allen, K.L., Molan, P.C., Reid,
G.M. A survey of the antibacterial
activity of some New Zealand
honeys. J Pharm Pharmacol 1991;
43: 12, 817–822.
5 Carter, D.A., Blair, S.E., Cokcetin,
N.N. et al. Therapeutic manuka
honey: no longer so alternative.
Front Microbiol 2016; 7: 569. doi:
10.89/fmicb.2016.00569.
6 Molan, P.C. The role of honey in
the management of wounds. J
Wound Care 1999; 8: 8, 415–418.
7 Cooper, R.A., Molan, P.C. Honey
in wound care. J Wound Care
1999; 8: 7, 340.
8 Cooper, R.A., Molan, P.C.,
Harding, K.G. Antibacterial activity
of honey against strains of
Staphylococcus aureus from
© 2016 MA Healthcare ltd
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by Richard White on October 1, 2016.
Use for licensed purposes only. No other uses without permission. All rights reserved.

education
JOURNAL OF WOUND CARE VOL 25, NO 9, SEPTEMBER 2016 543
infected wounds. J R Soc Med
1999; 92: 6, 283–285.
9 Topham, J. Sugar for wounds. J
Tissue Viability 2000; 10: 3, 86–89.
10 Yoon, Y.M., Newlands, C.
Quality standards of medical grade
Manuka honey. In: White, R.J.,
Cooper, R.A., Molan, P (eds.)
Honey: A modern wound
management product. Wounds UK
Publishing, Aberdeen, 2005.
11 Molan, P., Hill, C. Quality
standards for medical grade
honey. In: Cooper, R.A., Molan, P.,
White, R.J. (eds.) Honey in modern
wound management.
HealthComm UK, Aberdeen, 2009.
12 Packer, J.M., Irish, J., Herbert,
B.R. et al. Specic non-peroxide
antibacterial effect of manuka
honey on the Staphylococcus
aureus proteome. Int J Antimicrob
Agents 2012; 40: 1, 43–50.
13 Rabie, E., Serem, J.C.,
Oberholzer, H.M. et al. How
methylglyoxal kills bacteria: An
ultrastructural study. Ultrastruct
Pathol 2016; 40: 2, 107–111.
14 Molan, P., Rhodes, T. Honey: a
biologic wound dressing. Wounds
2015; 27: 6, 141–151.
15 Jenkins, R., Wootton, M.,
Howe, R., Cooper, R.
Susceptibility to manuka honey of
Staphylococcus aureus with
varying sensitivities to
vancomycin. Int J Antimicrob
Agents 2012; 40: 1, 88–89.
16 Jenkins, R.E., Cooper, R.
Synergy between oxacillin and
manuka honey sensitizes
methicillin-resistant
Staphylococcus aureus to
oxacillin. J Antimicrob Chemother
2012a; 67: 6, 1405–1407.
17 Biglari, B., vd Linden, P.H.,
Simon, A. et al. Use of Medihoney
as a non-surgical therapy for
chronic pressure ulcers in patients
with spinal cord injury. Spinal Cord
2012; 50: 2, 165–169.
18 Biglari, B., Moghaddam, A.,
Santos, K. et al. Multicentre
prospective observational study
on professional wound care using
honey (Medihoney™). Int Wound J
2013; 10: 3, 252–259.
19 Okhiria, O.A., Henriques, A.,
Burton, N.F. et al. Honey modulates
biolms of Pseudomonas
aeruginosa in a time and dose
dependent manner. J Api Prod
ApiMed Sci 2009; 1: 1, 6–10.
20 Maddocks, S.E., Jenkins, R.E.,
Rowlands, R.S. et al. Manuka
honey inhibits adhesion and
invasion of medically important
wound bacteria in vitro. Future
Microbiol 2013; 8: 12, 1523–1536.
21 Maddocks, S.E., Lopez, M.S.,
Rowlands, R.S., Cooper, R.A.
Manuka honey inhibits the
development of Streptococcus
pyogenes biolms and causes
reduced expression of two
bronectin binding proteins.
Microbiology 2012; 158: 3, 781–790.
22 Lu, J., Turnbull, L., Burke, C.M.
et al. Manuka-type honeys can
eradicate biolms produced by
Staphylococcus aureus strains
with different biolm-forming
abilities. Peer J 2014; 2, e326.
23 Majtan, J., Bohova, J.,
Horniackova, M. et al. Anti-biolm
effects of honey against wound
pathogens Proteus mirabilis and
Enterobacter cloacae. Phytother
Res 2014; 28: 1, 69–75.
24 Jenkins, R., Burton, N.,
Cooper, R. Manuka honey inhibits
cell division in methicillin-resistant
Staphylococcus aureus. J
Antimicrob Chemother 2011; 66:
11, 2536–2542.
25 Boateng, J., Diunase, K.N.
Comparing the antibacterial and
functional properties of
Cameroonian and manuka honeys
for potential wound healing-have
we come full cycle in dealing with
antibiotic resistance? Molecules
2015; 20: 9, 16068–16084.
26 Henriques, A., Jackson, S.,
Cooper, R., Burton, N. Free radical
production and quenching in
honeys with wound healing
potential. J Antimicrob Chemother
2006; 58: 4, 773–777.
27 Al-Maaini, R., Cooper, R.A.
(2016). Multiple inhibitory effects
on mutlidrug-resistant Gram
negative bacteria in vitro. J
Applied Microbiol. [Paper In press].
28 Jenkins, R., Cooper, R.
Improving antibiotic activity
against wound pathogens with
Manuka honey in vitro. PLoS One
2012b; 7: 9, e45600.
29 Cooper, R., Blair, S. Challenges
in modern wound microbiology
and the role for honey. In: Cooper,
R.A., Molan, P., White, R.J. (eds.)
Honey in modern wound
management. HealthComm UK,
Aberdeen, 2009.
30 Majtan, J. Honey: an
immunomodulator in wound
healing. Wound Repair Regen
2014; 22: 2, 187–192.
31 Kingsley, A. The practical use
of modern honey dressings in
chronic wounds. In: Cooper, R.A.,
Molan, P., White, R.J. (eds.) Honey
in modern wound management.
HealthComm UK, Aberdeen, 2009.
32 Robson, V. The use of
Leptospermum honey in chronic
wound management. In: Cooper,
R.A., Molan, P., White, R.J. (eds.)
Honey in modern wound
management. HealthComm UK,
Aberdeen, 2009.
33 White, R.J., Molan, P.C. A
summary of published clinical
research in honey in wound
management. In: Cooper, R.A.,
Molan, P., White, R.J. (eds.) Honey
in modern wound management.
HealthComm UK, Aberdeen, 2009.
34 Bolton, L.L. Leg ulcers and
honey: a recent review of
controlled studies. In: Cooper,
R.A., Molan, P., White, R.J. (eds.)
Honey in modern wound
management. HealthComm UK,
Aberdeen, 2009.
35 Doerler, M., Reich-Schupke, S.,
Altmeyer, P., Stücker, M. Impact on
wound healing and efcacy of
various leg ulcer debridement
techniques. J Dtsch Dermatol Ges
2012; 10: 9, 624–632.
36 Kamaratos, A.V., Tzirogiannis,
K.N., Iraklianou, S.A. et al. Manuka
honey-impregnated dressings in
the treatment of neuropathic
diabetic foot ulcers. Int Wound J
2014; 11: 3, 259–263.
37 Satish, L. Chemokines as
therapeutic targets to improve
healing efciency of chronic
wounds. Adv Wound Care (New
Rochelle) 2015; 4: 11, 651–659.
38 Kalish, B.T., Kieran, M.W.,
Puder, M., Panigrahy, D. The
growing role of eicosanoids in
tissue regeneration, repair, and
wound healing. Prostaglandins
Other Lipid Mediat 2013; 104–138.
39 Roy, S., Sen, C.K. miRNA in
wound inammation and
angiogenesis. Microcirculation
2012; 19: 3, 224–232.
40 Leong, A.G., Herst, P.M.,
Harper, J.L. Indigenous New
Zealand honeys exhibit multiple
anti-inammatory activities. Innate
Immun 2012; 18: 3, 459–466.
41 Tomblin, V., Ferguson, L.R.,
Han, D.Y. et al. Potential pathway
of anti-inammatory effect by New
Zealand honeys. Int J Gen Med
2014; 7: 149–158.
42 Albietz, J.M., Lenton, L.M.
Standardised antibacterial Manuka
honey in the management of
persistent post-operative corneal
oedema: a case series. Clin Exp
Optom 2015; 98: 5, 464–472.
43 Dunford, C.E., Hanano, R.
Acceptability to patients of honey
dressings for non-healing venous
leg ulcers. J Wound Care 2004; 13:
5, 193–197.
44 Robson, V., Cooper, R. Using
leptospermum honey to manage
wounds impaired by radiotherapy:
a case series. Ostomy Wound
Manage 2009; 55: 1, 38–47.
45 Tonks, A., Cooper, R.A., Price,
A.J. et al. Stimulation of TNF-alpha
release in monocytes by honey.
Cytokine 2001; 14: 4, 240–242.
46 Tonks, A., Cooper, R.A., Jones,
K.P. et al. Honey stimulates
inammatory cytokines production
from monocytes. Cytokine 2003;
21: 5, 242–247.
47 Shaheen, F., Shmygol, A.,
Rabbani, N., Thornalley, P.J. A
uorogenic assay for
methylglyoxal. Biochem Soc Trans
2014; 42: 2, 548–555.
48 Daniels, B.J., Prijic, G.,
Meidinger, S. et al. Isolation,
structural elucidation, and
synthesis of lepteridine from
manuka (Leptospermum
scoparium) honey. J Agric Food
Chem 2016; 64: 24, 5079–5084.
49 Bean, A. Investigating the
anti-inammatory activity of honey.
University of Waikato, New
Zealand. http://bit.ly/2bAgKcr
(accessed August 2016)
50 Creasey, S. Manuka honey: a
murky mire. http://bit.ly/2bv8AC2
(accessed August 2016)
51 Jull, A.B., Cullum, N., Dumville,
J.C. et al. Honey as a topical
treatment for wounds. Cochrane
Database Syst Rev 2015; 3,
CD005083.
Find out more about the JWC at:
www.journalofwoundcare.com
© 2016 MA Healthcare ltd
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by Richard White on October 1, 2016.
Use for licensed purposes only. No other uses without permission. All rights reserved.