Does the use of topical honey result in a faster rate of second intention wound healing in dogs?

a Knowledge Summary by

Louisa Marcombes MA VetMB AFHEA MRCVS ^1*

¹University of Liverpool, Leahurst Campus, Neston, CH64 7TE
^*Corresponding Author (louisa.marcombes@gmail.com)

Clinical scenario

A 7-year-old, male neutered Standard Poodle acquired an open wound to the left lateral thorax after having been accidentally scalded with boiling water. The initial dimensions of the wound were approximately 4 cm x 2 cm. The wound was irrigated daily with sterile saline solution and dressed with a non-adhesive dressing. The wound was considered fully healed, defined as fully epithelialised with no eschar or scabbing, 28 days after the accident. Would the topical application of honey have resulted in a shorter time to wound healing in this patient?

The evidence

A systematic literature search found three papers relevant to the PICO (Jalali et al., 2007a; Jalali et al., 2007b; and Jalali et al., 2007c). However, two papers (Jalali et al., 2007a; and Jalali et al., 2007b) were confirmed to be the same paper published in two separate journals and have been designated a duplicated publication. Consequently, two papers in total have been critically reviewed for this knowledge summary. It was also noted that Jalali et al. (2007a/b) and Jalali et al. (2007c) appear to have used data from the same experimental subjects, despite reporting different methodology.

Both the studies by Jalali et al. (2007a/b; and 2007c) were prospective randomised controlled trials using experimentally induced burn wounds in dogs. They both reported that honey decreased the time to wound healing in dogs when compared to the saline-treated control. Objective outcomes measured by Jalili et al. (2007a/b) and Jalali et al. (2007c) included observation of macroscopic wound changes during healing and qualitative and quantitative microbial assessment of the wounds at days 0 and/or 1, 3, 7, 14 and 21 and compared with a saline control. In addition, Jalali et al. (2007a/b) measured the reduction of the wound area over time and Jalali et al. (2007c) compared the microscopic appearance of honey-treated and control wounds at day 21.

Neither study provided a definition for complete wound healing nor had a clearly stated endpoint and both appear to have concluded before wound healing was complete (Jalali et al., 2007a/b; and Jalali et al. 2007c).  As a result, ‘time to wound healing‘, considered a fundamental outcome measure for the PICO was not reported, despite the authors claiming it was a primary objective. Furthermore, the results relied heavily on subjective descriptive narrative, were profoundly exposed to the influence of bias and often overstated. Consequently, the confidence that the effect reported resembles the actual effect of honey on wounds is low, the evidence cannot be used to answer the PICO reliably and, by extension, inform a change in clinical practice.

Summary of the evidence

Appraisal, application and reflection

Numerous clinical properties have been attributed to honey, including antimicrobial activity, a debriding action, anti-inflammatory effect, antioxidant activity, stimulation of wound granulation and epithelialisation (Van Hengel et al., 2013). This has prompted a degree of research activity in the veterinary and human medicine fields to determine if these properties have a clinical application in wound healing.

This Knowledge Summary seeks to appraise the evidence for the effect of topically applied honey on the healing rate in canine wounds when compared to a saline control. A literature search initially found three papers that met the search criteria (Jalali et al., 2007a; 2007b; and 2007c). Two papers (Jalali et al., 2007a; and 2007b) were found to be an identical manuscript in two different journals and therefore have been treated as a single publication in this summary. Furthermore, the third study by this group, (Jalali et al., 2007c), is strongly suspected of having derived data from the same experimental procedure, despite there being a disparity in the methods used and outcomes measured, which  degrades  the evidence.

The measurement of wound healing of the skin is a visual process and therefore, one would intuit, relatively easy to implement in the experimental setting. However, care must be taken to ensure that appropriate end points are used and to minimise the risk of bias in measurements (Gottrup et al., 2010). A further challenge to experiments involving topical wound treatments is the difficulty of implementing an effective blinding protocol. This is particularly tricky in the case of honey, with its distinct colour and odour.  Both papers (Jalali et al., 2007a/b; and Jalali et al., 2007c) used an unjustified end point of 21 days, and Jalali et al. (2007c) claimed that their trial was blinded, although the method of blinding was not reported. It was not stated by Jalali et al. (2007 a/b) whether or not blinding was used.

The experimental variable most relevant to the PICO is time to complete wound healing. Both studies (Jalali et al., 2007a/b; and Jalali et al., 2007c) claimed to have measured this, despite having failed to define complete wound healing. In addition, both used an end point which appeared to be set before wound healing was complete in the control groups. Overall, the results provided were ambiguous, with opaque, sweeping statements such as ‘on day 21, the wounds gaps of treatment group [sic] were approximately closed‘ (Jalali et al., 2007 a/b). As it is apparent that the trials were concluded before the wounds were fully healed, they cannot provide the evidence most pertinent to the PICO.

Jalali et al. (2007a/b) instead recorded the wound healing rate by measuring the reduction of wound area over time. This has been shown to be a useful comparator between treatment groups in human studies (Gotrupp et al., 2010). The method for measuring wound area, however, needs to be carefully standardised as measurements can be subject to over-estimation of up to 44% due to irregular wound shape (Schutz et al., 2005) and therefore risk of under-estimation of the rate of healing. Jalili et al. (2007 a/b) measured this outcome using computer-assisted analysis of digital photographs. The software used, SigmaScan Pro 5.0 (SPSS Science, Chicago, IL), has been shown to have an accuracy  within 4.7% (95% CI 3.4% – 5.9%) (Molnar et al., 2009) and so there is confidence that measurements taken using this method should yield reliable results, which here have demonstrated that the mean honey treated wound area was significantly smaller than the control at days 7, 14 and 21 (p < 0.05).

Both papers (Jalili et al., 2007a/b; and Jalali et al., 2007c) used qualitative and quantitative microbiological data as evidence that honey possesses antibacterial properties. The qualitative data consisted simply of a list of the micro-organisms isolated from each group at days 0 (Jalali et al., 2007 a/b), 1 (Jalali et al, 2007c), 3, 7, 14 and 21 days. The spectrum of isolates over time was similar for both groups, and the authors did not comment further on this, except to state the range organisms isolated were similar to those of a historical human study (Lawrence, 1994) Therefore the relevance of this variable to the PICO remains poorly elaborated and its evidential value doubtful.

The quantitative bacterial results (Jalili et al., 2007a/b; and Jalali et al., 2007c) showed bacterial counts from the honey-treated wounds were  significantly lower at day 21 (p < 0.05) and the authors claimed that this demonstrated an antimicrobial effect.  However, the data also showed a higher bacterial count in the honey-treated group up to day 14, which appears to contradict this claim, and this anomaly was not discussed. The discrepancy was, however, mitigated by the fact that wounds in the treatment group appeared to have had a significantly higher bacterial count at day 0. But then this would suggest the control and treatment groups were not equivalent and that the trial was not adequately controlled.

A systematic review has shown of human burns studies has shown that high wound bacterial counts may predict worse clinical outcomes (Halstead et al., 2018). They also found that wound swabs are relatively insensitive in discriminating clinically significant wound infection from incidental wound contamination, and that serial tissue culture, via biopsy, is a superior technique for quantifying bacterial load of wounds. Consequently, the quantitative microbial data derived from wound swabs by Jalali et al. (2007a/b; and 2007c) is unlikely to be reliable, and so this variable cannot be used to answer the PICO. It was also noted that the microbiological data reported by both papers were identical, suggesting it was derived from the same experimental procedure, despite differing methodology.

A recent Cochrane review of the use of honey in human wound healing (Jull et al., 2015) reported there was some good quality evidence that honey heals partial thickness burns more quickly than conventional dressings, and that honey is more effective than antiseptic for healing infected post-surgical wounds. However, the authors were ultimately obliged to downgrade most of the evidence derived from the 26 studies found, due to high risk of bias and problems of study design. Which are issues similar to those identified in the papers that have been appraised for this Knowledge Summary.

An early draft of the PICO had specified Manuka Honey as the treatment intervention. Honey from different flower sources vary in their biological properties, and monofloral Manuka honey is considered to possess antibiotic and antioxidant properties superior to those of honey derived from other sources (Alvarez-Suarez et al., 2014). It is the medical-grade form of Manuka honey that is used most widely and it was considered that studies using Manuka honey would be most relevant to clinical practice. Somewhat surprisingly, no studies using Manuka honey on canine wounds were found, and the PICO had to be expanded to encompass all forms of honey. Jalili et al. (2007a/b) and Jalali et al. (2007c) used Urmia honey, which was not medically graded and therefore likely to limit relevance to clinical veterinary practice.

A couple of studies were found that tested Manuka honey in experimental wounds in other species. A randomised, controlled study in equine patients (Bischofberger et al., 2013), of moderate evidential quality, supported the hypothesis that honey reduces time to complete wound healing, here defined as ‘when granulation tissue was no longer visible‘. In addition, Haryanto et al. (2012) have shown that Manuka honey accelerates the formulation of granulation tissue during wound healing in mice.

Honey is purported to possess properties that provide favourable healing conditions for every stage of the healing pathway (inflammatory, debridement, granulation, contraction/epithelialisation). However, this is in contrast to the general convention in veterinary clinical practice of limiting the use of honey to the inflammatory and debridement stages only (Van Hengel et al., 2013). Nakajima et al. (2013) observed that Japanese honey appeared to retard the granulation and contraction phases of wound healing in a murine model. Furthermore, Haryanto et al. (2012) demonstrated, also in a murine model, that Manuka honey might delay the wound-contraction phase. This highlights the need for future studies that adopt a study design which discriminates between the healing phases, as this may allow a more substantial treatment effect of honey to be demonstrated.

This Knowledge Summary has found that there is weak evidence (Jalali et al., 2007a/b; and Jalali et al., 2007c) that topical honey may have reduced the healing time from 28 days in the clinical scenario case. However, this evidence is of such low quality due to the high risk of bias, problems with the study design, and ambiguous results of the two papers appraised, that it cannot be used to justify a change in clinical practice. Although, supported by the better-quality evidence found elsewhere, it does justify further research effort into the effect of topical honey on wound healing rate. Adequately powered, randomised and blinded trials, using medical grade Manuka honey, and scrutinising each healing stage may be powerful enough to reveal a treatment effect that has been diluted in studies to date. The confirmed antibiotic effect of honey in the clinical setting would be of particular interest as a means of reducing the use of systemic antibiotics in canine wound care.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on OVID interface (1973–2020 week 05) PubMed on the NCBI interface (1960–2020 week 05)
Search strategy:	CAB Abstracts: (dog or dogs or canine* or canis or bitch* or puppy or puppies or pup or pups).mp. or exp dogs/ or exp bitches/ or exp puppies/ or exp canidae/ or exp canis/ (wound* or lesion* or burn* or abrasion* or ulcer* or 'infected wound' or 'open wound' or 'wound breakdown').mp. or exp wounds/ (honey* or Manuka or inhibines or apipharmacothera*).mp. or exp honey/ (heal* or improv* or regenerat* or epitheli* or harm* or advers* or toxic* or efficac* or safe* or effect* or hyperaem* or angiogen* or granulat* or contract* or antimicrob* or anti-microb* or 'anti microb' or antibacter* or anti-bacter* or 'anti bacter*' or 'secondary intention').mp. or exp antibacterial agents/ 1 and 2 and 3 and 4 PubMed: dog OR dogs OR canine OR canis OR bitch OR bitches OR puppy OR puppies OR pup OR pups wound OR lesion OR burn OR abrasion OR ulcer OR infected wound OR open wound OR wound breakdown  honey* or Manuka or inhibines or apipharmacothera* 1 and 2 and 3
Dates searches performed:	13 Feb 2020

Exclusion / Inclusion Criteria
Exclusion:	Conference proceedings, single case reports, case series, non-systematic reviews, articles not relevant to the PICO, articles that were not accessible and chapters from textbooks. Any language not in the English or French language. Studies that used honey mixed with another substance.
Inclusion:	Studies that used dogs as subjects, studies that involved more than one animal, or controlled trials. The studies were required to examine the effect of topical honey on canine wounds.

Search Outcome
Database	Number of results	Excluded – Proceedings, single case reports, etc.	Excluded – Not relevant to the PICO	Excluded – In a language other than English or French	Excluded – Duplicated publication	Excluded – Not accessible	Total relevant papers
CAB Abstracts	79	17	57	2	1	0	2
PubMed	23	1	22	0	0	0	0
Total relevant papers when duplicates removed							2

The author declares no conflicts of interest.

1. Alvarez-Suarez, J. M., Gasparrini, M., Forbes-Hernández, T. Y., Mazzoni, M. and Giampieri, F. (2014). The Composition and Biological Activity of Honey: A Focus on Manuka Honey. Foods, 3(3): 420–432. DOI: https://doi.org/10.3390/foods3030420
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7. Jalali, F. S. S., Tajik, H., Saifzaideh, S. and Fartash, B. (2007a). Topical Application of Natural Urmia Honey on Experimental Burn Wounds in the Dog: Clinical and Microbiological Studies. Asian Journal of Animal and Veterinary Advances, 2(3): 133–139. DOI: https://doi.org/ 3923/ajava.2007.133.139
8. Jalali, F. S. S., Tajik, H., Saifzaideh, S. and Fartash, B. (2007b). Topical Application of Natural Urmia Honey on Experimental Burn Wounds in the Dog: Clinical and Microbiological Studies. Iranian Journal of Veterinary Surgery, 2(2): 13–21.
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